Compounds, compositions, and methods for synthesis

Abstract

This invention provides compounds useful as chiral auxiliary groups for stereoselective oligonucleotide synthesis. [Solution] For example, the following compounds. TIFF2026053646001168.tif32162 TIFF2026053646001169.tif32162

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 523,175, filed on 21 June 2017, and U.S. Provisional Patent Application No. 62 / 560,169, filed on 18 September 2017, the entirety of each of those applications being incorporated herein by reference. [Background technology]

[0002] Many compounds contain chiral centers. Stereoisomers can have different properties and activities. [Overview of the project]

[0003] Various types of compounds, including oligonucleotides containing chiral modified nucleotide bonds, contain chiral centers. In particular, this disclosure provides techniques (e.g., compounds, compositions, methods, etc.) for the stereoselective preparation of various types of chiral compounds. In some embodiments, this disclosure provides compounds, compositions, and methods for the stereoselective (chiral-controlled) preparation of chiral nucleotide bonds in nucleic acids (e.g., oligonucleotides). In some embodiments, the nucleotide bond contains a chiral-bonded phosphorus atom and has a structure of formula VII, which is described later. In some embodiments, the chiral nucleotide bond is a phosphorothioate triester bond. In some embodiments, the chiral nucleotide bond is a phosphorothioate bond.

[0004] In particular, the techniques of this disclosure (e.g., compounds, compositions, methods, etc.) make it possible to improve yield, stereoselectivity, product purity, and / or chemical compatibility. For example, in some embodiments, surprisingly high yields, stereoselectivity, and / or product purity are obtained, so the techniques provided are particularly useful for forming difficult-to-form nucleotide interbonds in oligonucleotides. In some embodiments, with respect to the formation of difficult-to-form nucleotide interbonds, the techniques provided make it possible to obtain unexpectedly high yields while generally maintaining the same or equivalent very high stereoselectivity compared to those achieved with the best reported chiral auxiliary groups (e.g., about 99:1).

[0005] In some embodiments, the Disclosure provides techniques that are compatible with a variety of chemical conditions, and as a result, the techniques provided can be used in many types of reactions and / or conditions. For example, with respect to oligonucleotide synthesis, the Disclosure offers immeasurable versatility, partly because the techniques provided have a variety of compatibility, allowing them to be used under many chemical conditions and removed when desired, thereby providing immeasurable flexibility for the synthesis of oligonucleotides with a wide range of modifications (e.g., base modifications, sugar modifications, nucleotide bond modifications, etc.).

[0006] In some embodiments, the disclosure provides compounds for stereoselective synthesis. In some embodiments, the provided compounds are chiral auxiliary groups.

[0007] In some embodiments, this disclosure relates to formula I: [ka] The present invention provides a compound having the structure or a salt thereof, in which: L is either covalently bonded or optionally substituted with C 1-6 It is an alkylene, and the C 1-6In the alkylene, one or more methylene units are optionally and independently replaced by -L’-, Each L’ is independently a covalent bond, an optionally substituted divalent C 1-3 alkylene, -C(R 3 )(R 4 )-, -C(R 3 )(R 4 )-C(R 3 )(R 4 )-, -Cy-, or -C(R 3 )[C(R 4 )3]-, and R 1 , R 2 , R 3 , R 4 , and R 5 are each independently -H, -L s -R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2, and Each L s is independently a covalent bond or a straight-chain or branched divalent group optionally substituted from a C 1-30 aliphatic group and a C 1-30 heteroaliphatic group having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and one or more methylene units are C 1-6 alkylene, C 1-6Alkenylene, a divalent C1-C6 heteroaliphatic group having 1 to 5 heteroatoms independently selected from -C≡C-, oxygen, nitrogen, sulfur, phosphorus, and silicon, -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P The carbon atoms are optionally and independently replaced by any substitutional group selected from (S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR')[B(R')3]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O-, or -OP(OR')[B(R')3]O-, and one or more carbon atoms are replaced by any substitutional group selected from Cy L It can be replaced arbitrarily and independently. -Cy- are each independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Cy L Each of them is independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted tetravalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Each of R' is independently -R, -C(O)R, -CO2R, or -SO2R. R 6 is R', R 7 is -OH or SH, R 1 , R 2 , R 3 , and R 4 At least one of them is not -H, Each R is independently either -H or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 Heteroliphatic, C 6-30 Ariel, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 An optionally substituted group selected from aryl heteroaliphatic groups, 5-30 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or The two R groups can optionally and independently come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with that atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to that atom, or Two or more R groups on two or more atoms can optionally and independently combine with the intervening atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to the intervening atom.

[0008] In some embodiments, L is a covalent bond. In some embodiments, the provided compound is [ka] It has the structure of the salt thereof. In some embodiments, R 1 and R 2 One or both of the above, as well as R 5 These, together with the intervening atoms, form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 1 and R 2 One of them is R 5 and, together with the intervening atoms, form optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic rings having 1-5 heteroatoms. As broadly described in this disclosure, the formed rings can be of various sizes, monocyclic, bicyclic, or polycyclic, and can contain various numbers of heteroatoms. In some embodiments, the ring is a 3-membered ring. In some embodiments, the ring is a 4-membered ring. In some embodiments, the ring is a 5-membered ring. In some embodiments, the ring is a 6-membered ring. In some embodiments, the ring is monocyclic. In some embodiments, the ring contains additional ring heteroatoms in addition to the intervening heteroatoms. In some embodiments, the ring is a 3-membered ring containing one ring heteroatom. In some embodiments, the ring is a 3-membered ring containing two ring heteroatoms. In some embodiments, the ring is a 3-membered ring containing one carbon ring atom, one nitrogen ring atom, and one oxygen ring atom.

[0009] In some embodiments, L is -C(R 3 )(R 4 )-. In some embodiments, the compound provided is of formula Ia: [ka] The compound has the structure of formula I or the structure of a salt thereof, where each variable part is independently described herein. In some embodiments, the compound of formula I has the structure of formula Ia. In some embodiments, the provided compound is [ka] Having the structure of or the structure of a salt thereof, where each variable part is independently described in this disclosure, R 4 and R 5 It is not hydrogen.

[0010] In some embodiments, the provided compound is of formula (Ia-1): [ka] Having the structure of or the structure of a salt thereof, where each variable part is independently described in this disclosure, R 4 and R 5 It is not hydrogen, but R 2 R 1 It has a larger size compared to [another compound]. In some embodiments, the compound of formula Ia has the structure of formula Ia-1.

[0011] In some embodiments, the provided compound is of formula (Ia-2): [ka] Having the structure of or the structure of a salt thereof, where each variable part is independently described in this disclosure, R 4 and R 5 It is not hydrogen, but R 2 R 1 It has a larger size compared to [another compound]. In some embodiments, the compound of formula Ia has the structure of formula Ia-2.

[0012] In some embodiments, R 6 is -H. In some embodiments, R 6 is -H, and R 4 and R 5 These, together with the intervening atoms, form an optionally substituted 3-20 membered heterocyclyl ring having 1-5 heteroatoms. In some embodiments, R 4 and R 5These, together with the intervening atoms, form an optionally substituted 4- to 10-membered heterocyclyl ring in which the intervening nitrogen atom is the sole ring heteroatom. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered. In some embodiments, the formed ring is substituted. In some embodiments, the formed ring is not substituted. In some embodiments, the formed ring is monocyclic. In some embodiments, the formed ring is bicyclic. In some embodiments, the formed ring is polycyclic. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is R 5 Aside from the nitrogen atom to which it is bonded, it does not have any ring heteroatoms.

[0013] In some embodiments, R 1 and R 2 At least one of them is not hydrogen. In some embodiments, R 1 is hydrogen, and R 2 It is not hydrogen. In some embodiments, R 1 It is not hydrogen, but R 2 is hydrogen. In some embodiments, R 1 and R 2 None of them are hydrogen.

[0014] In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is not hydrogen. In some embodiments, R 1 and R 2 One of them is -H, and the other is C, which can be optionally substituted. 1-6 It is aliphatic. In some embodiments, R 1 and R 2 One of them is -H, and the other is C, which can be optionally substituted. 1-4 It is aliphatic. In some embodiments, R 1 and R 2One of them is -H, and the other is optionally substituted C 1-3 is aliphatic. In some embodiments, R 1 and R 2 One of them is -H, and the other is optionally substituted C 1-2 is aliphatic. In some embodiments, R 1 and R 2 One of them is -H, and the other is optionally substituted C 1-6 is alkenyl. In some embodiments, R 1 and R 2 One of them is -H, and the other is vinyl. In some embodiments, R 1 and R 2 One of them is -H, and the other is optionally substituted C 1-6 is alkynyl. In some embodiments, R 1 and R 2 One of them is -H, and the other is ethynyl. In some embodiments, R 1 and R 2 One of them is -H, and the other is optionally substituted benzyl. In some embodiments, R 1 and R 2 One of them is -H, and the other is benzyl, and the phenyl group of benzyl is optionally substituted. In some embodiments, R 1 is -H, and R 2 is benzyl. In some embodiments, R 1 [[ID=​​​​​​​​​​​​​​​ [ka] or its salt.

[0015] In some embodiments, R 1 It is R, not -H. 2 is not -H. In some embodiments, R 1 and R 2 R is independent of -H. In some embodiments, R 1 C is optionally substituted. 1-6 It is aliphatic, R 2 R is an optionally substituted phenyl. In some embodiments, R 1 It is methyl, and R 2 It is phenyl.

[0016] In some embodiments, R 1 and R 2 One of the sides is R, and R includes a ring portion. In some embodiments, R is C 3-20 Alicyclic, C 6-20 The group is optionally substituted, selected from aryl groups, 5-20 membered heteroaryl groups having 1-5 heteroatoms, and 3-20 membered heterocyclines having 1-5 heteroatoms. In some embodiments, R is optionally substituted with C 3-20 It is alicyclic. In some embodiments, R is optionally substituted with C 3-10 It is alicyclic. In some embodiments, R is optionally substituted with C 3-10 It is a cycloalkyl group. In some embodiments, R is optionally substituted with C 4-10It is a cycloalkyl group. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is optionally substituted cycloheptyl. In some embodiments, R is cyclopropyl. In some embodiments, R is cyclobutyl. In some embodiments, R is cyclopentyl. In some embodiments, R is cyclohexyl. In some embodiments, R is cycloheptyl. In some embodiments, R is optionally substituted C 6-20 It is an aryl compound. In some embodiments, R is an optionally substituted phenyl compound. In some embodiments, R is a phenyl compound. In some embodiments, R is an optionally substituted 5-20 member heteroaryl compound having 1-5 heteroatoms. In some embodiments, R is an optionally substituted 5 member heteroaryl compound having 1-5 heteroatoms. In some embodiments, R is an optionally substituted 6 member heteroaryl compound having 1-5 heteroatoms. In some embodiments, R is an optionally substituted 3-20 member heterocycline compound having 1-5 heteroatoms. In some embodiments, R 1 and R 2 The other is R, and R is not hydrogen. In some embodiments, R is optionally substituted with C. 1-6 It is aliphatic. In some embodiments, R is optionally substituted with C. 1-6 It is alkyl. In some embodiments, R is C 1-6 It is alkyl. In some embodiments, R is methyl. In some embodiments, R is substituted methyl. In some embodiments, R is ethyl. In some embodiments, R is substituted ethyl. In some embodiments, R 1 and R 2 One of them is R, which includes the cyclic portion described in this disclosure, and the other is the alkyl group described in this disclosure.

[0017] In some embodiments, R 1and R 2 Each of these is independently R, and R is a C that can be arbitrarily substituted. 1-20 It is aliphatic. In some embodiments, R is an unsubstituted C 1-20 It is aliphatic. In some embodiments, R is optionally substituted with C. 1-20 It is alkyl. In some embodiments, R is optionally substituted with C 1-6 It is alkyl. In some embodiments, R is C 1-6 It is a linear alkyl group. In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-6 It is an alkyl group, and the other is an optionally substituted C group. 1-6 It is alkyl. In some embodiments, R 1 and R 2 This is the same as R 1 and R 2 It is different.

[0018] In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-6 It is an alkyl group, and the other is an optionally substituted C group. 1-6 It is an alkenyl. 1 and R 2 One of them is optionally substituted methyl or ethyl, and the other is vinyl. In some embodiments, R 1 and R 2 One of them is methyl, and the other is vinyl.

[0019] In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-6 It is an alkyl group, and the other is an optionally substituted C group. 1-6 It is an alkynyl. In some embodiments, R 1 and R 2 One of them is optionally substituted methyl or ethyl, and the other is ethynyl. In some embodiments, R 1 and R 2One of them is methyl, and the other is ethynyl.

[0020] In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-6 It is an alkyl group, and the other is an optionally substituted C group. 1-6 It is alkyl. In some embodiments, R 1 and R 2 This means that C is the same as any other substitute. 1-6 It is alkyl. In some embodiments, R 1 and R 2 This means that C is the same as any other substitute. 1-2 It is alkyl, R 1 and R 2 The number of carbon atoms contained is 2 or less. In some embodiments, R 1 and R 1 Both are methyl. In some embodiments, R 1 and R 1 Both are ethyl. In some embodiments, R 1 and R 1 Both are isopropyl. In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-3 It is a linear alkyl group, and the other side is optionally substituted with C 3-10 It is cycloalkyl. In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-3 It is a linear alkyl group, and the other side is optionally substituted with C 5-6 It is cycloalkyl. In some embodiments, R 1 is methyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-3 One is a linear alkyl group, and the other is an optionally substituted benzyl group. In some embodiments, R 1It is methyl, and R 2 is benzyl which is optionally substituted. In some embodiments, R 2 is benzyl. In some embodiments, R 2 is p-CH3O-C6H4-CH2-. In some embodiments, R 1 is selected from methyl, ethyl, cyclohexyl, and benzyl which is optionally substituted with phenyl. In some embodiments, R 2 is selected from methyl, ethyl, cyclohexyl, and benzyl which is optionally substituted with phenyl. In some embodiments, R 1 and R 2 Each is independently selected from methyl, ethyl, cyclohexyl, and benzyl optionally substituted with phenyl. In some embodiments, the provided compound is [ka]

[0021] In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-6 One is alkyl, and the other is optionally substituted phenyl. In some embodiments, R 1 It is methyl, and R 2 R is an optionally substituted phenyl. In some embodiments, R 1 It is methyl, and R 2 is phenyl. In some embodiments, R 1 It is methyl, R 2 teeth, [ka]

[0022] In some embodiments, R 1 and R 2 R is independently R, where R is an optionally substituted aryl group. In some embodiments, R 1 and R 2R is an optional phenyl compound that can be substituted independently. In some embodiments, R 1 and R 2 is phenyl. In some embodiments, the provided compound is [ka] or its salt.

[0023] In some embodiments, R 1 and R 2 These, together with the carbon atoms to which they are bonded, form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-5 heteroatoms. In some embodiments, R 1 and R 2 These, together with the carbon atoms to which they are bonded, form an optionally substituted 3- to 7-membered monocyclic ring that does not contain heteroatoms. In some embodiments, the formed monocyclic ring is 3-membered, in some embodiments 4-membered, in some embodiments 5-membered, in some embodiments 6-membered, in some embodiments 7-membered, in some embodiments 8-membered, in some embodiments 9-membered, and in some embodiments 10-membered. In some embodiments, the formed ring is monocyclic. In some embodiments, the formed ring is bicyclic. In some embodiments, the formed ring is polycyclic. In some embodiments, the formed ring is aliphatic. In some embodiments, the formed ring does not contain an unsaturated moiety. In some embodiments, the formed ring is saturated, partially unsaturated, and / or partially aromatic, for example, a bicyclic or polycyclic ring containing a condensed saturated moiety, a partially unsaturated moiety, and / or an aromatic moiety. In some embodiments, the formed ring is substituted. In some embodiments, the formed ring is not substituted. In some embodiments, R 1 and R 2 The carbon atom to which it is bonded is not chiral. In some embodiments, R 1 and R 2It is the same as and the carbon to which they are bonded is not chiral. In some embodiments, R 1 and R 2 The carbon atom to which R is bonded 1 and R 2 The ring formed by the combination of R does not introduce asymmetry, 1 and R 2 The carbon atom to which it is bonded is not chiral. In some embodiments, R 1 and R 2 Unlike the carbon atoms to which they are bonded, the carbon atoms to which they are bonded are chiral. In some embodiments, R 1 and R 2 The carbon atom to which R is bonded 1 and R 2 Asymmetry is introduced by the ring formed when they come together, R 1 and R 2 The carbon atom to which it is bonded is not chiral. In some embodiments, the provided compound is, In some embodiments, the provided compound is [ka]

[0024] In some embodiments, R 4 and R 5 These, together with the intervening atoms, form optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic rings having 1-5 heteroatoms. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered. In some embodiments, the formed ring is 8-membered. In some embodiments, the formed ring is 9-membered. In some embodiments, the formed ring is 10-membered. In some embodiments, R 3 is -H, and R 4 and R 5These, together with the intervening atoms, form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 3 is -H, and R 4 and R 5 By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional 3-20 member monocyclic, bicyclic, or polycyclic ring having (a bonded to it). In some embodiments, R 3 is -H, and R 4 and R 5 By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional 4- to 7-member monocyclic ring having (a bonded to it). In some embodiments, R 3 is -H, and R 4 and R 5 By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional substituted four-membered monocyclic ring having (which is bonded to R). In some embodiments, R 3 is -H, and R 4 and R 5 By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional substituted 5-member monocyclic ring having (which is bonded to R). In some embodiments, R 3 is -H, and R 4 and R 5 By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional substituted 6-member monocyclic ring having (which is bonded to R). In some embodiments, 3 is -H, and R 4 and R 5 By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional substituted 7-member monocyclic ring having (which is bonded to R). In some embodiments, R 3 is -H, and R 4 and R 5By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional substituted 8-member monocyclic ring having (which is bonded to R). In some embodiments, R 3 is -H, and R 4 and R 5 By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional 9-member monocyclic ring having (which is bonded to R). In some embodiments, 3 is -H, and R 4 and R 5 By combining with those intervening atoms, nitrogen atoms (R 5 It forms an optional substituted 10-member monocyclic ring having (which is bonded to R). In some embodiments, 4 and R 5 The ring formed by the intervening atoms is substituted. In some embodiments, R 4 and R 5 The rings formed by them joining together with the intervening atoms are not substituted. In some embodiments, R 4 and R 5 The ring formed by the combination of these intervening atoms is monocyclic. In some embodiments, R 4 and R 5 The ring formed by the combination of these intervening atoms is bicyclic. In some embodiments, R 1 and R 2 One of the following, as well as R 3 and R 4One of these, together with the intervening atoms, forms an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-5 heteroatoms. In some embodiments, the formed ring is a 3-membered ring. In some embodiments, the formed ring is a 4-membered ring. In some embodiments, the formed ring is a 5-membered ring. In some embodiments, the formed ring is a 6-membered ring. In some embodiments, the formed ring is a 7-membered ring. In some embodiments, the formed ring is substituted. In some embodiments, the formed ring is not substituted. In some embodiments, the formed ring is monocyclic. In some embodiments, the formed ring is bicyclic. In some embodiments, the formed ring is polycyclic. In some embodiments, the formed ring has no additional heteroatoms other than the intervening atoms. In some embodiments, the formed ring has additional ring heteroatoms other than the intervening atoms. Examples of the formed rings are broadly described in this disclosure. In some embodiments, the provided compound is [ka] TIFF2026053646000013.tif81166

[0025] In some embodiments, R 1 and R 2 One or two of these are R 3 , R 4 , and R 5 Together with one or more of these and intervening atoms, they form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-5 heteroatoms. In some embodiments, R 1 and R 2 One or two of these are R 3 and R 4 One or two of these, along with intervening atoms, combine to form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-5 heteroatoms. In some embodiments, R 1 and R 2 One or two of these are R 5And together with intervening atoms, they form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 1 and R 2 One or two of these are R 3 and R 4 One or two of the following, R 5 Furthermore, together with intervening atoms, they form optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic rings having 1-5 heteroatoms. In some embodiments, R 1 and R 2 One or two of these are R 3 and R 4 One or two of the following, R 5 Furthermore, together with intervening atoms, they form an optionally substituted 6-20 member bicyclic or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 1 and R 2 One or two of these are R 3 and R 4 One or two of the following, R 5 Furthermore, together with intervening atoms, they form an optionally substituted 8-20 member bicyclic or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 1 and R 2 One of them is R 3 and R 4 One of them, R 5 Furthermore, together with intervening atoms, they form an optionally substituted 8-20 member bicyclic or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 1 and R 2 One of them is R 3 and R 4 One of them, R 5 Furthermore, together with intervening atoms, they form an optionally substituted 8-20 member bicyclic ring having 1-5 heteroatoms. In some embodiments, the formed ring is 8-membered. In some embodiments, the formed ring is 9-membered.

[0026] In some embodiments, R 5 R 1 and R 2 To combine with one of them and the intervening atoms, they form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 5 R 3 and R 4 To combine with one of them and the intervening atoms, they form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. Examples of the rings formed are broadly described in this disclosure. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, R 5 R 1 , R 2 , R 3 , or R 4 By being together, it does not form a ring that can be optionally substituted. In some embodiments, R 5 C is optionally substituted. 1-6 It is aliphatic. In some embodiments, R 5 C is optionally substituted. 1-6 It is alkyl. In some embodiments, R 5 is an unsubstituted C 1-6 It is alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 It is isopropyl.

[0027] [ka]

[0028] In some embodiments, L is -L'-C(R 3 )(R 4)-. In some embodiments, the compound provided is of formula Ib: [ka] The compound has the structure of formula I or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound of formula I has the structure of formula Ib.

[0029] In some embodiments, L' is a covalent bond. In some embodiments, L' is -C(R 3 )(R 4 )-. In some embodiments, the compound provided is of formula Ic: [ka] The compound has the structure of formula I or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound of formula I has the structure of formula Ic.

[0030] In some embodiments, R on C2 3 and R 4 One of them is R 5 And by coming together with the intervening atoms, nitrogen atoms (R 5 It forms an optional 3-20 member monocyclic, bicyclic, or polycyclic ring having (which is bonded to) C3. In some embodiments, R on C3 3 and R 4 One of them is R 5 And by coming together with the intervening atoms, nitrogen atoms (R 5 It forms an optional 3-20 member monocyclic, bicyclic, or polycyclic ring having (which is bonded to) C2. In some embodiments, R on C2 3 and R 4 One of them, as well as R on C3 3 and R 4One of these, together with the intervening atoms, forms an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-5 heteroatoms. In some embodiments, R on the same carbon atom 3 and R 4 When combined with the carbon atom, it forms an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-5 heteroatoms. In some embodiments, R on C2 3 and R 4 When combined with C2, it forms an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-5 heteroatoms. In some embodiments, R on C3 3 and R 4 When combined with C3, it forms a 3-20 member monocyclic, bicyclic, or polycyclic ring with 0-5 heteroatoms and optional substitutions. An example of such a ring portion is, for example, R 3 / R 4 and R 5 something formed by, R 3 / R 4 and R 3 / R 4 These include those formed by, and are broadly described in this disclosure, and may be, for example, four-membered, five-membered, six-membered, seven-membered, monocyclic, bicyclic, polycyclic, substituted, unsubstituted, and may include additional ring heteroatoms (in addition to intervening atoms), may not include additional heteroatoms, or be combinations thereof.

[0031] In some embodiments, R on C2 3 is hydrogen. In some embodiments, R on C2 4 is hydrogen. In some embodiments, R on C3 3 is hydrogen. In some embodiments, R on C3 4 is hydrogen. In some embodiments, R on C2 3 and R 4 Both are hydrogen. In some embodiments, R on C3 3 and R 4Both are hydrogen. In some embodiments, R on C2 3 and R 4 Both, as well as R on C3 3 and R 4 One of them is hydrogen. In some embodiments, R on C3 3 and R 4 Both, as well as R on C2 3 and R 4 One of them is hydrogen.

[0032] In some embodiments, the provided compound is [ka] or its salt.

[0033] In some embodiments, L is -Cy-. In some embodiments, the compound provided is of formula Id: The compound has the structure of TIFF2026053646000018.tif33166 or the structure of a salt thereof, where each variable part is independently described herein. In some embodiments, the compound of formula I has the structure of formula Id. In some embodiments, -Cy- is 1,2-divalent. In some embodiments, -Cy- is an optionally substituted cycloalkylene. In some embodiments, -Cy- is optionally substituted [ka] In some embodiments, -Cy- is optionally substituted. [ka] That is the case.

[0034] In some embodiments, R 1 and R 2 One of the following, as well as R 3 and R 4One of these is R, which, together with the intervening atoms, forms an optionally substituted 3-20 membered ring (e.g., an A ring as described herein) having 1-10 heteroatoms as described herein. In some embodiments, the provided compound is of formula Ie: [ka] The compound has the structure of formula I or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound of formula I has the structure of formula Ie.

[0035] In some embodiments, R 1 and R 2 One of the following, as well as R 4 These, together with the intervening atoms, form an optionally substituted 3-20 membered ring having 1-5 heteroatoms. In some embodiments, R 3 is -H, and R 1 and R 2 One of the following, as well as R 4 These, together with the intervening atoms, form an optionally substituted 3-20 membered ring having 1-5 heteroatoms. In some embodiments, R 2 and R 4These atoms, together with their intervening atoms, form optionally substituted rings (e.g., formula Ie). In some embodiments, the formed ring (e.g., ring A in formula Ie) is 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered. In some embodiments, the formed ring is 8-membered. In some embodiments, the formed ring is 9-membered. In some embodiments, the formed ring is 10-membered. In some embodiments, the formed ring is monocyclic. In some embodiments, the formed ring is bicyclic. In some embodiments, the formed ring is polycyclic. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring does not contain heteroatoms. In some embodiments, the formed ring is an optionally substituted 3-member saturated aliphatic ring. In some embodiments, the formed ring is an optionally substituted 4-member saturated aliphatic ring. In some embodiments, the formed ring is an optionally substituted 5-member saturated aliphatic ring. In some embodiments, the formed ring is an optionally substituted 6-member saturated aliphatic ring. In some embodiments, the formed ring is an optionally substituted 7-member saturated aliphatic ring. In some embodiments, the formed ring is an optionally substituted 8-member saturated aliphatic ring. In some embodiments, the formed ring is an optionally substituted 9-member saturated aliphatic ring. In some embodiments, the formed ring is an optionally substituted 10-member saturated aliphatic ring. In some embodiments, R 1 is not -H. In some embodiments, R 1 C is optionally substituted. 1-6 It is aliphatic. In some embodiments, R 1 -CH=CH2.

[0036] In some embodiments, R 3is -H, and R 1 C is optionally substituted. 1-6 It is aliphatic or phenyl, R 5 C is optionally substituted. 1-6 It is aliphatic, R 6 is -H. In some embodiments, R 3 is -H, and R 1 and R 5 These, together with the intervening atoms, form an optionally substituted ring, R 6 is -H. In some embodiments, R 3 is -H, and R 1 and R 5 These, by joining with the intervening atoms, form optionally substituted five-membered or six-membered rings, R 6 is -H. In some embodiments, R 3 is -H, and R 1 and R 5 R 5 It forms an optional substituted 5-membered saturated ring that has no heteroatoms other than the nitrogen to which it is bonded, R 6 is -H. In some embodiments, R 3 is -H, and R 1 and R 5 R 5 It forms an optional substituted 6-membered saturated ring that has no heteroatoms other than the nitrogen to which it is bonded, R 6 is -H. In some embodiments, R 1 and R 5 The ring formed by the combination of these elements is not substituted.

[0037] In some embodiments, -OH and -N(R 5 )(R 6 ) is a transformer. In some embodiments, -OH and -N(R 5 )(R 6 ) is cis. In some embodiments, R 1 The carbon atom to which the -OH group is bonded is R. In some embodiments, R 1And the carbon to which the -OH is bonded is S. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 It is not hydrogen. In some embodiments, R 1 C is optionally substituted. 1-6 It is aliphatic or phenyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is phenyl. In some embodiments, R 3 is hydrogen. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 It is not hydrogen. In some embodiments, R 5 C is optionally substituted. 1-6 It is aliphatic or phenyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is phenyl. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 It is not hydrogen. In some embodiments, as shown by certain data examples, -OH and -N(R 5 )(R 6 The arrangement of -OH and -N(R) in the trans compound can give high yield and / or diastereoselectivity. In some embodiments, as shown by certain data examples, -OH and -N(R) 5 )(R 6 Compounds in a trans configuration with ) can yield both high yield and high diastereoselectivity.

[0038] In some embodiments, the provided compound (e.g., a compound of formula Ie) [ka] TIFF2026053646000023.tif100166

[0039] In some embodiments, R 1 or R 2 R 5 and R6 One of the elements (for example, those in formula Id or formula Ie), together with the intervening atoms, forms an optionally substituted ring as described in this disclosure. In some embodiments, the formed ring is monocyclic. In some embodiments, the formed ring is bicyclic. In some embodiments, the formed ring is polycyclic. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring is 3 to 10-membered. In some embodiments, the formed ring is 3-, 4-, 5-, 6-, or 7-membered. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered. In some embodiments, the formed ring is R 5 and R 6 It has 0 to 3 heteroatoms in addition to the nitrogen atom to which it is bonded. In some embodiments, the ring formed is a 5-membered saturated monocyclic ring, and R 5 and R 6 It has no additional heteroatoms other than the nitrogen atom to which it is bonded. In some embodiments, the formed ring is a 6-membered saturated monocyclic ring, R 5 and R 6 It does not have any additional heteroatoms other than the nitrogen atom to which it is bonded. In some embodiments, the provided compound is [ka] or a salt thereof. In some embodiments, the provided compound is [ka] or its salt.

[0040] In some embodiments, the compound provided is of formula II: [ka] It has the structure of the salt thereof, in the formula: Ring A is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. R 3 , R 4 , and R 5 These are -H and -L, respectively, independently. s -R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2, L s Each of them is independently covalently bonded, or C 1-30 A carbon atom having an aliphatic group and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 A linear or branched divalent group optionally substituted from heteroaliphatic groups, wherein one or more methylene units are C 1-6 Alkilen, C 1-6Alkenylene, a divalent C1-C6 heteroaliphatic group having 1 to 5 heteroatoms independently selected from -C≡C-, oxygen, nitrogen, sulfur, phosphorus, and silicon, -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P The carbon atoms are optionally and independently replaced by any substitutional group selected from (S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR')[B(R')3]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O-, or -OP(OR')[B(R')3]O-, and one or more carbon atoms are replaced by any substitutional group selected from Cy L It can be replaced arbitrarily and independently. -Cy- are each independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Cy L Each of them is independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted tetravalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)2R. t is between 0 and 20. R 6 is R', R 8 -LR 7 , -LC(R 1 )(R 2 )-R 7 , or -L s -R 7 And, R 7 is -OH or SH, L is either covalently bonded or optionally substituted with C 1-6 It is an alkylene, and one or more methylene units can be optionally and independently replaced by -L'-. L' is a covalent bond, optionally substituted with a divalent C 1-3 Alkylene, -C(R 3 )(R 4 )-,-C(R 3 )(R 4 )-C(R 3 )(R 4 )-, -Cy-, or -C(R 3 )[C(R 4 )3]- and Each R is independently either -H or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 Heteroliphatic, C 6-30 Ariel, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 An optionally substituted group selected from aryl heteroaliphatic groups, 5-30 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or The two R groups can optionally and independently come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with that atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to that atom, or Two or more R groups on two or more atoms can optionally and independently combine with the intervening atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to the intervening atom.

[0041] In some embodiments, the compound provided is of formula II-a: [ka] The compound has the structure of formula II or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound of formula II has the structure of formula II-a.

[0042] In some embodiments, the compound provided for structure II-a is formula II-b: The compound has the structure of TIFF2026053646000028.tif34166 or the structure of a salt thereof, where each variable part is independently described herein. In some embodiments, the compound of formula II-a has the structure of formula II-b.

[0043] In some embodiments, the compound provided with structure II-a is of formula II-c: [ka] The compound has the structure of formula II-a or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound of formula II-a has the structure of formula II-c.

[0044] In some embodiments, R 8is -OH. In some embodiments, R 6 is -H. In some embodiments, R 5 R is an optionally substituted alkyl group. In some embodiments, R 5 is methyl. In some embodiments, t is 0. In some embodiments, R 3 R is an optionally substituted alkyl group. In some embodiments, R 3 is methyl. In some embodiments, R 3 R is an optionally substituted phenyl. In some embodiments, R 3 is phenyl. In some embodiments, R 3 C is optionally substituted. 3-10 It is cycloalkyl. In some embodiments, R 3 is a cyclohexyl which is optionally substituted. In some embodiments, R 3 It is cyclohexyl.

[0045] In some embodiments, ring A is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, ring A is at least one saturated or partially unsaturated monocyclic ring portion, or includes at least one saturated or partially unsaturated monocyclic ring portion, which is optionally included as part of a bicyclic or polycyclic system. In some embodiments, ring A is monocyclic. In some embodiments, ring A is bicyclic or polycyclic, including at least one saturated or partially unsaturated monocyclic ring portion and one or more optionally aromatic monocyclic portions. In some embodiments, ring A is at least one saturated monocyclic ring portion, or includes at least one saturated monocyclic ring portion. In some embodiments, R 8 This is the sp of ring A. 3 It is bonded to the ring atom. In some embodiments, R 8 This is the sp of ring A. 3 It is bonded to a carbocyclic atom. In some embodiments, R 3 This is the sp of ring A. 3It is bonded to the ring atom. In some embodiments, R 3 This is the sp of ring A. 3 It is bonded to a carbon ring atom. In some embodiments, -N(R 5 )(R 6 ) is the sp of ring A. 3 It is bonded to the ring atom. In some embodiments, -N(R 5 )(R 6 ) is the sp of ring A. 3 It is bonded to a carbon ring atom.

[0046] In some embodiments, ring A is optionally replaced by C 3-10 It is a cycloalkyl group. In some embodiments, the A ring is an optionally substituted cyclohexyl group. In some embodiments, the A ring is a cyclohexyl group. In some embodiments, R 8 and -N(R 5 )(R 6 ) is cis. In some embodiments, R 8 and -N(R 5 )(R 6 ) is a trans. In some embodiments, the compound provided by formula II is [ka]

[0047] In some embodiments, R 3 and R 8 One of the following, as well as R 5 and R 6One of these, together with the intervening atoms, forms an optionally substituted ring as described in this disclosure. For example, in some embodiments, the formed ring is monocyclic. In some embodiments, the formed ring is bicyclic. In some embodiments, the formed ring is polycyclic. In some embodiments, the formed ring is saturated. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring is 3 to 10-membered. In some embodiments, the formed ring is 3-, 4-, 5-, 6-, or 7-membered. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered. In some embodiments, the formed ring is R 5 and R 6 It has 0 to 3 heteroatoms in addition to the nitrogen atom to which it is bonded. In some embodiments, the ring formed is a 5-membered saturated monocyclic ring, and R 5 and R 6 It has no additional heteroatoms other than the nitrogen atom to which it is bonded. In some embodiments, the formed ring is a 6-membered saturated monocyclic ring, R 5 and R 6 It does not have any additional heteroatoms other than the nitrogen atom to which it is bonded. In some embodiments, R 3 and R 8 One of the following, as well as R 5 and R 6 One of them, together with the intervening atoms, forms the optionally substituted ring described in this disclosure, R 3 and R 8 The remainder is -OH. In some embodiments, the provided compound is compound II-b or a salt thereof. In some embodiments, the provided compound is compound II-c or a salt thereof. In some embodiments, R 3 and R 5 is R, and together they form an optionally substituted ring as described herein. In some embodiments, the compounds provided for formula II are [ka]

[0048] In some embodiments, the provided compound (e.g., compound of formula I) is a compound of formula III: [ka] It has the structure of the salt thereof, in the formula: The A' ring is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, wherein the A' ring is -N(R 6 )-Includes part, R 3 and R 4 These are -H and -L, respectively, independently. s -R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2, L s Each of them is independently covalently bonded, or C 1-30 A carbon atom having an aliphatic group and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 A linear or branched divalent group optionally substituted from heteroaliphatic groups, wherein one or more methylene units are C 1-6 Alkilen, C 1-6Alkenylene, a divalent C1-C6 heteroaliphatic group having 1 to 5 heteroatoms independently selected from -C≡C-, oxygen, nitrogen, sulfur, phosphorus, and silicon, -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P The carbon atoms are optionally and independently replaced by any substitutional group selected from (S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR')[B(R')3]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O-, or -OP(OR')[B(R')3]O-, and one or more carbon atoms are replaced by any substitutional group selected from Cy L It can be replaced arbitrarily and independently. -Cy- are each independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Cy L Each of them is independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted tetravalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)2R. t is between 0 and 20. R 6 is R', R 8 -LR 7 , -LC(R 1 )(R 2 )-R 7 , or -L s -R 7 And, R 7 is -OH or SH, L is either covalently bonded or optionally substituted with C 1-6 It is an alkylene, and one or more methylene units can be optionally and independently replaced by -L'-. L' is a covalent bond, optionally substituted with a divalent C 1-3 Alkylene, -C(R 3 )(R 4 )-,-C(R 3 )(R 4 )-C(R 3 )(R 4 )-, -Cy-, or -C(R 3 )[C(R 4 )3]- and Each R is independently either -H or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 Heteroliphatic, C 6-30 Ariel, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 An optionally substituted group selected from aryl heteroaliphatic groups, 5-30 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or The two R groups can optionally and independently come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with that atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to that atom, or Two or more R groups on two or more atoms can optionally and independently combine with the intervening atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to the intervening atom.

[0049] In some embodiments, the compound provided is of formula III-a: [ka] The compound has the structure of formula III or the structure of a salt thereof, where each variable part is independently described herein. In some embodiments, the compound of formula III has the structure of formula III-a.

[0050] In some embodiments, the provided compound is of formula III-b: The compound has the structure of TIFF2026053646000034.tif34166 or the structure of a salt thereof, where each variable part is independently described herein. In some embodiments, the compound of formula III-a has the structure of formula III-b.

[0051] In some embodiments, R 8 is -N(R 6 )-(N 1 ) the carbon atom (C) next to the nitrogen atom 2 ) is coupled to (e.g., formula III-a, formula III-b, etc.). In some embodiments, R 8 C 2 The carbon atom next to it (C 3 ) is coupled to R 8 C 3 The carbon atom next to it, C 2 Not a carbon atom (C4 ) is coupled to R 8 C 4 The carbon atom next to it, C 3 Not a carbon atom (C 5 ) is coupled to R 8 C 5 The carbon atom next to it, C 4 Not a carbon atom (C 6 It is joined to ().

[0052] In some embodiments, R 8 is -OH. In some embodiments, R 6 is -H. In some embodiments, R 5 R is an optionally substituted alkyl group. In some embodiments, R 5 is methyl. In some embodiments, t is 0. In some embodiments, R 3 R is an optionally substituted alkyl group. In some embodiments, R 3 is methyl. In some embodiments, R 3 R is an optionally substituted phenyl. In some embodiments, R 3 is phenyl. In some embodiments, R 3 C is optionally substituted. 3-10 It is cycloalkyl. In some embodiments, R 3 is a cyclohexyl which is optionally substituted. In some embodiments, R 3 It is cyclohexyl.

[0053] In some embodiments, the A' ring is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, wherein the A' ring is -N(R 6)-Includes a portion. In some embodiments, the A' ring is the A ring described in this disclosure, and the A ring includes a nitrogen ring atom. In some embodiments, the A' ring is at least one saturated or partially unsaturated monocyclic ring portion, or includes at least one saturated or partially unsaturated monocyclic ring portion, which optionally includes the monocyclic ring portion as part of a bicyclic or polycyclic system. In some embodiments, the A' ring is monocyclic. In some embodiments, the A' ring is bicyclic or polycyclic, including at least one saturated or partially unsaturated monocyclic ring portion and one or more optionally aromatic monocyclic portions. In some embodiments, the A' ring is at least one saturated monocyclic ring portion, or includes at least one saturated monocyclic ring portion. In some embodiments, R 8 This is the sp of the A' ring. 3 It is bonded to the ring atom. In some embodiments, R 8 This is the sp of the A' ring. 3 It is bonded to a carbocyclic atom. In some embodiments, R 3 This is the sp of the A' ring. 3 It is bonded to the ring atom. In some embodiments, R 3 This is the sp of the A' ring. 3 It is bonded to a carbocyclic atom. In some embodiments, R 6 The nitrogen atom to which it is bonded is sp 3 That is the case.

[0054] In some embodiments, the compound provided by formula III is [ka] and salts thereof are selected. In some embodiments, the compound provided by formula III is selected from the compounds and salts thereof listed in Table 4 below.

[0055] [Table 1] TIFF2026053646000037.tif239166TIFF2026053646000038.tif238166TIFF2026053646000039.tif237166TIFF2026053646000040.tif219166TIFF2026053646000041.tif245166TIFF2026053646000042.tif232166TIFF2026053646000043.tif235166TIFF2026053646000044.tif230166TIFF2026053646000045.tif237166TIFF2026053646000046.tif240166TIFF2026053646000047.tif235166TIFF2026053646000048.tif245166TIFF2026053646000049.tif243166TIFF2026053646000050.tif240166TIFF2026053646000051.tif243166TIFF2026053646000052.tif242166TIFF2026053646000053.tif239166TIFF2026053646000054.tif231166TIFF2026053646000055.tif242166TIFF2026053646000056.tif245166TIFF2026053646000057.tif236166TIFF2026053646000058.tif227166TIFF2026053646000059.tif220166TIFF2026053646000060.tif238166TIFF2026053646000061.tif240166TIFF2026053646000062.tif240166TIFF2026053646000063.tif235166TIFF2026053646000064.tif245166TIFF2026053646000065.tif236166TIFF2026053646000066.tif244166TIFF2026053646000067.tif242166TIFF2026053646000068.tif219166TIFF2026053646000069.tif146166

[0056] In some embodiments, the provided compound is an enantiomer of a compound selected from Table 1 or a salt thereof. In some embodiments, the provided compound is a diastereomer of a compound selected from Table 1 or a salt thereof.

[0057] [Table 2] TIFF2026053646000071.tif230166TIFF2026053646000072.tif235166TIFF2026053646000073.tif233166TIFF202 6053646000074.tif235166TIFF2026053646000075.tif240166TIFF2026053646000076.tif242166TIFF20260536460 00077.tif242166TIFF2026053646000078.tif239166TIFF2026053646000079.tif237166TIFF2026053646000080.t if243166TIFF2026053646000081.tif234166TIFF2026053646000082.tif228166TIFF2026053646000083.tif133166

[0058] In some embodiments, the provided compound is an enantiomer of a compound selected from Table 2 or a salt thereof. In some embodiments, the provided compound is a diastereomer of a compound selected from Table 2 or a salt thereof.

[0059] [Table 3] TIFF2026053646000085.tif243166TIFF2026053646000086.tif235166TIFF2026053646000087.tif241166TIFF2026053646000088.tif193166

[0060] In some embodiments, the provided compound is an enantiomer of a compound selected from Table 3 or a salt thereof. In some embodiments, the provided compound is a diastereomer of a compound selected from Table 3 or a salt thereof.

[0061] [Table 4] TIFF2026053646000090.tif224166TIFF2026053646000091.tif209166TIFF2026053646 000092.tif228166TIFF2026053646000093.tif216166TIFF2026053646000094.tif42166

[0062] In some embodiments, the provided compound is an enantiomer of a compound selected from Table 4 or a salt thereof. In some embodiments, the provided compound is a diastereomer of a compound selected from Table 4 or a salt thereof.

[0063] In some embodiments, the provided compounds (e.g., compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof) contain one or more chiral elements. In some embodiments, the provided compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof, are chiral. In some embodiments, the provided chiral compounds (compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b) or salts thereof are of the purity described in this disclosure. In some embodiments, the chiral compounds provided (compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b) or salts thereof have the stereopurity described in this disclosure. In some embodiments, the chiral compounds provided (compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b) or salts thereof have the diastereomer purity described in this disclosure. In some embodiments, the chiral compounds provided (compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b) or salts thereof have the enantiomer purity described in this disclosure. In some embodiments, the chiral compounds provided (compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b) or salts thereof have the diastereomer purity and enantiomer purity described in this disclosure.In some embodiments, the disclosure is prepared from compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof, and formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, The present invention provides compounds containing the chiral element of the compound of formula III-b (for example, compounds of formulas IV, IV-a, IV-b, IV-c-1, IV-c-2, IV-d, IV-e, V, Va, Vb, Vc-1, Vc-2, Vd, Ve, VI, VI-a, VI-b, VI-c-1, VI-c-2, VI-d, VI-e, and VIII) or salts thereof.

[0064] For example, in some embodiments, this disclosure relates to formula IV: [ka] The present invention provides a compound having the structure or a salt thereof, in which: P L This is P(=W), P, or P→B(R')3, L is either covalently bonded or optionally substituted with C 1-6 It is an alkylene, and one or more methylene units can be optionally and independently replaced by -L'-. L' is a covalent bond, optionally substituted with a divalent C 1-3 Alkylene, -C(R 3 )(R 4 )-,-C(R 3 )(R 4 )-C(R 3 )(R 4 )-, -Cy-, or -C(R 3 )[C(R 4 )3]- and R 1 , R 2 , R 3 , R 4 , and R 5 These are -H and -L, respectively, independently. s-R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2, L s Each of them is independently covalently bonded, or C 1-30 A carbon atom having an aliphatic group and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 A linear or branched divalent group optionally substituted from heteroaliphatic groups, wherein one or more methylene units are C 1-6 Alkilen, C 1-6 Alkenylene, a divalent C1-C6 heteroaliphatic group having 1 to 5 heteroatoms independently selected from -C≡C-, oxygen, nitrogen, sulfur, phosphorus, and silicon, -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P The carbon atoms are optionally and independently replaced by any substitutional group selected from (S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR')[B(R')3]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O-, or -OP(OR')[B(R')3]O-, and one or more carbon atoms are replaced by any substitutional group selected from Cy L It can be replaced arbitrarily and independently. -Cy- are each independent of C 3-20 Alicyclic ring, C 6-20An optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Cy L Each of them is independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted tetravalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)2R. L 7 It is -O- or -S-, R 1 , R 2 , R 3 , and R 4 At least one of them is not -H, BA is C 3-30 Alicyclic, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon. 5-30 C having 1 to 10 heteroatoms independently selected from heteroaryl, oxygen, nitrogen, sulfur, phosphorus, and silicon. 3-30 A group that is optionally substituted, selected from heterocyclines, native nucleic acid base moieties, and modified nucleic acid base moieties. SU is -L s -O- or [ka] And SU is linked to the phosphorus atom via the oxygen atom, R s These are independently -H, halogen, -CN, -N3, -NO, -NO2, and -L. s-R', -L s -Si(R)3, -L s -OR', -L s -SR', -L s -N(R')2, -OL s -R', -OL s -Si(R)3, -OL s -OR', -OL s -SR' or -OL s -N(R')2, t is between 0 and 20. A s The ring is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. R 5s R s And, Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)2R. Each R is independently either -H or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 Heteroliphatic, C 6-30 Ariel, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 An optionally substituted group selected from aryl heteroaliphatic groups, 5-30 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or The two R groups can optionally and independently come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with that atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to that atom, or Two or more R groups on two or more atoms can optionally and independently combine with the intervening atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to the intervening atom.

[0065] In some embodiments, P L P(=W) is. In some embodiments, P L P is P. In some embodiments, P L In some embodiments, P → B(R')3. L P is chiral. In some embodiments, P L In some embodiments, P is Rp. L P is Sp.

[0066] In some embodiments, SU is -L s -O-. In some embodiments, SU is [ka] In the formula, each variable part is independently described herein. In some embodiments, SU is [ka] And in the formula, R 1s , R 2s , R 3s , R 4s , and R 5s Each of them is independently R s In some embodiments, SU is [ka] In the formula, each variable part is independently described herein. In some embodiments, SU is [ka] In the formula, each variable part is independently described herein. In some embodiments, SU is [ka] In the formula, each variable part is independently described herein. In some embodiments, SU is [ka] In the formula, each variable part is independently described herein. In some embodiments, SU is [ka] In the formula, each variable part is independently described in this disclosure.

[0067] In some embodiments, the provided compound (e.g., the compound of formula IV) is formula IV-a: [ka] The compound has the structure of or a salt of the formula, where each variable part is independently described herein. In some embodiments, the compound provided for formula IV has the structure of formula IV-a. In some embodiments, L s is -Cy-. In some embodiments, L s is an optionally substituted 3-20 member monocyclic or bicyclic heterocycline ring having 1-5 heteroatoms. In some embodiments, L s is an optionally substituted 5-20 member monocyclic or bicyclic heterocycline ring having 1-5 heteroatoms, where at least one heteroatom is oxygen. In some embodiments, L sis an optionally substituted divalent tetrahydrofuran ring. In some embodiments, L s is an optional furanose moiety. In some embodiments, BA in formula IV-a is bonded to C1 of the furanose moiety, and -O- in formula IV-a is bonded to C3 of the furanose moiety.

[0068] In some embodiments, the provided compound (e.g., the compound of formula IV) is formula IV-b: [ka] The compound has the structure of formula IV or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound provided for formula IV has the structure of formula IV-b.

[0069] In some embodiments, the provided compound (e.g., compound of formula IV) is formula IV-c-1: [ka] The compound has the structure of formula IV or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula IV has the structure of formula IV-c-1.

[0070] In some embodiments, the provided compound (e.g., the compound of formula IV) is formula IV-c-2: [ka] The compound has the structure of formula IV or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula IV has the structure of formula IV-c-2.

[0071] In some embodiments, the provided compound (e.g., compound of formula IV) is formula IV-d: [ka] The compound has the structure of formula IV or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound provided for formula IV has the structure of formula IV-d.

[0072] In some embodiments, the provided compound (e.g., the compound of formula IV) is formula IV-e: [ka] The compound has the structure of formula IV or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound provided for formula IV has the structure of formula IV-e.

[0073] In some embodiments, compounds of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, or formula IV-e can be prepared from compounds such as formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, and formula III-b. In some embodiments, [ka] This description applies to formulas I, Ia, Ia-1, Ia-2, Ib, Ic, Id, Ie, II, II-a, II-b, III, III-a, III-b, etc. In some embodiments, compounds of formula IV, IV-a, IV-b, IV-c-1, IV-c-2, IV-d, or IV-e are described as follows: [ka] However, it has a compound having the structure I, Ia, Ia-1, Ia-2, Ib, Ic, Id, or Ie, or a salt thereof.

[0074] In some embodiments, this disclosure relates to formula IVa: [ka] The present disclosure provides compounds having the structure of formula IVa-a, where each variable part is independently described herein. In some embodiments, the present disclosure provides compounds having the structure of formula IVa-a: [ka] The present disclosure provides compounds having the structure of formula IVa or salts thereof, where each variable part is independently described herein. In some embodiments, the compound of formula IVa is the compound of formula IVa-a. In some embodiments, the present disclosure provides compounds of formula IVa-b: [ka] The present disclosure provides compounds having the structure of formula IVa or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound of formula IVa is the compound of formula IVa-b. In some embodiments, the present disclosure provides compounds of formula IVa-c-1: [ka] The present disclosure provides compounds having the structure of formula IVa or salts thereof, where each variable part is independently described herein. In some embodiments, the compound of formula IVa is the compound of formula IVa-c-1. In some embodiments, the present disclosure provides compounds of formula IVa-c-2: [ka] The present disclosure provides compounds having the structure of formula IVa or salts thereof, where each variable part is independently described herein. In some embodiments, the compound of formula IVa is the compound of formula IVa-c-2. In some embodiments, the present disclosure provides compounds of formula IVa-d: [ka] The present disclosure provides compounds having the structure of formula IVa or salts thereof, where each variable part is independently described herein. In some embodiments, the compound of formula IVa is a compound of formula IVa-d. In some embodiments, the present disclosure provides compounds of formula IVa-e: [ka] The present invention provides compounds having the structure of the formula or salts thereof, where each variable part is independently described herein. In some embodiments, the compound of formula IVa is a compound of formula IVa-e. In some embodiments, L 7 is -O-. In some embodiments, R 1 , R 5 , and R 6 Each of these can be substituted independently and arbitrarily. 1-6 It is alkyl. In some embodiments, R 5 and R 6 This is the same as P L is P. In some embodiments, -L 7 -R 1 It does not contain chiral elements. In some embodiments, -N(R 5 )(R 6 ) does not contain chiral elements. In some embodiments, -L 7 -R 1 and -N(R 5 )(R 6 ) does not contain chiral elements. In some embodiments, -L 7 -R 1 It is -O-CH2CH2-CN. In some embodiments, -N(R 5 )(R 6 ) is -N(i-Pr)2. In some embodiments, compounds of formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, or formula IVa-e, or salts thereof, are phosphoramidites for non-chiral controlled oligonucleotide synthesis (e.g., oligonucleotide synthesis using conventional phosphoramidite chemistry). In some embodiments, R 1 and R 5R is present, and together with the intervening atoms, they form the ring described in this disclosure. In some embodiments, the formed ring contains a chiral element, and compounds of formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, or formula IVa-e, or salts thereof, can be used for chiral-controlled oligonucleotide synthesis.

[0075] In some embodiments, this disclosure relates to formula V: [ka] The present invention provides a compound having the structure or a salt thereof, in which: P L This is P(=W), P, or P→B(R')3, Ring A is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. R 1 , R 2 , R 3 , R 4 , and R 5 These are -H and -L, respectively, independently. s -R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2, L s Each of them is independently covalently bonded, or C 1-30 A carbon atom having an aliphatic group and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 A linear or branched divalent group optionally substituted from heteroaliphatic groups, wherein one or more methylene units are C 1-6 Alkilen, C 1-6Alkenylene, a divalent C1-C6 heteroaliphatic group having 1 to 5 heteroatoms independently selected from -C≡C-, oxygen, nitrogen, sulfur, phosphorus, and silicon, -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P The carbon atoms are optionally and independently replaced by any substitutional group selected from (S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR')[B(R')3]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O-, or -OP(OR')[B(R')3]O-, and one or more carbon atoms are replaced by any substitutional group selected from Cy L It can be replaced arbitrarily and independently. -Cy- are each independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Cy L Each of them is independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted tetravalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)2R. t is between 0 and 20. L 8 -LO-, -LC(R 1 )(R 2 )-O-, or -L s -O-, L is either covalently bonded or optionally substituted with C 1-6 It is an alkylene, and one or more methylene units can be optionally and independently replaced by -L'-. L' is a covalent bond, optionally substituted with a divalent C 1-3 Alkylene, -C(R 3 )(R 4 )-,-C(R 3 )(R 4 )-C(R 3 )(R 4 )-, -Cy-, or -C(R 3 )[C(R 4 )3]- and BA is C 3-30 Alicyclic, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon. 5-30 C having 1 to 10 heteroatoms independently selected from heteroaryl, oxygen, nitrogen, sulfur, phosphorus, and silicon. 3-30 A group that is optionally substituted, selected from heterocyclines, native nucleic acid base moieties, and modified nucleic acid base moieties. SU is -L s -O- or [ka] And SU is linked to the phosphorus atom via the oxygen atom, R 5s R s And, R s These are independently -H, halogen, -CN, -N3, -NO, -NO2, and -L. s -R', -L s -Si(R)3, -L s-OR', -L s -SR', -L s -N(R')2, -OL s -R', -OL s -Si(R)3, -OL s -OR', -OL s -SR' or -OL s -N(R')2, A s The ring is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)2R. Each R is independently either -H or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 Heteroliphatic, C 6-30 Ariel, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 An optionally substituted group selected from aryl heteroaliphatic groups, 5-30 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or The two R groups can optionally and independently come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with that atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to that atom, or Two or more R groups on two or more atoms can optionally and independently combine with the intervening atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to the intervening atom.

[0076] In some embodiments, P L P(=W) is. In some embodiments, P L P is P. In some embodiments, P L In some embodiments, P → B(R')3. L P is chiral. In some embodiments, P L In some embodiments, P is Rp. L P is Sp.

[0077] In some embodiments, the provided compound (e.g., a compound of formula V) is of formula Va: [ka] The compound has the structure of formula V or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula V has the structure of formula Va.

[0078] In some embodiments, the provided compound (e.g., a compound of formula V) is of formula Vb: [ka] The compound has the structure of formula V or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula V has the structure of formula Vb.

[0079] In some embodiments, the provided compound (e.g., a compound of formula V) is of formula Vc-1: [ka] The compound has the structure of formula V or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula V has the structure of formula Vc-1.

[0080] In some embodiments, the provided compound (e.g., compound of formula V) is of formula Vc-2: [ka] The compound has the structure of formula V or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula V has the structure of formula Vc-2.

[0081] In some embodiments, the provided compound (e.g., a compound of formula V) is of formula Vd: [ka] The compound has the structure of formula V or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula V has the structure of formula Vd.

[0082] In some embodiments, the provided compound (e.g., a compound of formula V) is of formula Ve: [ka] The compound has the structure of formula V or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula V has the structure of formula Ve.

[0083] In some embodiments, compounds of formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, or formula Ve can be prepared from compounds such as formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, and formula III-b. In some embodiments, [ka] This description applies to formulas I, Ia, Ia-1, Ia-2, Ib, Ic, Id, Ie, II, II-a, II-b, III, III-a, III-b, etc. In some embodiments, compounds of formula IV, IV-a, IV-b, IV-c-1, IV-c-2, IV-d, or IV-e are described as follows: [ka] It has a structure that results in a compound having structure II, II-a, or II-b.

[0084] In some embodiments, this disclosure is related to formula VI: [ka] The present invention provides a compound having the structure or a salt thereof, wherein each variable part is independently described herein.

[0085] In some embodiments, the provided compound (e.g., a compound of formula VI) is formula VI-a: [ka] The structure of the A' ring or a salt thereof is P L The A ring contains a ring nitrogen atom bonded to P, and each variable part is independently described in this disclosure. In some embodiments, the compounds provided for formula VI have the structure of formula VI-a.

[0086] In some embodiments, the provided compound (e.g., the compound of formula VI) is formula VI-b: [ka] The compound has the structure of formula VI or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula VI has the structure of formula VI-b.

[0087] In some embodiments, the provided compound (e.g., the compound of formula VI) is formula VI-c-1: [ka] The compound has the structure of formula VI or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula VI has the structure of formula VI-c-1.

[0088] In some embodiments, the provided compound (e.g., the compound of formula VI) is formula VI-c-2: [ka] The compound has the structure of formula VI or a salt thereof, where each variable part is independently described herein. In some embodiments, the compound provided for formula VI has the structure of formula VI-c-2.

[0089] In some embodiments, the provided compound (e.g., the compound of formula VI) is formula VI-d: [ka] The compound has the structure of formula VI or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound provided for formula VI has the structure of formula VI-d.

[0090] In some embodiments, the provided compound (e.g., the compound of formula VI) is formula VI-e: [ka] The compound has the structure of formula VI or a salt thereof, where each variable part is independently described in this disclosure. In some embodiments, the compound provided for formula VI has the structure of formula VI-e.

[0091] In some embodiments, compounds of formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e can be prepared from compounds such as formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, and formula III-b. In some embodiments, [ka] This description applies to formulas I, Ia, Ia-1, Ia-2, Ib, Ic, Id, Ie, II, II-a, II-b, III, III-a, III-b, etc. In some embodiments, compounds of formula VI, VI-a, VI-b, VI-c-1, VI-c-2, VI-d, or VI-e are described as follows: [ka] It has a structure that results in a compound having structure III, III-a, or III-b.

[0092] In some embodiments, the Disclosure provides a synthesis method which includes providing a compound or a salt thereof comprising formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e. In some embodiments, the Disclosure provides a synthesis method which includes providing a compound or a salt thereof comprising formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e. In some embodiments, the Disclosure provides a method for stereoselective synthesis of a compound or salt thereof comprising formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e.In some embodiments, the Disclosure provides a method for stereoselective synthesis, which includes providing a compound or salt thereof of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e. In some embodiments, the compounds provided with formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof, are chiral auxiliary groups. In some embodiments, the present disclosure provides a method for preparing phosphoramidites, the method of preparation, which includes providing the compounds provided with formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof. In some embodiments, the Disclosure provides a method for the stereoselective preparation of phosphoramidites, the method comprising providing compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b. In some embodiments, the phosphoramidite has the structure of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or the structure of a salt thereof.In some embodiments, the phosphoramidite has the structure of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or the structure of a salt thereof. In some embodiments, the Disclosure provides a method for preparing nucleic acids, which includes providing compounds such as Formula I, Formula Ia, Formula Ia-1, Formula Ia-2, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula II, Formula II-a, Formula II-b, Formula III, Formula III-a, Formula III-b, Formula IV, Formula IV-a, Formula IV-b, Formula IV-c-1, Formula IV-c-2, Formula IV-d, Formula IV-e, Formula IVa, Formula IVa-a, Formula IVa-b, Formula IVa-c-1, Formula IVa-c-2, Formula IVa-d, Formula IVa-e, Formula V, Formula Va, Formula Vb, Formula Vc-1, Formula Vc-2, Formula Vd, Formula Ve, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c-1, Formula VI-c-2, Formula VI-d, and Formula VI-e. In some embodiments, the Disclosure provides a method for preparing nucleic acids, which includes providing compounds such as Formula I, Formula Ia, Formula Ia-1, Formula Ia-2, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula II, Formula II-a, Formula II-b, Formula III, Formula III-a, Formula III-b, Formula IV, Formula IV-a, Formula IV-b, Formula IV-c-1, Formula IV-c-2, Formula IV-d, Formula IV-e, Formula V, Formula Va, Formula Vb, Formula Vc-1, Formula Vc-2, Formula Vd, Formula Ve, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c-1, Formula VI-c-2, Formula VI-d, and Formula VI-e.In some embodiments, the present disclosure provides a method for the stereoselective (chiral-controlled) preparation of nucleic acids, the method comprising providing compounds such as formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, and formula VI-e. In some embodiments, the present disclosure provides a method for the stereoselective (chiral-controlled) preparation of nucleic acids, the method comprising providing compounds such as formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, and formula VI-e. In some embodiments, the provided compounds such as Formula I, Formula Ia, Formula Ia-1, Formula Ia-2, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula II, Formula II-a, Formula II-b, Formula III, Formula III-a, Formula III-b, Formula IV, Formula IV-a, Formula IV-b, Formula IV-c-1, Formula IV-c-2, Formula IV-d, Formula IV-e, Formula IVa, Formula IVa-a, Formula IVa-b, Formula IVa-c-1, Formula IVa-c-2, Formula IVa-d, Formula IVa-e, Formula V, Formula Va, Formula Vb, Formula Vc-1, Formula Vc-2, Formula Vd, Formula Ve, Formula VI, Formula VI-a, Formula VI-b, Formula VI-c-1, Formula VI-c-2, Formula VI-d, and Formula VI-e are useful for oligonucleotide synthesis.In some embodiments, the compounds provided for formulas IV, IV-a, IV-b, IV-c-1, IV-c-2, IV-d, IV-e, IVa, IVa-a, IVa-b, IVa-c-1, IVa-c-2, IVa-d, IVa-e, V, Va, Vb, Vc-1, Vc-2, Vd, Ve, VI, VI-a, VI-b, VI-c-1, VI-c-2, VI-d, or VI-e are phosphoramidites for oligonucleotide synthesis. In some embodiments, the provided compounds are particularly useful for the chiral-controlled synthesis of oligonucleotides containing one or more chiral internucleotide bonds, where at least one chiral internucleotide bond is formed in a chiral-controlled manner. In some embodiments, the Disclosure provides a method for synthesizing oligonucleotides, which includes providing compounds or salts thereof of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e. In some embodiments, the Disclosure provides a method for synthesizing oligonucleotides, which includes providing compounds or salts thereof relating to formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e.In some embodiments, the provided method is a chiral-controlled method for preparing an oligonucleotide comprising one or more chiral nucleotide interbonds, wherein at least one chiral nucleotide interbond is formed in a chiral-controlled manner. In some embodiments, the provided technique (reagents, method, etc.) gives a chiral-controlled oligonucleotide composition of an oligonucleotide comprising one or more chiral nucleotide interbonds, wherein at least one chiral nucleotide interbond has a diastereomer purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99% in the composition. In some embodiments, the provided technology gives a chiral-controlled oligonucleotide composition of oligonucleotides comprising one or more chiral nucleotide interbonds, each of which has a diastereomer purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99% in the composition. In some embodiments, the provided technology has a diastereomer purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, and at least 93% in at least one chiral nucleotide interbond. , gives oligonucleotides having a diastereomer purity of at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99%. In some embodiments, the provided technology gives oligonucleotides having a diastereomer purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99% in each of the chiral nucleotide interbonds. In some embodiments, the provided oligonucleotide comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-five, at least forty, at least forty, at least fifty, or at least fifty chiral nucleotide interbondings. In some embodiments, the provided oligonucleotide comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty, at least thirty, at least thirty, at least fifteen, at least fifteen, or at least fifty nucleic acid bases.In some embodiments, the provided oligonucleotide comprises at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 35, at least 40, at least 45, or at least 50 nucleic acid bases. In some embodiments, the provided oligonucleotide comprises at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 35, at least 40, at least 45, or at least 50 nucleic acid bases. In some embodiments, the provided oligonucleotide comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 35, at least 40, at least 45, or at least 50 nucleic acid bases. In some embodiments, the provided oligonucleotides contain 5 to 200, 5 to 150, 5 to 100, 5 to 50, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 10 to 200, 10 to 150, 10 to 100, 10 to 50, 10 to 40, 10 to 35, 10 to 30, 10 to 25, 15 to 200, 15 to 150, 15 to 100, 15 to 50, 15 to 40, 15 to 35, 15 to 30, or 15 to 25 nucleic acid bases.In some embodiments, the provided method involves oligonucleotide synthesis using a solid support. In some embodiments, the provided oligonucleotide is bound to a solid support. In some embodiments, the provided oligonucleotide is cleaved from the solid support. In some embodiments, the provided oligonucleotide contains at least two chemically distinct types of nucleotide internucleotide bonds. In some embodiments, the provided oligonucleotide contains at least two chemically distinct types of chiral nucleotide internucleotide bonds, each independently being Rp or Sp. In some embodiments, all chemically distinct types of chiral nucleotide internucleotide bonds are Sp. In some embodiments, all chemically distinct types of chiral nucleotide internucleotide bonds are Rp. In some embodiments, some of the chemically distinct types of chiral nucleotide internucleotide bonds are Rp and others are Sp. In some embodiments, some of the chemically distinct types of chiral nucleotide internucleotide bonds are Rp, some are Sp, and others are not chiral-controlled.

[0093] In some embodiments, the methods provided are those described in US / 2011 / 0294124, US / 2015 / 0211006, US / 2017 / 0037399, WO / 2017 / 015555, and WO / 2017 / 062862 (the methods described in each of these documents are incorporated herein by reference), and the chiral auxiliary groups in such methods are those of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula The chiral phosphorus-containing phosphoramidites in these methods are substituted with compounds of formula II-b, formula III, formula III-a, and formula III-b, and / or are substituted with compounds of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or salts thereof.

[0094] As will be readily apparent to those skilled in the art, the provided techniques enable the production of oligonucleotides of various base sequences with precisely controlled chemical modifications (e.g., base modifications, sugar modifications, nucleotide bond modifications, etc.) and / or chiral nucleotide bond stereochemistry. In some embodiments, the provided methods are useful for the preparation of oligonucleotides and their compositions described in US / 2015 / 0211006, US / 2017 / 0037399, WO / 2017 / 015555, and WO / 2017 / 062862, which are incorporated herein by reference, respectively. In some embodiments, this disclosure provides oligonucleotides described in US / 2011 / 0294124, US / 2015 / 0211006, US / 2017 / 0037399, WO / 2017 / 015555, and WO / 2017 / 062862, as well as oligonucleotides in the process of preparing the compositions thereof (for example, those whose base sequences are already complete but have not yet been cleaved from a solid support).

[0095] In some embodiments, the internucleotide bond formed by using the provided technology is described in US / 2015 / 0211006, US / 2017 / 0037399, WO / 2017 / 015555, and WO / 2017 / 062862, which are incorporated herein by reference, respectively. In some embodiments, the internucleotide bond is a chiral internucleotide bond in that it contains chiral-linked phosphorus. In some embodiments, the internucleotide bond is of formula VII: [ka] It has the structure or a salt form thereof, in the formula: P L This is P(=W), P, or P→B(R')3, W is O, S, or Se, R 1 and R 5 These are -H and -L, respectively, independently. s -R, halogen, -CN, -NO2, -L s-Si(R)3, -OR, -SR, or -N(R)2, X, Y, and Z are independently -O-, -S-, and -N(-L s -R 1 )-, or L s And, L s Each of them is independently covalently bonded, or C 1-30 A carbon atom having an aliphatic group and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 A linear or branched divalent group optionally substituted from heteroaliphatic groups, wherein one or more methylene units are C 1-6 Alkilen, C 1-6 Alkenylene, a divalent C1-C6 heteroaliphatic group having 1 to 5 heteroatoms independently selected from -C≡C-, oxygen, nitrogen, sulfur, phosphorus, and silicon, -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P The carbon atoms are optionally and independently replaced by any substitutional group selected from (S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR')[B(R')3]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O-, or -OP(OR')[B(R')3]O-, and one or more carbon atoms are replaced by any substitutional group selected from Cy L It can be replaced arbitrarily and independently. -Cy- are each independent of C 3-20 Alicyclic ring, C 6-20An optionally substituted divalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Cy L Each of them is independent of C 3-20 Alicyclic ring, C 6-20 An optionally substituted tetravalent group selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)2R. Each R is independently either -H or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 Heteroliphatic, C 6-30 Ariel, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 An optionally substituted group selected from aryl heteroaliphatic groups, 5-30 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or The two R groups can optionally and independently come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with that atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to that atom, or Two or more R groups on two or more atoms may, optionally and independently, combine with the intervening atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to the intervening atom, or HXL s -R 5 It has the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, or the structure of a salt thereof.

[0096] In some embodiments, the nucleotide internucleotide bond of formula VII is a chiral nucleotide internucleotide bond. In some embodiments, P L The P in the middle is chiral phosphorus. In some embodiments, the chiral phosphorus is Rp. In some embodiments, the chiral phosphorus is Sp. In some embodiments, P L P(=W) is. In some embodiments, P L P is P. In some embodiments, P L This is P→B(R')3.

[0097] In some embodiments, the internucleotide bond of formula VII is represented by formula VII-a-1: [ka] The formula has the structure or a salt form thereof, where each of the other variable parts is independently described herein.

[0098] In some embodiments, the internucleotide bond of formula VII or formula VII-a-1 is formula VII-a-2: [ka] It has the structure or a salt form thereof, in which P * This is an asymmetric phosphorus atom, and the other variable parts are each independently described in this disclosure.

[0099] In some embodiments, the internucleotide bond is represented by formula VII-b: [ka] The formula has the structure or a salt form thereof, where each variable part is independently described herein. In some embodiments, the internucleotide bond of formula VII has the structure of formula VII-b.

[0100] In some embodiments, the internucleotide bond of formula VII is represented by formula VII-c: [ka] It has the structure or a salt form thereof, in which P * This is an asymmetric phosphorus atom, and the other variable parts are each independently described in this disclosure.

[0101] In some embodiments, the internucleotide bond is represented by formula VII-d: [ka] The formula has the structure or a salt form thereof, where each variable part is independently described herein.

[0102] In some embodiments, the internucleotide bond of formula VII-e is [ka] It has the structure or a salt form thereof, in which P * This is an asymmetric phosphorus atom, and the other variable parts are each independently described in this disclosure.

[0103] In some embodiments, W is O. In some embodiments, W is S. In some embodiments, -XL s -R 5 It is -SR. In some embodiments, it is -XL s -R 5 This is -SH. In some embodiments, -XL s-R 5 is -SR, where R is not hydrogen. In some embodiments, -XL s -R 5 HXL s -R 5 The structure is one having the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or the structure of a salt thereof. In some embodiments, R 7 is -OH, and R 6 is -H or -R. In some embodiments, R 6 is -H. In some embodiments, R 6 is -R, and R is not hydrogen. In some embodiments, R is a capping group. Capping groups suitable for oligonucleotide synthesis are well known to those skilled in the art, for example, as described in US / 2015 / 0211006, US / 2017 / 0037399, WO / 2017 / 015555, and WO / 2017 / 062862, which are incorporated herein by reference, respectively. In some embodiments, R 6 is -C(O)R. As described in this disclosure, in some embodiments, immediately after coupling, is -XL s -R 5 HXL s -R 5 The structure is one having the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or the structure of a salt thereof, where R 5 is -H, and the bond may have the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof. In some embodiments, after capping, XL s -R 5 HXL s -R 5The structure is one having the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or the structure of a salt thereof, where R 5 is a capping group (for example, a group having the structure -C(O)R), and the bond may have the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof. In some embodiments, R 5 The nitrogen atom to which it is bonded is capped by an RC(O)- group, resulting in -N(R 5 The )(-C(O)-R) group is formed. In some embodiments, after additional chemical modification steps, the bond may have the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof.

[0104] In some embodiments, the disclosure provides oligonucleotides comprising one or more internucleotide bonds having the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof. In some embodiments, the oligonucleotide provided contains 1 to 100 internucleotide bonds having the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, or more). In some embodiments, the oligonucleotide provided contains one or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains two or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains three or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains four or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains five or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains six or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains seven or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains eight or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains nine or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains ten or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains eleven or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains twelve or more such internucleotide bonds.In some embodiments, the oligonucleotide provided contains 13 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 14 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 15 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 16 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 17 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 18 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 19 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 20 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 21 or more such internucleotide bonds. In some embodiments, the oligonucleotide provided contains 25 or more such internucleotide bonds. In some embodiments, such internucleotide bonds are chiral. In some embodiments, as described herein, -XL. s -R 5 Each of them is independent of HXL s -R 5 The structure is one having the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or the structure of a salt thereof. In some embodiments, the oligonucleotide provided has the structure of formula VIII or the structure of a salt thereof.

[0105] In some embodiments, the oligonucleotides provided comprise at least two types of internucleotide bonds, each type independently having the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof. In some embodiments, the oligonucleotides provided comprise at least two types of chiral internucleotide bonds, each type independently having the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof. In some embodiments, the two types may have the same or different phosphorus configurations (Rp or Sp), or one or both may be sterically disordered (e.g., formed without chiral-controlled synthesis). In some embodiments, the sterically irregular bonds have diastereomer purities of less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, or less than 55%. In some embodiments, P * It is not stereoirregular and is either Rp or Sp. In some embodiments, in one type W is S and in the other type W is O. In some embodiments, in one type W is S and in the other type W is O and for both types -XL s -R 5 HXL is independent. s -R 5 The structure is one having the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or the structure of a salt thereof. In some embodiments, one type is a natural phosphate bond (-OP(O)(OH)-O-((for example, at a certain pH and / or provided as a salt)-OP(O)(O - The other is a phosphorothioate bond (-OP(O)(SH)-O- ((for example, at a certain pH and / or provided as a salt)-OP(O)(S -It can exist as )-O-).

[0106] In some embodiments, the provided compound (e.g., an oligonucleotide) is of formula VIII: [ka] It has the structure of the salt thereof, in the formula: R 5s These are independently R' or -OR', L s Each of them is independently covalently bonded, or C 1-30 A carbon atom having an aliphatic group and 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 A linear or branched divalent group optionally substituted from heteroaliphatic groups, wherein one or more methylene units are C 1-6 Alkilen, C 1-6 Alkenylene, a divalent C1-C6 heteroaliphatic group having 1 to 5 heteroatoms independently selected from -C≡C-, oxygen, nitrogen, sulfur, phosphorus, and silicon, -C(R')2-, -Cy-, -O-, -S-, -SS-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2-, -S(O)2N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P The carbon atoms are optionally and independently replaced by any substitutional group selected from (S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR')[B(R')3]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O-, or -OP(OR')[B(R')3]O-, and one or more carbon atoms are replaced by any substitutional group selected from Cy Lis optionally and independently replaced with, -Cy- each independently is a C 3-20 alicyclic ring, C 6-20 aryl ring, 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, which is an optionally substituted divalent group selected from, Cy L each independently is a C 3-20 alicyclic ring, C 6-20 aryl ring, 5- to 20-membered heteroaryl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3- to 20-membered heterocyclyl ring having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, which is an optionally substituted tetravalent group selected from, A s rings each independently is an optionally substituted 3- to 20-membered monocyclic ring, bicyclic ring, or polycyclic ring having 0 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, [[ID=XX]] R s each independently is -H, halogen, -CN, -N3, -NO, -NO2, -L s -R’, -L s -Si(R)3, -L s -OR’, -L s -SR’, -L s -N(R’)2, -O-L s -R’, -O-L s -Si(R)3, -O-L s -OR’, -O-L s -SR’, or -O-L s -N(R’)2, t each independently is 0 to 20, BA each independently is a C 3-30 alicyclic, C 6-30 aryl, C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, It should be noted that there seems to be an "XX" in the original text where an ID number is expected in the sequence. This might be an error in the original input. If this is a critical issue for the correct understanding of the patent text, it would be advisable to double-check the original source.5-30 C having 1 to 10 heteroatoms independently selected from heteroaryl, oxygen, nitrogen, sulfur, phosphorus, and silicon. 3-30 A group that is optionally substituted, selected from heterocyclines, native nucleic acid base moieties, and modified nucleic acid base moieties. L P Each of these is an independent internucleotide bond, z is between 1 and 1000. L 3E is, -L s - or -L s -L s -and, R 3E -R', -L s -R', -OR', or a solid support, Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)2R. Each R is independently either -H or C 1-30 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-30 Heteroliphatic, C 6-30 Ariel, C 6-30 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-30 An optionally substituted group selected from aryl heteroaliphatic groups, 5-30 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-30 membered heterocyclyls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, or The two R groups can optionally and independently come together to form a covalent bond, or Two or more R groups on the same atom may, optionally and independently, combine with that atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to that atom, or Two or more R groups on two or more atoms can optionally and independently combine with the intervening atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, in addition to the intervening atom.

[0107] In some embodiments, L P Each independently has the structure of VII, VII-a-1, VII-a-2, VII-b, VII-c, VII-d, or VII-e, or a salt form thereof. In some embodiments, L P Each of them independently has the structure of VII, VII-a-1, VII-a-2, VII-b, VII-c, VII-d, or VII-e, and each L P So, -XL s -R 5 HXL s -R 5 It independently possesses structures that are compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof.

[0108] In some embodiments, at least one L P is a combination of two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, and twenty Ls. P is a , which includes W, where W is S. In some embodiments, at least one L Pis a void containing W, where W is O. In some embodiments, there are at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, and at least twenty L P It includes W, where W is O. In some embodiments, L P is, -XL s -R 5 It includes independently, HXL s -R 5 It has the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or the structure of a salt thereof.

[0109] In some embodiments, the provided compound is a compound selected from Table 1 or a salt thereof. In some embodiments, the provided compound is a stereoisomer of a compound selected from Table 1 or a salt thereof. In some embodiments, the provided compound is a diastereomer of a compound selected from Table 1 or a salt thereof. In some embodiments, the provided compound is an enantiomer of a compound selected from Table 1 or a salt thereof.

[0110] In some embodiments, the provided compound is a compound selected from Table 2 or a salt thereof. In some embodiments, the provided compound is a stereoisomer of a compound selected from Table 2 or a salt thereof. In some embodiments, the provided compound is a diastereomer of a compound selected from Table 2 or a salt thereof. In some embodiments, the provided compound is an enantiomer of a compound selected from Table 2 or a salt thereof.

[0111] In some embodiments, the provided compound is a compound selected from Table 3 or a salt thereof. In some embodiments, the provided compound is a stereoisomer of a compound selected from Table 3 or a salt thereof. In some embodiments, the provided compound is a diastereomer of a compound selected from Table 3 or a salt thereof. In some embodiments, the provided compound is an enantiomer of a compound selected from Table 3 or a salt thereof.

[0112] In some embodiments, the provided compound is a compound selected from Table 4 or a salt thereof. In some embodiments, the provided compound is a stereoisomer of a compound selected from Table 4 or a salt thereof. In some embodiments, the provided compound is a diastereomer of a compound selected from Table 4 or a salt thereof. In some embodiments, the provided compound is an enantiomer of a compound selected from Table 4 or a salt thereof.

[0113] In some embodiments, the provided compound has a purity of 60% to 100%. In some embodiments, the provided compound has a purity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the provided compound has a purity of at least 60%. In some embodiments, the provided compound has a purity of at least 70%. In some embodiments, the provided compound has a purity of at least 80%. In some embodiments, the provided compound has a purity of at least 85%. In some embodiments, the provided compound has a purity of at least 90%. In some embodiments, the provided compound has a purity of at least 91%. In some embodiments, the provided compound has a purity of at least 92%. In some embodiments, the provided compound has a purity of at least 93%. In some embodiments, the provided compound has a purity of at least 94%. In some embodiments, the provided compound has a purity of at least 95%. In some embodiments, the provided compound has a purity of at least 96%. In some embodiments, the provided compound has a purity of at least 97%. In some embodiments, the provided compound has a purity of at least 98%. In some embodiments, the provided compound has a purity of at least 99%. In some embodiments, the provided compound has a purity of at least 99.5%.

[0114] In some embodiments, the provided compound (e.g., chiral auxiliaries, phosphoramidites, oligonucleotides, etc.) has a diastereomer purity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the provided compound has a diastereomer purity of at least 60%. In some embodiments, the provided compound has a diastereomer purity of at least 70%. In some embodiments, the provided compound has a diastereomer purity of at least 80%. In some embodiments, the provided compound has a diastereomer purity of at least 85%. In some embodiments, the provided compound has a diastereomer purity of at least 90%. In some embodiments, the provided compound has a diastereomer purity of at least 91%. In some embodiments, the provided compound has a diastereomer purity of at least 92%. In some embodiments, the provided compound has a diastereomer purity of at least 93%. In some embodiments, the provided compound has a diastereomer purity of at least 94%. In some embodiments, the provided compound has a diastereomer purity of at least 95%. In some embodiments, the provided compound has a diastereomer purity of at least 96%. In some embodiments, the provided compound has a diastereomer purity of at least 97%. In some embodiments, the provided compound has a diastereomer purity of at least 98%. In some embodiments, the provided compound has a diastereomer purity of at least 99%. In some embodiments, the provided compound has a diastereomer purity of at least 99.5%.

[0115] In some embodiments, the chiral elements of the provided compound (e.g., chiral centers (carbon, phosphorus, etc.)) have a diastereomer purity of 60% to 100%. In some embodiments, the chiral elements of the provided compound (e.g., chiral centers (carbon, phosphorus, etc.)) have a diastereomer purity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the chiral element is a chiral carbon. In some embodiments, the chiral element is a chiral phosphorus (e.g., a bound phosphorus atom in a chiral nucleotide bond). In some embodiments, the chiral element has a diastereomer purity of at least 60%. In some embodiments, the chiral center has a diastereomer purity of at least 70%. In some embodiments, the chiral center has a diastereomer purity of at least 80%. In some embodiments, the chiral center has a diastereomer purity of at least 85%. In some embodiments, the chiral center has a diastereomer purity of at least 90%. In some embodiments, the chiral center has a diastereomer purity of at least 91%. In some embodiments, the chiral center has a diastereomer purity of at least 92%. In some embodiments, the chiral center has a diastereomer purity of at least 93%. In some embodiments, the chiral center has a diastereomer purity of at least 94%. In some embodiments, the chiral center has a diastereomer purity of at least 95%. In some embodiments, the chiral center has a diastereomer purity of at least 96%. In some embodiments, the chiral center has a diastereomer purity of at least 97%. In some embodiments, the chiral center has a diastereomer purity of at least 98%. In some embodiments, the chiral center has a diastereomer purity of at least 99%. In some embodiments, the chiral center has a diastereomer purity of at least 99.5%.

[0116] In some embodiments, each of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten chiral elements of the provided compound independently has the diastereomer purity described herein. In some embodiments, each of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten chiral carbon centers of the provided compound independently has the diastereomer purity described herein. In some embodiments, each of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten chiral phosphorus centers of the provided compound independently has the diastereomer purity described herein.

[0117] In some embodiments, at least 5% to 100% of all chiral elements of the provided compound each independently has the diastereomer purity described herein. In some embodiments, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% of all chiral elements of the provided compound each independently has the diastereomer purity described herein. In some embodiments, at least 5% to 100% of all chiral phosphorus centers of the provided compound each independently has the diastereomer purity described herein. In some embodiments, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% of all chiral phosphate centers of the provided compound independently have the diastereomer purity described herein.

[0118] In some embodiments, each chiral element independently has the diastereomer purity described herein. In some embodiments, each chiral center independently has the diastereomer purity described herein. In some embodiments, each chiral carbon center independently has the diastereomer purity described herein. In some embodiments, each chiral phosphorus center independently has the diastereomer purity described herein.

[0119] In some embodiments, the provided compound has an enantiomer purity of 60% to 100%. In some embodiments, the provided compound has an enantiomer purity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the provided compound has an enantiomer purity of at least 60%. In some embodiments, the provided compound has an enantiomer purity of at least 70%. In some embodiments, the provided compound has an enantiomer purity of at least 80%. In some embodiments, the provided compound has an enantiomer purity of at least 85%. In some embodiments, the provided compound has an enantiomer purity of at least 90%. In some embodiments, the provided compound has an enantiomer purity of at least 91%. In some embodiments, the provided compound has an enantiomer purity of at least 92%. In some embodiments, the provided compound has an enantiomer purity of at least 93%. In some embodiments, the provided compound has an enantiomer purity of at least 94%. In some embodiments, the provided compound has an enantiomer purity of at least 95%. In some embodiments, the provided compound has an enantiomer purity of at least 96%. In some embodiments, the provided compound has an enantiomer purity of at least 97%. In some embodiments, the provided compound has an enantiomer purity of at least 98%. In some embodiments, the provided compound has an enantiomer purity of at least 99%. In some embodiments, the provided compound has an enantiomer purity of at least 99.5%.

[0120] In some embodiments, the chiral elements of the provided compound (e.g., chiral centers (carbon, phosphorus, etc.)) have an enantiomer purity of 60% to 100%. In some embodiments, the chiral elements of the provided compound (e.g., chiral centers (carbon, phosphorus, etc.)) have an enantiomer purity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the chiral element is a chiral carbon. In some embodiments, the chiral element is a chiral phosphorus (e.g., a bound phosphorus atom in a chiral nucleotide bond). In some embodiments, the chiral element has an enantiomer purity of at least 60%. In some embodiments, the chiral center has an enantiomer purity of at least 70%. In some embodiments, the chiral center has at least 80% enantiomer purity. In some embodiments, the chiral center has at least 85% enantiomer purity. In some embodiments, the chiral center has at least 90% enantiomer purity. In some embodiments, the chiral center has at least 91% enantiomer purity. In some embodiments, the chiral center has at least 92% enantiomer purity. In some embodiments, the chiral center has at least 93% enantiomer purity. In some embodiments, the chiral center has at least 94% enantiomer purity. In some embodiments, the chiral center has at least 95% enantiomer purity. In some embodiments, the chiral center has at least 96% enantiomer purity. In some embodiments, the chiral center has at least 97% enantiomer purity. In some embodiments, the chiral center has at least 98% enantiomer purity. In some embodiments, the chiral center has at least 99% enantiomer purity. In some embodiments, the chiral center has at least 99.5% enantiomer purity.

[0121] In some embodiments, each of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten chiral elements of the provided compound independently has the enantiomer purity described herein. In some embodiments, each of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten chiral carbon centers of the provided compound independently has the enantiomer purity described herein. In some embodiments, each of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten chiral phosphorus centers of the provided compound independently has the enantiomer purity described herein.

[0122] In some embodiments, at least 5% to 100% of all chiral elements of the provided compound each independently has the enantiomer purity described herein. In some embodiments, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% of all chiral elements of the provided compound each independently has the enantiomer purity described herein. In some embodiments, at least 5% to 100% of all chiral phosphorus centers of the provided compound each independently has the enantiomer purity described herein. In some embodiments, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% of all chiral phosphate centers of the provided compound independently have the enantiomer purity described herein.

[0123] In some embodiments, each chiral element independently has the enantiomer purity described herein. In some embodiments, each chiral center independently has the enantiomer purity described herein. In some embodiments, each chiral carbon center independently has the enantiomer purity described herein. In some embodiments, each chiral phosphorus center independently has the enantiomer purity described herein.

[0124] In some embodiments, the Disclosure provides a method for the stereoselective formation of chiral elements (e.g., chiral centers). In some embodiments, the Disclosure provides a method for the stereoselective preparation of phosphoramidites, the method comprising providing compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, or salts thereof. In some embodiments, the phosphoramidite has the structure of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or the structure of a salt thereof. In some embodiments, the phosphoramidite has the structure of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or the structure of a salt thereof. In some embodiments, a compound is provided having the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, or the structure of a salt thereof (e.g., a chiral auxiliary group), or formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula Phosphoramidites having the structures of formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or the structures of salts thereof, are useful for the preparation of oligonucleotides. In some embodiments, this disclosure provides techniques (e.g., compounds, methods, etc.) for oligonucleotide synthesis.In some embodiments, the Disclosure provides a method for synthesizing oligonucleotides, which includes providing compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or salts thereof. In some embodiments, the Disclosure provides a method for synthesizing oligonucleotides, which includes providing compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or salts thereof. In some embodiments, the Disclosure provides a method for the synthesis of chiralally controlled oligonucleotides, the method comprising providing compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or salts thereof.In some embodiments, the Disclosure provides a method for synthesizing chiralally controlled oligonucleotides, the method comprising providing compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, formula III-b, formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or salts thereof. Examples of oligonucleotides prepared are broadly described in the Disclosure. In some embodiments, the oligonucleotide has, for example, the structure of formula VIII or the structure of a salt thereof.

[0125] In some embodiments, the disclosure provides methods having high stereoselectivity (e.g., methods for preparing chiral auxiliary groups, methods for preparing phosphoramidites, methods for preparing oligonucleotides, etc.). In some embodiments, the disclosure provides methods having high diastereoselectivity. In some embodiments, the disclosure provides methods having high enantioselectivity. In some embodiments, the disclosure provides methods having high diastereoselectivity and high enantioselectivity. In some embodiments, the selectivity is about 60% to 100%. In some embodiments, the selectivity is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the diastereoselectivity is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the enantioselectivity is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, both diastereoselectivity and enantioselectivity are at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the selectivity is at least 60%. In some embodiments, the selectivity is at least 70%. In some embodiments, the selectivity is at least 80%.In some embodiments, the selectivity is at least 85%. In some embodiments, the selectivity is at least 90%. In some embodiments, the selectivity is at least 91%. In some embodiments, the selectivity is at least 92%. In some embodiments, the selectivity is at least 93%. In some embodiments, the selectivity is at least 94%. In some embodiments, the selectivity is at least 95%. In some embodiments, the selectivity is at least 96%. In some embodiments, the selectivity is at least 97%. In some embodiments, the selectivity is at least 98%. In some embodiments, the selectivity is at least 99%. In some embodiments, the selectivity is at least 99.5%.

[0126] In some embodiments, the method provided gives a high yield. In some embodiments, the yield is 50% to 100%. In some embodiments, the yield is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the yield is at least 60%. In some embodiments, the yield is at least 65%. In some embodiments, the yield is at least 70%. In some embodiments, the yield is at least 75%. In some embodiments, the yield is at least 80%. In some embodiments, the yield is at least 85%. In some embodiments, the yield is at least 90%. In some embodiments, the yield is at least 91%. In some embodiments, the yield is at least 92%. In some embodiments, the yield is at least 93%. In some embodiments, the yield is at least 94%. In some embodiments, the yield is at least 95%. In some embodiments, the yield is at least 96%. In some embodiments, the yield is at least 97%. In some embodiments, the yield is at least 98%. In some embodiments, the yield is at least 99%.

[0127] In some embodiments, the methods provided provide high stereoselectivity as described herein, in addition to the high yield described herein. In some embodiments, the methods provided provide yields of 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, and diastereoselectivity of 95%, 96%, 97%, 98%, 99%, or more. In some embodiments, the methods provided provide yields of 70% or more and diastereoselectivity of 95% or more. In some embodiments, the methods provided provide yields of 75% or more and diastereoselectivity of 95% or more. In some embodiments, the methods provided provide yields of 80% or more and diastereoselectivity of 95% or more. In some embodiments, the methods provided provide yields of 85% or more and diastereoselectivity of 95% or more. In some embodiments, the methods provided provide yields of 90% or more and diastereoselectivity of 95% or more. In some embodiments, the provided method yields a yield of 95% or more and a diastereoselectivity of 95% or more. In some embodiments, the provided method yields a yield of 70% or more and a diastereoselectivity of 97% or more. In some embodiments, the provided method yields a yield of 75% or more and a diastereoselectivity of 97% or more. In some embodiments, the provided method yields a yield of 80% or more and a diastereoselectivity of 97% or more. In some embodiments, the provided method yields a yield of 85% or more and a diastereoselectivity of 97% or more. In some embodiments, the provided method yields a yield of 90% or more and a diastereoselectivity of 97% or more. In some embodiments, the provided method yields a yield of 95% or more and a diastereoselectivity of 97% or more. In some embodiments, the provided method yields a yield of 70% or more and a diastereoselectivity of 98% or more. In some embodiments, the provided method yields a yield of 75% or more and a diastereoselectivity of 98% or more. In some embodiments, the provided method yields a yield of 80% or more and a diastereoselectivity of 98% or more. In some embodiments, the provided method yields a yield of 85% or more and a diastereoselectivity of 98% or more.In some embodiments, the provided method yields a yield of 90% or higher and a diastereoselectivity of 98% or higher. In some embodiments, the provided method yields a yield of 95% or higher and a diastereoselectivity of 98% or higher.

[0128] In some embodiments, the Disclosure provides techniques for evaluating the ability of a compound to perform stereoselective synthesis (e.g., yield, purity, stereoselectivity, etc.). In some embodiments, the Disclosure provides techniques for evaluating chiral auxiliary groups (e.g., those of formula I, Ia, Ia-1, Ia-2, Ib, Ic, Id, Ie, II, II-a, II-b, III, III-a, III-b, or salts thereof) or chiral phosphoramidites (e.g., those of formula IV, IV-a, IV-b, IV-c-1, IV-c-2, IV-d, IV-e, V, Va, Vb, Vc-1, Vc-2, Vd, Ve, VI, VI-a, VI-b, VI-c-1, VI-c-2, VI-d, or VI-e, or salts thereof) for the stereoselective preparation of oligonucleotides (e.g., chiral-controlled formation of a predetermined chiral-controlled internucleotide bond). In some embodiments, the disclosure acknowledges that many systems cannot adequately distinguish the capabilities of one or more chiral auxiliaries. In particular, the disclosure provides techniques (e.g., reaction systems comprising a solid support, a linker, and a target oligonucleotide (e.g., a dimer, pentamer, etc.) as shown in the disclosure for evaluating chiral auxiliaries). In some embodiments, such reaction systems are far more stringent than typical oligonucleotide synthesis cycles, in that they typically yield and / or have lower selectivity. In some embodiments, the target oligonucleotide is a dC dimer on a solid support.

[0129] In some embodiments, the provided compound (e.g., chiral auxiliary group, oligonucleotide, etc.) may exist as a salt. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the hydrogen ions that can be donated to the base (e.g., under conditions such as aqueous solution, pharmaceutical composition, etc.) are non-H + It is replaced by a cation. For example, in some embodiments, all pharmaceutically acceptable salts of oligonucleotides are salts of metal ions, and for example, the hydrogen ions (e.g., -OH, -SH, etc.) of each internucleotide bond (e.g., a natural phosphate bond, a phosphorothioate diester bond, etc.) are replaced by metal ions, respectively. In some embodiments, all salts provided are salts of sodium. In some embodiments, all pharmaceutically acceptable salts provided are salts of sodium. In some embodiments, all salts provided are salts of sodium, and each internucleotide bond that is a natural phosphate bond (acid form -OP(O)(OH)-O-) exists as its sodium salt form (-OP(O)(ONa)-O-), if present, and each internucleotide bond that is a phosphorothioate diester bond (acid form -OP(O)(SH)-O-) exists as its sodium salt form (-OP(O)(SNa)-O-), if present.

[0130] In some embodiments, the present disclosure provides an oligonucleotide composition comprising a plurality of oligonucleotides, 1) Common base sequence, 2) Common patterns of skeletal connections, 3) The stereochemistry shared independently of at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty-one, at least twenty-two, at least twenty-three, at least twenty-four, at least twenty-five, at least twenty-six, at least twenty-seven, at least twenty-eight, at least twenty-nine, at least thirty, at least thirty-five, at least forty, at least forty, or at least fifty chiral nucleotide interbonds ("chiral controlled nucleotide interbonds") Share, The composition is chiral-controlled in that the levels of multiple oligonucleotides in the composition are predetermined.

[0131] In some embodiments, the present disclosure provides an oligonucleotide composition comprising a plurality of oligonucleotides, 1) Base sequence, 2) Patterns of skeletal connection, 3) Pattern of the skeletal chiral center, and 4) Patterns of skeletal phosphorus modification It is a specific oligonucleotide type as defined by The composition is chiral-controlled in that the levels of multiple oligonucleotides in the composition are predetermined.

[0132] In some embodiments, the present disclosure provides an oligonucleotide composition comprising a plurality of oligonucleotides, 1) Common base sequence, 2) Common patterns of skeletal connections, and 3) Common patterns of chiral centers in the skeleton Share, The composition is a substantially pure preparation of single oligonucleotides in that a predetermined level of oligonucleotides in the composition has a common base sequence and length, a common pattern of skeletal bonding, and a common pattern of skeletal chiral centers.

[0133] In some embodiments, an oligonucleotide composition comprising multiple oligonucleotides is chiral-controlled in that the multiple oligonucleotides share a stereochemistry that is independently common to one or more chiral nucleotide bonds. In some embodiments, the multiple oligonucleotides share a common stereochemistry for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twenty, twenty-one, twenty-two, twenty-two, twenty-two, twenty-threeth, twenty-fourth, twenty-fiveth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-nineth, thirty, thirty-fiveth, forty, forty-fiveth, fiftyth, or more chiral nucleotide bonds, each of which is independently Rp or Sp. In some embodiments, the multiple oligonucleotides share a common stereochemistry for each of their chiral nucleotide bonds. In some embodiments, a chiral nucleotide bond is referred to as a chiral-controlled nucleotide bond if a certain level of oligonucleotides in a composition share a common stereochemical configuration (independently Rp or Sp). In some embodiments, a certain level of oligonucleotides in a provided composition (e.g., a first group of oligonucleotides in a particular example composition) contains 1 to 50 chiral-controlled nucleotide bonds (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, or more). In some embodiments, at least 5 nucleotide bonds are chiral-controlled. In some embodiments, at least 10 nucleotide bonds are chiral-controlled. In some embodiments, at least 15 nucleotide interbonds are chiralized. In some embodiments, each chiral nucleotide interbond is chiralized. In some embodiments, 0.1% to 100% of the chiral nucleotide interbonds are chiralized.In some embodiments, 0.1% to 100% of chiral nucleotide interbonding (e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) are chiral-controlled.

[0134] In some embodiments, a predetermined level of oligonucleotides is 0.1% to 100% of all oligonucleotides in the provided composition (for example, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%). In some embodiments, a predetermined level of oligonucleotides is 0.1% to 100% (for example, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of all oligonucleotides containing a common base sequence or all oligonucleotides sharing a common base sequence in the provided composition.In some embodiments, all oligonucleotides containing a common base sequence or all oligonucleotides with a common base sequence in the provided composition constitute 0.1% to 100% of all oligonucleotides in the composition (for example, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%). In some embodiments, a predetermined level of oligonucleotides is 0.1% to 100% (for example, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of all oligonucleotides in the provided composition that have a common base sequence, base modification, sugar modification, and / or modified nucleotide bond (if present).In some embodiments, all oligonucleotides in the provided composition that have a common base sequence, base modification, sugar modification, and / or modified internucleotide bond, or all oligonucleotides that share a common base sequence, base modification, sugar modification, and / or modified internucleotide bond, constitute 0.1% to 100% (for example, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of all oligonucleotides in the composition. In some embodiments, a predetermined level of oligonucleotides is at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of all oligonucleotides in the provided composition that have a common base sequence, base modification pattern, sugar modification pattern, and / or modified nucleotide bond pattern.In some embodiments, all oligonucleotides in the provided composition that share a common base sequence, base modification pattern, sugar modification pattern, and / or modified nucleotide interbinding pattern, or all oligonucleotides that share a common base sequence, base modification pattern, sugar modification pattern, and / or modified nucleotide interbinding pattern, constitute 0.1% to 100% of all oligonucleotides in the composition (for example, at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%). In some embodiments, a predetermined level of oligonucleotides is 0.1% to 100% (e.g., at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) of all oligonucleotides in the provided composition that share a common base sequence, a common pattern of base modification, a common pattern of sugar modification, and / or a common pattern of modified nucleotide-to-nucleotide bonding.In some embodiments, all oligonucleotides in the provided composition that share a common base sequence, a common pattern of base modification, a common pattern of sugar modification, and / or a common pattern of modified nucleotide-to-nucleotide bonding constitute 0.1% to 100% of all oligonucleotides in the composition (e.g., at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%).

[0135] In some embodiments, the predetermined level is 0.1 to 100%. In some embodiments, the predetermined level is at least 1%. In some embodiments, the predetermined level is at least 5%. In some embodiments, the predetermined level is at least 10%. In some embodiments, the predetermined level is at least 20%. In some embodiments, the predetermined level is at least 30%. In some embodiments, the predetermined level is at least 40%. In some embodiments, the predetermined level is at least 50%. In some embodiments, the predetermined level is at least 60%. In some embodiments, the predetermined level is at least 65%. In some embodiments, the predetermined level is at least 70%. In some embodiments, the predetermined level is at least 75%. In some embodiments, the predetermined level is at least 80%. In some embodiments, the predetermined level is at least 85%. In some embodiments, the predetermined level is at least 90%. In some embodiments, the predetermined level is at least 91%. In some embodiments, the predetermined level is at least 92%. In some embodiments, the predetermined level is at least 93%. In some embodiments, the predetermined level is at least 94%. In some embodiments, the predetermined level is at least 95%. In some embodiments, the predetermined level is at least 96%. In some embodiments, the predetermined level is at least 97%. In some embodiments, the predetermined level is at least 98%. In some embodiments, the predetermined level is at least 99%. In some embodiments, the predetermined level is at least 5*(1 / 2 g ) where g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least 10*(1 / 2 g ) where g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least 100*(1 / 2 g ) where g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.80) gHerein, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.80) g Herein, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.80) g In the formula, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.85) g In the formula, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.90) g In the formula, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.95) g Herein, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.96) g In the formula, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.97) g In the formula, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.98) g In the formula, g is the number of chiral-controlled internucleotide bonds. In some embodiments, a given level is at least (0.99) gThe formula is where g is the number of chiral-controlled internucleotide bonds. In some embodiments, to determine the level in a composition of an oligonucleotide having g chiral-controlled internucleotide bonds, the product of the diastereopurities of each of the g chiral-controlled internucleotide bonds (diastereopurity of chiral-controlled internucleotide bond 1)*(diastereopurity of chiral-controlled internucleotide bond 2)*...*(diastereopurity of chiral-controlled internucleotide bond g) is used as the level, and the diastereopurity of each chiral-controlled internucleotide bond is independently indicated by the diastereopurity of a dimer comprising the same internucleotide bond and a nucleoside adjacent to said internucleotide bond, prepared under equivalent methods to those of the oligonucleotide (e.g., equivalent or preferably identical oligonucleotide preparation cycles, including equivalent or preferably identical reagents and reaction conditions). In some embodiments, the level and / or diastereopurity of an oligonucleotide can be determined by analytical methods (e.g., chromatography, spectrometry, spectroscopy, or any combination thereof).

[0136] In some embodiments, as described in this disclosure, the oligonucleotides (e.g., multiple and / or a predetermined level of oligonucleotides) of the provided composition include one or more internucleotide bonds having the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof. In some embodiments, the oligonucleotide comprises 1 to 100 internucleotide bonds having the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or the structure of a salt thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, or more). In some embodiments, as described herein, -XL s -R 5 Each of them is independent of HXL s -R 5 The structure is that of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or a salt thereof. In some embodiments, the oligonucleotide has the structure of formula VIII or a salt thereof. In some embodiments, the oligonucleotide has the structure of formula VIII or a salt thereof, where L P Each independently has the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or a salt form thereof. In some embodiments, the oligonucleotide has the structure of formula VIII or a salt thereof, where L PEach of these independently possesses the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or the structure of a salt thereof, and L has the structure of formula VII, formula VII-a-1, formula VII-a-2, formula VII-b, formula VII-c, formula VII-d, or formula VII-e, or the salt form thereof. P For each of them, -XL s -R 5 Each of them is independent of HXL s -R 5 The structure is one having the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or the structure of a salt thereof. [Brief explanation of the drawing]

[0137] [Figure 1] An example of pKa measurement data is shown. [Modes for carrying out the invention]

[0138] 1.Definition As used herein, unless otherwise indicated, the following definitions apply. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of Elements, CAS versions, and Handbook of Chemistry and Physics, 75th edition. Furthermore, general principles of organic chemistry are based on “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

[0139] Aliphatic: As used herein, “aliphatic” means a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a substituted or unsubstituted monocyclic, bicyclic or polycyclic hydrocarbon ring that is fully saturated or contains one or more unsaturated units, or a combination thereof. Unless otherwise specified, an aliphatic group contains 1 to 100 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 20 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 10 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 9 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 8 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 7 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In yet another embodiment, the aliphatic group contains 1 to 5 aliphatic carbon atoms, and in yet another embodiment, the aliphatic group contains 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.

[0140] Alkyl: As used herein, the term "alkyl" has the common sense in the art and may include linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and saturated aliphatic groups including cycloalkyl-substituted alkyl groups. In some embodiments, alkyl groups have 1 to 100 carbon atoms. In certain embodiments, linear alkyl groups or branched alkyl groups have about 1 to 20 carbon atoms in their main chain (for example, C1-C1 in the case of linear groups). 20 In the case of a branched structure, C2-C 20), or having about 1 to 10 carbon atoms. In some embodiments, the cycloalkyl ring has about 3 to 10 carbon atoms in its ring structure, whether the ring is monocyclic, bicyclic, or polycyclic, or about 5, 6, or 7 carbon atoms in its ring structure. In some embodiments, the alkyl group may be a lower alkyl group, which contains 1 to 4 carbon atoms (e.g., C1-C4 in the case of a linear lower alkyl group).

[0141] The term "aryl," used alone or as part of a larger phrase such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or polycyclic ring system having a total of 5 to 30 ring members, with at least one ring in the system being aromatic. In some embodiments, the aryl group is a monocyclic, bicyclic, or polycyclic ring system having a total of 5 to 14 ring members, with at least one ring in the system being aromatic, and each ring in the system containing 3 to 7 ring members. In some embodiments, the aryl group is a biaryl group. "Aaryl" may be used interchangeably with "aryl ring." In some embodiments of this disclosure, "aryl" refers to aromatic ring systems, including but not limited to phenyl, biphenyl, naphthyl, binaphthyl, anthracyl, etc., which may have one or more substituents. Furthermore, in some embodiments, the term "aryl" as used herein includes groups in which an aromatic ring is condensed with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridine, or tetrahydronaphthyl, in which case the bonded radical or bond site is located on the aryl ring.

[0142] Chiral Control: As used herein, “chiral control” refers to the control of the stereochemical designation of chiral phosphorus in chiral nucleotide interbonding within an oligonucleotide. In some embodiments, control is achieved via chiral elements not present in the sugar and base portions of the oligonucleotide. For example, in some embodiments, control is achieved using one or more chiral auxiliary groups during oligonucleotide preparation, as illustrated in this disclosure, and such chiral auxiliary groups are often part of the chiral phosphoramidite used during oligonucleotide preparation. In contrast to chiral control, those skilled in the art will recognize that conventional oligonucleotide synthesis without chiral auxiliary groups does not allow for stereochemical control of the chiral nucleotide interbonding when such conventional oligonucleotide synthesis is used to form the chiral nucleotide interbonding. In some embodiments, the stereochemical designation of each chiral phosphorus in the chiral nucleotide interbonding within an oligonucleotide is controlled.

[0143] Chiral-controlled oligonucleotide compositions: As used herein, terms such as “chiral-controlled oligonucleotide composition” and “chiral-controlled nucleic acid composition” refer to a composition comprising multiple oligonucleotides (or nucleic acids) that share 1) a common base sequence, 2) a common pattern of skeletal linkages, and 3) a common pattern of skeletal phosphorus modifications, wherein the multiple oligonucleotides (or nucleic acids) share the same stereochemistry at one or more chiral nucleotide interbondings (chiral-controlled nucleotide interbondings), and the levels of the multiple oligonucleotides (or nucleic acids) in the composition are predetermined (this is done, for example, through the preparation of chiral-controlled oligonucleotides to form one or more chiral nucleotide interbondings). In some embodiments, the multiple oligonucleotides in a chiral-controlled oligonucleotide composition share the same base sequence, the same nucleic acid base modifications, the same sugar modifications, and the same nucleotide interbonding modifications, and the same stereochemistry (Rp or Sp) may differ independently at the binding phosphorus chiral centers of one or more chiral-controlled nucleotide interbondings via the stereochemistry of a particular binding phosphorus chiral center.In some embodiments, approximately 0.1% to 100% of all oligonucleotides in a chiral-controlled oligonucleotide composition (e.g., approximately 1% to 100%, approximately 5% to 100%, approximately 10% to 100%, approximately 20% to 100%, approximately 30% to 100%, approximately 40% to 100%, approximately 50% to 100%, approximately 60% to 100%, approximately 70% to 100%, approximately 80% to 100%, approximately 90% to 100%, approximately 95% to 100%, approximately 50% to 90%, or approximately 5%, approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 85%, approximately 90%, approximately 91%). Approximately 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%, constitute the plurality of oligonucleotides.In some embodiments, in a chiral-controlled oligonucleotide composition, approximately 0.1% to 100% (e.g., approximately 1% to 100%, approximately 5% to 100%, approximately 10% to 100%, approximately 20% to 100%, approximately 30% to 100%, approximately 40% to 100%, approximately 50% to 100%, approximately 60% to 100%, approximately 70% to 100%, approximately 80% to 100%, approximately 90% to 100%, approximately 95% to 100%, approximately 50% to 90%, or approximately 5%, approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 85%, approximately 90%) of all oligonucleotides sharing a common base sequence. Approximately 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%, are the plurality of oligonucleotides.In some embodiments, in a chiral-controlled oligonucleotide composition, approximately 0.1% to 100% (e.g., approximately 1% to 100%, approximately 5% to 100%, approximately 10% to 100%, approximately 20% to 100%, approximately 30% to 100%, approximately 40% to 100%, approximately 50% to 100%, approximately 60% to 100%, approximately 70% to 100%, approximately 80% to 100%, approximately 90% to 100%, approximately 95% to 100%, approximately 50% to 90%, or approximately 5%, approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%) of all oligonucleotides sharing a common base sequence, a common pattern of skeletal linkage, and a common pattern of skeletal phosphorus modification. Approximately 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%) are the plurality of oligonucleotides.In some embodiments, a predetermined level is about 0.1% to 100% (e.g., about 1% to 100%, about 5% to 100%, about 10% to 100%, about 20% to 100%, about 30% to 100%, about 40% to 100%, about 50% to 100%) of all oligonucleotides in the composition, or all oligonucleotides in the composition that share a common base sequence (e.g., multiple oligonucleotides or one oligonucleotide type), a common base sequence, a common pattern of skeletal bonding, and a common pattern of skeletal phosphorus modification, a common base sequence, a common pattern of base modification, a common pattern of sugar modification, a common pattern of internucleotide bond type, and / or a common pattern of internucleotide bond modification. Approximately 60% to 100%, approximately 70% to 100%, approximately 80% to 100%, approximately 90% to 100%, approximately 95% to 100%, approximately 50% to 90%, or approximately 5%, approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99%, or at least 5%, at least 10%, At least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) are the plurality of oligonucleotides.In some embodiments, the number of oligonucleotides is 1 to 50 (for example, about 1 to 10, about 1 to 20, about 5 to 10, about 5 to 20, about 10 to 15, about 10 to 20, about 10 to 25, about 10 to 30, about or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20, or fewer). They share the same stereochemistry in the inter-chiral nucleotide bonds of one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, or at least twenty. In some embodiments, multiple oligonucleotides make up about 0.1% to 100% of the chiral nucleotide interbonding (e.g., about 1% to 100%, about 5% to 100%, about 10% to 100%, about 20% to 100%, about 30% to 100%, about 40% to 100%, about 50% to 100%, about 60% to 100%, about 70% to 100%, about 80% to 100%, about 90% to 100%, about 95% to 100%, about 50% to 90%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about They share the same stereochemistry in 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, or approximately 100%, or at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%). In some embodiments, each chiral nucleotide bond is a chiral-controlled nucleotide bond, and the composition is a fully chiral-controlled oligonucleotide composition.In some embodiments, not all but some chiral nucleotide interbondings are chiral-controlled nucleotide interbondings, and the composition is a partially chiral-controlled oligonucleotide composition. In some embodiments, the chiral-controlled oligonucleotide composition contains a predetermined level of individual oligonucleotide types or nucleic acid types. For example, in some embodiments, the chiral-controlled oligonucleotide composition contains one oligonucleotide type at a predetermined level. In some embodiments, the chiral-controlled oligonucleotide composition contains two or more oligonucleotide types, each independently at a predetermined level. In some embodiments, the chiral-controlled oligonucleotide composition contains multiple oligonucleotide types, each independently at a predetermined level. In some embodiments, the chiral-controlled oligonucleotide composition is a composition of an oligonucleotide of a certain oligonucleotide type, and the composition contains multiple oligonucleotides of that oligonucleotide type at a predetermined level.

[0144] Alicyclic: As used herein, the term “alicyclic” refers to saturated or partially unsaturated aliphatic monocyclic, aliphatic bicyclic, or aliphatic polycyclic systems (e.g., those having 3 to 30 members), which are optionally substituted. Alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, cycloalkyl groups have 3 to 6 carbon atoms. The term “alicyclic” may also include aliphatic rings condensed to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, in which case the binding radical or bond site is located on the aliphatic ring. In some embodiments, the carbocyclic group is bicyclic. In some embodiments, the carbocyclic group is tricyclic. In some embodiments, the carbocyclic group is polycyclic. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) is a monocyclic C3-C6 hydrocarbon or C8-C hydrocarbon that is not aromatic but contains one or more fully saturated or unsaturated units. 10 Bicyclic hydrocarbons, or C9-C hydrocarbons that are fully saturated or contain one or more unsaturated units but are not aromatic. 16 This refers to tricyclic hydrocarbons.

[0145] Halogen: The term "halogen" refers to F, Cl, Br, or I.

[0146] Heteroaliphatic: The term "heteroaliphatic" is given in the ordinary sense in the art and refers to the aliphatic groups described herein in which one or more carbon atoms are substituted with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.).

[0147] Heteroalkyl: The term "heteroalkyl" is given its common meaning in the art and refers to alkyl groups as described herein, in which one or more carbon atoms are substituted with heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, etc.). Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, and morpholinyl.

[0148] Heteroaryl: When used alone or as part of a larger term, such as "heteroaralkyl" or "heteroarcoxy," the terms "heteroaryl" and "heteroar-" refer to a monocyclic, bicyclic, or polycyclic ring system (e.g., having a total of 5 to 30 ring members), where at least one ring in the system is aromatic, and at least one aromatic ring atom is a heteroatom. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. A heteroaryl group is a group having 5 to 10 ring atoms (i.e., monocyclic, bicyclic, or polycyclic) in some embodiments, and 5, 6, 9, or 10 ring atoms in some embodiments. In some embodiments, the heteroaryl group has 6, 10, or 14 π electrons, shared in a cyclic arrangement and having 1 to 5 heteroatoms in addition to the carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. In some embodiments, the heteroaryl is a heterobiaryl group, such as bipyridyl. As used herein, the terms "heteroaryl" and "heteroaralkyl" also include groups in which a heteroaromatic ring is condensed to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or bond site is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. The heteroaryl group may be monocyclic, bicyclic, or polycyclic."Heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", and any of these terms includes a ring that may be substituted. The term "heteroalkyl" refers to an alkyl group substituted with a heteroaryl group, and the alkyl portion and the heteroaryl portion may be independently substituted.

[0149] Heteroatom: The term "heteroatom" means an atom that is neither carbon nor hydrogen. In some embodiments, the heteroatom is (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, any basic nitrogen or quaternized form of a substitutable nitrogen in a heterocyclic ring (e.g., N in 3,4-dihydro-2H-pyrrolyl), (NH in pyrrolidinyl), or (NR in N-substituted pyrrolidinyl)) oxygen, sulfur, nitrogen, phosphorus, boron, or silicon. In some embodiments, the heteroatom is boron, nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. + etc.) including). In some embodiments, the heteroatom is boron, nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur.

[0150] Heterocyclyl: As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are interchangeable and refer to monocyclic, bicyclic, or polycyclic ring moieties (e.g., 3 to 30 members) that are saturated or partially unsaturated and have one or more heteroatom ring atoms. In some embodiments, the heteroatom is boron, nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, silicon, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, sulfur, or phosphorus. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In some embodiments, the heterocyclyl group is a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has one or more heteroatoms, preferably 1 to 4 as defined above, in addition to the carbon atom. When used with respect to the ring atoms of a heterocyclic ring, the term “nitrogen” includes substituted nitrogen. For example, in saturated or partially unsaturated rings having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen is N (in 3,4-dihydro-2H-pyrrolyl), NH (in pyrrolidinyl), or (in N-substituted pyrrolidinyl) +It can be NR. The heterocyclic ring can be bonded to its pendant group with any heteroatom or carbon atom that results in a stable structure, and any ring atom may be substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and include a heterocyclyl ring condensed to one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl, in which case the bonded radical or bond site is located on the heteroaliphatic ring. The heterocyclyl group may be monocyclic, bicyclic, or polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, where the alkyl moiety and the heterocyclyl moiety may be independently substituted.

[0151] Bound Phosphorus: As defined herein, the expression “bound phosphorus” is used to indicate that the particular phosphorus atom referred to is a phosphorus atom present in an internucleotide bond, and that phosphorus atom corresponds to the phosphodiester phosphate atom in internucleotide bonds present in natural DNA and RNA. In some embodiments, the bound phosphorus atom is in a modified internucleotide bond, where each oxygen atom of the phosphodiester bond is optionally and independently replaced by an organic or inorganic moiety. In some embodiments, the bound phosphorus atom is P of formula VII. L This is phosphorus. In some embodiments, the bound phosphorus atom is chiral. In some embodiments, the bound phosphorus is chiral (e.g., as in the natural phosphate bond).

[0152] Oligonucleotide type: As used herein, the term "oligonucleotide type" refers to a specific base sequence, skeletal bonding pattern (i.e., internucleotide bonding pattern, e.g., phosphate, phosphorothioate, etc.), skeletal chiral center pattern (i.e., bonding phosphorus stereochemistry pattern (Rp / Sp)), and skeletal phosphorus modification pattern (e.g., "-XLR" in formula VII). 5 This is used to define oligonucleotides having a pattern of groups. In some embodiments, oligonucleotides of a common designated "type" are structurally identical to one another, including stereochemically.

[0153] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a moiety containing at least one double or triple bond. The term “partially unsaturated” is intended to include groups having multiple unsaturated moies, but not to include either aryl or heteroaryl moies.

[0154] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an activator formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the activator is present in a unit dose suitable for administration in a therapeutic regimen that demonstrates a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those adapted for: oral administration, e.g., drenches (aqueous or non-aqueous or suspension), tablets, e.g., tablets targeted for oral, sublingual and systemic absorption, bolus administration, powder, granules, paste for application to the tongue; parenteral administration, e.g., as sterile solution or suspension or sustained-release formulation, subcutaneous, intramuscular, intravenous or epidural injection; topical administration, e.g., cream, ointment or controlled-release patch or spray applied to the skin, lung or oral cavity; vaginal or rectal administration, e.g., pessary, cream or foam; sublingual administration; intraocular administration; transdermal administration; or administration to the nasal, pulmonary and other mucosal surfaces.

[0155] Pharmacopoeia: When used herein, the term "pharmacopoeia" means a compound, substance, composition, and / or dosage form that, within reasonable medical judgment, is appropriate for use in contact with human and animal tissues, given a reasonable benefit-to-risk ratio, without excessive harm, irritation, allergic response, or other problems or complications.

[0156] pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, or solvent encapsulant, that is involved in the transport or delivery of the compound of interest from one organ or body part to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the subject. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffer solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic, suitable substances used in pharmaceutical formulations.

[0157] pharmaceutically acceptable salts: As used herein, the term “pharmaceutically acceptable salt” means a salt of such compound that is appropriate for use in a pharmaceutical context, i.e., a salt that, within the bounds of reasonable medical judgment, is commensurate with a reasonable benefit / risk ratio and is appropriate for use in contact with human and lower animal tissues without excessive harm, irritation, allergic response, etc. pharmaceutically acceptable salts are well known. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other known methods such as ion exchange. In some embodiments, pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodide, and 2-hydroxyethanes. Examples of such salts include, but are not limited to, rufonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonic acids, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrinates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates.In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic base addition salts, such as those formed with a base by an acidic group of the compound (e.g., a phosphate group of an oligonucleotide, a phosphorothioate group of an oligonucleotide, etc.). Typical alkali or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, and magnesium salts. In some embodiments, pharmaceutically acceptable salts include ammonium salts (e.g., -N(R)3). + ) In some embodiments, the pharmaceutically acceptable salt is a sodium salt. In some embodiments, pharmaceutically acceptable salts may include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations produced using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls, sulfons, and arylsulfons having 1 to 6 carbon atoms.

[0158] "Predetermined": "Predetermined" (or predetermined) means intentionally selected, as opposed to occurring or occurring randomly without control. Those skilled in the art will understand, by reading this specification, that this disclosure provides techniques that enable the selection of specific chemistry and / or stereochemistry to be incorporated into oligonucleotide compositions, and further, techniques that enable the control of the preparation of oligonucleotide compositions having such chemistry and / or stereochemical properties. Such provided compositions are "predetermined" as described herein. A composition that may contain a particular oligonucleotide is not a "predetermined" composition if it is produced incidentally through a process that is not controlled to intentionally produce a particular chemistry and / or stereochemistry. In some embodiments, a predetermined composition is a composition that can be intentionally reproduced (e.g., through controlled process iterations). In some embodiments, a predetermined level of multiple oligonucleotides in a composition means that the absolute and / or relative amounts (ratios, proportions, etc.) of multiple oligonucleotides in the composition are controlled. In some embodiments, a predetermined level of multiple oligonucleotides in a composition is achieved through chiral-controlled oligonucleotide preparation.

[0159] Protecting Groups: As used herein, the term “protecting group” refers to a transient substituent that protects a potentially reactive functional group from undesirable chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. “Si protecting groups” are protecting groups containing a Si atom, such as Si-trialkyl (e.g., trimethylsilyl, tributylsilyl, t-butyldimethylsilyl), Si-triaryl, Si-alkyl-diphenyl (e.g., t-butyldiphenylsilyl), or Si-aryl-dialkyl (e.g., Si-phenyldialkyl). Generally, Si protecting groups are bonded to an oxygen atom. The field of protecting group chemistry has been outlined (Greene, TW; Wuts, PGMP Rotective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Such protecting groups (and related protected moieties) are described in detail below.

[0160] Protected hydroxyl groups are well known in the art, and examples of such protected hydroxyl groups include Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3 rdProtecting groups are described in detail in edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. Examples of appropriately protected hydroxyl groups include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suitable esters include formates, acetates, propionates, pentanoates, crotonates, and benzoates. Specific examples of suitable esters include formates, benzoyl acid, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoates, 4,4-(ethylenedithio)pentanoates, pivaloates (trimethylacetates), crotonates, 4-methoxy-crotonates, benzoates, p-benzylbenzoates, and 2,4,6-trimethylbenzoates. Examples of suitable carbonates include 9-fluorenylmethyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, vinyl carbonates, allyl carbonates, and p-nitrobenzyl carbonates. Suitable silyl ethers include trimethylsilyl ether, triethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, triisopropylsilyl ether, and other trialkylsilyl ethers. Suitable alkyl ethers include methyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trityl ether, t-butyl ether, and allyl ether, or their derivatives.Examples of alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2-methoxyethoxy)methyl ether, benzyloxymethyl ether, beta-(trimethylsilyl)ethoxymethyl ether, and tetrahydropyran-2-yl ether. Examples of suitable arylalkyl ethers include benzyl ether, p-methoxybenzyl (MPM) ether, 3,4-dimethoxybenzyl ether, O-nitrobenzyl ether, p-nitrobenzyl ether, p-halobenzyl ether, 2,6-dichlorobenzyl ether, p-cyanobenzyl ether, 2-picolyl ether, and 4-picolyl ether.

[0161] Protected amines are well known in the art, and such protected amines are described in detail in Greene (1999). Suitable amines protected by a single protecting group include, but are not limited to, aralkylamines, carbamates, allylamines, amides, and the like. Suitable amino moieties protected by a single protecting group include t-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxocarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamide, acetamide, chloroacetamide, dichloroacetamide, trichloroacetamide, phenylacetamide, trifluoroacetamide, benzamide, t-butyldiphenylsilyl, and the like. Suitable amines protected by two protecting groups include amines that have been substituted with two substituents, independently selected from the single-protected amines listed above, such as cyclic imides (phthalimides, maleimides, succinimides, etc.) and the like. Suitable amines protected by two protecting groups include pyrroles and the like, 2,2,5,5-tetramethyl-[1,2,5]azadisilolidine and the like, and azides.

[0162] Protected aldehydes are well known in the art, and such protected aldehydes are described in detail in Greene (1999). Suitable protected aldehydes include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, and the like. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3-dioxane, 1,3-dioxolane, semicarbazone, and their derivatives.

[0163] Protected carboxylic acids are well known in the art, and such protected carboxylic acids are described in detail in Greene (1999). Suitable protected carboxylic acids include, but are not limited to, optionally substituted C 1-6 Further examples include aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl esters, each of which may be optionally substituted. Suitable protected carboxylic acids further include oxazolines and orthoesters.

[0164] Protected thiols are well known in the art, and such protected thiols are described in detail in Greene (1999). Suitable protected thiols include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates, and similar groups. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioesters, but these are only a few examples.

[0165] Substitution: As described herein, the compounds of this disclosure may optionally contain substituted and / or substituted moieties. Generally, “substituted” means that one or more hydrogens of a given moiety are substituted with a preferred substituent, whether or not the term “optionally” precedes it. Unless otherwise specified, a “may be substituted” group may have preferred substituents at each substitutedable position of the group, and if two or more positions in any given structure can be substituted with two or more substituents selected from a particular group, the substituents may be the same or different at all positions. The substituent combinations envisioned by this disclosure are preferably substituents that result in the formation of a stable or chemically feasible compound. As used herein, “stable” means a compound that is substantially unchanged when exposed to conditions that enable the production, detection, and, in some embodiments, their recovery, purification, and use for one or more purposes disclosed herein. In some embodiments, examples of substituents are described below.

[0166] A suitable monovalent substituent is halogen;-(CH2) 0-4 R o ;-(CH2) 0-4 Ure o ;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 CH(OR o )2;R o It may be replaced with -(CH2) 0-4 Ph;R o It may be replaced with -(CH2) 0-4 O(CH2) 0-1 Ph;R o -CH=CHPh;R o It may be replaced with -(CH2) 0-4 O(CH2) 0-1 -Pyridyl;-NO2;-CN;-N3;-(CH2) 0-4 N(R o )2;-(CH2) 0-4N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)N(R o )2;-N(R o )C(S)N(R o )2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)N(R o )2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSi(R o )3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o 、-SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)N(R o )2;-C(S)N(R o )2;-C(S)SR o ;-SC(S)SR o 、-(CH2) 0-4 OC(O)N(R o )2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2)0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2N(R o )2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2N(R o )2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)N(R o )2;-Si(R o )3;-OSi(R o )3;-P(R o )2;-P(OR o )2;-P(R o )(OR o );-OP(R o )2;-OP(OR o )2;-OP(R o )(OR o );-P[N(R o )2]2;-P(R o )[N(R o )2];-P(OR o )[N(R o )2];-OP[N(R o )2]2;-OP(R o )[N(R o )2];-OP(OR o )[N(R o )2];-N(R o )P(R o )2;-N(R o )P(OR o )2;-N(R o )P(R o )(OR o );-N(R o )P[N(R o )2]2;-N(R o )P(R o )[N(R o )2];-N(R o)P(OR o )[N(R o )2];-B(R o )2;-B(R o )(OR o );-B(OR o )2;-OB(R o )2;-OB(R o )(OR o );-OB(OR o )2;-P(O)(R o )2;-P(O)(R o )(OR o );-P(O)(R o )(SR o );-P(O)(R o )[N(R o )2];-P(O)(OR o )2;-P(O)(SR o )2;-P(O)(OR o )[N(R o )2];-P(O)(SR o )[N(R o )2];-P(O)(OR o )(SR o );-P(O)[N(R o )2]2;-OP(O)(R o )2;-OP(O)(R o )(OR o );-OP(O)(R o )(SR o );-OP(O)(R o )[N(R o )2];-OP(O)(OR o )2;-OP(O)(SR o )2;-OP(O)(OR o )[N(R o )2];-OP(O)(SR o )[N(R o )2];-OP(O)(OR o )(SR o );-OP(O)[N(R o )2]2;-SP(O)(R o )2;-SP(O)(R o )(OR o );-SP(O)(R o )(SR o);-SP(O)(R o )[N(R o )2];-SP(O)(OR o )2;-SP(O)(SR o )2;-SP(O)(OR o )[N(R o )2];-SP(O)(SR o )[N(R o )2];-SP(O)(OR o )(SR o );-SP(O)[N(R o )2]2;-N(R o )P(O)(R o )2;-N(R o )P(O)(R o )(OR o );-N(R o )P(O)(R o )(SR o );-N(R o )P(O)(R o )[N(R o )2];-N(R o )P(O)(OR o )2;-N(R o )P(O)(SR o )2;-N(R o )P(O)(OR o )[N(R o )2];-N(R o )P(O)(SR o )[N(R o )2];-N(R o )P(O)(OR o )(SR o );-N(R o )P(O)[N(R o )2]2;-P(R o )2[B(R o )3];-P(OR o )2[B(R o )3];-P(NR o )2[B(R o )3];-P(R o )(OR o )[B(R o )3];-P(R o )[N(R o )2][B(R o)3];-P(OR o )[N(R o )2][B(R o )3];-OP(R o )2[B(R o )3];-OP(OR o )2[B(R o )3];-OP(NR o )2[B(R o )3];-OP(R o )(OR o )[B(R o )3];-OP(R o )[N(R o )2][B(R o )3];-OP(OR o )[N(R o )2][B(R o )3];-N(R o )P(R o )2[B(R o )3];-N(R o )P(OR o )2[B(R o )3];-N(R o )P(NR o )2[B(R o )3];-N(R o )P(R o )(OR o )[B(R o )3];-N(R o )P(R o )[N(R o )2][B(R o )3];-N(R o )P(OR o )[N(R o )2][B(R o )3];-P(OR')[B(R')3]-;-(C 1-4 Linear or branched alkylene) ON(R o )2; or, -(C 1-4 Linear or branched alkylenes)C(O)ON(R o )2, (where each R o These may be substituted as defined below, independently of hydrogen, C 1-20C having 1 to 5 heteroatoms independently selected from aliphatic, nitrogen, oxygen, sulfur, silicon, and phosphorus. 1-20 , heteroaliphatic, -CH2-(C 6-14 aryl), -O(CH2) 0-1 (Aryl), (C 6-14 A 5-20 member monocyclic, bicyclic, or polycyclic saturated, partially unsaturated, or aryl ring having 0-5 heteroatoms independently selected from aryl, -CH2- (5-14 member heteroaryl ring), nitrogen, oxygen, sulfur, silicon, and phosphorus, or, notwithstanding the above definition, two independently occurring R o These, together with the intervening atoms, form a 5-20 membered monocyclic, bicyclic, or polycyclic saturated, partially unsaturated, or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, sulfur, silicon, and phosphorus, which may be substituted as defined below.

[0167] Suitable R o The monovalent substituent above (or two independently occurring R o The ring formed by the intervening atom is independently a halogen, -(CH2) 0-2 R ● ,-(HaroR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 Ure ● ,-(CH2) 0-2 CH(OR ● )2;-O(HaroR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● ,-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● ,-(CH2) 0-2 SR ● ,-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● ,-(CH2) 0-2 NR ● 2, -NO2, -SiR● 3. -OSiR ● 3. -C(O)SR ● ,-(C 1-4 Linear or branched alkylene) C(O)OR ● , or -SSR ● , (where each R ● These are unsubstituted, or substituted with only one or more halogens if preceded by "halo", and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 (Ph, or selected from 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). o Suitable divalent substituents on the saturated carbon atom include =O and =S.

[0168] Preferred divalent substituents are =O, =S, and =NNR. * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, (Each R that appears independently in the formula) * C may be substituted with hydrogen as defined below. 1-6 The group is an aliphatic or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A preferred divalent substituent bonded to an adjacent substituted carbon of the "may be substituted" group is -O(CR * 2) 2-3 O-, (Each R that appears independently in the formula) * C may be substituted with hydrogen as defined below. 1-6 It comprises an aliphatic, or unsubstituted, 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0169] R * Suitable substituents for the aliphatic group are halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where R ● Each of these is either not substituted, or if preceded by "halo", it is substituted by only one or more halogens, R ● Each of them is independent of C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, and sulfur.

[0170] In some embodiments, a suitable substituent for the substituted nitrogen is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † And in the formula, R † Each of these may be independently substituted with hydrogen, or C as defined below. 1-6 An aliphatic, unsubstituted -OPh, or an unsubstituted, 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the above definition, two independently occurring R †These atoms, together with the intervening atoms (or multiple atoms), form unsubstituted, 3-12 membered monocyclic or bicyclic saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0171] R † Suitable substituents for the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where R ● Each of these is either not substituted, or if preceded by "halo", it is substituted by only one or more halogens, R ● Each of them is independent of C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from pH, nitrogen, oxygen, and sulfur.

[0172] Unsaturated: As used herein, the term “unsaturated” means that a part has one or more unsaturated units.

[0173] Unless otherwise specified, the provided compounds include salts (such as pharmaceutically acceptable hydrochloric acid or base addition salts), stereoisomers, and tautomers.

[0174] 2. Detailed description of a specific embodiment As those skilled in the art will understand, stereoselective synthesis is a very important challenge. In particular, this disclosure recognizes that, under certain demanding conditions, there is a need for techniques that can increase yield, enhance stereoselectivity, improve product purity, reduce costs, and / or broaden chemical compatibility for the stereoselective (chiral-controlled) preparation of oligonucleotides. In particular, this disclosure provides such techniques as required. In some embodiments, this disclosure provides compounds useful as chiral auxiliary groups for stereoselective synthesis (e.g., chiral-controlled formation of chiral nucleotide bonds). In some embodiments, this disclosure provides compounds useful as reagents for stereoselective synthesis, for example, certain provided compounds useful as monomer phosphoramidites for preparing chiral-controlled oligonucleotide compositions. In some embodiments, this disclosure provides methods for preparing chiral compounds (e.g., oligonucleotides containing one or more chiral nucleotide bonds). In some embodiments, the provided methods are useful for the chiral-controlled preparation of chiral-controlled oligonucleotide compositions. In some embodiments, the disclosure provides compounds and compositions obtained from a provided method (e.g., chiral-controlled preparation of oligonucleotides). In some embodiments, the disclosure provides chiral-controlled oligonucleotide compositions. In some embodiments, the disclosure provides diastereomers of high purity containing one or more chiral nucleotide interbonds.

[0175] In some embodiments, the disclosure provides conditions for evaluating the ability of compounds in stereoselective synthesis. For example, as shown in the examples (e.g., solid support, linker, nucleoside, configuration, any combination thereof), in some embodiments, the disclosure provides conditions for evaluating the ability of compounds as chiral auxiliary groups, monomer phosphoramidites, etc., in the chiral-controlled formation of chiral nucleotide bonds. In some embodiments, the conditions provided are particularly useful in that they are more stringent than those in the typical chiral-controlled formation of chiral nucleotide bonds, and as a result, it becomes possible to distinguish the ability of chiral auxiliary groups, where in a particular typical chiral-controlled formation of chiral nucleotide bonds, the difference exhibited by such chiral auxiliary groups may be very small or nonexistent.

[0176] In some embodiments, for the formation of internucleotide bonds that are difficult to form, the techniques provided yield unexpectedly high yields while maintaining very high stereoselectivity (generally the same as or equivalent to the best results reported to date). As shown by the examples, in some embodiments, the disclosure provides techniques that provide high stereoselectivity (e.g., at least 90:10, 91:9, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, or 99:1). In some embodiments, the disclosure provides techniques that provide high yields. In some embodiments, the techniques provided provide alternative chemical capabilities. In some embodiments, the techniques provided reduce costs. In some embodiments, the techniques provided provide alternative preparation methods. In particular, the disclosure provides immeasurable flexibility for the chiral-controlled preparation of oligonucleotides, and those skilled in the art can undertake specific preparations in accordance with the disclosure by selecting from the various techniques provided. For example, if the oligonucleotide contains multiple chiral nucleotide bonds and high yield and purity are required, one can choose a technology that provides the highest purity and yield. Conversely, if the oligonucleotide has only one or very few chiral nucleotide bonds and purification is easily achievable, one can choose a technology that offers high stereoselectivity but relatively low yield (or higher yield but relatively low stereoselectivity) but lower overall cost.

[0177] In some embodiments, the Disclosure provides a technique that is compatible with a variety of chemical conditions, and as a result, the technique provided can be used in many types of reactions and / or conditions. In some embodiments, the Disclosure provides a chiral auxiliary that can be cleaved under acidic conditions. In some embodiments, the Disclosure provides a chiral auxiliary that can be cleaved under basic conditions. In some embodiments, the Disclosure provides a chiral auxiliary that can be cleaved, for example, using a fluorine source (e.g., HF, HF-Et3N, HF-pyridine, TBAF, etc.).

[0178] In some embodiments, the disclosure provides compounds useful as auxiliary groups for synthesis (e.g., preparation of oligonucleotides). In some embodiments, the disclosure provides compounds useful as chiral auxiliary groups for synthesis (e.g., chiral-controlled preparation of oligonucleotides).

[0179] In some embodiments, the provided compound is a compound or salt thereof having the structure of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b. In some embodiments, the provided compound is a stereoisomer of a compound or salt thereof of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b. In some embodiments, the provided compound is a diastereomer of a compound or salt thereof of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b. In some embodiments, the provided compounds are enantiomers of compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b or their salts. In some embodiments, the provided compounds are chiral auxiliary groups in that they are asymmetric and can be used in stereoselective synthesis (e.g., chiral-controlled formation of chiral nucleotide bonds).

[0180] In some embodiments, the disclosure provides compounds useful as building blocks for synthesis (for example, as monomer phosphoramidites for the chiral-controlled preparation of oligonucleotides).

[0181] In some embodiments, the provided compound is a compound having the structure of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula IVa, formula IVa-a, formula IVa-b, formula IVa-c-1, formula IVa-c-2, formula IVa-d, formula IVa-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e, or a salt thereof. In some embodiments, the provided compound is a compound or salt thereof having the structure of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e. In some embodiments, the provided compound is a stereoisomer of a compound or salt thereof of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e. In some embodiments, the provided compound is a diastereomer of a compound or salt of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e. In some embodiments, the provided compound is an enantiomer of a compound or salt of formula IV, formula IV-a, formula IV-b, formula IV-c-1, formula IV-c-2, formula IV-d, formula IV-e, formula V, formula Va, formula Vb, formula Vc-1, formula Vc-2, formula Vd, formula Ve, formula VI, formula VI-a, formula VI-b, formula VI-c-1, formula VI-c-2, formula VI-d, or formula VI-e. In some embodiments, the provided compound is a chiral auxiliary in that it is asymmetric and can be used in stereoselective synthesis (e.g., chiral-controlled formation of chiral nucleotide bonds).

[0182] In some embodiments, the disclosure provides oligonucleotides. In some embodiments, the disclosure provides oligonucleotides of a certain diastereomer purity. In some embodiments, the disclosure provides chiral-controlled oligonucleotide compositions. In some embodiments, the provided oligonucleotides include at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twentyone, at least twenty two two, at least twenty three, at least twenty fourteen, at least twenty fiveteen, at least twenty sixteen, at least twenty seventeen, at least twenty eighteen, at least twenty nineteen, or at least thirty chiral nucleotide interlinks. In some embodiments, the provided oligonucleotide comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty, at least twenty one, at least twenty two two, at least twenty three, at least twenty fourteen, at least twenty five, at least twenty sixteen, at least twenty seventeen, at least twenty eighteen, at least twenty nineteen, or at least thirty chiral nucleotide interbondings. In some embodiments, the provided oligonucleotide comprises at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 chiral nucleotide interbonds.In some embodiments, the provided oligonucleotide contains at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 chiral nucleotide bonds. In some embodiments, the provided oligonucleotide contains at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 chiral nucleotide bonds. In some embodiments, the provided oligonucleotide contains at least one chiral nucleotide bond. In some embodiments, the oligonucleotide provided contains at least two chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least three chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least four chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least five chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least six chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least seven chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least eight chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least nine chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least ten chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least eleven chiral nucleotide bonds.In some embodiments, the oligonucleotide provided contains at least 12 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 13 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 14 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 15 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 16 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 17 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 18 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 19 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 20 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 21 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 22 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 23 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 24 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 25 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 26 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 27 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 28 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 29 chiral nucleotide bonds. In some embodiments, the oligonucleotide provided contains at least 30 chiral nucleotide bonds.In some embodiments, the chiral nucleotide bond is a structure of formula VII or its salt form (e.g., -OP(O)(S). - )O- is a salt form of -OP(O)(SH)O-). In some embodiments, the chiral nucleotide bond has the structure of formula VII-a or a salt form thereof. In some embodiments, the chiral nucleotide bond has the structure of formula VII-b or a salt form thereof. In some embodiments, the chiral nucleotide bond has the structure of formula VII-c or a salt form thereof. In some embodiments, the chiral nucleotide bond has the structure of formula VII-d or a salt form thereof. In some embodiments, the chiral nucleotide bond has the structure of formula VII-e or a salt form thereof. In some embodiments, HXLR 5 This refers to compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof.

[0183] In some embodiments, R 1 -H, -L s -R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2. In some embodiments, R 1 is -H. In some embodiments, R 1 is, -L s -R is, and in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 1 R is R (for example, the R embodiment described in this disclosure). In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -F. In some embodiments, R 1 is -Cl. In some embodiments, R 1 is -Br. In some embodiments, R 1 is -I. In some embodiments, R 1 is -CN. In some embodiments, R 1is -NO2. In some embodiments, R 1 is, -L s -Si(R)3, in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 1 R is -CH2-Si(R)3, where the -CH2- group is optionally substituted and R is independently described herein. In some embodiments, R 1 is -CH2-Si(R)3, where R is independently one of the compounds described herein. In some embodiments, the R in -Si(R)3 is not -H. In some embodiments, the R in -Si(R)3 is independently one of C 1-6 The group is optionally substituted, selected from alkyl and phenyl groups. In some embodiments, at least one of the R groups in -Si(R)3 is optionally substituted with C 1-6 It is alkyl, and at least one of the R's in -Si(R)3 is optionally substituted with phenyl. In some embodiments, two of the R's in -Si(R)3 are independently optionally substituted with C 1-6 It is alkyl, and one of the Rs in -Si(R)3 is optionally substituted with phenyl. In some embodiments, -Si(R)3 is -Si(Ph)2Me. Other non-hydrogen embodiments of R are broadly described in this disclosure and may be used in -Si(R)3. In some embodiments, R 1 is -OR, where R is one of the values ​​described herein. In some embodiments, R 1 R is -SR, where R is as described in this disclosure. In some embodiments, R 1 is -N(R)², where R is independently one of the values ​​described herein.

[0184] In some embodiments, R 2 -H, -L s -R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2. In some embodiments, R 2 is -H. In some embodiments, R2 is, -L s -R is, and in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 2 R is R (for example, the R embodiment described in this disclosure). In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -F. In some embodiments, R 2 is -Cl. In some embodiments, R 2 is -Br. In some embodiments, R 2 is -I. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -NO2. In some embodiments, R 2 is, -L s -Si(R)3, in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 2 R is -CH2-Si(R)3, where the -CH2- group is optionally substituted and R is independently described herein. In some embodiments, R 2 is -CH2-Si(R)3, where R is independently one of the compounds described herein. In some embodiments, the R in -Si(R)3 is not -H. In some embodiments, the R in -Si(R)3 is independently one of C 1-6 It is an optionally substituted group selected from alkyl and phenyl. In some embodiments, -Si(R)3 is -Si(Ph)2Me. Other non-hydrogen embodiments of R are broadly described in this disclosure and may be used in -Si(R)3. In some embodiments, R 2 is -OR, where R is one of the values ​​described herein. In some embodiments, R 2 R is -SR, where R is as described in this disclosure. In some embodiments, R 2 R is -N(R)², where R is independently one of those described herein. In some embodiments, R 2 R 1Same as, or R 1 Unlike in this disclosure, R 1 It is a group selected from any group described for the target.

[0185] In some embodiments, R 1 and R 2 At least one of them is not hydrogen. In some embodiments, R 1 is hydrogen, and R 2 It is not hydrogen. In some embodiments, R 1 It is not hydrogen, but R 2 is hydrogen. In some embodiments, R 1 and R 2 None of them are hydrogen.

[0186] In some embodiments, R 1 and R 2 One of them is -H and the other is R, where R is as described in this disclosure and is not hydrogen. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is C, which is optionally replaced as described in this disclosure. 1-6 It is aliphatic. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is optionally substituted with C. 1-4 It is aliphatic. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is optionally substituted with C. 1-3 It is aliphatic. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is optionally substituted with C. 1-2 It is aliphatic. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is optionally substituted with C. 1-6 It is an alkenyl. 1 and R 2One of them is -H, and the other is R, where R is vinyl. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is optionally substituted with C. 1-6 It is an alkynyl. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is ethynyl. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is benzyl which can be optionally substituted. In some embodiments, R 1 and R 2 One of them is -H, and the other is R, where R is benzyl, and the phenyl group of benzyl is optionally substituted. In some embodiments, R 1 is -H, and R 2 is benzyl. In some embodiments, the provided compound is [ka] or a salt thereof. In some embodiments, the provided compound is [ka] or a diastereomer of its salt. In some embodiments, the provided compound is [ka] or the enantiomer of its salt.

[0187] In some embodiments, R 1 and R 2 One of them is R, which is described in this disclosure and includes an annular portion. In some embodiments, R is C 3-20 Alicyclic, C 6-20R is an optionally substituted group selected from aryls, 5-20 membered heteroaryls having 1-5 heteroatoms, and 3-20 membered heterocyclines having 1-5 heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, phosphorus, and silicon. In some embodiments, R is C 3-20 Alicyclic, C 6-20 The optionally substituted group is selected from aryl groups, 5-20 membered heteroaryl groups having 1-5 heteroatoms, and 3-20 membered heterocyclines having 1-5 heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted with C 3-20 It is alicyclic. In some embodiments, R is optionally substituted with C 3-10 It is alicyclic. In some embodiments, R is optionally substituted with C 3-10 It is a cycloalkyl group. In some embodiments, R is optionally substituted with C 4-10 It is a cycloalkyl group. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is optionally substituted cycloheptyl. In some embodiments, R is cyclopropyl. In some embodiments, R is cyclobutyl. In some embodiments, R is cyclopentyl. In some embodiments, R is cyclohexyl. In some embodiments, R is cycloheptyl. In some embodiments, R is optionally substituted C 6-20It is an aryl compound. In some embodiments, R is an optionally substituted phenyl compound. In some embodiments, R is a phenyl compound. In some embodiments, R is an optionally substituted 5-20 member heteroaryl compound having 1-5 heteroatoms. In some embodiments, R is an optionally substituted 5 member heteroaryl compound having 1-5 heteroatoms. In some embodiments, R is an optionally substituted 6 member heteroaryl compound having 1-5 heteroatoms. In some embodiments, R is an optionally substituted 3-20 member heterocycline compound having 1-5 heteroatoms. In some embodiments, R 1 and R 2 The other is R, and R is not hydrogen. In some embodiments, R is optionally substituted with C. 1-6 It is aliphatic. In some embodiments, R is optionally substituted with C. 1-6 It is alkyl. In some embodiments, R is C 1-6 It is alkyl. In some embodiments, R is methyl. In some embodiments, R is substituted methyl. In some embodiments, R is ethyl. In some embodiments, R is substituted ethyl. In some embodiments, R 1 and R 2 One of them is R, which includes the cyclic portion described in this disclosure, and the other is the alkyl group described in this disclosure.

[0188] In some embodiments, R 1 and R 2 One of them is R, and R is C which can be optionally substituted. 1-6 One side is alkyl, and the other side is R, where R is optionally substituted with C. 1-6 It is an alkenyl. 1 and R 2 One of them is optionally substituted methyl or ethyl, and the other is vinyl. In some embodiments, R 1 and R 2 One of them is methyl, and the other is vinyl.

[0189] In some embodiments, R 1 and R 2One of them is R, and R is C which can be optionally substituted. 1-6 One side is alkyl, and the other side is R, where R is optionally substituted with C. 1-6 It is an alkynyl. In some embodiments, R 1 and R 2 One of them is optionally substituted methyl or ethyl, and the other is ethynyl. In some embodiments, R 1 and R 2 One of them is methyl, and the other is ethynyl.

[0190] In some embodiments, R 1 and R 2 Each of these is independently R, and R is a C that can be arbitrarily substituted. 1-20 It is aliphatic. In some embodiments, R is an unsubstituted C 1-20 It is aliphatic. In some embodiments, R is optionally substituted with C. 1-20 It is alkyl. In some embodiments, R is optionally substituted with C 1-6 It is alkyl. In some embodiments, R is C 1-6 It is a linear alkyl group. In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-6 It is an alkyl group, and the other is an optionally substituted C group. 1-6 It is alkyl. In some embodiments, R 1 and R 2 This is the same as R 1 and R 2 It is different.

[0191] In some embodiments, R 1 and R 2 Each of these is independently R, and R is a C that can be arbitrarily substituted. 1-6 It is alkyl. In some embodiments, R 1 and R 2 This is the same as R. In particular, this disclosure is R 1 and R 2This demonstrates that when the same compound, or a phosphoramidite prepared from said compound, is used in the preparation of chiralally controlled oligonucleotides, it can provide high stereoselectivity, yield, and / or purity. In some embodiments, R 1 and R 2 This means that C is the same as any other substitute. 1-2 It is alkyl, R 1 and R 2 The number of carbon atoms contained is 2 or less. In some embodiments, R 1 and R 1 Both are methyl. In some embodiments, R 1 and R 1 Both are ethyl. In some embodiments, R 1 and R 1 Both are isopropyl. In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-3 It is a linear alkyl group, and the other side is optionally substituted with C 3-10 It is cycloalkyl. In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-3 It is a linear alkyl group, and the other side is optionally substituted with C 5-6 It is cycloalkyl. In some embodiments, R 1 is methyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 1 and R 2 One of them is C which can be optionally replaced. 1-3 One is a linear alkyl group, and the other is an optionally substituted benzyl group. In some embodiments, R 1 It is methyl, and R 2 is benzyl which is optionally substituted. In some embodiments, R 2 is benzyl. In some embodiments, R 2 is p-CH3O-C6H4-CH2-. In some embodiments, R 1is selected from methyl, ethyl, cyclohexyl, and benzyl which is optionally substituted with phenyl. In some embodiments, R 2 is selected from methyl, ethyl, cyclohexyl, and benzyl which is optionally substituted with phenyl. In some embodiments, R 1 and R 2 Each of these is independently selected from methyl, ethyl, cyclohexyl, and benzyl, which is optionally substituted with phenyl.

[0192] In some embodiments, the provided compound is [ka] TIFF2026053646000150.tif243166TIFF2026053646000151.tif118166

[0193] In some embodiments, R 1 and R 2 One of them is R, and R is C which can be optionally substituted. 1-6 One is alkyl, and the other is R, where R has 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-20 Heteroliphatic, C 6-20 Ariel, C 6-20 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-20 The optionally substituted group is selected from aryl heteroaliphatic groups, 5-20 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclyls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R 1 and R 2 One of them is R, and R is C which can be optionally substituted. 1-6 It is alkyl, and the other is R, and R is C 3-20 Alicyclic, C 6-20The optionally substituted group is selected from 5-20 membered heteroaryls having 1-10 heteroatoms independently selected from aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclils having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R 1 and R 2 One of them is R, and R is C which can be optionally substituted. 1-6 It is alkyl, and the other is R, and R is C 3-20 Alicyclic, C 6-20 The optionally substituted group is selected from 5-20 membered heteroaryls having 1-10 heteroatoms independently selected from aryl, oxygen, nitrogen, and sulfur, and 3-20 membered heterocyclines having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 and R 2 One of them is R, and R is C which can be optionally substituted. 1-6 It is alkyl, and the other is R, and R is C 6-20 The optionally substituted group is selected from aryls and 5-20 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R 1 and R 2 One of them is R, and R is C which can be optionally substituted. 1-6 One side is alkyl, and the other side is R, where R is optionally substituted with C. 6-20 It is an arrow. In some embodiments, R 1 and R 2 One of them is R, and R is C which can be optionally substituted. 1-6 One is alkyl, and the other is R, where R is optionally substituted with phenyl. In some embodiments, optionally substituted with C 1-6 R as an alkyl group is methyl. In some embodiments, R as an optionally substituted phenyl group is [ka] TIFF2026053646000153.tif222166TIFF2026053646000154.tif200166

[0194] In some embodiments, R 1 and R 2 R is independently R, and R is as described in this disclosure. In some embodiments, R is C 3-20 Alicyclic, C 6-20 The optionally substituted group is selected from 5-20 membered heteroaryls having 1-10 heteroatoms independently selected from aryl, oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclils having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is C 3-20 Alicyclic, C 6-20 The optionally substituted group is selected from 5-20 membered heteroaryls having 1-10 heteroatoms independently selected from aryl, oxygen, nitrogen, and sulfur, and 3-20 membered heterocyclines having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R is C 3-20 The group is optionally substituted, selected from alicyclic groups and 3-20 membered heterocyclines having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is C 6-20 The group is optionally substituted, selected from aryls and 5-20 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is C 3-20 Alicyclic and C 6-20 It is an optionally substituted group selected from aryl groups. In some embodiments, R is an optionally substituted group selected from 5-20 membered heteroaryl groups having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclyl groups having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted C3-20 It is alicyclic. In some embodiments, R is optionally substituted with C 3-20 It is cycloalkyl. In some embodiments, R is optionally substituted with C having 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-20 It is heteroaliphatic. In some embodiments, R is optionally substituted with C. 6-20 It is an aryl. In some embodiments, R is an optionally substituted 5-20 member heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted 3-20 member heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is a phenyl compound. In some embodiments, R 1 and R 2 R is an optionally substituted phenyl. In some embodiments, R 1 and R 2 is phenyl. In some embodiments, the provided compound is [ka] or a salt thereof. In some embodiments, the provided compound is [ka] or a diastereomer of its salt. In some embodiments, the provided compound is [ka] or the enantiomer of its salt.

[0195] In some embodiments, R 1 and R 2 The carbon atom to which it is bonded is not chiral. In some embodiments, R 1 and R 2 This is the same as R 1 and R2 These are the same, and neither is hydrogen. In some embodiments, R 1 and R 2 is methyl. In some embodiments, R 1 and R 2 is ethyl. In some embodiments, R 1 and R 2 R is an optionally substituted phenyl. In some embodiments, R 1 and R 2 is phenyl. In some embodiments, R 1 and R 2 is R, and the two R groups combine to form an optionally substituted ring as described herein. In some embodiments, the formed ring does not contain any chiral elements. In some embodiments, the formed ring is an optionally substituted five-membered alicyclic ring. In some embodiments, [ka] In particular, this disclosure is R 1 and R 2 We have shown that a compound provided in which the bonded carbon atom is not chiral can provide surprisingly high stereoselectivity when used in chiral-controlled oligonucleotide synthesis. In some embodiments, such compounds yield high yields.

[0196] In some embodiments, R 3 -H, -L s -R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2. In some embodiments, R 3 is -H. In some embodiments, R 3 is, -L s -R is, and in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 3 R is R (for example, the R embodiment described in this disclosure). In some embodiments, R 3 is a halogen. In some embodiments, R 3is -F. In some embodiments, R 3 is -Cl. In some embodiments, R 3 is -Br. In some embodiments, R 3 is -I. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -NO2. In some embodiments, R 3 is, -L s -Si(R)3, in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 3 R is -CH2-Si(R)3, where the -CH2- group is optionally substituted and R is independently described herein. In some embodiments, R 3 is -CH2-Si(R)3, where R is independently one of the compounds described herein. In some embodiments, the R in -Si(R)3 is not -H. In some embodiments, the R in -Si(R)3 is independently one of C 1-6 It is an optionally substituted group selected from alkyl and phenyl. In some embodiments, -Si(R)3 is -Si(Ph)2Me. Other non-hydrogen embodiments of R are broadly described in this disclosure and may be used in -Si(R)3. In some embodiments, R 3 is -OR, where R is one of the values ​​described herein. In some embodiments, R 3 R is -SR, where R is as described in this disclosure. In some embodiments, R 3 R is -N(R)², where R is independently one of those described herein. In some embodiments, R 2 R 1 Same as, or R 1 Unlike in this disclosure, R 1 It is a group selected from any group described for the target.

[0197] In some embodiments, R 4 -H, -L s -R, halogen, -CN, -NO2, -Ls -Si(R)3, -OR, -SR, or -N(R)2. In some embodiments, R 4 is -H. In some embodiments, R 4 is, -L s -R is, and in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 4 R is R (for example, the R embodiment described in this disclosure). In some embodiments, R 4 is a halogen. In some embodiments, R 4 is -F. In some embodiments, R 4 is -Cl. In some embodiments, R 4 is -Br. In some embodiments, R 4 is -I. In some embodiments, R 4 is -CN. In some embodiments, R 4 is -NO2. In some embodiments, R 4 is, -L s -Si(R)3, in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 4 R is -CH2-Si(R)3, where the -CH2- group is optionally substituted and R is independently described herein. In some embodiments, R 4 is -CH2-Si(R)3, where R is independently one of the compounds described herein. In some embodiments, the R in -Si(R)3 is not -H. In some embodiments, the R in -Si(R)3 is independently one of C 1-6 It is an optionally substituted group selected from alkyl and phenyl. In some embodiments, -Si(R)3 is -Si(Ph)2Me. Other non-hydrogen embodiments of R are broadly described in this disclosure and may be used in -Si(R)3. In some embodiments, R 4 is -OR, where R is one of the values ​​described herein. In some embodiments, R 4 R is -SR, where R is as described in this disclosure. In some embodiments, R4 R is -N(R)², where R is independently one of those described herein. In some embodiments, R 2 R 1 Same as, or R 1 Unlike in this disclosure, R 1 It is a group selected from any group described for the target.

[0198] In some embodiments, R 1 , R 2 , R 3 , and R 4 At least one of them is not -H. In some embodiments, the compounds provided for formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, or formula Ie contain one or more chiral elements. In some embodiments, R 3 and R 4 In some embodiments, R 1 and R 2 At least one of them is not hydrogen, but R 1 and R 2 Unlike the carbon atoms to which they are bonded, the carbon atoms to which they are bonded are chiral centers. In some embodiments, R 1 and R 2 At least one of them is not hydrogen, but R 1 and R 2 It is the same as, and the carbon to which it is bonded is not a chiral center. In particular, this disclosure is R 1 and R 2 This demonstrates that a compound provided, in which the bonded carbon atom is not chiral, can confer surprisingly high stereoselectivity when used as a chiral auxiliary in oligonucleotide synthesis.

[0199] In some embodiments, R 5 -H, -L s -R, halogen, -CN, -NO2, -L s -Si(R)3, -OR, -SR, or -N(R)2. In some embodiments, R 5 is -H. In some embodiments, R5 is, -L s -R is, and in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 5 R is R (for example, the R embodiment described in this disclosure). In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -F. In some embodiments, R 5 is -Cl. In some embodiments, R 5 is -Br. In some embodiments, R 5 is -I. In some embodiments, R 5 is -CN. In some embodiments, R 5 is -NO2. In some embodiments, R 5 is, -L s -Si(R)3, in the formula, L s And R are each independently described in this disclosure. In some embodiments, R 5 R is -CH2-Si(R)3, where the -CH2- group is optionally substituted and R is independently described herein. In some embodiments, R 5 is -CH2-Si(R)3, where R is independently one of the compounds described herein. In some embodiments, the R in -Si(R)3 is not -H. In some embodiments, the R in -Si(R)3 is independently one of C 1-6 It is an optionally substituted group selected from alkyl and phenyl. In some embodiments, -Si(R)3 is -Si(Ph)2Me. Other non-hydrogen embodiments of R are broadly described in this disclosure and may be used in -Si(R)3. In some embodiments, R 5 is -OR, where R is one of the values ​​described herein. In some embodiments, R 5 R is -SR, where R is as described in this disclosure. In some embodiments, R 5 R is -N(R)², where R is independently one of those described herein. In some embodiments, R 2 R 1Same as, or R 1 Unlike in this disclosure, R 1 It is a group selected from any group described for the target.

[0200] In some embodiments, R 1 and R 2 One or both of the above, as well as R 5 R is, together with the intervening atoms, to form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 5 and R 1 R is, together with the intervening atoms, to form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 1 and R 2 one of the following, as well as R 5 R is a group that, together with the intervening atoms, forms an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. As broadly described in this disclosure, the rings formed by the combination of two R groups can be of various sizes, monocyclic, bicyclic, or polycyclic, and may contain various numbers of heteroatoms. In some embodiments, the ring is a 3-membered ring. In some embodiments, the ring is a 4-membered ring. In some embodiments, the ring is a 5-membered ring. In some embodiments, the ring is a 6-membered ring. In some embodiments, the formed ring is R 5 The ring contains no ring heteroatoms other than the nitrogen atom to which it is bonded. In some embodiments, the ring is a saturated ring. In some embodiments, the ring is a monocyclic ring. In some embodiments, the ring contains additional ring heteroatoms in addition to the intervening heteroatom. In some embodiments, the ring is a three-membered ring containing one ring heteroatom. In some embodiments, the ring is a three-membered ring containing two ring heteroatoms. In some embodiments, the ring is a three-membered ring containing one carbon ring atom, one nitrogen ring atom, and one oxygen ring atom.

[0201] In some embodiments, R 1, R 2 , R 3 , R 4 , and R 5 Two or more of these are independently R, and the R groups optionally and independently come together to form the ring described herein. In some embodiments, R 1 and R 2 is R, and the two R groups together form an optionally substituted ring as described herein. In some embodiments, R 1 and R 2 One of the following, as well as R 3 and R 4 One of them is R, and the two R groups together form an optionally substituted ring as described herein. In some embodiments, R 3 and R 4 one of the following, as well as R 5 is R, and the two R groups together form an optionally substituted ring as described herein.

[0202] In some embodiments, a ring is formed (for example, R 1 and R 2 something formed by, or R 1 and R 2 One of the following, as well as R 3 and R 4The ring formed by one of the following is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-5 heteroatoms. In some embodiments, the formed ring is monocyclic. In some embodiments, the formed ring is bicyclic. In some embodiments, the formed ring is polycyclic. In some embodiments, the formed ring is aliphatic. In some embodiments, the formed ring does not contain an unsaturated moiety. In some embodiments, the formed ring is partially unsaturated. In some embodiments, the formed ring contains one or more saturated monocyclic ring moieties. In some embodiments, the formed ring contains one or more monocyclic partially unsaturated ring moieties. In some embodiments, the formed ring contains one or more monocyclic aromatic ring moieties. In some embodiments, the formed ring contains one or more saturated ring moieties, partially unsaturated ring moieties, and / or aromatic ring moieties (e.g., a bicyclic or polycyclic ring containing a condensed saturated monocyclic moiety, a partially unsaturated monocyclic moiety, and / or an aromatic monocyclic moiety). In some embodiments, the formed ring is optionally substituted. In some embodiments, the formed ring is substituted. In some embodiments, the formed ring is not substituted. In some embodiments, the formed ring does not contain chiral elements. In some embodiments, the formed ring contains one or more chiral elements. In some embodiments, the formed ring contains one or more chiral elements and is chiral. In some embodiments, the chiral elements are chiral centers. In some embodiments, the formed ring is an optionally substituted 3- to 10-membered monocyclic ring that does not have heteroatoms. In some embodiments, the formed monocyclic ring is 3-membered, in some embodiments 4-membered, in some embodiments 5-membered, in some embodiments 6-membered, in some embodiments 7-membered, in some embodiments 8-membered, in some embodiments 9-membered, and in some embodiments 10-membered. In some embodiments, the formed ring is a 3-membered saturated alicyclic ring. In some embodiments, the formed ring is an optionally substituted 5-membered saturated alicyclic ring. In some embodiments, the formed ring is an optionally substituted 5-membered saturated alicyclic ring that does not contain a chiral element.In some embodiments, the formed ring is an unsubstituted, five-membered saturated alicyclic ring that does not contain chiral elements. In some embodiments, the five-membered ring described herein is condensed with another optionally substituted ring, which may be saturated, partially unsaturated, or aryl. In some embodiments, the five-membered ring described herein is condensed with an optionally substituted aryl ring. In some embodiments, the five-membered ring described herein is condensed with an optionally substituted phenyl ring. In some embodiments, the five-membered ring described herein is condensed with a phenyl ring. In some embodiments, the condensation is C3 and C4 (C1 is R). 1 and R 2 It occurs at the carbon atom to which it is bonded. In some embodiments, the ring that is formed is [ka] In some embodiments, the formed ring is an optionally substituted six-membered saturated alicyclic ring. In some embodiments, the formed ring is an optionally substituted six-membered saturated alicyclic ring that does not contain chiral elements. In some embodiments, the formed ring is an unsubstituted six-membered saturated alicyclic ring that does not contain chiral elements. In some embodiments, one or more ring portions can be condensed into a six-membered ring, for example, as described above for a five-membered ring. The ring embodiments described herein are applicable to other variable portions in which two of the variable portions may be R, and these two Rs together may form an optionally substituted ring. In some embodiments, [ka]

[0203] In some embodiments, the provided compound is [ka] TIFF2026053646000162.tif238166TIFF2026053646000163.tif34165

[0204] In some embodiments, R1 and R 2 One of the following, as well as R 3 and R 4 one of them (for example, R in equation Ia) 1 and R 2 One of the following, as well as R of formula Ia 3 and R 4 One of them is R, and the two R groups together form an optionally substituted ring as described in this disclosure. In some embodiments, R 1 and R 3 is R, and the two R groups together form an optionally substituted ring as described herein. In some embodiments, R 1 and R 4 is R, and the two R groups together form an optionally substituted ring as described herein. In some embodiments, R 2 and R 3 is R, and the two R groups together form an optionally substituted ring as described herein. In some embodiments, R 2 and R 4 is R, and the two R groups, together, form an optionally substituted ring as described in this disclosure. In some embodiments, the provided compounds have the structure of formula Ie or a salt thereof. As described in this disclosure, in some embodiments, the formed ring is optionally substituted C3- 20 It is an alicyclic ring. In some embodiments, the ring formed is optionally substituted with C 3-10 It is an alicyclic ring. In some embodiments, the ring formed is optionally substituted with C 5-7 It is an alicyclic ring. In some embodiments, the formed ring is an optionally substituted C5 alicyclic ring. In some embodiments, the formed ring is an optionally substituted C6 alicyclic ring. In some embodiments, the formed ring is an optionally substituted C7 alicyclic ring. In some embodiments, the formed ring is an optionally substituted C8 alicyclic ring. In some embodiments, the formed ring is an optionally substituted C9 alicyclic ring. In some embodiments, the formed ring is an optionally substituted C 10It is an alicyclic ring. As described in this disclosure, in some embodiments the ring formed may be monocyclic, bicyclic, or polycyclic and may contain one or more saturated, partially unsaturated, and / or aromatic monocyclic moieties. In some embodiments the ring formed may optionally be substituted C3- 20 It is a saturated monocyclic or alicyclic ring. In some embodiments, the formed ring is optionally substituted with C 3-10 It is a saturated monocyclic or alicyclic ring. In some embodiments, the formed ring is optionally substituted with C 5-7 It is a saturated monocyclic alicyclic ring. In some embodiments, the formed ring is an optionally substituted C5 saturated monocyclic alicyclic ring. In some embodiments, the formed ring is an optionally substituted C6 saturated monocyclic alicyclic ring. In some embodiments, the formed ring is an optionally substituted C7 saturated monocyclic alicyclic ring. In some embodiments, the formed ring is an optionally substituted C8 saturated monocyclic alicyclic ring. In some embodiments, the formed ring is an optionally substituted C9 saturated monocyclic alicyclic ring. In some embodiments, the formed ring is an optionally substituted C 10 It is a saturated monocyclic alicyclic ring. In some embodiments, R 1 and R 2 One of the following, as well as R 3 and R 4 One of them is R, and the two R groups together form an optionally substituted ring as described herein, R 5 is R, and R is C 1-20 C having 1 to 10 heteroatoms independently selected from aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 1-20 Heteroliphatic, C 6-20 Ariel, C 6-20 C having 1 to 10 heteroatoms independently selected from aryl aliphatic, oxygen, nitrogen, sulfur, phosphorus, and silicon. 6-20 An optionally substituted group selected from aryl heteroaliphatic groups, 5-20 membered heteroaryls having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and 3-20 membered heterocyclils having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, R6 is -H, and R 7 is -OH. In some embodiments, R 1 and R 2 One of the following, as well as R 3 and R 4 One of them is R, and the two R groups together form an optionally substituted ring as described herein, R 5 is R, and R is C which can be optionally substituted. 1-20 It is aliphatic, R 6 is -H, and R 7 is -OH. In some embodiments, R 1 and R 2 One of the following, as well as R 3 and R 4 One of them is R, and the two R groups together form an optionally substituted ring as described herein, R 5 is R, and R is C which can be optionally substituted. 1-6 It is alkyl, R 6 is -H, and R 7 is -OH. In some embodiments, R 1 and R 2 One of the following, as well as R 3 and R 4 One of them is R, and the two R groups together form an optionally substituted ring as described herein, R 5 is R, and R is methyl, and R 6 is -H, and R 7 is -OH. In particular, this disclosure provides R in the provided compound. 5 and R 6 We have shown that when the bonded N atom is not contained within the ring, the provided compound can yield surprisingly high stereoselectivity and / or yield when used in the chiral-controlled preparation of oligonucleotides.

[0205] In some embodiments, the provided compound (e.g., a compound of formula Ie) [ka] TIFF2026053646000165.tif53166

[0206] [ka] TIFF2026053646000167.tif163166

[0207] [ka] TIFF2026053646000169.tif244166

[0208] In some embodiments, R 3 and R 4 is R, and the two R groups together form an optionally substituted ring as described herein.

[0209] In some embodiments, R 3 and R 5 is R, and the two R groups together form an optionally substituted ring as described herein. In some embodiments, R 4 and R 5 is R, and the two R groups together form an optionally substituted ring as described herein. In some embodiments, R 4 and R 5 is R, and the two R groups, together, form an optionally substituted ring as described herein, R 6 is -H, and R 7 It is -OH.

[0210] In some embodiments, the formed ring is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, the formed ring is an optionally substituted 4-6 member monocyclic ring having 1 or fewer heteroatoms. In some embodiments, the formed ring is an optionally substituted 4-6 member saturated monocyclic ring having only one ring heteroatom, where the sole ring heteroatom is R 5It is nitrogen to which is bonded. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered. In some embodiments, the formed ring is 8-membered. In some embodiments, the formed ring is 9-membered. In some embodiments, the formed ring is 10-membered. In some embodiments, R 3 is -H, and R 4 and R 5 R is R, and these Rs, together with their intervening atoms, form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5 It forms an optional 3-20 member monocyclic, bicyclic, or polycyclic ring having (a bonded to it). In some embodiments, R 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5 It forms an optional 4- to 7-member monocyclic ring having (a bonded to it). In some embodiments, R 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5 It forms an optional substituted four-membered monocyclic ring having (which is bonded to R). In some embodiments, R 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5It forms an optional substituted 5-member monocyclic ring having (which is bonded to R). In some embodiments, R 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5 It forms an optional substituted 6-member monocyclic ring having (which is bonded to R). In some embodiments, 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5 It forms an optional substituted 7-member monocyclic ring having (which is bonded to R). In some embodiments, R 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5 It forms an optional substituted 8-member monocyclic ring having (which is bonded to R). In some embodiments, R 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5 It forms an optional 9-member monocyclic ring having (which is bonded to R). In some embodiments, 3 is -H, and R 4 and R 5 These R atoms, together with the intervening atoms, form nitrogen atoms (R 5It forms an optionally substituted 10-membered monocyclic ring having (a bonded to it). In some embodiments, the formed ring is substituted. In some embodiments, the formed ring is not substituted. In some embodiments, the formed ring is monocyclic. In some embodiments, the formed ring is bicyclic. In some embodiments, the formed ring has no additional heteroatoms other than the intervening atom. In some embodiments, the formed ring has additional ring heteroatoms other than the intervening atom. In some embodiments, the formed ring is an optionally substituted 4-membered saturated monocyclic ring with a ring heteroatom content of 1 or less, and the sole ring heteroatom is nitrogen. In some embodiments, the formed ring is an optionally substituted 5-membered saturated monocyclic ring with a ring heteroatom content of 1 or less, and the sole ring heteroatom is nitrogen. In some embodiments, the formed ring is an optionally substituted 6-membered saturated monocyclic ring with a ring heteroatom content of 1 or less, and the sole ring heteroatom is nitrogen. In some embodiments, the formed ring is an optionally substituted 7-membered saturated monocyclic ring with a ring heteroatom content of 1 or less, where the sole ring heteroatom is nitrogen. In some embodiments, the formed ring is an optionally substituted 8-membered saturated monocyclic ring with a ring heteroatom content of 1 or less, where the sole ring heteroatom is nitrogen. In some embodiments, the formed ring is an optionally substituted 9-membered saturated monocyclic ring with a ring heteroatom content of 1 or less, where the sole ring heteroatom is nitrogen. In some embodiments, the formed ring is an optionally substituted 10-membered saturated monocyclic ring with a ring heteroatom content of 1 or less, where the sole ring heteroatom is nitrogen. In some embodiments, the formed ring is [ka]

[0211] In some embodiments, the provided compound is [ka] TIFF2026053646000172.tif80166

[0212] In some embodiments, the provided compound is [ka] TIFF2026053646000174.tif85166

[0213] TIFF2026053646000175.tif153166TIFF2026053646000176.tif183166

[0214] In some embodiments, R 1 and R 2 One or both of the above, as well as R 5 R is R, and these Rs, together with their intervening atoms, form an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. In some embodiments, R 1 and R 2 one of the following, as well as R 5 R is the intervening atom, and the R group, together with its intervening atoms, forms an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 1-5 heteroatoms. As broadly described in this disclosure, the formed rings can be of various sizes, monocyclic, bicyclic, or polycyclic, and can contain various numbers and / or types of heteroatoms. In some embodiments, the ring is a 3-membered ring. In some embodiments, the ring is a 4-membered ring. In some embodiments, the ring is a 5-membered ring. In some embodiments, the ring is a 6-membered ring. In some embodiments, the ring is monocyclic. In some embodiments, the ring contains additional ring heteroatoms in addition to the intervening heteroatoms. In some embodiments, the ring is a 3-membered ring containing one ring heteroatom. In some embodiments, the ring is a 3-membered ring containing two ring heteroatoms. In some embodiments, the ring is a 3-membered ring containing one carbon ring atom, one nitrogen ring atom, and one oxygen ring atom.

[0215] In some embodiments, R 6R' is R', and R' is as described in this disclosure. In some embodiments, for example, when the provided compound has the structure of I, Ia, Ia-1, Ia-2, Ib, Ic, Id, Ie, II, II-a, II-b, III, III-a, or III-b or the structure of a salt thereof, R 6 is -H. In some embodiments, R 6 R is a suitable capping group used in oligonucleotide synthesis, and many such capping groups are widely known and can be used in accordance with this disclosure. In some embodiments, R 6 is -C(O)R, where R is as described in this disclosure. In some embodiments, R 6 In oligonucleotide synthesis, is a capping group when included in the provided structure (e.g., the structure of formula VII or formula VIII, or the structure of a salt thereof). In some embodiments, the capping group has the structure -C(O)R, where R is as described in this disclosure. In some embodiments, R 6 is -C(O)R, where R is one of the formulas described herein. In some embodiments, R is methyl. In some embodiments, R is -CF3.

[0216] In some embodiments, R 6 is -H. In some embodiments, R 6 is -H, and R 4 and R 5 R is R, and the R group, together with the intervening atoms, forms an optionally substituted 3-20 membered heterocyclyl ring having 1-5 heteroatoms as described in this disclosure. In some embodiments, R 6 is -H, and R 4 and R 5R is the R group, and the R group, together with the intervening atoms, forms an optionally substituted 4-6 membered heterocyclyl ring having 1-5 heteroatoms as described in this disclosure. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered.

[0217] In some embodiments, R 7 is -OH. In some embodiments, R 7 is -SH. In some embodiments, the present disclosure provides compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof, where R 7 is -OH. In some embodiments, the present disclosure provides compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b, or salts thereof, where R 7 It is -SH.

[0218] In some embodiments, R 8 -LR 7 , -LC(R 1 )(R 2 )-R 7 , or -L s -R 7 In the formula, each variable part is independently described herein. In some embodiments, R 8 The R described in this disclosure is 7 In some embodiments, R 8 is -OH. In some embodiments, R 8 is -SH. In some embodiments, R 8 -LR 7 In the formula, L and R 7Each of these is independently described in this disclosure. In some embodiments, R 8 is -L-OH, where L s This is described in the present disclosure. In some embodiments, R 8 is -L-SH, where L s This is described in the present disclosure. In some embodiments, R 8 is -LC(R 1 )(R 2 )-R 7 In the formula, each variable part is independently described herein. In some embodiments, R 8 -C(R 1 )(R 2 )-R 7 In the formula, each variable part is independently described herein. In some embodiments, R 8 is -CH2-R 7 And in the formula, R 7 This is described in the present disclosure. In some embodiments, R 8 is -CH2OH. In some embodiments, R 8 is -CH2SH. In some embodiments, R 8 is, -L s -R 7 In the formula, each variable part is independently described herein. In some embodiments, R 8 is, -L s -OH, and in the formula, L s This is described in the present disclosure. In some embodiments, R 8 is, -L s -SH, and in the formula, L s This is as described in this disclosure.

[0219] In some embodiments, R 4 and R 5 R is R, and these Rs, together with their intervening atoms, form an optionally substituted 4- to 10-membered heterocyclyl ring, along with the intervening nitrogen atom as the sole ring heteroatom. In some embodiments, R 4 and R 5R is R, and these Rs, together with their intervening atoms, form an optionally substituted 4-10 member saturated monocyclic heterocyclyl ring, along with the intervening nitrogen atom as the sole ring heteroatom. In some embodiments, R 4 and R 5 R is R, and these Rs, together with their intervening atoms, together with the intervening nitrogen atom as the sole ring heteroatom, form an optionally substituted 4- to 10-membered saturated bicyclic heterocyclyl ring. In some embodiments, the formed ring is 3-membered. In some embodiments, the formed ring is 4-membered. In some embodiments, the formed ring is 5-membered. In some embodiments, the formed ring is 6-membered. In some embodiments, the formed ring is 7-membered. In some embodiments, the formed ring is an optionally substituted pyrrolidine moiety. In some embodiments, R 7 is -OH. In some embodiments, R 7 It is -SH.

[0220] In some embodiments, the number of chiral elements in the compounds provided by formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b is 1 or less. In some embodiments, the number of chiral elements in the compounds provided by formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b is 1 or less, and the sole chiral element is a chiral carbon atom. In some embodiments, the number of chiral elements in the provided compounds of formula I, formula Ia, formula Ia-1, formula Ia-2, formula Ib, formula Ic, formula Id, formula Ie, formula II, formula II-a, formula II-b, formula III, formula III-a, or formula III-b is 1 or less, and the sole chiral element is R 3 and R 4 It is a chiral carbon atom to which R is bonded. In some embodiments, 1 and R 2 This is the same as R 1 and R2 This is the same as C, which can be optionally substituted. 1-3 It is a linear alkyl group. In some embodiments, R 1 and R 2 This is the same as C, which can be optionally substituted. 1-3 It is a linear alkyl group and does not contain substituents containing carbon atoms. In some embodiments, R 1 and R 2 This is the same as C, which can be optionally substituted. 1-2 It is a linear alkyl group. In some embodiments, R 1 and R 2 This is the same as C, which can be optionally substituted. 1-2 It is a linear alkyl group and does not contain substituents containing carbon atoms. In some embodiments, R 1 and R 2 is methyl. In some embodiments, R 1 and R 2 is ethyl. In some embodiments, R 1 and R 2 is n-propyl. In some embodiments, R 1 and R 2 These, together, form the optionally substituted ring described herein. In some embodiments, R 1 and R 2 When combined, they form an arbitrarily substituted ring that does not contain chiral elements.

[0221] In some embodiments, L is covalently bonded or optionally substituted with C 1-6 It is an alkylene, and one or more methylene units are optionally and independently replaced by -L'-, where L' is as described in this disclosure. In some embodiments, L is a covalent bond. In some embodiments, L is optionally substituted with C 1-6 It is an alkylene, and one or more methylene units are optionally and independently replaced by -L'-, where L' is as described in this disclosure. In some embodiments, L is optionally replaced by C 1-6 It is an alkylene, and one or more methylene units are independently replaced by -L'-, where each L' is independently one of those described herein.

[0222] In some embodiments, L is a covalent bond. In some embodiments, the provided compound (e.g., compound of formula I) [ka] It has the structure of or the structure of a salt thereof.

[0223] In some embodiments, L is -C(R 3 )(R 4 )-. In some embodiments, the compound provided is of formula Ia: [ka] The compound has the structure of or the structure of a salt of the formula, where each variable part is independently described herein. In some embodiments, the compound of formula I has the structure of formula Ia. In some embodiments, the provided compound is [ka] Having the structure of or the structure of a salt thereof, where each variable part is independently described in this disclosure, R 4 and R 5 It is not hydrogen. In some embodiments, the provided compound is [ka] Having the structure of or the structure of a salt thereof, where each variable part is independently described in this disclosure, R 4 and R 5 R is R, and together they form the optionally substituted ring described herein. In some embodiments, R 1 and R 2 This is different. In some embodiments, R 1 and R 2 This is the same as R 1 and R 2 It is the same as hydrogen. In some embodiments, R 1 and R 2It is the same as, and not hydrogen. In some embodiments, R 1 and R 2 This is the same as C, which can be optionally substituted. 1-6 It is aliphatic. In some embodiments, R 1 and R 2 This is the same as C, which can be optionally substituted. 1-6 It is alkyl.

[0224] In some embodiments, the provided compound is of formula (Ia-1): [ka] Having the structure of or the structure of a salt thereof, where each variable part is independently described in this disclosure, R 4 and R 5 It is not hydrogen, but R 2 R 1 It has a larger size compared to. In some embodiments, the compound of formula Ia has the structure of formula Ia-1. In some embodiments, R 4 and R 5 R is R, and together they form the optionally substituted ring described herein. In some embodiments, R 1 and R 2 This is different. In some embodiments, R 1 and R 2 This is the same as R 1 and R 2 It is the same as hydrogen. In some embodiments, R 1 and R 2 It is the same as, and not hydrogen. In some embodiments, R 1 and R 2 This is the same as C, which can be optionally substituted. 1-6 It is aliphatic. In some embodiments, R 1 and R 2 This is the same as C, which can be optionally substituted. 1-6 It is alkyl.

[0225] In some embodiments, the provided compound is of formula (Ia-2): [ka] has the structure of or the structure of its salt, wherein the variable parts are each, independently, as described in the present disclosure, R 4 and R 5 are not hydrogen, and R 2 is R 1 has a larger size compared to R 4 and R 5 are R, and together form an optionally substituted ring as described in the present disclosure. In some embodiments, R 1 is different from R 2 In some embodiments, R 1 is the same as R 2 In some embodiments, R 1 is the same as R 2 and is hydrogen. In some embodiments, R 1 is the same as R 2 and is not hydrogen. In some embodiments, R 1 is the same as R 2 and is optionally substituted C 1-6 is aliphatic. In some embodiments, R 1 is the same as R 2 and is optionally substituted C 1-6 is alkyl.

[0226] In some embodiments, L is -L'-C(R 3 )(R 4 )-, wherein the variable parts are each, independently, as described in the present disclosure. In some embodiments, the provided compound has the formula I-b:

Chemical formula

[0227] In some embodiments, L’ is a covalent bond. In some embodiments, L’ is an optionally substituted divalent C 1-3 alkylene. In some embodiments, L’ is -C(R 3 )(R 4 )-, wherein R 3 and R 4 are each independently as described in the present disclosure. In some embodiments, L’ is -C(R 3 )(R 4 )-C(R 3 )(R 4 )-, wherein R 3 and R 4 are each independently as described in the present disclosure. In some embodiments, L’ is -Cy- of the present disclosure. In some embodiments, L’ is -C(R 3 )[C(R 4 )3]-, wherein R 3 and R 4 are each independently as described in the present disclosure.

[0228] In some embodiments, L’ is a covalent bond. In some embodiments, L’ is an optionally substituted divalent C 1-3 alkylene. In some embodiments, L’ is -C(R 3 )(R 4 )-. In some embodiments, the provided compound is of formula I-c:

Chemical formula

[0229] In some embodiments, the formed ring is an optionally substituted heterocyclyl moiety as described in this disclosure. In some embodiments, the formed ring is an optionally substituted 4-membered, 5-membered, or 6-membered saturated monocyclic heterocyclyl ring having 1 nitrogen ring atom and 1 or less of the other heteroatoms described in this disclosure. In some embodiments, the formed ring is an optionally substituted trivalent azetidinyl moiety as described in this disclosure. In some embodiments, the formed ring is an optionally substituted trivalent pyrrolidinyl moiety as described in this disclosure. In some embodiments, the formed ring is an optionally substituted trivalent piperidinyl moiety as described in this disclosure. In some embodiments, R bonded to C2 3 and R 4 One of them is R, and R is bonded to C3. 3 and R 4 One of them is R, and the two R groups combine to form an optionally substituted ring as described herein. In some embodiments, the formed ring is an optionally substituted alicyclic ring. In some embodiments, the formed ring is an optionally substituted saturated alicyclic ring. In some embodiments, the formed ring is 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered. In some embodiments, the formed ring is an optionally substituted 5-membered saturated monocyclic alicyclic ring. In some embodiments, the provided compound is [ka]

[0230] In some embodiments, L' is -C(R 3 )(R 4 )-C(R 3 )(R 4 )-, where each variable part is independently described herein. In some embodiments, L' is -Cy-. In some embodiments, L' is -C(R 3 )[C(R 4 )3]- is.

[0231] In some embodiments, -Cy- is independently C3-20 Alicyclic ring, C 6-20 The optionally substituted divalent group is selected from an aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted ring as described in this disclosure (e.g., R and Cy L This disclosure is intended for use with respect to the divalent substance described herein.

[0232] In some embodiments, -Cy- is monocyclic. In some embodiments, -Cy- is bicyclic. In some embodiments, -Cy- is polycyclic. In some embodiments, -Cy- is saturated. In some embodiments, -Cy- is partially unsaturated. In some embodiments, -Cy- is aromatic. In some embodiments, -Cy- includes a saturated cyclic part. In some embodiments, -Cy- includes a partially unsaturated cyclic part. In some embodiments, -Cy- includes an aromatic cyclic part. In some embodiments, -Cy- includes a combination of a saturated cyclic part, a partially unsaturated cyclic part, and / or an aromatic cyclic part. In some embodiments, -Cy- is 3-membered. In some embodiments, -Cy- is 4-membered. In some embodiments, -Cy- is 5-membered. In some embodiments, -Cy- is 6-membered. In some embodiments, -Cy- is 7-membered. In some embodiments, -Cy- has 8 members. In some embodiments, -Cy- has 9 members. In some embodiments, -Cy- has 10 members. In some embodiments, -Cy- has 11 members. In some embodiments, -Cy- has 12 members. In some embodiments, -Cy- has 13 members. In some embodiments, -Cy- has 14 members. In some embodiments, -Cy- has 15 members. In some embodiments, -Cy- has 16 members. In some embodiments, -Cy- has 17 members. In some embodiments, -Cy- has 18 members. In some embodiments, -Cy- has 19 members. In some embodiments, -Cy- has 20 members.

[0233] In some embodiments, -Cy- is optionally substituted with a divalent C 3-20 It is an alicyclic ring. In some embodiments, -Cy- is optionally substituted with a divalent saturated carbon. 3-20 It is an alicyclic ring. In some embodiments, -Cy- is optionally substituted with a divalent partially unsaturated C 3-20 It is an alicyclic ring. In some embodiments, -Cy- includes an aromatic moiety. In some embodiments, [ka]

[0234] In some embodiments, -Cy- is optionally replaced by C. 6-20 It is an aryl ring. In some embodiments, -Cy- is an optionally substituted phenylene. In some embodiments, -Cy- is an optionally substituted 1,2-phenylene. In some embodiments, -Cy- is an optionally substituted 1,3-phenylene. In some embodiments, -Cy- is an optionally substituted 1,4-phenylene. In some embodiments, -Cy- is an optionally substituted divalent naphthalene ring. In some embodiments, -Cy-H is an optionally substituted aryl as described in this disclosure (e.g., an aryl embodiment targeting R).

[0235] In some embodiments, -Cy- is an optionally substituted divalent 5-20 member heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus, and silicon. In some embodiments, -Cy- is an optionally substituted divalent 5-20 member heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is an optionally substituted divalent 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In som...

Claims

1. Formulas IV-a, IV-b, IV-c-1, IV-c-2, IV-d, or IV-e: 【Chemistry 1】 A method for preparing oligonucleotides, comprising coupling using a compound having the structure or a salt thereof, wherein the formula is: P L is P, L is -C(R3)(R4)-, R1 and R2, together with the carbon atoms they bond to, form a 5- or 6-membered monocyclic ring that does not contain heteroatoms and is optionally substituted, or a 9- to 15-membered bicyclic or tricyclic ring that does not contain heteroatoms and is optionally substituted. R3 is -H, -Ls-R, halogen, -CN, -NO2, -Ls-Si(R)3, -OR, -SR, or -N(R)2. R4 and R5, together with the intervening atoms, form an optionally substituted four- or five-membered monocyclic ring having only one heteroatom, which is the nitrogen to which R5 is bonded, or an optionally substituted seven- to ten-membered bicyclic ring having only one heteroatom, which is the nitrogen to which R5 is bonded. Each L s is independently a covalent or divalent, optionally substituted linear or branched group selected from C1-30 aliphatic groups and C1-30 heteroaliphatic groups having 1 to 10 heteroatoms, and one or more methylene units are optionally and independently C1-6 alkylene, C1-6 alkenylene, -C≡C-, a divalent C1-C6 heteroaliphatic group having 1 to 5 heteroatoms, -C(R')2-, -Cy-, -O-, -S-, -S-S-, -N(R')-, -C(O)-, -C(S)-, -C(NR')-, -C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -S(O)-, -S(O)2 -, -S(O) 2 N(R')-, -C(O)S-, -C(O)O-, -P(O)(OR')-, -P(O)(SR')-, -P(O)(R')-, -P(O)(NR')-, -P(S)(OR')-, -P(S)(SR')-, -P(S)(R')-, -P(S)(NR')-, -P(R')-, -P(OR')-, -P(SR')-, -P(NR')-, -P(OR') [B(R') 3 Replaced with any substituted group selected from ]-, -OP(O)(OR')O-, -OP(O)(SR')O-, -OP(O)(R')O-, -OP(O)(NR')O-, -OP(OR')O-, -OP(SR')O-, -OP(NR')O-, -OP(R')O-, or -OP(OR')[B(R')3]O-, and one or more carbon atoms are optionally and independently replaced with CyL, Each -Cy- is independently a divalent group that is optionally substituted from a C3-20 alicyclic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms. Each Cy L is independently a tetravalent group that is optionally substituted with a C3-20 alicyclic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms. Each R' is independently -R, -C(O)R, -C(O)OR, or -S(O)²R, L7 is -O- or -S-, BA is a nucleic acid base that can be optionally substituted, selected from A, T, C, G, U, and their tautomers. Each of R1s, R2s, R3s, R4s, and R5s is independently Rs, Each R s is independently -H, halogen, -CN, -N3, -NO, -NO2, -Ls-R', -Ls-Si(R)3, -Ls-OR', -Ls-SR', -Ls-N(R')2, -O-Ls-R', -O-Ls-Si(R)3, -O-Ls-OR', -O-Ls-SR', or -O-Ls-N(R')2. t is between 0 and 20. Ring A s is an optionally substituted 3-20 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms. R 5s is R s, Each R is independently -H, or an optionally substituted group selected from C1-30 aliphatic, C1-30 heteroaliphatic having 1 to 10 heteroatoms, C6-30 aryl, C6-30 aryl aliphatic, C6-30 aryl heteroaliphatic having 1 to 10 heteroatoms, 5 to 30-membered heteroaryl having 1 to 10 heteroatoms, and 3 to 30-membered heterocyclyl having 1 to 10 heteroatoms, or The two R groups, either independently or separately, come together to form a covalent bond, or Two or more R groups on the same atom may, independently and arbitrarily, combine with the atom to form an optionally substituted 3-30 member monocyclic, bicyclic, or polycyclic ring having 0-10 heteroatoms in addition to the atom, or The method comprising two or more R groups on two or more atoms, either and independently, joining with the intervening atoms to form an optionally substituted 3- to 30-membered monocyclic, bicyclic, or polycyclic ring having 0 to 10 heteroatoms in addition to the intervening atoms.

2. The compound is of formula IV-e: 【Chemistry 2】 The method according to claim 1, having the structure described above.

3. The method according to any one of claims 1 to 2, wherein R 2s is -OR and R is optionally substituted C 1-6 alkyl.

4. The method according to any one of claims 1 to 2, wherein R 2s is -H, -F, -OMe, or -OCH 2 CH 2 OMe.

5. The method according to any one of claims 1 to 4, wherein R 4s is -H.

6. The compound is of formula IV-d: 【Transformation 3】 Having a structure, The method according to claim 1, wherein R 4s and R 2s combine to form an optionally substituted -O-CH2-, and O is bonded to the carbon at position 2. 【Request Item 7】 【Chemistry 4】 but, 【Transformation 5】 The method according to claim 6.

8. The method according to any one of claims 1 to 7, wherein R 5s is DMTrO-.

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