FR2900151A1 - Preparation of disulfonyl compound useful e.g. in the sulfinylation of enolates, comprises reaction of a silane compound with a sulfide compound - Google Patents

Abstract

Preparation of disulfonyl compound (I) comprises reaction of a silane compound (II) with a sulfide compound (VII). Preparation of disulfonyl compound (I) of formula (R1-S(O)x-S(O)y-R2) comprises reaction of a silane compound (II) of formula (R1-S(O)x-R3-Si(R4)(R5)(R6)) with a sulfide compound (VII) of formula (R2-S(O)y-X). R1, R2molecular hydrocarbon residue (optionally substituted and/or interrupted by N, O, P, S, Si and/or X), preferably R1 is 2',3'-didesoxy-2',3'-deshydroribonucleosides and the sulfur atom is bound to 2' or 3' carbon of ribose and R2 is ortho-nitrophenyl, para-nitrophenyl or trichloromethyl; X : halo; x, y : 0-1; R32C hydrocarbon (optionally unsaturated and/or substituted); and R4-R6hydrocarbon group, preferably methyl group. Provided that the sum of x and y is >=1. Independent claims are included for: (1) the preparation of a disulfide compound (III) of formula (R1-S-S-R2) comprising reacting a silane derivative (IIa) of formula (R1-S-R3-Si(R4)(R5)(R6)) with a halide compound (VIIa) of formula (R2-S-X); (2) the preparation of a thiosulfinate compound (IV) of formula R1-S-SO-R2 comprising reacting (IIa) with a sulfinyl halide (VIIb) of formula R2SOX; (3) the preparation of a thiosulfinate compound (V) of formula R1-SO-S-R2 comprising oxidation of (IIa) to obtain a silane compound (IIb) of formula (R1-SO-R3-Si(R4)(R5)(R6)) and reacting (IIb) with a sulfinyl halide (VIIa) of formula R2-S-X; (4) preparation of a disulfide compound (IIIa) of formula R1-S-S-R21 comprising obtaining (III) and reacting (III) with a sulfide compound of formula R21-SH; (5) the preparation of a disulfide compound (VI) of formula (R1-S-S-R1) comprising reacting (IIa) with a dihalide of formula X2 or halo cyanide of formula XCN to obtain in situ sulfide of formula R1-S-X followed by obtaining (VI); and (6) preparation of thiols of formulae R1-SH, R2-SH and R21-SH comprising preparing (III) to obtain (R1-SH), or (VI) to obtain R2-SH, or (IIIa) to obtain R21-SH, respectively, after reduction.

Description

The present invention relates to the preparation of sulfide compounds

  mixed and symmetrical and indirectly, after easy reduction of these disulfides, the preparation of the corresponding thiols. It also concerns according to the same principle the preparation of thiosulfinates and in particular asymmetric thiosulfinates. Disulfides are important reaction intermediates in organic synthesis. They can for example be used as reagents in the context of palladium catalyzed additions (Kuniyasu et al, J. Am Chem Soc 1991, 113, 9796), giving access in the presence of mercury salts to sulfenamides ( Davis et al., 1 Org Chem 1977, 42, 967) or else be used for the electrophilic sulfenylation of enolates (Bischoff et al Org Chem 1997, 62, 4848). On the other hand, reversible redox disulfide-thiol transformation plays a central role in the regulation of many physiological systems, particularly at the level of proteins (Xiao et al., J. Biol Chem 2005, 280, 21099). Many molecules comprising one or more disulfide functions thus have very interesting biological activities: for example, garlic acid has anticancer properties (Block, E. Angew Chem Int.Ed. 1992, 31, 1135) and the maurotoxin acts on K + membrane ion channels (Kharrat et al., FEBS Letters 1997, 284). In addition, the ability of disulfides to be readily reduced within the cell makes the SUS bond a widely used link in a prodrug approach (Kyung Ryu et al., Biorg, Med Chem 2004, 12, 859). Vrudhula et al Bioorg, Chem Chem Lett, 2002, 12, 3591). It makes it possible to associate a bioactive group with a vector making it possible to reach a target, the two partners then being able to be separated by in vivo reduction of the disulfide function (for example, Liu et al., Proc Natl Acad Sci USA 1996, 93, 8618). The interest of thiol functions and of disulfide functions in biology, particularly in the field of nucleic acids, is therefore very broad, as illustrated by the review article by Chambert and Décout (Org Prep, Proc Int Int 2002, 34, 27-85). Thus, the recent development of thionucleosides as analogs of enzyme substrates involved in the biosynthesis of nucleic acids with antiviral and / or antitumor biological properties, has demonstrated the importance of introducing a disulfide function. mixed on a nucleoside. The protected thiol function in the form of a methyl disulfide can thus be reduced in vivo to give the active form of the nucleoside. This prodrug approach of in situ release makes it possible to avoid the degradation of the unstable free thiol (rapid air oxidation to symmetrical disulfide and / or intramolecular decomposition by deglycosylation) (Roy Roy et al., J. Med Chem 2003 , 46, 2565). The nucleoside in its active form can then interact after phosphorylation with the target enzymes.

  While the synthesis of symmetrical disulfides can be carried out simply by oxidative coupling of two molecules of the same thiol, obtaining mixed disulfides remains more difficult in organic synthesis due to obtaining a mixture containing the symmetrical disulfides. Generally, a sulfenylating agent reacts with a first thiol, and then is displaced by nucleophilic substitution by a second thiol to obtain the desired disulfide. Many synthetic routes can then be considered because of the wide variety of possible sulfenylating agents. The latter can be of N-trifluoroacetylarenesulfenamide type (Bao et al., Tetrahedron 2003, 9655), dithioperoxyesters (Lerévérend et al., Synthesis 1994, 761), sulfenylthiocarbonates (Brois et al., Am Chem Chem S 1970, 92, 7629). ), sulfenyl hydrazines (Mukaiayama et al., Tetrahedron Lett., 1968, 5907), 2,2'-dithiopyridyl disulfide and the like (Matsueda et al Chem Chem Lett, 1981, 737, Barton et al., J. Org Chem. 1991, 56, 6697), 2,2'-dithiobenzothiazole disulfide (E. Brzezinska and Ternay J. Org Chem 1994, 59, 8239). Mixed disulfides can also be obtained by reaction of a thiol with sulfenyl halides (Kueele Synthesis 1970, 561, Kueele Synthesis 1971, 563). The use of these various methods in synthesis and in particular in nucleoside series, however, has a major drawback which is the use of an unstable thiol function due to its easy oxidation to air which leads to symmetrical disulfide. This function is also very reactive and can be problematic in the case of multi-functional compounds. In nucleoside series, the introduction of a thiol function requires the use of methods of protection and deprotection of alcohol and amine functions. On the other hand, the instability of the function carried for example at the 2 'position of nucleosides has been demonstrated (Johnson et al., Tetrahedron 1995, 51, 5093). After the work of the Fuchs group (Anderson et al., J. Org Chem 1988, 53, 3125), Chambert et al. (J. Org Chem 2000, 65, 249) have proposed a method for the synthesis of methyl disulfides, of the formula R-S-S-CH3 where R represents a nucleoside, which avoids the passage through unstable nucleoside thiols. This method consists of preparing a very stable intermediate sulphide compound, a 2- (trimethylsilyl) ethyl sulphide, of the formula R-S-CH 2 -CH 2 -Si (CH 3) 3. Such intermediates can be formed by reaction of 2- (trimethylsilyl) ethanethiol, which can easily be prepared in the laboratory in large quantities (Stamm J. Org. Chem, 1963, 3264) or by radical reaction of trimethylvinylsilane with a thiol (Mahadevan et al. Commun Synth 1994, 3099). The intermediate 2- (trimethylsilyl) ethyl sulfide, obtained in series nucleosides according to the first method mentioned, is then reacted with dimethyl (methylthio) sulfonium tetrafluoroborate to obtain the corresponding methyl disulfides. The authors thus prepared the methyl 2'-disulfides of 2'-deoxyuridine, 2'-deoxycytidine and 3'-deoxythymidine, respectively. More recently, in S. Chambert et al. (J. Org Chem 2002, 67, 1898-1904), the same authors have demonstrated the interest of the above-mentioned 2- (trimethylsilyl) ethyl sulphides for the preparation of thiocyanates, in particular nucleoside thiocyanates, by reaction. in methanol, with cyanogen bromide. During this work, the authors have also discovered that this same reaction, when carried out in dichloromethane, leads to the corresponding symmetrical disulfide of formula R-S-S-R when R represents 2'-deoxyuridine substituted at the 2 'position. It emerges from these studies that 2- (trimethylsilyl) ethyl sulfides. of formula R-SCH2-CH2-Si (CH3) 3, are critical intermediates in the synthesis of methyl disulfides. The synthetic route used by Chambert et al. allows to have access selectively to mixed disulfides of methyl and nucleoside without having recourse to the protection of the functions alcohol and amines of the nucleosides. However, in the context of a prodrug approach, it is interesting to be able to synthesize a disulfide associating a first active nucleoside element and a second element bearing a second thiol vector function and / or bioactive element. Access to new mixed disulfides enriches the range of potentially active molecules. The authors of the present invention have discovered that the above 2- (trimethylsilyl) ethyl sulfides may be the starting point for the synthesis of a large number of mixed or symmetrical disulphides, but also the starting point of the synthesis. of thiosulfinate compounds.

  The latter can be obtained by oxidation of mixed or symmetrical disulfides (Colonna et al., J. Org Chem 2005, 1727, Liu et al J. Am Chem Soc 1997, 117, 9913) by rearrangement. [2,3] sigmatropic when the disulphides are of dialkoxy allyl or propargyl type (Bravermen et al 7etrahedron Lett 2004, 45, 8235). Similarly, the reaction between benzenesulfinyl azide and various thiols leads to the preparation of thiosulfinates (Maricich et al., J. Org Chem 1984, 49, 1931) as well as the reaction of the alkene sulphonate anion with trimethylsilyl (Refvik et al, Can J. Chem 1998, 76, 213). Thiosulfinates can lead to disulfides, sulfinic acids, sulfoxides and thiosulfonates (Lacombe Reviews Heteroatom Chem 1999, 21, 1). They are in the form of two enantiomers or two diastereoisomers when the function is carried by the sugar in series nucleosides. They are therefore also interesting intermediates in asymmetric synthesis (see, for example, Liu et al., J. Org Chem 1997, 119, 9913). On the other hand, some of them are natural products with interesting biological properties, for example they exhibit antimicrobial and / or anti-inflammatory activities (Whitmore et al., Nat Food Antimicrob Systems 2000, 349). An object of the present invention is a process for obtaining a compound corresponding to the general formula (I) R 1 -S (O), -S (O) y-R 2, in which R 1 represents a hydrocarbon molecular residue which can to be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P, S, Si, X where X represents a halogen; R2 represents, independently of R1, a carbon group or a hydrocarbon molecular residue which may be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P, S, Si, X where X represents a halogen, and x and y are selected from 0 and 1 such that the sum of x and y is at most equal to 1. The authors have developed reaction conditions which are subject to of the present invention and which make it possible to obtain, from an intermediate compound of general formula (II) R 1 -S (O) n - R 3 -Si (R 4) (R 5) (R 6) (II a for x = 0 and lab for x = 1) and in which R3 represents a hydrocarbon chain of two carbon atoms, optionally unsaturated and / or substituted, compounds of general formula (I) which embrace in particular all the following groups of compounds: ) R 1 -SR-R2, mixed disulfide compounds of formula I wherein x = y =: O (IV) R1-S-SO-R2, thiosulfin compounds ate of formula I wherein x = 0 and y = 1 (V) R 1 -SO-S-R 2, thiosulfinate compounds of formula I wherein x = 1 and y = O (VI) RI-SS-R 1, symmetrical disulfide compounds, formulas (III), (IV), (V) and (VI) wherein R1 and R2 are as defined above. Thus, an object of the present invention is a process for obtaining compounds of formula (I) R1-S (O), -S (O) y-R2 as defined above, according to which a compound of formula (II) R1-S (O) X-R3-Si (R4) (R5) (R6) wherein R3 represents a hydrocarbon chain of two carbon atoms, optionally unsaturated and / or substituted, and R4, R5 and R6 , identical or different, each represent, independently of one another, a hydrocarbon group with a compound of formula (VII) R2-S (O) yX where X represents a halogen and R2 and y have the definition given above (VIIa when y = 0 and VIIb when y = 1). According to this process, it is thus possible, according to the invention, to obtain a disulfide of formula (III) R1-SS-R2, by reacting a compound of formula (IIa) R1-S-R3-Si (R4) (R5) (R6) with a compound of formula (VIIa) R2-SX. According to this process, it is also possible, according to the invention, to obtain a thiosulfinate of formula (IV) R1-S-SO-R2, by reacting a compound of formula (IIa) R1-S-R3-Si (R4) ( R5) (R6) with a sulfinyl halide of formula (VIIb) R2-SO-X. The process of the invention also makes it possible to obtain a thiosulfinate of formula (V) R1 • -SO-S-R2, as follows: an oxidation of the compound of formula (IIa) R1-S-R3-Si (R4 ) (R5) (R6) to obtain a compound of formula (IIb) R1-SO-R3-Si (R4) (R5) (R6), and then the compound of formula (IIb) is reacted with a sulfenyl halide of formula (VIIa) R2-SX. The reactions involved in the processes of the invention and the various compounds of formula (I) obtainable are below illustrated from the compound (IIa) where R3 represents CH2-CH2- and R4, R5 and R6. represent each -CH3, without the scope of the invention being limited to these groups R3, R4, R5 and R6. According to the invention, to obtain a mixed disulphide of formula (III) above, a compound of formula (IIa) R1-S-R3-Si (R4) (R5) (R6) is reacted with a compound of formula (VIIa) R2-SX.

  Embedded image To prepare a thiosulfinate of formula (IV) according to the invention, the compound of formula (IIa) R1-S-R3-Si is reacted with (IIa) ## STR2 ## R4) (R5) (R6) with a compound of formula (VIIb) R2-SO-X. The reaction involved is shown below from compound (IIa) wherein R 3 is ethyl and R 4, R 5 and R 6 are each methyl: ## STR1 ## A thiosulfinate of formula (V), by reacting a compound of formula (Iib) R1-SO-R3-Si (R4) (R5) (R6) with a compound of formula (VIIa) R2-SX, the compound (IIb) being obtained by performing an oxidation of the compound of formula (IIa). R ~ R1 oxidation S i O '\ Sü IIb / \ R2 Vila R

  Advantageously, the reaction of the compound (IIa) with a compound (VIIa) or (VIIb) to prepare a mixed disulfide (III) and to prepare a thiosulfinate (IV), respectively, and the reaction of the compound (IIb) with a compound (VIIa) to obtain a thiosulfinate (V) can be carried out in the presence of fluoride ions, in a preferentially catalytic amount. The fluoride ions are preferably provided by an ammonium fluoride, a tetrabutylammonium fluoride, a triethylammonium fluoride or their mixtures.

  From the same intermediate of formula (IIa), the authors discovered that in the preparation of mixed disulfides of formula (III), the compound (VIIa) R2-SX could be formed in situ, in the reaction medium comprising the intermediate (IIa) and a compound of formula (VIII) R2-SS-R2, in the presence of X2 or XCN, where X is halogen. The intermediate (IIa) then reacts with the compound (VIIa) thus formed, to give the mixed disulfide (III). This reaction of the compound (IIa) with the compound (VIIa) formed in situ can be advantageously carried out in the presence of fluoride ions. These may be provided by an ammonium fluoride, a tetrabutylammonium fluoride, a triethylammonium fluoride or their mixtures and they are preferably present in a catalytic amount. Similarly, the preparation of symmetrical disulfides of formula (VI) can be carried out from compound (IIa), in the presence of an X 2 dihalogen or a halide. This reaction can be advantageously carried out in the presence of fluoride ions, which can be provided by an ammonium fluoride, a tetrabutylammonium fluoride, a triethylammonium fluoride or their mixtures and they are preferably present in a catalytic amount. X2 or XCN Ila S VI

  The invention also relates to a process for obtaining a compound of formula (III '), wherein R 1 represents a hydrocarbon molecular moiety which can be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P, S, Si, X where X represents a halogen; R2 'represents, independently of R1, a carbon group or a hydrocarbon molecular residue which may be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P, S, Si, X where X represents a halogen, comprising the following steps: a compound (III) is obtained according to the process of the invention defined above, and then the compound (III) is reacted with a compound of formula R2'-SH. Before describing in more detail and illustrating the various objects of the invention, the R 1 -R 6 groups of the compounds involved in the processes of the invention and the compounds obtained according to the invention are hereinafter more precisely defined. Without departing from the scope of the invention, the following definitions are to be considered independently of one another or in combination with each other. R1 advantageously represents, according to the invention, a nucleoside molecular residue chosen from nucleosides and modified nucleosides. By modified nucleosides is meant any modification made to the sugar and / or the base, in particular by one or more substitutions, one or more unsaturations, an isomerism, for example of structure. Thus, R 1 may represent a molecular residue chosen from the 2'-deoxyribonucleosides, the 3'-deoxyribonucleosides, the 2 ', 3'-10-dideoxyribonucleosides, the 2', 3'-dideoxy-2 ', 3'-didehydroribonucleosides and their derivatives. ; by way of examples, R1 represents a molecular residue chosen from 2'-deoxyuridine, 2 ', 3'-dideoxyuridine, 2', 3'-dideoxy-2 ', 3'-didehydrouridine, 2'-deoxycytidine 2 ', 3'-dideoxycytidine, 2', 3'-dideoxy-2 ', 3'-didehydrocytidine, 3'-deoxythymidine, 3'-deoxy-2', 3'-dehydrothymidine and their derivatives; advantageously, when R 1 represents a molecular radical chosen from 2'-deoxyribonucleosides, 3'-deoxyribonucleosides and 2 ', 3'-dideoxyribonucleosides, then the S atom is bonded to the 2' carbon or the 3 'carbon of the ribose of the nucleoside, and when R1 represents a molecular residue selected from 2 ', 3'-dideoxy-2', 3'-dehydroribonucleosides, then the S atom is bonded to the carbon 2 'or carbon 3' ribose ; R2, R2 'advantageously represent a carbohalogen group, or a linear or branched hydrocarbon molecular or aromatic radical. wherein R 2 is preferably selected from ortho-nitrophenyl, para-nitrophenyl and trichloromethyl when the fluoride ions are not used. R3 is advantageously -CH2-CH2-. R4, R5 and R6, which may be identical or different, advantageously represent an alkyl group comprising from 1 to 6 carbon atoms, representative elements of which are, for example, the following groups: methyl, ethyl, n-propyl, iso-propyl, n butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl. Preferably, R4, R5 and R6 are identical and represent the methyl group. Another subject of the invention is a process for obtaining a thiol, chosen from the thiols corresponding to the following formulas R 1 -SH, R 2 -SH and R 2 '-SH, formulas in which R 1 represents a hydrocarbon molecular residue which may be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P, S, Si, X where X represents a halogen; R2 or R2 'represents a carbon group or a hydrocarbon molecular residue which can be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P , S, Si, X where X represents a halogen, said process being characterized in that a disulfide according to the invention is prepared, that is to say a disulfide of formula (III) to obtain the thiol R 1 -SH, or a disulfide of formula (VI) to obtain the thiol R2-SH, or a disulfide of formula (III '), to obtain the thiol R2'-SH, the definition of R1, R2 and R2' and the reaction conditions being chosen from those defined above, in the context of the invention, and the disulfide thus obtained is reduced. The invention also relates to novel compounds obtained according to the invention. The preparation of the compounds bearing a reference is illustrated later in the description.

  Thus, it relates to compounds of formula (IIa) R 1 -S-CH 2 -CH 2 -Si (R 4) (R 5) (R 6) as intermediate compounds in the preparation of disulphides and thiosulfinates, chosen from: 3'-Didesoxy-3 '- (2- (trimethylsilyl) ethyl) thiouridine 5-Bromo-2', 3'-dideoxy-3 '- (2- (trimethylsilyl) ethyl) thiouridine 36-1 2'-Deoxy- 2 '- (2- (trimethylsilyl) ethyl) thiothymidine 46 2'-Deoxy-3' - (O-mesyl) -2 '- (2- (trimethylsilyl) ethyl) thiouridine 5'-O- (tert-butyldiphenylsilyl) 2 '- (2-trimethylsilyl) ethyl) thiocytidine 48 N-4-benzoyl-3' - (O-mesyl) -5 '- (O-tert-butyldiphenylsilyl) -2' (2-trimethylsilyl) ethyl) thiocytidine 49 1- (3 '- (2- (Trimethylsilyl) ethylthio) - (3-D-xylofuranose-1-yl) thymine 2,2'-Anhydro-5' - (O-benzoyl) -1- (3'- (2- (trimethylsilyl) ethylthio) (3-D-xylofuranose-1-yl) thymine 53 2 ', 3'-Didesoxy-3' - (2- (trimethylsilyl) ethyl) thiocytidine The invention also relates to compounds of formula (IIa) R1-S-CH2-CH2-Si (R4) (R5) (R6) as intermediate compounds of in the preparation of disulphides and thiosulfinates, in which formula (IIa), R1 is selected from 2 ', 3'-didehydro-2', 3'-dideoxynucleosides and R4, R5 and R6, which may be identical or different, each represent, independently of one another, an alkyl or aryl group. Preferred compounds are chosen from the following: 2 ', 3'-Didehydro-2', 3'-dideoxy-2 '- (2- (trimethylsilyl) ethyl) thiothymidine 14', 3'-D-dehydro-2 ' 3 '-diodeoxy-3' - (2-trimethylsilyl) ethyl) thiothymidine 2 ', 3'-Dideshydro-2', 3'-dideoxy-2 '- (2-trimethylsilyl) ethyl) thiouridine 18 2' 3 '-Dideshydro2', 3'-dideoxy-5 '- (O-tert-butyldiphenylsilyl) -2' - (2-trimethylsilyl) ethyl) thiocytidine 2 ', 3'-Dideshydro-2', 3'-dideoxy-2 Other objects of the invention are the following: Compounds of formula (IIb) R 1 -SO-R 3 -Si (R 4) (R 5) (R 6) as a compound Intermediate in the preparation of thiosulfinates of formula (V), selected from: 3'-deoxy-3 '- (2- (trimethylsilyl) ethyl) thiothymidine sulfoxide 2'-deoxy-2' - (2) sulfoxide - (trimethylsilyl) ethyl) thiouridine Compounds of formula (III) R1-SS-R2, wherein R1 is 2 ', 3'-dideoxy-2', 3'-didehydronucleoside; such compounds are illustrated by the following: 3'-deoxythymidin-3'-yl disulfide and trichloromethyl 2'-deoxythymidin-3'-yl disulfide and 4-nitrophenyl 3'-deoxythymidin-3'-disulfide and 2-nitrophenyl 4 2'-deoxyuridin-2'-yl disulfide and trichloromethyl 7 2'-deoxycytidin-2'-yl disulfide and trichloromethyl 8'-deoxyuridine-2'-yl disulfide 4-nitrophenyl 9'-Deoxycytidin-2'-yl and 4-nitrophenyl disulfide 2'-Deoxyuridin-2'-yl and 2-nitrophenyl disulfide 2'-Deoxycytiddin-2'-yl disulfide and 2-nitrophenyl -Nitrophenyl 12 3'-deoxythymidin-3'-yl and propyl disulfide 13 2 ', 3'-d'déshydro-2', 3'-ddehyde oxythymidin-2'-yl and trichloromethyl disulfide Disulfide 2 ', 3'-Ideshydro-2', 3'-dideoxythymidin-2 '-yl and 4-nitrophenyl 2', 3'-dihydro-2 ', 3'-dioxythymidin-2' -y disulfide and 2-20 nitrophenyl 17 isisulfide 2 ', 3' -di dehydro-2 ', 3'-dideoxyuridin-2'-yl and trichloromethyl 2', 3'-didehydro-2 ', 3'-dideoxyuridin-2'-yl and 4-nitrophenyl 2-disulfide disulfide ', 3'-Didehydro-2', 3'-dideoxyuridin-2'-yl and 2-nitrophenyl 2 ', 3'-dideoxyuridin-3'-yl disulfide and methyl 2', 3 'disulfide 5-bromo-2 ', 3'-dideoxyuridin-3'-yl and methyl 5-bromo-2', 3'-dideoxyuridin-3'-yl and compounds of formula (IV) R1-S-SO-R2 are selected among thiosulfinates 25 and 27. Compounds of formula (V) RI-SO-S-R2 are selected from thiosulfinates 29, 30, 33a. Compounds of formula (III '), R1-SS-R2' selected from: 3'-deoxythymidin-3'-yl disulfide and allyl 3'-deoxythymidin-3'-yl disulfide and 2- hydroxyethyl 3'-deoxythymidin-3'-yl disulfide and 2-aminoethyl chlorohydrate 39 3'-deoxythymidin-3'-yl and butyl disulfide 40 3'-deoxythymidin-3'-yl disulfide Hexyl 41 3'-deoxythymidin-3'-yl and octyl disulfide 42 3'-deoxythymidin-3'-yl and 6-hydroxyhexyl disulfide Compounds of formula (VI) R1-SS-R1, selected from the following disulphides: bis- (3'-dideoxythymidin-3-yl) disulfide Bis (5-bromo-2 ', 3'-dideoxyuridine-3'-yl) disulfide 36 bis (2', 3) disulfide 2'-didehydro-3'-dideoxyuridine-2'-yl)

  The references assigned to the compounds are reported in the experimental part below, illustrating the production of these compounds according to the invention.

  The objects of the invention are now illustrated by the following examples. These more particularly relate to obtaining disulfide compounds or thiosulfinate nucleosides, but in no way constitute a limitation of the invention to the preparation of these compounds.

  EXAMPLE 1 Preparation of a Mixed Disulfide of Formula (III) from an Intermediate (IIa) and a Sulphenyl Halide (VIIa)

  Preparation of 3'-deoxythymidine 3'-mixed disulphides from a stable sulphenyl halide ## STR5 ##

  NO2 Preparation of mixed 2'-disulfides of 2'-deoxyuridine 7, 9 and 11 and mixed 2'-disulphides of 2'-deoxycytidine 8, 10 and 12 from a stable sulfenyl halide Y 7: Y = OH 8: Y = NH 2 Ar = NO 2 NO 2 11: Y = OH 9: Y = OH 10: Y = NH 2 O 12: Y = NH 2 HO 5: Y = OH 6: Y = NH 2 Cl 3 C 3 YNO HO AT ArSCI HO OH SSAr Example 2 : Preparation of a mixed disulfide of formula (III) from an intermediate (IIa) and a sulfenyl halide (VIIa) formed in situ Preparation of a 3'-mixed disulphide of 3'-deoxythymidine 13 to from a sulfenyl halide (VIIa) formed in situ from a propyl (VIII) disulfide in the presence of bromine (Br2) or cyanogen bromide. C3H7SSC3H7 Br2 or BrCN IOI NNH HOC 13 Example 3: Preparation of vinyl disulfide-type mixed disulfides of formula (III) from an intermediate (IIa) and a sulfenyl halide ( VIIa) Preparation of 2'-mixed disulphides of 2 ', 3'-dideoxy-2', 3 '- didehydroribonucleosides (thymidine, uridine and cytidine) 15 to 17 and 20 to 22 from a stable sulfenyl halide IOI ## STR5 ## 17: R 2 = -Ph 2 -NO 2, -NH 2 O: Y = OH Y 19: Y = NH 2 I HOC N 2 O Y = OH, R2 = -CCI3 21: Y = OH, R2 = -Ph4-NO2 NO: 22 = Y = OH, R2 = -Ph2-NO2 SSR2 The disulfide synthesis protocol 15, 16, 17 , 20, 21 and 22 are described in more detail in the following description. These reactions can be replicated with nucleosides with other nucleic bases such as cytosine and other unsaturated nucleoside or non-nucleoside silyl sulfides.

  EXAMPLE 4 Preparation of thiosulfinates of formula (IV) from an intermediate (IIa) and a sulfinyl halide (VIIb) 9NH4, FO 0.2 equiv. EXAMPLE 5 Preparation of a thiosulfinate of formula (V) from an intermediate (IIb) and a sulphenyl halide (VIIa) Preparation of 3'-thiosulfinates of 3'- deoxythymidine from a sulfenyl halide o NH

  R2SCI HO 0 I I S S 0 ~ SR2 SR2 29: R2 = -CCI3 (46%) 2: R2 = _ -CCI3 (54%)

  30: R2 = -Ph4NO2 (40%) 3: R2 = -Ph4NO2 (60%) This example can be reproduced to obtain thiosulfinates of other nucleosides (2'-deoxycytidine, uridine, cytidine). ## STR2 ## where ## STR2 ## or oxon ## STR2 ##

  EXAMPLE 6 Enantioselective Preparation of Nucleoside Thiosulfinates of Formula (V) by Reaction of an Intermediate (IIb) with a Sulfenyl Halide (VIIa) OO NH NH HOC LLN ~ O HOC N ~ O 32a: S Isolated with a Rend of 38 , 5% OH 32b: R isolated with a yield of 31.5% w / o 32%: S 9 NO 2 O NH CISHO NO 2 1 OHSiS O 33: essentially only one of the 2 possible diastereoisomers (NMR) NO + N O2 CIS NO2 - 33: same diastereoisomer as previously very predominant + 9 (NMR) Example 7: Preparation of symmetrical disulfides (VI) from an intermediate (IIa) in the presence of cyanogen bromide or dibrome IOI NH

BrCN or Br2

  ## STR2 ## (IIa) The nucleoside and 4-nitrophenyl disulfide 3 prepared was used to prepare new mixed nucleoside and alkyl disulfides: 37: R2 = -CH2-CH = CH2 38: R2 = -CH2-CH2- ## STR3 ## ## STR2 ## ## STR2 ## where: ## STR2 ## 9: Preparation of new vinyl thiols from an intermediate vinyl disulfide (III) HO HO + 21 2 45 This reaction can be carried out with nucleosides 15 to 17, 20 to 22 and all the derivatives (III) The experimental part ci following the synthesis protocols followed for obtaining mixed disulfides obtained according to the invention by the process which is the subject of Example 1.

  Protocol A1: Synthesis of Nucleoside / 4-nit: Rophenyl Disulfide Derivatives To a solution of nucleoside in anhydrous dichloromethane, maintained under argon, is added 4-nitrobenzene sulphenyl chloride (3 equivalents). The mixture is stirred for 15 hours and the solvent is evaporated. The residue obtained is taken up in the minimum dichloromethane to be chromatographed on silica gel in a mixture of dichloromethane-methanol (98: 2) and then (95: 5) to give the expected compound.

  Protocol A2: Synthesis of disulfide derivatives nucleoside / 4-nitrophenyl To a solution of nucleoside in anhydrous methanol, maintained under argon, is added 4-nitrobenzene sulfenyl chloride (3 equivalents). The mixture is stirred for 15 hours and the solvent is evaporated. The residue obtained is taken up in the minimum dichloromethane to be chromatographed on silica gel in dichloromethane-methanol (95: 5) and then (90:10) to give the expected compound.

  Protocol B I: synthesis of disulfide derivatives nucleoside / 2-nitrophenyl To a solution of nucleoside in anhydrous dichloromethane, maintained under argon, is added 2-nitrobenzene sulfenyl chloride (3 equivalents). The mixture is stirred for 15 hours and the solvent is evaporated. The residue obtained is taken up in the minimum dichloromethane to be chromatographed on silica gel in a mixture of dichloromethane-methanol (98: 2) and then (95: 5) to give the expected compound.

  Protocol B2: Synthesis of disulfide derivatives nucleoside / 2-nitrophenyl To a solution of nucleoside in anhydrous methanol, maintained under argon, is added 2-nitrobenzene sulfenyl chloride (3 equivalents). The mixture is stirred for 15 hours and the solvent is evaporated. The residue obtained is taken up in the minimum dichloromethane to be chromatographed on silica gel in dichloromethane-methanol (95: 5) and then (90:10) to give the expected compound.

  Protocol B3: Synthesis of disulfide derivatives nucleoside / 2-nitrophenyl To a solution of nucleoside in anhydrous dichloroethane, maintained under argon, is added 2-nitrobenzene sulfenyl chloride (3 equivalents). The mixture is stirred and refluxed for 48 hours. The solvent is evaporated and the residue obtained is taken up in the minimum dichloromethane to be chromatographed on silica gel in a dichloromethane-methanol (98: 2) and then (95: 5) to give the expected compound.

  Protocol C: Synthesis of Disulfide Derivatives Nucleoside / Trichloromethane To a solution of nucleoside in anhydrous dichloromethane, maintained under argon, is added trichloromethanesulfenyl chloride (3 equivalents). The mixture is left stirring overnight and the solvent is evaporated under a stream of nitrogen under the hood because of the toxicity of the reagent used. The residue obtained is taken up in the minimum of eluent to be chromatographed on silica gel in a dichloromethane-methanol mixture (95: 5) and give the expected compound.

  Protocol C2: synthesis of disulfide derivatives nucleoside / trichloromethane To a solution of nucleoside in anhydrous methanol, maintained under argon, is added trichloromethanesulfenyl chloride (3 equivalents). The mixture is left stirring overnight and the solvent is evaporated under a stream of nitrogen under the hood because of the toxicity of the reagent used. The residue obtained is taken up in the minimum of eluent to be chromatographed on silica gel in a dichloromethane-methanol mixture (95: 5) and give the expected compound.

  Protocol C3: synthesis of disulfide derivatives nucleoside / trichloromethane To a solution of nucleoside in anhydrous dichloromethane, maintained under argon, is added trichloromethanesulfenyl chloride (3 equivalents). The mixture is stirred and refluxed for 48 hours. The solvent is then evaporated under a stream of nitrogen under the hood because of the toxicity of the reagent used. The residue obtained is taken up in the minimum of eluent to be chromatographed on silica gel in a dichloromethane-methanol mixture (95: 5) and give the expected compound.

  3'-deoxythymidin-3'-yl and trichloromethyl disulfide 2-Clone 3'-deoxy-3 '- (2- (trimethylsilyl) ethyl) thiothymidine 1 (40 mg, 0.11 mmol) anhydrous dichloromethane (1.5 mL) trichloromethanesulfenyl chloride (60 L, 0.66 mmol) (37 mg, 0.09 mmol, 81%) as a white powder.

  1H NMR (400MHz, CDCl3) δ 9.36 (1H, s, NH); 7.48 (1H, s, 6-H); 6.13 (1H, dd, J = 6.4Hz, J = 12.7Hz, 1H); 4.26 (1H, m, 3'-H); 4, 18 (1H, m, 4'-H); 4.09-3.88 (2H, m, 5'-H x 2); 2.77-2.56 (2H, m, 2'-H x 2).

  13 C NMR (100 MHz, CDCl 3) δ 163.9 (C2); 150.4 (C4); 136.7 (C6); 115.2 (C5); 100.4 (C-Cl3); 86.2 (Cl '); 85.4 (C4 '); 61.3 (5'-CH 2); 47.9 (C3 '); 38.4 (2'-CH 2); 12.5 (5-CH3). MS (DCI, NH3-isobutane): m / z 409 [M + H] +; 429 [M + NH 3] +; 127 [thymine + H] +.

  MS high resolution mass: ion type [M + Na] +; Crude formula: C11H13N2O4Cl3NaS2 m / z theoretical: 428.9280 m / z found: 428.9283 HOC 3'-deoxythymidin-3'-yl and 4-nitrophenyl disulfide 3'Al 3'-deoxy-3 '- ( 2- (trimethylsilyl) ethyl) thiothymidine 1 (300 mg, 0.84 mmol) anhydrous dichloromethane (5 mL) 4-nitrobenzene sulfenyl chloride (476 mg, 2.5 mmol) 3 (0.331 g, 0.80 mmol; %) in the form of a pale yellow powder. 1 H NMR (400 MHz, CDCl 3) δ 8.48 (1H, s, NH); 8.20 (2H, d, Ar); 7.70 (2H, d, Ar) 7.46 (1H, s, 6-H); 6.07 (1H, dd, J = 5.2Hz, J = 11.6Hz, 1H); 4.05 (1H, m, 5'-H); 4.02 (1H, m, 4'-H); 3.88 (1H, m, 5'-H x 2); 3.50 (1H, m, 3'-H); 2.60-2.51 (2H, m, 2'-H x 2); 1.89 (3H, s, 5-CH3). 13 C NMR (100 MHz, CDCl 3) δ 163.4 (C2); 150.1 (C4); 145.6 (C-NO2); 136.8 (C6); 136.6 (C-SS); 126.1 (2 C Ar); 124.3 (2 C Ar); 111.1 (C5); 85.9 (C: 1 '); 84.7 (C4 '); 61.2 (5'-CH 2); 45.8 (C3 '); 37.6 (2'-CH 2); 12.5 (5-CH3). MS (DCI, NH3-isobutane): m / z 412 [M + H] +; 429 [M +] H + NH 3] +; 127 [thymine + H] + 3'-deoxythymidin-3-yl and 2-nitrophenyl: disulfide 4 O 02N 3'-Deso: xy-3 '- (2- (trimethylsilyl) ethyl) thiothymidine Protocol 1 (300 mg, 0.84 mmol) 2-nitrobenzene sulfenyl chloride (476 mg, 2.5 mmol) (0.314 g, 0.76 mmol, 91%) as a bright yellow powder.

  1H NMR (400MHz, CDCl3) δ 9.26 (1H, s, NH); 8.29 (1H, m, Ar); 8.25 (1H, m, Ar); 7.74 (1H, m, Ar); 7.52 (1H, s, 6-H); 7.42 (1H, m, Ar); 6.04 (1H, dd, J = 4.8Hz, J = 11.6Hz, 1H); 4.08-4.05 (2H, m, 4'-H and 5'-H); 3.85 (1H, m, 5'-H); 3.50 (1H, m, 3'-H); 2.56-2.44 (2H, m, 2'-H); 1.89 (3H, s, 5-CH3).

  13 C NMR (100 MHz, CDCl 3) δ 163.9 (C2); 150.3 (C4); 145.6 (C-NO2); 136.8 (C6); 136.6 (C-SS); 134.3; 127.1; 126.8; 126.3 (4 C Ar); 110.8 (C5); 85.9 (Cl '); 85.0 (C4 '); 61.1 (5'-CH2); 45.3 (C3 '); 37.8 (2'-CH 2); 12.4 (5-CH3).

  MS (DCI, NH3-isobutane): m / z 412 [M + H] +; 429 [M + H + NH 3] +; 127 [thymine + H] +.

  2'-Deoxyuridin-2'-yl and trichloromethyl disulfide 7 C2 2'-deoxy-2 '- (2- (trimethylsilyl) ethyl) thiouridine 5 (50 mg, 0.14 mmol) methanol anhydrous (1.5 mL) trichloromethanesulfenyl chloride (44 L, 0.42 mmol) (48 mg, 0.12 mmol, 84%) as a white powder.

  1 H NMR (400 MHz, MeOD) δ 8.01 (1H, d, J = 8 Hz, 6-H); 6.38 (1H, d, J = 8.8 Hz, 1'-H); 5.78 (1H, d, J = 8 Hz, 5-H); 4.54 (1H, m, 3'-H); 4.25 (1H, dd, J = 5.6Hz, J = 8.8Hz, 2'-H); 4.09 (1H, m, 1H); 3.78 (2H, m, 5'-H 2).

  13 C NMR (100 MHz, MeOD) δ 164.4 (C2); 151.1 (C4); 141.0 (C6); 102.2 (C5); 100.2 (C-C13); 88.6 (Cl '); 87.3 (C4 '); 72, 8 (C3 '); 61.6 (5'-CH 2); 59.0 (C2 ').

  MS (DCI, NH3-isobutane): m / z 411 [M + H] +.

  2'-Deoxycytidin-2'-yl and trichloromethyl disulfide 8 2'-Deoxy-2 '- (2- (trimethylsilyl) ethyl) thiocytidine 6 (40 mg, 0.11 mmol) anhydrous methanol (1 mL) trichloromethanesulfenyl chloride (38 L, 0.33 mmol) (53 mg, 0.13 mmol, 86%) as a white powder.

  1H NMR (400MHz, MeOD) δ 7.99 (1H, d, J = 7.6Hz, 6-H); 6.43 (1H, d, J = 8.8 Hz, 1 H); 5.78 (1H, d, J = 7.6 Hz, 5-H); 4.55 (1H, m, 3'-H); 4.25 (1H, dd, J = 5.2 Hz, J = 8.8 Hz, 2'-H); 4.09 (1H, m, 1H); 3.78 (2H, m, 5'-H x 2).

  13 C NMR (100 MHz, MeOD)? 165.8 (C4); 156.8 (C2); 141.9 (C6); 100.3 (C-Cl3); 95.6 (C5); 89.7 (Cl '); 87.1 (C4 '); 72, 8 (C3 '); 61.7 (5'-CH2); 59.5 (C2 ').

  MS (DCI, NH3-isobutane): m / z 410 [M + H] +.

  2'-Deoxyuridin-2'-yl and 4-nitrophenyl 9NO 2 -ammonium 2'-deoxy-2 '- (2- (trimethylsilyl) ethyl) thiouridine disulfide (400 mg, 1.11 mmol) anhydrous methanol ( 8 mL) 4-nitrobenzene sulfenyl chloride (632 mg, 3.33 mmol) (421 mg, 1.02 mmol, 92%) as a pale yellow powder.

  NMR 111 (400 MHz, MeOD) δ 8.18 (2H, d, Ar); 7.78 (1H, d, J = 8.2, Hz, 6-H); 7.66 (2H, d, AR); 6.35 (1H, d, J = 9.2 Hz, 1H); 5.56 (1H, d, J = 8.4 Hz, 5-H); 4.48 (1H, m, 3'-H); 4.02 (1H, m, 4'-H); 3.79 (1H, m, 2'-H); 3.70 (2H, m, 5'-H x 2).

  13 C NMR (100 MHz, MeOD) δ 163.9 (C2); 150.8 (C4); 146.5 (C-NO2); 145.7 (CSS); 140.6 (C6); 125.9 (2 C, Ar); 123.7 (2 C, Ar); 101.9 (C5); 87.9 (Cl '); 86.8 (C4 '); 72.9 (C3 '); 61.5 (C2 '); 60.1 (5'-CH2).

  MS (DCI, NH3-isobutane): m / z 414 [M + H] +; 431 [M + H + NH 3] + 2'-Deoxycytidin-2'-yl and 4-nitrophenyl disulfide Protocol A2 2'-deoxy-2 '- (2- (trimethylsilyl) ethyl) thiocytidine 6 (200 mg 0.56 mmol) anhydrous methanol (6 mL) 4-nitrobenzene sulfenyl chloride (316 mg, 1.66 mmol) (158 mg, 0.38 mmol, 69%) obtained after recrystallization from methanol (2 mL) ) in the form of a bright yellow powder.

  NMR 111 (400 MHz, DMSO) δ 8.13 (2H, Ar); 7.65 (2H, Ar) 7.60 (1H, d, J = 7.6Hz, 6-H); 7.16 (2H, 1s, 2H NH); 6.27 (1H, d, J = 9.2Hz, 1H); 6.13 (1H, d, J = 5.2 Hz, 3'-OH); 5.57 (1H, d, J = 7.6 Hz, 5-H); 5.05 (1H, t, J = 5.2Hz, 5'-OH); 4.33 (1H, m, 3'-H); 3.89 (1H, m, 4'-H); 3.70 (1H, m, 2'-H); 3.51 (2H, 1s, 5'-H x 2).

  13C NMR (100 MHz, DMSO)? 165.7 (C4); 150.1 (C2); 146.3 (C-NO2); 146.1 (CSS); 141.6 (C6); 126.2 (2 C Ar); 124.4 (2 C Ar); 95.1 (C5); 88.6 (C1 '); 86.7 (C4 '); 72.7 (C3 '); 61.8 (5'-CH 2); 59.7 (C2 ').

MS (FAB +, NAB): m / z 413 [M + H] +.

  2'-Deoxyuridin-2'-yl and 2-nitrophenyl disulfide 11 O 02N Protocol B2 2'-deoxy-2 '- (2- (trimethylsilyl) ethyl) thiouridine 5 (200 mg, 0.55 mmol) methanol anhydrous (4 mL) 2-nitrobenzene sulfenyl chloride (316 mg, 1.66 mmol) (220 mg, 0.53 mmol, 96%) as a bright yellow powder.

  1 H NMR (400 MHz, DMSO) δ 11.14 (1H, s, NH); 8.21 (1H, m, Ar); 7.79 (1H, m, Ar) (1H, d, J = 8.1 Hz, 6-H); 7.49 (2H, m, Ar); 6.23 (1H, d, J = 9.2Hz, 1H); 6.17 (1H, m, 3'-OH); 5.42 (1H, d, J = 8.0 Hz, 5-H); 5.03 (1H, m, 3'-H); 4.35 (1H, m, 5'-OH); 3.91 (1H, m, 4'-H); 3.69 (1H, dd, J = 5.2 Hz, J = 9.1 Hz, 2'-H); 3.51 (2H, m, 5'-H x 2).

  13 C NMR (100 MHz, DMSO)? 162.8 (C2); 151.0 (C4); 145.3 (C-NO2); 145.7 (CSS); 140.3 (C6); 136.0 (C-SS); 135.3; 127.7; 127.5; 126.40 (4 C, Ar); 102.7 (C5); 87.3 (Cl '); 86.9 (C4 '); 72.7 (C3 '); 61.6 (5'-CH 2); 58.3 (C2 '). MS (DCI, NH3-isobutane): m / z 414 [M + H] +; 431 [M + H + NH3] +20 2'-Deoxycytidin-2'-yl and 2-nitrophenyl 12 02N 2'-deoxy-2 '- (2- (trimethylsilyl) ethyl) thiocytidine 6 (100) mg, 0.28 mmol) anhydrous methanol (4 mL) 4-nitrobenzene sulfenyl chloride (158 mg, 0.83 mmol) 12 (43 mg, 0.10 mmol, 42%) as a bright yellow powder .

  1 H NMR (400 MHz, MeOD) 8.21 (2H, m, Ar); 7.73 (2H, m, Ar + 6H, J = 7.5Hz); 7.44 (1H, m, Ar); 6.42 (1H, d, J = 9.3 Hz, 1 H); 5.70 (1H, d, J = 7.4 Hz, 5-H); 4.47 (1H, m, 3'-H); 4.03 (1H, 1s, 4'-H); 3.70-3.62 (3H, m, 5'-H x2 + 2'-H).

  13 C NMR (100 MHz, MeOD) δ 165.1 (C4); 157.4 (C2); 145.3 (C-NO2); 141.3 (C6); 135.9 (1 C Ar); 145.3 (C-SS); 127.0; 126.6; 125.5 (3 C Ar); 96.1 (C5); 88.8 (Cl '); 86.9 (C4 '); 72.7 (C3 '); 61.6 (5'-CH 2); 59.2 (C2 ').

  MS (FAB +, NAB): mlz 413 [M + H] +. The experimental part below describes the synthesis protocols followed for obtaining mixed disulphides of formula (III) obtained according to the invention by the method which is the subject of Example 2. 3'-deoxythymidin-3'-yl and propyl disulfide 13

  To a solution of nucleoside silane 1 (50 mg, 0.14 mmol), compound (IIa) as obtained according to the invention, in anhydrous dichloromethane (3 ml) are added propane disulfide ( 108 L, 0.70 mmol) followed by cyanogen bromide (73 mg, 70 mmol). The mixture is left stirring under argon for 96 h at 40 ° C. The symmetrical disulfide gradually appears in the form of a beige precipitate while the second product remains in solution. After hydrolysis with a phosphate buffer solution (0.5 M, pH 7, 2 mL) for 30 min, the solvents are evaporated to dryness. The residue obtained is chromatographed on silica gel with a dichloromethanemethanol (95: 5) mixture. The mixed disulfide is obtained in the form of a white powder (18 mg, 0.05 mmol, 39%). The symmetrical disulfide 34 is thus obtained in the form of a white powder (8 mg, 0.015 mmol, 22%). To a solution of silylated nucleoside 1 (30 mg, 0.08 mmol) in anhydrous dichloromethane (4 mL) is added propane disulfide (131 L, 0.42 mmol) followed by dibromine in solution in dichloromethane (209 mL). L, 2 M, 0.84 mmol). The mixture is stirred and under argon for 6 h. A solution of 5% sodium thiosulfate is added. The organic phase is washed twice with water (5 ml) and the organic phases are combined to be dried over magnesium sulphate and evaporated to dryness. The residue obtained is chromatographed on silica gel with a dichloromethane-methanol mixture (98: 2 and then 95: 5). The symmetrical disulfide 13 is thus obtained in the form of a white powder (8 mg, 0.02 mmol, 28%).

  1H NMR 1H (400MHz, CDCl3) δ 9.11 (1H, s, NH); 7.56 (1H, s, 6-H); 6.12 (1H, dd, J = 4.4Hz, J = 6.8Hz, 1H); 4.09-4.01 (2H, m, 4'-H and 5'-H); 3.90 (1H, m, 5'-H); 3.60 (1H, m, 3'-H); 2.73 (2H, m, CH 2 -S); 2.72-2.53 (2H, m, CH 2 x 2); 1.95 (5- CH3); 1.73 (2H, m, S-CH 2 -CH 2); 1.04 (2H, m, CH 2 -CH 3).

  13 C NMR (100 MHz, CDCl 3) δ 163.2 (C2); 151.2 (C4); 136.5 (C6); 110.8 (C5); 85.9 (Cl '); 85.4 (C4 '); 61.5 (5'-CH2); 45, 2 (C3 '); 39.8 (CH2-S); 38.1 (2'-CH 2); 22.5 (CH2-CH3); 13.0 (CH 2 -CH 3); 12.5 (5-CH3). The experimental part below describes the synthesis protocols followed for obtaining mixed disulphides obtained according to the invention by the process which is the subject of Example 3.

  2 ', 3'-Didehydro-2', 3'-dideoxythymidin-2'-yl and trichloromethyl disulfide C3 2 ', 3'-dihydro-2', 3'-dideoxy-2 '- (2') trimethylsilyl) ethyl) thiothymidine 14 (50 mg, 0.14 mmol) anhydrous dichloromethane (3 mL) trichloromethanesulfenyl chloride (45 L, 0.42 mmol). (36 mg, 0.09 mmol, 63%) as a white powder.

  1 H NMR (400 MHz, CDCl 3) δ 7.43 (1H, 1s, 6-H); 7.05 (1H, m, 1H); 6.62 (1H, m, 3'-H); 5.99 (1H, m, 4'-H); 3.92 (1H, dd, J = 2.4Hz, J = 12.4Hz, 5'-H); 3.82 (1H, dd, J = 2.8Hz, J = 12.4Hz, 5'-H); 1, 94 (3H, s, 5-CH3). 13 C NMR (100 MHz, CDCl 3)? 162.7 (C2); 150.8 (C4); 135, 24 (C3 '); 135.16 (C6); 131.8 (C2 '); 110.6 (C5); 100.1 (C-C13); 91.4 (Cl '); 86.8 (C4 '); 63.3 (5'-CH 2); 13.1 (5-CH3). MS (DCI, NH3-isobutane): m / z 407 [M + H] +.

  2 ', 3'-Didehydro-2', 3'-dideoxythymidin-2'-yl and 4-nitrophenyl disulfide 16 NO 2 Al 2 ', 3'-didehydro-2', 3'-dideoxy-2 ' (2-trimethylsilyl) ethyl) thiothymidine 14 (50 mg, 0.14 mmol) anhydrous dichloromethane (3 mL) 4-nitrobenzene sulfenyl chloride (80 mg, 0.42 mmol) 16 (32 mm, 0.08 mmol; %) in the form of a yellow powder

  1 H NMR (400 MHz, CDCl 3) δ 8.18 (2H, m, Ar); 7.60 (2H, m, Ar); 7.35 (1H, s, 6-H):; 6.91 (1H, bs, 1H); 6.39 (1H, s, 3'-H); 4.92 (1H, 1s, 4'4); 3.84 (1H, m, 5'-H); 3.73 (1H, m, 5'-H); 1.83 (3H, s, 5-CH3).

  NMR-C (100 MHz, CDCl 3)? 162.5 (C2); 150.7 (C4); 146.7 (C-NO2); 144.2 (CSS); 135.1 (C6); (C2 '), 132.4 (C3'), 126.7 (2 C, Ar), 124.2 (2 C, Ar), 102.5 (C5), 91.2 (C1 '), (C4 ') 63.2 (5'-CH2) 13.1 (5-CH3) MS (DCI, NH3-isobutane): m / z 432 [M + Na] + 2' Disulfide , 3'-didehydro-2 ', 3'-dideoxythymidin-2'-yl and 2-nitrophenyl 17 o Protocol B3 2', 3'-didehydro-2 ', 3'-dideoxy-2' - (2-trimethylsilyl) ethyl) thiothymidine 14 (50 mg, 0.14 mmol) anhydrous dichloroethane (3 mL) 4-nitrobenzene sulfenyl chloride (80 mg, 0.42 mmol) (30 mg, 0.07 mmol, 53%) bright yellow powder, 1H NMR (400MHz, CDCl3) δ 8.30 (1H, m, Ar), 8.01 (1H, m, Ar), 7.70 (1H, m, Ar, 7.44 (1H, m, Ar), 7.28 (1H, s, 6H), 7.43 (1H, m, Ar), 6.81 (1H, m, 6.30 (1H, m, 3'-H), 4.90 (1H, m, 4'-H), 3.81 (1H, dd, J = 2.8 Hz). J = 12.4 Hz; 5'-H); 3.69 (1H, m, dd, J = 3.2 Hz; J = 12.4 Hz; 5'-H); 1.86 (3H; , s, 5-CH3).

  13 C NMR (100 MHz, CDCl 3) δ 162.3 (C2); 150.7 (C4); 145.2 (C-NO2); 135.3 (C-SS); 135.1 (C6); 134.4 (1 C, Ar); 132.7 (C3 '); 131.9 (C2 '); 127.1; 126.9; 126.1 (3 C, Ar); 11.0.4 (C5); 89.9 (Cl '); 86.9 (C4 '); 63.3 (5'-CH 2); 13.0 (5-CH3). MS (DCI, NH 3 -isobutane): m / z 410 [M + H] + 2 ', 3'-didehydro-2', 3'-dideoxyuridin-2'-yl and trichloromethyl disulfide 20 C3 Protocol 2 ', 3'-Didehydro-2', 3'-dideoxy-2 '- (2- (trimethylsilyl) ethyl) thiouridine 18 (50 mg, 0.15 mmol) anhydrous dichloromethane (3 mL) trichloromethanesulfenyl chloride (48 L 0.44 mmol). (55 mg, 0.14 mmol, 96%) as a white powder.

  NMR 111 (400 MHz, CDCl3) δ 9.23 (1H, s, NH); 7.75 (1H, d, J = 8Hz, 6-H); 7.15 (1H, m, 1H); 6.68 (1H, m, 3'-H); 5.74 (1H, d, J = 8 Hz, 5-H); 5.04 (1H, m, 4'-H); 3.97 (1H, dd, J = 2.4Hz, J = 12.8Hz, 5'-H); 3.84 (1H, dd, J = 2.4 Hz, J = 12.4 Hz, 5'-H).

  13 C NMR (100 MHz, CDCl 3)? 164.6 (C2); 150.6 (C4); 141.2 (C6); 136.0 (C3 '); 131.3 (C2 '); 102.9 (C5); 99.9 (C-C13); 90.0 (Cl '); 87.4 (C4 '); 62.9 (5'-CH 2).

  MS (DCI, NH3-isobutane): m / z 393 [M + H] +.

  2 ', 3'-Didehydro-2', 3'-dideoxyuridin-2'-yl and 4-nitrophenyl disulfide 21 NO2 Al 2 ', 3'-didehydro-2', 3'-dideoxy-2 ' - (2-trimethylsilyl) ethyl) thiouridine 18 (200 mg, 0.58 mmol) anhydrous dichloromethane (6 mL) 4-nitrobenzene sulfenyl chloride (333 mg, 1.75 mmol) (152 mg, 0.38 mmol; 66%) in the form of a yellow powder.

  1 H NMR (400 MHz, CDCl 3) δ 9.40 (1H, s, NH); 8.16 (2H, m, Ar); 7.65 (1H, d, J = 8.0 Hz, 6-H); 7.60 (2H, m, Ar); 7.04 (1H, m, 1H); 6.48 (1H, m, 3'-H); 5.70 (1H, d, J = 8.4 Hz, 5-H); 4.99 (1H, s, 4'-H); 3.94 (1H, m, 5'-H); 3.83 (1H, m, 5'-H).

  13 C NMR (100 MHz, CDCl 3)? 162.9 (C2); 150.3 (C4); 146.8 (C-NO); 143.9 (C-SS); 140.8 (C6); 135.1 (C2 '); 131.8 (C3 '); 126.6 (2 C, Ar); 126.3 (2 C, Ar); 102.8 (C5); 89.7 (C1 '); 87.0 (C4 '); 63.0 (5'-CH 2).

  MS (DCI, NH3-isobutane): m / z 396 [M + H] +; 413 [M + NH 3] + 2 ', 3'-Didehydro-2', 3'-dideoxyuridin-2'-yl and 2-nitrophenyl 22N 2N 2 ', 3'-didehydro-2', 3'-dideoxy-2 '- (2-trimethylsilyl) ethyl) thiouridine: 18 (100 mg, 0.29 mmol) anhydrous dichloroethane (3 mL) 2-nitrobenzene sulfenyl chloride (166 mg, 0.88 mmol) ( 82 mg, 0.21 mmol, 71%) as a bright yellow powder.

  1 H NMR (400 MHz, CDCl 3) δ 8.31 (2H, m, NH + Ar); 8.02 (1H, m, Ar); 7.68 (2H, m, Ar, J = 8.0 Hz, 6-H); 7.43 (1H, m, Ar); 6.98 (1H, m, 1H); 6.40 (1H, m, 3'-H); 5.66 (1H, d, J = 8.4 Hz, 5-H); 4.97 (1H, m, 4'-H); 3.94-3.77 (2H, m, 5'-H 2).

  13 C NMR (100 MHz, CDCl 3)? 162.6 (C2); 150.1 (C4); 145.4 (C-NO2); 140.7 (C6); 135.1 (C-SS); 134.3 (1 C, Ar); 133.1 (C3 '); 132.4 (C2 '); 127.0; 126.9; 126.2 (3 C, Ar); 102.8 (C5); 89.9 (Cl '); 87.0 (C4 '); 63.1 (5'-CH 2).

  MS (DCI, NH3-isobutane): m / z 396 [M + H] +; 413 [M + NH3] + The experimental part below describes the synthesis protocols followed to obtain thiosulfinates of formula (IV) obtained according to the invention by the process which is the subject of Example 4.

  Thiosulfinate To a solution of silylated sulfide 23 (50 mg, 0.26 mmol) in anhydrous dichloroethane (1 mL) and under argon is added successively sulfenyl chloride 24 (203 mg, 1%). , 3 mmol) and tetrabutylammonium fluoride (0.5 M / MeOH solution, 105 L, 0.2 eq.). The reaction mixture is stirred for 15h at room temperature and then refluxed for 4h, and concentrated to give the thiosulfinate as an orange oil. NMR only shows the presence of thiosulfinate and more silylated sulphide. The product is characterized without special purification.

  1 H NMR (400 MHz, CDCl 3) δ 3.00 (2H, t, CH 2 S); 1.60 (2H, m, CH12); 1.35 (2H, m, CH 2); 0.84 (3H, m, CH 3).

  13 C NMR (100 MHz, CDCl 3) δ 61.1 (CH 2 SO); 38.3 (CH 2 S); 34.3 (C112); 32.6 (CH2); 31.9 (CH2); 27.0 (CH); 22.1 (CH3); 22.0 (CH3 x2).

  MS (DCI / NH 3 -isobutane): m / z 215 [M + H], 232 [M + NH 3], 248 [M + 2 NH 3]. Thiosulfinate 27 ws A silyl sulfide solution 23 (50 mg, 0, 26 mmol) in anhydrous dichloroethane (1 mL) and under argon is added sulfenyl chloride 26 (83 mg, 0.52 mmol). The reaction mixture is stirred for 15h at room temperature and then concentrated to give thiosulfinate 27 as a brown oil. NMR only shows the presence of thiosulfinate and more silylated sulphide. The product is characterized without special purification.

  1 H NMR (400 MHz, CDCl 3) δ 8.00-7.30 (5H, m, Ar), 3.00 (2H, t, CH 2 S), 1.60 (2H, m, CH 2), 1.35 ( 2H, m, CH 2), 0.84 (3H, m, CH 3).

  13 C NMR (100 MHz, CDCl 3) δ 143.0; 136.6; 129.4; 127.5; 35.7 (Cl-12S); 30.6 (CH2); 21.6 (CH2); 13.4 (CH3).

  MS (DCI / NH3-isobutane): m / z 209 [M + H], 225 [M + NH3], 242 [M + 2NH3]. The experimental part below describes the synthesis protocols followed to obtain thiosulfinates of formula (V) obtained according to the invention by the process which is the subject of Example 5. Thiosulfinate 29

  To a solution of silylated sulfide (43 mg, 0.11 mmol) in anhydrous dichloroethane (1 mL) and under argon is added trichloromethanesulfenyl chloride (56 mg, 0.30 mmol). The reaction mixture is refluxed for 48 hours and then concentrated in a hood under a stream of nitrogen. The residue is chromatographed on silica gel in a dichloromethane-methanol (95: 5) mixture. Two non-separable products by chromatography are obtained in the form of a white powder (27 mg, 55%).

  Ratio 54 A (disulfide 2) / 46 B (thiosulfinate 29)

  1 H NMR (400 MHz, CDCl 3) δ 8.36 (1H, br, NH); 8.28 (1H, s, NH); 7.47 (1H, s, 6-H A); 7.2: 2 (1H, s, 6-H B) 6.12 (1H, m, 1H-A); 5.87 (1H, m, 1H-B); 4.94 (1H, m, 3'-H B); 4.71 (1H, m, 4'-H B); 4.29-4.09 (4H, m, 3'-HA, 4'-HA, 5'-HA, 5'-H B); 3.92- 3.84 (2H, m, 5'-H A, 5'-H B); 3.07-2.91 (2H, m, 2'-H B x2); 2.80-2.57 (2H, m, 2'-H Ax2); 1.94 (6H, 1s, 5-CH 3 A, 5-CH 3 B).

  1H NMR (100 MHz, MeOD)? 164.9 (C2 A, B); 150.8 (C4 A, B); 136.7 (C6 'A); 136.4 (C6 'B); 110.8 (C5 A, B); 100.0 (C-C13 A, B); 85.5 (C4 'A); 85.5 (Cl 'B); 85.1 (Cl '25 A); 84.7 (Cl 'A); 79.4 (C, 4A); 71.4 (C, 3B); 62.1 (5'-CH2); 61.3 (5'-CH 2); 48.4 (C3 'A); 38.0 (C2 'A); 29.3 (C2 'B); 11.0 (5-CH3 A, B).

  MS (DCI, NH 3 -isobutane): m / z A 409 [M + H] +, B 441 [M + NH 3] +.

  Thiosulfinate To a solution of silylated sulfide 1 (28 mg, 0.07 mmol) in anhydrous dichloroethane (1 mL) and under argon is added 4-nitrobenzene sulfenyl chloride (56 mg, 0.30 mmol). The reaction mixture is refluxed for 48 hours and then concentrated. The residue is chromatographed on silica gel in a dichloromethane-methanol (95: 5) mixture. Two non-separable products by chromatography are obtained in the form of a yellow powder (12 mg, 48%).

  Ratio 40 A (thiosulfinate 30) / 60 B (disulfide 3)

  1 H NMR (400 MHz, MeOD) δ 8.36 (2H, d, As A); 8.24 (2H, d, Ar B); 8.05 (2H, d, Ar A); 7.88 (1H, s, 6-H B); 7.83 (2H, d, Ar B); 7.18 (1H, s, 6-H A); 6.25 (1H, m, 1H-A); 6.13 (1H, m, 1H-B); 4.51 (1H, m, 4'-H A); 4.34 (1H, m, 3'-H A); 4.01 (1H, m, 4'-H B); 3.89-4.05 (2H, m, 5'-H A, 5'-H B); 3.79 (1H, m, 3'-H B); 3.73 (2H, m, 5'-H A, 5'-H B); 2.86 (1H, m, 2'-H A); 2.61-2.42 (3H, m, 2'-H x 2 B, 2'-H A); 1.82 (6H, 1s, 5-CH3A, 5-CH3B).

  13 C NMR (100 MHz, MeOD)? 164.9 (C2 A, B); 150.8 (C4 A, B); 149.7; 146.6, 145.9; 136.9 (C6 'B); 136.7; 136.5 (C6'A); 126.1; 124.1; 123.8; 110.4 (C5 A); 109.8 (C5 B); 84.0 (Cl 'B, C4' B); 84.5 (Cl 'A); 79.4 (C, 4A); 68.8 (C3 'A); 61.9 (5'-CH 2); 60.3 (5'-CH 2); 46.0 (C, 3 B); 37.5 (C2 'B); 29.3 (C2 'A); 11.0 (5-CH3 A, B) MS (DCI, NH3-isobutane): m / z A 429 [M + H] +, B412 [M + H] + The following experimental part describes the synthesis protocols followed for obtaining thiosulfinates of formula (V) obtained according to the invention by the method which is the subject of Example 6.

  Thiosulfinate NO2 To a solution of the silylated sulfoxide 32a (diastereoisomer 1) (20 mg, 0.05 mmol) in anhydrous methanol / dichloroethane (2 mL, 1: 1) and under argon, the chloride of 4- nitrobenzene sulfenyl (30 mg, 0.16 mmol). The reaction mixture is refluxed for 48 hours and then concentrated. The residue is chromatographed on silica gel in a dichloromethane-methanol mixture (90:10). Two non-separable products by chromatography are obtained in the form of a yellow powder (6 mg, 26%).

  Ratio 45 (disulfide 9) A / 55 (Thiosulfinate 33) B

  1 H NMR (400 MHz, MeOD) δ 8.44 (2H, d, Ar B); 8.17 (2H, d, Ar A); 8.10 (2H, d, 20 Ar B); 7.90 (1H, d, J = 8.0 Hz, 6-H B); 7.77 (1H, d, J = 8.4 Hz, 6-H B); 7.66 (2H, d, Ar A); 6.35 (1H, d, J = 9.2 Hz, H-A); 6.21 (1H, d, J = 9.2 Hz, H-B); 5.65 (1H, d, J = 8.0Hz, 5-HB), 5.66 (1H, d, J = 8.0Hz, 5-HA), 4.48 (1H, m, 3H); -HA); 4.34 (1H, m, 3'-H B); 4.13 (1H, m, 2'-H B); 4.08 (1H, m, 4'-H B); 4.04 (1H, m, 4'-H A); 3.79-3.52 (4H, m, 2'-HA + 5'-Hx2A, 5'-Hx2B). To a solution of the silylated sulfoxide 32b (diastereoisomer 2) (30 mg, 0.08 mmol) in anhydrous methanol / dichloroethane (2 mL, 1: 1) and under argon is added 4-nitrobenzene sulfenyl chloride ( 45 mg, 0.24 mmol). The reaction mixture is refluxed for 48 hours and then concentrated. The residue is chromatographed on silica gel in a dichloromethane-methanol mixture (90:10). Two non-separable products by chromatography are obtained in the form of a yellow powder (12 mg, 35%).

  Ratio 37 (disulfide 9) A / 63 (thiosulfinate 33) B

  NMR 11-I (400 MHz, MeOD) δ 8.44 (2H, d, Ar B); 8.18 (2H, d, Ar A); 8.11 (2H, d, Ar B); 7.90 (1H, d, J = 8.4 Hz, 6-H B); 7.78 (1H, d, J = 8.4 Hz, 6-H B); 7.65 (2H, d, Ar A); 6.35 (1H, d, J = 9.2 Hz, H-A); 6.21 (1H, d, J = 9.2 Hz, H-B); 5.66 (1H, d, J = 8.0 Hz, 5-H B); 5.66 (1H, d, J = 8.0 Hz, 5-H A); 4.48 (1H, m, 3'-H A); 4.34 (1H, m, 3'-H B); 4.13 (1H, m, 2'-H B); 4.08 (1H, m, 4'-H B); 4.02 (1H, m, 4'-H A); 3.79 (1H, m, 2'-H A); 3.75-3.70 (4H, m, 5'-Hx2A, 5'-Hx2 ', B). MS (ES +): m / z A 413 [M + H] +, B 429 [M + H] +. The experimental part below describes the synthesis protocols followed for obtaining symmetrical disulfides of formula (VI) obtained according to the invention by the method which is the subject of Example 7.

  Bis (3'-dideoxythymidin-3-yl) disulfide A solution of silylated nucleoside 1 (10 mg, 0.03 mmol) in anhydrous dichloromethane (4 mL) is added in solution in dichloroethane (69 L, 2 M, 0.015 mmol). The mixture is stirred and under argon for 4 h. A solution of 5% sodium thiosulfate is added. The organic phase is washed twice with water (5 ml) and the organic phases are combined to be dried over magnesium sulphate and evaporated to dryness. The residue obtained is chromatographed on silica gel with a dichloromethanemethanol mixture (98: 2 and then 95: 5). The symmetrical disulfide 34 is thus obtained in the form of a white powder (5 mg, 0.01 mmol, 70%).

  To a solution of silylated nucleoside 1 (40 mg, 0.11 mmol) in anhydrous dichloroethane (3 mL) was added cyanogen bromide (0.06 mg, 0.57 mmol). The mixture is left stirring under argon for 96 h at 40 ° C. The symmetrical disulfide gradually appears in the form of a beige precipitate while the second product remains in solution. After hydrolysis with a phosphate buffer solution (0.5 M, pH 7, 2 mL) for 30 min, the solvents are evaporated to dryness. The residue obtained is chromatographed on silica gel with a dichloromethane-methanol (95: 5) mixture. The symmetrical disulfide 34 is thus obtained in the form of a white powder (12 mg, 0.02 mmol, 43%).

  1 H NMR (400 MHz, MeOD) δ 8.59 (1H, s, NH); 7.54 (1H, s, 6-H); 6.15 (1H, dd, J = 3.2Hz, J = 7.6Hz, 1H); 4.09-4.06 (1H, dd, J = 2.4Hz, J = 12.0Hz, 5H); 3.86 (1H, m, 4'-H); 3.81 (1H, dd, J = 2.4 Hz, J = 12.0 Hz, 5H); 3.55 (1H, m, 3'-H); 2.66-2.41 (2H, m, 2'H x2); 1, 92 (5-CH3).

  13 C NMR (100 MHz, MeOD) δ 163.5 (C2); 150.1 (C4); 136.2 (C6); 110.8 (C5); 88.6 (C4 '); 85.0 (Cl '); 60.6 (5'-CH2); 42.7 (C-3 '); 33.7 (2'-CH 2); 12.5 (5-CH3);

  MS (DCI, NH3-isobutane): m / z 515 [M + H] +.

  Bis- (5-bromo-2 ', 3'-dideoxyuridine-3'-yl) disulfide 36 and 5-bromo-2', 3'-dideoxy-3 '- (2- (trimethylsilyl) ethyl) thiouridine 36- 1 sss,., - ^ s:. To the silylated nucleoside solution (0.150 g, 0.44 mmol) in dry dichloromethane (4 mL) is added the cyanogen bromide (0.230 mg, 2.17 mmol). The mixture is left stirring under argon for 96 h at 40 ° C. The symmetrical disulfide gradually appears in the form of a beige precipitate while the second product remains in solution. After hydrolysis with a phosphate buffer solution (0.5 M, pH 7, 2 mL) for 30 min, the solvents are evaporated to dryness. The residue obtained is taken up in the minimum dichloromethane to be chromatographed on silica gel with a dichloromethanemethanol mixture (98: 2 and then 95: 5). The symmetrical disulfide 36 is thus obtained in the form of a white powder (27 mg, 0.04 mmol, 21%). The bromosilyl derivative 36-1 above is obtained in the form of a white powder (42 mg, 0.1 mmol, 25%).

  Symmetric disulfide 36 1H NMR (400 MHz, CDCl3) δ 8.63 (1H, s, 6-H); 6.12 (1H, dd, J = 6.5Hz, J = 4.0Hz, 1H); 4.05 (1H, s, 4'-H); 3.97 (1H, dd, J = 2.4Hz, J = 12.3Hz, 5'-H); 3.86 (1H, dd, J = 2.7Hz, J = 12.3Hz, 5'-H); 3.66 (1H, m, 3'-H); 2.61 (2H, m, 2'-1 x 2).

  13 C NMR (100 MHz, CDCl 3) δ 160.3 (C2); 150.1 (C4); 140.7 (C6); 96.3 (C5); 86.2 (Cl '); 85.3 (C4 '); 60.0 (5'-CH 2); 45.3 (2'-C); 38.3 (C3 '). MS (FAB +, NBA): m / z = 645 [M + H] +.

Bromosylated derivative 36-1

  1H NMR (400MHz, CDCl3) δ 8.41 (1H, s, 6-H); 6.09 (1H, dd, J = 6.7 Hz, J = 3.2 Hz, 1 H); 4.14 (1H, s, 5'-H); 4.93 (2H, m, 4'-H and 5'-H); 3.95 (1H, n, 3'-H); 2.66 (2H, m, S-CHZ); 2.60-2.44 (2H, m, 2'-H x 2); 1.28 (1H, t, 5'-OH); 0.88 (2H, m, CH 2 -Si); -0.02 (9H, s, Si (CH3) 3).

  13 C NMR (100 MHz, CDCl 3) δ 158.8 (C2); 149.3 (C4); 140.4 (C6); 96.1 (C5); 86.3 (Cl '); 86.2 (C4 '); 60.8 (5'-CH 2); 41.2 (2'-CH 2); 39, 6 (C3 '); 27.6 (S-CH 2); 17.5 (CH2-Si); -1.5 (Si (CH3) 3). MS (FAB +, NBA) m / z = 423 [M + H] +.

  The experimental part below describes the synthesis protocols followed for obtaining mixed disulphides of formula (III ') identified by references 37-43.

  DA protocol a solution of the thiol (10 equivalents) in 5% phosphate buffer (pH = 9.5) previously degassed by bubbling under argon (1 equivalent) is added 3 (1 equivalent) previously dissolved in THF / phosphate buffer degassed by bubbling under argon. The solution is kept under stirring and under argon for 2 hours. The solvents are evaporated and the residue is chromatographed on silica gel in a dichloromethane-methanol (95-5) mixture.

  Protocol EA a solution of the thiol (10 equivalents) in the imidazole buffer (10-3 M, pH = 6.0, ionic strength 1 M) previously degassed by bubbling under argon (qsp a concentration of 0.5 mol.LI) is added 3 (1 equivalent) previously dissolved in the THF / phosphate buffer previously degassed by bubbling under argon. The solution is stirred and under argon for 15 hours. The solvents are evaporated and the residue is chromatographed on silica gel in a dichloromethanemethanol (90-10) mixture.

  Protocol FA a solution of the thiol (1 equivalent) in the imidazole buffer (pH = 6.0, 1 M ionic strength) previously degassed by bubbling under argon (1 equivalent) is added 3 (1 equivalent) previously dissolved in the THF / buffer phosphate previously degassed by bubbling under argon. The solution is stirred and under argon for 15 hours. Dichloromethane is added and then the organic phase is washed with water (5 mL). The organic phases are combined, dried over magnesium sulphate and evaporated to dryness. The residue is chromatographed on silica gel in a dichloromethane-methanol (90-10) mixture to give symmetrical disulfide. The aqueous phase is evaporated to dryness and the residue is taken up to be chromatographed on reverse phase in a water-methanol mixture (90-10) to yield the mixed difulide.

  3'-deoxythymidin-3'-yl and allyl disulfide 37 o HOC D disulfide protocol of 3'-deoxythymidin-3'-yl and 4-nitrophenyl 3 (70 mg, 0.17 mmol) / 10 mL of tetrahydrofuran allylthiol (476 gL, 2.5 mmol) / 425 gL phosphate buffer 37 (45 mg, 0.14 mmol, 80%) as a pale yellow oil.

  1 H NMR (400 MHz, CDCl 3) δ 8.56 (1H, s, NH); 7.53 (1H, s, 6-H); 6.1 (1H, dd, J = 4.8Hz, J = 6.8Hz, 1H); 5.90-5.81 (1H, m, H allyl); 5.26-5.20 (2H, m, 2H allyl); 4.09-4.01 (2H, m, 4'-H and 5'-H); 3.90 (1H, m, 5'-H); 3.62 (1H, m, 3'-H); 3.90 (2H, m, CH 2 -Sallyl); 2.55 (2H, m, 2'-H 2); 1.93 (3H, s, 5-CH3).

  1H NMR (100 MHz, CDCl3) δ 163.3 (C2); 150.0 (C4); 136.5 (C6); 134.1 (CH-allyl); 117.2 (CH2-allyl); 110.8 (C5); 85.8 (Cl '); 85.4 (C4 '); 45, 2 (C3 '); 61.5 (5'-CH2); 38.2 (2'-CH 2); 34.7 (CH2-S); 12.5 (5-CH3).

  MS (DCI, NH 3 -isobutane): m / z 331 [M + H] + 3'-deoxythymidin-3'-yl and 2-hydroxyethyl disulfide 383 3'-deoxythymidin 3 'disulfide protocol 4-Nitrophenyl 3 (100 μg, 0.24 mmol) / 2.5 ml, tetrahydrofuran and 2.5 ml of imidazole mercaptoethanol buffer (170 μL, 2.43 mmol) / 5 mL of imidazole buffer. (41 mg, 0.043 mmol, 50%) as a white powder bis (3'-dideoxythymidin-3-yl) disulfide (14 mg, 0.027 mmol, 23%) as a powder white.

  NMR [H (400 MHz, CDCl3) δ 8.25 (1H, s, NH); 7.59 (1H, s, 6-H); 6.08 (1H, dd, J = 5.2Hz, J = 6.4Hz, 1H); 4.12-4.00 (3H, m, 4'-H and 5'-H 2); 3.94 (2H, m, CH 2 -OH); 3.73 (1H, m, 3'41); 3.01-2.93 (2H, m, CH 2 -S); 2.54 (2H, m, 2'-H x 2); 1.94 (3H, s, 5-CH3).

  13 C NMR (100 MHz, CDCl 3) δ 165.0 (C2); 150.8 (C4); 136.8 (C6); 109.7 (C5); 85.6 (C4 '); 84.5 (Cl '); 60.6 (5'-CH 2); 59.8 (CH 2 -OH); 45.4 (C3 '); 41.8 (CH2-S); 37.9 (2'-CH 2); 11.0 (5-CH3).

  MS (DCI, NH 3 -isobutane): m / z 335 [M + H] + HOC OH 3'-deoxythymidin-3'-yl disulfide and 2-aminoethyl chlorohydrate 39 o HOC NH 2, HCl protocol F disulfide 3 3-deoxythymidin-3'-yl and 4-nitrophenyl 3 (50 mg, 0.12 mmol) / 2 mL of tetrahydrofuran and 2 mL of 2-aminoethanethiol imidazole hydrochloride buffer (28 mg, 0.24 mmol) / 400 1 L of imidazole buffer 39 (9 mg, 0.043 mmol, 20%) as a white powder bis (3'-dideoxythymidin-3-yl) bisulfite (34 mg, 0.012 mmol, 48%) form of a white powder. 7.54 (1H, s, 6-H); 6.08 (1H, dd, J = 4Hz, J = 7.2Hz, 1H NMR (400MHz, D2 O) 1H); 4.02 (1H, m, 4'-H); 3.87 (1H, dd, J = 2.8 Hz, J = 12.8 Hz, 5'-H); 3.76 (1H, dd, J = 2.8 Hz, J = 12.8 Hz, 5'-H); 3.52 (1H, m, 3'-H); 3.30 (2H, m, CH 2 -NH 2); 2.93 (2H, m, CH 2 -S); 2.60-2.43 (2H, m, 2'-H x 2); 1.80 (3H, s, 5-CH3). 1H NMR (100 MHz, D 2 O) 166.4 (C2); 151.5 (C4); 137.5 (C6); 111.1 (C5); 85.1 (C4 '); 84.8 (C1 '); 60.5 (5'-CH2); 45.1 (C-3 '); 37.8 (CH 2 -NH 2); 36.9 (2'-CH 2); 35.0 (CH 2 -S); 11.5 (5-CH3).

  MS (DCI, NH3-isobutane): m / z 335 [M + H] +.

  3'-deoxythymidin-3'-yl and butyl disulfide 40 ° HOC 3'-deoxythymidin-3'-yl disulfide and 4-nitrophenyl 3 disulfide (40 mg, 0.097 mmol) / 6 mL of tetrahydrofuran butanethiol ( 107.0 mmol) / 243 L of phosphate buffer 40 (15 mg, 0.043 mmol, 45%) as a white powder bis (3'-dideoxythymidin-3-yl) disulfide (6) mg, 0.012 mmol, 24%) as a white powder.

  1 H NMR (400 MHz, CDCl 3) δ 8.56 (1H, s, NH); 7.54 (1H, s, 6-H); 6.12 (1H, dd, J = 4.4Hz, J = 6.8Hz, 1H); 4.10-4.02 (2H, m, 4'-H and 5'-H); 3.90 (1H, m, 5'-H); 3.60 (1H, m, 3'-H); 2.75 (2H, m, CH 2 -S); 2.64-2.51 (2H, m, CH 2>: 2); 1.93 (3H, s, 5-CH3); 1.68 (2H, m, S-CH 2 -CH 2); 1.43 (2H, m, CH 2 -CH 3); 0.95 (2H, m, CH 2 -CH 3).

  13 C NMR (100 MHz, CDCl 3) δ 163.3 (C2); 150.0 (C4); 136.5 (C6); 110.8 (C5); 85.8 (C1 '); 85.4 (C4 '); 61.5 (5'-CH2); 45, 2 (C3 '); 39.8 (CH2-S); 38.2 (2'-CH 2); 31.2 (S-CH2-CH2); 21.5 (CH 2 -CH 3); 13.6 (CH2-CH3); 12.5 (5-CH3).

  MS (FAB +, NBA template): m / z 347 [M + H] +, 369 [M + Na] +.

  3'-deoxythymidin-3'-yl and hexyl disulfide 41 o 3'-deoxythymidin-3'-yl disulfide protocol and 4-nitrophenyl 3 (34 mg, 0.083 mmol) / 6 mL of tetrahydrofuran hexanethiol ( 123 L, 0.83 mmol) / 243 L of phosphate buffer 41 (22 mm, 0.059 mmol, 71%) as a white powder.

  1 H NMR (400 MHz, CDCl 3) δ 8.66 (1H, s, NH); 7.56 (1H, s, 6-H); 6.12 (1H, dd, J = 4.7Hz, J = 7.2Hz, 1H); 4.10-4.01 (2H, m, 4'-H and 5'H); 3.90 (1H, m, 5'-H); 3.60 (1H, m, 3'-H); 2.70 (2H, m, CH 2 -S); 2.64-2.48 (2H, m, 2H x2); 1, 92 (3H, s, 5-CH3); 1.68 (2H, m, CH 2 -CH 2 -S); 1.44-1.25 (6H, m, CH 2 -CH 2 -CH 2); 0.91 (3H, m, CH2- • CH3).

  13 C NMR (100 MHz, CDCl 3) δ 163.4 (C2); 150.1 (C4); 133.4 (C6); 110.8 (C5); 85.8 (Cl '); 85.5 (C4 '); 61.5 (5'-CH2); 45.3 (C3 '); 40.2 (CH2-S); 38.2 (2'-CH 2); 31.3 (1C, CH 2); 29.1 (CH 2 -CH 2 -S); 28.0; 22.4 (2 C, CH 2); 13.9 (CH2-CH3); 12.4 (5- CH3).

  MS (DCI, NH3-isobutane): m / z 375 [M + H] +.

  3'-deoxythymidin-3'-yl and octyl disulfide 42 o 3'-deoxythymidin-3'-yl disulfide protocol and 4-nitrophenyl 3 (75 mg, 0.18 mmol) / 2.5 mL tetrahydrofuran and 2.5 mL of imidazole octanethiol buffer (316 gL, 1.82 mmol) / 5 mL of imidazole buffer 42 (12 mg, 0.030 mmol, 16%) as a white powder. 3'-dideoxythymidin-3-yl) (30 mg, 0.027 mmol, 65%) as a white powder. 1 H NMR (400 MHz, CDCl 3) δ 8.66 (1H, s, NH); 7.68 (1H, s, 6-H); 6.13 (1H, dd, J = 4.4Hz, J = 6.8Hz, 1H); 4.09-3.88 (3H, m, 4'-H and 5'H x 2); 3.60 (1H, m, 3'-H); 2.73 (2H, m, CH 2 -S); 2.74-2.51 (2H, m, 2H x2); 1.93 (3H, s, 5-CH3); 1.68 (2H, m, CH 2 -CH 2 -S); 1.39-1.20 (10H, m, CH2-CH2-CH2-CH2-CH2); 0.90 (3H, m, CH 2 -CH 3).

  1 + C NMR (100 MHz, CDCl 3) δ 163.5 (C2); 150.1 (C4); 136.5 (C6); 110.8 (C5); 85.8 (Cl '); 85.4 (C4 '); 61.4 (5'-CH2); 45.2 (C-3 '); 40, 1 (CH2-S); 38.1. (2'-CH 2); 31.7 (CH2); 29.2 (CH 2 -CH 2 -S); 29.1; 28.4; 22.6 (4C, CH 2); 14.0 (CH; -CH3); 12.5 (5-CH3).

  MS (DCI, NH3-isobutane): m / z 403 [M + H] +. HOC s-s25 3'-deoxythymidin-3'-yl and 6-hydroxyhexyl disulfide 43 o HOC protocol D 3'-deoxythymidin-3'-yl disulfide and 4-nitrophenyl 3 (55 mg, 0.13 mmol) 6 mL of tetrahydrofuran 6-mercaptohexanol (183 L, 1.34 mmol) / 334 L of phosphate buffer 43 (37 mg, 0.094 mmol, 71%) as a white powder.

  1 H NMR (400 MHz, MeOD) δ 7.94 (1H, s, 6-H); 6.16 (1H, dd, J = 4.8Hz, J = 6.8Hz, 1H); 4.02-3.92 (2H, m, 4'-H and 5'H); 3.81 (1H, m, 5'-H); 3.58 (3H, m, 3'-H + CH 2 -OH); 2.79 (2H, m, CH 2 -S); 2.62-2.42 (2H, m, 2H x2); 1.90 (3H, s, 5-CH3); 1.74 (2H, m, CH 2 -CH 2 -S); 1.56 (2H, m, CH 2 -CH 2 -OH); 1.44 (4H, m, CH 2 -CH 2).

  1H NMR (100 MHz, MeOD) δ 162.2 (C2); 150.8 (C4); 136.8 (C6); 109.8 (C5); 85.6 (C4 '); 84.5 (Cl '); 61.4 (CH 2 -OH); 60.6 (5'-CH2); 45.4 (C-3 '); 39.2 (CH2-S); 38.0 (2'-CH 2); 32.0 (CH 2 -CH 2 -OH); 28.7 (CH 2 -CH 2 -S); 27.8; 25.0 (2 C, CH 2); 11.0 (5-CH3).

  MS (DCI, NH3-isobutane): m / z 391 [M + H] +. The experimental part below describes the synthesis protocols followed for obtaining new vinyl thiols identified by reference 44.

  Preparation of a vinyl thiol 44 and a bis (2 ', 3'-didehydro-2', 3'-dideoxyuridin-2'-yl) disulfide 45 o O NH HOC ~ N ~ O OYN HO HN SH Y To a solution of 21 (10 mg, 0.03 mmol) in deuterated methanol is added DTT (2.1 mg, 0.03 mmol). The solution is stirred for 15 minutes and then a first proton NMR spectrum is recorded. The rapid formation of a single first product corresponding to vinyl thiol 44 is observed (mixed with 50% of starting compound). The reaction is then monitored for 4 hours every hour by NMR. It reaches a stationary state with a vinyl thiol / starting material mixture (70/30). A product precipitates at the bottom of the tube. The NMR spectrum of the solution shows the disappearance of the aromatic protons carried by the 4-nitrophenyl group while that of the precipitate obtained reveals only the presence of aromatic protons. The tube is then stored at room temperature. After one night, the vinyl thiol was converted essentially and completely to the corresponding symmetrical disulfide 45.

Vinyl thiol 44

  1 H NMR (400 MHz, MeOD) δ 7.90 (1H, d, J = 8.0 Hz, 6-H); 7.06 (1H, m, 1H); 6.55 (1H, m, 3'-H); 5.72 (1H, d, J = 8.4 Hz, 5-H); 4.93 (1H, s, 4'-H); 3.73 (2H, m, 5'-H x 2).

  Symmetric disulfide 455 1H NMR (400 MHz, MeOD) δ 7.88 (1H, d, J = 8.0 Hz, 6-H); 6.83 (1H, m, 1H); 6.22 (1H, m, 3'-H); 5.75 (1H, d, J = 8.0 Hz, 5-H); 4.91 (1H, s, 4'-H); 3.71 (2H, m, 5'-H x 2). MS (FAB +, NBA) m / z = 242 [M / 2 + H] + The following experimental part illustrates the synthesis of compounds of formula (IIa) and (IIb) as intermediate compounds. 2 ', 3'-Didehydro-2', 3'-dideoxy-2 '- (2- (trimethylsilyl) ethyl) thiotthymidine 14H A solution of 2'-deoxy-2' - (2- (trimethylsilyl) ethyl) Thiothymidine 46 (2.51 g, 6.68 mmol) in anhydrous pyridine (15 mL), maintained at 0 ° C. under argon, is added 4,4'-dimethoxytrityl chloride (1.99 g, 5.87 g). mmol). After 24 hours, the solvent is evaporated and coevaporated with toluene. The residue is taken up in dichloromethane, is washed with water (100 ml) and is dried over magnesium sulphate. After evaporation to dryness, the product is chromatographed on silica gel in dichloromethanemethanol (98: 2) with 2% triethylamine and is a white solid (3.46 g, 5.11 mmol; 76%). To this protected compound, previously dissolved in 25 ml of dichloromethane, are added triethylamine (2.14 ml, 1.53 mmol) and then mesyl chloride (0.88 g, 7.71 mmol). After 15 hours at room temperature, 5 ml of water are added and the solvents are evaporated. The residue obtained is taken up in dichloromethane (100 ml), washed with water (50 ml) and dried over magnesium sulphate before being evaporated to dryness. The residue obtained (2.71 g, 4 mmol) is treated with 30 ml of 2% dichloroacetic acid in dichloromethane. This solution is left under stirring and under argon for 30 min, before being neutralized with a solution of sodium bicarbonate (5%, 80 ml). The aqueous phase is extracted with dichloromethane (100 mL), the organic phases are dried over sodium sulfate and evaporated to dryness. The residue is purified on silica gel with dichloromethane-methanol (98: 2) to afford product 14 (1.21 g, 2.67 mmol, 45% for both steps). This compound (297 mg, 0.66 mmol) is dissolved in 15 ml of acetonitrile and potassium carbonate (525 mg, 3.8 mmol) is added. After 3 days at 90 ° C., the solvents are evaporated and the product 14 after purification on silica gel in a dichloromethane-methanol (98: 2) mixture, is in the form of a white solid (198 mg, 55 mmol; 84%). The overall yield of the reaction for the 4 steps is 28%. F: 69 C

  1 H NMR (400 MHz, CDCl 3) δ 8.73 (1H, s, NH); 7.38 (1H, s, 6-H); 6.94 (1H, m, 1H); 5.81 (1H, s, 3'-H); 4.98 (1H, s, 4'-H); 3.97-3.74 (2H, m, 5'-H); 2.85 (2H, m, S-CH 2); 1.87 (3H, s, 5-CH3); 0.94 (2H, m, CH 2 -Si); 0.07 (9H, s, Si (CH3) 3.

  1H NMR (100 MHz, DMSO) δ 164.0 (C2); 150.6 (C4); 136.9 (C6); 135.2 (C2 '); 123.5 (C3 '); 110.9 (C5); 90.3 (C1 '); 87.4 (C4 '); 63.5 (5'-CH 2); 28.5 (S-CH 2); 16.3 (CH2-Si); 12.4 (CH3); -1.8 (Si (CH3) 3). MS (DCI, NH 3 -isobutane) m / z 357 [M + H] + 2 ', 3'-Didehydro-2', 3'-dideoxy-2 '- (2-trimethylsilyl) ethyl) thiouridine 18 O HO Compound 47 (3.766 g, 7.24 mmol) is dissolved in 50 ml of acetonitrile and potassium carbonate (6.04 g, 43.44 mmol) is added. After 3 days at 90 ° C., the solvent is evaporated and the product 18 after purification on silica gel in a dichloromethane-methanol (98: 2) mixture, is in the form of a white solid (2.55 g; 7.44 mmol, 85%).

  1 H NMR (400 MHz, CDCl 3) δ 9.30 (1H, s, NH); 7.61 (1H, d, J = 8Hz, 6H); 6.94 (1H, m, 1H); 5.81 (1H, s, 3H); 5.70 (1H, d, J = 8Hz, 5-H); 4.99 (1H, m, 4'-H); 3.94 - 3.74 (2H, m, 5'-H 2); 2.85 (2H, m, S-CH 2); 0.94 (2H, m, CH 2 -Si); 0.09 (9H, s, Si (CH3) 3.

  1H NMR (100 MHz, CDCl 3) δ 164.1 (C2); 150.8 (C4); 141.3 (C6); 134.9 (C2 '); 123.6 (C3 '); 102.5 (C5); 90.2 (Cl '); 87.5 (C4 '); 63.4 (5'-CH 2); 284 (S-CH 2); 16.2 (CH2-Si); -1.9 (Si (CH3) 3). MS (DCI, NH 3 -isobutane) m / z 343 [M + H] +. Microanalysis for C14H22N2O4SSi, 0.5H2O: C, 47.84; H,; N, 7.97; S, 9.12. Found C 47.92; H, 76, 17.96; S, 9.86. 2 ', 3'-Dideshydro-2', 3'-dideoxy-2 '- (2-trimethylsilyl) ethyl) thiocytidine 19 HO A 50 (0.150 g, 0.31 mmol) is added ammonium fluoride in solution in methanol (813, 0.5 M, 0.41 mmol). The solution is refluxed for 6 hours and then allowed to come to room temperature overnight. The solvents are evaporated and then a dry silica gel deposition is carried out to chromatograph the final product on silica gel with a dichloromethanemethanol (90:10) mixture. The derivative 19 (0.81 g, 0.24 mmol, 76%) is thus obtained in the form of a white foam.

  F: 91-115 ° C (dec.) 1H NMR (400MHz, MeOD) δ 7.86 (1H, d, J = 7.6Hz, 6-H); 6.99 (1H, m, 1H); 5.94 (1H, s, 3'-H); 5.89 (1H, d, J = 7.6 Hz, 5-H); 4.90 (1H, m, 4'-H); 3.73 (2H, m, 5'-H x 2); 2.89 (2H, m, S-CH 2); 0.95 (2H, m, CH 2 -Si); 0.07 (9H, s, Si (CH 3) 3). 13 C NMR (100 MHz, MeOD) 166.2 (C4); 157.3 (C2); 142.1 (C6); 135.4 (C2 '); 123.9 (C3 '); 95.1 (C5); 90.6 (Cl '); 87.4 (C4 '); 62.8 (5'-CH 2); 27.6 (S-CH 2); 15.9 (CH2-Si); -3.3 (Si (CH3) 3). MS (DCI, NH 3 -isobutane) m / z 342 [M + H] +. Microanalysis for C30H43N3O4SSi, 0.7 H2O: C 48.55; H, 7.13, N, 11.58; S 8.84. Calculated Found C 48.26; H, 7.15, N, 11.59; S 9.08.25 3'-Deoxy-3 '- (2- (trimethylsilyl) ethyl) thiothymidine sulfoxide 28 HOC A solution of 1 (0.1 g, 0.28 mmol) in methanol (1.4 g) ml) is added at 0 C a solution of sodium periodate (0.06 g, 0.28 mmol) in water (700 L). The reaction is allowed to warm to room temperature overnight. The precipitate is filtered on cotton and the filtrate is evaporated under vacuum. The residue obtained is chromatographed on flash silica gel in a dichloromethane-methanol (95: 5) mixture to give the two non-separable diastereoisomers 28 (0.104 g, 0.16 mmol, quantitative) in the form of a white powder.

  Ratio 43A / 57B 1 H NMR (400 MHz, CDCl 3) δ 9.80 (2H, 1s, 2XNH); 7.57 (1H, s, 6-H A); 7.40 (1H, s, 6H); 5.98 (1H, m, 1H); 5.87 (1H, dd, J = 7.5Hz, J = 4.6Hz, 1H-B); 4.60 (1H, m, 4'-H A); 4.32 (1H, m, 4'-H B); 4.08-4.05 (2H, m, 5'-H A, 5'-H B); 3.86-3.80 (2H, m, 5'-H A, 5'-H B); 3.70 (2H, m, 3'-H A, 3'-H B); 3.06 (1H, m, 2'-H B); 2.76 - 2.50 (4H, m, S-CH 2); 2.48-2.44 (3H, m, 2'-H x 2 A, 2'-H B); 1.89 (6H, 1s, 5-CH3A, 5-CH3B); 1.04 (2H, m, CH-Si A, CH-Si B); 0.83 (2H, m, CH-Si A, CH-Si B); 0830.06 (9H, s, Si (CH 3) 3.

  13 C NMR (100 MHz, CDCl 3) δ 164.1 (C2 A, B); 150.5 (C4 A, B); 138. 0 (C6 'B); 136.8 (C6'A); 110.8 (C5 A, B); 88.9 (Cl 'B); 87.0 (Cl 'A); 81.4 (C4 'A, B); 63.3 (5'-CH 2); 61.5 (5'-CH 2); 56.7 (C3 '); 55.6 (C3 '); 47.0 (S-CH 2); 46.9 (S-CH 2); 33.8 (C2 'A); 27.6 (C2 'B); 12.4 (5-CH3 A, B); 9.7 (CH2-Si); 8.8 (CH2-Si); -2.0 (Si (CH3) 3x2).

  MS (DCI, NH3-isobutane) m / z 375 [M + H] +.

  2'-Deoxy-2 '- (2- (trimethylsilyl) ethyl) thiouridine sulphoxide To a solution of 2'-deoxy-2' - (2- (trimethylsilyl) ethyl) thiouridine (0.2 g, 0.55 mmol), in methanol (5.5 mL) is added at 0 C a solution of sodium periodate (119 mg, 0.55 mmol) in water (2.8 mL). The reaction is allowed to warm to room temperature overnight. The precipitate is filtered on cotton and the filtrate is evaporated under vacuum. The residue obtained is chromatographed on flash silica gel in a dichloromethane-methanol mixture (90:10) and then (80:20). The two diastereoisomers 32a and 32b are obtained in the form of a white powder (1: 0.080 g, 0.21 mmol, 2: 0.065 g, 0.17 mmol, 55/45, 70%).

  Diastereoisomer 32a (S-configuration) 1H NMR (400MHz, CD3OD) δ 8.15 (1H, d, J = 8.0Hz, 6-H); 6.48 (1H, d, J = 8.0Hz, 1H); 5.81 (1H, d, J = 8.0 Hz, 5-H); 4.74 (1H, m, 4'-H); 4.13 (1H, m, 3'-H); 3.86 (1H, m, J = 8.4 Hz, J = 5.6 Hz, 2'-H); 3.79 (2H, m, 5'-H 2); 2.98 (2H, m, SCH 2); 0.88 (2H, m, CH 2 Si); -0.05 (9H, s, Si (CH3) 3).

  13 C NMR (100 MHz, CD3OD) δ 164.1 (C2); 150.8 (C4); 140.9 (C6); 102.7 (C5); 87.7 (C3 '); 82.7 (Cl '); 72.7 (C4 '); 66.9 (C2 '); 61.5 (5'-CH2); 44.6 (S-CH 2); 7.7 (CH2-Si); - 3.5 (Si (CH3) 3). MS (DCI, NH3-isobutane) m / z 377 [M + H] +. Diastereoisomer 32b (R-configuration) 1H-NMR (400MHz, CD3OD) δ 7.91 (1H, d, J = 8.0Hz, 6-H); 6.69 (1H, d, J = 8.0 Hz, 1'41); 5.81 (1H, d, J = 8.2 Hz, 5-H); 4.74 (1H, m, 4'-H); 4.13 (1H, m, 3'-H); 3.77 (1H, dd, J = 8.4 Hz, J = 5.6 Hz, T-H); 3.79 (2H, m, 5'-H); 2.75 (2H, m, SCH2); 1.04 (1H, m, CHSi); 0.80 (1H, m, CHSi); 0.88 (2H, m, CH 2 Si); 0.10 (9H, s, Si (CH3) 3) •

  13 C NMR (100 MHz, CD3OD)? 164.5 (C2); 150.2 (C4); 141.5 (C6); 102.0 (C5); 85.7 (C4 '); 83.5 (C1 '); 69.7 (C3 '); 65.6 (C2 '); 60.1 (5'-CH2); 45.4 (S-CH 2); 8.7 (CH2-Si); 3.4 (Si ((-H3) 3) MS (DCI, NH3-isobutane) m / z 377 [M + H] + 2 ', 3'-Didesoxy-3' - (2- ( trimethylsilyl) ethyl) thiouridine If a suspension of sodium hydride (60%, 234 mg, 7.02 mmol) in anhydrous DMF (8 mL) is added a solution of 2- (trimethylsilyl) is added ethanethiol (980 L, 7.02 mmol) in DMF (8 mL), this mixture is left stirring under argon for 15 min, then the derivative 51 (3 g, 5.85 mmol) is added, after 24 h under argon at 90 ° C., the unreacted sodium hydride is neutralized with 3 ml of methanol and the solvents are evaporated off under reduced pressure, the residue is then taken up in dichloromethane (100 ml) and the solution is neutralized with a solution of NaH2PO4 (10%, 10 mL), washed with water (100 mL) and dried over sodium sulfate before being evaporated to dryness The residue is taken up in dichloromethane to be chromatographed on silica gel with a mixture of dichloromethane-ethyl acetate (8: 2) containing 1 % triethylamine and give the sulfide as a yellow foam. The pale yellow foam obtained is dissolved in a solution of dichloroacetic acid in dichloromethane (2%, 80 ml). The orange solution obtained is left stirring under argon for 4 hours before being neutralized with a solution of sodium bicarbonate (5%, 30 ml). The aqueous phase is extracted with dichloromethane (50 mL) and the organic phases are combined to be dried over sodium sulfate before being evaporated to dryness. The residue is taken up in dichloromethane to be chromatographed on silica gel with dichloromethane-ethyl acetate (6: 4) and give the sulfide (1.06 g, 3.08 mmol, 56% (2 steps)). ) in the form of a white solid.

  1H NMR (400 MHz, CDCl3) δ 9.47 (1H, s, NH); 7.82 (1H, d, J = 8.4 Hz, 6-H); 6.12 (1H, dd, J = 7.0Hz, J = 3.6Hz, 1H); 5.73 (1H, d, J = 8.4 Hz, 5-H); 4.05 (1H, m, 3'-H); 3.85 (2H, m, 5'-H x 2); 3.47 (1H, m, 4'-H); 2.64-2.50 (4H, m, 2'-F1 x 2, SCH2); 0.84 (2H, m, CH 2 -Si); -0.02 (9H, s, Si (CH3) 3).

  13 C NMR (100 MHz, CDCl 3)? 163.9 (CO); 150.4 (CO); 140.9; 101.9; 86.2; 85.7; 61.0 (5'-CH 2); 40.7; 40.1 (2'-CH 2); 27.5 (S-CH 2); 17, 4 (CH2-Si); -1.8 (Si (CH3) 3).

  MS (FAB +, glycerol) m / z = 345 [M + H] +. Microanalysis for C14H24N2O4SSi, 0.33 H2O: Calculated C 47.97; H, 7.09; N, 7.99; S, 9.15. Found C 47.82; H, 7.13; N, 7.79; S, 9.66. 2'-Deoxy-2 '- (2- (trimethylsilyl) ethyl) thiothymidine 46 To a suspension of 2,2'-anhydrothymidine (5 g, 22 mmol) and anhydrous potassium carbonate (11 g, 79 mmol) in DMF (110 mL) is added 2- (trimethylsilyl) ethanethiol (3.5 g, 26 mmol). The solution is stirred and under argon at 120 ° C. for 3 h. After filtration and rinsing of the inorganic salts with dichloromethane, the solvents are evaporated under reduced pressure to give a yellow oil. This residue is chromatographed on silica gel in a dichloromethanemethanol (95: 5) mixture. Sulfide 46 is obtained as a white solid (6.9 g, 19 mmol, 88%). F: 58-60 C 1 H NMR (400 MHz, CDCl3) δ 8.73 (1H, s, NH); 7.25 (1H, d, J = 8.0 Hz, 6-H); 5.46 (1H, d, J = 9.2Hz, 1H); 4.36 (1H, m, 3'-H); 4.24 (1H, m, 4'-H); 3.99 (2H, m, 2H + 5'-H); 3.81 (1H, m, 5'-H); 2.60 (2H, m, S-CH 2); 1.96 (3H, s, 5-CH3); 0.85 (2H, m, CH 2 Si); -0.02 (9H, s, Si (CH3) 3).

  13 C NMR (100 MHz, CDCl 3) δ 163.4 (C2); 150.5 (C4); 138.87 (C6); 111.4 (C5); 93.3 (Cl '); 86.6 (C4 '); 71.5 (C3 '); 63.1 (5'-CH 2); 52.8 (C2 '); 28.4 (S-CH 2); 18.1 (CH2-Si); 12.4 (CH3); -1.8 (Si (CH3) 3).

  MS (DCI, NH3-isobutane) m / z 375 [M + H] +, 392 [M + H + NH3] +25 2'-Deoxy-3 '- (O-mesyl) -2' - (2- ( trimethylsilyl) ethyl) thiouridine HOC To a solution of 2'-deoxy-2 '- (2- (trimethylsilyl) ethyl) thiouridine (3 g, 13.8 mmol), compound of formula (IIa), in anhydrous pyridine (50 mL), maintained at 0 ° C. under argon, is added 4,4'-dimethoxytrityl chloride (5.20 g, 15.3 mmol). After 24 hours, the solvent is evaporated and coevaporated with toluene. The residue is taken up in dichloromethane, washed with water (100 ml) and dried over magnesium sulphate. After evaporation to dryness, the product is purified on silica gel in a dichloromethane-methanol (98: 2) mixture containing 2% triethylamine, and is in the form of a white solid (7.23 g, 10.91 g). mmol, 91%). To this tritylated compound (7.1 g, 10.71 mmol), previously dissolved in 50 ml of anhydrous pyridine, was added mesyl chloride (1 mL, 12.85 mmol). The solution is kept under argon and at 0 ° C. for one hour and is then allowed to return to ambient temperature for 15 hours. 5 ml of water are then added and the solvents evaporated. The residue obtained is taken up in dichloromethane (100 mL), washed with water (50 mL) and dried over magnesium sulfate before being evaporated to dryness. The residue obtained (8.36 g, 11.28 mmol) dissolved in 20 ml of dichloromethane is treated with 80 ml of 2% dichloroacetic acid in dichloromethane. This solution is left stirring for 4 hours, before being neutralized with a solution of sodium bicarbonate (5%, 80 ml). The aqueous phase is extracted twice with dichloromethane (100 ml), the combined organic phases are dried over magnesium sulphate and then evaporated to dryness. The residue is purified on silica gel with dichloromethane-methanol (98: 2) to yield product 47 (3.716 g, 7.24 mmol, ie 71% for the 3 steps). 1H NMR (400MHz, CDCl3) δ 7.50 (1H, d, J = 8.0Hz, 6-H); 5.83 (1H, d, J = 8.1 Hz, 5-H); 5.70 (1H, d, J = 9.3 Hz, 1 H); 5.31 (1H, m, 3'-H); 4.47 (1H, s, 4'-H); 4.04 (1H, dd, J = 9.3Hz, J = 5.5Hz, 2'-H); 3.93 (2H, m, 5'-H 2); 3.18 (3H, s, CH3); 2.58 (2H, m, S-CH 2); 0.80 (2H, m, CH 2 Si); 0.01 (9H, s, Si (CH3) 3).

  13 C NMR (100 MHz, CDCl 3)? 162.4 (C2); 150.3 (C4); 142.5 (C6); 103.2 (C5); 93.9 (Cl '); 85.5 (C4 '); 81.9 (C3 '); 62.2 (5'-CH 2); 48.7 (C2 '); 38.5 (CH3, Ms); 28.2 (SCH2); 17.8 (CH2-Si); -1.9 (Si (CH3) 3). MS (DCI, NH3-isobutane) m / z 439 [M + H] +, 456 [M + H + Na] +. 5'-O- (tert-butyldiphenylsilyl) -2 '- (2-trimethylsilyl) ethyl) thiocytidine TBDPSO Compound 6 (1 g, 2.78 mmol) is dissolved in anhydrous pyridine (15 mL) at 0 ° C. under argon. After 15 minutes, tertbutyldiphenylsilyl chloride (870 μl, 3.34 mmol) is added and the mixture is stirred for 48 h. after evaporation and coevaporation with toluene, the residue obtained is dissolved in dichloromethane (100 mL) and then washed with water (50 mL). The organic phase is then dried over magnesium sulfate, evaporated and coevaporated with toluene (100 mL). The solid obtained is chromatographed on silica gel in a dichloromethanemethanol (95: 5) mixture and gives compound 48 (1.37 g, 2.29 mmol, 83%) in the form of a white powder.

F: 126 C

  1H NMR (400MHz, CDCl3) δ 7.89 (1H, d, J = 7.2Hz, 6-H); 7.69-7.65 (4H, m, Ar); 7.51-7.37 (6H, m, Ar); 6.28 (1H, d, J = 6.8Hz, 1H); 5.50 (1H, d, J = 7.6 Hz, 5-H); 4.41 (1H, m, 3'-H); 4.08-4.03 (2H, m, 5'-H 2); 3.85 (1H, m, 4'-H); 3.47 (1H, m, 2'-H); 2.65 (2H, m, S-CH 2); 1.16 (9H, s, tBu); 0.86 (2H, m, CH 2 -Si); 0.08 (9H, s, Si (CH3) 3). 13C NMR (100 MHz, CDCl3) δ 165.6 (C4); 155.9 (C2); 140.7 (C6); 135.6 (2C, Ar); 135.3 (2C, Ar); 132.7 (1C, Ar); 132.1 (1C, Ar); 130.1 (1C, Ar); 130.01 (1C, Ar); 127.9 (2C, Ar); 127.91 (2C, Ar); 95.1 (C5); 88.2 (Cl '); 85.2 (C4 '); 70.3 (C3 '); 63.8 (5'-CH 2); 56.0 (C2 '); 28.2 (S-CH 2); 26.9 ((CH3) 3); 18.4 (C (CH 3) 3); 17.8 (CH2-Si); -1.8 (Si (CH3) 3).

  MS (FAB +, NAB + NaCl) m / z 598 [M + H] +, 620 [M + Na] +, 112 [cyl: osine + H] +.

  Microanalysis for C30H43N3O4SSi: C, 60.26; H, 7.25, N, 7.03; S, 5.36. Found C 60.03; H, 7.38; N, 6.82; S, 5.32.

  N-4-benzoyl-3 '- (O-mesyl) -5' - (O-tert-butyldiphenylsilyl) -2 '- (2-trimethylsilyl) ethyl) thiocytidine 49 o TBDPSO ,, OMs S \ _ \ Si- To a solution of 48 (1.3 g, 2.2 mmol) in anhydrous DMF (15 mL) was added benzoic anhydride (497 mg, 2.2 mmol). The mixture is refluxed for 24 hours and then 0.2 equivalents of anhydride are added again. After one night, the solvent is evaporated and the residue is dissolved in dichloromethane to be extracted twice with water. Mesyl chloride (194 L, 2.5 mmol) is added to the crude residue in pyridine (15 mL) at 0 ° C under argon. The mixture is stirred for 15 h and then neutralized by adding water (15 mL) at 0 C. After 30 minutes the solvents are evaporated and the residue is coevaporated with toluene. It is then dissolved in dichloromethane to be washed with water (50 mL) and dried over magnesium sulfate before being evaporated to dryness. The resulting foam is chromatographed on silica gel with dichloromethane-methanol (98: 2) to give the white solid 49 (1.57 g, 2.01 mmol, 91% for both steps).

  1H NMR (400MHz, CDCl3) δ 8.71 (1H, 1s, NH); 8.41 (1H, d, J = 7.4 Hz, 6-H); 7.69 -7.28 (15H, m, Ar); 7.68 (5H, m, Ar-H); 7.56-7.43 (10H, m, Ar-H); 7.27 (1H, d, J = 7.6 Hz, 5-H); 6.43 (1H, d, J = 7.6Hz, 1H); 5.34 (1H, m, 3'-H); 4.43 (1H, m, 4H); 4.09- 3.95 (2H, m, J = 1.9Hz, J = 12.0Hz, 5'-H x 2); 3.64 (1H, m, 2'-H); 3.15 (3H, s, CH3, Ms); 2.65 (2H, m, S-CH 2); 1.16 (9H, s, tBu); 0.80 (2H, m, Si-CH 2); 0.04 (9H, s, Si (CH1) 3).

  13 C NMR (100 MHz, CDCl 3) δ 169.5 (CO); 162.3 (C4); 150.1 (C2); 144.1 (C6); [135.6; 135.3, 133.2; 132.2; 131.58; 130.4; 130.3; 129.0; 128.3; 128.2; 127.6] (Ar); 97.9 (C5); 89.2 (Cl '); 84.2 (C4 '); 79.3 (C3 '); 62.9 (5'-CH 2); 52.0 (C2 '); 38.7 (CH 3 Ms); 27.8 (S-CH 2); 27.1 ((CH3) 3); 17.5 (C (CH3) 3); 17.5 (CH2-Si); -1.9 (Si (CH3) 3). MS (FAB +, NAB + NaCl) m / z 780 [M + H] +, 802 [M + Na] +. Microanalysis for C38H49N3O7S2Si2: Calculated C 58.51; H, 6.33; N, 5.39; S, 8.22. Found C 58.26; H, 6.45; N, 5.32; S, 8.45. 2 ', 3'-Dides hydro-2', 3'-dideoxy-5 '- (O-tert-butyldiphenylsilyl) -2' - (2-trimethylsilyl) ethyl) thiocytidine TBDPSiO To a solution of 49 (1, 4 g, 1.79 mmol) in ethanol is added aqueous ammonia (10 ml). The solution is stirred at room temperature for 24 hours. The solvent is then evaporated and the residue is chromatographed on silica gel with dichloromethane-methanol (95: 5) to give a white solid (1.15 g, 1.71 mmol, 95%). Potassium carbonate (1.24 g, 8.82 mmol) is added to the product (1 g, 1.47 mmol) dissolved in acetonitrile (10 mL) and the reaction mixture is maintained at room temperature and under argon 48 h. The inorganic salts are removed by filtration on celite and evaporated solvents. The product is taken up in dichloromethane to be chromatographed on silica gel with a dichloromethane-methanol (95: 5) mixture. The derivative 50 (0.510 g, 1.06 mmol, 72%) is thus obtained in the form of a white foam.

  F: 122-123C 1H NMR (400MHz, CDCl3) δ 7.66 (4, m, Ar); 7.57 (1H, d, J = 7.6Hz, 6-H); 7.42 (6H, m, Ar); 7.12 (1H, m, 1H); 5.74 (1H, m, 3'-H); 5.28 (1H, d, J = 7.6 Hz, 5-H); 4.92 (1H, m, 4'-H); 4.08-4.03 (2H, m, J = 3.2Hz, J = 12.0Hz, 5'-H 2); 2.82 (2H, m, S-CH 2); 1.09 (9H, s, tBu); 0.96 (2H, m, CH 2 -Si); 1.01 (9H, s, Si (CH3) 3). 13C NMR (100 MHz, CDCl3)? 165.5 (C4); 156.2 (C2); 141.9 (C6); 136.5 (Ar); 135.5 (C2 '); 133.4 (Ar); 129.9 (Ar); 127.8 (Ar); 122.9 (C3 '); 127.9 1 (2C Ar); 95.1 (C5); 90.4 (Cl '); 86.5 (C4 '); 65.7 (5'-CHZ); 28.2 (S-CH 2); 26.9 ((CH3) 3); 19.3 (C (CH 3) 3); 16.4 (CH2-Si); -1.8 (Si (CH3) 3).

  MS (FAB +, NAB + NaCl) m / z 580 [M + H] +, 602 [M + Na] +.

  Microanalysis for C30H43N3O4SSi, 0.5 MeOH: Calculated C 61.47; H, 7.27; N, 7.05; 55.38. Found C 61.49; H, 7.36 N, 7.05; S, 5.75. 2,3'-Anhydro-2'-deoxy-5'-O- (4,4'-dimethoxytrityl) uridline 51 DMTrO To a solution of 2'-deoxyuridine (3.3 g, 14.5 mmol) in pyridine Anhydrous (50 ml), kept under argon at 0 ° C., is added 4,4'-dimethoxytrityl chloride (5.39 g, 15.9 mmol). The mixture is stirred for 1 hour at 0 ° C. and then for 24 hours at room temperature. Mesyl chloride (1.35 mL, 17.4 mmol) is added and the mixture is allowed to react for 4 hours. Water (5 mL) is then added and after 30 minutes the solvents are evaporated and coevaporated with toluene. The residue obtained is taken up in dichloromethane (100 mL), washed with water (50 mL) and dried over sodium sulfate before being evaporated to dryness. The yellow foam obtained is dissolved in a minimum of dichloromethane to be chromatographed on silica gel in a dichloromethane-methanol (95: 5) mixture containing 1% triethylamine. The white foam obtained is dissolved in anhydrous acetonitrile (60 mL) and potassium carbonate (6 g, 43.1 mmol) is added. The mixture is left stirring and under argon for 48 hours at room temperature and then for 2 hours under reflux before being filtered. The filtrate is then evaporated to dryness and the residue obtained is taken up in dichloromethane (100 mL) to be washed with water (80 mL) and dried over sodium sulfate. After evaporation, the solid obtained is chromatographed on silica gel in a dichloromethane-methanol (95: 5) mixture containing 1% triethylamine to give the tritylated compound 51 (5.79 g, 11.3 mmol, 78%) under form of a white powder.

  F: 255 C NMR 1 H (400 MHz, CDCl 3) δ 7.42-7.07 (10H, m, Ar-H); 6.84-6.08 (3H, m, Ar-H); 5.90 (1H, d, J = 7.36Hz, 6-H); 5.52 (1H, d, J = 4.01Hz, 5-H); 5.15 (1H, m, 1H); 4.26 (1H, m, 3'-H); 3.79 (6H, s, 2 x O-CH 3); 3.40-3.31 (2H, m, 5'-H x 2); 2.61 (1H, m, 4'-H); 2.38 (2H, m, 2H x 2).

  1H NMR (100 MHz, CDCl3) b 171.0; 158.5; 153.5; 144.4; 139.1, 135.3; 135.3; 129.9; 127.9; 127.8; 126.8; 113.2; 109.5; 87.6; 86.7; 84.5; 61.9; 55.2 (O-CH 3); 32.7 (2'-CH 2).

  MS (FAB +, glycerol) m / z 513 [M + H] +.

  Microanalysis for C30H28N2O6, 0.5 H2O: Calculated C 69.09; H, 5.60; N, 5.37. Found C 68.99; H, 5.57; N, 5.37. 1- (3 '- (2- (trimethylsilyl) ethylthio) -6-d-xylofuranose-1-yl) thymine, 52 OH to a suspension of 2,2'-anhydrothymidine (0.6 g, 2.49 mmol) in the anhydrous DMF (15 mL) is added with sodium hydride (65%, 1.10 g, 29.9 mmol) at 0 ° C. and then, after 3 hours at room temperature under argon and with stirring, the 2- ( trimethylsilyl) ethanethiol (0.75 mL, 3.96 mmol). The solution is stirred and under argon at room temperature for 3 h. The reaction mixture is then placed at 0 ° C. and an aqueous solution of ammonium chloride (10%, 10 ml) is added. The solvents are evaporated under reduced pressure and the residue obtained is taken up in dichloromethane (100 mL) to be washed twice with water (50 mL). The organic phases are combined, dried over magnesium sulphate and then evaporated to dryness. The yellow residue obtained is chromatographed on silica gel in a dichloromethanemethanol (95: 5) mixture. Sulfide 52 is obtained as a white solid (0.734 g, 1.96 mmol, 79%).

  NMR III (400 MHz, CDCl3) δ 10.34 (1H, s, NH); 7.66 (1H, s, 6-H); 5.68 (1H, 1d, J = 4.2Hz, 1H); 5.78 (1H, d, J = 8.0 Hz, 5-H); 4.55 (1H, m, 4'-H); 4.38 (1H, m, 2'-H); 3.91-3.87 (2H, m, 5'-H); 2.67 (2H, m, S-CH 2); 0.85 (2H, m, CH 2 Si); -0.01 (9H, s, Si (CH3) 3).

  13 C NMR (100 MHz, CDCl 3) δ 164.3 (C2); 151.3 (C4); 136.5 (C6); 110.4 (C5); 91.2 (C1 '); 80.6 (C4 '); 80.9 (C2 '); 62.8 (5'-CH 2); 50.5 (C3 '); 28.6 (S-CH 2); 16.2 (CH2-Si); -1.8 (Si (CH3) 3).

  MS (DCI, NH3 / Isobutane) m / z 375 [M + H] +2.2'-Anhydro-5 '- (O-benzoyl) -1- (3' - (2- (trimethylsilyl) ethylthio) -fl -D-xylofuranose-1-yl) thymine To a mixture of 52 (0.135 g, 0.36 mmol), triphenylphosphine (0.144 g, 0.56 mmol) and benzoic acid (0.068 g, 0.56 mmol) ) in anhydrous THF (3 mL) is added diisoethylazodicarboxylate (DEAD) (87 l, 0.56 mmol). The mixture was stirred at room temperature for one and a half hours, then triphenylphosphine (0.144 g, 0.56 mmol) and DEAD (87.1.56 mmol) were added. After three hours, the solvent is evaporated and the residue obtained is chromatographed on silica gel in a dichloromethane-methanol (98: 2) mixture. Sulfide 53 is obtained in the crude form of a white solid (0.100 g).

  1 H NMR (400 MHz, CDCl 3) δ 7.51 (5H, m, Ar); 7.19 (1H, s, 6-H); 6.21 (1H, d, J = 5.6 Hz, 1H); 5.29 (1H, t, J = 5.6Hz, J = 11.6Hz, 2'-H); 4.83 (1H, m, 4'-H); 4.64 (1H, dd, J = 4.4 Hz, J = 12.4 Hz, 5'-H); 4.01 (1H, dd, J = 3.2 Hz, J 12.4 Hz, 5'-H); 3.73 (1H, m, 3'-H); 2.75 (2H, m, S-CH 2); 0.92 (2H, m, CH 2 Si); 0.03 (9H, s, Si (CH3) 3).

  13 C NMR (100 MHz, CDCl 3) δ 172.2 (CO); 165.7 (C2); 159.4 (C4); 136.8 (C6); 132.1 (Ar); 130.4 (Ar); 129.6 (2 C Ar); 128.5 (2 C Ar) 119.1 (C5); 90.0 (Cl '); 83.7 (C4 '); 80.2 (C2 '); 64.2 (5'-CH 2); 48.3 (C3 '); 29.0 (S-CH 2); 17.6 (CH2-Si); 13.9 (CH3); -1.9 (Si (CH 3) 3) 2 ', 3'-Dideshydro-2', 3'-dideoxy-3 '- (2-trimethylsilyl) ethyl) thiothymidine 54 To a solution of compound 53 (0 1 g, 0.22 mmol) in anhydrous acetonitrile is added potassium carbonate (0.2 g, 1.44 mmol). The reaction is stirred and under argon for 15 hours. Then, the inorganic salts are removed by filtration on celite and the evaporated solvent. The product is taken up in methanol and then a solution of aqueous ammonia (2 mL) is added. The mixture is allowed to react for 4 hours and then the solvents are evaporated. The residue is chromatographed on silica gel in a mixture of dichloromethanemethanol (98: 2) and then (95: 5). The unsaturated compound 54 is obtained as a white solid (0.02 g, 0.056 mmol, 16%).

  1 H NMR (400 MHz, CDCl 3) δ 8.60 (1H, s, NH); 7.64 (1H, s, 6-H); 7.07 (1H, m, 1H); 5.3 (1H, s, 2'-H); 4.79 (1H, s, 4'-H); 3.98-3.78 (2H, m, 5'-H 2); 2.94 (2H, m, S-CH 2); 1.88 (3H, s, 5-CH3); 1.02 (2H, m, CH 2 -Si); 0.07 (9H, s, Si (CH3) 3.

  NMR'3C (100 MHz, CDCl3) b 163.9 (C2); 150.6 (C4); 144.4 (C2 '); 136.8 (C6); 114.1 (C3 '); 110.6 (C5); 89.5 (Cl, 87.7 (C4 '), 62.4 (5'-CH2), 28.8 (S-CH2), 15.9 (CH2-Si), 12.3 (CH3); -1.9 (Si (CH3) 3) •

  MS (DCI, NH 3 -isobutane) m / z 357 [M + H] +, 373 [M + NH 3] + 2 ', 3'-Didesoxy-3' - (2- (trimethylsilyl) ethyl) thiocytidine 55 H 0 A solution 35 (0.3 g, 0.87 mmol) in anhydrous pyridine (3 mL) at 0 ° C. is added dropwise acetic anhydride (1.23 mL). The solution is stirred at room temperature and under argon for 24 h. At 0 ° C, absolute ethanol (lmL) is then added. After 30 min the solvents are evaporated, the residue obtained is taken up in dichloromethane (10 mL) and the resulting solution is washed with water (10 mL). The aqueous phase is extracted with dichloromethane (15 mL), the organic phases are then combined, dried over sodium sulfate, evaporated to dryness and coevaporated with toluene (10 mL) to give the acetyl compound in the form of a solid yellow. Under argon, 1,2,4-triazole (0.902 g, 13.06 mmol) was added to a solution of POCl3 (292 L, 2.87 mmol) in anhydrous acetonitrile (5 mL). The solution is left stirring for 15 min at 0 ° C. and then triethylamine (5 mL, 35.76 mmol) is added dropwise. The mixture obtained is allowed to return to ambient temperature and remains stirred overnight, and then a solution of the acetylated nucleoside obtained previously dissolved in acetonitrile (5 mL) is added. The mixture is stirred at room temperature for 48 h, then water (1 mL) is added and the solvents are evaporated. The yellow oil obtained is dissolved in dichloromethane (10 mL), neutralized with sodium bicarbonate solution (10%, 2 mL) and then washed with water (20 mL). The organic phase is then dried over magnesium sulfate, evaporated and coevaporated with toluene (10 mL).

  The residue is dissolved in a solution of ammonia in dioxane (50 mL, 0.5 M). The solution is stirred and under argon for 48 hours before being evaporated to dryness.

  The resulting yellow solid is dissolved in ethanol (10 mL) and concentrated ammonia solution (30%, 10 mL) is added. After stirring for 12 h, the solvents are evaporated and coevaporated with ethanol. The residue obtained is chromatographed on silica gel with a dichloromethane-methanol mixture (90:10). The derivative of cytidine 55 (0.25 g, 0.695 mmol, 80%) is thus obtained in the form of a white powder.

  1 H NMR (400 MHz, MeOD) S; 7.45 (1H, d, J = 7.5 Hz, 6-H); 6.10 (1H, dd, J = 10.0Hz, J = 4.8Hz, 1H); 5.99 (1H, d, J = 7.5Hz, 5-H); 3.95 (1H, m, 5'-H); 3.81 (1H, m, 4'-H); 3.80 (1H, m, 5'-H); 3.38 (1H, m, 3'-H); 2.70-2.50 (2H, m, 2'-H x 2); 2.71-2.42 (2H, m, S-CH 2); 0.89 (2H, m, CH 2 -Si); 0.05 (9H, s, Si (CH3) 3) •

  13 C NMR (100 MHz, MeOD) 166.2 (C4); 156.7 (C2); 141.3 (C6); 94.0 (C5); 86.5 (Cl '); 85.8 (C4 '); 60.3 (5'-CH 2); 40.7 (2'-CH 2); 39, 9 (C4 '); 20.6 (S-CH 2); 16.9 (CH2-Si); -3.2 (Si (CH3) 3).

  MS (FAB +, glycerol): m / z = 291 [M + H] +.

  Microanalysis for C 14 H 25 N 2 O 3 S 2, 0.6 H 2 O: Calc C 47.46; H, 7.45, N, 11.86; S 9.05. Found C, 47.65; H, 7.45; N, 11.64; S 9.28.

  The experimental part below describes the influence of fluoride ions on obtaining a disulfide according to the invention.

  To a solution of nucleoside 18 (20 mg, 0.06 mmol) in anhydrous dichloroethane, maintained under argon, the catalyst (0.2 equivalents) or 2-nitrobenzene sulfenyl chloride (32 mg, 0, 17 mmol). The mixture is stirred and refluxed only overnight to ensure that the reaction is not complete. Experiment 1: without catalyst (control) Experiment 2: in the presence of ammonium fluoride in solution in methanol (22 L, 0.5 M, 0.012 mmol) Experiment 3: in the presence of ammonium fluoride in solution in methanol (22 L, 0.5 M, 0.012 mmol) but without addition of 2-nitrobenzene sulfenyl chloride Experiment 4: in the presence of ammonium bromide (1 mg, 0.012 mmol). The solvent is evaporated and the residue obtained is chromatographed on silica gel in a dichloromethane-methanol mixture (98: 2) and then (95: 5) before determining the progress of the reaction by integration of the 3'H proton signal ( in CDCl3) in proton NMR.

  For the mixture, ratio of amount of disulfide formed / starting material: Experiment 1: 56/44 Experiment 2: 67/33 Experiment 3: 0/100 Experiment 4: 47/53 The silylated starting reagent undergoes no decomposition: the silylated sulphide unit remains stable in the presence of fluoride ions. On the other hand, the reaction is accelerated in the presence of fluoride ions whereas it is slowed down in the presence of presence of bromide ions.

Claims (12)

  A process for obtaining a compound having the formula (I) R 1 -S (O), -S (O) y-R 2 in which R 1 represents a hydrocarbon molecular residue which can be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P, S, Si, X where X represents a halogen; R 2 represents, independently of R 1, a carbon group or a hydrocarbon molecular residue which may be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O , Where X represents a halogen, and x and y are chosen from 0 and 1 such that the sum of x and y is at most equal to 1, characterized in that a compound of formula (II) R1-S (O) X R3-Si (R4) (R5) (R6) wherein R3 represents a hydrocarbon chain of two carbon atoms, optionally unsaturated and / or substituted, and R4, R5 and R6 , which may be identical or different, each represent, independently of one another, a hydrocarbon group, with a compound of formula (VII) R2-S (O) yX in which X represents a halogen.   2. Process according to claim 1, for obtaining a disulphide of formula (III), R1-SS-R2, characterized in that a compound of formula (IIa) R1-S-R3-Si is reacted. (R4) (R5) (R6) with a compound of formula (VIIa) R2-SX.   3. Process according to claim 2, for obtaining a compound corresponding to formula (III), RI-SS-R2, characterized in that the compound of formula (VIIa) R2-SX is obtained in situ by reaction. a compound of formula (VIII) R2-SS-R2, in the presence of X2 or XCN, where X represents a halogen, in the reaction medium containing the compound (IIa). 35   4. Process according to claim 1, for obtaining a thiosulfinate of formula (IV), R1-S-SO-R2, characterized in that a compound of formula (IIa) R1-S-R3- is reacted. Si (R4) (R5) (R6) with a sulfinyl halide (VIIb) R2SOX.   5. Process according to claim 1, for obtaining a thiosulfinate of formula (V), R1-SO-S-R2, characterized in that an oxidation of the compound of formula (IIa) R1-S-R3 is carried out. -Si (R4) (R5) (R6) to obtain a compound of formula (IIb) R1-SO-R3-Si (R4) (R5) (R6), then reacting the compound of formula (IIb) with a sulfenyl halide of formula (VIIa) R2-SX.   6. Process according to any one of claims 2 to 5, characterized in that a compound (IIa) or (IIb) is reacted respectively with a compound (VIIa) or a compound (IIa) is reacted with a compound (VIIb), in the presence of fluoride ions.   7. Process according to claim 6, characterized in that the fluoride ions are provided by an ammonium fluoride, a tetrabutylammonium fluoride, a triethylammonium fluoride or their mixtures.   8. Process according to claim 6 or 7, characterized in that the fluoride ions are in catalytic quantity.   9. A process for obtaining a compound having the formula (III '), R1-SS-R2' wherein R1 represents a hydrocarbon molecular residue which may be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P, S, Si, X where X represents a halogen; R 2 represents, independently of R 1, a carbon group or a hydrocarbon molecular residue which may be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O , P, S, Si, X wherein X is halogen, characterized in that a compound (III) according to claim 2, and optionally any one of claims 6, 7 and 8, is obtained and the reaction is carried out. compound (III) with a compound of formula R2'-SH.20   10. Process for obtaining a compound corresponding to formula (VI) R1-SS-R1, in which R1 represents a hydrocarbon molecular residue which can be substituted and / or interrupted by one or more atoms and / or by one or groups comprising one or more atoms, said atoms being chosen from N, O, S, P, S, Si and X, where X represents a halogen, characterized in that a compound of formula (IIa) R1- Wherein R 3 represents a hydrocarbon chain of two carbon atoms, optionally unsaturated and each other, a hydrocarbon group, with a dihalogen X 2 or a cyanogen halide XCN to obtain in situ a compound of formula (VIIa) R 1 -SX, X representing a halogen, before obtaining the compound of formula (VI) R1-SS-R1.   11. Process according to claim 10, characterized in that the compound (IIa) is reacted in the presence of fluoride ions.   12. Process according to claim 11, characterized in that the fluoride ions are provided by an ammonium fluoride, a tetrabutylammonium fluoride, a triethylammonium fluoride or their mixtures. 3. Process according to claim 11 or 12, characterized in that the fluoride ions are in catalytic amount. 14. Process according to any one of the preceding claims, characterized in that R1 represents a molecular residue chosen from nucleosides and modified nucleosides. 15. Process according to claim 14, characterized in that R1 represents a molecular residue chosen from 2 ', 3'-dideoxy-2', 3'-dehydroribonucleosides. 16. Process according to claim 14 or 15, characterized in that the S atom is bonded to the 2 'carbon or the 3' carbon of the ribose. 2017. Process according to any one of the preceding claims, characterized in that R2 is chosen from the ortho-nitrophenyl, para-nitrophenyl and trichloromethyl groups. 18. Process according to any one of the preceding claims, characterized in that R4, R5 and R6 are identical and represent the methyl group. 19. Process for obtaining a thiol, chosen from thiols corresponding to the following formulas: R 1 -SH, R 2 -SH and R 2'-SH, formulas in which R 1 represents a hydrocarbon molecular residue that can be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P, S, Si, X where X represents a halogen; R2 or R2 'represents a carbon group or a hydrocarbon molecular residue which can be substituted and / or interrupted by one or more atoms and / or by one or more groups comprising one or more atoms, said atoms being chosen from N, O, P , S, Si, X where X represents a halogen, said process being characterized in that a disulfide of formula (III) according to any one of claims 2, 3, 6 to 8, 14-18 is prepared to obtain the thiol Rl-SH, or a disulfide of formula (VI) according to any one of claims 10 to 18, for obtaining the thiol R2-SH, or a disulfide of formula (III ') according to claim 9, 14-18, to obtain the thiol R2'-SH, and the disulfide thus obtained is reduced. 20. Compounds of formula (IIa) R1-S-CH2-CH2-Si (R4) (R5) (R6) as intermediate compounds in the preparation of disulfides and thiosulfinates, selected from: 2 ', 3'- 5'-Bromo-2 ', 3'-di-deoxy-3' - (2- (trimethylsilyl) ethyl) thiouridine, desoxy-3 '- (2- (trimethylsilyl) ethyl) thiouridine. 2 '- (2- (trimethylsilyl) ethyl) thiothymidine 46 2'-Deoxy-3' - (O-mesyl) -2 '- (2- (trimethylsilyl) ethyl) thiouridine 47 5'-O- (tert N-4-Benzoyl-3 '- (O-mesyl) -5' - (O-tert-butyldiphenylsilyl) -2 '- (2-trimethylsilyl) -butyl-diphenylsilyl) -2' - (2-trimethylsilyl) ethyl) thiocytidine ethyl) thiocytidine 49 1- (3 '- (2- (trimethylsilyl) ethylthio) - (3-D-xylofuranose-1-yl) thymine 5252,2'-Anhydro-5' - (O-benzoyl) -1 - (3 '- (2- (trimethylsilyl) ethylthio) (3-D-xylofuranose-1-yl) thymine 53 2', 3'-Didesoxy-3 '- (2- (trimethylsilyl) ethyl) thiocytidine 55 21. Compounds of formula (IIa) R1-S-CH2-CH2-Si (R4) (R5) (R6) as intermediate compounds in the preparation of disulfide and in which R1 is selected from 2 ', 3'-didehydro-2', 3'-dideoxynucleoside groups and R4, R5 and R6, which may be identical or different, each represent, independently of one another, a hydrocarbon group. 22. Compounds according to claim 21, characterized in that they are chosen from: 2 ', 3'-Didéshydro-2', 3'-dideoxy-2 '- (2- (trimethylsilyl) ethyl) thiothymidine 14 2', 2 ', 3'-Didehydro-2', 3'-dideoxy-2 '- (2-trimethylsilyl) 2', 3'-didehydro-2 ', 3'-dideoxy-3' - (2-trimethylsilyl) ethyl) thiothymidine ethyl) thiouridine 18 2 ', 3'-Dideshydro-2', 3'-dideoxy-5 '- (O-tert-butyldiphenylsilyl) -2' - (2-trimethylsilyl) ethyl) thiocytidine 50 2 ', 3' - Didehydro-2 ', 3'-dideoxy-2' - (2-trimethylsilyl) ethyl) thiocytidine 19 23. Compounds of formula (IIb) R1-SO-R3-Si (R4) (R5) (R6) as a compound intermediate in the preparation of thiosulfinates of formula (V), selected from: 3'-deoxy-3 '- (2- (trimethylsilyl) ethyl) thiothymidine sulfoxide 2'-deoxy-2' - (2-) sulfoxide 24. Compounds of formula (III) R 1 -SR-R2 wherein R 1 is 2 ', 3'-dideoxy-2', 3'-didehydronucleoside. 25. Compounds of formula (III) RI-S-SR-2 chosen from: I) 3'-deoxythymidin-3'-yl isulfide and trichloromethyl 2'-deoxythymidin-3'-yl disulfide and 4- nitrophenyl 3 3'-deoxythymidin-3'-yl and 2-nitrophenyl disulfide 4 2'-deoxyuridin-2'-yl and trichloromethyl disulfide 7 2'-deoxycytidin-2'-yl and trichloromethyl disulfide 8 Disulfide of 2'-deoxyuridin-2'-yl and 4-nitrophenyl 2'-deoxycytidin-2'-yl disulfide and 4-nitrophenyl 2'-deoxyuridin-2'-yl disulfide and 2-nitrophenyl 11Sulfide of 2 2'-deoxycytidin-2'-yl and 2-nitrophenyl 3'-deoxythymidin-3'-yl and propyl disulfide 13 2 ', 3'-dihydro-2', 3'-dideoxythymidin-2'-disulfide Yl and trichloromethyl 2 ', 3'-didehydro-2', 3'-dideoxythymidin-2'-yl and 4-nitrophenyl disulfide 16 ', 3'-Didehydro-2', 3'-dideoxythymidine disulfide -2'-yl and 2-nitrophenyl 2 ', 3'-didehydro-2', 3'-dideoxyuridi disulfide n-2'-yl and trichloromethyl 2 ', 3'-didehydro-2', 3'-dideoxyuridin-2'-yl and 4-nitrophenyl 2 ', 3'-didehydro-2' disulfide , 3'-dideoxyuridin-2'-yl and 2-nitrophenyl 2 ', 3'-dideoxyuridin-3'-yl disulfide and methyl 2', 3'-dideoxycytidin-3'-yl disulfide and Methyl 57 5-bromo-2 ', 3'-dideoxyuridin-3'-yl and methyl disulfide 58 26. Compounds of formula (IV) R1-S-SO-R2, selected from thiosulfinates 25 and 27. 27. Compounds of formula (V) R1-SO-S-R2, selected from thiosulfinates 29, 30, 33a. 28. Compounds of formula (III '), R1-SS-R2' chosen from: 3'-deoxythymidin-3'-yl and allyl disulfide 37] 3'-deoxythymidin-3'-yl disulfide and 2 1-hydroxyethyl 38] 3'-deoxythymidin-3'-yl disulfide and 2-aminoethyl chlorohydrate 39] 3'-deoxythymidin-3'-yl and butyl disulfide 40] 3'-deoxythymidin-3'-disulfide Yl and hexyl 41] 3'-deoxythymidin-3'-yl and octyl disulfide 42 3'-deoxythymidin-3'-yl and 6-hydroxyhexyl disulfide 29. Compounds of formula (VI), R1-SS-R1 selected from the following disulfides: bis- (3'-dideoxythymidin-3-yl) disulfide Bis (2-bromo-2 ', 3'-dideoxyuridine-3'-yl) disulfide 36 bis (2 ', 3'-didehydro-2', 3'-dideoxyuridin-2'-yl)