Synthesis of isomerically pure polyol-based phosphoramidites

Abstract

The present disclosure relates to a process for the regiochemically and enantiomerically controlled synthesis of phosphoramidite-containing monomers, as well as intermediates of the process. In some embodiments, the phosphoramidite-containing monomers or their precursors are regioisomerically and / or enantiomerically pure and can be polymerized into polymers or copolymers.

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Application No. 63 / 353,942, filed June 21, 2022, and also claims the benefit of the filing date of U.S. Application No. 63 / 324,272, filed March 28, 2022, the disclosures of which are incorporated by reference herein in their entireties. [Background technology]

[0002] The "sequencing by extension" (SBX) protocol developed by Stratos Genomics (e.g., Kokoris et al., U.S. Patent No. 7,939,259, "High-Throughput Nucleic Acid Sequencing by Extension") is based on the polymerization of highly modified non-natural nucleotide analogs called "XNTPs". In general, SBX uses biochemical polymerization to transcribe the sequence of a DNA template onto a measurable polymer called an "Xpandomer". The transcribed sequence is encoded along the Xpandomer backbone in high signal-to-noise reporters spaced approximately 10 nm apart, which are designed for high signal-to-noise, highly differentiated response. Xpandomers can facilitate several next-generation DNA sequencing detection technologies and are well suited for nanopore sequencing.

[0003] XNTPs are scalable 5' triphosphate modified non-natural nucleotide analogs compatible with template-dependent enzymatic polymerization. XNTPs and their constituents are described in PCT Publication No. WO 2020 / 236526, the disclosure of which is incorporated herein by reference in its entirety. Essentially, XNTPs have the following structure: [ka]

[0004] where R is OH or H, the nucleobase is adenine, cytosine, guanine, thymine, uracil or a nucleobase analog, the reporter construct is a polymer having a first end and a second end and comprises, consecutively from the first end to the second end, a first reporter code, a symmetric chemical branch carrying a mobility control element, and a second reporter code, and linker A links the oxygen atom of the alpha phosphoramidate group to the first end of the reporter construct and linker B links the nucleobase to the second end of the reporter construct.

[0005] The polymer reporter construct and its components include repeating monomer units derived from phosphoramidite-containing monomers (non-limiting examples of phosphoramidite-containing monomers and their synthesis are described in PCT Publication No. WO 2020 / 236526). For example, the translocation control element may be a polymer or copolymer derived from repeating phosphoramidite-containing monomer units (e.g., 1,3-O-bis(phosphodiester)-2S-O-mPEG4-propane). Similarly, the first and second reporter codes may be polymers or copolymers derived from repeating phosphoramidite-containing monomer units.

[0006] The nanopore used for sequencing is a chiral environment.Positional and enantiomeric impurities in oligomers, polymers or copolymers contained in any component of XNTPs can affect signal generation (base calling) and processing speed in nanopore sequencing.Positional and enantiomeric pure phosphoramidite-containing monomers are desirable in the synthesis of oligomers, polymers or copolymers for incorporation into XNTPs. Summary of the Invention

[0007] Applicants have developed methods for synthesizing regioisomerically and enantiomerically pure phosphoramidite-containing monomers and their intermediates. Applicants have unexpectedly discovered that the selection of specific protecting groups facilitates the synthesis of such regioisomerically pure phosphoramidite-containing monomers in high yield. In particular, Applicants have developed a protecting group strategy that utilizes non-transferable protecting groups to generate products free of isomerization and that are stable throughout the course of downstream transformations and deprotection reactions. Furthermore, Applicants have surprisingly discovered that the protecting groups used are completely removable without significant decomposition or transformation of other functional groups of the protected molecule, such as base-labile esters, acid-labile trityl-protected alcohols, or oxidation-sensitive PEG linkers.

[0008] In view of the above, a first aspect of the present disclosure is a compound having a structure according to any one of formulas (IA) and (IB): [ka]

[0009] (In the formula,

[0010] R 1 -OH, -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms; Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, acyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0011] R 2is -OH, -O-trityl or a derivative or analog thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analog thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analog thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analog thereof, -O-1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, -O-[(chloro-4-methyl)phenyl]-4'-methoxypiperidin-4-yl, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether;

[0012] A is CH,

[0013] PG 2 is H,

[0014] PG 1 teeth, [ka] -O-CH2-S-CH3, -O-CH2-N3, or -O-CH2-CH=CH2, or

[0015] PG 1 -A-PG 2 are combined to form C(O)H, C(O)OMe, -C(O)OT, [ka] Forming

[0016] T is a C1-C6 branched or unbranched alkyl group;

[0017] f is 0 or 2;

[0018] Each R u are independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl;

[0019] Each R z are independently a branched or unbranched C1-C6 alkyl group.

[0020] In some embodiments, PG 1 -A-PG 2 together form C(O)H, C(O)OMe, or [ka] If R 1 and R 2 Neither of are -OH.

[0021] In some embodiments, R 2 teeth, [ka]

[0022] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, R 2 teeth, [ka] It is.

[0023] In some embodiments, PG 1 teeth, [ka] It is.

[0024] In some embodiments, PG 1 teeth [ka] and f is 2.

[0025] In some embodiments, PG 1 teeth [ka] and f is 0.

[0026] In some embodiments, PG 1 teeth [ka] and R 1 is -OH.

[0027] In some embodiments, PG 1 teeth [ka] and R 1 --OR w -Z.

[0028] In some embodiments, PG 1 teeth [ka] and Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, or acyl.

[0029] In some embodiments, PG 1 teeth [ka] and Z is alkyl.

[0030] In some embodiments, PG 1 teeth [ka] and Z is alkynyl or -CH2-alkynyl.

[0031] In some embodiments, PG 1 teeth [ka] And each R z is a C1-C6 branched or unbranched alkyl group. In some embodiments, PG 1 teeth [ka] And each R z is a C1-C3 branched or unbranched alkyl group.

[0032] In some embodiments, PG 1 teeth, [ka] It is.

[0033] In some embodiments, PG 1 teeth, [ka] It is.

[0034] In some embodiments, PG 1 teeth, [ka] It is.

[0035] In some embodiments, PG 1 is -O-CH2-N3.

[0036] In some embodiments, PG 1 is -O-CH-S-CH. In some embodiments, PG 1 is -O-CH2-S-CH3, and Z is alkynyl or -CH2-alkynyl. In some embodiments, PG 1 is --O-CH2-S-CH3 and Z is -CH2-Het.

[0037] In some embodiments, PG 1is -O-CH-CH=CH. In some embodiments, PG 1 is -O-CH-CH=CH. Z is alkynyl or -CH-alkynyl. In some embodiments, PG 1 is -O-CH2-CH=CH2 and Z is -CH2-Het.

[0038] In some embodiments, PG 1 -A-PG 2 together, C(O)H, C(O)OMe, -C(O)OT [ka] Form.

[0039] In some embodiments, R 1 and R 2 are both -OH and PG is

[0040] [ka] -O-CH2-S-CH3, -O-CH2-N3, or -O-CH2-CH=CH2.

[0041] A second aspect of the present disclosure is a compound represented by formula (IIIA) and (IIIB): [ka]

[0042] (In the formula,

[0043] PG is [ka] -CH2-S-CH3, -CH2-N3, or -CH2-CH=CH2;

[0044] f is 0 or 2;

[0045] Each R uare independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl;

[0046] Each R z are independently a branched or unbranched C1-C6 alkyl group).

[0047] A third aspect of the present disclosure is a compound represented by formula (IVA) and (IVB): [ka]

[0048] (In the formula,

[0049] PG is [ka] -CH2-S-CH3, -CH2-N3, or -CH2-CH=CH2;

[0050] f is 0 or 2;

[0051] Each R u are independently H, -O-C1-C4, or -C1-C4;

[0052] Each R z is independently a branched or unbranched C1-C6 alkyl group;

[0053] R x and R y are each independently a branched or unbranched C1-C4 alkyl group).

[0054] A fourth aspect of the present disclosure is a compound represented by formula (VA) and (VB): [ka]

[0055] (In the formula,

[0056] PG is [ka] -CH2-S-CH3, -CH2-N3, or -CH2-CH=CH2;

[0057] R 3 teeth, [ka] or -O-9-phenylthioxanthryl or a derivative or analogue thereof;

[0058] f is 0 or 2;

[0059] Each R u are independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl;

[0060] Each R s are independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl;

[0061] Each R z are independently a branched or unbranched C1-C6 alkyl group).

[0062] A fifth aspect of the present disclosure relates to compounds of formula (VIIA) and (VIIB): [ka]

[0063] (In the formula,

[0064] PG is [ka] -CH2-S-CH3, -CH2-N3, or -CH2-CH2=CH2;

[0065] R 3 teeth, [ka] or -O-9-phenylthioxanthryl or a derivative or analogue thereof;

[0066] Y is alkyl, alkenyl, alkynyl, acyl, -CH2-alkynyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0067] Each R u are independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl;

[0068] Each R s are independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl;

[0069] Each R z is independently a branched or unbranched C1-C6 alkyl group;

[0070] e is an integer ranging from 1 to about 36;

[0071] and f is 0 or 2).

[0072] A sixth aspect of the present disclosure is a compound represented by formula (XA) and (XB): [ka] A compound having any one of the structures

[0073] W is H, -O-CH3 or -OT, where T is a C1-C6 branched or unbranched alkyl group;

[0074] R 7 -OR w -Z, where R wis a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms; Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, acyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety.

[0075] In some embodiments, R 7 Formula (VIIIA) and (VIIIB) [ka] and

[0076] R a and R b are each independently H or a saturated C1-C4 alkyl group;

[0077] Y is alkyl, alkenyl, alkynyl, acyl, -CH2-alkynyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0078] d is an integer ranging from 1 to about 10;

[0079] e is an integer ranging from 1 to about 36.

[0080] A seventh aspect of the present disclosure is a compound represented by formula (XIA) and (XIB): [ka] A compound having any one of the structures W is H, -O-CH3 or -OT, where T is a C1-C6 branched or unbranched alkyl group;

[0081] R 8is -OH, -O-trityl or a derivative or analog thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analog thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analog thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analog thereof, -O-1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, -O-[(chloro-4-methyl)phenyl]-4'-methoxypiperidin-4-yl, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether.

[0082] An eighth aspect of the present disclosure is [ka] [ka] [ka] is a compound selected from

[0083] In the formula, R 3 is 4,4'-dimethoxytrityl ether, 4-methoxytrityl ether, or -O-(9-phenylthioxanthyl), and R 4 is -O-PEG3-Y or -O-PEG4-Y, where Y is methyl, -CH=CH2, or [ka] It is.

[0084] A ninth aspect of the present disclosure is a method for producing a semiconductor device comprising: [ka] [ka] [ka] is a compound selected from

[0085] wherein n ranges from 1 to 24, Y is alkyl, alkenyl, alkynyl, acyl, -CH2-alkynyl, the "click functional group" -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety, and -ODMTr is 4,4'-dimethoxytrityl ether.

[0086] A tenth aspect of the present disclosure is a method for manufacturing a semiconductor device comprising: [ka] [ka] It is.

[0087] In the formula, ODMTr is 4,4'-dimethoxytrityl ether.

[0088] An eleventh aspect of the present disclosure is a compound represented by formula (XIIIA) or (XIIIB): [ka]

[0089] (In the formula,

[0090] R 12a and R 12b are independently -OH, -O-trityl or a derivative or analog thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analog thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analog thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analog thereof, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether;

[0091] R13a and R 13b are independently -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms; Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, acyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0092] R 14a and R 14b is -OH or

[0093] or R 12a and R 14a and / or R 12b and R 14b Let's get together [ka] or

[0094] A twelfth aspect of the present disclosure is a compound represented by the formula (IXA) and (IXB), respectively: [ka]

[0095] (In the formula,

[0096] W is H, -O-CH3, or -OT; T is a C1-C6 branched or unbranched alkyl group;

[0097] R 5is -OH, -O-trityl or a derivative or analogue thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analogue thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analogue thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analogue thereof, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether;

[0098] R 6 -OH, -OR w -Z, where R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms; Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, acyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0099] However, R 5 and R 6 is a compound having either one of the following:

[0100] A thirteenth aspect of the present disclosure is a regioisomeric and enantiomerically pure phosphoramidite-containing monomer derived from any of the compounds of the first through twelfth aspects of the present disclosure. In some embodiments, the present disclosure provides an oligomer, polymer, or copolymer derived from one or more regioisomeric and enantiomerically pure phosphoramidite-containing monomers, which are themselves derived from any of the compounds of the first through tenth aspects of the present disclosure.

[0101] For a general understanding of the features of the present disclosure, reference is made to the drawings, in which like reference numerals are used throughout to identify identical elements. [Brief description of the drawings]

[0102] [Figure 1] FIG. 1 is a 31P NMR spectrum showing the regioisomeric impurities produced during the synthesis outlined in Scheme 2. [Diagram 2] FIG. 2 is a 31P NMR spectrum showing the product recovered according to the process described in Example 1. [Diagram 3] FIG. 3 is a 31P NMR spectrum showing the product recovered according to the process described in Example 2. [Figure 4] FIG. 4 is a 31P NMR spectrum showing the product recovered according to the process described in Example 3. [Diagram 5] FIG. 5 is a 31P NMR spectrum showing the product recovered according to the process described in Example 4. [Figure 6] FIG. 6 is a 31P NMR spectrum showing the product recovered according to the process described in Example 6. [Figure 7] FIG. 7 is a 31P NMR spectrum showing the product recovered according to the process described in Example 14. [Figure 8] FIG. 8 is a 31P NMR spectrum showing the product recovered according to the process described in Example 15. [Figure 9] FIG. 9 is a 31P NMR spectrum showing the product recovered according to the process described in Example 18. [Figure 10] FIG. 10 is a 31P NMR spectrum showing the product recovered according to the process described in Example 19. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0103] It is also to be understood that, unless expressly indicated otherwise, in any method claimed herein that includes two or more steps or actions, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited.

[0104] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. The term "includes" is defined inclusively, such that "including A or B" means including A, B, or A and B.

[0105] As used herein and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., including at least one of an element or list of elements, but also including more than one of an element or list of elements, and optionally including additional items not listed. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," refer to the inclusion of exactly one element of an element or list of elements. In general, the term "or" as used herein shall be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") only when preceded by a term of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0106] As used herein, terms such as "comprising," "including," "having," and the like are used interchangeably and have the same meaning. Similarly, "comprises," "includes," "has," and the like are used interchangeably and have the same meaning. Specifically, each term is defined consistent with the general U.S. patent law definition of "comprising," and therefore is to be interpreted as an open term meaning "at least the following," and not to exclude additional features, limitations, aspects, and the like. Thus, for example, "an apparatus having components a, b, and c" means that the apparatus includes at least components a, b, and c. Similarly, the phrase "a method including steps a, b, and c" means that the method includes at least steps a, b, and c. Additionally, although steps and processes may be outlined in a particular order herein, one of ordinary skill in the art will recognize that the ordering of steps and processes may vary.

[0107] As used herein in the specification and claims, the phrase "at least one" in connection with a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, may optionally be present, whether or not related to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one A, optionally including more than one, with no B (and optionally including elements other than B); in another embodiment to at least one B, optionally including more than one, with no A (and optionally including elements other than A); in yet another embodiment to at least one A, optionally including more than one, and at least one B, optionally including more than one (and optionally including other elements); etc.

[0108] References throughout this specification to "one embodiment" or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in one embodiment" in various places throughout this specification do not necessarily all refer to the same aspect. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0109] As used herein, "C" is a formula in which "a" and "b" are integers. a -C b" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, cycloalkenyl, cycloalkynyl, or aryl group ring, or the total number of carbon atoms and heteroatoms in a heteroalkyl, heterocyclyl, heteroaryl, or heteroalicyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring, aryl ring, heteroaryl ring, or heteroalicyclyl ring can contain from "a" to "b" carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkylcycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heteroalicyclyl group, the broadest range described in these definitions is intended.

[0110] As used herein, the term "acyl" refers to a residue derived from a substituted or unsubstituted acid, including, but not limited to, carboxylic acid, carbamic acid, carbonic acid, sulfonic acid, and phosphorous acid, such as, for example, aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl, aromatic sulfinyl, aliphatic sulfinyl, aromatic phosphate, aliphatic phosphate, and the like.

[0111] As used herein, the term "alkyl" includes saturated aliphatic groups, including straight chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight or branched chain alkyl has 50 or fewer carbon atoms in its backbone (e.g., 1-C for straight chain). 50 , C1-C for branched chain 50 ).

[0112] Moreover, the term alkyl includes both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. An "alkylaryl" or an "arylalkyl" moiety is an alkyl substituted with an aryl (eg, phenylmethyl (benzyl)).

[0113] As used herein, the term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl- or alkenyl-substituted cycloalkenyl groups, and cycloalkyl- or cycloalkenyl-substituted alkenyl groups. The term alkenyl further includes alkenyl groups that contain oxygen, nitrogen, sulfur, or phosphorus atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, straight-chain or branched-chain alkenyl groups have 50 or fewer carbon atoms in their backbone (e.g., C2-C4 for straight chain). 50 , C3-C for branched chain 50 ).

[0114] Moreover, the term alkenyl includes both "unsubstituted alkenyls" and "substituted alkenyls," the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl groups, alkenyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0115] Other examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-l-butenyl, 2-methyl-l-butenyl, 3-methyl-l-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-l-pentenyl, 2-methyl-l-pentenyl, 3-methyl-l-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl , 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3- Butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,Examples of double bonds that may be included include, but are not limited to, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl groups. Groups that contain multiple double bonds may include, but are not limited to, buta-1,3-dienyl, penta-1,3-dienyl, or penta-1,4-dienyl groups.

[0116] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl- or cycloalkenyl-substituted alkynyl groups. The term alkynyl further includes alkynyl groups which contain oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In some embodiments, a straight-chain or branched-chain alkenyl group has 50 or fewer carbon atoms in its backbone (e.g., C2-C4 for straight chain). 50 , C3-C for branched chain 50 ).

[0117] Moreover, the term alkynyl includes both "unsubstituted alkynyls" and "substituted alkynyls," the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl groups, alkenyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Groups containing multiple triple bonds can include, but are not limited to, buta-1,3-diynyl, penta-1,3-diynyl or penta-1,4-diynyl groups.

[0118] As used herein, "analog" or "derivative" is used according to its plain and ordinary meaning in chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, for example, in the replacement of an atom with an atom of a different element, or in the presence of a particular functional group, or in the replacement of one functional group with another, or in the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but not similar or equivalent in structure or origin.

[0119] As used herein, the terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, refer to cyclic versions of "alkyl" and "heteroalkyl", respectively, unless otherwise stated. In some embodiments, "heterocycloalkyl" is also referred to as a "heterocyclic" group or moiety. Cycloalkyls and heterocycloalkyls are not aromatic. Cycloalkyls and heterocycloalkyls can be further substituted, e.g., with any of the substituents described herein.

[0120] Each term (e.g., "alkyl," "aromatic," "heteroalkyl," "cycloalkyl," "heterocyclic," etc.) includes both substituted and unsubstituted forms of the indicated radical. In that regard, whenever a group or moiety is described as "substituted" or "optionally substituted" (or "optionally having" or "optionally containing"), the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as being "substituted or unsubstituted," if the group is substituted, the substituents can be selected from one or more of the indicated substituents. If no substituents are indicated, the indicated "optionally substituted" or "substituted" group can be any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, cyanato, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N ... It means that the moiety may be substituted with one or more groups individually and independently selected from octyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, ether, amino (e.g., mono- or di-substituted amino groups), and protected derivatives thereof. Any of the above groups may contain one or more heteroatoms, including O, N, or S. For example, when a moiety is substituted with an alkyl group, the alkyl group may contain a heteroatom selected from O, N, or S (e.g., -(CH2-CH2-O-CH2-CH3)).

[0121] As used herein, the term "heteroatom" is meant to include boron (B), oxygen (O), nitrogen (N), sulfur (S), phosphorus (P) and silicon (Si). As described herein, in some embodiments, a "heterocycle" can contain one or more heteroatoms. In other embodiments, an aliphatic group can contain or be substituted with one or more heteroatoms.

[0122] As used herein, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, where the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyls are not cyclized. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-O-CH3, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH-CH-O-CH3, -Si(CH3)3, -CH2-CH-N-OCH3, -CH-CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3.

[0123] As used herein, the term "couple" or "coupling" refers to the joining, bonding (e.g., covalent bonding), or linking of one molecule or atom to another molecule or atom.

[0124] As used herein, the term "leaving group" refers to any group that is a conjugate base of a strong acid.Leaving groups useful in the present invention include, but are not limited to, halogen, alkylsulfonyl, substituted alkylsulfonyl, arylsulfonyl, substituted arylsulfonyl, heterocyclosulfonyl or trichloroacetimidate.In some embodiments, the leaving group is chloro, fluoro, bromo, iodo, p-(2,4-dinitroanilino)benzenesulfonyl, benzenesulfonyl, methylsulfonyl (mesylate), p-methylbenzene-sulfonyl (tosylate), p-bromobenzenesulfonyl, trifluoromethyl-sulfonyl (triflate), trichloroacetimidate, acyloxy, 2,2,2-trifluoroethanesulfonyl, imidazolesulfonyl and 2,4,6-trichlorophenyl, with chloro being preferred.

[0125] As used herein, the term "phosphoramidite" refers to the trivalent phosphorus group typically used in oligonucleotide synthesis.The detailed description of the chemistry used to form oligonucleotides by phosphoramidite method is provided in U.S. Patent No. 4,458,066 and No. 4,415,732 to Caruthers et al.; Caruthers et al., Genetic Engineering, 4:1-17 (1982); Users Manual Model 392 and 394 Polynucleotide Synthesizers, pages 6-1 through 6-22, Applied Biosystems, Part No. 901237 (1991) (each of which is incorporated herein by reference in its entirety).

[0126] As used herein, the term "protecting group" refers to a moiety that, when attached to a reactive group in a molecule, masks, reduces or prevents the reactivity. A "protected" molecule has one or more reactive groups (e.g., hydroxyl, amino, thiol, etc.) protected by a protecting group. Examples of protecting groups can be found in TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley&Sons, New York, 1999, Harrison and Harrison et al. Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996), and "Protection of Nucleosides for Oligonucleotide Synthesis," Current Protocols in Nucleic Acid Chemistry, ed. by Boyle, AL, John Wiley&Sons, Inc., 2000, New York, NY (all of which are incorporated herein by reference in their entirety).Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl (BOC), isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl (Alloc), acetyl (Ac), formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl (Bz), methyl, t-butyl, 2,2,2-trichloroacetyl ... Examples of substituted or unsubstituted aryl groups include, but are not limited to, diphenylethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (Bn), para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), 4,4'-dimethoxytriphenylmethyl (DMT), substituted or unsubstituted 9-(9-phenyl)xanthenyl (pixyl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.

[0127] As used herein, the term "reactive group" or "reactive functional group" refers to a functional group that can chemically associate, interact, hybridize, hydrogen bond, or couple with a functional group of a different moiety. In some embodiments, a "reaction" between two reactive groups or two reactive functional groups can mean that a covalent bond is formed between the two reactive groups or two reactive functional groups, or that the two reactive groups or two reactive functional groups associate with each other, interact with each other, hybridize with each other, hydrogen bond with each other, etc. Thus, in some embodiments, a "reaction" includes a binding event, such as the binding of a hapten with an anti-hapten antibody, or a guest molecule binding to a supramolecular host molecule.

[0128] As used herein, the symbols [ka] refers to the position where one moiety is attached to another moiety.

[0129] As used herein, the abbreviations "DMT" or "DMTr" (used interchangeably) refer to the chemical structure [ka] 4,4 ’ -refers to dimethoxytrityl.

[0130] overview The present disclosure relates to a process for the regiochemically and enantiomerically controlled synthesis of phosphoramidite-containing monomers, as well as intermediate products of the process. In some embodiments, the phosphoramidite-containing monomers are derived from polyols, such as glycerol, mannitol, erythrulose, dihydroxypropanal or dihydroxypropanoate, or derivatives or analogs thereof. In some embodiments, the phosphoramidite-containing monomers are at least 97% regioisomerically and / or enantiomerically pure. In other embodiments, the phosphoramidite-containing monomers are at least 98% regioisomerically and / or enantiomerically pure. In still other embodiments, the phosphoramidite-containing monomers are at least 99% regioisomerically and / or enantiomerically pure. In some embodiments, an oligomer, polymer, or copolymer, such as an oligomer, polymer, or copolymer incorporated into an XNTP molecule, may be derived from one or more phosphoramidite-containing monomers (see PCT Publication No. WO 2020 / 236526, which provides examples of phosphoramidite-containing monomers, the disclosure of which is incorporated by reference in its entirety herein).

[0131] In some embodiments, the intermediates described herein include a protecting group that includes a methylene group (-CH2-) between the protected alcohol and the remaining portion of the protecting group moiety. As an example, -CH2-N3 can be used as a protecting group, where the -CH2-N3 moiety includes a methylene group between the protected alcohol and the azide. Non-limiting examples of other protecting groups that meet this criteria are described herein.

[0132] In some embodiments, the protecting group is selected such that its incorporation and subsequent removal provides an isomerization-free product, i.e., at least 97% regioisomerically and / or enantiomerically pure product, at least 98% regioisomerically and / or enantiomerically pure product, or at least 99% regioisomerically and / or enantiomerically pure product. In some embodiments, the protecting group is selected such that it is not mobile in subsequent downstream reactions or transformations. In some embodiments, the protecting group is selected such that during the course of the protection, transformation and deprotection reactions, the protecting group and the reagents utilized do not cause racemization of other carbon atoms in any starting material or intermediates subsequently synthesized, for example, racemization of secondary carbon atoms in polyols such as glycerol, mannitol, erythrulose, dihydroxypropanal or dihydroxypropanoate starting materials.

[0133] In some embodiments, the protecting group is selected from those that are stable in subsequent synthetic steps. For example, the protecting group is selected from those that are (i) primarily stable under mild to moderate acidic conditions, and / or (ii) stable under basic and alkylation conditions. In some embodiments, the protecting group is selected to allow medium to high yields in subsequent substitution reactions with long and / or bulky side chains, such as polyalkylene oxides (e.g., polyalkylene oxide linkers), alkyl, acyl, alkenyl or alkynyl side chains or derivatives or analogs thereof. In some embodiments, the protecting group is selected to be completely removable without significant decomposition or conversion of other functional groups in the protected molecule, such as base-labile esters, acid-labile trityl-protected alcohols, or oxidation-sensitive polyalkylene oxide-linkers (e.g., polyalkylene oxide linkers).

[0134] Suitable protecting groups meeting one or more of the above criteria are described in Wuts, PGM, & Greene, TW (2007). Greene's protective groups in organic synthesis, fourth edition (4th ed.) Wiley-Interscience; TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 5; E. Haslam, "Protective Groups in Organic Chemistry," JGW MacOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and TW Greene, "Protective Groups in Organic Synthesis," John Wiley and Sons, New York, NY, 1981, Chapter 5, the disclosures of which are incorporated herein by reference in their entireties.

[0135] Intermediates for the synthesis of phosphoramidite-containing monomers

[0136] One aspect of the present disclosure is intermediates useful for the synthesis of phosphoramidite-containing monomers. Examples of phosphoramidite-containing monomers are shown in formulas (VIIIA)-(VIIID). In some embodiments, the phosphoramidite-containing monomer intermediates disclosed herein are substantially regioisomerically and / or enantiomerically pure, i.e., at least 97% regioisomerically and / or enantiomerically pure, at least 98% regioisomerically and / or enantiomerically pure, or at least 99% regioisomerically and / or enantiomerically pure.

[0137] In some embodiments, intermediates in the synthesis of phosphoramidite-containing monomers have formulas (IA) and (IB): [ka]

[0138] (In the formula,

[0139] R 1 -OH, -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms; Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, acyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0140] R 2is -OH, -O-trityl or a derivative or analog thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analog thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analog thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analog thereof, -O-1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, -O-[(chloro-4-methyl)phenyl]-4'-methoxypiperidin-4-yl, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether;

[0141] A is CH,

[0142] PG 2 is H,

[0143] PG 1 teeth, [ka] -O-CH2-S-CH3, -O-CH2-N3, or -O-CH2-CH=CH2, or

[0144] PG 1 -A-PG 2 are combined to form C(O)H, C(O)OMe, -C(O)OT, [ka] Forming

[0145] T is a C1-C6 branched or unbranched alkyl group;

[0146] f is 0 or 2;

[0147] Each R u are independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl;

[0148] Each R z is independently a branched or unbranched C1-C6 alkyl group;

[0149] However, P.G. 1 -A-PG 2 together form C(O)H, C(O)OMe or [ka] If R 1 and R 2 are not both -OH) The compound has any one of the following structures:

[0150] In some embodiments, PG 1 -A-PG 2 teeth, [ka] and R 2 is -O-trityl or a derivative or analog thereof. 1 -A-PG 2 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH. In some embodiments, PG 1 -A-PG 2 teeth [ka] and R 2 is -O-pixil or a derivative or analog thereof. 1 -A-PG 2 teeth, [ka] and R 2 is -O-pixyl or a derivative or analogue thereof, and R1 is -OH.

[0151] In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH.

[0152] In some embodiments, PG 1 teeth, [ka] and R 2 is -O-pixyl or a derivative or analog thereof. In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH.

[0153] In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and PG 1 is one R u R u The group is -CH. In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH and PG 1 is one R u R u The group is -CH3.

[0154] In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH.

[0155] In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH.

[0156] In some embodiments, PG 1 teeth, [ka] and R 2 is -O-pixyl or a derivative or analog thereof. In some embodiments, PG 1 teeth, [ka] and R 2 is -O-pixyl or a derivative or analogue thereof, and R 1 is -OH.

[0157] In some embodiments, PG 1 is --O-CH2-N3, R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG is -O-CH-N and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH. In some embodiments, PG 1 is -O-CH2-N3, R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG 1 is -O-CH2-N3. 2 is -O-pixyl or a derivative or analogue thereof, and R 1 is -OH.

[0158] In some embodiments, PG 1 is -O-CH2-S-CH3, and R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG is -O-CH-S-CH and R 2 is -O-trityl or a derivative or analogue thereof; R 1 is -OH. In some embodiments, PG 1 is -O-CH2-S-CH3, and R 2 is -O-pixyl or a derivative or analog thereof. In some embodiments, PG 1 is --O-CH2-S-CH3, and R 2is -O-pixyl or a derivative or analogue thereof, and R 1 is -OH.

[0159] In some embodiments, PG 1 is -O-CH2-CH=CH2, and R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG 1 is -O-CH2-CH=CH2, and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH. In some embodiments, PG 1 is -O-CH2-CH=CH2, and R 2 is -O-pixyl or a derivative or analog thereof. In some embodiments, PG 1 is -O-CH2-CH=CH2, and R 2 is -O-pixyl or a derivative or analogue thereof, and R 1 is -OH.

[0160] In some embodiments, PG 1 -A-PG 2 is C(O)H or C(O)OMe, and R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG 1 -A-PG 2 is C(O)H or C(O)OMe, and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH. In some embodiments, PG 1 -A-PG 2 is C(O)H or C(O)OMe, and R 2 is -O-pixyl or a derivative or analog thereof. In some embodiments, PG 1 -A-PG 2 is C(O)H or C(O)OMe, and R 2 is -O-pixyl or a derivative or analogue thereof, and R 1 is -OH.

[0161] In some embodiments, PG 1 -A-PG 2 teeth, [ka] and R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG 1 -A-PG 2 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH. In some embodiments, PG 1 -A-PG 2 teeth, [ka] and R 2 is -O-pixyl or a derivative or analog thereof. In some embodiments, PG 1 -A-PG 2 teeth, [ka] and R 2 is -O-pixyl or a derivative or analogue thereof, and R 1 is -OH.

[0162] In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analog thereof. In some embodiments, PG 1 teeth, [ka] and R 2 is -O-trityl or a derivative or analogue thereof, and R 1 is -OH.

[0163] In some embodiments, PG 1 teeth, [ka] and R 2 is -O-pixyl or a derivative or analog thereof. In some embodiments, PG 1 teeth, [ka] and R 2 is -O-pixyl or a derivative or analogue thereof, and R 1 is -OH.

[0164] In some embodiments, PG 1 teeth [ka] and f is 0. In some embodiments, PG 1 teeth [ka] where f is 0 and R 2 is -O-trityl. In some embodiments, PG 1 teeth [ka] where f is 0 and R 2 is -O-trityl and R 1 is -OH.

[0165] In another embodiment, PG 1 teeth [ka] and f is 2. In some embodiments, PG 1 teeth [ka] where f is 2 and R 2 is -O-trityl. In some embodiments, PG 1 teeth [ka] where f is 2 and R 2 is -O-trityl and R 1 is -OH. In some embodiments, PG 1 teeth [ka] where f is 0 and R z is a branched or unbranched C1-C6 group.

[0166] In another embodiment, PG 1 teeth [ka] where f is 2 and R z is a branched or unbranched C1-C6 group.

[0167] In some embodiments, PG 1 teeth [ka] where f is 0 and R z is a branched or unbranched C1-C6 group.

[0168] In some embodiments, PG 1 teeth [ka] where f is 0 and R z is a branched or unbranched C1-C3 group.

[0169] In another embodiment, PG 1 teeth [ka] where f is 2 and R z is a branched or unbranched C1-C6 group.

[0170] In another embodiment, PG 1 teeth [ka] where f is 2 and R z is a branched or unbranched C1-C3 group.

[0171] In some embodiments, R 2 The structure [ka]

[0172] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s is independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. In some embodiments, each R s is independently selected from H, -O-CH3, or -CH3.

[0173] In some embodiments, R 2 The structure [ka]

[0174] (In the formula, each R sis independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s is independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. In some embodiments, each R s is independently selected from H, -O-CH3, or -CH3.

[0175] In some embodiments, R 2 The structure [ka] It is.

[0176] In some embodiments, R 2 is -O-pixil or a derivative or analog thereof. Non-limiting examples of derivatives or analogs of the pixil moiety are described in U.S. Patent Application Publication No. 2007 / 0276139, the disclosure of which is incorporated herein by reference in its entirety.

[0177] In some embodiments, R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 2 to 80 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 2 to 60 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 48 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 24 carbon atoms, optionally containing one or more oxygen heteroatoms.w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 12 carbon atoms, optionally containing one or more oxygen heteroatoms.

[0178] In some embodiments, R w is an unsubstituted alkyl moiety having 2 to 80 carbon atoms and optionally containing one or more oxygen heteroatoms. w is an unsubstituted alkyl moiety having 2 to 60 carbon atoms and optionally containing one or more oxygen heteroatoms. w is an unsubstituted alkyl moiety having 4 to 48 carbon atoms and optionally containing one or more oxygen heteroatoms. w is an unsubstituted alkyl moiety having 4 to 24 carbon atoms and optionally containing one or more oxygen heteroatoms. In some embodiments, R w is an unsubstituted alkyl moiety having from 4 to 12 carbon atoms and optionally containing one or more oxygen heteroatoms.

[0179] In some embodiments, R w comprises at least 1 polyethylene glycol group ("PEG"), at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups.

[0180] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an alkyl group, e.g., a C1-C4 alkyl group, methyl or ethyl.

[0181] In some embodiments, R wcomprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an alkenyl group, e.g., -CH=CH2 or -CH2-CH=CH2.

[0182] In some embodiments, R w comprises at least one PEG group, at least two PEG groups, at least three PEG groups, at least four PEG groups, at least eight PEG groups, at least twelve PEG groups, or at least twenty-four PEG groups, and Z is an alkenyl group, e.g. [ka] It is.

[0183] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an acyl group.

[0184] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z comprises a substituted heterocyclic moiety. In some embodiments, the heterocyclic moiety is substituted with an alkylaryl group. In some embodiments, the substituted heterocyclic moiety comprises a triazole. In some embodiments, the triazole is substituted with an alkylaryl group. In some embodiments, the triazole is substituted with -CH2-CH2-O-Ph. In some embodiments, the triazole is substituted with -CH2-CH2-O-Bz.

[0185] In some embodiments, the "click functional group" is selected from DBCO, TCO, maleimide, -N3, tetrazine, thiol, 1,3-nitrone, hydrazine, and hydroxylamine.

[0186] In some embodiments, the compounds of formula (IA) and (IB) are regioisomerically and / or enantiomerically pure, for example at least 97%, at least 98%, at least 99% regioisomerically and / or enantiomerically pure.

[0187] In some embodiments, intermediates in the synthesis of phosphoramidite-containing monomers have formulas (IIA) and (IIB): [ka]

[0188] (In the formula,

[0189] PG is [ka] CH2-S-CH3, -CH2-N3, or -CH2-CH=CH2;

[0190] R 1 -OH, -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms; Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, acyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0191] R 2is -OH, -O-trityl or a derivative or analogue thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analogue thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analogue thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analogue thereof, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether;

[0192] or R 1 and R 2 taken together to form a substituted or unsubstituted 5-membered ring,

[0193] f is 0 or 2;

[0194] Each R u are independently H, -O-C1-C4 alkyl or -C1-C4 alkyl;

[0195] Each R z are independently a branched or unbranched C1-C6 alkyl group).

[0196] In some embodiments, the "click functional group" is selected from DBCO, TCO, maleimide, -N3, tetrazine, thiol, 1,3-nitrone, hydrazine, and hydroxylamine.

[0197] In some embodiments, PG is [ka] and f is 0. In another embodiment, PG is [ka] and f is 2.

[0198] In some embodiments, PG is [ka] where f is 0 and R z is a branched or unbranched C1-C3 group. In another embodiment, PG is [ka] where f is 2 and R z is a branched or unbranched C1-C6 group. In another embodiment, PG is [ka] where f is 2 and R z is a branched or unbranched C1-C3 group.

[0199] In some embodiments, PG is [ka] It is.

[0200] In some embodiments, PG is [ka] It is.

[0201] In some embodiments, R 2 The structure [ka]

[0202] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s is independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. In some embodiments, each Rs is independently selected from H, -O-CH3, or -CH3.

[0203] In some embodiments, R 2 The structure [ka]

[0204] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s are independently H, -OC 1 In some embodiments, each R s are independently H, -O-CH 3 or -CH3.

[0205] In some embodiments, R 2 The structure [ka] It is.

[0206] In some embodiments, R 2 is pixil or a derivative or analog thereof. Non-limiting examples of pixil derivatives or analogs are described in U.S. Patent Application Publication No. 2007 / 0276139, the disclosure of which is incorporated herein by reference in its entirety.

[0207] In some embodiments, R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 2 to 80 carbon atoms, optionally containing one or more oxygen heteroatoms. wis a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 2 to 60 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 48 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 24 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 12 carbon atoms, optionally containing one or more oxygen heteroatoms.

[0208] In some embodiments, R w is an unsubstituted alkyl moiety having 2 to 80 carbon atoms and optionally containing one or more oxygen heteroatoms. w is an unsubstituted alkyl moiety having 2 to 60 carbon atoms and optionally containing one or more oxygen heteroatoms. w is an unsubstituted alkyl moiety having 4 to 48 carbon atoms and optionally containing one or more oxygen heteroatoms. w is an unsubstituted alkyl moiety having 4 to 24 carbon atoms and optionally containing one or more oxygen heteroatoms. In some embodiments, R w is an unsubstituted alkyl moiety having from 4 to 12 carbon atoms and optionally containing one or more oxygen heteroatoms.

[0209] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups.

[0210] In some embodiments, R wcomprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an alkenyl group, e.g., -CH=CH2 or -CH2-CH=CH2.

[0211] In some embodiments, R w comprises at least one PEG group, at least two PEG groups, at least three PEG groups, at least four PEG groups, at least eight PEG groups, at least twelve PEG groups, or at least twenty-four PEG groups, and Z is an alkenyl group, e.g. [ka] It is.

[0212] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an acyl group.

[0213] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z comprises a substituted heterocyclic moiety. In some embodiments, the heterocyclic moiety is substituted with an alkylaryl group. In some embodiments, the substituted heterocyclic moiety comprises a triazole. In some embodiments, the triazole is substituted with an alkylaryl group. In some embodiments, the triazole is substituted with -CH2-CH2-O-Ph. In some embodiments, the triazole is substituted with -CH2-CH2-O-Bz.

[0214] In some embodiments, the intermediates of formula (IIA) and (IIB) are represented by formula (IIIA) and (IIIB), respectively: [ka]

[0215] where PG is as defined above.

[0216] Non-limiting examples of compounds having any one of formulas (IIIA) or (IIIB) include the following: [ka] [ka]

[0217] In some embodiments, the intermediates of formula (IIA) and (IIB) are represented by formula (IVA) and (IVB), respectively: [ka]

[0218] where PG is as defined above,

[0219] R x and R y are independently a C1-C4 branched or unbranched alkyl group.

[0220] In some embodiments, R x and R y are each independently a C1-C2 alkyl group. In some embodiments, R x and R y are both methyl.

[0221] In some embodiments, the intermediates of formula (IIA) and (IIB) have the formula (VA) and (VB), respectively: [ka]

[0222] (wherein PG is as defined above and R 3 is -O-trityl or a derivative or analog thereof, or -O-pixyl or a derivative or analog thereof).

[0223] In some embodiments, R 3 The structure [ka]

[0224] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s is independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. In some embodiments, each R s is independently selected from H, -O-CH3, or -CH3.

[0225] In some embodiments, R 3 The structure [ka]

[0226] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s is independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. In some embodiments, each Rs is independently selected from H, -O-CH3, or -CH3.

[0227] In some embodiments, R 3 The structure [ka] It is.

[0228] Non-limiting examples of compounds having any one of formulas (VA) or (VB) include the following: [ka] [ka]

[0229] (In the formula, R 3 is 4,4'-dimethoxytrityl ether, 4-methoxytrityl ether, or -O-(9-phenylthioxanthyl).

[0230] In some embodiments, the intermediates of formula (IIA) and (IIB) have the formula (VIA) and (VIB), respectively: [ka]

[0231] where PG is as defined above and R 3 is -O-trityl or a derivative or analogue thereof, or -O-pixyl or a derivative or analogue thereof, and R 4 Formula (XIIIA) and (XIIIB) [ka]

[0232] During the ceremony,

[0233] R a and Rb are independently H or C1-C4 alkyl;

[0234] Y is alkyl, alkenyl, alkynyl, acyl, -CH2-alkynyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0235] d is an integer ranging from 1 to about 10;

[0236] and e is an integer ranging from 1 to about 36.

[0237] In some embodiments, d is an integer ranging from 1 to about 8. In other embodiments, d is an integer ranging from 1 to about 6. In yet other embodiments, d is an integer ranging from 1 to about 2. In a further embodiment, d is 2. In yet a further embodiment, d is 1.

[0238] In some embodiments, e is an integer ranging from 1 to about 24. In other embodiments, e is an integer ranging from 1 to about 20. In still other embodiments, e is an integer ranging from 1 to about 16. In further embodiments, e is an integer ranging from 1 to about 12. In still further embodiments, e is an integer ranging from 1 to about 8. In still further embodiments, e is an integer ranging from 1 to about 4. In still further embodiments, e is 12. In still further embodiments, e is 8. In still further embodiments, e is 4. In still further embodiments, e is 2.

[0239] In some embodiments, d is 1 and e is an integer ranging from 1 to 24. In some embodiments, d is 1 and e is an integer ranging from 1 to 12. In some embodiments, d is 1 and e is an integer ranging from 1 to 8. In some embodiments, d is 1 and e is an integer ranging from 1 to 4.

[0240] In some embodiments, Y is substituted with an alkylaryl group. In some embodiments, the substituted heterocyclic moiety comprises a triazole. In some embodiments, the triazole is substituted with an alkylaryl group. In some embodiments, the triazole is substituted with -CH2-CH2-O-Ph. In some embodiments, the triazole is substituted with -CH2-CH2-O-Bz.

[0241] In some embodiments, d is 1, e is an integer ranging from 1 to 24, and Y is alkynyl or -CH2-alkynyl. In some embodiments, d is 1, e is an integer ranging from 1 to 12, and Y is alkynyl or -CH2-alkynyl. In some embodiments, d is 1, e is an integer ranging from 1 to 8, and Y is alkynyl or -CH2-alkynyl. In some embodiments, d is 1, e is an integer ranging from 1 to 4, and Y is alkynyl or -CH2-alkynyl.

[0242] In some embodiments, d is 2, e is an integer ranging from 1 to 24, and Y is alkynyl or -CH2-alkynyl. In some embodiments, d is 2, e is an integer ranging from 1 to 12, and Y is alkynyl or -CH2-alkynyl. In some embodiments, d is 2, e is an integer ranging from 1 to 8, and Y is alkynyl or -CH2-alkynyl. In some embodiments, d is 2, e is an integer ranging from 1 to 4, and Y is alkynyl or -CH2-alkynyl.

[0243] In some embodiments, d is 1, e is an integer ranging from 1 to 24, and Y is alkenyl. In some embodiments, d is 1, e is an integer ranging from 1 to 12, and Y is alkenyl. In some embodiments, d is 1, e is an integer ranging from 1 to 8, and Y is alkenyl. In some embodiments, d is 1, e is an integer ranging from 1 to 4, and Y is alkenyl.

[0244] In some embodiments, d is 1, e is an integer ranging from 1 to 24, and Y is alkyl. In some embodiments, d is 1, e is an integer ranging from 1 to 12, and Y is alkyl. In some embodiments, d is 1, e is an integer ranging from 1 to 8, and Y is alkyl. In some embodiments, d is 1, e is an integer ranging from 1 to 4, and Y is alkyl.

[0245] In some embodiments, d is 1, e is an integer ranging from 1 to 24, and Y is a substituted 5-membered heterocyclic moiety. In some embodiments, d is 1, e is an integer ranging from 1 to 12, and Y is a substituted 5-membered heterocyclic moiety. In some embodiments, d is 1, e is an integer ranging from 1 to 8, and Y is a substituted 5-membered heterocyclic moiety. In some embodiments, d is 1, e is an integer ranging from 1 to 4, and Y is a substituted 5-membered heterocyclic moiety.

[0246] In some embodiments, R 3 The structure [ka]

[0247] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s is independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. In some embodiments, each R s is independently selected from H, -O-CH3, or -CH3.

[0248] In some embodiments, R 3 The structure [ka]

[0249] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s is independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. In some embodiments, each R s is independently selected from H, -O-CH3, or -CH3.

[0250] In some embodiments, R 3 The structure [ka] It is.

[0251] Non-limiting examples of compounds having any one of formulas (VIA) or (VIB) include: [ka] [ka]

[0252] (In the formula, R 3 is 4,4'-dimethoxytrityl ether, 4-methoxytrityl ether, or -O-(9-phenylthioxanthyl), and R 4 -O-PEG2-Y, -O-PEG3-Y, -O-PEG4-Y, -O-PEG8-Y, -O-PEG 12 -Y, or -O-PEG 24 -Y, where Y is methyl, -CH=CH2, [ka] or a substituted or unsubstituted 5-membered heterocyclic moiety.

[0253] In some embodiments, the intermediates of formula (IIA) and (IIB) are represented by formula (VIIA) and (VIIB), respectively: [ka]

[0254] (Wherein, PG, Y, R 3 and e is as defined above.

[0255] In some embodiments, e is an integer ranging from 1 to about 24. In other embodiments, e is an integer ranging from 1 to about 20. In still other embodiments, e is an integer ranging from 1 to about 16. In further embodiments, e is an integer ranging from 1 to about 12. In still further embodiments, e is an integer ranging from 1 to about 8. In still further embodiments, e is an integer ranging from 1 to about 4. In still further embodiments, e is 2.

[0256] In some embodiments, e is an integer ranging from 1 to about 24 and Y is an alkynyl group, e.g., [ka] In another embodiment, e is an integer ranging from 1 to about 20 and Y is an alkynyl group, e.g., [ka] In yet other embodiments, e is an integer ranging from 1 to about 16 and Y is an alkynyl group, e.g. [ka] In further embodiments, e is an integer ranging from 1 to about 12 and Y is an alkynyl group, e.g. [ka] In still further embodiments, e is an integer ranging from 1 to about 8 and Y is an alkynyl group, e.g. [ka] In still further embodiments, e is an integer ranging from 1 to about 4 and Y is an alkynyl group, e.g. [ka] In still further embodiments, e is an integer ranging from 1 to about 3 and Y is an alkynyl group, e.g. [ka] In still further embodiments, e is 2 and Y is an alkynyl group, e.g. [ka] It is.

[0257] In some embodiments, e is an integer ranging from 1 to about 24 and Y is an alkyl group. In other embodiments, e is an integer ranging from 1 to about 20 and Y is an alkyl group (e.g., -CH3). In still other embodiments, e is an integer ranging from 1 to about 16 and Y is an alkyl group. In further embodiments, e is an integer ranging from 1 to about 12 and Y is an alkyl group. In still further embodiments, e is an integer ranging from 1 to about 8 and Y is an alkyl group. In still further embodiments, e is an integer ranging from 1 to about 4 and Y is an alkyl group. In still further embodiments, e is 2 and Y is an alkyl group.

[0258] In some embodiments, e is an integer ranging from 1 to about 24, and Y is a methyl group. In other embodiments, e is an integer ranging from 1 to about 20, and Y is a methyl group. In still other embodiments, e is an integer ranging from 1 to about 16, and Y is a methyl group. In further embodiments, e is an integer ranging from 1 to about 12, and Y is a methyl group. In still further embodiments, e is an integer ranging from 1 to about 8, and Y is a methyl group. In still further embodiments, e is an integer ranging from 1 to about 4, and Y is a methyl group. In still further embodiments, e is 2, and Y is a methyl group.

[0259] In some embodiments, e is an integer ranging from 1 to about 24, and Y is an alkenyl group. In other embodiments, e is an integer ranging from 1 to about 20, and Y is an alkenyl group. In still other embodiments, e is an integer ranging from 1 to about 16, and Y is an alkenyl group. In further embodiments, e is an integer ranging from 1 to about 12, and Y is an alkenyl group. In still further embodiments, e is an integer ranging from 1 to about 8, and Y is an alkenyl group. In still further embodiments, e is an integer ranging from 1 to about 4, and Y is an alkenyl group. In still further embodiments, e is 2, and Y is an alkenyl group.

[0260] In some embodiments, e is an integer ranging from 1 to about 24, and Y is an acyl group. In other embodiments, e is an integer ranging from 1 to about 20, and Y is an acyl group. In still other embodiments, e is an integer ranging from 1 to about 16, and Y is an acyl group. In further embodiments, e is an integer ranging from 1 to about 12, and Y is an acyl group. In still further embodiments, e is an integer ranging from 1 to about 8, and Y is an acyl group. In still further embodiments, e is an integer ranging from 1 to about 4, and Y is an acyl group. In still further embodiments, e is 2, and Y is an acyl group.

[0261] In some embodiments, intermediates of formula (II)-(VII) may be utilized in the synthesis of phosphoramidite-containing monomers having the structure of any one of formulas (VIIIA)-(VIIID). [ka]

[0262] (In the formula, Y, R 3 , R 4 and e is as defined above, and PPA is a phosphoramidite species).

[0263] In some embodiments, the trans diastereomer is [ka]

[0264] (In the formula, R 9 is a substituted or unsubstituted C1-C6 alkyl group terminating in a cyano moiety, R 10 and R 11 are independently a branched or unbranched C1-C6 alkyl group.

[0265] In some embodiments, intermediates in the synthesis of phosphoramidite-containing monomers of formula (IA) and (IB) have formula (IXA) and (IXB), respectively. [ka]

[0266] During the ceremony,

[0267] W is H, -O-CH3, or -OT; T is a C1-C6 branched or unbranched alkyl group;

[0268] R 5 is -OH, -O-trityl or a derivative or analogue thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analogue thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analogue thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analogue thereof, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether;

[0269] R 6 -OH, -OR w -Z and R wis a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms; Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, acyl, a "click functional group", -Het, -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0270] However, R 5 and R 6 are not both -OH).

[0271] In some embodiments, W is H.

[0272] In some embodiments, W is -O-CH3.

[0273] In some embodiments, the "click functional group" is selected from DBCO, TCO, maleimide, -N3, tetrazine, thiol, 1,3-nitrone, hydrazine, and hydroxylamine.

[0274] In some embodiments, R 5 or 9-phenylthioxanthryl or a derivative or analogue thereof.

[0275] In some embodiments, R 5 is --O-trityl or a derivative or analog thereof.

[0276] In some embodiments, R 5 The structure [ka]

[0277] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R sis independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. In some embodiments, R s are each independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. s is independently selected from H, -O-CH3, or -CH3.

[0278] In some embodiments, R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 2 to 80 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 2 to 60 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 48 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 24 carbon atoms, optionally containing one or more oxygen heteroatoms. w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl moiety having 4 to 12 carbon atoms, optionally containing one or more oxygen heteroatoms.

[0279] In some embodiments, R w is an unsubstituted alkyl moiety having 2 to 80 carbon atoms and optionally containing one or more oxygen heteroatoms. w is an unsubstituted alkyl moiety having 2 to 60 carbon atoms and optionally containing one or more oxygen heteroatoms. w is an unsubstituted alkyl moiety having 4 to 48 carbon atoms and optionally containing one or more oxygen heteroatoms. wis an unsubstituted alkyl moiety having 4 to 24 carbon atoms and optionally containing one or more oxygen heteroatoms. In some embodiments, R w is an unsubstituted alkyl moiety having from 4 to 12 carbon atoms and optionally containing one or more oxygen heteroatoms.

[0280] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups.

[0281] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an alkyl group, e.g., a C1-C4 alkyl group, methyl or ethyl.

[0282] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an alkenyl group, e.g., -CH=CH2 or -CH2-CH=CH2.

[0283] In some embodiments, R w comprises at least one PEG group, at least two PEG groups, at least three PEG groups, at least four PEG groups, at least eight PEG groups, at least twelve PEG groups, or at least twenty-four PEG groups, and Z is an alkenyl group, e.g. [ka] It is.

[0284] In some embodiments, Rw comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an acyl group.

[0285] In some embodiments, R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z comprises a substituted heterocyclic moiety. In some embodiments, the heterocyclic moiety is substituted with an alkylaryl group. In some embodiments, the substituted heterocyclic moiety comprises a triazole. In some embodiments, the triazole is substituted with an alkylaryl group. In some embodiments, the triazole is substituted with -CH2-CH2-O-Ph. In some embodiments, the triazole is substituted with -CH2-CH2-O-Bz.

[0286] In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R 6 -OR w -Z, where R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, or -CH-alkynyl. 5 is -O-trityl or a derivative or analogue thereof, and R 6 -OR w -Z, where R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 48 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, or -CH-alkynyl. 5is -O-trityl or a derivative or analogue thereof, and R 6 -OR w -Z, where R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 24 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, or -CH2-alkynyl.

[0287] In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R 6 -OR w -Z, where R w is an unsubstituted alkyl group having 1 to 60 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, or -CH-alkynyl. In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R 6 -OR w -Z, where R w is an unsubstituted alkyl group having 1 to 48 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, or -CH-alkynyl. 5 is -O-trityl or a derivative or analogue thereof, and R 6 -OR w -Z, where R w is an unsubstituted alkyl group having 1 to 24 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, or -CH2-alkynyl.

[0288] In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R wcomprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups.

[0289] In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an alkyl group, e.g., a C1-C4 alkyl group, methyl or ethyl.

[0290] In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an alkenyl group, e.g., -CH=CH2, or -CH2-CH=CH2.

[0291] In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R w comprises at least one PEG group, at least two PEG groups, at least three PEG groups, at least four PEG groups, at least eight PEG groups, at least twelve PEG groups, or at least twenty-four PEG groups; and Z is an alkynyl group, e.g. [ka] It is.

[0292] In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R wcomprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z is an acyl group.

[0293] In some embodiments, R 5 is -O-trityl or a derivative or analogue thereof, and R w comprises at least 1 PEG group, at least 2 PEG groups, at least 3 PEG groups, at least 4 PEG groups, at least 8 PEG groups, at least 12 PEG groups, or at least 24 PEG groups, and Z comprises a substituted heterocyclic moiety. In some embodiments, the heterocyclic moiety is substituted with an alkylaryl group. In some embodiments, the substituted heterocyclic moiety comprises a triazole, e.g., a 1,2,4-triazole. In some embodiments, the triazole is substituted with an alkylaryl group. In some embodiments, the triazole is substituted with -CH2-CH2-O-Ph. In some embodiments, the triazole is substituted with -CH2-CH2-O-Bz.

[0294] Non-limiting examples of compounds having any one of formulas (IXA) or (IXB) include: [ka]

[0295] wherein DMTO is 4,4'-dimethoxytrityl ether, Z is as defined above, and e is an integer ranging from 1 to 24. In some embodiments, Z is allyl or alkyl. In some embodiments, e is 2. In other embodiments, e is 3. In other embodiments, e is 4. In still other embodiments, e is 8. In some embodiments, e is 4 and Z is allyl or alkyl. Compounds containing an ether of 9-phenylthioxantyl or a derivative or analog thereof in place of DMTO are also contemplated.

[0296] In some embodiments, the intermediates of formula (IXA) and (IXB) are represented by formula (XA) and (XB): [ka]

[0297] (Wherein W is as defined above;

[0298] R 7 -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is an alkyl, alkenyl, alkynyl, acyl, a "click functional group," or a substituted or unsubstituted 5-membered heterocyclic moiety.

[0299] In some embodiments, R 7 Formula (XIIIA) and (XIIIB) [ka]

[0300] During the ceremony,

[0301] R a and R b are independently H or C1-C4 alkyl;

[0302] Y is alkyl, alkenyl, alkynyl, acyl, -CH2-alkynyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0303] d is an integer ranging from 1 to about 10;

[0304] and e is an integer ranging from 1 to about 36.

[0305] In some embodiments, d is an integer ranging from 1 to about 8. In other embodiments, d is an integer ranging from 1 to about 6. In yet other embodiments, d is an integer ranging from 1 to about 2. In a further embodiment, d is 2. In yet a further embodiment, d is 1.

[0306] In some embodiments, e is an integer ranging from 1 to about 24. In other embodiments, e is an integer ranging from 1 to about 20. In still other embodiments, e is an integer ranging from 1 to about 16. In further embodiments, e is an integer ranging from 1 to about 12. In still further embodiments, e is an integer ranging from 1 to about 8. In still further embodiments, e is an integer ranging from 1 to about 4. In some embodiments, e is 4. In some embodiments, e is 3. In some embodiments, e is 2. In some embodiments, e is 1.

[0307] In some embodiments, the heterocyclic moiety is substituted with an alkylaryl group. In some embodiments, the substituted heterocyclic moiety comprises a triazole. In some embodiments, the triazole is substituted with an alkylaryl group. In some embodiments, the triazole is substituted with -CH2-CH2-O-Ph. In some embodiments, the triazole is substituted with -CH2-CH2-O-Bz.

[0308] In some embodiments, the intermediates of formula (IXA) and (IXB) are represented by formula (XIA) and (XIB): [ka]

[0309] (Wherein W is as defined above;

[0310] R 8is -OH, -O-trityl or a derivative or analog thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analog thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analog thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analog thereof, -O-1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, -O-[(chloro-4-methyl)phenyl]-4'-methoxypiperidin-4-yl, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether.

[0311] In some embodiments, R 8 is -O-pixil or a derivative or analog thereof. Non-limiting examples of pixil derivatives or analogs are described in U.S. Patent Application Publication No. 2007 / 0276139, the disclosure of which is incorporated herein by reference in its entirety.

[0312] In some embodiments, R 8 is --O-trityl or a derivative or analog thereof.

[0313] In some embodiments, R 8 The structure [ka]

[0314] (In the formula, each R s is independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl. In some embodiments, each R s is independently selected from H, -O-C1-C3 alkyl, or -C1-C3 alkyl. s is independently selected from H, -O-C1-C2 alkyl, or -C1-C2 alkyl. In some embodiments, each R sis independently selected from H, -O-CH3, or -CH3.

[0315] In some embodiments, each R 8 is 4,4'-dimethoxytrityl ether or 4-methoxytrityl ether.

[0316] In some embodiments, an intermediate of formula (IXA) or (IXB) may be utilized in the synthesis of a phosphoramidite-containing monomer having the structure of any one of formulas (XIIA)-(XIID). [ka]

[0317] (In the formula, Y, R 5 , R 6 and e is as defined above, and PPA is a phosphoramidite species).

[0318] In some embodiments, the trans diastereomer is [ka]

[0319] (In the formula, R 9 is a substituted or unsubstituted C1-C6 alkyl group terminating in a cyano moiety, R 10 and R 11 are independently a branched or unbranched C1-C6 alkyl group.

[0320] In some embodiments, the present disclosure provides a compound of formula (XIIIA) or (XIIIB): [ka]

[0321] (In the formula,

[0322] R 12a and R 12bare independently -OH, -O-trityl or a derivative or analog thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analog thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analog thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analog thereof, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether;

[0323] R 13a and R 13b are independently -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms; Z is alkyl, alkenyl, alkynyl, -CH2-alkynyl, acyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0324] R 14a and R 14b is -OH or

[0325] or R 12a and R 14a and / or R 12b and R 14b Let's get together [ka] or

[0326] In some embodiments, the compounds of formula (XIIIA) and (XIIIB) serve as starting materials for the preparation of regioisomerically pure phosphoramidite-containing monomers. As described herein, such monomers may be polymerized into polymers or copolymers, and such formed polymers or copolymers may be incorporated into XNTP molecules.

[0327] In some embodiments, R w In another embodiment, R w In yet another embodiment, R w contains from about 9 to about 12 carbon atoms.

[0328] In some embodiments, R w contains from about 4 to about 12 carbon atoms and further contains at least two heteroatoms, e.g., at least two oxygen heteroatoms, at least three oxygen heteroatoms, at least four oxygen heteroatoms, etc. In some embodiments, R w contains from about 6 to about 12 carbon atoms and further contains at least two heteroatoms, e.g., at least two oxygen heteroatoms, at least three oxygen heteroatoms, at least four oxygen heteroatoms, etc. In yet other embodiments, R w contains about 8 to about 12 carbon atoms and further contains at least two heteroatoms, such as at least two oxygen heteroatoms, at least three oxygen heteroatoms, at least four oxygen heteroatoms, and the like.

[0329] In some embodiments, R 12a and R 14a The city comes together [ka] and 12b and R 14b Together [ka] and Z is alkyl, alkenyl, alkynyl, or -CH2-alkynyl.

[0330] In some embodiments, Z is alkyl, alkenyl, alkynyl, -CH-alkynyl, and R 14a and R 14b In some embodiments, Z is alkyl, alkenyl, alkynyl, -CH-alkynyl, and R 14a and R 14b are -OH, and R 12a and R 12b is -O-trityl or a derivative or analog thereof. In some embodiments, Z is alkyl, alkenyl, alkynyl, -CH-alkynyl, and R 14a and R 14b are -OH and R 12a and R 12b is -O-pixyl or a derivative or analog thereof, respectively.

[0331] Non-limiting examples of compounds having any one of formulas (XIIIA) or (XIIIB) include the following: [ka] [ka] It is.

[0332] Synthesis of intermediates and phosphoramidite-containing monomers

[0333] The present disclosure also provides a method for synthesizing phosphoramidite-containing monomers. In some embodiments, the synthesis method provides high yields of regioisomeric and enantiomerically pure phosphoramidite-containing monomers. The present disclosure also provides a method for synthesizing intermediates of phosphoramidite-containing monomers, including any of the intermediates described herein.

[0334] Scheme 1 shows a method for synthesizing phosphoramidite-containing monomers (see also Example 1 herein). Classical silyl groups such as TIPS or TBDPS have been used to temporarily protect the hydroxyl functions of glycerol in the course of the synthesis of chiral phosphoramidite-containing monomers (see Scheme 1, compound 1). The transfer of the introduced silyl group is observed between two adjacent hydroxyl functions, leading to the conversion of compound 3 to 4 or vice versa. As a result, a mixture of positional isomers is obtained, which is difficult to separate by chromatography. Thus, the obtained phosphoramidite-containing monomers contain the respective positional isomeric impurities. When starting from the TIPS-protected compound 3, the corresponding phosphoramidite-containing monomer 1 was obtained with up to 15% impurity of phosphoramidite-containing monomer 2. When starting from the TBDPS-protected compound 3, the corresponding phosphoramidite-containing monomer 1 was obtained with up to 6% of phosphoramidite-containing monomer 2. [ka]

[0335] The amount of regioisomeric impurity phosphoramidite-containing monomers can be reduced in some embodiments by utilizing kinetic resolution in the deprotection step of TBDPS-protected compounds 5 and 6 (mixture). With TBAF, PEGylated compound 5 deprotects faster than compound 6 (see Scheme 2). This requires stopping the reaction before reaching full conversion. Table 1 shows the dependence of deprotection time, yield and regioisomeric impurity in the final phosphoramidite-containing monomer product. Shortening the reaction time could reduce the impurity to 0.7% (measured by 31P-NMR), but the yield of intermediates 7 and 8 decreased from 86% to 41%. This effect could be explained by steric hindrance and potential π-stacking of adjacent DMT and TBDPS groups in PEGylated compound 6. The bulky TBAF reagent may encounter stronger steric repulsion with compound 6 than with compound 5 (see Figure 1). [ka] [Table 1]

[0336] Applicants have surprisingly discovered that the selection of certain protecting groups facilitates the synthesis of regiochemically and enantiomerically pure phosphoramidite-containing monomers. Synthetic schemes 3 and 4 show methods for preparing such stereochemically pure phosphoramidite-containing monomers and intermediates thereof, such as intermediates having either one of formulas (IIA) or (IIB). Those skilled in the art will appreciate that schemes 3 and 4 utilize starting materials (compounds A and A') with different stereochemical centers (R vs. S). In particular, the respective stereochemical centers of schemes 3 and 4 are retained during each step of the synthesis, resulting in phosphoramidite-containing monomers (compounds F and F') with the same stereochemistry as the starting materials (compounds A and A', respectively). [ka] [ka]

[0337] In general, compounds A and A' can be reacted with a protecting group, such as Br-CH2-CH=CH2, in the presence of a base (e.g., a non-nucleophilic base such as NaH) to form protected compounds B and B', respectively. Examples of suitable protecting groups are described in Wuts, PGM, & Greene, TW (2007), the disclosure of which is incorporated herein by reference in its entirety. Other suitable protecting groups are disclosed in the examples provided herein. Other non-nucleophilic bases include N,N-diisopropylethylamine (DIPEA); silicon-based amides such as sodium and potassium bis(trimethylsilyl)amide (NaHMDS and KHMDS, respectively); 1,8-diazabicycloundec-7ene (DBU); and 2,6-di-tert-butylpyridine, and lithium tetramethylpiperidide (LiTMP or harpoon base).

[0338] Compounds B and B' can then be reacted with an acid (e.g., a weak acid such as acetic acid) to form compounds C and C'. One of skill in the art will appreciate that some protecting groups are more sensitive to acid than others. Other suitable acids include, but are not limited to, formic acid, benzoic acid, oxalic acid, hydrofluoric acid, nitrous acid, hydrochloric acid, sulfurous acid, and phosphoric acid. The choice of acid will depend on the protecting group being introduced. Compounds C and C' can then be reacted with trityl chloride or a derivative or analog thereof in the presence of a base (e.g., TEA) to provide tritylated compounds D and D'. Side chains (e.g., -OR as described herein) can then be added to the compound. w -Z) can be introduced into the tritylated compounds D and D' in the presence of NaH or another base (eg, a strong base such as NaOH or KOtBu) to give compounds E and E'.

[0339] Compounds E and E' can then be deprotected according to methods known to those skilled in the art to provide orthogonally deprotected compounds F and F'. For example, in some embodiments, the SEM protecting group or 2-O-triisopropylsilyloxymethyl can be orthogonally deprotected using tetrabutylammonium fluoride. In other embodiments, the 2'-thiomorpholine-4-carbothioate protecting group can be removed by ethylenediamine. In still other embodiments, the benzyl group can be oxidized by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or reduced in the presence of Pd / C or Pd(OH)2 / C. In still other embodiments, the azidomethyl protecting group can be removed by mild Staudinger reduction. In further embodiments, the allyl group can be cleaved by Pd(0) and morpholine.

[0340] Finally, a phosphoramidite species (including any of those listed herein) can be coupled to compounds F and F' in the presence of a base (e.g., TEA) to give a phosphoramidite-containing monomer.

[0341] In some embodiments, when the group Z in Schemes 3 and 4 is alkynyl, the group Z can react with another substrate in a "click chemistry" reaction. For example, when the group Z in Schemes 3 and 4 is alkynyl, the group Z can react with a substrate having an azido group, such as azidoethylbenzoate. Still other suitable substrates having an azido group include, but are not limited to, azidopentaerythritol, azidobenzoic acid / ester, diether phosphoryl azide, crown ether azide, azido sugar, and azido amino acid.

[0342] In some embodiments, the present disclosure provides a method for synthesizing a regioisomerically and / or enantiomerically pure monomer having any one of formulas (VIIIA)-(VIIID), comprising:

[0343] (a) preparing a compound having any one of formulas (IIIA) and (IIIB) from 2,3-isopropylidene-sn-glycerol, the compound having any one of formulas (IIIA) and (IIB) being [ka]

[0344] (In the formula,

[0345] PG is [ka] -CH2-S-CH3, -CH2-N3, or -CH2-CH2=CH2;

[0346] f is 0 or 2;

[0347] Each R u are independently H, -O-C1-C4 alkyl, or -C1-C4 alkyl;

[0348] Each R z is independently a branched or unbranched C1-C6 alkyl group;

[0349] (b) reacting trityl chloride or a derivative or analog thereof with a compound having any one of formulas (IIIA) and (IIIB) to provide a compound having any one of formulas (VA) and (VB), respectively, [ka]

[0350] (wherein PG is as defined above and R 3is -O-trityl or a derivative or analog thereof) with a compound having any one of formulas (IIIA) and (IIIB) to provide a compound having any one of formulas (VA) and (VB), respectively;

[0351] (c) reacting a reagent having formula (XIV) with a compound having any one of formulae (VA) and (VB) to provide a conjugate having any one of formulae (VIA) and (VIB), respectively;

[0352] The reagent having the formula (XIV) [ka]

[0353] During the ceremony,

[0354] R a and R b are independently H or C1-C4 alkyl;

[0355] Y is alkyl, alkenyl, alkynyl, acyl, -CH2-alkynyl, a "click functional group", -Het, or -CH2-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0356] d is an integer ranging from 1 to about 10;

[0357] e is an integer ranging from 1 to about 36;

[0358] LG is a leaving group,

[0359] The conjugate having any one of formulas (VIA) and (VIB) [ka]

[0360] (Wherein, PG and R 3 is as defined above,

[0361] R 4 has the formula (XIIIA) [ka]

[0362] (In the formula, R a and R b , Y, d and e are as defined above), with a compound having any one of formulas (VA) and (VB) to provide a conjugate having any one of formulas (VIA) and (VIB), respectively;

[0363] (d) deprotecting the conjugate having any one of formulas (VIA) and (VIB) to provide a respective deprotected conjugate;

[0364] (e) coupling a compound having formula (XV) to the deprotected conjugate to provide a regioisomerically and / or enantiomerically pure monomer having any one of formulas (VIIIA) to (VIIID), respectively, wherein the compound having formula (XV) is [ka]

[0365] (wherein LG is a leaving group and R 9 is a substituted or unsubstituted C1-C6 alkyl group terminating in a cyano moiety, R 10 and R 11 are independently a branched or unbranched C1-C6 alkyl group,

[0366] The compound having any one of the formulas (VIIIA) to (VIIID) is [ka]

[0367] (In the formula, Y, R 3 , R 4 and e is as defined above, and PPA is a phosphoramidite species).

[0368] In some embodiments, the present disclosure provides a method of converting a compound having any one of formulas (XA) and (XB) to a compound having any one of formulas (IXA) and (IXB). In these embodiments, the method comprises obtaining a compound having any one of formulas (XA) and (XB) and reacting it with trityl chloride (or a derivative or analog thereof) solvent (e.g., DCM) (see Example 9 herein).

[0369] In some embodiments, the disclosure provides a method of converting a compound having any one of formulas (XIA) and (XIB) to a compound having any one of formulas (IXA) and (IXB). In these embodiments, the method includes obtaining a compound having any one of formulas (XIA) and (XIB) and reacting it with a base (e.g., NaH) in a solvent (e.g., THF) in the presence of a side chain, such as a side chain having formula (XIV) (see Examples 10 and 11 herein).

[0370] Another aspect of the present disclosure is a method for producing a method for manufacturing a semiconductor device comprising the steps of: [ka]

[0371] (In the formula, R 13a and R 13b are independently -OR w -Z and R wis a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, -CH-alkynyl, acyl, a "click functional group", -Het, or -CH-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety;

[0372] The method comprises:

[0373] Lower alcohols and acids are [ka]

[0374] (In the formula, R 15 is a substituted or unsubstituted 5- or 6-membered aromatic or heteroaromatic group) to a starting material having one of the structures. Specific methods for preparing these compounds are described in Examples 16 and 17 herein.

[0375] In some embodiments, the lower alcohol is selected from the group consisting of methanol and ethanol. In some embodiments, the acid is hydrochloric acid. In some embodiments, Z is alkyl, alkenyl, alkynyl, or -CH-alkynyl. In some embodiments, R w In some embodiments, R w In some embodiments, R w In some embodiments, R w further comprises at least two oxygen heteroatoms.

[0376] Another aspect of the present disclosure is a method for producing a method for manufacturing a semiconductor device comprising the steps of: [ka]

[0377] (In the formula, R 13a and R 13b are independently -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, -CH-alkynyl, acyl, a "click functional group", -Het, or -CH-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety,

[0378] The method comprises:

[0379] 4,4'Dimethoxytrityl chloride is [ka] with a compound having any one of the structures:

[0380] Specific methods for preparing these compounds are described in Examples 16 and 17 herein.

[0381] In some embodiments, Z is alkyl, alkenyl, alkynyl, or -CH-alkynyl. w In some embodiments, R w In some embodiments, R w In some embodiments, R w further comprises at least two oxygen heteroatoms.

[0382] In another aspect, the present disclosure provides compounds of formula (IXA) and (IXB), respectively: [ka]

[0383] During the ceremony,

[0384] W is H;

[0385] R 5 is -O-trityl,

[0386] R 6 -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, -CH-alkynyl, acyl, a "click functional group", -Het, or -CH-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety,

[0387] The method comprises the steps of: [ka]

[0388] (In the formula, R 13a and R 13b are independently -OR w -Z and R w is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, optionally containing one or more oxygen heteroatoms, and Z is alkyl, alkenyl, alkynyl, -CH-alkynyl, acyl, a "click functional group", -Het, or -CH-Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety,

[0389] Oxidative cleavage is carried out in the presence of sodium metaperiodate (NaIO4) and base to give R 6 , R 13a , and R 13b But the method is the same.

[0390] Specific methods for preparing these compounds are described in Examples 16 and 17 herein.

[0391] In some embodiments, Z is alkyl, alkenyl, alkynyl, or -CH-alkynyl. w In some embodiments, R w In some embodiments, R w In some embodiments, R w further comprises at least two oxygen heteroatoms.

[0392] In some embodiments, the synthesized compound has the structure [ka] [ka] It is.

[0393] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, precipitation, recrystallization, etc. Additional methods for synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. Furthermore, the various synthetic steps may be performed in an alternate sequence or order to obtain the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are known in the art, and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PG M Huts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. EXAMPLES

[0394] The following materials with the abbreviations shown were obtained from the mentioned supplier in the United States unless otherwise stated. TOM-Cl (2-O-triisopropylsilyloxymethyl) was purchased from Astatech, Inc. (Bristol, PA). NaH (sodium hydride), MeOH (methanol), toluene, THF (tetrahydrofuran), TBAF (tetrabutylammonium fluoride), DCM (dichloromethane), DMSO (dimethylsulfoxide), Na ascorbate (sodium ascorbate), sodium bicarbonate, copper sulfate and acetic acid were obtained from Sigma-Aldrich (St. Louis, MO). DMT-Cl (4,4'-dimethoxytrityl chloride) and PPA-Cl (N,N-diisopropylaminocyanoethylphosphonamidyl chloride) were from ChemGenes Corporation (Wilmington, MA). Toluene, TEA (triethylamine), hexane, EtOAc (ethyl acetate), EDTA (ethylenediaminetetraacetic acid), diethyl ether, L-(+)-erythrylose from EMD Millipore (Billerica, MA). m-PEG4-Tos was made from m-PEG4-OH (2,5,8,11 tetraoxatridecan-13-ol, catalog number BP-23742) from BroadPharm (San Diego, CA). Alkyne-PEG4-OT was made from alkyne-PEG4-OH (triethylene glycol mono(2-propynyl) ether, catalog number T3114), 1,1'-thiocarbonyldiimidazole, L-mannitol, D-mannitol, benzaldehyde, NaIO4 (sodium periodate), NaBH4 (sodium borohydride), MBn (4-methoxybenzyl chloride), DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and thiomorpholine were purchased from TCI, Inc. (Portland, OR). 2,3-Isopropylidene-sn-glycerol was purchased from Biosynth Ltd. TBDPSCl, SEM-Cl, pTsOH, Ph3P, Pd / C and Pd(OH)2 / C were purchased from Sigma-Aldrich.

[0395] High performance liquid chromatography (HPLC) was performed on a ProStar Helix™ HPLC system from Agilent Technologies, Inc. (Santa Clara, CA) consisting of two pumps (ProStar 210 Solvent Delivery Module) with 10 ml titanium pump heads, a column oven (ProStar 510 Air Oven), and a UV detector (ProStar 320 UV / Vis Detector) set at 292 nm. The system is controlled by Star Chromatography Workstation Software (version 6.41). The columns used were Cadenza Guard Column System CD-C18 (2.0 mm x 5 mm), both from Imtakt USA (Portland, OR). The buffers used were Buffer A (100 mM triethylammonium acetate, pH 7.0) and Buffer B (100 mM triethylammonium acetate, pH 7.0, with 95% acetonitrile by volume). Automated solid-phase phosphoramidite synthesis was performed on a MerMade™ 12 synthesizer (Bioautomation Corp., Plano, TX). MerMade™ synthesis solutions were purchased from Glen Research (Sterling, VA). NuMega operates 500 MHz Bruker NMR spectrometers, Avance II and AV-500 (San Diego, CA).

[0396] Example 1: Synthesis of DMT phosphoramidite via TBDPS protecting group using kinetic resolution [ka]

[0397] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in anhydrous ACN and TEA. DMAP and TBDPS-Cl were added. The solvent was evaporated and the residue was extracted with EtOAc from water and purified by flash chromatography to give product 10 in 99% yield.

[0398] The silyl ether 10 was dissolved in 90% AcOH and heated at 80° C. for 20 min. The solvent was removed under reduced pressure. The residue was resuspended in EtOAc and extracted with water and brine. Evaporation of the solvent gave the diol 11 in 100% yield.

[0399] Diol 11 was dissolved in toluene and TEA. A solution of DMT-Cl in toluene was added dropwise at room temperature. The reaction mixture was extracted with water and brine. The solvent was evaporated and the residue was purified by flash chromatography to give the mono-trityl product 3 in 64% yield.

[0400] The secondary alcohol 3 was dissolved in THF, and NaH (60% dispersion in mineral oil) and mPEG4Tos were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 5 and approximately 15% of 6 in 77% yield.

[0401] A mixture of mPEG4 ethers 5 and 6 was resuspended in THF, TBAF (1M in THF) was added and stirred at room temperature for 50 min. The reaction was quenched with a saturated solution of NaHCO3 and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 7 in 80% yield.

[0402] DMT PEG4 alcohol 7 was dissolved in ACN and TEA. PPA-Cl was added and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and the solvent was dried under reduced pressure. The crude product was purified by flash chromatography to give 1 in 70% yield. TLC(EtOAc+0.5%TEA):Rf=0.75,1H NMR(500MHz,ACETONITRILE-d3)δ ppm1.04-1.22(m,12H),2.49-2.62(m,2H),3.05-3.19(m,2H),3.22-3.28(m,3H),3.44(br dd,J=5.94,3.17Hz,3H),3.48-3.58(m,14H),3.60-3.76(m,13H),6.81- 6.87(m,H),7.16-7.25(m,1H),7.26-7.34(m,6H),7.41-7.48(m,2H),31P NMR(500MHz,ACETONITRILE-d3)δ ppm148.43,148.47,149.23,149.72 (see FIG.2).

[0403] Example 2: Synthesis of phosphoramidite 1 via TOM protecting group [ka]

[0404] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in anhydrous THF, and NaH (60% dispersion in mineral oil) and TOMCl were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 12 in 49% yield.

[0405] The TOM-protected ether 12 was dissolved in 90% AcOH and heated for 30 min at 80° C. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography to give the diol 13 in 80% yield.

[0406] Diol 13 was dissolved in toluene, TEA and DMTCl were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with toluene. The combined extracts were dried and concentrated in vacuum. The crude product was purified by flash chromatography to give 14 in 59% yield.

[0407] The secondary alcohol 14 was dissolved in THF, and NaH (60% dispersion in mineral oil) and mPEG4Tos were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 15 in 82% yield.

[0408] mPEG4 ether 15 was dissolved in THF, TBAF (1M in THF) was added, and the reaction mixture was stirred at room temperature. After the reaction was complete, a saturated solution of NaHCO3 was added, and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 7 in 71% yield.

[0409] DMT PEG4 alcohol 7 was dissolved in DCM, TEA and PPACl were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with DCM. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 1 in 67% yield. The structure of phosphoramidite 1 is: 1 H and 31 Confirmed by P NMR (CD3CN). No positional isomers were detected.

[0410] Example 3: Synthesis of DMT phosphoramidites via azidomethyl protection [ka]

[0411] The azidomethyl group was introduced in the following two steps based on the methods described in the literature: (1) PNAS 2008, 105(27), 9145-9150; (2) Russian Journal of Bioorganic Chemistry, 2009, 35, 270-273.

[0412] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in DMSO, AcOH and Ac2O. The reaction mixture was stirred at room temperature for 50 h. The reaction was quenched with a saturated solution of NaHCO3 and the aqueous phase was extracted with EtOAc. The EtOAc was evaporated and the residue was dried under vacuum to give 16 as crude product in 63% yield.

[0413] The crude thioether 16 was dissolved in DMF and 2-nitrobenzenesulfonyl chloride was added. After 5 min, the reaction mixture was cooled to 0° C. and NaN3 was added. After 1 h, the reaction was quenched with semi-concentrated NaHCO3 solution and the aqueous phase was extracted with EtOAc. The crude product was purified by flash chromatography to give 17 in 58% yield.

[0414] The azidomethyl ether 17 was dissolved in 90% AcOH and heated at 80° C. for 20 min. The solvent was removed under reduced pressure. The residue was resuspended in EtOAc and extracted with water and brine. Evaporation of the solvent gave the diol 18 in 87% yield.

[0415] Diol 18 was dissolved in toluene and TEA. A solution of DMT-Cl in toluene was added dropwise at room temperature. The reaction mixture was extracted with water and brine. The solvent was evaporated and the residue was purified by flash chromatography to give the mono-trityl product 19 in 88% yield.

[0416] The secondary alcohol 19 was dissolved in THF, and NaH (60% dispersion in mineral oil) and mPEG4Tos were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 20 in 70% yield.

[0417] mPEG4 ether 20 was dissolved in THF and PPh3 and H2O were added. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the crude product was purified by flash chromatography to give 7 in 90% yield.

[0418] DMT PEG4 alcohol 7 was dissolved in ACN and TEA. PPA-Cl was added and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and the solvent was dried under reduced pressure. The crude product was purified by flash chromatography to give 1 in 49% yield. The structure of phosphoramidite 1 is shown in Figure 1. 31 Confirmed by P NMR (CD3CN). No positional isomers were detected.

[0419] Example 4: Synthesis of DMT phosphoramidites via allyl protecting groups [ka]

[0420] 2,3-Isopropylidene-sn-glycerol 9 was added to an ice-cold suspension of NaH (60% dispersion in mineral oil) in anhydrous THF. Allyl bromide was added and the reaction mixture was warmed to room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were washed with water and brine. The organic phase was dried and concentrated in vacuo. The crude product was dissolved in 90% AcOH and heated to 80° C. for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography to give diol 22 in 63% yield.

[0421] Diol 22 was dissolved in toluene, TEA and DMTCl were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with toluene. The combined extracts were dried and concentrated in vacuum. The crude product was purified by flash chromatography to give 23 in 79% yield.

[0422] The secondary alcohol 23 was dissolved in THF, and NaH (60% dispersion in mineral oil) and mPEG4Tos were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 24 in 90% yield.

[0423] The mPEG4 ether 24 was dissolved in MeOH, morpholine and (Ph3P)4Pd were added, and the reaction mixture was stirred in a microwave at 90° C. for 4 h. The catalyst was filtered off, the filtrate was concentrated in vacuo, and the crude product was purified by flash chromatography to give 7 in 63% yield.

[0424] DMT PEG4 alcohol 7 was dissolved in DCM, TEA and PPACl were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with DCM. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 1 in 67% yield. The structure of phosphoramidite 1 was confirmed by 1H and 31P NMR (CD3CN). No regioisomers were detected.

[0425] Example 5: Synthesis of DMT phosphoramidite via SEM protecting group [ka]

[0426] Compound 26 was prepared according to Bull. Soc. Chem. Jpn. 1987, 60, 2169-2172.

[0427] 2,3-Isopropylidene-sn-glycerol 9 was added to an ice-cold suspension of NaH in THF (60% dispersion in mineral oil). SEMCl was added and the reaction mixture was stirred in an ice bath. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 25.

[0428] The SEM protected ether 25 was dissolved in 90% AcOH and heated for 30 min at 80° C. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography to give the diol 26.

[0429] Diol 26 was dissolved in toluene, TEA and DMTCl were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with toluene. The combined extracts were dried and concentrated in vacuum. The crude product was purified by flash chromatography to give 27.

[0430] The secondary alcohol 27 was dissolved in THF, and NaH (60% dispersion in mineral oil) and mPEG4Tos were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 28.

[0431] Compound 28 was dissolved in THF, TBAF (1M in THF) was added, and the reaction mixture was stirred in a microwave at 100° C. After the reaction was complete, a saturated solution of NaHCO3 was added, and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 7.

[0432] DMT PEG4 alcohol 7 was dissolved in ACN, TEA and PPACl were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with DCM. The combined extracts were dried and concentrated in vacuum. The crude product was purified by flash chromatography to give 1.

[0433] Example 6: Synthesis of phosphoramidite 1b via TOM protecting group [ka]

[0434] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in anhydrous THF. Sodium hydride was added to generate the alkoxide. TOM-Cl was dissolved in THF and charged with NaI and added in portions. The reaction was stirred for 24 h. Excess NaH was quenched with MeOH, then diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. An oil was isolated by extraction with ACN. The residue was purified by flash chromatography to give the protected 12.

[0435] The product 12 was dissolved in a mixture of acetic acid and water (2:1). The solution was heated to 40° C. and stirred for 120 min, then neutralized with sodium bicarbonate and extracted with EtOAc. The organics were separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the diol 13.

[0436] The diol 13 was dissolved in DCM and TEA. A solution of DMT-Cl in DCM was added in portions. MeOH was added and the reaction was dried under reduced pressure. The residue was resuspended in toluene and separated from the salts, then purified by flash chromatography to give the mono-trityl product 14.

[0437] 1-O-TOM-3-O-DMTr-propane-1,2,3 triol 14 (from Example 2) was dissolved in anhydrous THF. Sodium hydride was added to generate the alkoxide. Once bubbling ceased, the alkyne tosylate (catalog no. BP-21657, prepared via tosylation from Broadpharm) was added portionwise. The reaction was incubated with stirring for 24-48 hours. Excess NaH was quenched with water, then the solution was transferred to a separatory funnel and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was resuspended in toluene, separated from remaining salts, and purified by flash chromatography to give alkyne 29.

[0438] The alkyne 29 was resuspended in THF, TBAF was added, and stirred for 2 h. The reaction was concentrated under reduced pressure and purified by flash chromatography to give 30.

[0439] To a solution of alkyne 30 in DMSO was added 2-azidoethyl acetate. In a separate vial, the catalyst mixture was prepared by dissolving sodium ascorbate in water / DMSO followed by 1M CuSO4. The catalyst mixture was added dropwise to the alkyne / azide solution over 10 minutes. Upon completion, the reaction was quenched with 0.5M EDTA and stirred for 15 minutes. Dilute with water and extract three times with ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate. The residue was resuspended in toluene and purified by flash chromatography to give triazole 31.

[0440] Alcohol 31 was dissolved in DCM and TEA under an inert atmosphere. PPA-Cl was added and the reaction was stirred for 60 min. The reaction was dried under reduced pressure, resuspended in toluene with 0.5% TEA, and then purified by flash chromatography (silica gel basified with 0.5% TEA mobile phase). Phosphoramidite 1b was isolated and regiopurity was confirmed by 1H and 31P NMR.

[0441] Example 7: Synthesis of DMT phosphoramidite 1 via TC protecting group [ka]

[0442] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in anhydrous ACN. The reaction mixture was charged with thiocarbonyldiimidazole in portions, followed by DMAP in portions, and stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography to give 32.

[0443] Thiocarbamate glycerol 32 was dissolved in anhydrous ACN and thiomorpholine was charged in portions. The reaction mixture was stirred overnight under inert atmosphere and then concentrated under reduced pressure. The crude residue was purified by flash chromatography to give 2'-thiomorpholine-4-carbothioate 33.

[0444] The product 33 was dissolved in a mixture of acetic acid and water (2:1). The solution was heated to 40° C. and stirred for 120 min, then neutralized with sodium bicarbonate and extracted with EtOAc. The organics were separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the diol 34.

[0445] Diol 34 was dissolved in DCM and TEA. A solution of DMT-Cl in DCM was added in portions. MeOH was added and the reaction was dried under reduced pressure. The residue was resuspended in toluene and separated from the salts, then purified by flash chromatography to give 35.

[0446] The secondary alcohol 35 was dissolved in anhydrous THF. Sodium hydride was added to generate the alkoxide. Once bubbling ceased, mPEGn-OT was dissolved in THF and added portionwise. The reaction was stirred vigorously overnight at ambient temperature. Excess NaH was quenched with water, then diluted with water and extracted with EtOAc. The combined organic layers were dried under reduced pressure. The residue was resuspended in toluene, separated from the remaining salts, and purified by flash chromatography to give 36.

[0447] 2'-Thiomorpholine-4-carbothioate 36 was resuspended in toluene and ethylenediamine (1:1) under an inert atmosphere. The reaction was stirred overnight and then concentrated under reduced pressure. The residue was purified by flash chromatography to give the free alcohol 7.

[0448] Alcohol 7 was dissolved in DCM and TEA under an inert atmosphere. PPA-Cl was added and the reaction was stirred for 60 min. The reaction was dried under reduced pressure, resuspended in toluene with 0.5% TEA, and then purified by flash chromatography (silica gel basified with 0.5% TEA mobile phase) to give phosphoramidite 1.

[0449] Example 8: Synthesis of DMT phosphoramidite 1b via MBn protecting group [ka]

[0450] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in anhydrous DMF. The reaction mixture was charged with NaH in portions to form the alkoxide, followed by para-methylbenzyl chloride (MBn-Cl) and stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography to give 37.

[0451] The product 37 was dissolved in a mixture of acetic acid and water (2:1). The solution was heated to 40° C. and stirred for 120 min, then neutralized with sodium bicarbonate and extracted with EtOAc. The organics were separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the diol 38.

[0452] The diol 38 was dissolved in DCM and TEA. A solution of DMT-Cl in DCM was added in portions. MeOH was added and the reaction was dried under reduced pressure. The residue was resuspended in toluene and separated from the salts, then purified by flash chromatography to give the mono-trityl product 39.

[0453] Alcohol 39 was dissolved in anhydrous THF. Sodium hydride was added to generate the alkoxide. Once bubbling ceased, the alkyne tosylate (catalog no. BP-21657, prepared via tosylation from Broadpharm) was added portionwise. The reaction was incubated with stirring for 24-48 hours. Excess NaH was quenched with water, then the solution was transferred to a separatory funnel and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was resuspended in toluene, separated from remaining salts, and purified by flash chromatography to give alkyne 40.

[0454] 40 was resuspended in DCM, DDQ was added and stirred for 60 min. The reaction was concentrated under reduced pressure and purified by flash chromatography to give 30.

[0455] To a solution of alkyne 30 in DMSO was added 2-azidoethyl acetate. In a separate vial, the catalyst mixture was prepared by dissolving sodium ascorbate in water / DMSO followed by 1M CuSO4. The catalyst mixture was added dropwise to the alkyne / azide solution over 10 minutes. Upon completion, the reaction was quenched with 0.5M EDTA and stirred for 15 minutes. Dilute with water and extract three times with ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate. The residue was resuspended in toluene and purified by flash chromatography to give triazole 31.

[0456] Alcohol 31 was dissolved in DCM and TEA under an inert atmosphere. PPA-Cl was added and the reaction was stirred for 60 min. The reaction was dried under reduced pressure, resuspended in toluene with 0.5% TEA, and then purified by flash chromatography (silica gel basified with 0.5% TEA mobile phase). Phosphoramidite 1b was isolated and regiopurity was confirmed by 31P NMR.

[0457] Example 9: Synthesis of DMT phosphoramidite via mannitol [ka]

[0458] L-Mannitol was dissolved in DMF, then sulfuric acid was slowly charged and benzaldehyde was added dropwise at 0°C. The reaction was equilibrated to ambient temperature and stirred until complete by TLC. Excess sulfuric acid was quenched with sodium bicarbonate and extracted with EtOAc. The organics were separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography to give the diacetal product 41.

[0459] The corresponding diol 41 was dissolved in anhydrous THF. Sodium hydride was added to generate the alkoxide. Once bubbling ceased, the alkyne tosylate (catalog no. BP-21657, prepared via tosylation from Broadpharm) was added portionwise. The reaction was incubated with stirring for 24-48 hours. The excess NaH was quenched with water, then the solution was transferred to a separatory funnel and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was resuspended in toluene, separated from remaining salts, and purified by flash chromatography to give the bis-alkyne 42.

[0460] 42 was dissolved in MeOH and HCl was added. The solution was incubated for 20 min, then neutralized with sodium bicarbonate and dried under reduced pressure. The residue was resuspended in ethyl acetate and purified by flash chromatography to give the tetraol 43.

[0461] 43 was dissolved in sodium periodate in water and incubated at room temperature for 2 h. The solution was transferred to a separatory funnel and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was resuspended in toluene, separated from the remaining salts, and purified by flash chromatography to give 2 molar equivalents of the aldehyde 44.

[0462] The free alcohol 44 was dissolved in DCM and TEA. A solution of DMT-Cl in DCM was added in portions and stirred for 2 hours. MeOH was added and the reaction was dried under reduced pressure. The residue was resuspended in toluene and separated from the salts, then purified by flash chromatography to give the mono-trityl product 45.

[0463] 45 was dissolved in MeOH and cooled to 0 C. Sodium borohydride (NaBH4) was added portionwise under inert atmosphere and stirred for 60 min. Water was added and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give alcohol 30.

[0464] To a solution of alkyne 30 in DMSO was added 2-azidoethyl acetate. In a separate vial, the catalyst mixture was prepared by dissolving sodium ascorbate in water / DMSO followed by 1M CuSO4. The catalyst mixture was added dropwise to the alkyne / azide solution over 10 minutes. Upon completion, the reaction was quenched with 0.5M EDTA and stirred for 15 minutes. Dilute with water and extract three times with ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate. The residue was resuspended in toluene and purified by flash chromatography to give triazole 31.

[0465] Alcohol 31 was dissolved in DCM and TEA under an inert atmosphere. PPA-Cl was added and the reaction was stirred for 60 min. The reaction was dried under reduced pressure, resuspended in toluene with 0.5% TEA, and then purified by flash chromatography (silica gel basified with 0.5% TEA mobile phase). Phosphoramidite 1b was isolated and regiopurity established by 31P NMR.

[0466] Example 10: Synthesis of DMT phosphoramidite via erythrulose [ka]

[0467] L-(+)-erythritol was dissolved in acetone, charged with zinc chloride and stirred under inert atmosphere. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography to give acetonide 46.

[0468] 46 was dissolved in MeOH and cooled to 0° C. Sodium borohydride (NaBH4) was added portionwise under inert atmosphere and stirred for 60 min. Water was added and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give alcohol 47.

[0469] 47 was dissolved in sodium periodate in water and incubated at room temperature for 2 h. The solution was transferred to a separatory funnel and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was resuspended in toluene, separated from the remaining salts, and purified by flash chromatography to give aldehyde 48.

[0470] 48 was dissolved in MeOH and HCl was added. The solution was incubated for 20 min, then neutralized with sodium bicarbonate and dried under reduced pressure. The residue was resuspended in ethyl acetate and purified by flash chromatography to give diol 49.

[0471] 49 was dissolved in DCM and TEA. A solution of DMT-Cl in DCM was added in portions and stirred for 2 h. MeOH was added and the reaction was dried under reduced pressure. The residue was resuspended in toluene and separated from the salts, then purified by flash chromatography to give the mono-trityl product 50.

[0472] Alcohol 50 was dissolved in anhydrous THF. Sodium hydride was added to generate the alkoxide. Once bubbling ceased, the alkyne tosylate (catalog no. BP-21657, prepared via tosylation from Broadpharm) was added portionwise. The reaction was incubated with stirring for 24-48 hours. Excess NaH was quenched with water, then the solution was transferred to a separatory funnel and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was resuspended in toluene, separated from remaining salts, and purified by flash chromatography to give alkyne 51.

[0473] 51 was dissolved in MeOH and cooled to 0° C. Sodium borohydride (NaBH4) was added portionwise under inert atmosphere and stirred for 60 min. Water was added and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give alcohol 30.

[0474] To a solution of alkyne 30 in DMSO was added 2-azidoethyl acetate. In a separate vial, the catalyst mixture was prepared by dissolving sodium ascorbate in water / DMSO followed by 1M CuSO4. The catalyst mixture was added dropwise to the alkyne / azide solution over 10 minutes. Upon completion, the reaction was quenched with 0.5M EDTA and stirred for 15 minutes. Dilute with water and extract three times with ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate. The residue was resuspended in toluene and purified by flash chromatography to give triazole 31.

[0475] Alcohol 31 was dissolved in DCM and TEA under an inert atmosphere. PPA-Cl was added and the reaction was stirred for 60 min. The reaction was dried under reduced pressure, resuspended in toluene with 0.5% TEA, and then purified by flash chromatography (silica gel basified with 0.5% TEA mobile phase). Phosphoramidite 1b was isolated and regiopurity established by 31P NMR.

[0476] Example 11: Synthesis of DMT phosphoramidite via dihydroxypropanal [ka]

[0477] Diol 49 was dissolved in DCM and TEA. A solution of DMT-Cl in DCM was added portionwise. MeOH was added and the reaction was dried under reduced pressure. The residue was then purified by flash chromatography to give the mono-tritylated product 50.

[0478] The secondary alcohol 50 was dissolved in anhydrous THF. Sodium hydride was added to generate the alkoxide. Once bubbling ceased, mPEGn-OT was dissolved in THF and added portionwise. The reaction was stirred vigorously overnight at ambient temperature. Excess NaH was quenched with water, then diluted with water and extracted with EtOAc. The combined organic layers were dried under reduced pressure. The residue was resuspended in toluene, separated from the remaining salts, and purified by flash chromatography to give 52.

[0479] 52 was dissolved in MeOH and cooled to 0° C. Sodium borohydride (NaBH4) was added portionwise under inert atmosphere and stirred for 60 min. Water was added and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give alcohol 7.

[0480] Alcohol 7 was dissolved in DCM and TEA under an inert atmosphere. PPA-Cl was added and the reaction was stirred for 60 min. The reaction was dried under reduced pressure, resuspended in toluene with 0.5% TEA, and then purified by flash chromatography (silica gel basified with 0.5% TEA mobile phase). Phosphoramidite 1 was isolated and regiopurity established by 31P NMR.

[0481] Example 12: Synthesis of DMT phosphoramidites via dihydrobenzo protecting groups [ka]

[0482] (S)-1-(1,5-dihydrobenzo[e][1,3]dioxepin-3-yl)ethane-1,2-diol 53 was dissolved in DCM and TEA. A solution of DMT-Cl in DCM was added portionwise. MeOH was added and the reaction was dried under reduced pressure. The residue was then purified by flash chromatography to give the mono-tritylated product 54.

[0483] The secondary alcohol 54 was dissolved in anhydrous THF. Sodium hydride was added to generate the alkoxide. Once bubbling ceased, mPEGn-OT was dissolved in THF and added portionwise. The reaction was stirred vigorously overnight at ambient temperature. Excess NaH was quenched with water, then diluted with water and extracted with EtOAc. The combined organic layers were dried under reduced pressure. The residue was resuspended in toluene, separated from the remaining salts, and purified by flash chromatography to give 55.

[0484] The product 55 was dissolved in a mixture of acetic acid and water (2:1). The solution was heated to 40° C. and stirred for 120 min, then neutralized with sodium bicarbonate and extracted with EtOAc. The organics were separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography to give alcohol 56.

[0485] Alcohol 56 was dissolved in DCM and TEA. A solution of DMT-Cl in DCM was added in portions. MeOH was added and the reaction was dried under reduced pressure. The residue was then purified by flash chromatography to give the trityl product 57.

[0486] 57 was dissolved in MeOH and cooled to 0° C. Sodium borohydride (NaBH4) was added portionwise under inert atmosphere and stirred for 60 min. Water was added and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography to give the common intermediate alcohol 7.

[0487] Alcohol 7 was dissolved in DCM and TEA under an inert atmosphere. PPA-Cl was added and the reaction was stirred for 60 min. The reaction was dried under reduced pressure, resuspended in toluene with 0.5% TEA, and then purified by flash chromatography (silica gel basified with 0.5% TEA mobile phase). Phosphoramidite 1 was isolated and regiopurity established by 31P NMR.

[0488] Example 13: Synthesis of DMT phosphoramidite starting from (S)-methyl 2,3-dihydroxypropanoate [ka]

[0489] (S)-Methyl 2,3-dihydroxyglycerate was dissolved in toluene, TEA and DMTCl were added, and the reaction mixture was stirred at room temperature. After the reaction was completed, water was added and the aqueous phase was extracted with toluene. The combined extracts were dried and concentrated in vacuum, and the crude product was purified by flash chromatography to give product 29.

[0490] Hydroxyester 29 was dissolved in THF, and NaH and propargyl-1PEG4 were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 30.

[0491] 30 was dissolved in MeOH and cooled to 0° C. Sodium borohydride (NaBH4) was added portionwise under inert atmosphere and stirred for 60 min. Water was added and extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 7.

[0492] DMT mPEG4 alcohol 7 was dissolved in DCM, TEA and PPACl were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with DCM. The combined extracts were dried and concentrated in vacuum. The crude product was purified by flash chromatography to give 1.

[0493] Example 14: Synthesis of DMT phosphoramidite 1b via azidomethyl protection [ka]

[0494] The azidomethyl group was introduced in the following two steps based on the method described in the literature: (1) PNAS 2008, 105(27), 9145-9150; (2) Russian Journal of Bioorganic Chemistry 2009, 35, 270-273.

[0495] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in DMSO, AcOH and Ac2O. The reaction mixture was stirred at room temperature for 50 h. The reaction was quenched with a saturated solution of NaHCO3 and the aqueous phase was extracted with EtOAc. The EtOAc was evaporated and the residue was dried under vacuum to give 16 as crude product in 63% yield.

[0496] The crude thioether 16 was dissolved in DMF and 2-nitrobenzenesulfonyl chloride was added. After 5 min, the reaction mixture was cooled to 0° C. and NaN3 was added. After 1 h, the reaction was quenched with semi-concentrated NaHCO3 solution and the aqueous phase was extracted with EtOAc. The crude product was purified by flash chromatography to give 17 in 58% yield.

[0497] The azidomethyl ether 17 was dissolved in 90% AcOH and heated at 80° C. for 20 min. The solvent was removed under reduced pressure. The residue was resuspended in EtOAc and extracted with water and brine. Evaporation of the solvent gave the diol 18 in 87% yield.

[0498] Diol 18 was dissolved in toluene and TEA. A solution of DMT-Cl in toluene was added dropwise at room temperature. The reaction mixture was extracted with water and brine. The solvent was evaporated and the residue was purified by flash chromatography to give the mono-trityl product 19 in 88% yield.

[0499] The secondary alcohol 19 was dissolved in THF, and NaH (60% dispersion in mineral oil) and propargyl PEG4Tos were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 31 in 70% yield.

[0500] Propargyl PEG ether 31 was dissolved in THF and PPh3 and H2O were added. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the crude product was purified by flash chromatography to give 32 in 89% yield.

[0501] DMT PEG4 alcohol 32 was dissolved in EtOH and 2-azidoethyl benzoate dissolved in DMSO was added. CuSO4 in H2O and sodium ascorbate in H2O were added to the reaction mixture. After 60 min, the reaction was quenched with 0.5 mol EDTA solution. The solvent was removed under reduced pressure. The residue was resuspended in H2O and extracted with EtOAc. The combined extracts were extracted with H2O and brine. The solvent was evaporated and the residue was purified by flash chromatography to give the product 33 in 93% yield.

[0502] DMT PEG alcohol 33 was dissolved in ACN and TEA. PPA-Cl was added and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and the solvent was dried under reduced pressure. The crude product was purified by flash chromatography to give 34 in 64% yield. The phosphoramidite 34 was confirmed by 1H and 31P NMR. [(TLC nHex / EtOAc25 / 75+0.5%TEA Rf=0.32), 1H NMR (500MHz, ACETONITRILE-d3) δ ppm1.05-1.15(m,12H)2.18(s,1H)2.56(dt,J=12.17,5.89Hz,2H)3.07-3.1 7(m,2H)3.48-3.56(m,12H)3.60-3.76(m,13H)4.53(s,2H)4.63-4.68(m,2H )4.67-4.73(m,2H)6.82-6.87(m,4H)7.17-7.22(m,1H)7.26-7.34(m,6H)7. 42-7.48(m,4H)7.58(t,J=7.46Hz,1H)7.81(s,1H)7.93(d,J=7.35Hz,2H),31 P NMR(500MHz,ACETONITRILE-d3)δ ppm147.81,147.87.

[0503] Example 15 - Synthesis of DMT phosphoramidite 1a via benzyl protecting group [ka]

[0504] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in anhydrous THF, the reaction mixture was cooled in an ice bath, NaH (60% dispersion in mineral oil) and BnBr were added, and the reaction mixture was stirred at room temperature for 20 h. Water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 35 in 89% yield.

[0505] The Bn-protected ether 35 was dissolved in 90% AcOH and heated to 90° C. for 1 h, then stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography to give the diol 36 in 85% yield.

[0506] The diol 36 was dissolved in toluene, TEA was added, the reaction mixture was cooled in an ice bath, DMTCl was added, and the reaction mixture was stirred at room temperature for 18 h. Water was added and the aqueous phase was extracted with toluene. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 37 in 78% yield.

[0507] The secondary alcohol 14 was dissolved in THF, the reaction mixture was cooled in an ice bath, and NaH (60% dispersion in mineral oil) and after 15 min mPEG4Tos were added. The reaction was stirred at room temperature for 66 h, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 38 in 91% yield.

[0508] The mPEG4-ether was dissolved in THF and 0.2 eq. TEA, 0.15 eq. Pd / C and 0.15 eq. Pd(OH)2 / C were added. The reaction mixture was stirred under H2 atmosphere at 70°C for 13 h and at room temperature for another 18 h. The catalyst was filtered off, washed with EtOAc and the solvent was evaporated in vacuum. The crude product was purified by flash chromatography to give 7 in 66% yield.

[0509] DMT mPEG4 alcohol 7 was dissolved in DCM, TEA and PPACl were added, and the reaction mixture was stirred at room temperature. After the reaction was complete, water was added and the aqueous phase was extracted with DCM. The combined extracts were dried and concentrated in vacuum. The crude product was purified by flash chromatography to give 1. The structure of phosphoramidite 1 is 1 H and 31 Confirmation by P NMR (CD3CN) gave the values ​​of 148.46 ppm and 148.42 ppm.

[0510] Example 16 - Synthesis of DMT phosphoramidite via mannitol [ka]

[0511] Synthesis of product 1B

[0512] The materials included 25 g of D-mannitol CAS:69-65-8, 29 g of benzaldehyde CAS:100-52-7, 10.3 mL of sulfuric acid CAS:7664-93-9, and 82.3 mL of DMF.

[0513] To a solution of 25 g of D-mannitol and benzaldehyde (29.3 g, 27.9 mL) in 300 mL of DMF, 10.3 mL of concentrated sulfuric acid was added dropwise. The initially heterogeneous mixture was stirred vigorously at ambient temperature for 3 days and became clear. The reaction mixture was poured slowly in small portions into 3 L of crushed ice water containing 30 g of potassium carbonate and 500 mL of hexane. The mixture was stirred vigorously and a white precipitate formed as the ice melted. The PPT was filtered off and washed with hexane. An analytical sample was washed with cold DCM. The bulk material was dried under HIVAC overnight and then recrystallized from 200 mL of MeOH to give 9 g of a white powder in 18% yield.

[0514] Purification: Recrystallization from MeOH

[0515] Process Control: TLC: 5:95 MeOH in EtOAc

[0516] Yield: Product 1B 9 g, approximately 18%

[0517] Synthesis of product 2B

[0518] The materials included 10 g of 1,3:4,6-di-O-benzylidene-D-mannitol CAS: 28224-73-9 (product 1B), 4.46 g of sodium hydride (60% in mineral oil), 28.66 g of product 3, 120 mL of THF.

[0519] A dry 1000 mL round bottom flask equipped with a stir bar was purged with argon. To this was added 10 g of product 1B followed by 120 mL of dry THF and stirred until product 1B was completely dispersed (at this concentration, the benzylidene does not appear to be completely soluble). Once a uniform dispersion was achieved, it was cooled in an ice bath and stirred for 5 minutes. 4.46 g of sodium hydride was added to the cold dispersion, stopping the effervescence after each addition.

[0520] Then, 28.66 g of product 3B was added slowly with stirring. After the addition was complete, the mixture was stirred in the ice bath for an additional 5 minutes, then the mixture was allowed to warm to room temperature and left under argon atmosphere for about 60 hours. The reaction was monitored by TLC (3:2 EtOAc:Hexane) Rf=0.38 (note that the Rf of the starting material and product were very close SM: Rf=0.44, and slight variations in the proportions of the solvent system could cause them to overlap. However, they can be distinguished, and when stained using PAA, SM is black-bluish and the product is purple-redish).

[0521] The reaction was quenched by placing two 1 L Erlenmeyer flasks in an ice bath and then splitting the reaction mixture between them. First, 5 mL of water was added to each, and 100 mL of EtOAc was also quickly added, allowing the bubbling to dissipate and gently swirling. Then, 5 mL of water was added to each, followed by 50 mL of EtOAc, and this was repeated 2-3 more times until the bubbling after each water addition stopped. Then, 100 mL of water was added, followed by 100 mL of EtOAc, swirling the Erlenmeyer flasks, letting stand for 3-5 minutes, then more water and EtOAc were added until about 200 mL of water and about 400 mL of EtOAc were completed. This mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was then extracted 3-4 times with EtOAc until no more product was observed by TLC. Some brine (20-30 mL) can be added to help separate the emulsion more quickly. Finally, dried over sodium sulfate for 30 minutes.

[0522] Purification: The organic layer was decanted and the sodium sulfate was rinsed with additional EtOAc. The collected liquid was then rotary evaporated until a thick brown oil was obtained. This oil was placed under high vacuum for 1 h. It was then loaded onto a 220 g silica cartridge using a minimum of DCM. (Flow rate: 120 mL / min; Eluent: Hex / EtOAc; Gradient profile 6 min 100% Hex, 15 min gradient 0 to 50% EtOAc, 10 min isocratic 50% EtOAC, 10 min gradient 50% to 65% EtOAc).

[0523] Process Control: TLC: 3:2 EtOAc:Hexane

[0524] NMR 1H and 13C (ACN-d3)

[0525] MS(ESI)

[0526] Yield: 16.97 g of product 2B, ca. 87%

[0527] Synthesis of product 3B

[0528] The materials included 25 g of Propargyl-PEG-OH, CAS: [208827-90-1], 32.9 g of tosyl chloride, 26.884 g (37.030 mL) of triethylamine and 265.67 mL of DCM.

[0529] In an argon purged round bottom flask, propargyl-PEG4-OH was dissolved in 270 mL of DCM. Then, 37 mL of TEA was added and the solution was stirred for 5 min. Tosyl chloride was added in small portions as a solid over 10 min with stirring. Stirring was continued overnight at ambient temperature. In process control (TLC MeOH:DCM 2%). After the reaction was complete, 10-20 mL of hexane was added and the precipitate (triethylammonium chloride) was filtered, then the solvent mixture was rotary evaporated to dryness and left under high vacuum for 30 min to 1 h.

[0530] Purification: The oil was then loaded onto a 220 g silica cartridge using toluene (flow rate: 120 mL / min; eluent: Hex / EtOAc; gradient profile 5 min isocratic 20% EtOAc, 15 min gradient 20 to 60% EtOAc, 5 min isocratic 60% EtOAc, 5 min gradient 60% to 100% EtOAc, 5 min isocratic 100% EtOAc).

[0531] Yield: about 77%, 34.9 g of product 3B

[0532] Synthesis of product 4B

[0533] The materials included 16.975 g of Benzylidene-D-mannitol-di-4PEGAlkyne, 28 g (23.3 mL) of hydrochloric acid 37%, 173.5 mL of methanol, and 28.7 g (39.6 mL) of triethylamine.

[0534] 175 mL of MeOH was added to a round bottom flask purged with argon containing product 2B. After product 2B was dissolved, 23.3 mL of 37% HCl was added and the flask was stirred while kept under a static atmosphere of argon. The reaction was left at room temperature for 15 hours. Process control (TLC EtOAc:Hexane 6:1) Rf: 0.15. In an attempt to push the equilibrium towards the product and maximize the yield, 100 mL of diethyl ether, 150 mL of water and 50 mL of hexane were added to form a hydrophobic layer on top and push some of the benzaldehyde into this layer. The reaction was left under these conditions for an additional 2 hours (top layer turned slightly yellow). Workup: First, the reaction was neutralized and titrated with triethylamine until an observable pH of approximately 6.5-7.5 (pH strip, bottom layer) was reached.

[0535] After neutralization, the more volatile components were evaporated on a rotary evaporator and 150 mL to 200 mL of liquid was collected, including MeOH. The remaining layer was transferred to a separatory funnel and 200 mL of water was added, followed by 50 mL of diethyl ether (to extract the benzaldehyde and non-polar residues). The mixture was shaken and the organic layer turned yellow before being separated.

[0536] Afterwards, an additional 50 mL of diethyl ether was added and the process was repeated. The aqueous layer was set aside and then the combined organic layer was back-extracted by adding 10 mL of hexane (the organic layer turned cloudy) and extracting twice with 30 mL of water. TLC showed that both aqueous layers (original and back extract) contained mainly product, and the organic layer contained mainly benzaldehyde and some starting material. The aqueous layers were combined and the water was evaporated on a rotary evaporator to form triethylammonium chloride, which precipitated with an oil (product 4B). This oil-salt mixture was azeotroped with acetonitrile, dried under high vacuum and kept under an argon atmosphere.

[0537] The resulting dried oil-salt mixture was taken directly to the next step without further treatment.

[0538] Process Control: TLC: EtOAc:Hex 6:1

[0539] NMR 1H and 13C (ACN-d3)

[0540] MS(ESI)

[0541] Yield: Assume approximately 100% for the following reaction.

[0542] Synthesis of product 5B

[0543] The materials included 12.7 g of D-Mannitol-di-4PEGAlkyne (Product 4B), 16.05 g of DMT-Cl, 7.37 g (10.16 mL) of triethylamine, and 40 mL of DCM.

[0544] The flask containing the dried product 4B and triethylammonium chloride was purged with fresh argon and equipped with a stir bar. 40 mL of DCM was then added to dissolve the product 4B, followed by 10.2 mL of triethylamine and stirred for 2 minutes. To this was added 16.05 g of DMT-Cl as a solid in small portions over 5 minutes. The reaction turned reddish, then yellow, and later greenish in color. The reaction was monitored by TLC (4:1 EtOAc:Hex Rf: 0.55 or 5% MeOH:DCM Rf: 0.41) until completion.

[0545] Workup: 10 mL of hexane was added, the triethylammonium chloride was filtered through a frit, the collected crystals were rinsed with 20 mL of DCM, and the solvent was then rotary evaporated to dryness.

[0546] Purification (The oil was then loaded onto a 220 g silica cartridge using toluene to filter off remaining triethylammonium chloride. Flow rate: 120 mL / min; eluent: Hex / EtOAc; gradient profile: 8 min isocratic 100% Hex, 15 min gradient 0-50% EtOAc, 3 min isocratic 50% EtOAc, 10 min gradient 50% to 85% EtOAc, 6 min isocratic 100% EtOAc).

[0547] Process control: NMR 1H and 13C (CAN-d3), MS (ESI)

[0548] Yield: 59%, 16 g of product 5B (2 steps)

[0549] Synthesis of product 7B

[0550] The materials included 16 g of D-Mannitol-di-4PEGAlkyne-di-DMT (Product 5B), 4.55 g of NaIO4, 2.02 g (2.07 mL) of pyridine, 85 mL of THF, and 15 mL of water.

[0551] The round bottom flask containing product 5B was purged with fresh argon and product 5B was dissolved in 85 mL of THF. After complete dissolution, 2.1 mL of pyridine was added and stirred for 1 min, then 4.55 g of NaIO4 was added with stirring. Water was then added in 3 mL portions and a white precipitate began to form. Since DMT can be eliminated in the presence of NaIO4 / NaIO3 / H2O, it was essential to monitor the progress of the reaction and adjust the amounts of water and pyridine accordingly when the major DMT by-product was observed by TLC.

[0552] At this scale and under these conditions, the reaction took 6-7 hours to complete, but could be sped up by adding more NaIO4 or heating slightly (~40 °C). Of course, this was done, but the ratio of water and pyridine would also need to be adjusted to avoid decomposition. TLC (5:1 EtOAc:Hex Rf: 0.68). After the reaction appeared to be complete, the white solid was filtered, more THF (~180 mL) was added, and the resulting solution was taken to the next step without further treatment, assuming a yield of 200% (2 equiv. formed).

[0553] reduction

[0554] 16g (estimated) of DMT-4PEGAlkyne-Aldehyde (Product 6B)

[0555] 1.07g NaBH4

[0556] 283 mL of THF

[0557] The filtrate from the oxidation was collected in an argon purged round bottom flask equipped with a stir bar. The solution was cooled to 0°C in an ice bath, then 1.07g of NaBH4 was added while keeping the vessel in the ice bath for the first part of the reaction, after 15 min the flask was removed from the ice bath and left at room temperature while being monitored by TLC (5:1 EtOAc:Hex Rf: 0.48). Once the reaction was complete it was quenched with acetone, 100mL of water was added, and the product 7B was extracted 4 times with 50mL of EtOAc (10mL of brine can be added to the aqueous layer to improve the results). The isolated organic extract was then dried over sodium sulfate and then evaporated on a rotary evaporator.

[0558] purification

[0559] The oil was then loaded onto a 220 g silica cartridge using toluene.

[0560] Flow rate: 120mL / min

[0561] Eluent: Hex / EtOAc, then EtOAc / MeOH*

[0562] Gradient Profile

[0563] 10 min isocratic 100% hexane

[0564] 28 min gradient 0-100% EtOAc

[0565] 3 min isocratic 100% EtOAc

[0566] 10 min gradient 0% to 5% MeOH*

[0567] 10 min isocratic 5% MeOH

[0568] Process control: NMR 1H and 13C (ACN-d3), MS (ESI)

[0569] Yield 166% over two steps, 13.3 g product 7B (2 equivalents produced)

[0570] Synthesis of product 8B

[0571] The materials included 20 g of 2-azidoethanol, 41.9 g of benzoyl chloride, 75.5 g (104.1 mL) of triethylamine, and 306.27 mL of DCM.

[0572] In a round bottom flask equipped with a stir bar, 20 g of 2-azidoethanol was diluted with DCM. Under an argon blanket, 75.5 g (104.1 mL) of TEA was added, followed by the slow addition of benzoyl chloride. The reaction was allowed to proceed for 16-24 h at room temperature monitored by TLC (1:4 EtOAc:Hex Rf: 0.61). Workup: 30 mL of hexane was added, then the precipitate was filtered using a frit (triethylammonium chloride), rinsed with DCM, and evaporated on a rotary evaporator.

[0573] purification

[0574] The oil was then loaded neat onto a 220 g silica cartridge and first filtered to remove residual triethylammonium chloride and then chased with hexane.

[0575] Flow rate: 120mL / min

[0576] Eluent: Hex / EtOAc

[0577] Gradient Profile

[0578] 5 min isocratic 100% hexane

[0579] 5 min gradient 0-5% EtOAc

[0580] 15 min isocratic 5% EtOAc

[0581] 5 min gradient 5% to 20% EtOAc

[0582] 10 min isocratic 20% EtOAc

[0583] Process control: NMR 1H and 13C (ACN-d3)

[0584] Yield: quantitative

[0585] Synthesis of product 9B

[0586] The materials included 13.4 g of DMT-Gly-4PEGalkyne-OH (Product 7B), 5.87 g of azido-ethyl-benzoyl (Product 8B), 9.36 g of sodium ascorbate, 1.18 g of CuSO4 pentahydrate, 53 mL of water, and 107.4 mL of DMSO.

[0587] In a separate flask, the catalyst mixture was prepared by dissolving sodium ascorbate in water / DMSO and dissolving CuSO4 pentahydrate in water. The remaining DMSO (2 / 3) was used to dissolve 13.4 g of product 7B in a round bottom flask under an argon blanket. The sodium ascorbate and CuSO4 solutions were combined first. Meanwhile, 5.87 g of azido-ethyl-benzoyl (product 8B) was added to the round bottom flask. After stirring for 3 minutes, the catalyst mixture was added to the solution of products 7B and 8B. The reaction was left at room temperature and monitored by TLC (100% EtOAc Rf: 0.25 or 5% MeOH:DCM Rf: 0.38).

[0588] Quenching: The reaction was quenched with a solution of EDTA 0.5 molar, pH 8, then 200 mL of EtOAc, 200 mL of water and 50 mL of brine were added and the mixture was swirled until the yellow / brownish solid dissolved and a blue / greenish layer (aqueous) and a clear layer (organic) were obtained. This was transferred to a separatory funnel and the aqueous layer was washed 4 times with EtOAc. The combined organic fractions were dried over sodium sulfate, then decanted and the liquid was evaporated on a rotary evaporator.

[0589] purification

[0590] The oil was then loaded neat onto a 220 g silica cartridge using toluene.

[0591] Flow rate: 120mL / min

[0592] Eluent: Hex / EtOAc, then EtOAc / MeOH*

[0593] Gradient Profile

[0594] 5 min isocratic 100% hexane

[0595] 20 min gradient 0-100% EtOAc

[0596] 10 min isocratic 100% EtOAc

[0597] 8 min gradient 0% to 6% MeOH*

[0598] 12 min gradient 6% to 10% MeOH

[0599] Process control: NMR 1H, TLC

[0600] Yield 75% 13.4g of product 9B

[0601] Synthesis of product 10B

[0602] The materials included 13.4 g of product 9B, 3.76 g (3.54 mL) of 2-cyanoethyl N,N-diisopropylchlorophosphoramidite (PPA-Cl), 3.57 (4.92 mL) of triethylamine, 100.8 mL of DCM, and 60 mL of toluene.

[0603] Product 9B was dried extensively under high vacuum (1 day). On the day of reaction, the flask containing product 9B was filled with argon and product 9B was dissolved in dry DCM. Then, 3.76 g (3.54 mL) of PPA-Cl and triethylamine (4.92 mL) were measured in a glove box. Triethylamine was first added to the flask under positive argon pressure and stirred for 1 min, then PPA-Cl was added slowly also under positive argon pressure. The reaction was left stirring at room temperature under argon and monitored by TLC (1% triethylamine in EtOAc Rf: 0.67). Once the reaction was complete, the solvent was evaporated on a rotary evaporator, the round-bottom flask was filled with argon while releasing the vacuum, and then the product was purified after keeping it under high vacuum.

[0604] purification

[0605] After evacuating most of the air and creating an argon blanket, dry toluene was transferred to a 50 mL Falcon tube and then a drying trap was immersed in the solvent to further / maintain dryness. Product 10B was dissolved in dry toluene and loaded onto a 220 g silica cartridge.

[0606] Flow rate: 120mL / min

[0607] Eluent: Hex0.5%TEA / EtOAc0.5%TEA

[0608] A dry trap was added to each solvent at least 1 hour prior to purification, and dry TEA was used for basification of hexanes and EtOAc.

[0609] Extended equilibration (14 min) to ensure neutralization of the silica-cartridge before the run.

[0610] Gradient Profile

[0611] 8 minutes isocratic 100% (Hex 0.5% TEA)

[0612] 12 min gradient 0-66% (EtOAc 0.5% TEA)

[0613] 20 min isocratic 100% (EtOAc 0.5% TEA)

[0614] Process control: NMR 1H and 31P (ACN-d3)

[0615] Yield: 71% of product 10B

[0616] Example 17 - Synthesis of DMT phosphoramidite via mannitol [ka]

[0617] Synthesis of compound 11C

[0618] The materials included 10 g of 1,3:4,6-di-O-benzylidene-D-mannitol CAS: 28224-73-9 (Product 1C) (see procedure in Example 16 for synthesis of Product 1B), 4.46 g of sodium hydride (60% in mineral oil), 30.34 g of Product 12C (see procedure below), and 120 mL of THF.

[0619] A dry 1000 mL round bottom flask equipped with a stir bar was purged with argon. To this was added 10 g of product 1C followed by 120 mL of dry THF and stirred until product 1C was completely dispersed (at this concentration, the benzylidene does not appear to completely dissolve). Once a uniform dispersion was achieved, it was cooled in an ice bath and stirred for 5 minutes. To the cold dispersion was added 4.46 g of sodium hydride, allowing effervescence to cease after each addition. Then 28.66 g of product 12C was added slowly with stirring. After the addition was complete, the mixture was stirred in an ice bath for an additional 5 minutes, then the mixture was allowed to warm to room temperature and left under an argon atmosphere for approximately 60 hours. The reaction was monitored by TLC (3:2 EtOAc:Hexane) Rf=0.12.

[0620] The reaction was quenched by placing two 1 L Erlenmeyer in an ice bath and then splitting the reaction mixture between them. First, 5 mL of water was added to each, and 100 mL of EtOAc was also added quickly, allowing the bubbling to dissipate and gently swirling. Then, 5 mL of water was added to each, followed by 50 mL of EtOAc, and this was repeated 2-3 more times until the bubbling after each water addition stopped. Then, 100 mL of water was added, followed by 100 mL of EtOAc, swirled the Erlenmeyer, allowed to stand for 3-5 minutes, then more water and EtOAc were added until about 200 mL of water and about 400 mL of EtOAc were completed. This was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was then extracted 3-4 times with EtOAc until no more product was observed by TLC. Some brine (20-30 mL) can be added to help separate the emulsion more quickly. Finally, dried over sodium sulfate for 30 minutes.

[0621] purification

[0622] The organic layer was decanted and the sodium sulfate was rinsed with additional EtOAc. The collected liquid was then rotary evaporated until a thick yellow oil was obtained. This oil was placed under high vacuum for 1 hour. It was then loaded onto a 220 g silica cartridge using a minimum of DCM.

[0623] Flow rate: 120mL / min

[0624] Eluent: Hex / EtOAc

[0625] Gradient Profile

[0626] 6 min 100% hexane

[0627] 15 min gradient 0-55% EtOAc

[0628] 10 min isocratic 55% EtOAC

[0629] 15 min gradient 55% to 100% EtOAc

[0630] 35 min isocratic 100% EtOAc

[0631] Process Control

[0632] TLC: 3:2 EtOAc:Hexane

[0633] NMR 1H and 13C (ACN-d3)

[0634] MS(ESI)

[0635] Yield: 79% 16.18g of product 11C

[0636] Synthesis of product 12C

[0637] The materials included 25 g of m-PEG4-OH, CAS: [23783-42-8], 29.75 g of tosyl chloride, 24.29 g (33.4 mL) of triethylamine and 240.1 mL of DCM.

[0638] In an argon purged round bottom flask, m-PEG4-OH was dissolved in 240 mL of DCM. Then, 33 mL of TEA was added and the solution was stirred for 5 min. Tosyl chloride was added in small portions as a solid over 10 min with stirring. Stirring was continued overnight at ambient temperature. In process control (TLC MeOH:DCM 2%). After the reaction was complete, 10-20 mL of hexane was added and the precipitate (triethylammonium chloride) was filtered, then the solvent mixture was rotary evaporated to dryness and left under high vacuum for 30 min to 1 h.

[0639] purification

[0640] The oil was then loaded onto a 220 g silica cartridge using toluene.

[0641] Flow rate: 120mL / min

[0642] Eluent: Hex / EtOAc

[0643] Gradient Profile

[0644] 3 min isocratic 100% hexane

[0645] 5 min gradient 20% EtOAc

[0646] 5 min isocratic 20% EtOAc

[0647] 16 min gradient 20-60% EtOAc

[0648] 5 min isocratic 60% EtOAc

[0649] 5 min gradient 60% to 100% EtOAc

[0650] 5 min isocratic 100% EtOAc

[0651] Yield: 75% 32.6g of product 12C

[0652] Synthesis of compound 13C

[0653] The materials included 16.18 g of Benzylidene-D-mannitol-di-4PEGAlkyne, 25.25 g (21.04 mL) of hydrochloric acid 37%, 156.4 mL of methanol, and 25.9 g (35.7 mL) of triethylamine.

[0654] 156 mL of MeOH was added to a round bottom flask purged with argon containing product 11C. After product 11C was dissolved, 21 mL of 37% HCl was added and the flask was stirred while kept under a static atmosphere of argon. The reaction was left at room temperature for 15 hours. Process control (TLC EtOAc:Hexane 6:1) Rf: 0.05. In an attempt to push the equilibrium towards the product and maximize the yield, 100 mL of diethyl ether, 150 mL of water and 50 mL of hexane were added to form a hydrophobic layer on top and push some of the benzaldehyde into this layer. The reaction was left under these conditions for an additional 2 hours (top layer turned slightly yellow). Workup: First, the reaction was neutralized and titrated with triethylamine until an observable pH of approximately 6.5-7.5 (pH strip, bottom layer) was reached.

[0655] After neutralization, the more volatile components were evaporated on a rotary evaporator and 150 mL to 200 mL of liquid containing MeOH was collected. The remaining layer was transferred to a separatory funnel and 200 mL of water was added followed by 50 mL of diethyl ether (to extract the benzaldehyde and non-polar residues). The mixture was shaken and the organic layer turned yellow before being separated. An additional 50 mL of diethyl ether was then added and the process repeated. The aqueous layer was set aside and then the collected organic layer was back-extracted by adding 10 mL of hexane (the organic layer turned cloudy) and extracting twice with 30 mL of water. TLC showed that both aqueous layers (original extract and back extract) contained mainly product and the organic layer contained mainly benzaldehyde and some starting material. The aqueous layers were combined and the water was evaporated on a rotary evaporator to form triethylammonium chloride which precipitated with an oil (product 13C). The oil-salt mixture was azeotroped with acetonitrile, dried under high vacuum and kept under an atmosphere of argon.

[0656] The resulting dried oil-salt mixture was taken directly to the next step without further treatment.

[0657] Process Control

[0658] TLC: EtOAc:Hexane 6:1

[0659] NMR 1H and 13C (CAN-d3)

[0660] MS(ESI)

[0661] Yield: Assume 100% for the following reactions.

[0662] Synthesis of product 14C

[0663] The materials contained 12.3 g of D-mannitol-di-mPEG4 (product 13C), 14.47 g of DMT-Cl.

[0664] It contained 6.65 g (9.16 mL) of triethylamine and 36 mL of DCM.

[0665] The flask containing the dried product 13C and triethylammonium chloride was purged with fresh argon and equipped with a stir bar. 36 mL of DCM was then added to dissolve the product 13C, 9.2 mL of triethylamine was added, and after stirring for 2 minutes, 14.47 g of DMT-Cl was added in small portions over 5 minutes. The reaction turned reddish, then yellow, and later greenish in color. The reaction was monitored by TLC (4:1 EtOAc:Hex Rf: 0.14 or 5% MeOH:DCM Rf: 0.3) until completion.

[0666] Workup: 10 mL of hexane was added, the triethylammonium chloride was filtered through a frit, the collected crystals were rinsed with 20 mL of DCM, and the solvent was then rotary evaporated to dryness.

[0667] purification

[0668] The oil was then loaded onto a 220 g silica cartridge using toluene to filter off the remaining triethylammonium chloride.

[0669] Flow rate: 120mL / min

[0670] Eluent: Hex / EtOAc, then EtOAc / MeOH*

[0671] Gradient Profile

[0672] 8 min isocratic 100% hexane

[0673] 15 min gradient 0-75% EtOAc

[0674] 10 min isocratic 75% EtOAc

[0675] 5 min gradient 75% to 100% EtOAc

[0676] 1 min isocratic 100% EtOAc

[0677] 1 min gradient 0% to 5% MeOH*

[0678] 20 min isocratic 5% MeOH

[0679] Process control: NMR 1H and 13C (ACN-d3), MS (ESI)

[0680] Yield: 72% 18.5g of product 14C

[0681] Synthesis of product 16C

[0682] oxidative cleavage

[0683] The materials included 18.505 g of D-mannitol-di-m4PEG-di-DMT (product 14C), 5.09 g of NaIO4, 2.26 g (2.31 mL) of pyridine, 95 mL of THF, and 17 mL of water.

[0684] The round bottom flask containing product 14C was purged with fresh argon and product 14C was dissolved in 95 mL of THF. After complete dissolution, 2.3 mL of pyridine was added and stirred for 1 min, then 5.09 g of NaIO4 was added with stirring. Water was then added in 3 mL portions and a white precipitate began to form. Since DMT can be eliminated in the presence of NaIO4 / NaIO3 / H2O, it was essential to monitor the progress of the reaction and adjust the amount of water and pyridine accordingly when the major DMT by-product was observed by TLC.

[0685] At this scale and under these conditions, the reaction takes 6-7 hours to complete, but could be accelerated by adding more NaIO4 or heating slightly (~40 °C). If this was done, the water and pyridine ratios also needed to be adjusted to avoid decomposition. TLC (5:1 EtOAc:Hex Rf: 0.22). After the reaction appeared to be complete, the white solid was filtered, more THF (~150 mL) was added, and the resulting solution was taken to the next step without further treatment, assuming a yield of 200% (2 equiv. formed).

[0686] As an alternative to NaIO4, any reagent capable of oxidizing vicinal diols in a similar manner may be utilized. Suitable reagents include, but are not limited to, IBX (2-iodoxybenzoic acid), Dess-Martin periodinane, Pb(OAc)4 or periodic acid and its several salt forms.

[0687] reduction

[0688] The materials are:

[0689] It contained 18.5 g (assumed) DMT-m4PEG-aldehyde (product 15C), 1.24 g NaBH4 and 328 mL THF.

[0690] The filtrate from the oxidation was collected in an argon purged round bottom flask equipped with a stir bar. The solution was cooled to 0°C in an ice bath, then 1.24g of NaBH4 was added while keeping the vessel in the ice bath for the first part of the reaction, after 15 min the flask was removed from the ice bath and left at room temperature while being monitored by TLC (5:1 EtOAc:Hex Rf: 0.11). Once the reaction was complete it was quenched with acetone, 100mL of water was added, and the product 16C was extracted 4 times with 50mL of EtOAc (10mL of brine can be added to the aqueous layer to improve the results). The isolated organic extract was then dried over sodium sulfate and then evaporated on a rotary evaporator.

[0691] purification

[0692] The oil was then loaded onto a 220 g silica cartridge using toluene.

[0693] Flow rate: 120mL / min

[0694] Eluent: Hex / EtOAc, then EtOAc / MeOH*

[0695] Gradient Profile

[0696] 7 min isocratic 100% hexane

[0697] 30 min gradient 0-100% EtOAc

[0698] 10 min isocratic 100% EtOAc

[0699] 10 min gradient 0% to 5% MeOH*

[0700] 15 min gradient 5% to 8% MeOH

[0701] Process control: NMR 1H and 13C (ACN-d3), MS (ESI)

[0702] Synthesis of product 17C

[0703] The materials included 14.9 g of product 16C, 5.42 g (5.11 mL) of 2-cyanoethyl N,N-diisopropylchlorophosphoramidite (PPA-Cl), 5.15 (7.09 mL) of triethylamine, 145 mL of DCM, and 70 mL of toluene.

[0704] Product 16C was dried extensively under high vacuum (1 day). On the day of reaction, the flask containing product 16C was filled with argon and product 16C was dissolved in dry DCM. Then, 5.42 g (5.11 mL) of PPA-Cl and triethylamine (7.09 mL) were measured in a glove box. Triethylamine was first added to the flask under positive argon pressure and stirred for 1 min, then PPA-Cl was added slowly also under positive argon pressure. The reaction was left stirring at room temperature under argon and monitored by TLC (1% triethylamine in EtOAc Rf: 0.7). Once the reaction was complete, the solvent was evaporated on a rotary evaporator, the round-bottom flask was filled with argon while releasing the vacuum, and then the product was purified after keeping it under high vacuum.

[0705] purification

[0706] After evacuating most of the air and creating an argon blanket, dry toluene was transferred to a 50 mL Falcon tube and then a drying trap was immersed in the solvent to further / maintain dryness. The product 17C was dissolved in dry toluene and loaded onto a 220 g silica cartridge.

[0707] Flow rate: 120mL / min

[0708] Eluent: Hex0.5%TEA / EtOAc0.5%TEA

[0709] A dry trap was added to each solvent 1 h prior to purification, and dry TEA was used for basification of hexanes and EtOAc.

[0710] Extended equilibration (14 min) to ensure neutralization of the silica-cartridge before the run.

[0711] Gradient Profile

[0712] 5 min isocratic 100% (Hex 0.5% TEA)

[0713] 10 min gradient 0-50% (EtOAc 0.5% TEA)

[0714] 15 min isocratic 50% (EtOAc 0.5% TEA)

[0715] Process Control NMR 1H and 31P (ACN-d3)

[0716] Yield: 73% 14.6g of product 17C

[0717] Example 18: Synthesis of DMT phosphoramidite via MTM protecting group [ka]

[0718] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in anhydrous THF and cooled to 0° C., and NaH (60% dispersion in mineral oil), MTM-Cl and NaI were added and stirred at room temperature. After the reaction was complete, 5% aqueous NH4Cl was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 16 in 76% yield.

[0719] Thioether 16 was dissolved in 90% AcOH and heated at 80° C. for 20 min. The solvent was removed under reduced pressure. The residue was resuspended in EtOAc and extracted with water and brine. Evaporation of the solvent gave diol 39 in 90% yield.

[0720] The diol 39 was dissolved in toluene and TEA. A solution of DMT-Cl in toluene was added dropwise at room temperature. The reaction mixture was extracted with water and brine. The solvent was evaporated and the residue was purified by flash chromatography to give the mono-trityl product 40 in 60% yield.

[0721] The secondary alcohol 40 was dissolved in THF, and NaH (60% dispersion in mineral oil) and mPEG4Tos were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 41 in 63% yield.

[0722] The mPEG4 ether 41 was dissolved in THF / H2O 4 / 1 and 100-fold excess of lutidine and AgNO3 was added. After 3 h, the precipitate was filtered off. The solvent was evaporated and the crude product was purified by flash chromatography to give the alcohol 7 in 60% yield.

[0723] Alcohol 7 was dissolved in ACN and TEA. PPA-Cl was added and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and the solvent was dried under reduced pressure. The crude product was purified by flash chromatography to give 1 in 60% yield. The structure of phosphoramidite 1 was confirmed by 1H and 31P NMR (CD3CN). No regioisomers were detected.

[0724] Example 19: Synthesis of DMT phosphoramidite 1b via MTM protection [ka]

[0725] 2,3-Isopropylidene-sn-glycerol 9 was dissolved in anhydrous THF and cooled to 0° C., and NaH (60% dispersion in mineral oil), MTM-Cl and NaI were added and stirred at room temperature. After the reaction was complete, 5% aqueous NH4Cl was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 16 in 76% yield.

[0726] Thioether 16 was dissolved in 90% AcOH and heated at 80° C. for 20 min. The solvent was removed under reduced pressure. The residue was resuspended in EtOAc and extracted with water and brine. Evaporation of the solvent gave diol 39 in 90% yield.

[0727] The diol 39 was dissolved in toluene and TEA. A solution of DMT-Cl in toluene was added dropwise at room temperature. The reaction mixture was extracted with water and brine. The solvent was evaporated and the residue was purified by flash chromatography to give the mono-trityl product 40 in 60% yield.

[0728] The secondary alcohol 40 was dissolved in THF, and NaH (60% dispersion in mineral oil) and pPEG4Tos were added. After the reaction was complete, water was added and the aqueous phase was extracted with EtOAc. The combined extracts were dried and concentrated in vacuo. The crude product was purified by flash chromatography to give 42 in 72% yield.

[0729] DMT PEG4 MTM protected alcohol 42 was dissolved in EtOH and 2-azidoethyl benzoate dissolved in DMSO was added. CuSO4 in H2O and sodium ascorbate in H2O were added to the reaction mixture. After 60 min, the reaction was quenched with 0.5 mol EDTA solution. The solvent was removed under reduced pressure. The residue was resuspended in H2O and extracted with EtOAc. The combined extracts were extracted with H2O and brine. The solvent was evaporated and the residue was purified by flash chromatography to give the product 43 in 68% yield.

[0730] Compound 43 was dissolved in THF / H2O 4 / 1 and 20-fold excess of lutidine and AgNO3 was added. After 4 h at 40 °C, the precipitate was filtered off. The solvent was evaporated and the crude product was purified by flash chromatography to give 33 in 54% yield.

[0731] DMT PEG alcohol 33 was dissolved in ACN and TEA. PPA-Cl was added and the reaction was stirred at room temperature for 1 h. The precipitate was filtered off and the solvent was dried under reduced pressure. The crude product was purified by flash chromatography to give 34 in 76% yield. The structure of phosphoramidite 34 was confirmed by 1H and 31P NMR (CD3CN) at 148.42 ppm, 148.37 ppm.

[0732] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to herein and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. Aspects of the above embodiments can be modified, if necessary, to employ concepts from the various patents, applications and publications to provide further embodiments.

[0733] Although the present disclosure has been described with reference to certain exemplary embodiments, it should be understood that many other modifications and embodiments may be devised by those skilled in the art that would fall within the spirit and scope of the principles of the present disclosure. More specifically, reasonable variations and modifications are possible in the components and / or arrangements of the combined configuration of the subject matter within the scope of the foregoing disclosure, the drawings, and the appended claims without departing from the spirit of the present disclosure. In addition to modifications and changes in the components and / or arrangements, alternative uses will also be apparent to those skilled in the art.

Claims

1. Formulae (IA) and (IB) 【Chemistry 1】 (In the formula, R １ is -OH, -O-R ｗ -Z and R ｗ is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, which may contain one or more oxygen heteroatoms; Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl, acyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety; R ２ is -OH, -O-trityl or a derivative or analogue thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analogue thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analogue thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analogue thereof, -O-1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, -O-[(chloro-4-methyl)phenyl]-4'-methoxypiperidin-4-yl, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether; A is CH; P.G. ２ is H, P.G. １ teeth, 【Chemistry 2】 -O-CH ２ -S-CH ３ , —O—CH ２ -N ３ , or -O-CH ２ -CH=CH ２ or P.G. １ -A-PG ２ are taken together as C(O)H, C(O)OMe, -C(O)OT, 【Chemistry 3】 Forming T is for C １ ~C ６ is a branched or unbranched alkyl group, f is 0 or 2; Each R ｕ are independently H, —O—C １ ~C ４ Alkyl, or -C １ ~C ４ is alkyl, Each R ｚ is independently a branched or unbranched C １ ~C ６ is an alkyl group, However, P.G. １ -A-PG ２ together form C(O)H, C(O)OMe or 【Chemistry 4】 When forming １ and R ２ are not both -OH) A compound having any one of the structures:

2. R ２ but, 【Chemistry 5】 (In the formula, each R ｓ are independently H, —O—C １ ~C ４ Alkyl, or -C １ ~C ４ 2. The compound of claim 1, wherein

3. R ２ but, 【Chemistry 6】 3. The compound of claim 2,

4. PG １ が、 【Chemistry 7】 4. The compound of claim 3,

5. The compound of claim 4 , wherein f is 2.

6. The compound of claim 4 , wherein f is 0.

7. R １ The compound of claim 4, wherein is -OH.

8. R １ Ga-O-R ｗ The compound of claim 4, wherein:

9. Z is an alkyl, alkenyl, alkynyl, -CH ２ The compound according to claim 8, wherein the aryl group is -alkynyl or acyl.

10. The compound of claim 8 wherein Z is alkyl.

11. Z is alkynyl or -CH ２ -alkynyl.

12. PG １ が、 【Chemistry 8】 4. The compound of claim 3,

13. R １ The compound of claim 12, wherein is -OH.

14. R １ Ga-O-R ｗ The compound of claim 12, wherein

15. Z is an alkyl, alkenyl, alkynyl, -CH ２ 15. The compound of claim 14, wherein said aryl group is -alkynyl or acyl.

16. 15. The compound of claim 14, wherein Z is alkyl.

17. Z is alkynyl or -CH ２ -alkynyl.

18. PG １ が、 【Chemistry 9】 4. The compound of claim 3,

19. R １ The compound of claim 18, wherein is -OH.

20. R １ But -O-R ｗ The compound of claim 18, wherein:

21. Z is an alkyl, alkenyl, alkynyl, -CH ２ 21. The compound of claim 20, wherein said aryl group is -alkynyl or acyl.

22. 21. The compound of claim 20, wherein Z is alkyl.

23. Z is alkynyl or -CH ２ -alkynyl.

24. P.G. １ But -O-CH ２ -N ３ or -O-CH ２ -S-CH ３ 4. The compound of claim 3,

25. R １ The compound of claim 24, wherein is -OH.

26. R １ Ga-O-R ｗ The compound of claim 24, wherein:

27. Z is an alkyl, alkenyl, alkynyl, -CH ２ 27. The compound of claim 26, wherein said aryl group is -alkynyl or acyl.

28. 27. The compound of claim 26, wherein Z is alkyl.

29. Z is alkynyl or -CH ２ -alkynyl.

30. P.G. １ But -O-CH ２ -CH=CH ２ 4. The compound of claim 3,

31. R １ The compound of claim 30, wherein is -OH.

32. R １ Ga-O-R ｗ The compound of claim 30, wherein:

33. Z is an alkyl, alkenyl, alkynyl, -CH ２ 33. The compound of claim 32, wherein said aryl group is -alkynyl or acyl.

34. 33. The compound of claim 32, wherein Z is alkyl.

35. Z is alkynyl or -CH ２ -alkynyl.

36. P.G. １ -A-PG ２ Together, they form C(O)H, C(O)OMe, -C(O)OT, 【Chemistry 10】 The compound according to claim 3, which forms:

37. R １ The compound of claim 36, wherein is -OH.

38. R １ Ga-O-R ｗ The compound of claim 36, wherein:

39. Z is an alkyl, alkenyl, alkynyl, -CH ２ 39. The compound of claim 38, wherein said aryl group is -alkynyl or acyl.

40. 39. The compound of claim 38, wherein Z is alkyl.

41. Z is alkynyl or -CH ２ -alkynyl.

42. R １ and R ２ are both -OH, and PG １ but, 【Chemistry 11】 -O-CH ２ -S-CH ３ , —O—CH ２ -N ３ or —O—CH ２ -CH=CH ２ 2. The compound of claim 1 ,

43. PG １ が 【Chemistry 12】 and f is 0.

44. PG １ が 【Chemistry 13】 and f is 2.

45. PG １ が 【Chemistry 14】 and each R ｚ C １ ~C ６ 43. The compound of claim 42, which is a branched or unbranched alkyl group.

46. PG １ が、 【Chemistry 15】 43. The compound of claim 42, wherein

47. 47. The compound of any one of claims 1 to 46, wherein the compound is regiomerically and enantiomerically pure.

48. Formula (IIIA) or (IIIB) 【Chemistry 16】 (In the formula, The P.G. 【Chemistry 17】 -CH ２ -S-CH ３ , -CH ２ -N ３ , or -CH ２ -CH=CH ２ and f is 0 or 2; Each R ｕ are independently H, —O—C １ -C ４ , or -C １ ~C ４ and Each R ｚ is independently a branched or unbranched C １ ~C ６ is an alkyl group) A compound having any one of the following structures:

49. P.G. 【Chemistry 18】 and f is 2.

50. P.G. 【Chemistry 19】 and f is 0.

51. P.G. 【Chemistry 20】 and each R ｚ C １ ~C ６ 49. The compound of claim 48, which is a branched or unbranched alkyl group.

52. PG, 【Chemistry 21】 49. The compound of claim 48, wherein:

53. The compound is 【Chemistry 22-1】 【Chemistry 22-2】 49. The compound of claim 48, selected from the group consisting of:

54. Formulae (IVA) and (IVB) 【Chemistry 23】 (In the formula, The P.G. 【Chemistry 24】 -CH ２ -S-CH ３ , -CH ２ -N ３ , or -CH ２ -CH=CH ２ and f is 0 or 2; Each R ｕ are independently H, —O—C １ -C ４ , or -C １ ~C ４ and Each R ｚ is independently a branched or unbranched C １ ~C ６ is an alkyl group, R ｘ and R ｙ is independently １ ~C ４ is an alkyl group) A compound having any one of the following structures:

55. R ｘ and R ｙ and R are both methyl.

56. P.G. 【Chemistry 25】 and f is 2.

57. P.G. 【Chemistry 26】 and f is 0.

58. P.G. 【Chemical 27】 and each R ｚ C １ ~C ６ 56. The compound of claim 55, which is a branched or unbranched alkyl group.

59. PG, 【Chemistry 28】 56. The compound of claim 55,

60. Formulae (VA) and (VB) 【Chemical 29】 (In the formula, The P.G. 【Chemistry 30】 -CH ２ -S-CH ３ , -CH ２ -N ３ , or -CH ２ -CH=CH ２ and R ３ teeth, 【Chemistry 31】 or —O-9-phenylthioxanthryl or a derivative or analogue thereof; f is 0 or 2; Each R ｕ are independently H, —O—C １ -C ４ Alkyl, or -C １ ~C ４ is alkyl, Each R ｓ are independently H, —O—C １ -C ４ Alkyl, or -C １ ~C ４ is alkyl, Each R ｚ is independently a branched or unbranched C １ ~C ６ is an alkyl group) A compound having any one of the following structures:

61. R ３ but, 【Chemistry 32】 61. The compound of claim 60,

62. P.G. 【Chemical 33】 and f is 0.

63. P.G. 【Chemical 34】 and f is 2.

64. P.G. 【Chemistry 35】 and each R ｚ C １ ~C ６ 61. The compound of claim 60, which is a branched or unbranched alkyl group.

65. PG, 【Chemical 36】 61. The compound of claim 60,

66. The compound is 【Hua 37-1】 【Hua 37-2】 (In the formula, R ３ is 4,4'-dimethoxytrityl ether, 4-methoxytrityl ether, or -O-(9-phenylthioxanthyl).

61. The compound of claim 60, selected from the group consisting of:

67. Formulae (VIIA) and (VIIB) 【Chemical Formula 38】 (In the formula, The P.G. 【Chemical Formula 39】 -CH ２ -S-CH ３ , -CH ２ -N ３ , or -CH ２ -CH ２ =CH ２ and R ３ teeth, 【Chemistry 40】 or —O-9-phenylthioxanthryl or a derivative or analogue thereof; Y is an alkyl, alkenyl, alkynyl, acyl, -CH ２ -alkynyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety; Each R ｕ are independently H, —O—C １ -C ４ Alkyl, or -C １ ~C ４ is alkyl, Each R ｓ are independently H, —O—C １ -C ４ Alkyl, or -C １ ~C ４ is alkyl, Each R ｚ is independently a branched or unbranched C １ ~C ６ is an alkyl group, e is an integer ranging from 1 to about 36; f is 0 or 2. A compound having any one of the following structures:

68. R ３ but, 【Chemistry 41】 68. The compound of claim 67,

69. P.G. 【Chemistry 42】 and f is 0.

70. P.G. 【Chemistry 43】 and f is 2.

71. P.G. 【Chemistry 44】 and each R ｚ C １ ~C ６ 68. The compound of claim 67, which is a branched or unbranched alkyl group.

72. PG, 【Chemistry 45】 68. The compound of claim 67,

73. 68. The compound of claim 67, wherein e is in the range of 2 to 24.

74. 68. The compound of claim 67, wherein e is in the range of 2 to 12.

75. 68. The compound of claim 67, wherein e is 3 or 4.

76. 68. The compound of claim 67, wherein Y is alkyl.

77. Y is -CH ３ 68. The compound of claim 67,

78. Y is alkynyl or -CH ２ -alkynyl.

79. Y, 【Chemistry 46】 68. The compound of claim 67,

80. Y is (i) -Het, or (ii) or -CH ２ 68. The compound of claim 67, comprising any of the following: -Het, wherein "Het" is a substituted 5-membered heterocyclic moiety.

81. 81. The compound of claim 80, wherein the five-membered heterocyclic moiety is a triazole.

82. 82. The compound of claim 81, wherein the triazole is substituted with an alkylaryl group.

83. below, 【Chemistry 47-1】 【Chemistry 47-2】 (In the formula, R ３ is 4,4'-dimethoxytrityl ether, 4-methoxytrityl ether, or -O-(9-phenylthioxanthyl), R ４ is -O-PEG ３ -Y or -O-PEG ４ -Y, Y is methyl, -CH=CH ２ , 【Chemistry 48】 -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety. A compound selected from the group consisting of:

84. 84. The compound of any one of claims 48 to 83, wherein the compound is regiomerically and enantiomerically pure.

85. Formulae (XA) and (XB) 【Chemistry 49】 (In the formula, W is H, —O—CH ３ or -OT, T being C １ ~C ６ is a branched or unbranched alkyl group, R ７ is -O-R ｗ -Z and R ｗ is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, which may contain one or more oxygen heteroatoms; Z is an alkyl, alkenyl, -CH ２ -alkynyl, alkynyl, acyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety. A compound having any one of the following structures:

86. R ｗ 86. The compound of claim 85, wherein contains 2 to about 50 carbon atoms and contains one or more oxygen heteroatoms.

87. R ｗ 86. The compound of claim 85, wherein contains 2 to about 40 carbon atoms and contains one or more oxygen heteroatoms.

88. R ｗ 86. The compound of claim 85, wherein contains 2 to about 20 carbon atoms and contains one or more oxygen heteroatoms.

89. Z is alkynyl or -CH ２ -alkynyl.

90. Z is -CH ３ 86. The compound of claim 85,

91. Z is (i) -Het, or (ii) or -CH ２ 86. The compound of claim 85, comprising any of the following: -Het, wherein "Het" is a substituted 5-membered heterocyclic moiety.

92. 86. The compound of claim 85, wherein Z is a 5-membered heterocyclic moiety substituted with an alkylaryl group.

93. The alkylaryl group is —CH ２ -CH ２ 93. The compound of claim 92, which is -O-Bz.

94. R ７ has formula (VIIIA) or (VIIIB): 【Chemistry 50】 and R ａ and R ｂ are independently H or C １ ~C ４ is alkyl, Y is alkyl, alkenyl, alkynyl, acyl, -CH ２ -alkynyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety; d is an integer ranging from 1 to about 10; 86. The compound of claim 85, wherein e is an integer ranging from 1 to about 36.

95. 95. The compound of claim 94, wherein d is 1 and e is in the range of 2 to 24.

96. 95. The compound of claim 94, wherein d is 2 and e is in the range of 2 to 24.

97. R ａ Or R ｂ At least one of the groups is -CH ３ 95. The compound of claim 94, wherein:

98. 95. The compound of claim 94, wherein d is 1 or 2, e ranges from 2 to 24, and Y is alkyl.

99. 99. The compound of claim 98, wherein e is 3 or 4.

100. d is 1 or 2, e is in the range of 2 to 24, and Y is alkynyl or -CH ２ -alkynyl.

101. 100. The compound of claim 99, wherein e is 4.

102. 95. The compound of claim 94, wherein d is 1 or 2, e ranges from 2 to 24, and Y is acyl.

103. 95. The compound of claim 94, wherein d is 1 or 2, e ranges from 2 to 24, and Y is alkenyl.

104. 【Chemical 51】 86. The compound of claim 85, selected from the group consisting of:

105. Formulae (XIA) and (XIB) 【Chemistry 52】 (In the formula, W is H, —O—CH ３ or -OT, T being C １ ~C ６ is a branched or unbranched alkyl group, R ８ is -OH, -O-trityl or a derivative or analog thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analog thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analog thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analog thereof, -O-1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, -O-[(chloro-4-methyl)phenyl]-4'-methoxypiperidin-4-yl, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether. A compound having any one of the following structures:

106. R ８ But, 【Chemistry 53】 (Each R ｓ are independently H, —O—C １ -C ４ Alkyl, or -C １ -C ４ is alkyl) 106. The compound of claim 105, selected from the group consisting of:

107. R ８ but, 【Chemical 54】 The compound of claim 105,

108. below 【Chemistry 55】 where e is an integer ranging from 1 to about 24, and Y is an alkyl, alkenyl, alkynyl, acyl, -CH ２ -alkynyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety. A compound selected from the group consisting of:

109. The compound of claim 108, wherein e is 8.

110. Y is alkynyl or -CH ２ -alkynyl.

111. The compound of claim 108, wherein e is 3 or 4.

112. Y is alkynyl or -CH ２ -alkynyl.

113. The compound of claim 108, wherein e is 12.

114. The compound of any one of claims 85 to 113, wherein the compound is regiomerically and enantiomerically pure.

115. 48. A regioisomerically pure phosphoramidite-containing monomer derived from the regioisomerically pure compound of claim 47.

116. 116. A polymer derived from the regioisomerically pure phosphoramidite-containing monomers of claim 115.

117. 116. A copolymer derived from a first regioisomerically pure phosphoramidite-containing monomer as described in claim 115 and a second regioisomerically pure phosphoramidite-containing monomer as described in claim 115, wherein the first regioisomerically pure phosphoramidite-containing monomer and the second regioisomerically pure phosphoramidite-containing monomer are different.

118. 118. An XNTP comprising the polymer of claim 116 or the copolymer of claim 117.

119. 85. A regioisomerically pure phosphoramidite-containing monomer derived from the regioisomerically pure compound of claim 84.

120. 120. A polymer derived from the regioisomerically pure phosphoramidite-containing monomers of claim 119.

121. 120. A copolymer derived from a first regioisomerically pure phosphoramidite-containing monomer as described in claim 119 and a second regioisomerically pure phosphoramidite-containing monomer as described in claim 119, wherein the first regioisomerically pure phosphoramidite-containing monomer and the second regioisomerically pure phosphoramidite-containing monomer are different.

122. 122. An XNTP comprising the polymer of claim 120 or the copolymer of claim 121.

123. 115. A regioisomerically pure phosphoramidite-containing monomer derived from the regioisomerically pure compound of claim 114.

124. 124. A polymer derived from the regioisomerically pure phosphoramidite-containing monomers of claim 123.

125. 124. A copolymer derived from a first regioisomerically pure phosphoramidite-containing monomer as described in claim 123 and a second regioisomerically pure phosphoramidite-containing monomer as described in claim 123, wherein the first regioisomerically pure phosphoramidite-containing monomer and the second regioisomerically pure phosphoramidite-containing monomer are different.

126. 126. An XNTP comprising the polymer of claim 124 or the copolymer of claim 125.

127. A method for the synthesis of a regioisomerically and enantiomerically pure monomer having any one of formulae (VIIIA) to (VIIID), comprising the steps of: (a) preparing a compound having any one of formulas (IIIA) and (IIIB) from 2,3-isopropylidene-sn-glycerol, said compound having any one of formulas (IIIA) and (IIB) being represented by the following: 【Chemistry 56】 (In the formula, The P.G. 【Chemistry 57】 -CH ２ -S-CH ３ , -CH ２ -N ３ , or -CH ２ -CH=CH ２ and f is 0 or 2; Each R ｕ are independently H, —O—C １ -C ４ Alkyl, or -C １ ~C ４ is alkyl, Each R ｚ is independently a branched or unbranched C １ ~C ６ is an alkyl group) preparing a compound having any one of formulas (IIIA) and (IIIB) from 2,3-isopropylidene-sn-glycerol having the structure: (b) reacting trityl chloride or a derivative or analogue thereof with said compound having any one of formulas (IIIA) and (IIIB) to provide a compound having any one of formulas (VA) and (VB), respectively, wherein said compound having any one of formulas (VA) and (VB) has the following structure: 【Chemistry 58】 (In the formula, R ３ is -O-trityl or a derivative or analog thereof or a derivative or analog thereof, with said compound having any one of formulas (IIIA) and (IIIB) to provide a compound having any one of formulas (VA) and (VB), respectively; (c) coupling a reagent having formula (XIV) with a compound having any one of formulas (VA) and (VB) to provide a conjugate having any one of formulas (VIA) and (VIB), respectively; The reagent having the formula (XIV) 【Chemistry 59】 (In the formula, R ａ and R ｂ are independently H or C １ ~C ４ is alkyl, Y is an alkyl, alkenyl, alkynyl, acyl, -CH ２ -alkynyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety; d is an integer ranging from 1 to about 10; e is an integer ranging from 1 to about 36; LG is a leaving group. The structure is The conjugate having any one of formulas (VIA) and (VIB) 【Chemistry 60】 (In the formula, R ４ is represented by formula (XIIIA) 【Chemistry 61】 (having coupling said reagent having formula (XIV), having the structure: (d) deprotecting the conjugate having any one of formulas (VIA) and (VIB) to provide a respective deprotected conjugate; (e) coupling a reagent having formula (XV) to the deprotected conjugate to provide a regioisomerically and enantiomerically pure monomer having any one of formulas (VIIIA) to (VIIID), respectively, wherein the compound having formula (XV) is 【Chemistry 62】 (wherein LG is a leaving group, R ９ is a substituted or unsubstituted C terminating in a cyano moiety １ ~C ６ is an alkyl group, R １０ and R １１ is independently a branched or unbranched C １ ~C ６ is an alkyl group) The structure is The compound having any one of formulas (VIIIA) to (VIIID) is 【Chemistry 63】 (Wherein, PPA is -P(O-R ９ )-N(R １０ ) (R １１ ) and coupling a reagent having formula (XV), having the structure:

128. 128. The method of claim 127, wherein the preparation of the compound having any one of formulas (IIIA) and (IIIB) from 2,3-isopropylidene-sn-glycerol comprises introducing a protecting group into 2,3-isopropylidene-sn-glycerol.

129. The protecting group has the formula X-PG, where X is a leaving group and PG is 【Chemistry 64】 -CH ２ -S-CH ３ , -CH ２ -CH=CH ２ The method of claim 128, wherein:

130. 128. The method of claim 127, further comprising coupling a substituted or unsubstituted heterocyclic moiety to either (i) the deprotected conjugate having any one of formulas (VIA) and (VIB) or (ii) the protected conjugate having any one of formulas (VIA) and (VIB).

131. 128. The method of claim 127, further comprising polymerizing a regioisomerically pure monomer having any one of formulas (VIIIA)-(VIIID).

132. 128. An oligomer derived from a regioisomerically and enantiomerically pure monomer prepared according to the process of claim 127.

133. 128. A polymer derived from regioisomerically and enantiomerically pure monomers prepared according to the process of claim 127.

134. 128. A copolymer derived from a first regioisomerically and enantiomerically pure monomer and a second regioisomerically and enantiomerically pure monomer, wherein the first regioisomerically and enantiomerically pure monomer and the second regioisomerically and enantiomerically pure monomer are each prepared according to the process of claim 127, and the first regioisomerically and enantiomerically pure monomer and the second regioisomerically and enantiomerically pure monomer are different.

135. A process for preparing a regioisomerically and enantiomerically pure compound having any one of formulae (VA) and (VB), comprising the steps of: a) obtaining a compound having any one of formulas (IIIA) and (IIIB), wherein said compound having any one of formulas (IIIA) and (IIIB) is selected from the group consisting of: 【Chemistry 65】 (In the formula, The P.G. 【Chemistry 66】 -CH ２ -S-CH ３、 -CH ２ -N ３ , or -CH ２ -CH=CH ２ and f is 0 or 2; Each R ｕ are independently H, —O—C １ -C ４ Alkyl, or -C １ -C ４ is alkyl, Each R ｚ is independently a branched or unbranched C １ ~C ６ is an alkyl group) obtaining a compound having any one of formulas (IIIA) and (IIIB) having the structure: b) reacting the resulting compound having any one of formulas (IIIA) and (IIIB) with trityl chloride or a derivative or analogue thereof to provide a compound having any one of formulas (VA) and (VB), wherein the compound having any one of formulas (VA) and (VB) is selected from the group consisting of: 【Chemistry 67】 (In the formula, R ３ is -O-trityl or a derivative or analog thereof and reacting the resulting compound having any one of formulas (IIIA) and (IIIB), having the structure: with trityl chloride or a derivative or analogue thereof to provide a compound having any one of formulas (VA) and (VB).

136. A process for preparing a regioisomerically and enantiomerically pure compound having any one of formulae (VIA) and (VIB), comprising the steps of: (a) obtaining a compound having any one of formulas (VA) and (VB), wherein said compound having any one of formulas (VA) and (VB) is selected from the group consisting of: 【Chemistry 68】 (In the formula, The P.G. 【Chemistry 69】 -CH ２ -S-CH ３、 -CH ２ -N ３ , or -CH ２ -CH=CH ２ and f is 0 or 2; Each R ｕ are independently H, —O—C １ ~C ４ Alkyl, or -C １ ~C ４ is alkyl, Each R ｚ is independently a branched or unbranched C １ ~C ６ is an alkyl group, R ３ is -O-trityl or a derivative or analog thereof, or -O-phenylthioxantyl or a derivative or analog thereof. obtaining a compound having any one of formulas (VA) and (VB) having the structure: (b) reacting the resulting compound having any one of formulas (VA) and (VB) with a reagent having formula (XIV) to provide a regioisomerically and enantiomerically pure compound having any one of formulas (VIA) and (VIB), respectively; The reagent having the formula (XIV) 【Chemistry 70】 (In the formula, R ａ and R ｂ are independently H or C １ ~C ４ is alkyl, Y is an alkyl, alkenyl, alkynyl, acyl, -CH ２ -alkynyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety; d is an integer ranging from 1 to about 10; e is an integer ranging from 1 to about 36; LG is a leaving group. The structure is The compound having any one of formulas (VIA) and (VIB) 【Chemistry 71】 (In the formula, R ４ is represented by formula (XIIIA) 【Chemical 72】 (having having the structure reacting the resulting compound having any one of formulas (VA) and (VB) with a reagent having formula (XIV) to provide a regioisomerically and enantiomerically pure compound having any one of formulas (VIA) and (VIB), respectively.

137. 137. The method of claim 136, further comprising deprotecting the regioisomerically and enantiomerically pure compound having any one of formulas (VIA) and (VIB).

138. and reacting the deprotected regioisomerically and enantiomerically pure compound with a reagent having formula (XV) to provide a regioisomerically and enantiomerically pure compound having any one of formulas (VIIIA) to (VIIID), wherein the reagent having formula (XV) is 【Chemical Formula 73】 (wherein LG is a leaving group, R ９ is a substituted or unsubstituted C terminating in a cyano moiety １ ~C ６ is an alkyl group, R １０ and R １１ is independently a branched or unbranched C １ ~C ６ is an alkyl group) The structure is The regioisomerically and enantiomerically pure compound having any one of formulae (VIIIA) to (VIIID) is 【Chemical Formula 74】 (Wherein, PPA is -P(O-R ９ )-N(R １０ ) (R １１ ) having the structure The method of claim 137.

139. below 【Chemistry 75-1】 【Chemistry 75-2】 (wherein ODMTr is 4,4'-dimethoxytrityl ether). A compound selected from the group consisting of:

140. below, 【Hua 76-1】 【Hua 76-2】 【Chemistry 76-3】 wherein n ranges from 1 to 24; Y is an alkyl, alkenyl, alkynyl, acyl, -CH ２ -alkynyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety; -ODMTr is 4,4'-dimethoxytrityl ether. A compound selected from the group consisting of:

141. Formula (XIIIA) or (XIIIB) 【Chemical 77】 (In the formula, R １２ａ and R １２ｂ are independently -OH, -O-trityl or a derivative or analog thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analog thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analog thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analog thereof, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether; R １３ａ and R １３ｂ are independently -O-R ｗ -Z and R ｗ is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, which may contain one or more oxygen heteroatoms; Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl, acyl, "clickable group", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety; R １４ａ and R １４ｂ is —OH, or Or R １２ａ and R １４ａ and / or R １２ｂ and R １４ｂ Let's get together 【Chemical 78】 may be) A compound having any one of the following:

142. R １２ａ and R １２ｂ is independently -O-trityl or a derivative or analog thereof.

143. Z is alkyl, alkenyl, alkynyl or -CH ２ -alkynyl.

144. R ｗ 144. The compound of any one of claims 141 to 143, wherein contains 4 to 16 carbon atoms.

145. R ｗ 144. The compound of any one of claims 141 to 143, wherein contains 6 to 12 carbon atoms.

146. R ｗ 144. The compound of any one of claims 141 to 143, wherein contains 8 to 12 carbon atoms.

147. R ｗ 147. The compound of any one of claims 144-146, further comprising at least two oxygen heteroatoms.

148. R １２ａ and R １２ｂ is each independently -OH.

149. Z is alkyl, alkenyl, alkynyl or -CH ２ -alkynyl.

150. R ｗ 150. The compound of claim 149, wherein contains 4 to 16 carbon atoms.

151. R ｗ 150. The compound of claim 149, wherein contains 6 to 12 carbon atoms.

152. R ｗ 150. The compound of claim 149, wherein contains 8 to 12 carbon atoms.

153. R ｗ 153. The compound of any one of claims 150-152, further comprising at least two oxygen heteroatoms.

154. R １２ａ and R １４ａ But together 【Chemical 79】 and R １２ｂ and R １４ｂ But together 【Chemistry 80】 and Z is alkyl, alkenyl, alkynyl, or -CH ２ -alkynyl.

155. R ｗ The compound of claim 154, wherein contains 4 to 16 carbon atoms.

156. R ｗ The compound of claim 154, wherein contains 6 to 12 carbon atoms.

157. R ｗ The compound of claim 154, wherein contains 8 to 12 carbon atoms.

158. R ｗ 158. The compound of any one of claims 155-157, further comprising at least two oxygen heteroatoms.

159. below, 【Chemistry 81-1】 【Chemistry 81-2】 A compound selected from the group consisting of:

160. below, 【Chemistry 82】 (In the formula, R １３ａ and R １３ｂ are independently -O-R ｗ -Z and R ｗ is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, which may contain one or more oxygen heteroatoms; Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl, acyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety. A method for preparing a compound having any one of the structures The method further comprising: Lower alcohols and acids are hereinafter referred to as 【Chemistry 83】 (In the formula, R １５ is a substituted or unsubstituted 5- or 6-membered aromatic or heteroaromatic group. The method comprises introducing into a starting material having the structure of any one of

161. 161. The method of claim 160, wherein the lower alcohol is selected from the group consisting of methanol and ethanol.

162. 162. The method of any one of claims 160 to 161, wherein the acid is hydrochloric acid.

163. Z is alkyl, alkenyl, alkynyl or -CH ２ -alkynyl.

164. R ｗ The method of any one of claims 160 to 163, wherein contains 4 to 16 carbon atoms.

165. R ｗ The method of any one of claims 160 to 163, wherein contains 6 to 12 carbon atoms.

166. R ｗ The method of any one of claims 160 to 163, wherein contains 8 to 12 carbon atoms.

167. R ｗ 167. The method of any one of claims 164-166, wherein further comprises at least two oxygen heteroatoms.

168. below, 【Chemistry 84】 (In the formula, R １３ａ and R １３ｂ are independently -O-R ｗ -Z and R ｗ is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, which may contain one or more oxygen heteroatoms; Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl, acyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety. A method for preparing a compound having any one of the structures The method further comprising: 4,4'-dimethoxytrityl chloride is hereinafter referred to as 【Chemistry 85】 With a compound having any one of the structures:

169. Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl.

170. R ｗ The method of any one of claims 168 to 169, wherein contains 4 to 16 carbon atoms.

171. R ｗ The method of any one of claims 168 to 169, wherein contains 6 to 12 carbon atoms.

172. R ｗ The method of any one of claims 168 to 169, wherein contains 8 to 12 carbon atoms.

173. R ｗ 170. The method of any one of claims 168-169, wherein further comprises at least two oxygen heteroatoms.

174. Formulae (IXA) and (IXB), respectively: 【Chemistry 86】 (In the formula, W is H; R ５ is -O-trityl, R ６ is -O-R ｗ -Z and R ｗ is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, which may contain one or more oxygen heteroatoms; Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl, acyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety. A method for preparing a compound having any one of the following formulas: The method comprises: 【Chemistry 87】 (In the formula, R １３ａ and R １３ｂ are independently -O-R ｗ -Z and R ｗ is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, which may contain one or more oxygen heteroatoms; Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl, acyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety. The method includes oxidatively cleaving a compound having any one of the structures The oxidative cleavage may be carried out using sodium metaperiodate (NaIO ４ ) and a base, ６ , R １３ａ , and R １３ｂ But the same way.

175. 175. The method of claim 174, wherein the base is pyridine.

176. Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl.

177. R ｗ The method of any one of claims 174 to 175, wherein contains 4 to 16 carbon atoms.

178. R ｗ The method of any one of claims 174 to 175, wherein contains 6 to 12 carbon atoms.

179. R ｗ The method of any one of claims 174 to 175, wherein contains 8 to 12 carbon atoms.

180. R ｗ 180. The method of any one of claims 177-179, further comprising at least two oxygen heteroatoms.

181. Formulae (IXA) and (IXB), respectively: 【Chemistry 88】 (In the formula, W is H, —O—CH ３ or -OT, T being C １ ~C ６ is a branched or unbranched alkyl group, R ５ is -OH, -O-trityl or a derivative or analogue thereof, -O-9-phenylthioxanthyl (pixyl) or a derivative or analogue thereof, -O-2-(2-nitrophenyl)prop-1-oxycarbonyl ("NPPOC"), -O-(2-nitrobenzyl) or a derivative or analogue thereof, -O-(1-(2-nitrophenyl)ethyl) or a derivative or analogue thereof, tetrahydropyranyl ether, ethoxyethyl ether, methallyl ether, prenyl ether or methoxymethyl ether; R ６ is -OH, -O-R ｗ -Z and R ｗ is a substituted or unsubstituted, branched or unbranched, saturated or unsaturated alkyl group having 1 to 100 carbon atoms, which may contain one or more oxygen heteroatoms; Z is an alkyl, alkenyl, alkynyl, -CH ２ -alkynyl, acyl, "click functionality", -Het, or -CH ２ -Het, where "Het" is a substituted or unsubstituted 5-membered heterocyclic moiety; However, R ５ and R ６ are not both -OH) A compound having any one of the following:

182. 182. The compound of claim 181, wherein W is -H.

183. R ５ is -O-trityl or a derivative or analogue thereof.

184. R ６ But -O-R ｗ The compound according to any one of claims 182 to 184, wherein

185. Z is alkyl, alkenyl, alkynyl or -CH ２ -alkynyl.

186. R ｗ 186. The compound of claim 185, wherein contains 4 to 16 carbon atoms.

187. R ｗ The compound of claim 185, wherein contains 6 to 12 carbon atoms.

188. R ｗ 186. The compound of claim 185, wherein contains 8 to 12 carbon atoms.

189. R ｗ 189. The compound of any one of claims 184-188, further comprising at least two oxygen heteroatoms.

190. The compound is as follows: 【Chemistry 89-1】 【Chemistry 89-2】 The compound of claim 181, selected from the group consisting of:

191. 191. A regioisomerically pure phosphoramidite-containing monomer derived from a regioisomerically pure compound according to any one of claims 181 to 190.

192. 202. A polymer derived from the regioisomerically pure phosphoramidite-containing monomer of claim 191.

193. A copolymer derived from a first regioisomerically pure phosphoramidite-containing monomer as described in claim 191 and a second regioisomerically pure phosphoramidite-containing monomer as described in claim 191, wherein the first regioisomerically pure phosphoramidite-containing monomer and the second regioisomerically pure phosphoramidite-containing monomer are different.

194. 194. An XNTP comprising the polymer of claim 192 or the copolymer of claim 193.

Images