Methods and reagents for synthesizing haloaldehydes, and their applications.

Abstract

This invention relates to a method and intermediates for synthesizing haloaldehydes.

Description

field

[0001] This invention relates to a method and intermediates for synthesizing haloaldehydes. Background

[0002] Nucleosides play crucial roles in a variety of cellular processes, from cellular signaling to metabolism (1). Nucleosides consist of a nucleic acid base (typically adenine, guanine, cytosine, thymine, and uracil) and a sugar moiety (typically ribose or 2'-deoxyribose). Nucleosides can be further modified with a 5'-phosphate or phosphate-like group, and RNA oligomers contain nucleotides linked via phosphate or phosphate-like bonds from the 5'- to 3' ends. Nucleosides can be modified in several ways, including modifications to the ribose moiety, the base moiety, or the phosphate moiety, which produce compounds called “nucleoside analogs” (NAs).

[0003] Na has a long and rich history in the field of medicinal chemistry and is also considered a tool compound in chemical biology. Naturally occurring nucleosides are involved in numerous biological processes, making them a unique and valuable starting point in drug design. Synthetic na has been designed to mimic its natural counterparts (2-18). Single na has been used primarily as a treatment for parasitic, bacterial, and fungal infections, and as a potent and effective anticancer agent. In addition to this "small molecule" form, na can be incorporated into oligomeric structures that can regulate gene expression, thus avoiding the complexities associated with protein inhibition. Such oligomeric structures can include small interfering RNA (siRNA), microRNA (miRNA), inhibitory antisense oligonucleotide (ASO), small activating RNA (saRNA), and messenger RNA (mRNA).

[0004] NA is used in cancer treatment (2, 6) and also occupies the largest class of small molecule antiviral agents (3, 4). Its mechanism involves NA acting as a toxic antimetabolite that inhibits nucleic acid synthesis (4). Alternatively, nucleotide analogs produced by phosphorylation reactions in vivo can inhibit enzymes involved in cancer cell proliferation and viral replication (e.g., DNA / RNA polymerase, ribonucleotide reductase, nucleoside phosphorylation enzymes) (2, 4). NA also shows promise as an epigenetic modulator, and both decitabine and azacitidine inhibit DNA methyltransferase and are approved as cancer treatments (4).

[0005] Decades of advancements in organic and medicinal chemistry have led to the creation of numerous useful nucleoside analogs; however, several challenges remain in the synthesis of further nucleoside analogs. Nucleoside analogs are often synthesized from naturally occurring carbohydrates, limiting substitution patterns and furanose configurations (e.g., 19-29). Addition of nucleic acid bases to activated ribose derivatives often fails or proceeds with low diastereoselectivity for nucleosides modified at the C2' or C4' position, limiting efficient methods for producing C4'-modified nucleosides, including thionucleosides. The synthesis of nucleosides and nucleoside analogs is described by Meanwell et al. (30) and WO 2021 / 191830. Summary

[0006] This invention relates to a method and intermediates for synthesizing haloaldehydes.

[0007] In one embodiment, the present invention provides a method for synthesizing haloaldehyde compounds by reacting a halogen or halogen-containing compound with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I) to produce a haloaldehyde compound. In formula JPEG2026511607000001.jpg70113, R1, R2, R3, and R4 may each be independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl, and Cx may be the counterion of the salt.

[0008] In another embodiment, the present invention provides a method for producing an intermediate in the synthesis of a nucleoside or its analogues by reacting a halogen or halogen-containing compound with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I), and then carrying out an enantioselective aldol reaction catalyzed by proline to produce a halohydrin compound, which is an intermediate in the synthesis of a nucleoside or its analogues. In formula JPEG2026511607000002.jpg70104, R1, R2, R3, and R4 may each be independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl, and Cx may be the counterion of the salt. In some embodiments, the method may further include reducing the halohydrin compound to obtain a halohydrindiol compound.

[0009] In another embodiment, the present invention provides a method for synthesizing nucleosides or analogues by reacting a halogen or halogen-containing compound with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I); carrying out an enantioselective aldol reaction with a proline catalyst to produce a halohydrin compound; reducing the halohydrin compound to produce a halohydrin diol compound; and contacting the halohydrin diol compound with a Lewis acid or base in a cyclohalide substitution (AHD) reaction to produce a nucleoside or an analogue. In formula JPEG2026511607000003.jpg6894, R1, R2, R3, and R4 may each be independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl, and Cx may be the counterion of the salt.

[0010] In some embodiments, the halogenation may be enantioselective.

[0011] In some embodiments, the proline may be L-proline or D-proline. In some embodiments, the proline may be a halophilic Lewis acid.

[0012] In some embodiments, the Lewis acid may be InCl3 or Sc(OTf)3.

[0013] In some embodiments, the AHD promoted by the Lewis acid may generate a nucleoside or its analog with the C2' and C3' positions protected or a nucleoside or its analog with the acetonide protecting group migrated, or deprotection may occur.

[0014] In some embodiments, the halohydrin diol compound may be separated before being treated with the base.

[0015] In some embodiments, the base may be NaOH, K2CO3, KHCO3, Na2CO3, NaHCO3, KOH, LiOH, Li2CO3, LiHCO3, Cs2CO3, CsHCO3, or CsOH.

[0016] In some embodiments, the AHD promoted by the base may generate a nucleoside or its analog with the C3' and C5' positions protected.

[0017] In some embodiments, the halohydrin compound may be JPEG2026511607000004.jpg5879, wherein NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be halogen.

[0018] In some embodiments, the halohydrin compound may be JPEG2026511607000005.jpg50162.

[0019] In some embodiments, the halohydrin diol compound may be JPEG2026511607000006.jpg5765, where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be halogen.

[0020] In some embodiments, the halogen may be fluorine, bromine, chlorine, or iodine.

[0021] In some embodiments, the halogen-containing compound may be an electrophilic halogenating agent such as, for example, N-fluorobenzenesulfonimide (NFSI), Selectfluor®, Xtalfluor®, N-halosucinimide, N-chlorinated hydantoin, Palau'chlor®, or N-fluoropyridinium.

[0022] In some embodiments, the counterion of the salt may be HCl, TFA, HBr, or MsOH.

[0023] In some embodiments, the catalyst compound may be as follows. JPEG2026511607000007.jpg84146

[0024] In some embodiments, the aryl or heteroaryl-substituted compound may include the following chemical structure JPEG2026511607000008.jpg36122 where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0025] In some embodiments, the haloaldehyde compound may include the following chemical structure: In formula 35116, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, X may be a halogen, and * indicates enantioenrichment.

[0026] In some embodiments, the haloaldehyde compound is JPEG2026511607000010.jpg42151 or JPEG2026511607000011.jpg6178 is also acceptable.

[0027] In some embodiments, the nucleoside or its analogue is JPEG2026511607000012.jpg43133 or It may also be JPEG2026511607000013.jpg5361, where NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and each R may independently be -OH, -OC(CH3)2O-, -(CH2)3-, -CH2SCH2-, or -CH2OCH2-.

[0028] In some embodiments, the nucleoside or its analogue may be a C3' / C5' protected NA, a C4' modified NA, a C2' modified NA, a C-linked NA, an L-configured NA, a D-nucleoside or its analogue, an L-nucleoside or its analogue, a loc nucleic acid, an iminonucleoside, or a thionucleoside.

[0029] In another embodiment, the present invention relates to a halohydrin compound Provides JPEG2026511607000014.jpg52167.

[0030] The summary of this invention does not necessarily describe all of its features. Detailed description

[0031] This disclosure partially provides a method for synthesizing haloaldehyde compounds and their applications.

[0032] In some embodiments, the method for synthesizing the haloaldehyde compound includes reacting a halogenating agent (halogen or halogen-containing compound) with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I). JPEG2026511607000015.jpg71106 In the formula, R1, R2, R3, and R4 may each be independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl, and Cx may be the counterion of the salt.

[0033] As used herein, “aryl or heteroaryl substituted compound” means a compound having the following structure: In formula JPEG2026511607000016.jpg33120, NB may be optionally substituted with an aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0034] As used herein, a catalyst compound is a compound according to formula (I). In formula JPEG2026511607000017.jpg76108, R1, R2, R3, and R4 may each be independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl, and Cx may be the counterion of the salt.

[0035] In some embodiments, the catalyst compounds according to this disclosure may be "enantiopure" or "enantioconcentrated".

[0036] In some embodiments, the catalyst compounds according to this disclosure may include, but are not limited to, the following compounds. JPEG2026511607000018.jpg91154

[0037] As used herein, “haloaldehyde compound” or “haloaldehyde” means a compound containing a functional group in which a halogen and an aldehyde (e.g., acetaldehyde) are bonded to adjacent groups. Haloaldehydes may have the following general structures: In formula JPEG2026511607000019.jpg78169, N may be any substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be a halogen.

[0038] In some embodiments, the haloaldehyde compound may include, but is not limited to, the following compounds: JPEG2026511607000020.jpg77158

[0039] "Alkyl" refers to a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, unsaturated, containing, for example, 1 to 10 carbon atoms, or any value in between, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and bonded to the rest of the molecule by single bonds. In some embodiments, alkyl may refer to a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, unsaturated, containing 1 to 6 carbon atoms, or any value in between, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms, and bonded to the rest of the molecule by single bonds. Unless otherwise specified herein, the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified herein, it is understood that this substitution may occur on any carbon of the alkyl group.

[0040] "Acyl" is expressed in the formula -C(O)R aThis refers to the group represented by the formula, where R a C as described in this specification 1-10 Alkyl or C 1-6 It is an alkyl group. The alkyl group may be optionally substituted as described herein.

[0041] "Aryl" means a monocyclic or bicyclic aromatic ring containing only carbon atoms, such as 5- to 14-membered rings like 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14-membered rings. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, and 1,4-benzodioxanyl. Unless otherwise specified herein, the term "aryl" means an aryl group optionally substituted with one or more substituents as described herein.

[0042] "Heteroaryl" refers to a single or fused aromatic ring group containing one or more heteroatoms, such as N, O, S, etc., in the ring, containing 5 - 14 members, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 members. Examples of heteroaryl groups include furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1,2,3 - oxadiazole, triazole (e.g., 1,2,3 - triazole or 1,2,4 - triazole), 1,3,4 - thiadiazole, tetrazole, pyrazole, pyridine, pyridazine, pyrimidine, 2,6 - dichloropyrimidine pyrazine, 1,3,5 - triazine, imidazole, benzimidazole, benzoxazole, benzothiazole, indolizine, indole, isoindole, benzofuran, benzothiophene, 1H - indazole, purine, 4H - quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8 - naphthyridine, pteridine, uracil, thymine, deazadenine, phthalimide, and adenine, etc., but are not limited thereto. Unless otherwise specifically described herein, the term "heteroaryl" means including heteroaryl groups optionally substituted by one or more substituents described herein.

[0043] "Arylalkyl" refers to a group represented by the formula -R a R b wherein R a is a C 1-10 alkyl group described herein, and R b is one or more aryl moieties described herein. The arylalkyl group may be optionally substituted as described herein. Examples of arylalkyl groups include benzyl, phenethyl, phenylpropyl, (4 - methylphenyl)methyl, (4 - methylphenyl)ethyl, (2 - methylphenyl)methyl, and (2,4,6 - trimethylphenyl), etc., but are not limited thereto.

[0044] "Heteroarylalkyl" refers to a group represented by the formula -R a Rc This refers to the group represented by the formula, where R a C as described in this specification 1-10 It is an alkyl group, R c This is one or more heteroaryl moieties as described herein. The heteroarylalkyl group may be optionally substituted as described herein. Examples of heteroarylalkyl groups include, but are not limited to, furanylmethyl, tiphenylmethyl, pyridylmethyl, imidazolylmethyl, and uridinylmethyl.

[0045] "Cx" refers to the counterion of the salt. In some embodiments, Cx is not limited to hydrochloric acid (HCl), trifluoroacetic acid (TFA), hydrobromic acid (HBr), and methanesulfonic acid (MsOH), etc.

[0046] "X" refers to halogens such as bromine, chlorine, fluorine, and iodine. In some embodiments, the halogen may include chlorine or fluorine. Thus, "halo" refers to bromine, chlorine, fluorine, and iodine. A halide is a negatively charged halogen atom. "Halogenation" means introducing a halogen atom into a compound or molecule. It should be understood that halogens may also be "halogen-containing compounds," such as N-fluorobenzenesulfonimide (NFSI), Selectfluor®, Xtalfluor®, N-halosuccinimide (e.g., N-chlorosuccinimide (NCS)), N-chlorinated hydantoin, Palau'chlor®, and N-fluoropyridinium salts. In some embodiments, the halogen-containing compound may be an electrophilic halogenating agent. Thus, as used herein, halogen includes halogen-containing compounds or "halogenating agents."

[0047] "Optional" or "optionally" means that the events in the situations described below may or may not occur, and the description includes both cases where the events occur once or more and cases where they do not occur. For example, "optionally substituted alkyl" means that the alkyl group may be substituted or unsubstituted, and the description includes both substituted and unsubstituted alkyl groups, and the alkyl group may be substituted once or more. Examples of optionally substituted alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, and tert-butyl. Examples of suitable optional substituents include H, F, Cl, CH3, OH, OCH3, CF3, CHF2, CH2F, CN, halo, and C 1-10 Examples of alkoxys include, but are not limited to, alkoxys. Similarly, "optionally substituted aryl or heteroaryl groups" means aryl or heteroaryl groups that may or may not be substituted, and the description includes both substituted and unsubstituted aryl or heteroaryl groups, and such aryl or heteroaryl groups may be substituted one or more times. Suitable examples of optional substituents include H, F, Cl, CH3, OH, OCH3, CF3, CHF2, CH2F, CN, halo, and C 1-10 Examples include, but are not limited to, alkoxy groups.

[0048] In some embodiments, the disclosure includes, for example, a method for synthesizing haloaldehyde compounds according to Scheme 1. JPEG2026511607000021.jpg86151

[0049] In Scheme 1, R1, R2, R3, and R4 may each be independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl. Cx may be the counterion of a salt of the catalytic compound according to formula (I). NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl. X may be a halogen. Also, X+ may be an electrophilic halogenating agent (e.g., NFSI, NCS, etc.).

[0050] In some embodiments, the haloaldehyde compound may be used to prepare a halohydrin compound, for example, according to Scheme 2. JPEG2026511607000022.jpg112152

[0051] In Scheme 2, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl. X may be a halogen. Y may be CH2, O, S, or NR', where R' may be an alkyl or aryl group. Z may also be an alcohol protecting group, which may include, but is not limited to, acetonides, sylyl protecting groups, alkyl protecting groups, or aryl protecting groups (including cyclic and acyclic groups).

[0052] A "halohydrin" refers to a compound containing a functional group in which a halogen and a hydroxyl atom are bonded to adjacent groups. Halohydrins can have the following general structures: In formula JPEG2026511607000023.jpg4654, R may be any suitable element, and X may be a halogen.

[0053] In some embodiments, the halohydrin compound may have the following general structure: In formula JPEG2026511607000024.jpg5269, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be a halogen.

[0054] In some embodiments, the halohydrin compound is The filename could also be JPEG2026511607000025.jpg54163.

[0055] In some embodiments, the halohydrindiol compound may have the following general structure: In formula JPEG2026511607000026.jpg5574, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be a halogen.

[0056] In some embodiments, the halohydrin compound may be used, for example, in the synthesis of a nucleoside or its analogues according to Scheme 3. JPEG2026511607000027.jpg97157

[0057] In scheme 3, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl. X may be a halogen. Y may be CH2, O, S, or NR', where R' may be alkyl or aryl, and Z may be an alcohol protecting group, which includes, but is not limited to, acetonides, sylyl protecting groups, alkyl protecting groups, or aryl protecting groups (including cyclic or acyclic).

[0058] In some embodiments, the compounds disclosed herein, such as catalyst compounds, haloaldehydes, halohydrins, etc., may be enantiopurified or enantioenriched, i.e., they may be available primarily in a single specific enantiomeric form or “enantioenriched.” In the case of haloaldehydes, halohydrins, etc., the purity or enrichment of the enantiomer depends on the stereochemistry of the catalyst compound. While complete enantiomeric purity or enrichment is not essential, it should be noted that the enantiopurified or enantioenriched compounds according to this disclosure may be enriched to at least 95% of their enantiomerity. In some embodiments, the enantiopurified or enantioenriched compounds according to this disclosure are completely, i.e., 100%, enriched. Thus, methods for obtaining enantiopurified or enantioenriched compounds are referred to herein as “enantioselective” or “enantioselective” reactions.

[0059] In some embodiments, the present disclosure provides a method for producing intermediates in the synthesis of nucleosides or their analogues, the method being - Reacting a halogen or halogen-containing compound with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I). JPEG2026511607000028.jpg66101 (wherein R1, R2, R3, and R4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl, and Cx may be the counterion of the salt); - To carry out an enantioselective aldol reaction using a proline catalyst to produce a halohydrin compound; and - The halohydrin compound is reduced to obtain a halohydrindiol compound. It contains and generates intermediates in the synthesis of nucleosides or their analogues.

[0060] In some embodiments, the present disclosure provides a method for synthesizing nucleosides or analogs thereof, the method being - Reacting a halogen or halogen-containing compound with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I). JPEG2026511607000029.jpg75104 (wherein R1, R2, R3, and R4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl, and Cx may be the counterion of the salt); - To produce halohydrin compounds by carrying out an enantioselective aldol reaction using a proline catalyst; - Reducing the aforementioned halohydrin compound to produce a halohydrindiol compound; and - Contacting the halohydrindiol compound with a Lewis acid or base via a cyclohalide substitution (AHD) reaction. This includes obtaining nucleosides or their analogues.

[0061] In some embodiments, the proline may be L-proline or D-proline.

[0062] In some embodiments, the Lewis acid may be a halophilic Lewis acid, but is not limited to this example.

[0063] In some embodiments, the Lewis acid may be, but is not limited to, InCl3 or Sc(OTf)3.

[0064] In some embodiments, AHDs facilitated by Lewis acids may produce nucleosides or NAs with protected C2' and C3' positions.

[0065] In some embodiments, AHD facilitated by a Lewis acid can undergo protecting group migration, that is, it can produce NA with a migrated acetonide protecting group.

[0066] In some embodiments, AHD facilitated by Lewis acids can lead to deprotection.

[0067] In some embodiments, the base may be, but is not limited to, NaOH, K2CO3, KHCO3, Na2CO3, NaHCO3, KOH, LiOH, Li2CO3, LiHCO3, Cs2CO3, CsHCO3, or CsOH.

[0068] In some embodiments, the AHD promoted by the base may produce NA with protected C3' and C5' positions.

[0069] In some embodiments, the product of the αHAR reaction can be reduced and separated before treatment with a Lewis base.

[0070] In some embodiments, the present disclosure provides the following nucleosides or analogues (including, but not limited to, diastereomers thereof): In formula JPEG2026511607000030.jpg30148, NB is an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and each R may independently be -OH, -OC(CH3)2O-, -(CH2)3-, -CH2SCH2-, or -CH2OCH2-.

[0071] In some embodiments, the present disclosure provides the following compounds or their enantiomers for use as intermediates in the synthesis of nucleosides or their analogues: In formula JPEG2026511607000031.jpg5183, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl. X may be a halogen. In addition, each R may independently be -OH, -OC(CH3)2O-, -(CH2)3-, -CH2SCH2-, or -CH2OCH2-.

[0072] In some embodiments, the present disclosure provides the following compounds or their enantiomers for use as intermediates in the synthesis of nucleosides or their analogues: In formula JPEG2026511607000032.jpg88129, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be a halogen. Y may be CH2, O, S, or NR', where R' may be alkyl or aryl, and Z may be an alcohol protecting group, which includes, but is not limited to, acetonides, sylyl protecting groups, alkyl protecting groups, or aryl protecting groups (including cyclic and acyclic).

[0073] In some embodiments, the present disclosure provides the following compounds or their enantiomers for use as intermediates in the synthesis of nucleosides or their analogues: In formula JPEG2026511607000033.jpg12984, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be a halogen.

[0074] In some embodiments, the present disclosure provides the following compounds or their enantiomers for use as intermediates in the synthesis of nucleosides or their analogues: In formula JPEG2026511607000034.jpg12292, NB may be an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl. X may be a halogen. Also, Y may be CH2, O, S, or NR', where R' may be an alkyl or aryl.

[0075] In some embodiments, the methods disclosed herein allow for the rapid acquisition of intermediates in the synthesis of nucleosides or their analogues, for example, in amounts greater than about 10 g to about 400 g, or any value in between, such as 10 g, 15 g, 20 g, 25 g, 50 g, 75 g, 100 g, 125 g, 150 g, 200 g, 250 g, 300 g, 350 g, or 400 g, with good enantioselectivity and / or yield. Accordingly, the methods disclosed herein can be used for process-scale production of nucleosides and / or NA.

[0076] In some embodiments, the methods disclosed herein enable direct access to NA with the C3' / C5' position protected (where R may be alkyl, alkynyl, or aryl, and NB may be optionally substituted with aryl, arylalkyl, heteroaryl, or heteroarylalkyl (thus, NA with the C2' position modified)), providing flexibility in nucleic acid base substitution and / or providing a direct pathway to NA with the C4' position modified. JPEG2026511607000035.jpg91170

[0077] In some embodiments, the methods disclosed herein enable the direct incorporation of a wide range of nucleic acid bases and the selective functionalization of the C2' position of the furanose skeleton of natural nucleosides and NA (including, but not limited to, C-linked or L-configured NA).

[0078] In some embodiments, the methods disclosed herein allow direct access to a range of C4'-modified NAs, including but not limited to LOK nucleic acids (LNAs), by replacing the reducing agent with an organomagnesium reagent.

[0079] In some embodiments, the synthetic methods disclosed herein may be useful in the production of D- and L-nucleosides and nucleoside analogs, loc nucleic acids, iminonucleosides, thionucleosides, nucleosides with modified C4' positions, and / or nucleosides with modified C2' positions, but are not limited thereto.

[0080] In some embodiments, the methods disclosed herein may be useful as tools for drug design.

[0081] In some embodiments, the nucleoside analogs disclosed herein may be used as small molecule therapeutic agents or as monomers in oligonucleotide therapeutic agents.

[0082] In some embodiments, the methods disclosed herein may be useful for constructing diversity libraries. For example, the methods described herein can be used to construct a larger collection of nucleic acids (NAs) with altered C4' positions (e.g., a focused screening library).

[0083] A "nucleoside" refers to a glycosylamine having a nitrogenous base or "nucleic acid base" or "NB," and a sugar ring (e.g., ribose or deoxyribose) whose anomeric carbon is linked via a glycosidic bond to the N9 of a purine (e.g., adenine or guanine) or the N1 of a pyrimidine (e.g., cytosine, thymine, or uracil). Nucleosides include both L-nucleoside isomers and D-nucleoside isomers. Examples of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine, and inosine.

[0084] Nucleoside analogs (NAs) are compounds that are structurally similar to naturally occurring nucleosides. NAs may include, but are not limited to, compounds in which the C1', C2', C3', C4', and / or C5' positions of the sugar ring are modified. In some embodiments, NAs exist as free triols, and the C3' and / or C5' positions may be phosphorylated. In some embodiments, NAs may include, but are not limited to, compounds having saturated or unsaturated carbon rings. In some embodiments, NAs may contain nitrogen or sulfur in the sugar ring, and / or an NR group, for example, as a substitution for naturally occurring oxygen. In the formula, R may be, but is not limited to, alkyl, aryl, alkynyl, or benzyl. In some embodiments, the nucleoside analogs disclosed herein may be modified to function as phosphoramidate or phosphonamide compounds, e.g., "ProTide". "ProTide" contains a 5'-nucleoside monophosphate with two hydroxyl groups masked by amino acid esters, and an aryloxy component that can be enzymatically metabolized to deliver free 5'-monophosphate. Upon delivery to cells, the free 5'-monophosphate is further converted to the active 5'-triphosphate form of the nucleoside analog.

[0085] The "NB" or nucleic acid base in NA may be any aryl or heteroaryl bonded to a carbon or nitrogen atom from the C1 position. NB may be modified to include, for example, 5,6-dihydrouracil, 5-methylcytosine, 5-hydroxymethylcytosine, 5,5,5-trifluoromethylthymine, 5-fluorouracil, 2-thiouracil, 4-methylbenzimidazole, hypoxanthine, 7-deazaguanine, 7-deazaadenine, indole, imidazole, triazole, pyrrole, and pyrazole. The enantiomer (halohydrin) of the aldol product can be prepared using a proline catalyst (e.g., L-proline or D-proline). It should be understood that the choice between L-proline and D-proline depends on the stereochemistry of the catalyst compound to which proline can appropriately pair. For example, for illustrative purposes only, in Scheme 4, if L-catalyst 1 pairs appropriately with L-proline, the resulting NA will have its natural configuration. On the other hand, if D-catalyst 1 pairs appropriately with D-proline, the resulting NA will have the enantiomer of the NA in its natural configuration. However, if D-catalyst 1 pairs with L-proline, the resulting NA will have an unpredictable and therefore unknown configuration. JPEG2026511607000036.jpg122148

[0086] As used herein, the singular forms “a,” “and,” and “the” include multiple references unless the context clearly indicates otherwise. For example, “one compound” refers to one or more such compounds. Throughout this application, the terms “compound” or “compounds (plural)” refer to the compounds discussed herein, and also include their precursors and derivatives. The compounds of the present invention may contain one or more chiral centers and thus may exist as racemates and racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. Additional chiral centers may exist due to the properties of various substituents on the molecule. Each of these chiral centers independently produces two optical isomers. Unless otherwise specified, all optical isomers and diastereomers that may exist in mixtures and as pure or partially purified compounds are included in the scope of the present invention. If a specific stereochemistry is not specified in the formula, structure, or name of a compound described herein, it means, as stated above, that it includes all existing isomers and mixtures of any proportion thereof. Where a stereochemistry is specified, the present invention means that the particular isomer is included in its pure form or as part of a mixture of other isomers in any proportion. A single enantiomer, i.e., an optically active compound, can be obtained by asymmetric synthesis or racemic resolution. Racemic resolution can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, chromatography using a chiral HPLC column, or derivatization of the racemic mixture with a resolving reagent to produce diastereomers, separation of the diastereomers by chromatography, and removal of the resolving agent to obtain the original compound in an enantiomer-enriched form. These steps can be repeated as needed to increase the enantiomer purity of the compound. Where a compound described herein contains an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compound shall include cis, trans, Z-, and E- configurations. Similarly, all tautomers shall also be included.

[0087] The starting materials can be obtained from commercially available sources, prepared from commercially available organic compounds, and / or prepared using known synthetic methods.

[0088] The present invention will be further explained by the following examples. [Examples]

[0089] Materials and methods:

[0090] Nuclear magnetic resonance (NMR) spectra were recorded using deuterated chloroform (CDCl3), deuterated methanol (CD3OD), deuterated acetone ((CD3)2CO), deuterated acetonitrile (CD3CN), or deuterated dimethyl sulfoxide (DMSO-d6) as solvents. The signal position (δ) is shown in ppm from tetramethylsilane (δ 0) and measured relative to the solvent signal. 1 H NMR:CDCl3:δ 7.26; CD3OD:δ 3.31; (CD3)2CO:δ 2.05; CD3CN: δ 1.96; DMSO-d6:δ 2.50; 13 ¹³C NMR: CDCl3: δ 77.16; CD3OD: δ 49.00; (CD3)2CO: δ 29.84; CD3CN: δ 1.32; DMSO-d6: 39.5). The coupling constants (J values) are shown in Hertz (Hz) and displayed to the nearest 0.1 Hz. 1 The 1H NMR spectral data are summarized in a table in the following order: multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, sept: septet, m: multiplet, br: broad), coupling constant, and proton number. NMR spectra were recorded using a Bruker Avance 600, Bruker 400 (400 MHz), or Bruker 500 (500 MHz) equipped with a QNP or TCI cryoprobe (600 MHz). The diastereomer ratio (dr) is crude. 1 Based on 1H NMR analysis. 1 The attribution of H is, 1 H- 1 This analysis was based on H-COSY and nOe spectra. 13The assignment of C is based on the analysis of the HSQC spectrum. Example 1: JPEG2026511607000037.jpg75155

[0091] Catalyst 1 (50 mg, 0.27 mmol) was stirred in acetonitrile (2.4 mL) at 4°C. Catalyst 2 ((S)-5-benzyl-2,2,3-trimethylimidazolidined-4-one-HCl) (1 equivalent, 59 mg, 0.27 mmol), NFSI (1 equivalent, 23 mg, 0.27 mmol), and NaHCO3 (1 equivalent, 59 mg, 0.27 mmol) were added, and the reaction mixture was stirred for 48 hours. After the starting materials were completely consumed, a DMF solution (2 mL) of D-proline (1 equivalent, 31 mg, 0.27 mmol) and 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) (0.66 equivalents, 23 mg, 0.18 mmol) was added. After 4 days, the starting materials were completely consumed, and the reaction was workd up. A saturated solution of NH4Cl was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over NaSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by SiO2 column chromatography using ethyl acetate:hexane (7:3) as the mobile phase, and product 3 was obtained as a mixture of diastereomers (5:1). The main product was syn-fluorohydrin.

[0092] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final optical purity of 97% ee. JPEG2026511607000038.jpg61152

[0093] 2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)acetaldehyde (thymine aldehyde) (10 g, 59.6 mmol), ((R)-5-benzyl-2,2,3-trimethylimidazolidined-4-one-HCl (3.8 g, 14.9 mmol, 25 mol%), and NaHCO3 (5.02 g, 59.6 mmol) were added to a 1 L flask. 200 mL of CH3CN was added, and the resulting slurry was stirred in an ice bath for 15 minutes. Then NFSI (18.8 g, 596 mmol) was added as a solid, and the slurry was stirred for a further 30 minutes at 0°C. The reaction mixture was stirred overnight at 3°C.

[0094] After fluorination, the reaction mixture was heated to room temperature, 400 mL of DCM was added, followed by L-proline (6.86 g, 59.6 mmol) and 2,2-dimethyl-1,3-dioxan-5-one (14 mL, 119.8 mmol). The resulting reaction mixture was stirred overnight at room temperature.

[0095] At this point, Celite was added to the stirring reaction mixture, the solution was filtered, and the filtrate was washed with CH2Cl2. The resulting clear red solution was evaporated to dryness using a rotary evaporator and redissolved in 50 mL of CH2Cl2. Next, the solution was slowly added dropwise to 600 mL of rapidly stirring siRNA to form a precipitate. After the addition was complete, the mixture was rapidly stirred for a further 1 hour, then filtered and concentrated to dryness. The resulting red residue was dissolved in the smallest amount of CH2Cl2, passed through a silica (approximately 160 g) column, eluted with 75% siRNA / Hex, and collected in 50 mL fractions. The product (approximately 18 g) was collected and crystallized in a toluene solution of 10% iPrOH in 50 mL. The crystals were filtered and washed with ice-cold toluene to obtain 8.3 g of crystals. These crystallized in 1 / 2 equivalent of toluene. This could be removed by dissolving the crystals in hot CH3CN and then reconcentrating them.

[0096] 3: 1H NMR (500 MHz, CDCl3) δ 1.46 (s, 4H), 1.51 (s, 3H), 1.94 (t, J = 1.6 Hz, 4H), 3.69 (s, 1H), 4.12 (d, J = 17.7 Hz, 1H), 4.33 (dd, J = 17.8, 1.5 Hz, 1H), 4.40 (dd, J = 8.9, 1.5 Hz, 1H), 6.66 (dd, J = 42.5, 2.0 Hz, 1H), 7.57 (s, 1H), 8.65 (s, 1H).

[0097] 19 F NMR (471 MHz, CDCl3) δ -159.88, -161.58, -169.65, -177.99.

[0098] 13 C NMR (150 MHz, CDCl3) δ 211.18, 163.40, 149.87, 137.09, 137.06, 110.84, 101.95, 90.82, 89.43, 71.38, 71.37, 70.63, 70.48, 66.36, 23.61, 23.24, 12.53.

[0099] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final purity of 97% ee. Example 2: JPEG2026511607000039.jpg75154

[0100] Phthalamideacetaldehyde (100 mg, 0.483 mmol) was stirred in acetonitrile (2.4 mL) at room temperature. (S)-5-benzyl-2,2,3-trimethylimidazolidined-4-one (catalyst 1)-HCl (1 equivalent, 123 mg, 0.483 mmol), NFSI (1 equivalent, 152 mg, 0.483 mmol), and 2,6-lutidine (1 equivalent, 51.7 mg, 0.483 mmol) were added, and the reaction mixture was stirred for 48 hours. Once the starting materials were completely consumed, a solution of DCM (1.9 mL) of D-proline (1 equivalent, 31 mg, 0.24 mmol) and 2,2-dimethyl-1,3-dioxan-5-one (0.66 equivalents, 41.9 mg, 0.322 mmol) was added. After 2 days, the starting materials were completely consumed, and the reaction was work-up. A saturated solution of NH4Cl was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over NaSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by SiO2 column chromatography using ethyl acetate:hexane (1:1) as the mobile phase to obtain a mixture of diastereomers (8:1) (45% yield). The main product was syn-fluorohydrin.

[0101] 8: 1 H NMR (600 MHz, CD3CN) δ 1.81 (d, J = 0.8 Hz, 3H), 2.09 (s, 3H), 4.29 (d, J = 3.8 Hz, 1H), 4.31 - 4.39 (m, 1H), 4.45 (dd, J = 8.8, 5.9 Hz, 1H), 4.55 - 4.64 (m, 2H), 5.31 (d, J = 4.2 Hz, 1H), 5.64 (dddd, J = 11.1, 7.8, 5.9, 4.2 Hz, 1H), 6.95 (dd, J = 48.5, 7.9 Hz, 1H), 8.74 - 8.79 (m, 2H), 8.79 - 8.84 (m, 2H).

[0102] 19 F NMR (471 MHz, CD3CN) δ -162.27.

[0103] 13 C NMR (150 MHz, CD3CN) δ 167.89, 136.10, 132.57, 124.71, 99.16, 91.83, 90.48, 73.45, 73.40, 71.93, 71.76, 65.19, 64.56, 28.21, 19.34.

[0104] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final optical purity of 99% ee. Example 3: JPEG2026511607000040.jpg51161

[0105] N-(6-oxo-9-(2-oxoethyl)-6,9-dihydro-1H-purine-2-yl)isobutylamide hydrochloride (protected guanidine aldehyde hydrochloride) (91.2 mg, 0.304 mmol), (R)-5-benzyl-2,2,3-trimethylimidazolidinedione-4-one-HCl (15.5 mg, 0.0608 mmol), and NFSI (144.5 mg, 0.456 mmol) were slurryed in dimethylformamide (1.22 mL). 2,6-lutidine (106 mL, 0.913 mmol) was added, and the reaction mixture was stirred overnight at 3°C. After 18 hours, 2,2-dimethyl-1,3-dioxan-5-one (72 mL, 0.609 mmol) was added, followed by L-proline (70.1 mg, 0.609 mmol) and acetonitrile (4.88 mL). The reaction mixture was stirred overnight at room temperature. After 23 hours, the acetonitrile was removed using a rotary evaporator. Water was added, and the solution was extracted three times with ELISA. The combined organic layers were washed twice with saturated NaCl. The organic layers were dried over MgSO4, filtered, and concentrated to obtain the crude product. This was purified by flash chromatography (70% ethyl acetate: petroleum ether) to obtain the product N-(9-((1S,2R)-2-((S)-2,2-dimethyl-5-oxo-1,3-dioxan-4-yl)-1-fluoro-2-hydroxyethyl)-6-oxo-6,9-dihydro-1H-purine-2-yl)isobutylamide (38.4 mg, 0.093 mmol, 31%, dr = 10:1) as a colorless foam.

[0106] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final purity of 96% ee. JPEG2026511607000041.jpg90145

[0107] d H(500.1 MHz, CDCl3) 11.99 (1H, br. s, H-1), 8.21 (1H, s, H-2), 8.18 (1H, br. s, H-3), 6.50 (1H, dd, J 46.6, 1.6 Hz, H-4), 4.50 (1H, d, J 8.4 Hz, H-5), 4.39 (1H, ddd, J 22.7, 8.4, 1.6 Hz, H-6), 4.31 (1H, ABq, J 17.7 Hz, H-7), 4.14 (1H, ABq, J 17.7 Hz, H-7), 2.62 (1H, septet, J 6.9 Hz, H-8), 1.54 (3H, s, H-9), 1.48 (3H, s, H-9), 1.29 (6H, d, J 6.9 Hz, H-10). Example 4: JPEG2026511607000042.jpg51152

[0108] N-(9-(2-oxoethyl)-9H-purine-6-yl)benzamide (protected adenine aldehyde) (1.01 g, 3.59 mmol), (R)-5-benzyl-2,2,3-trimethylimidazolidined-4-one-HCl (911 mg, 3.59 mmol), and Selectfluor (1.40 g, 3.95 mmol) were placed in a round-bottom flask. Acetonitrile (10 mL) was added, followed by lutidine (831 μL, 7.18 mmol). The reaction mixture was then stirred overnight at 3°C. After 24 hours, L-proline (413 mg, 3.59 mmol) was added as a solid, followed by 2,2-dimethyl-1,3-dioxan-5-one (633 μL, 5.39 mmol). The solution was stirred at 3°C ​​for 48 hours. At this point, ethyl acetate was added, and the resulting solution was washed twice with saturated NaCl. The crude product was flushed on silica using an isocratic solution of 3% methanol saturated with NH3HCO3 / DCM, and the product (1.1 g, 71% yield) was obtained as an off-white foam.

[0109] d H(500 MHz, CDCl3) 8.85 (s, 1H), 8.70 (s, 1H), 8.06 (m, 2H), 7.64 (m, 1H), 7.55 (m, 2H), 6.94 (dd, J = 46, 1.4 Hz, 1H), 4.58 (m, 1H), 4.35 (m, 2H), 4.15 (m, 1H), 3.44 (s, 1H), 1.59 (s, 3H), 1.52 (s, 3H).

[0110] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final optical purity of 99% ee. Example 5: JPEG2026511607000043.jpg48138

[0111] 2-(2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)acetaldehyde (70 mg, 0.45 mmol, 1.0 equivalent) and (R)-5-benzyl-2,2,3-trimethylimidazolidined-4-one-HCl (29 mg, 0.11 mmol, 0.25 equivalents) were weighed into a flame-dried round-bottom flask. They were dissolved in 4.5 mL of dry DMF / MeCN (75:25). Lutidine (50 μL, 0.45 mmol, 1.0 equivalent) was added to the stirring reaction mixture. The reaction mixture was cooled to 3°C with stirring. NFSI (140 mg, 0.45 mmol, 1.0 equivalent) was added to the stirring reaction mixture and stirred at 3°C ​​for 48 hours. The reaction mixture was diluted with an additional 3.1 mL of dry DMF, and 190 μL, 1.6 mmol, 3.0 equivalents of 2,2-dimethyl-1,3-dioxan-5-one and 99 mg, 0.86 mmol, 1.9 equivalents of L-proline were added. The reaction mixture was stirred at 3°C ​​for 72 hours and diluted with 80 mL of ethyl acetate. The organic solution was washed in a separatory funnel with 1:1 brine and saturated NaHCO3 (aq) (4 × 10 mL). The organic layer was collected and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated using a rotary evaporator. It was purified by flash column chromatography (50% ethyl acetate:hexane) to obtain an amorphous white solid (47 mg, yield 34%, 14:1 syn:anti).

[0112] 1 H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 1H), 6.69 (dd, J = 42.3, 1.9 Hz, 1H), 5.79 (dd, J = 8.2, 2.3 Hz, 1H), 4.43 (dd, J = 9.0, 1.5 Hz, 1H), 4.36 (dd, J = 17.8, 1.5 Hz, 1H), 4.19 - 4.07 (m, 2H), 1.54 (s, 3H), 1.49 (s, 3H).

[0113] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final purity of 96% ee. Example 6: JPEG2026511607000044.jpg50149

[0114] In a flame-dried round-bottom flask, 2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-7-yl)acetaldehyde (100 mg, 0.31 mmol, 1.0 equivalent) and (R)-5-benzyl-2,2,3-trimethylimidazolidined-4-one-HCl (40 mg, 0.15 mmol, 0.5 equivalent) were dissolved in dry DMF (3.1 mL). 2,4,6-trimethylpyridine (41 μL, 0.31 mmol, 1.0 equivalent) was added. The reaction mixture was cooled to 3°C with stirring. NFSI (101 mg, 0.32 mmol, 1.03 equivalent) was added to the stirring reaction mixture. The mixture was stirred at 3°C ​​for 6 hours. NaHCO3 (26 mg, 0.31 mmol, 1.0 equivalent), 2,2-dimethyl-1,3-dioxan-5-one (113 μL, 0.96 mmol, 3.1 equivalents), and L-proline (49 mg, 0.43 mmol, 1.4 equivalents) were added. The reaction mixture was stirred at 3°C ​​for 72 hours. The reaction mixture was diluted with ethyl acetate (40 mL). The organic solution was washed with brine (5 x 6 mL) in a separatory funnel. The organic layer was collected and dried over anhydrous Na2SO4. It was filtered and concentrated using a rotary evaporator. Purification by flash column chromatography (30% ethyl acetate:hexane) yielded an amorphous white solid (74.4 mg, yield 51%, 10:1 syn:anti).

[0115] 1H NMR (500 MHz, DMSO) δ 8.74 (s, 1H), 8.25 (s, 1H), 6.85 (dd, J = 48.0, 6.1 Hz, 1H), 6.39 (d, J = 6.5 Hz, 1H), 4.75 (dtd, J = 16.8, 6.3, 4.6 Hz, 1H), 4.31 (dd, J = 4.6, 0.9 Hz, 1H), 3.95 - 3.92 (m, 2H), 1.33 (s, 3H), 1.30 (s, 3H).

[0116] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final purity of 99% ee. Example 7: JPEG2026511607000045.jpg56153

[0117] In a flame-dried vial, 2-(5-iodo-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)acetaldehyde (50 mg, 0.18 mmol, 1.0 equivalent), (R)-5-benzyl-2,2,3-trimethylimidazolidined-4-one-HCl (23 mg, 0.09 mg, 0.5 equivalent), and 2,4,6-trimethylpyridine (22 mg, 0.18 mmol, 1.0 equivalent) were added. The mixture was dissolved in dry DMF (1.8 mL, 0.1 M), and the reaction mixture was cooled to 3°C. NFSI (58 mg, 0.18 mmol, 1.0 equivalent) was added to the reaction mixture. The reaction mixture was stirred at 3°C ​​for 48 hours. 2,2-dimethyl-1,3-dioxan-5-one (70 mg, 0.54 mmol, 3.0 equivalents) and L-proline (26 mg, 0.22 mmol, 1.25 equivalents) were added to the reaction mixture and the mixture was stirred at 3°C ​​for 72 hours. The reaction solution was diluted with ethyl acetate (40 mL). The organic solution was washed with brine (10 mL x 4) in a separatory funnel. The organic layer was collected and dried over anhydrous sodium 2SO4. After filtration, the organic layer was concentrated using a rotary evaporator. The product was purified by flash column chromatography (60% ethyl acetate:hexane) to obtain the product (31 mg, 9:1 syn:anti, 41%) as a white solid.

[0118] 1 H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H) 6.67 (d, J = 42.28 Hz, 1H), 4.42 (d, J = 9.09 Hz, 1H), 4.37 (dd, J = 17.95, 1.51 Hz, 1H), 4.17 (d, J =13.45 Hz, 1H), 4.14 (m, 1H), 1.54 (s, 3H), 1.49 (s, 3H).

[0119] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final purity of 99% ee. Example 8: JPEG2026511607000046.jpg62155

[0120] In a flame-dried round-bottom flask, weighed 2-(1H-pyrazole-1-yl)ethane-1,1-diol (103 mg, 0.80 mmol, 1.0 equivalent), (R)-5-benzyl-2,2,3-trimethylimidazolidined-4-one-HCl (51 mg, 0.20 mmol, 0.25 equivalents), and sodium bicarbonate (135 μL, 1.60 mmol, 2.0 equivalents) were added and slurryed with 2.7 mL of dry MeCN. The reaction mixture was cooled to 3°C with stirring. NFSI (256 mg, 0.80 mmol, 1.0 equivalent) was added to the stirring reaction mixture and stirred at 3°C ​​for 24 hours. The reaction mixture was diluted with additional dry DMF (5.3 mL). 2,2-dimethyl-1,3-dioxan-5-one (94 μL, 0.80 mmol, 1.0 equivalent) and L-proline (116 mg, 1.0 mmol, 1.25 equivalents) were added. The reaction mixture was stirred at 3°C ​​for 72 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic solution was washed in a separatory funnel with 1:1 brine and saturated NaHCO3(aq) (3 x 10 mL). The organic layer was collected and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated using a rotary evaporator. It was purified by flash column chromatography (30% ethyl acetate:hexane) to obtain an amorphous white solid (47 mg, yield 47%, 5:1 syn:anti).

[0121] 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, 2.42 1H), 7.58 - 7.56 (m, 1H), 6.45 (dd, J = 49.3, 3.8 Hz, 1H), 6.32 (t, J = 2.2 Hz, 1H), 4.52 (ddd, J = 19.0, 6.3, 3.8 Hz, 1H), 4.27 (dd, J = 6.4, 1.5 Hz, 1H), 4.18 (dd, J = 17.3, 1.5 Hz, 1H), 3.98 (d, J = 17.3 Hz, 1H), 1.43 (s, 3H), 1.41 (s, 3H).

[0122] The ketone was reduced according to the procedure in reference (30), and subsequently subjected to chiral HPLC analysis, which showed a final purity of 97% ee.

[0123] References 1. GM Blackburn, Gait, MJ, Loakes, D., Williams, DM, Ed., Nucleic Acids in Chemistry and Biology, (Royal Society of Chemistry, Cambridge, UK, 2006), pp. 503. 2. CM Galmarini, JR Mackey, C. Dumontet. Nucleoside Analogues and Nucleobases in Cancer Treatment. Lancet Oncol. 3, 415-424 (2002). 3. E. De Clercq. Highlights in Antiviral Drug Research: Antivirals at the Horizon. Med. Res. Rev. 33, 1215-1248 (2013). 4. LP Jordheim, D. Durantel, F. Zoulim, C. Dumontet. Advances in the Development of Nucleoside and Nucleotide Analogues for Cancer and Viral Diseases. Nat. Rev. Drug Discov. 12, 447-464 (2013). 5. DM Huryn, M. Okabe. AIDS-Driven Nucleoside Chemistry. Chem. Rev. 92, 1745-1768 (1992). 6. J. Shelton et al. Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs. Chem. Rev. 116, 14379-14455 (2016). 7. B. Ewald, D. Sampath, W. Plunkett. Nucleoside Analogs: Molecular Mechanisms Signaling Cell Death. Oncogene 27, 6522-6537 (2008). 8. K. L. Seley-Radtke, M. K. Yates. The Evolution of Nucleoside Analogue Antivirals: A Review for Chemists and Non-Chemists. Part 1: Early Structural Modifications to the Nucleoside Scaffold. Antiviral Res. 154, 66-86 (2018). 9. M. K. Yates, K. L. Seley-Radtke. The Evolution of Antiviral Nucleoside Analogues: A Review for Chemists and Non-Chemists. Part II: Complex Modifications to the Nucleoside Scaffold. Antiviral Res. 162, 5-21 (2019). 10.H. Ma et al. Characterization of the Metabolic Activation of Hepatitis C Virus Nucleoside Inhibitor Beta-D-2'-Deoxy-2'-Fluoro-2'-C-Methylcytidine (PSI-6130) and Identification of a Novel Active 5'-Triphosphate Species. J. Biol. Chem. 282, 29812-29820 (2007). 11.E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 58, 8315-8359 (2015). 12.J. Deval, M. H. Powdrill, C. M. D'Abramo, L. Cellai, M. Gotte. Pyrophosphorolytic Excision of Nonobligate Chain Terminators by Hepatitis C Virus NS5B Polymerase. Antimicrob. Agents Chemother. 51, 2920-2928 (2007). 13.H. Ohrui. 2'-Deoxy-4'-C-Ethynyl-2-Fluoroadenosine, a Nucleoside Reverse Transcriptase Inhibitor, is Highly Potent Against All Human Immunodeficiency Viruses Type 1 and Has Low Toxicity. Chem. Rec. 6, 133-143 (2006). 14.J. T. Witkowski, R. K. Robins, R. W. Sidwell, L. N. Simon. Design, Synthesis, and Broad Spectrum Antiviral Activity of 1-Beta-D-Ribofuranosyl-1,2,4-Triazole-3-Carboxamide and Related Nucleosides. J. Med. Chem. 15, 1150-1154 (1972). 15.J. Zeidler, D. Baraniak, T. Ostrowski. Bioactive Nucleoside Analogues Possessing Selected Five-Membered Azaheterocyclic Bases. Eur. J. Med. Chem. 97, 409-418 (2015). 16.G. Ni et al. Review of α-Nucleosides: From Discovery, Synthesis to Properties and Potential Applications. RSC Advances 9, 14302-14320 (2019). 17.G. Gumina, G. Y. Song, C. K. Chu. L-Nucleosides as Chemotherapeutic Agents. FEMS Microbiol. Lett. 202, 9-15 (2001). 18.H. Cui et al. Synthesis and Evaluation of alpha-Thymidine Analogues as Novel Antimalarials. J. Med. Chem. 55, 10948-10957 (2012). 19.Chemical Synthesis of Nucleoside Analogues. P. Merino, Ed., (John Wiley & Sons, Inc., 2013), pp. 895. 20.M. Brodszki et al. Synthesis of the Hepatitis B Nucleoside Analogue Lagociclovir Valactate. Org. Process. Res. Dev. 15, 1027-1032 (2011). 21.M. McLaughlin et al. Enantioselective Synthesis of 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) via Enzymatic Desymmetrization. Org. Lett. 19, 926-929 (2017). 22.W. T. Markiewicz, M. Wiewiorowski. A New Type of Silyl Protecting Groups in Nucleoside Chemistry. Nucleic Acids Res. 5, s185-s190 (1978). 23.K. R. Campos et al. The Importance of Synthetic Chemistry in the Pharmaceutical Industry. Science 363, eaat0805 (2019). 24.M. Peifer, R. Berger, V. W. Shurtleff, J. C. Conrad, D. W. MacMillan. A General and Enantioselective Approach to Pentoses: a Rapid Synthesis of PSI-6130, the Nucleoside Core of Sofosbuvir. J. Am. Chem. Soc. 136, 5900-5903 (2014). 25.D. Chapdelaine et al. A stereoselective approach to nucleosides and 4'-thioanalogues from acyclic precursors. J. Am. Chem. Soc. 131, 17242-17245 (2009). 26. R. Britton, B. Kang. alpha-Haloaldehydes: Versatile Building Blocks for Natural Product Synthesis. Nat. Prod. Rep. 30, 227-236 (2013). 27. W. Ren et al. Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level. Nat. Commun. 9, 3243 (2018). 28. A. Quintard, J. Rodriguez. Bicatalyzed Three-Component Stereoselective Decarboxylative Fluoro-Aldolization for the Construction of Elongated Fluorohydrins. ACS Catalysis 7, 5513-5517 (2017). 29.TC Britton, ME LeTourneau. (1995). Process for Anomerizing Nucleosides. US 5,420,266. Eli Lilly and Company. 30.Meanwell et al, Science, 2020, 369, 725-730

[0124] All cited references are incorporated herein by reference.

[0125] The present invention has been described in relation to one or more embodiments. However, it will be apparent to those skilled in the art that many modifications and alterations are possible without departing from the scope of the invention as defined in the claims. Accordingly, although various embodiments of the invention are disclosed herein, many adaptations and alterations are possible within the scope of the invention according to the common general knowledge of those skilled in the art. Such alterations include replacing known equivalents for any aspect of the invention with those known in order to achieve the same results in substantially the same way. Numerical ranges include numerical values ​​that define the range. In this specification, the word “comprising” is used as an open-ended term and is substantially synonymous with the phrase “including, but not limited to,” and the word “comprises” has a corresponding meaning. However, it should be understood that where the words “contains” or “includes,” or variations of the same etymology, are used herein, variations or modifications to the words “constituted” or “composed of” (excluding unspecified elements, processes, or components), or variations or modifications to the words “essentially composed of” or “essentially composed of” (limiting to specific materials or described processes, along with those that do not substantially affect the basic and novel features of the claimed invention), are also conceivable. While the elements of the invention described herein may be shown in specific embodiments, it should be understood that they can be combined in any way and in any number to create additional embodiments. The various examples and preferred embodiments described herein should not be construed as limiting the invention to only the explicitly described embodiments. This specification should be understood to support and encompass embodiments that combine the explicitly described embodiments with any number of the disclosed elements and / or preferred elements. Furthermore, any permutations and combinations of all elements described herein should be considered disclosed by this specification unless otherwise stated in the context. The references made herein should not be construed as an admission that such references constitute prior art of the present invention.All publications are incorporated herein by reference in such a manner that it is specifically and individually indicated that each publication is incorporated herein by reference, and as if it were fully described herein. The present invention includes substantially the embodiments and variations described above, and all embodiments referring to the embodiments described above.

Claims

1. A method for synthesizing a haloaldehyde compound, comprising reacting a halogen or halogen-containing compound with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I) to produce a haloaldehyde compound, In the formula, R 1 , R 2 , R 3 , and R 4 Each of these is independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx is the counterion of the salt. method.

2. A method for producing intermediates in the synthesis of nucleosides or their analogues, i) Reacting a halogen or halogen-containing compound with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I) to produce a haloaldehyde compound; In the formula, R 1 , R 2 , R 3 , and R 4 Each of these is independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx is the counterion of the salt; ii) To produce halohydrin compounds by performing an enantioselective aldol reaction catalyzed with proline. A method for producing intermediates in the synthesis of nucleosides or their analogues.

3. The method of claim 2, further comprising reducing the halohydrin compound to obtain a halohydrindiol compound.

4. A method for synthesizing nucleosides or their analogues, i) Reacting a halogen or halogen-containing compound with an aryl or heteroaryl-substituted compound in the presence of a catalyst compound according to formula (I) to produce a haloaldehyde compound; wherein, R 1 , R 2 , R 3 , and R 4 are each independently H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and, Cx is a counterion of the salt; ii) Producing halohydrin compounds by carrying out enantioselective aldol reactions catalyzed by proline; iii) Reducing the halohydrin compound to produce a halohydrindiol compound; and iv) Contacting the halohydrindiol compound with a Lewis acid or base via a cyclohalide substitution (AHD) reaction. A method for producing a nucleoside or its analogues, including a nucleoside.

5. The method according to any one of claims 1 to 4, wherein the halogenation is enantioselective.

6. The method according to any one of claims 2 to 5, wherein the proline is L-proline or D-proline.

7. The method according to any one of claims 4 or 6, wherein the Lewis acid is a halophilic Lewis acid.

8. The Lewis acid is InCl 3 Or Sc(OTf) 3 The method according to any one of claims 4 or 7.

9. The method according to any one of claims 4 to 8, wherein the AHD promoted by the Lewis acid produces a nucleoside or analogue thereof with protected C2' and C3' positions, or a nucleoside or analogue thereof with a migrated acetonide protecting group, or undergoes deprotection.

10. The method according to any one of claims 3 to 9, wherein the halohydrindiol compound is separated before treatment with the base.

11. The aforementioned base is NaOH, K 2 CO 3 , KHCO 3 kaNa 2 CO 3 NaHCO 3 , KOH, LiOH, Li 2 CO 3 LiHCO 3 , Cs 2 CO 3 , CsHCO 3 The method of claim 4, 5, 6, or 9, wherein the material is CsOH.

12. The method of claim 4, 5, 10, or 11, wherein the AHD promoted by the base produces a nucleoside or analogue with protected C3' and C5' positions.

13. The aforementioned halohydrin compound The method of any one of claims 2 to 12, wherein NB is an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X is a halogen.

14. The aforementioned halohydrin compound The method according to any one of claims 2 to 13.

15. The aforementioned halohydrindiol compound The method of any one of claims 3 to 14, wherein NB is an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X is a halogen.

16. The method according to any one of claims 1 to 15, wherein the halogen is fluorine, bromine, chlorine, or iodine.

17. The method according to any one of claims 1 to 15, wherein the halogen-containing compound is an electrophilic halogenating agent.

18. The method according to any one of claims 1 to 15, wherein the halogen-containing compound is N-fluorobenzenesulfonimide (NFSI), Selectfluor®, Xtalfluor®, N-haloscuscinimide, N-chlorinated hydantoin, Palau'chlor®, or N-fluoropyridinium.

19. The method according to any one of claims 1 to 18, wherein the counterion of the salt is HCl, TFA, HBr, or MsOH.

20. The catalyst compound is The method according to any one of claims 1 to 19.

21. The aryl or heteroaryl substituted compound comprises the following chemical structure: The method according to any one of claims 1 to 19, wherein NB is optionally substituted with an aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

22. The aforementioned haloaldehyde compound comprises the following chemical structure: The method according to any one of claims 1 to 21, wherein NB is an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, X is a halogen, and * indicates enantioenrichment.

23. The aforementioned haloaldehyde compound The method according to any one of claims 1 to 22.

24. The nucleoside or its analogues The formula is such that NB is an optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and each R is independently -OH, -OC(CH 3 ) 2 O-,-(CH 2 ) 3 -, -CH 2 SCH 2 -, or -CH 2 OCH 2 - The method according to any one of claims 4 to 23.

25. The method according to any one of claims 4 to 24, wherein the nucleoside or its analogue is a C3' / C5' protected NA, a C4' modified NA, a C2' modified NA, a C-linked NA, an L-configured NA, a D-nucleoside or its analogue, an L-nucleoside or its analogue, a loc nucleic acid, an iminonucleoside, or a thionucleoside.

26. A halohydrin compound.

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