Catalytic glycosylation process of arenes

Abstract

The present invention relates to a catalytic arene glycosylation process that enables the rapid synthesis of GS-441524, a nucleoside analog of the antiviral prodrug remdesivir.

Description

[Technical field]

[0001] The present invention relates to a catalytic arene glycosylation process that, among other things, allows for the rapid synthesis of a nucleoside analog of the antiviral prodrug remdesivir, developed by Gilead Sciences and designated GS-441524, which is the major plasma metabolite of the antiviral prodrug remdesivir and has a half-life of approximately 24 hours in human patients. [Background technology]

[0002] Since the beginning of 2020, scientists have been striving to find effective solutions to combat SARS-CoV-2, especially by developing reliable vaccines to stop the spread of the disease and repurposing drugs to combat its effects on the human body. Remdesivir, an antiviral prodrug, remains the most widely used treatment for early infection. However, current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and low-temperature conditions.

[0003] Society has witnessed the remarkable effectiveness of applied and basic science in curbing the impact of SARS-CoV-2. The pandemic has seen a particular focus on the pharmaceutical sector, including small molecule therapeutics, vaccinations, and biomedical devices. The pandemic has also driven a global effort to repurpose existing medicines to enable a rapid and targeted response. Remdesivir (Vekluly), an antiviral prodrug originally evaluated in clinical trials to combat the Ebola virus, has shown somewhat mixed results against COVID-19 but remains the most widely used treatment in the early stages of the infection.

[0004] As a result, there is a need for improved processes for preparing antiviral nucleosides.

[0005] CHEMICAL REVIEWS, VOL.117, pages1687-1764, 2017 discloses a single example of direct C-glycosylation of an arene compound with a monosaccharide in the presence of a Lewis acid catalyst without protecting the hydroxyl group. No further details are available from the disclosure. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] CHEMICAL REVIEWS,VOL.117,pages1687-1764,2017 Summary of the Invention [Problem to be solved by the invention]

[0007] The inventors therefore focused on developing the direct addition of arenes and (hetero)arenes to unprotected monosaccharides. Here, the inventors discovered a fully stereoselective silylium-catalyzed method for C-C bond formation that affords ring-opened polyols that can be selectively cyclized to provide either the kinetically favored α-furanose or the thermodynamically favored β-anomer. This method facilitates the synthesis of the remdesivir precursor GS-441524 after subsequent Mn-catalyzed C-H oxidation and deoxycyanation.

[0008] In a first aspect, the present invention relates to a method for the glycosylation of arenes, in which a monosaccharide is reacted in the presence of a Lewis acid catalyst with a silylating agent to introduce one or more silyl groups into the monosaccharide and an aromatic hydrocarbon selected from arenes or heteroarenes, each of which optionally bears one or more substituents, followed by removal of the one or more silyl groups to obtain a nucleoside analogue.

[0009] In the method of the present invention, the monosaccharide is preferably selected from tetroses, pentoses, hexoses and any deoxy form thereof, more preferably the monosaccharide is selected from ribose or deoxyribose.

[0010] In the process of the present invention, the silylating agent may be selected from hydrosilanes, allylsilanes, methallylsilanes, arylsilanes, trifluoromethylsilanes, benzylsilanes, disilazanes, silyl halides, silyl cyanides, silyl azides, silyl phosphites, silyl ketene acetals, bis(silyl)acetamides, in particular tri-(C1-C6-alkyl)-substituted silyl compounds, preferably bis(silyl)acetamides, more preferably (N,O-bis(trimethylsilyl)trifluoroacetamide), which are preferably used to transfer tri-(C1-C6-alkyl)-substituted silyl groups in hemiacetal form to each hydroxyl group of a monosaccharide, i.e. in the form of a furanose or pyranose. In the process of the present invention, BSTFA (N,O-bis(trimethylsilyl)trifluoroacetamide) is the preferred silylating agent, which also functions as a solvent for the reactants.

[0011] The reaction conditions are not critical, but the reaction temperature and reaction pressure can be adjusted according to the reaction partners. A solvent for the reactants can be used and can be selected from non-polar to polar aprotic organic solvents such as pentane, hexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, 1,4-dioxane, ethyl acetate, dimethylformamide, acetonitrile, etc. Preferably, the reaction is carried out as a one-pot reaction at room temperature to a slightly higher temperature of 50°C to 70°C and at atmospheric pressure.

[0012] The Lewis acid catalyst is not particularly limited, and can be selected from boron trifluoride etherate (ether acid), calcium (II) bis(trifluoromethanesulfonimide), aluminum chloride, iron (III) chloride, tin (IV) chloride, indium (III) trifluoromethanesulfonate, bismuth (III) trifluoromethanesulfonate, rare earth metal trifluoromethanesulfonate, zirconocene dichloride, tritylium tetrafluoroborate, silyl trifluoromethanesulfonate, silyl perchlorate, silyl bis(trifluoromethanesulfonyl)imide, silyl disulfonimide (DSI), silyl binaphthyl-allyl-tetrasulfone (BALT), silyl imide diphosphorimidate (IDPis), N,N'-bis(trifluoromethanesulfonyl) phosphoramidimidate (PADI). In the method of the present invention, TMSOTf (trimethylsilyl) trifluoromethanesulfonate is the preferred Lewis acid.

[0013] The aromatic hydrocarbon may be selected from arenes containing 1 to 4 aromatic rings, each of which is optionally substituted with one or more heterosubstituents, or heteroarenes containing 1 to 4 rings, each of which is optionally substituted with one or more heterosubstituents, as further defined below. Preferred arenes or heteroarenes, respectively, are anisole, aniline, pyrrole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, triazole, oxadiazole, tetrazole, pyrazole, azepine, pyridine, pyridazine, pyrimidine, pyrazine, oxazine, thiazine, triazine, each of which is optionally substituted with one or more heterosubstituents.

[0014] In a second embodiment, the nucleoside analogue, in which the monosaccharide is ribose and the heteroarene is pyrrolo[2,1-f][1,2,4]triazine-4-amine, obtainable according to the method of the present invention, can be further treated with a protecting agent for the hydroxyl group to provide the reactive agent GS-441524. The resulting protected nucleoside analogue is treated with an oxidizing agent to introduce a hydroxyl group (hydroxyl group) on the anomeric carbon atom, the resulting reaction product having a hydroxyl group on the anomeric carbon atom is treated with a cyanating agent to replace the hydroxyl group on the anomeric carbon atom with a nitrile group, and the reaction product is finally treated with a deprotecting agent to remove the protecting group from the hydroxyl group on the ribose moiety.

[0015] The protecting agent for the hydroxyl group of the ribose moiety is selected from alkyl halides, alkyl carboxylic anhydrides, aryl carboxylic anhydrides, alkyl carboxylic acid chlorides, aryl carboxylic acid chlorides, silyl halides, bis(silyl)acetamide, silyl trifluoromethanesulfonate, acetone, alkyl chloromethyl ethers, and 2-(silyl)ethoxychloromethyl ethers, and is preferably acetic anhydride or benzoic anhydride.

[0016] After protecting the hydroxyl groups, the protected nucleoside analogue is treated with an oxidizing agent in a non-polar aprotic organic solvent to introduce a hydroxyl group at the anomeric carbon atom of the ribonucleoside. Preferably, the oxidizing agent is iodosylbenzene in the presence of Mn(TPP)Cl ((5,10,15,20-tetraphenyl-21H,23H-porphine manganese(III) chloride) as a catalyst.

[0017] In the next reaction step, the resulting oxidized ribonucleoside reaction product is treated with a cyanating agent selected from silyl cyanide, alkali metal cyanide, preferably trimethylsilyl cyanide (TMSCN) in a non-polar aprotic organic solvent in the presence of a strong acid as a catalyst, such as bis(trifluoromethane)sulfonimide, thereby obtaining a mixture of α:β diastereomers, where the α-diastereomer (2R,3R,4R,5R)-2-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(acetoxymethyl)-2-cyanotetrahydrofuran-3,4-diyl diacetate is obtained as the major product. Preferably, the reaction is carried out at a temperature up to 0° C. and at atmospheric pressure.

[0018] In the next reaction step, the mixture of α:β diastereomers is treated with a base selected from an alkali metal alcoholate, an alkali metal carbonate, preferably sodium methanolate, preferably in an aliphatic alcohol, such as methanol, ethanol or iso-propanol, to remove the acetate protecting group, yielding the single α-diastereomer (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-2-carbonitrile.

[0019] In the context of the present invention, the following definitions are used to define elements and groups used in the claims and the specification.

[0020] definition The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0021] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 ” is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5, C 3-4 , C 4-6 , C 4-5 , C 5-6 .

[0022] The term "aliphatic" includes both saturated and unsaturated, straight-chain (i.e., unbranched), branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by those skilled in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, the term "alkyl" includes straight-chain, branched, and acyclic alkyl groups. A similar definition applies to other general terms, such as "alkenyl," "alkynyl," and the like. Furthermore, terms such as "alkyl," "alkenyl," and "alkynyl" encompass both substituted and unsubstituted groups. In certain embodiments, "lower alkyl" is used to refer to alkyl groups (acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 6 carbon atoms.

[0023] As used herein, "alkyl" refers to the radical of a linear, cyclic or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 "Alkyl"). C 1-6 Examples of alkyl groups are methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 It is an alkyl.

[0024] "Aromatic hydrocarbon or arene or aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms provided to the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0025] "Aralkyl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted with an optionally substituted aryl group. In certain embodiments, an aralkyl is an optionally substituted benzyl. In certain embodiments, an aralkyl is a benzyl. In certain embodiments, an aralkyl is an optionally substituted phenethyl. In certain embodiments, an aralkyl is phenethyl.

[0026] "Heteroaromatic hydrocarbon or heteroarene or heteroaryl" refers to a radical of a 5-18 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen and sulfur ("5-18 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups in which the point of attachment is on the heteroaryl ring, in such cases the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, in which case the point of attachment can be on either the aryl ring or the heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be in either ring, i.e., either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0027] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0028] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0029] "Heteroaralkyl" is a subset of alkyl and heteroaryl, and refers to an optionally substituted alkyl group substituted with an optionally substituted heteroaryl group.

[0030] An atom, moiety, or group described herein, unless expressly stated otherwise, can be unsubstituted or substituted, where valences permit. The term "optionally substituted" means substituted or unsubstituted.

[0031] Alkyl, aryl and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl groups, "substituted" or "unsubstituted" aryl groups, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on the group (e.g., a carbon atom or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that upon substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. For purposes of the present invention, heteroatoms such as nitrogen may have any suitable substituents as described herein that satisfy the hydrogen substituents and / or the valence of the heteroatom and result in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituents are oxygen atom substituents. In certain embodiments, the substituents are sulfur atom substituents.

[0032] Exemplary substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR, -ON(R)2, -N(R)2, -N(R)X3. +-, -SH, -SR, -SSR, -C(=O)R, -CO2H, -CHO, -C(OR)3, -CO2R, -OC(=O)R, -OCO2R,-C(=O)N(R)2,-OC(=O)N(R)2,-NR C(=O)R,-NRCO2R,-NRC(=O)N(R)2,-C(=NR)R,-C(=NR)OR,-OC(=NR)R,-OC(=NR)OR,-C(=NR)N(R)2,-OC(=NR)N (R)2,-NRC(=NR)N(R)2,-C(=O)NRSO2R,-NRSO2R,-SO2N(R)2,-SO2R, SO2OR, -OSO2R, -S(=O)R, -OS(=O)R, -Si( R)3, -OSi(R)3-C(=S)N(R)2, -C(=O)SR, -C(=S)SR, -SC(=S)SR, -SC(=O)SR, -OC(=O)SR, -SC(=O)OR, -SC(=O)R, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R groups; or two geminal hydrogens on a carbon atom are replaced with the groups =O, =S, =NN(R)2, =NNRC(=O)R, =NNRC(=O)OR, =NNRS(=O)2R, =NR, or =NOR; wherein each instance of R is independently C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14or two R groups joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is selected from halogen, -OH, -OR, -CN, -NO-NR 2,2 wherein R is hydrogen or C1-6 alkyl.

[0033] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I). [Brief description of the drawings]

[0034] Diagrams and Examples The invention is further illustrated by the accompanying figures and examples. Figure 1. A. Examples of nucleoside-based antivirals. B. Established sequence for the synthesis of remdesivir. C. Our design: arylation of free D-ribose. Figure 2. A. Diastereoselective functionalization of D-ribose by transient silylation. Mechanistic considerations for BC-C bond formation. C. Examples of other sugars with other (hetero)arenes. Figure 3. Selective synthesis of α- and β-C-glycosylated nucleosides by varying the cyclization temperature. Figure 4. Benzylic CH oxidation of peracetylated ribonucleosides and diastereoselective deoxycyanation α-6.

[0035] Nucleotide analogs such as remdesivir are generally a class of compounds prominent for their RNA antiviral properties (Figure 1A), as shown in Figure 1. Besides the ubiquitous presence of monosaccharide derivatives, their synthesis still relies on multi-step sequences and the use of protecting groups due to the selectivity issues inherent in the functionalization of unprotected sugars.

[0036] In the case of remdesivir, Gilead's industrial route to perbenzylated D-ribonolactone (Fig. 1B) - which can be obtained in four steps from D-ribose - requires sensitive reagents and cryogenic conditions for some steps. This need has inspired new approaches to construct heterocyclic arenes and the refinement of organocatalytic asymmetric phosphoramides to introduce monophosphate-like side chains. However, efforts to streamline the construction of the core nucleoside itself remain elusive. Recent progress in the direct assembly of nucleosides has focused on the formation of C-heteroatom bonds at the anomeric position, while examples of CC cleavage are scarce.

[0037] We aimed to develop a novel and significantly simplified route to remdesivir, with silylium-catalyzed arylation of D-ribose as the key step (Figure 1C). We report the regioselective and stereoselective addition of (hetero)arenes to unprotected sugars, which affords nucleoside intermediates in one pot. Branching of α- or β-anomers is achieved by kinetically controlled or thermodynamically driven epimerization, respectively. Finally, the new methodology enabled the facile synthesis of remdesivir precursor GS-441524 by selective Mn-catalyzed benzylic C-H oxidation and diastereoselective deoxycyanation.

[0038] As shown in Figure 2, our approach exploits the inherent nucleophilicity of the heterocycle and does not require prefunctionalization or the preparation of air-sensitive organometallic reagents. Furthermore, we utilized Lewis acid-catalyzed transient silylation of carbohydrates to simultaneously achieve two main objectives: in situ protection of all protic functional groups and selective anomeric activation (Figure 2A). We found that D-ribose was rapidly activated by catalytic TMSOTf at 25 °C and regenerated by protodesilylation of the pristine silicon source N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). The formation of the major C-C bond occurs under neat conditions at 50 °C, affording only a single linear isomer, 1-TMS6, in quantitative yield. However, this dynamic mixture diastereoselectively converges to a single product during the transformation. Subsequent desilylation of the crude reaction mixture with TBAF affords the linear analogue 1 in one pot (86%), without any trace of silicon usage. Preliminary attempts have revealed that the method is also valid for functionalizing alternative sugars and (hetero)arenes (Figure 2C); here, we show three further examples, but a more comprehensive study is currently underway in our laboratory. Reaction with D-xylose also affords the product 2 as a single diastereoisomer, but in slightly lower yield (53%). Furthermore, addition of an indole derivative affords the polyol 3 in good yield (69%) at 25 °C. Finally, 1,3,5-trimethoxybenzene similarly allows derivatization to compound 4 in 71% yield.

[0039] Lewis acid-catalyzed nucleophilic addition reactions to carbohydrate derivatives are generally believed to proceed via an oxocarbenium intermediate derived from the activation of an anomeric substituent. However, this assumption is questioned here in light of the formation of a single linear product. Instead, we propose a mechanism in which TMSOTf coordinates to the oxygen atom in the sugar ring before reacting with the heterocycle and opening the ring (Figure 2B). Extensive NMR analysis confirmed the silylation of the sugar at 25 °C and the reduction in the amount of isomers (see Supporting Information, Figures S10-23). ​​We were indeed able to observe TMS-protected ribopyranoses and -furanoses (77% and 21%, respectively). For both intermediates, only the β-anomer is present, and for steric reasons, the anomeric group is trans-oriented with respect to the neighboring siloxy group (see Supporting Information, Figure S46 for DFT calculations). As a result, the S N Successive nucleophilic substitutions via a type 2 mechanism led to the convergence of the products to a single diastereoisomer. Kinetic analysis at 50 °C revealed that the consumption of arene reflected the formation of product, with the pyranose isomer reacting faster than the furanose. Evidence of a double addition was also detected.

[0040] As shown in Figure 3, we found that subjecting the reaction mixture to acid treatment rather than fluorine treatment afforded the corresponding C-ribofuranosylated product (Figure 3). When acid treatment was carried out at 25°C, the formation of α-product 5 was achieved in good yield and with high diastereoselectivity (71%, α / β=90:10). In contrast, acid treatment at 50°C directly led to the thermodynamically favorable β-nucleoside 5 (48%, α / β=14:86). The α- to β-epimerization was carried out by redissolving the isolated product α-5 in hydrochloric acid in dioxane at 50°C, followed by elution with 10% ethanol. 1 HNMR could be monitored (see Supporting Information, Figure S27).

[0041] As shown in Figure 4, the synthesis of the antiviral drug GS-441524 required the oxidative introduction of a nitrile moiety. We therefore envisioned first performing a CH oxidation to give the sterically hindered hemiacetal 7 (Figure 4), which would then be deoxycyanoated in a diastereoisotropic manner to give GS-441524.

[0042] After exploring various approaches, the desired reactivity was obtained by Mn-catalyzed benzylic CH oxidation reaction. Of note, the exclusive reactivity of α-anomer 5 was observed. This is likely due to the higher accessibility of the β-hydrogen atom to the Mn-porphyrin complex according to the DFT-optimized ground-state structure (see Supporting Information, Figure S31). The short reaction time and partial addition of oxidant were the key factors determining the chemoselectivity, with the fragmentary overoxidation to ribonolactone being the most prominent side reaction. Starting from peracetylated α-ribonucleoside 6, the oxidation product 7, synthesized on a 15 mmol scale from D-ribose in 60% yield in a single purification via column chromatography, was obtained as an unwanted mixture of isomers in 27% overall yield (57% brsm) (equilibrium distribution 2:46:54 ketone / hemiacetal, α:β=63:37 in CDCl2).

[0043] Previous reports on the deoxycyanation of benzyl-protected hemiacetals provided great suggestions for the final step of this pathway. However, due to the adjacent acetoxy group, intermediate 7 was significantly less reactive. As a result, we replaced the original mixture of TfOH / TMSOTf with the even stronger Brønsted acid HNTf2, which was treated with TMSCN to generate in situ the active Lewis acid TMS-NTf2. Furthermore, reducing the equivalents of TMSCN prevented further reaction of the product (see Supporting Information, Table S3), and overnight reaction at -40 °C afforded the peracetylated cyanated product in 84% yield and good diastereoselectivity (α:β = 87:13). Remarkably, GS-441524 precipitated as a single stereoisomer in 81% yield and 68% from hemiacetal 7 in the subsequent methanolysis. EXAMPLES

[0044] Experimental Part 1.1 Arylation of unprotected sugars General Procedure for the Arylation of Unprotected Sugars (1S,2S,3R,4R)-1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)pentane-1,2,3,4,5-pentaol, 1 [ka] TMSOTf (trimethylsilyl trifluoromethanesulfonate, 9 μL, 11.1 mg, 50.0 μmol, 0.25 equiv.) was added slowly to a stirred suspension of D-(-)-ribose (30.1 mg, 0.2 mmol, 1.0 equiv.) and pyrrolo[2,1-f][1,2,4]triazin-4-amine (40.3 mg, 0.3 mmol, 1.5 equiv.) in BSTFA (N,O-bis(trimethylsilyl)trifluoroacetamide, 0.53 mL, 516 mg, 2.0 mmol, 10 equiv.) at room temperature. The mixture was stirred at this temperature for 5 min, at which point the solution became homogeneous, and then heated to 50 °C. After 24 h, thin layer chromatography (TLC) analysis indicated complete consumption of the ribose starting material, at which point the reaction was cooled to room temperature and then to 0 °C. A solution of TBAF (tetrabutylammonium fluoride, 2.2 mL, 1 M in THF, 2.2 mmol, 11 equiv.) was then added slowly and the solution was stirred at this temperature for 2 h before being concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc → 10% MeOH in EtOAc) to give 1 (48.7 mg, 0.17 mmol, 86%) as a white solid. HRMS(ESI + ) is C 11 H 17 N4O5[M+H + ] was calculated to be 285.119345 and observed to be 285.119410.

[0045] Additional substrates for arylation of unprotected sugars (1S,2S,3S,4R)-1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)pentane-1,2,3,4,5-pentaol, 2 [ka] TMSOTf (9 μL, 11 mg, 50 μmol, 0.25 equiv) was added slowly to a stirred suspension of D-(-)-xylose (45.0 mg, 0.3 mmol, 1.5 equiv) and pyrrolo[2,1-f][1,2,4]triazine-4-amine (26.8 mg, 0.2 mmol, 1.0 equiv) in BSTFA (0.53 mL, 516 mg, 2.0 mmol, 10 equiv) at room temperature. The mixture was stirred at this temperature for 5 min and then heated to 50 °C. After 4 days, thin layer chromatography (TLC) analysis indicated complete consumption of the arene starting material, at which point the reaction was cooled to room temperature and then to 0 °C. A solution of TBAF (2.2 mL, 1 M in THF, 2.2 mmol, 11 equiv) was then added slowly and the solution was stirred at this temperature for 2 h before being concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc→10% MeOH in EtOAc) to give 2 (30.1 mg, 0.1 mmol, 53%) as an off-white solid. HRMS(ESI + ) is C 11 H 17 N4O5[M+H + ] was calculated to be 285.119345 and observed to be 285.119100.

[0046] (1S,2S,3R,4R)-1-(5-bromo-1-methyl-1H-indol-3-yl)pentane-1,2,3,4,5-pentanol, 3 [ka] To a stirred suspension of D-(-)-ribose (45.1 mg, 0.3 mmol, 1.5 equiv) in BSTFA (0.53 mL, 516 mg, 2.0 mmol, 10 equiv) was slowly added TMSOTf (9 μL, 11 mg, 50 μmol, 0.25 equiv) at room temperature. The mixture was stirred at this temperature for 5 min, after which the solution became homogeneous and 5-bromo-1-methyl-1H-indole (42.2 mg, 0.2 mmol, 1.0 equiv) was added in one portion. The reaction mixture was stirred at room temperature. After 48 h, thin layer chromatography (TLC) analysis indicated complete consumption of the indole starting material, at which point the reaction was cooled to room temperature and then to 0 °C. A solution of TBAF (2.2 mL, 1 M in THF, 2.2 mmol, 11 equiv) was then slowly added and the solution was stirred at this temperature for 2 h before being concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2 → 10% MeOH in CH2Cl2; Note: silica needs to be pretreated with 5% Et3N solution in CH2Cl2 before chromatography) to give 3 (49.8 mg, 0.1 mmol, 69%) as a white solid. HRMS(ESI + ) is C 14 H 18 NO5BrNa[M+Na + ] was calculated as 382.026068 and observed as 382.026000.

[0047] (1S,2S,3R,4R)-1-(2,4,6-trimethoxyphenyl)pentane-1,2,3,4,5-pentanol, 4 [ka] To a stirred suspension of D-(-)-ribose (44.9 mg, 0.3 mmol, 1.5 equiv) in BSTFA (1.06 mL, 1.03 g, 4.0 mmol, 20 equiv) was slowly added TMSOTf (9 μL, 11 mg, 50 μmol, 0.25 equiv) at room temperature. The mixture was stirred at this temperature for 5 min, after which the solution became homogeneous and 1,3,5-trimethoxybenzene (33.7 mg, 0.2 mmol, 1.0 equiv) was added in one portion. The reaction mixture was heated to 50 °C. After 48 h, thin layer chromatography (TLC) analysis indicated complete consumption of the arene starting material, at which point the reaction was cooled to room temperature and then to 0 °C. A solution of TBAF (4.4 mL, 1 M in THF, 4.4 mmol, 22 equiv) was then slowly added and the solution was stirred at this temperature for 2 h before being concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc → 10% MeOH in EtOAc; note: silica needs to be pretreated with 5% EtN solution in EtOAc prior to chromatography) to give 4 (45.1 mg, 0.1 mmol, 71%) as a white solid. HRMS(ESI + ) C 14 H 22 O8Na[M+Na + ] was calculated to be 341.120689 and observed to be 341.120290.

[0048] Different cyclization conditions result in different products [ka]

[0049] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl)tetrahydro-furan-3,4-diol, α-5) [ka] TMSOTf (90 μL, 111 mg, 0.5 mmol, 0.25 equiv) was added slowly to a stirred suspension of D-(-)-ribose (302 mg, 2.0 mmol, 1.0 equiv) and pyrrolo[2,1-f][1,2,4]triazine-4-amine (326 mg, 2.4 mmol, 1.2 equiv) in BSTFA (5.0 mL, 4.87 g, 18.9 mmol, 10 equiv) at room temperature. The mixture was stirred at this temperature for 5 min, at which point the solution became homogeneous, and then heated to 50 °C. After 48 h, thin layer chromatography (TLC) analysis indicated complete consumption of the ribose starting material, at which point the reaction was cooled to room temperature and then to 0 °C. A solution of HCl (20 mL, 4 M in 1,4-dioxane, 80 mmol, 40 equiv.) was then slowly added and the suspension was stirred vigorously at this temperature for 10 min before being allowed to warm to room temperature. After 24 h, the mixture was diluted with Et2O (30 mL), filtered on a glass frit, and the solid was washed with Et2O before being dried under vacuum. The crude mixture was then dissolved in MeOH (20 mL) and NaHCO3 (11 g) was added. The mixture was stirred for 30 min before being filtered, washed with MeOH, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc → 10% MeOH in EtOAc) to give α-5 (377 mg, α / β = 9:1, 1.4 mmol, 71%) as an off-white solid. HRMS(ESI + ) is C 11 H 15 N4O4[M+H + ] was calculated to be 267.108780 and the observed value was 267.108860.

[0050] (2S,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol, β-5) [ka] TMSOTf (45 μL, 55.2 mg, 0.25 mmol, 0.25 equiv) was added slowly to a stirred suspension of D-(-)-ribose (150 mg, 1.0 mmol, 1.0 equiv) and pyrrolo[2,1-f][1,2,4]triazine-4-amine (202 mg, 1.5 mmol, 1.5 equiv) in BSTFA (2.6 mL, 2.53 g, 9.84 mmol, 10 equiv) at room temperature. The mixture was stirred at this temperature for 5 min, at which point the solution became homogeneous, and then heated to 50 °C. After 48 h, thin layer chromatography (TLC) analysis indicated complete consumption of the ribose starting material, at which point the reaction was cooled to room temperature and then to 0 °C. A solution of HCl (10 mL, 4 M in 1,4-dioxane, 40 mmol, 40 equiv) was then slowly added and the suspension was stirred vigorously at this temperature for 10 min before being warmed to 50 °C. After 48 h, the mixture was cooled to room temperature, diluted with Et2O (30 mL), filtered on a glass frit, and the solid was washed with Et2O before being dried under vacuum. The crude mixture was then dissolved in MeOH (10 mL) and NaHCO3 (5.5 g) was added. The mixture was stirred for 30 min before being filtered, washed with MeOH, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc → 10% MeOH in EtOAc) to give β-5 (127.5 mg, α / β = 1:6, 0.48 mmol, 48%) as an off-white solid. HRMS(ESI - ) is C 11 H 13 N4O4[MH] - The calculated value was 265.094230 and the observed value was 265.094460.

[0051] Peracetylation of ribonucleosides (2R,3S,4R,5R)-2-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(acetoxymethyl)-tetrahydrofuran-3,4-diyl diacetate, α-6 [ka] Nucleoside α-5 (133 mg, 0.5 mmol, 1.0 equiv) and DMAP (6.1 mg, 50 μmol, 0.1 equiv) were suspended in triethylamine (0.7 mL, 508 mg, 5.0 mmol, 10 equiv) at 0 °C. Acetic anhydride (0.21 mL, 227 mg, 2.2 mmol, 4.4 equiv) was then added dropwise and the reaction was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with EtOAc and H2O and the organic layer was washed with water (2 times), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (1:1 CHCl2 / EtOAc) to give α-6 (187 mg, α / β=10:1, 0.4 mmol, 86%) as an off-white solid. HRMS(ESI + ) C 19 H 22 N4O8Na[M+Na + ] was calculated as 457.132984 and observed as 457.133320.

[0052] (2S,3S,4R,5R)-2-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(acetoxymethyl)-tetrahydrofuran-3,4-diyl diacetate, β-6 [ka] Nucleoside β-5 (52.6 mg, 0.2 mmol, 1.0 equiv) and DMAP (2.4 mg, 20 μmol, 0.1 equiv) were suspended in triethylamine (275 μL, 200 mg, 2.0 mmol, 10 equiv) at 0 °C. Acetic anhydride (82 μL, 89 mg, 0.9 mmol, 4.4 equiv) was then added dropwise and the reaction was allowed to warm to room temperature and stirred for 12 h. The mixture was diluted with EtOAc and H2O and the organic layer was washed with water (2 times), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (1:1 CHCl2 / EtOAc) to give β-6 (85.8 mg, α / β=1:7, 0.1 mmol, 38%) as an off-white solid. HRMS(ESI + ) C 19 H 22 N4O8[M + ] was calculated to be 434.14376 and the observed value was 434.14360.

[0053] Large-scale / telescope processes [ka]

[0054] Arylation / cyclization / acetylation sequence on a 15mmol scale TMSOTf (0.68 mL, 835 mg, 3.75 mmol, 0.25 equiv) was added slowly to a stirred suspension of D-(-)-ribose (2.25 g, 15.0 mmol, 1.0 equiv) and pyrrolo[2,1-f][1,2,4]triazine-4-amine (2.41 g, 18.0 mmol, 1.2 equiv) in BSTFA (40 mL, 38.6 g, 150 mmol, 10 equiv) at room temperature. The mixture was stirred at this temperature for 5 min, at which point the solution became homogeneous, and then heated to 50 °C. After 60 h, thin layer chromatography (TLC) analysis indicated complete consumption of the ribose starting material, at which point the reaction was cooled to room temperature and then to 0 °C. A solution of HCl (150 mL, 4 M in 1,4-dioxane, 600 mmol, 40 equiv) was then slowly added and the suspension was stirred vigorously at this temperature for 10 min before being allowed to warm to room temperature. After 24 h, the mixture was filtered on a glass frit and the solid was washed with Et2O before being dried under vacuum. The solid and DMAP (183 mg, 1.5 mmol, 0.1 equiv) were suspended in triethylamine (22 mL, 16.0 g, 158 mmol, 10 equiv) at 0 °C. Acetic anhydride (6.4 mL, 6.91 g, 67.7 mmol, 4.5 equiv) was then added dropwise and the reaction was allowed to warm to room temperature and stirred for 16 h. TLC analysis indicated that the reaction was still incomplete, so the mixture was once again cooled to 0 °C and more acetic anhydride (1.4 mL, 1.51 g, 14.8 mmol, 1.0 equiv) was added. After stirring at room temperature for 6 h, the mixture was diluted with EtOAc and H2O, and the organic layer was washed with water (2x), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (4:3→1:1 CH2Cl2 / EtOAc) to give 6 (3.91 g, α / β=9:1, 9.0 mmol, 60%) as an off-white solid.

[0055] A general procedure for the Mn(TPP)-catalyzed oxidation of ribonucleosides. (3R,4R,5R)-2-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(acetoxymethyl)-2-hydroxytetrahydrofuran-3,4-diyl diacetate, 7 [ka] In a flame-dried Schlenk flask at room temperature, Mn(TPP)Cl (4 mol%) and acetylated ribonucleoside α-6 (1.0 equiv.) were dissolved in freshly degassed benzene (0.05 mol / L). Iodosylbenzene (2.3 equiv. total, 0.29 equiv. per batch) was added in portions over 8 h (1 h intervals), and after complete addition, the reaction mixture was stirred for an additional 2 h. Solids were removed by filtration over cotton wool, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (1:1 → 0:1 CHCl / EtOAc) to give 7 as a mixture of isomers (isomer distribution in CDCl, open:α:β = 46:34:20, 23–32% yield, 50–68% yield based on recovered starting material).

[0056] [ka] HRMS(ESI - ) is C 19 H 21 N4O9[MH] - The calculated value was 449.131405 and the observed value was 449.131880. mp (melting point) = 60-63℃ 1 HNMR(600MHz,CD2Cl2)δ8.28(s,1H,NH),8.15(s,1H,C 12 H), 7.08(d, J=4.8Hz, 1H, C 9 H), 6.93(d, J=4.7Hz, 1H, C 8 H), 5.72(d, J=6.9Hz, 1H, C 3 H), 5.37(dd, J=6.9, 3.8Hz, 1H, C 4 H), 4.56(q, J=3.7Hz, 1H, C 5 H), 4.44(dd, J=12.0, 3.5Hz, 1H, C 6H), 4.27 (dd, J = 12.0, 4.7 Hz, 1H, C 6’ H), 2.53 (s, 3H, CH 14 3), 2.14 (s, 3H, CH 18 3), 2.07 (s, 3H, CH 17 3), 2.06 (s, 3H, CH 20 3). 13 C NMR (151 MHz, CD2Cl2) δ 170.8 (C 19 ), 170.7 (C 13 ), 170.5 (C 17 ), 169.7 (C 15 ), 151.3 (C 11 ), 146.2 (C 12 H), 129.3 (C 7 ), 116.5 (C 10 ), 112.1 (C 8 H), 104.5 (C 9 H), 100.5 (C 2 ), 80.4 (C 5 H), 73.0 (C 3 H), 70.7 (C 4 H), 63.7 (CH 6 2), 26.0 (CH 14 3), 21.0 (CH 20 3), 20.9 (CH 18 3), 20.7 (CH 16 3).

[0057]

Chem.

[0058]

Chem.

[0059] Cyanation procedure for oxidized ribonucleosides

Chem.

[0060] (2R,3R,4R,5R)-2-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(acetoxymethyl)-2-cyanotetrahydrofuran-3,4-diyl diacetate, α-S4 [ka] HRMS(ESI - ) is C 20 H 20 N5O8[MH] - The calculated value was 458.131738 and the observed value was 458.131900.

[0061] Deprotection procedure for cyanated ribonucleosides [ka] Following a literature procedure (O.-M. Soueidan, BJ Trayner, TN Grant, JR Henderson, F. Wuest, FG West, CICheeseman, OrgBiomolChem 2015, 13, 6511-6521.), compound S4 (54.0 mg, 0.12 mmol, 1.0 equiv, α:β=88:12) was reacted with NaOMe (8.0 μL, 7.6 mg, 25% by weight in methanol, 0.3 equiv) in methanol (2.4 mL, 0.05 mol / L) at room temperature. After 1 h, precipitation of a white solid was observed and the solvent was decanted. The precipitate was treated with 1.0 mL of methanol and hexane, the liquid was decanted, and the solid was dried under high vacuum to give GS-441524 as a single stereoisomer (27.6 mg, 81%, 92% based on α-S4).

[0062] (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-furan-2-carbonitrile, GS-441524 [ka] Analytical data is based on the literature (T. Cihlar, S. Bavari et al., Nature 2016, 531, 381-385). HRMS(ESI + ) is C 12 H 14 N5O4[M+H] + The calculated value was 292.104028 and the observed value was 292.103860.

[0063] As mentioned above, we have designed and developed a more practical and efficient synthetic method for remdesivir starting from free D-ribose. The route features a novel and completely stereoselective nucleophilic addition of (hetero)arenes to carbohydrates without prior introduction of protecting or activating groups. The method involves convergent silylation of TMS-protected β-ribopyranoses and -furanoses prior to the formation of C-C bonds, providing diastereoselective linear products via silyl catalysis. The anomeric structure of the C-nucleoside is simply adjusted by thermodynamic control during the acid-mediated cyclization reaction. Benzylic C-H oxidation followed by deoxycyanation streamlines the chemical synthesis of GS-441524 to just three steps requiring purification from D-ribose and an artificial nucleobase.

Claims

1. A method for the glycosylation of arenes, comprising reacting a monosaccharide with a silylating agent for introducing one or more silyl groups into the monosaccharide and an aromatic hydrocarbon selected from arenes or heteroarenes each optionally having one or more substituents in the presence of a Lewis acid catalyst, and then removing one or more silyl groups to obtain a nucleoside analog.

2. The method for the glycosylation of arenes according to claim 1, wherein the monosaccharide is selected from tetroses, pentoses, hexoses and any deoxy forms thereof, preferably ribose or deoxyribose.

3. The silylating agent is a tri-(C １ ~C ６ -alkyl)-substituted silyl compound, preferably (N,O-bis(trimethylsilyl)trifluoroacetamide, for the glycosylation of the arenes according to claim 1 or 2.

4. The method for the glycosylation of arenes according to claim 1 or 2, wherein the aromatic hydrocarbon is selected from arenes or heteroarenes having 1 to 4 aromatic or heteroaromatic rings, each optionally substituted with one or more hetero substituents.

5. A method for further reacting a glycosylated arene obtained according to the method of claim 1, wherein the monosaccharide is ribose and the heteroarene is pyrrolo[2,1-f][1,2,4]triazin-4-amine, comprising: a) treating the nucleoside analog with a protecting agent to protect the hydroxyl groups of the ribose moiety; b) treating the resulting protected nucleoside analog with an oxidizing agent in the presence of a catalyst to introduce a hydroxyl group on the anomeric carbon atom; c) treating the resulting reaction product having a hydroxyl group on the anomeric carbon atom with a cyanating agent to substitute the hydroxyl group on the anomeric carbon atom; and d) treating the resulting cyanation reaction product with a deprotecting agent to remove the protecting group from the hydroxyl groups of the ribose moiety The method as described above.

6. The method according to claim 5, wherein the protecting agent is selected from alkyl halides, alkyl carboxylic acid anhydrides, aryl carboxylic acid anhydrides, alkyl carboxylic acid chlorides, aryl carboxylic acid chlorides, silyl halides, bis(silyl)acetamides, silyl trifluoromethanesulfonates, acetone, alkyl chloromethyl ethers, 2-(silyl)ethoxychloromethyl ethers, preferably acetic anhydride or benzoic anhydride.

7. The method according to claim 5 or 6, wherein the oxidizing agent is iodosylbenzene in the presence of the catalyst Mn(TPP)Cl ((5,10,15,20-tetraphenyl-21H,23H-porphine manganese(III) chloride)). Claim 8 The method according to claim 5 or 6, wherein the cyanating agent is selected from silyl cyanide, alkali metal cyanide, preferably trimethylsilyl cyanide (TMSCN). Claim 9 The method according to claim 5 or 6, wherein the deprotecting agent is preferably an alkali alcoholate or an alkali carbonate in an aliphatic alcohol.

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