FI102279B - Intermediates for diastereoselective synthesis methods of nucleosides - Google Patents

Description

102279

INTERMEDIATES FOR DIASTEREOSELECTIVE SYNTHESIS METHODS OF NUCLEOSIDES

This invention relates to novel intermediates useful in diastereoselective methods for the preparation of optically active cis nucleosides and nucleoside analogs and derivatives. These methods allow the desired enantiomer of a cis nucleoside or nucleoside analog or derivative to be synthesized in optically high purity.

Nucleosides and their analogs and derivatives form an important class of therapeutic agents. For example, a number of nucleosides have been shown to have antiviral activity against retroviruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and human T lymphotropic virus (HTLV) (PCT publication WO 89/04662 and EP publication 0349242 A2). Nucleosides with antiviral activity include 3'-azido-3'-deoxythymidine (AZT) and 2'3'-dideoxycytidine (DDC), 2-hydroxymethyl-5- (cytosin-1'-yl) -1,3- oxathiolane and 2-hydroxymethyl-4- (guanin-9'-yl) -1,3-dioxolane (EP 0382526 A2 and EP 0377713 A2).

Most nucleosides and nucleoside analogs and derivatives contain at least two chiral centers (indicated by * in formula (A)) and exist in the form of two pairs of optical isomers (i.e., two in the cis configuration and two in the trans configuration). In general, however, only the cis isomers have useful biological activity.

«A • · ·« ·: O purine or pyrimidine base: T: "y t« «♦« ♦ • a 2 102279

However, different enantiomeric forms of the same cis nucleoside may have very different antiviral activities. M. M. Mansur i et al., "Preparation of the Geometric Isomers of DDC, DDA, D4C and D4T as Potential Anti-HIV Agents", Bioorg.Med.Chem.

Lett., 1 (1), ss. 65-68 (1991). Therefore, an important goal is the general and economically attractive stereoselective synthesis of biologically active cis-nucleoside enantiomers.

Many of the known methods for preparing optically active nucleosides and their analogs and derivatives modify naturally occurring (i.e., optically active) nucleosides by base exchange or sugar exchange by reduction methods such as deoxygenation or radical-initiated reductions. C. K. Chu et al., "General Synthesis of 2 ', 3'-Dideoxynucleosides and 2', 3'-Didehydro-2 ', 3'-Dideoxynucleosides," J. Org. Chem., 54, p. 2217-2225 (1989). These transformations have many steps, such as protection and deprotection, and usually yield low yields. In addition, they initiate and maintain the optical activity of the parent nucleoside. Thus, nucleosides prepared by these methods are limited to certain analogs of the enantiomeric form of the naturally occurring nucleoside. In addition, these methods require the availability of a naturally occurring nucleoside, which is often an expensive starting material.

Other known methods for preparing optically active nucleosides are based on conventional glycosylations to add sugar to the base. These methods alternatively give anomeric mixtures of cis and trans isomers which require: ...: long-term separation and give low yields of the desired biologically active cis nucleoside. Improved glycosylation methods designed to obtain only the cis nucleoside require the addition of a 2 'or 3' substituent. sugar. Since the 2 'or 3' substituent is only useful in controlling cis nucleoside synthesis in one configuration (when the 2 'or 3' substituent is in the trans position to the 4 'substituent many steps are required to attach this substituent to the appropriate position. The 2 'or 3' substituent must then be removed after glycosylation, which requires further steps. L. Wilson and D. Liotta, "A General Method for Controlling · ;·· Stereochemistry in the Synthesis of 2'-Deoxyribose Nucleosides," Tetrahedron Lett. 31, p. 1815-1818 (1990). In addition, to obtain an optically 3 102279 pure nucleoside product, the starting sugar must be optically pure * This also requires a series of time consuming syntheses and purification steps.

The difficulties and shortcomings of the prior art are overcome and methods for the preparation of optically active cis-nucleosides (1,2-oxathiolanes, 2,4-dioxolanes and 1,3-dithiolanes) or nucleoside analogues and derivatives of formula (I) are provided. according to F ^ OCH, Rj

X J

wherein W is S, S = O, SO 2, or O; X is S, S = O, SO 2, or O R 2 is hydrogen or acyl; and R 2 is a purine or pyrimidine base or an analog or derivative thereof;

The methods comprise the step of glycosylating the desired purine or pyrimidine base or an analogue or derivative thereof with an intermediate of formula (IIa) or (Hb) «· * = ::: = (IIa)« ...... Ύ'L, IIb) • · · X y

··· A

• · · • · · • · ·. wherein R 3 is a substituted carbonyl or carbonyl derivative and • * · 1 is a leaving group. Glycosylation is performed using a Lewis acid of formula V * (HI) R6 · :··: Rs - $ i - R * (Hi). * ··; R 7 wherein R 5, R 6, R 7 and R 6 are as defined below, and the resulting intermediate ____: is reduced to give a nucleoside or nucleoside analogue or derivative of formula (I).

4 102279

The methods have the advantages of allowing the preparation of a nucleoside of formula (I) (or its analogues or derivatives) without the use of expensive starting materials, cumbersome protection and deprotection steps or the addition and removal of 2 'or 3' substituents. By the methods, the nucleosides are obtained in high yields, very pure and optically very specific. The methods further have the advantage of generating nucleosides whose stereoisomeric configuration can be easily controlled simply by selecting the appropriate starting materials.

Intermediates are compounds of formula (II) wherein W is S, S = O, SO 2 or O; X is S, S = O, SO 2 or O; R 3 is a substituted carbonyl or carbonyl derivative; and L is a leaving group and compounds of formula (VI) R 3 -T (VI) wherein W is S, S = O, SO 2 or O; X is S, S = O, SO 2 or O; R 3 is a substituted carbonyl or carbonyl derivative; R4 is a chiral auxiliary group; and L is a leaving group.

• · • · • · ·

The following definitions are used in methods for preparing optically active compounds in a configuration and diastereoselective manner: V't R2 is a purine or pyrimidine base or an analog or derivative thereof.

* A purine or pyrimidine base is a purine or pyrimidine base in naturally occurring nucleosides. Their analogue is • * · *. a base that mimics such naturally occurring bases in such a way that their structures (atomic species and their order) are the same as in the naturally occurring base, but they may either have more or lack certain functional properties of naturally occurring bases. These analogs are those obtained by replacing the CH moiety with a nitrogen atom, e.g. 5-azapyrimidines such as 5-azacytosine) or vice versa (e.g. 7-deazapurines such as 7-deazaadenine or 7-deazaguanine). or both (e.g. 7-deaza, 8-azapurines). Derivatives of these bases or analogs refer to those bases in which ring substituents have been either added, removed or modified with conventional substituents known in the art, e.g. halogen, hydroxyl, amino, C 1-6 alkyl. Such purine or pyrimidine bases, analogs and derivatives are well known to those skilled in the art.

A "nucleoside analog or derivative" is 1,3-oxathiolane, 2,4-dioxolane, or 1,3-dithiolane modified in any of the following ways or a combination of the following: base modifications, such as addition of a substituent (e.g., 5-fluorocytosine); ) or by replacing one group with an isosteric group (e.g. 7-deazaadenine); sugar modifications such as substitution of C-2 and C-3 hydroxyl groups with any substituent, including hydrogen (e.g., 2 ', 3'-dideoxy nucleosides); altering the attachment site on the sugar base (e.g., pyrimidine bases normally attached to N-1 may be attached to N-3 or N-6, for example, and purines normally attached to N-9 may be attached to N-7, for example); changing the attachment site of the base in the sugar (e.g., the base may be attached to the sugar at C-2, such as iso-DDA)? or by changing the configuration of the sugar-base bond (e.g., cis or trans configurations).

R3 is carbonyl substituted by hydrogen, hydroxy, trialkyl. silyl, trialkylsiloxy, C 1-10 alkyl, C 7.30 aralkyl • · ·

III, C 1-30 alkoxy, C 1-10 amine (primary, secondary or tertiary), C 1-30 thiol; C6_20 aryl; Cx.20 alkenyl;

! ‘C 1-20’ alkynyl; 1,2-dicarbonyl, such as O O

«'/ J. CH3-1-1 substituted with Cx6 alkyl or Cx6 aryl; anhydride, such as

f S

CH 3 -C-O-C- substituted with C 1-6 alkyl or C 6-20 aryl; azomethine substituted on nitrogen by hydrogen, C 1-20 alkyl or C 1-10 alkoxy or C 1-10 dialkylamino, or * 102279 on carbon is substituted by hydrogen, C 1-10 alkyl or C 7-20 alkoxy; thiocarbonyl (C = S) substituted by hydroxyl,

C 1-20 alkoxy or C 1-10 thiol; carbonyl homologue, e.g., O

f. .... -CCH2-; thiocarbonyl homologue, e.g. -CCH2-; or an azomethane homologue such as -Ich2-.

Preferred substituted carbonyl / carbonyl derivatives include alkoxycarbonyls such as methyl, ethyl, isopropyl, t-butyl, and menthyl; carboxyl; diethylcarboxamide; pyr rolidiiniamidi; methyl ketone and phenyl ketone. More preferred carbonyl / carbonyl derivatives are esters and carboxyls, and most preferred are esters.

R4 is a chiral auxiliary group. The term "chiral auxiliary group" describes asymmetric molecules used to provide chemical resolution of a racemic mixture. Such chiral auxiliaries may have a single chiral center, such as in methylbenzylamine, or multiple chiral centers, such as in menthol. The purpose of the chiral auxiliary group, when attached to the starting material, is to allow simple separation of the resulting diastereomeric mixture. See, e.g., J. Jacques et al., Enantiomers. Racemates and Resolutions, ss. 251-369, John Wiley &

Sons, New York (1981).

R 1, R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl (e.g. methyl, ethyl, t-butyl), optionally substituted with halogens (F, Cl, Br, I), C 6-20 * *** alkoxy (e.g. methoxy) or C6-20 aryloxy (e.g. phenoxy); C 7-20 aralkyl (e.g. benzyl), optionally substituted · · · * * Halogen, C 1-4 alkyl or C 1-4 alkoxy (e.g. p-methoxybenzyl); C 6-20 aryl (e.g. phenyl), optionally substituted with halogens, C 1-4 alkyl or C 1-6 alkoxy-J 1a; trialkylsilyl; halogens (F, Cl, Br, I).

R 8 is selected from the group consisting of halogen (F, Cl, Br, I); • C 1-20 sulfonate esters, optionally substituted with halogens (e.g. trifluoromethanesulfonate); C 1-6 alkyl esters, optionally substituted with halogens (e.g. trifluoroacetate); polyvalent halides (e.g. triiodide); trisubstituted silyl groups of the general formula (R 5) (R E) (R 7) Si (wherein R 5, R c and R 7 are as defined above); saturated or unsaturated selenyl-C6-20 aryl; substituted or unsubstituted C 6-20 arylsulfenyl; substituted or unsubstituted C 1-10 alkoxyalkyl; and trialkylsiloxy.

L is an "leaving group", i. an atom or group which can be replaced during the reaction by a suitable purine or pyrimidine base, in the presence or absence of a Lewis acid. Suitable leaving groups include acyloxy groups, alkoxy groups, e.g. alkoxycarbonyl groups such as ethoxycarbonyl; halogens such as iodine, bromine, chlorine or fluorine; amido; azido; diisocyanate; substituted or unsubstituted, saturated or unsaturated thiolates, such as thiomethyl or thiophenyl; substituted or unsubstituted, saturated or unsaturated seleno-, seleninyl or selenonyl compounds, such as phenylselenide or alkylselenide.

A suitable leaving group may also be -OR, wherein R is a substituted or unsubstituted, saturated or unsaturated alkyl group, e.g. a C 1-8 alkyl or alkenyl group; a substituted or unsubstituted aliphatic or aromatic acyl group, e.g. a C 1-4 aliphatic acyl group such as acetyl, and a substituted or unsubstituted aromatic acyl group such as benzoyl; a substituted or unsubstituted, saturated or unsaturated alkoxy or aryloxycarbonyl group such as methyl carbonate and phenyl carbonate; substituted or unsubstituted sulfonylimidazole; a substituted or unsubstituted aliphatic i :: or aromatic aminocarbonyl group such as phenyl carbamate; a substituted or unsubstituted alkyl imidate group such as trichloroacetamidate; substituted or unsubstituted,. a saturated or unsaturated phosphonate such as diethyl phosphonate * * * ·, ···, ti; a substituted or unsubstituted aliphatic or aromatic sulfinyl or sulfonyl group such as tosylate; or hydrogen.

«*

As used herein, the term "alkyl" means a substituted (halogen, hydroxyl or C 6-20 aryl) or unsubstituted straight, branched or cyclic hydrocarbon moiety having from 1 to 30 carbon atoms, and preferably from 1 to 6 carbon atoms. .

β 102279

The terms "alkenyl" and "alkynyl" denote a substituted (halogen, hydroxyl or C 6-20 aryl) or unsubstituted straight-chain, branched or cyclic hydrocarbon chain having 1 to 20 carbon atoms and preferably 1 to 5 carbon atoms and containing at least one unsaturated group ( e.g. allyl).

The term "alkoxy" denotes a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, and preferably 1 to 6 carbon atoms, wherein the alkyl group is covalently attached to an adjacent element via oxygen (e.g., methoxy and ethoxy).

The term "amine" denotes alkyl, aryl, alkenyl, alkynyl or aralkyl groups containing from 1 to 30 carbon atoms and preferably from 1 to 12 carbon atoms, covalently attached to an adjacent element via a nitrogen atom (e.g. pyrrolidine). They are primary, secondary and tertiary amines as well as quaternary ammonium salts.

The term "thiol" denotes alkyl, aryl, aralkyl, alkenyl or alkynyl groups containing from 1 to 30 carbon atoms and preferably from 1 to 6 carbon atoms, covalently bonded to an adjacent element via a sulfur atom (e.g. thiomethyl).

The term "aryl" denotes a carboxyl moiety which may be substituted by at least one heteroatom (e.g. N, O or S) and contains at least one benzenoid type ring and preferably 1 contains 6-15 carbon atoms (e.g. phenyl and naphthyl) .

• · · m ** t:: *

The term "aralkyl" means an aryl group attached to an adjacent atom through an alkyl (e.g., benzyl).

• · «# · ·« t »» i * *. The term "alkoxyalkyl" means an alkoxy group attached to an adjacent group through an alkyl group (e.g., methoxymethyl) '

The term "aryloxy" means a substituted (halogen, trifluoromethyl or C 1-4 alkoxy) or unsubstituted aryl moiety covalently bonded via an oxygen atom (e.g., phenoxy).

The term "acyl" refers to a radical derived from a carboxylic acid-Posta, substituted (with halogen (F, Cl, Br, I), C 6-20 aryl, or C 1-4 alkyl) or unsubstituted, by replacing the group -OH. Like the acid from which it is derived, the acyl radical may be aliphatic or aromatic, substituted (by halogen, C 1-4 alkoxyalkyl, nitro or O 2) or unsubstituted, and whatever the structure of the rest of the molecule, the properties of the functional group remain essentially the same (e.g. acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl, trifluoroacetyl, chloroacetyl and cyclohexanoyl).

A key feature of the methods is the use of a substituted carbonyl or carbonyl derivative as R 3 instead of a protected hydroxymethyl group, as previously described in the art. Surprisingly, the substituted carbonyl or carbonyl derivative does not cleave upon contact with a Lewis acid, as one skilled in the art would expect, when a Lewis acid of formula (III) is added to a mixture of a silylated purine or pyrimidine base and a chiral auxiliary sugar compound in Step 3. the substituted carbonyl / carbonyl derivative in the intermediate of formula (VI) forces the purine or pyrimidine base (R2) to include the cis-configuration relative to the substituted carbonyl / carbonyl derivative group. Without a substituted carbonyl or carbonyl derivative attached to the C4 'position (for example, when 4 hydroxymethyl groups are used instead), the coupling steps described below in Step 4

»M

,. ·. the methods result in a mixture of cis and trans isomers.

I · · 1 i »· ·· 'M:

Another key feature of the methods is the choice of Lewis acid. The Lewis acids used in the preparation of the compounds of formula (I)

* <I

'1' ·· 'has the general formula (III) i · («I» n f6 ·: ··: R5 - 5i - Re (lii) .Ti where R5, R6, R7 and R8 are as described above. These Lewis acids may be formed in the reaction situation or may be prepared using any method known in the art (e.g. AH

10 102279

Schmidt, "Bromotrimethylsilane and Iodotrimethylsilane-Versatile Reagents for Organic Synthesis", Aldrichimica Acta. 14, ss. 31-38 (1981). Preferred Lewis acids are iodotrimethylsilane and trimethylsilyl triflate. Preferred R5, R6 and R7 groups are methyl or iodine. The most preferred R5, Re and R7 group is methyl. Preferred Re groups are iodine, chlorine, bromine or sulfonate esters. The most preferred groups R n are iodine and trifluoromethanesulfonate.

In the preferred method described in Schemes 1 and 2, the cis and trans isomers of the sugar of formula (II) are separated by fractional crystallization and the desired configuration isomer is selected. The selected cis or trans isomer can then be chemically separated using a chiral auxiliary group, or by other methods known in the art. The pure diastereomer is then coupled to a silylated purine or pyrimidine base in the presence of a Lewis acid to give an optically active nucleoside having the cis configuration, which is then reduced to give a nucleoside of formula (I).

• · • · ·

Formulas IA and IB illustrate this preferred method, which

• M

. to any 1,3-oxathiolane, 2,4-dioxolane or • · · 1,3-dithiolane.

• · «• · · • · · · · 1 <» 111 · · • · · t t t U 102279

GRAPH IA

/ Υ ° STEP 1 w ^ OH 0H

- <J · ^ y (V) X 'STEP 2 (Π) / W \ ^ L W (TRANS)

Ri \ (CIS) + J \ L

(+) CHIRAL AUXILIARY GROUP ^. X

^^ STEP 3 ^ \ (-) CHIRAL AUXILIARY GROUP i Ö- "L R4. W.

(VI)

• * ·: I STEP 4 I

= ::: = + I

/ W ^ r “'' R2 r4 <vv.

r / s ..... (j W R, ^ X

‘I

STEP 5 I

*

F ^ OCH, _ T

// λ ^ 2 P (V'u n / ^ γ ·· Η, οα ^ w a Ό xy 12 102279

GRAPH IB

... O W ^ OH w. \ OH

yw -> ^ 0 STEP 1 / Ύ

"- <J -" - <J + "- <J

x (IV) x (V) x / step 2, (U) (TRANS)

W ^ / L W

J (CIS) + R 2 J-L

(+) CHIRAL AUXILIARY GROUP CHIRAL

help groups

STEP 3

σ1- W ^. ,, vL r44 RS / W- ^ L

j (VO j λ> Ε R4 W ^^ l

Rj— ^ V ·· / "4 * x- ^ x- ^

***** I

: ...: | STEP 4 T: w ^ R2 R «. w. ^ R,

, / j ™ "-Q

• · · • · · * * STEP 5 | R, OCHj> * R2 R, OCH2 w a'Rj

Xf m Ό 102279 13

The different steps described in formulas IA and IB can be briefly described as follows:

Step 1: The carbonyl sugar of formula (IV) as starting material can be prepared by any method known in the art, e.g. J.M. McIntosh et al., M2-Mercaptoaldehyde Dimers and 2,5-Dihydrothiophenes from 1,3-oxathiolan-5-onesH, Can. J. Chem. 61, ss. 1872-1875 (1983). The carbonyl group of this starting material is chemoselectively reduced with a suitable reducing agent such as disiamylborane to give the cis and trans isomers of formula (V). Usually less cis-isomer is formed than trans-isomer.

Step 2: The hydroxyl group in intermediate (V) is converted to a readily leaving group by any method known in the art (e.g., TW Greene Protective Groups in Organic Synthesis. Pp. 50-72, John Wiley & Sons, New York (1981)) to give new compounds of formula Intermediates according to (II).

This anomeric mixture is then separated by fractional crystallization into two configuration isomers. The solvent can be adjusted to select either the cis or trans isomer. D.J. Pasto and C.R. Johnson, Organic Structure Determination, ss. 7-10, Prentice-Hall, Inc.

New Jersey (1969).

Step 3: Either the cis- (Scheme IA) or trans-isomer (Scheme IB) of formula (II) is chemically decomposed using a choral auxiliary group (R4). A suitable chiral auxiliary group is one which * · · ... * is optically very pure and in which a mirror image already exists, * ··; * such as d- and 1-menthol. The diastereomers of formula (VI) obtained · 'Rs are easily separated by fractional crystallization. Alternatively, either the cis or trans isomer may be degraded enzymatically or by other methods known in the art. J. Jacques et al., J / - Enantiomers, Racemates and Resolutions. ss. 251-369, John Wiley r * · *? & Sons, New York (1981).

The optical purity of the diastereomer (VI, VII or I) can be determined by chiral HPLC, measurement of specific rotation and NMR. In general, if the opposite enantiomer is desired, it can be obtained by using a mirror image of the chiral auxiliary group 102279 14 originally used. For example, if the chiral auxiliary group d-menthol produces the (+) - enantiomeric nucleoside, its mirror image of 1-menthol produces the (-) - enantiomer.

Step 4: The previously silylated (or silylated in the reaction itself) purine or pyrimidine base or analog or derivative thereof is then glycolysed with the resulting pure diastereomer in the presence of a Lewis acid of formula (III) such as iodotrimethylsilane (TMSI) or trimethylsilyl triflate (TMS) the cis configuration of the nucleoside of formula (VII). This nucleoside is optically active and is substantially free of the corresponding trans isomer (i.e. it does not contain more than 20%, preferably not more than 10% and even more preferably not more than 5% of the trans isomer).

Preferred silylating agents for pyrimidine bases are t-butyldimethylsilyl triflate, 1,1,1,3,3,3-hexamethyldisilazane and trimethylsilyl triflate. It is believed that the large t-butyl group increases yields by inducing an interaction between the Lewis acid and the silylated pyrimidine base.

A preferred method of mixing the reagents in step 4 is to first add a chiral auxiliary sugar of formula (VI) to the silylated purine or pyrimidine base. The Lewis acid of formula (III) is then added to the mixture.

Step 5: The cis nucleoside obtained in Step 4 can then be reduced. with a suitable reducing agent to remove the chiral auxiliary group to give a specific stereoisomer of formula (I). The absolute configuration of this stereoisomer corresponds to the configuration of the nucleoside intermediate of formula (VII).

V; As shown in Scheme 1, either the cis (Scheme IA) or trans isomers (Scheme IB) obtained in Step 2 result in the cis: final product.

• · «* ·· • · ·

Schemes 2A and 2B illustrate the use of the method of Schemes IA and IB for the 1st synthesis of cis-2-hydroxymethyl-5- (cytosin-1'-yl) -1,3-oxathiolanes. Although this method is described using specific reagents and starting materials, it will be apparent to those skilled in the art that suitable analogous reagents and starting materials can be used to prepare analogous compounds.

• · · • · • ·

• »I

• · · • · · t:: • 1 · • · · • · · · • «I · j: is 102279

SCHEME 2A O

f I + Il phase i / ° \> »0H

JL J HCCOjH - ^ HOjCi ·· - / T

H0 s cvm) 0 /

IL / STEP 2 (CIS) Il <WOCCH * (IX) 0 g H ° C 2 S + + V. . S (TRANS) d-menthol \ 1-menthol

Jr STEP 3 \ j ..... CXj .....

..... +

STEP A I

? 'o il

Ck! ..... «> JV« HE 5 «H, O 'IS ¥" * = ... = f' N <= S | f, T: O ..... o? .... . (° y «D KXjUSjS1

i JfAIHE 6 I

'? '„* I Λ

o® "" V ^ 5 "J

:?; '0 -J

17 102279

FIGURE 2B

oh o / ° ^ 0H

f T * ico2 „- HOlC ..... <J

/ (vm)

M (TRANS) S

0 OCCHj (D ° o. Il VA1HE 2 "0iC ^ γ +" o ^ y-occH, (CIS) ss d-menthol / \ 1-menthol / STEP 3 \ Π M CL · ^ OCCH, O - ^ "- o "..... <y (X) CAoL .. ^ 0 ™ 'f | + o

(STEP 4 'I

1 \ o Γ ^} Il o., JcH3 C ^ L M / ^ occ * υυ-ο a σ d, h ·· λ i i · Ά $ Φ-ι <τ ”» YHr

5 :::: step e I NH

::: "nh, + A> r ν · ^ Ν t N il 7 ™ ~, Jp <™

:: L w sJ

«·

The various steps described in Schemes 2A and 2B can be briefly described as follows: ie 102279

Step 1: The mercaptoacetaldehyde monomer, preferably prepared from a dimer such as 2,5-dihydroxy-1,4-mother tongue, is reacted in a suitable solvent (preferably t-butyl dimethyl ether) with glyoxylic acid to give the trans-hydroxy acid of formula (VIII) alone. .

Step 2: The acid of formula (VIII) is reacted with an acid chloride such as acetyl chloride in the presence of pyridine and an acylating catalyst such as 4-dimethylaminopyridine, or preferably an acid anhydride such as acetic anhydride with acetic acid and an acylating catalyst such as sulfuric acid. A diastereomeric mixture of cis- and trans-acetoxy acids according to (IX).

The racemic diastereomeric acid mixture obtained in Step 2 is fractionally crystallized using any combination of solvents (preferably benzene and ether) to give either cis- or trans-acetoxy acid of formula (IX) alone, each as a racemic mixture.

Step 3: Either the cis- or trans-acetoxy acid of formula (IX) is reacted with a suitable chiral auxiliary group, preferably 1-menthol or d-menthol, in a suitable organic solvent such as dichloromethane using an activating agent such as dicyclohexylcarbodiimide and an esterifying catalyst. such as 4-dimethylaminopyridine to give the corresponding ··· t. ·. correspondingly a diastereomeric mixture of cis or trans esters.

i · · • · · «·· i::

Alternatively, the compound of formula (IX) may be converted to the acid chloride by any method known in the art, such as oxalyl chloride in a suitable solvent, e.g. dichloromethane or N, N-dimethylformamide. The acid chloride is then reacted with a chiral auxiliary in a suitable organic solvent using an esterifying catalyst.

Step 4: The above diastereomeric mixture of either cis or trans esters is fractionally crystallized using any combination of solvents (preferably ether and petroleum ether (40-60 ° C)), preferably at low temperature, to give only the compound of formula (X). cis- or trans-acetoxymethyl ester, respectively.

Step 5: Either the cis- or trans-acetoxy compound of formula (X) is reacted with cytosine or another purine or pyrimidine base or an analog thereof. The purine or pyrimidine base is preferably previously silylated with hexamethyldisilazane or more preferably silylated by reaction with t-butyl diraethylsilyl triflate in a compatible organic solvent such as dichloromethane containing a protected base, preferably 2,4,6-collidine. A Lewis acid of formula (III), preferably iodotrimethylsilane or trimethylsilyl triflate, is then added to give a cis compound of formula (XI) in a highly diastereoselective manner.

Step 6: The optically active cis nucleoside of formula (XI) is stereospecifically reduced with a reducing agent, preferably lithium triethylborohydride or more preferably lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether to give a compound of formula (XII) and menthol.

Another method for diastereoselectively synthesizing compounds of formula (I) is described in Schemes 3A and 3B and 4A and 4B. In the process of Schemes 3A and 3B, the carbonyl sugar and the R3 substituent at C4 'are reacted with a chiral auxiliary group (R4) to give diastereomeric groups. a mixture of two optically active chiral auxiliaries •; * f. The actual diastereomer formed depends on whether a (+) - or (-) - chiral auxiliary group is used. This optically. the active mixture can be chemoselectively reduced and the resulting hydroxyl group converted to a leaving group to give a diastereomeric mixture of four chiral auxiliary sugars, two in the cis configuration and two in the trans configuration (Scheme 3B). Subsequent fractional crystallization gives one diastereomer.

Alternatively, the optically active mixture of chiral auxiliary sugars can first be separated chromatographically or by fractional crystallization and then reduced and the resulting hydroxyl group converted to a leaving group (Scheme 3A). Subsequent fractional crystallization affords any desired diastereomer. The solvent can be adjusted to a selection of either the cis or trans isomer. Each isolated optically active diastereomer can be further processed into compounds of formula (I) in a manner analogous to that described in Schemes 1 and 2.

Schemes 3A and 3B show another method applied to 1,3-oxathiolane, 2,4-dioxolane or 1,3-dithiolane.

I i

I I

4 4 • 1 * «· • · I · * ·« t · »« ». ·: • · · i« «* ·· · · • · ·» · «* 2i 102279

FIGURE 3A

οαπ)

R 3 is (+) or (-) chiral. auxiliary group W O

(IV) X STEP 1 r / '\ _J + R / a ..... ζ ^ / STEP 2 r / (xm) STEP 3 (XIV) VV. ^ OH w. au. ., '- 0 STEP 4,' - <r. ..wy .. ^ STEP 5

! '·: · / S- "L

· Ϊ · * R, · - </

^ \ J

PHASE (VH)! ·! '«.' ''“ Λ J STEP 7

X — 1 W

R, OCHj w o

«* · I

x— ^ 22 1 0 2 2 7 9

FIGURE 3B

w n <™> r - / (+) or (-) chiral auxiliary group /

π ”λ ^ —mSn- + R / '<J

(IV) K «x— ^ R« x ^ (XIV)

W ^ 0H W * OH W ^ V> H W * OH

./'~Q V, _0 *, / 'vj · ..-' "Ό (VI)

/ W'V, L / S- "L / W ^ -" L

p / 5 “<J + R ^ - <J *„ />.....<XJ + ^ ..... O

STEP 5 / V w)

..... <J

• *** | STEP 6 • · · ^

T

• · · ::: w ^. ^ Ra R / 3 ..... (xJ (VII) • * * \ STEP 7 riOCH2 w ^ xRj W (I) 23 1 0 2 2 7 9

The various steps in the synthesis of the nucleosides of formula (I) shown in Scheme 3A can be briefly described as follows:

Step 1: The starting material of formula (IV) prepared by any method known in the art is reacted with a chiral auxiliary group (see e.g. TW Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981)). to give a mixture of two diastereomers of formula (XIII) The type of mixture formed depends on which chiral auxiliary group (+ or -) is used.

Step 2: A mixture of the two diastereomers of formula (XIII) is separated by fractional crystallization or chromatography to give one diastereomer of formula (XIII).

Step 3: The single isomer of formula (XIII) is chemoselectively reduced with a suitable reducing agent such as diaciamylborane to give a mixture of the two diastereomers of formula (XIV).

Step 4: The hydroxyl groups of the two diastereomers of formula (XIV) are converted to leaving groups by any method known in the art to give a mixture of the two diastereomers of formula (VI).

Step 5: Either the cis or trans isomer is separated from the mixture of two diastereomers of formula (VI) obtained in Step 4 by fractional crystallization or chromatography. The solvent can be • · • * · {adjusted to select the cis or trans isomer.

• ·· • «• ·

• M

; Step 6: The individual diastereomer of formula (VI) is reacted

Ml. *: ·. with a previously silylated (or silylated in reaction) purine or pyrimidine base or analog or derivative. Then, the addition of a Lewis acid of formula (III) such as iodotrimethylsilane (TMSI) or trimethylsilyl triflate (TMSOTf) gives a nucleoside of formula (VII) having the cis configuration. This nucleoside is substantially free of the corresponding trans isomer.

Step 7: The optically active cis nucleoside of formula (VII) is stereospecifically reduced with a reducing agent, preferably lithium triethylborohydride, or more preferably lithium aluminum hydride, in a suitable solvent such as tetrahydrofuran or diethyl ether to give Compound (I) and menthol.

Alternatively, as shown in Scheme 3B, the mixture of diastereomers of formula (XIII) is reduced with a suitable reducing agent such as disiamylborane to give a mixture of four diastereomers of formula (XIV). The hydroxyl groups of this mixture of four diastereomers of formula (XIV) are converted to leaving groups by any method known in the art to give a mixture of four diastereomers of formula (VI). Either the cis or trans isomer of formula (VI) is separated from a mixture of four diastereomers by fractional crystallization or chromatography. The solvent can be adjusted to a selection of the cis or trans isomer. The single diastereomer of formula (VI) is reacted with a previously silylated (or silylated in the reaction itself) purine or pyrimidine base or analog or derivative. Thereafter, addition of a Lewis acid of formula (III), such as iodotrimethylsilane (TMSI) or trimethylsilyl litriflate (TMSOf), gives a nucleoside of formula (VII) having the cis configuration, which is reduced with a suitable reducing agent to give formula (I). ).

Schemes 4A and 4B illustrate the use of the method of Scheme 3 for cis-2-. . for the synthesis of enantiomers of hydroxymethyl-5- (cytosin-1'-yl) -1,3-oxathiolanes. Although this method is described using: ***: specific reagents and starting materials, one skilled in the art will be able to • · ·; . *. it will be appreciated that suitable reactants and starting materials may be used to prepare analogous compounds.

• · · ♦ · · • · · »* · j" **: «· · t 25 1 0 2 2 7 9

FIGURE 4A

(XV) jj STEP 1 / hsch2co2h + hcco2h - ho2c— (s— ^ (XVI) ^ / STEP 2 kX il y ° ^ ° CX II / ^ °

il 0C ^ \ J * V ^ oc ..... J

(ΧΥΠ) j STEP 3 ex n / ° ^ °

A, A

STEP 4

Xl./yoH + Xl / v0 "^ Λ, s— (xvm) ^! STEP 5 X? ..... / γ °“ Η> 1 X01_ / V “CH3 ϊ ·: A ^ <χ) λ s - '. 0 Αλιηε 6 ^

: ·· ;: rS o 0 II

*:!; · U ^ g ..... / ° Y0CCH1: i \ / nh2 ^ (X), ”|) NH2. I <L jJPENSE 8 / yrrs STEP 7- ^. A o 0? ^ (ΧΠ) Γ 1 LA 11 / ° s ° r I C _J R1 ° CH2 ,, / v (XI) s 26 102279

FIGURE 4B O

Il STEP 1 O o

HSCHjCOjH * HCCOjH - HO.C-V T

(XV) ΛJ «v.

LkT. L <Y

^ S (XVH) s ^ j STEP 4 9 ^ -cr. cu / y "^ s (xvm) j STEP 5

L-οΛ »Lh-L

^ / TOPIC 6

0 o 0 I

LL II / v ^ OCCH, r ^ - (j ·.: S— \ STEP 7 NHj ϊ 'I _ „0 V ^ OC ..... jSTEP 8 ™!'; ·: ^ (XD HOCH, / t '0 27 102279

The various steps in the synthesis of the nucleosides of formula (I) shown in Scheme 4 can be briefly described as follows:

Step 1: A known mercaptoacetic acid of formula (XV) is reacted with an appropriate aldehyde of formula R 3 CHO, wherein R 3 is preferably an alkoxycarbonyl such as menthyl glyoxylate and more preferably a carboxyl group such as glyoxylic acid (see e.g. JM McIntosh et al., "2-Mercap and 2,5-Dihydrothiophenes from 1,3-oxathiolan-5-ones ", Can. J.

Chem., 61, ss. 1872-1875 (1983)) in a suitable organic solvent such as toluene to give an intermediate of formula (XVI).

Step 2: The compound of formula (XVI) is reacted with a suitable chiral auxiliary group, preferably 1-menthol or d-menthol in a compatible organic solvent such as dichloromethane, using an activating agent such as dicyclohexylcarbodiimide and an esterification catalyst such as 4- dimethylaminopyridine to give compounds of formula (XVII).

Step 3: The diastereomeric compounds of formula (XVII) are preferably separated by fractional crystallization (Scheme 4A), but can be further processed without separation (Scheme 4B).

Step 4. Compounds of formula (XVII) are reduced by appropriate ... with a reducing agent such as disiamylborane in a compatible organic solvent such as tetrahydrofuran (A. Pelter. et al., "Borane Reagents" Academic Press, p. 426 (1988)) to give the formula (XVIII ).

Step 5s The compounds of formula (XVIII) are reacted with an acid chloride or an acid anhydride such as acetic anhydride in the presence of a pyridine and an acylation catalyst such as 4-dimethylaminopyridine to give a compound. compounds of formula (X) are obtained.

Step 6: The diastereomeric compounds of formula (X), if not already separated (Scheme 4B) are now preferably separated by fractional crystallization (Scheme 4B) to give either the formula (X). ) cis- or trans-acetoxy compound.

Step 7: Either the cis- or trans-acetoxy compound of formula (X) is reacted with cytosine or another purine or pyrimidine base or analog thereof. The purine or pyrimidine base or analog is preferably previously silylated with hexamethyldisilazane or more preferably silylated itself by reaction with t-butyldimethylsilyl triflate in a compatible organic solvent such as dichloromethane containing a protected base, preferably 2,4,6-collidine. A Lewis acid, preferably one obtained from a compound of formula (III), more preferably iodotrimethylsilane or trimethylsilyl triflate, is then added to give a cis compound of formula (XI) in a highly diastereoselective manner.

Step 8: The optically active cis nucleoside of formula (XI) is stereospecifically reduced with a reducing agent, preferably lithium triethylborohydride or more preferably lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether to give a compound of formula (XII).

The following intermediates are of particular importance in diastereoselective methods:

VV. -L

• i - “CT

mi y «1 •« Λ • # f ·· «

t »I I I I

• «c • f · 1 · '• I« • «! · · • ·« «« I I I <«« VV. -Λ

S

t »· *« ·

I t »B

29 1 0 2 2 7 9 s ..... Ci 'v "' /" S ** 0 R3, / \ / ixIV) wherein R3, R4 and L are as defined above; trans-5-hydroxyoxathiolane-2-carboxylic acid; (L'R, 2'S, 5'R) -menthyl-l, 3-oxathiolane-5-one-2S-carboxylate; i: (1'R, 2'S # 5'R) -menthyl 1,3-oxathiolan-5-one 2R-carboxylate;

I <I

1 t w * · \ J (1'R, 2'S, 5'R) -menthyl-5S-hydroxy-1,3-oxathiolane-2S-carboxy -. * ··, tile; • Ψ · «· i>.

J · · (1'R, 2'S, 5'R) -menthyl 5R-hydroxy-1,3-oxathiolane-2R-carboxylate; *,;, 5 (1'R, 2'S, 5'R) -menthyl 5S-hydroxy-1,3-oxathiolane-2R-carboxylate; (1'R, 2'S, 5'R) -menthyl-5R-hydroxy-l, 3-oxathiolane-2S-carboxylate-methacrylate; I * 30 1 0 2 2 7 9 (1'R, 2'S, 5'R) -menthyl 5S-acetoxy-1,3-oxathiolane-2S-carboxylate; (1'R, 2'S, 5'R) -menthyl 5R-acetoxy-1,3-oxathiolane-2R-carboxylate; (1'R, 2'S, 5'R) -menthyl-5S-acetoxy-l, 3-oxathiolane-2R-carboxylate-methacrylate; (1'R, 2'S, 5'R) -menthyl 5R-acetoxy-1,3-oxathiolane-2S-carboxylate; (L'S, 2'R, 5'S) -menthyl-5R-acetoxy-l, 3-oxathiolane-2S-carboxylate-methacrylate; (L'S, 2'R, 5'S) -menthyl-5S-acetoxy-l, 3-oxathiolane-2R-carboxylate-methacrylate; (L'S, 2'R, 5'S) -menthyl-5R-acetoxy-l, 3-oxathiolane-2R-carboxylate-methacrylate; (L ^ S 'R / S'S) -menthyl-5S-acetoxy-l, 3-oxathiolane-2S-carboxylate-methacrylate; (1'R, 2'S, 5'R) -menthyl 5S- (cytosin-1 "-yl) -1,3-oxathiolane-2R-carboxylate; (1'S, 2'R, 5'S) -xnentyl-5S- ( cytosin-1 "-yl) -1,3-oxathiolane-2R-carboxylate; • · • · 4 · * (1'R, 2'S, 5'R) -menthyl-5R- (cytosin-1H-yl) -1,3-oxathiolane-2S-: carboxylate; (1'S, 2'R, 5'S) -menthyl 5R- (cytosin-1 "-yl) -1,3-oxathiolane-2S-carboxylate; (1'R, 2'S / 5'R) -menthyl-5R- (5 "-fluorocytosin-1" -yl) -1,3-oxa-thiolane-2S-carboxylate; (1'S, 2'R, 5'S) -methyl - 5S- (5 "-fluorocytosin-1" yl) -1,3-oxo-1 ', 10'-thiolane-2R-carboxylate; (1'S, 2'R, 5'S) -menthyl-5S- (N-4 "-acetylcytosin-1" -yl) -1,3-octhathiolane-2R-carboxylate; (1'R, 2'S, 5'R) -menthyl-5S- (cytosin-1 "-yl) -1,3-oxathiolane-2R-carboxylate; (L'S, 2'R, 5'S) -menthyl-l, 3-oxathiolane-2R-carboxylate; (1'S, 2'R, 5'S) -menthyl 4R-hydroxy-1,3-oxathiolane-2R-carboxylate and (1'S, 2'R, 5'S) -menthyl-4S-hydroxy-1,3-oxathiolane- 2R-carboxylate; (1'S, 2'R, 5'S) -menthyl 4R-chloro-1,3-oxathiolane-2R-carboxylate and (1'S, 2'R, 5'S) -menthyl-4S-chloro-1,3-oxathiolane- 2R-carboxylate; cis-2- (N-methyl-N-methoxyaminocarbonyl) -5- (uracil-1'-yl) -1,3-oxathiolane; cis- and trans-2-benzoyl-5-acetoxy-1,3-oxathiolane; cis-2- (1'-pyrrolidinocarbonyl) -5-acetoxy-l, 3-oxathiolane; cis-2-carbomethoxy-5- (5'-bromouracil-1'-yl) -1,3-oxathiolane; cis-2-carboxyl-5- (uracil-1'-yl) -1,3-oxathiolane; • · · «· · • · • ·. cis-2- (1'-pyrrolidinecarbonyl) -5- (uracil-1'-yl) -1,3-oxa-3-thiolane; Cis-2-benzoyl-5- (uracil-1'-yl) -1,3-oxathiolane; . cis- and trans-isopropyl-5-acetoxy-1,3-oxathiolane-2-carboxylate; cis-isopropyl-5- (cytosin-1'-yl) -1,3-oxathiolane-2-carboxylate; ♦ «32 102279 cis- and trans-t-butyl-5-acetoxy-1,3 -oxathiolane-2-carboxylate, cis-t-butyl-5- (cytosin-1'-yl) -1,3-oxathiolane-2-carboxylate, cis- and trans-2-N, N-diethylaminocarbonyl -5-acetoxy-1,3-oxa-thiolane, cis-2-N, N-diethylaminocarbonyl-5- (cytosin-1'-yl) -1,3-oxa-thiolane, cis- and trans-2-carboethoxy -4-acetoxy-1,3-dioxolane, cis- and trans-2-carboethoxy-4- (thymin-1'-yl) -1,3-dioxolane, and cis- and trans-2-carboethoxy-4- ( N-4'-acetylcytosin-1'-yl) -1,3-dioxolane.

The following examples illustrate the way in which this can be accomplished, but as such should not limit the overall scope of the methods. When not specifically indicated, all [aJD measurements were recorded at ambient temperature.

Example 1

1.3- OXATHIOLAN-5-ONI-2-CARBOXYLIC ACID

• <1 * * O (XVI) S ~ \ 'T' • · · w • · · • · ·: - * Toluene (700 ml), mercaptoacetic acid (38 ml, 50.03 g, 0.543 mol) and p- toluenesulfonic acid (1.0 g) was added to a solution of glyoxylic acid monohydrate (50.0 g, 0.543 mol) in 200 mL of THF in a 2 L round bottom flask equipped with a Dean-Stark trap and condenser. The resulting reaction mixture was refluxed for 3 hours until 24.0 mL of H 2 O was azeotroped for 3 hours until 24.0 mL of H 2 O was azeotropically removed. The reaction mixture was cooled, after which the solvent was removed under reduced pressure to give an off-white solid. This material was purified by recrystallization (hexane-EtOAc) to give 6.0 g of product as a crystalline white solid, m.p. 140-143 ° C; 1 H NMR (DMSO) δ 3.84 (g, 2H, JAB-16.7 Hz), 6.00 (s, 1H).

Example 2

TRANS-5-HYDROKSIOKSATIOIAANI-2-carboxylic acid

O

^ OH

A suspension of dithian-1,4-diol (82.70 g, 0.54 mol) and glyoxylic acid monohydrate (100.0 g, 1.09 mol) in tert-butyl methyl ether (1.1 L) was stirred under nitrogen and heated to reflux under Dean-Stark conditions. Reflux cooling was continued for 8 hours during which time 15.3 mL (0.85 mol) of water was collected. The slightly turbid mixture was filtered and the solvent was distilled off at atmospheric pressure until a volume of 600 ml was reached. Cyclohexane (340 ml) was added and the solution was cooled to 5 ° C, seeded and allowed to stir at 0-5 ° C for 2 hours. The product was isolated by filtration, washed with 100 ml of tert-butyl methyl ether-cyclohexane (2: 1), and dried overnight at room temperature (94.44 g): m.p. 94,5eC; 2 H NMR (DMSO) 5.84 (brs, 1H), 6.95 (d, 1H, J-4.7 Hz).

Example 3

TRANS-5-ACETOXY-1,3-OKSATIQLAANI-2-carboxylic acid

O

1: H0 \ "Js0C0CHj (! X): T: 34 102279

One drop of concentrated H 2 SO 4 was added to a thoroughly stirred solution of trans-5-hydroxyoxathiolane-2-carboxylic acid (7.0 g, 46.7 mmol) in glacial acetic acid (40 mL) and acetic anhydride (15 mL, 15.9 mmol). ) at ambient temperature. The resulting clear solution was stirred for 1 hour and then poured onto crushed ice and brine (20 mL). This mixture was extracted with CH 2 Cl 2 (100 mL) and the combined extracts were dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 8.5 g (95%) of a pale yellow syrup consisting of trans- and cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acids in a ratio of 2: 1. The mixture was dissolved in benzene (20 ml) and allowed to stand overnight, during which time white crystals formed. A small amount of ether was added and the solid was collected by filtration and washed with more ether to give 2 g (22%) of trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid: m.p. 111,3eC;

1 H NMR

(DMSO) δ 2.03 (s, 3H), 3.21 (d, 1H, J = 12 Hz), 3.32 (dd, 1H, J = 3, 12 Hz), 5.65 (s, 1H), 6.65 (d, 1H, J = 4 Hz); 13 C NMR (DMSO) δ 20.91, 36.51, 78.86, 99.15, 169.36, 170.04.

Example 4

CIS-5-ACETOXY-1,3-OXATHIOLANE-2-carboxylic acid

«T · · o ococh3: ··· *: iIX)

l · · C

• · · • · · • · · • ·. The filtrate from Example 3 was concentrated under reduced pressure and redissolved in ether. This solution was kept at room temperature and cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid slowly crystallized as a white solid (2.1 g, 23%): M.p. 111.7 ° C 1 H NMR (DMSO) δ 1.96 (s, 3H), 3.25-3.33 (a, 2H), 5.74 (S, 1H), 6.69 (d, 1H, J 3 3 Hz); 13 C NMR (DMSO) δ 21.0, 37.16, 79.57, 98.58, 169.36, 170.69.

35 102279

Example 5

tl'R.2'S.5'm-MENTHYL-1,3-OXATIOLAN-5-QNI-2S-CARBOXYLATE AND f 1 'R. 2 'S. 5' Ri-MENTHYL-1,3-OXATIOLAN-5-ONI-2R-CARBOXYLATE

Q '^ j0 <χνιι>

Oxalyl chloride (11 mL, 123.6 mmol) was added via addition funnel over 30 minutes to a stirred solution of 1,3-oxathiolan-5-one-2-carboxylic acid (12.2 g, 82.4 mmol) in anhydrous THF ( 20 mL) and CH 2 Cl 2 (40 mL) at room temperature under argon. The resulting solution was heated at 65 ° C for 30 minutes and then concentrated in vacuo to give an oily product (11.6 g, 90%). The resulting crude acid chloride was redissolved in dry CH 2 Cl 2 (40 mL) and cooled to 0 ° C. (1R, 2S, 5R) -menthol (12.8 g, 82.4 mmol) dissolved in CH 2 Cl 2 (25 mL) was added slowly to this cooled solution. The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with CH 2 Cl 2 (200 mL) and washed with water, saturated NaHCO 3, brine and then dried over anhydrous Na 2 SO 4. The solvent was removed and the crude product thus obtained was filtered through a short column of silica (100 g, • · • • V Merck) eluting with EtOAc-hexane. Concentration of the appropriate fractions gave a 1: 1 mixture of (1'R, 2'S, 5'R) -menthyl • 1,3-oxathiolan-5-one 2S-carboxylate and (1'R). R, 2'S, 5'R) -men-. · *: Style 1,3-oxathiolan-5-one-2R-carboxylate (total 20 g,: * · *: 84.7%) as a viscous oil: m % NMR (CDCl 3) δ 0.77 (3H), 0.91 (6H), 1.00-1.15 (2H), 1.40-2.10 (6H), 3.56 (1H), 3.82 (1H), 4.80 (1H).

5.62 (1 H); 13 C NMR δ 16.7, 21.2, 21.3, 22.5, 23.80, 23.84, 26.7, 26.8, 30.6, 31.91, 31.94, 34.57, 40.6, 41.07, 47.5, 47.6, 74.1, 74.2, 77.7, 168.1, 172.8.

36 1 0 2 2 7 9

The above mixture (20 g) was dissolved in a minimum amount of pentane-petroleum ether (40-60 ° C) (1: 2, 30 ml). The resulting solution was cooled to -70 ° C for 10 minutes and the resulting crystalline compound was quickly collected by filtration and washed with more cold Petro ether (10 mL). This crystalline compound, isolated in 12.5% yield, was found to contain one isomer as indicated by 1 H NMR and 13 C NMR spectroscopy: m.p. 78,5eC; [α] D +31.7 «(c, 0.984, CHCl 3); 1 H NMR (CDCl 3) δ 0.77 (3H), 0.91 (6H), 1.00-1.15 (2H), 1.40-2.10 (6H), 3.56 (1H), 3.82 (1H), 4.79 (1H), 5.62 (1H); 13 C NMR (CDCl 3) δ 16.7, 21.2, 22.5, 23.8, 26.7, 30.0, 32.0, 34.6, 41.1, 47.6, 77.7, 168.1, 172.9.

Example 6

fl1R.21S.5rRl-menthyl-5S-HYDRQKSI-1,3-OKSATIQLAANI-2S-carboxylate-methacrylate. and R (S.S'R) -MENTHYL-5R-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE. f 1f R.2 1 S.B »R1-MENTHYL-5S-HYDROXY-1,3-OXA-THIOLANE-2R-CARBOXYLATE. f 1> R.2 ^ .Β'Ν ^ -ΜΕΝΤΥΎΙ, Ι-ΰΝ-ΗΥΡΝΟΚΒΙ-Ι .3-OXATIQLAAN-2S-CARBOXYLATE

Λ o ^ Y ^ '<yÄy °' Y'OH (XVIII) • · · ^ ^ i • ·· • · · • · · • ·

A freshly prepared solution of disiamylborane (13.4, Λ mmol, 0.5 M in THF) was added via cannula to a stirred solution of a 1: 1 mixture of menthyl ether ticarboxylate of formula (XVII) (1.28 g, 4, 47 mmol) in THF (10 mL) at 0 ° C under argon. The resulting clear solution was stirred for 15 minutes at 0 ° C and 18 hours at ambient temperature. The reaction was quenched with methanol (5 mL), concentrated, and diluted with methylene chloride (20 mL). The resulting solution was washed with brine (5 x 2 mL) and dried over anhydrous magnesium sulfate. This material was subjected to silica gel column chromatography (EtOAc-hexane, 1: 2, v / v) to give 0.65 g (50%) of the expected lactols in four diastereomeric forms: ΧΗ NMR (CDCl 3) δ 0.71-2.09 (o, 18H ), 3.01-3.09 (m, 1H), 3.24-3.33 (m, 1H), 4.66-4.83 (m, 1H), 5.53-5.59 (m, 1H), 5.88-6.09 (m, 1H).

Example 7 (1'R.2'S.5-MENTHYL-5S-ACETOXY-1,3-OXATIOANANE-2S-CARBOXYLATE. CARBOXYLATE Γ1'R.2'S.5'R1-MENTHYL-5S-ACETOXY-1,3-OXA-THIOLANE-2R-CARBOXYLATE (1> R.2'S.5'R1-MENTHYL-SR-ACETOXY-

1,3-OXATHIOLANE-2S-CARBOXYLATE

• · 1 h · · ♦ 1 · »* * a« (* I · 4 4 ·: 'The four title compounds were prepared as a mixture by the following two methods.

38 102279

Method A

The lactols of formula (XVIII) (0.65 g, 2.25 mmol) were dissolved in anhydrous pyridine (1.5 mL) and methylene chloride (5 mL). Acetyl chloride (0.5 mL, 7.0 mmol) was added slowly to this solution at 0 ° C. The resulting white suspension was stirred at ambient temperature for 3 hours. The reaction was then quenched with saturated ammonium chloride (1 mL). The mixture was extracted with methylene chloride (5 x 2 mL) and the combined extracts were concentrated to give a brown gum. This material was subjected to column chromatography (EtOAc-hexane, 1: 3 v / v) to give 0.3 g of four acetates as a pale yellow oil: 1 H NMR (CDCl 3) δ 0.75 (d, 6H, J = 7 Hz), 0.78 (d , 6H, J = 7 Hz), 0.88-0.94 (m, 24H), 0.97-2.03 (Π, 36H), 2.10 (s, 9H), 2.13 (s, 3H), 3.15 (d, 2H, J = 12 Hz), 3.23-3.30 (m, 4H), 3.42 (dd, 1H, J-4, 12 Hz), 3.44 (dd, 1H, J <4, 12 Hz), 4.65-4.75 (m, 4H), 5.61 (s, 1H), 5.62 (s, 1H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 4H).

Method B

A solution of dicyclohexylcarbodiimide (21.86 g, 0.106 mmol) in dichloromethane (100 mL) was added to a 500 mL round bottom flask containing trans- and cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acids ( X) (18.5 g, 0.096 mol), (1R, 2S, 5R) - (-) - men-toluene (16.5 g, 0.106 mol) and 4-dimethylaminopyridine (1.17 g, » · 9.63 mmol) in dichloromethane (200 ml) at 0 ° C. The resulting thick white slurry was stirred at room temperature for 3 hours during which time methanol (4.0 mL) and glacial acetic acid (2.0 mL) were added.

· · ·

After stirring for 10 minutes, the reaction mixture was diluted with hexanes (200 mL) and filtered through Celite. After removal of the solvent, 32.5 g of crude product were obtained. This material was redissolved in hexane (100 mL), filtered through% Celite and concentrated to give 30.5 g of material which was further purified by flash chromatography (eluent: 100% hexane to 5% EtOAc-hexane). to give 5.5 g of a mixture. (t 1: 1) (1'R, 2'S, 5'R) -menthyl-5R-acetoxy-1,3-oxathiolane- «« * t • * 39 102279 2S-carboxylate and (1'R, 2'S, 5'R) -menthyl 5S-acetoxy-1,3-oxathiolane-2R-carboxylate; 10.28 g of a substance consisting essentially of the two diastereomers above together with (1'R, 2'S, 5'R) -menthyl 5S-acetoxy-1,3-oxathiolane-2S-carboxylate and (1'R, 2'S, 5'R) -menthyl-5R-acetoxy-l, 3-oxathiolane-2R-carboxylate; 7.6 g of a rare mixture of the four diastereomers above; and 2.2 g of a mixture of (about 1: 1) (1'R, 2'S, 5'R) -menthyl 5S-acetoxy-1,3-oxathiolane-2S-carboxylate and (1'R, 2'S, 5'R) -menthyl 5R-acetoxy-1,3-oxathiolane-2R-carboxylate.

Example 8

Π'R.2'S.5'Rl-menthyl-5R-ACETOXY-1,3-OXATHIOLANE-2R-carboxylate-methacrylate

(1'R, 2'S, 5'R) -Mentyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate was prepared by the following three methods.

Method A

* t · · * · * The mixture obtained in Example 7 containing (1'R, 2'S, 5'R) -menthyl 5S- *: acetoxy-1,3-oxathiolane-2S-carboxylate and (1'R, 2'S) , 5 'R) -

• M

Mentyl 5R-acetoxy-1,3-oxathiolane-2R-carboxylate (5.5 L: 9) was dissolved in petroleum ether (40-60 ° C) containing a minimum amount of diethyl ether and cooled to dryness with acetone. in the bath. A white solid precipitate was collected. immediately recovered by suction filtration to give 1.6 g / · *, (1'R, 2'S, 5'R) -menthyl 5R-acetoxy-1,3-oxathiolane-2R-carboxylate: m.p. 105,2eC; (a) D -60 · (c, 0.51, i «« 9 * CHCl3); 1 H NMR (CDCl 3) δ 0.77 (d, 3H, J = 7 Hz), 0.91 (d, 3H, J <7 Hz), 0.92 (d, 3H, J * 7 Hz), 0.86-2.06 (m, 9H ), · 2.10 (s, 3H), 3.16 (d, 1H, J <12 Hz), 3.44 (dd, 1H, J = 4,.: 12 Hz), 4.74 (dt, 1H, J <5, 12 Hz), ), 5.63 (S, 1H), 6.79 40 102279 (d, 1H, J-4 Hi); 13 C NMR (CDCl 3) δ 16.16, 20.74, 21.11, 21.97, 23.29, 26.08, 31.38, 34.13, 37.24, 40.62, 47.07, 76.11, 79.97, 99.78, 168.60, 169.68.

Method B

A mixture of four diastereomers of formula (X) (300 mg) was dissolved in n-pentane containing a minimum amount of diethyl ether and kept at -20 ° C for 24 hours. The resulting white needles were rapidly filtered while still cold to give 25 mg of material. The substance thus isolated was found to be identical in all respects to that obtained by Method A or C.

Method C

A solution of dicyclohexylcarbodiimide (1.362 g, 6.6 mmol) in dichloromethane (5 mL) was added to a 50 mL round bottom flask containing a solution of trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (1.16 g, 6.04 mmol), (1R, 2S, 5R) - (-) - menthol (1.038 g, 6.60 mmol) and 4-dimethylaminopyridine (75 mg, 0.62 mmol) in dichloromethane (10 mL) at 0 ° C. The resulting white slurry was stirred at room temperature for 3 hours during which time methanol (0.2 mL) and glacial acetic acid (0.2 mL) were added. After stirring for 10 minutes, the reaction mixture was diluted with hexane (25 mL), filtered through Celite and concentrated. The crude product thus obtained was dissolved in hexane (25 mL), filtered through Celite and concentrated to give 1.98 g (100%) of (1'R, 2'S, 5'R) -menthyl-5R-acetoxy-1,3 -oxathiolane-2R-carboxylate and (1'R, 2'S, 5'R) -menthyl 5S-acetoxy-1,3-oxathiolane-2S-carboxylate: • · · «« * H NMR (CDCl 3) δ 0.75 (d, 3H, J = 7 Hz), 0.78 (d, 3H, J = 7 Hz), 0.85-0.92 (m, 12H), 0.95-2.19 (a, 18H), 2.10 (s , 6H), 3.15 (d, 2H, J = 12 Hz), 3.42 (dd, 1H, J = 4, 12 Hz), 3.44 (dd, 1H, J-4, 12 Hz), 4.74 (dt, 2H, J = 5, 12 Hz), 5.61 (s, 1H), 5.62 (s, 1H), 6.65 (s, 2H) 4i 102279

The above mixture of diastereomers was dissolved in petroleum ether (40-60 ° C) containing a minimum amount of diethyl ether and cooled in a bath of dry ice and acetone. The white solid precipitate was collected immediately (620 mg) by suction filtration. This material was recrystallized again under the same conditions to give 450 mg of a white solid. This compound was found to be identical in all respects to either the compound prepared by Method A or Method B.

Example 9

fl'S.2 Ή.5 fS1-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE

A solution of dicyclohexylcarbodiimide (491 mg, 2.38 mmol) in dichloromethane (7 mL) was added to a 50 mL round bottom flask containing trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid ( IX) (416 mg, 2.2 mmol), a mixture of (1S, 2R, 5S) - (+) - menthol (372 mg, 2.38 mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in dichloromethane ( 5 ml) at 0 ° C. The resulting thick slurry was stirred at room temperature for 3 hours, during which time methanol (0.2 mL) and glacial acetic acid (0.2 mL) were added. After stirring for 10 min, the mixture was diluted with hexane (25 mL), filtered through Celite and concentrated. The crude product thus obtained was dissolved in hexane (25 ml), filtered through Celite, and concentrated to give 0.715 mg (100%) of two diastereomers, namely (1'S, 2'R, 5'S) -menthyl-5S -acetoxy-1,3-oxa-thiolane-2S-carboxylate and (1'S, 2'R, 5'S) -menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate: ijj | q] r (CDCl3 ) S 0.75 (d, 6H, J = 7 Hz), 0.85-0.92 (m, 12H), 0.95-2.19 (m, 18H), 2.10 (s, 6H), 3.15 (d, 2H, J-12 Hz) , 3.42 (dd, 1H, J <4, 12 Hz), 3.44 (dd, 1H, J <4, 12 Hz), 4.72 (dt, 2H, J <5, 12 Hz), 5.61 (s, 1H), 5.62 (s, 1 H), 6.65 (S, 2 H).

42 102279

The mixture of the above diastereoreal acetoxymethyl esters was dissolved in petroleum ether (40-60 ° C) containing a minimum amount of diethyl ether and cooled in a bath of dry ice and acetone. A white solid precipitate (200 mg) was immediately collected by suction filtration. This material was recrystallized again under the same conditions to give 130 mg (34% based on one enantiomer) of (1'S, 2'R, 5'S) -menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate mp 104.2 ° C. C; (α) D +59.2 "(C, 1.02, CHCl 3); 1 H NMR (CDCl 3) δ 0.77 (d, 3H, J-7 Hz), 0.91 (d, 3H, J = 7 Hz), 0.92 (d, 3H , J = 7 Hz), 0.86-2.06 (m, 9H), 2.10 (s, 3H), 3.16 (d, 1H, J = 12 Hz), 3.44 (dd, 1H, J = 4, 12 Hz), 4.74 (dt, 1H, J-5, 12 Hz), 5.63 (S, 1H), 6.79 (d, 1H, J = 4 Hz); 13 C NHR (CDCl 3) δ 16.16, 20.74, 21.11, 21.97, 23.29, 26.08, 31.38, 34.13, 37.24, 40.62, 47.07, 76.11, 79.96, 99.78, 168.60, 169.68.

Example 10

(1'R.2'S.5'Rl-menthyl-5R-ACETOXY-1,3-OXATHIOLANE-2S-carboxylate-methacrylate

(· "·· t <x> • · · • · · · • • •: Y: (1'R, 2'S, 5'R) -Mentyl-5R-acetoxy-1,3-oxathiolane-2S The carboxylate was prepared by the following two methods.

t I

. · Method A

* A mixture of the four diastereomers (12.28 g) obtained in Example 7 was prepared in petroleum ether containing a small amount of 4 4 * diethyl ether and kept at -20 ° C for 72 hours. . The white crystalline solid was isolated by filtration to give 1.6 g of (1'R, 2'S, 5'R) -menthyl 5R-acetoxy-1,3-oxathiolane-2S-carboxylate: m.p. 110,2eC; [α] D -177 · (c, 0.7, CHCl 3); 1 H NMR (CO 3 Cl 3) δ 0.75 (d, 3H, J-7 Hz), 0.88 (d, 3H, J-7 Hz), 0.92 (d, 3H, J-7 Hz), 0.97-2.02 (m, 9H ), 2.12 (s, 3H), 3.22 (d, 1H, J-11 Hz), 3.29 (dd, 1H J-4, 11 Hz), 4.74 (dt, 1H, J-4, 11 Hz), 5.63 ( s, 1H), 6.65 (d, 1H, J-3 Hz); 13 C NMR (COCl 3) δ 16.9, 20.69, 21.19, 21.95, 23.29, 26.10, 31.34, 34.0, 37.62, 40.32, 46.82, 75.69, 80.20, 99.36, 168.55, 170.23.

Method B

A solution of dicyclohexylcarbodiimide (118 mg, 0.572 mmol) in dichloromethane (5 mL) was added to a 25 mL round bottom flask containing cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (100 mg, 0.52 mmol). ), a solution of (1R, 2S, 5R) - (-) - menthol (85 mg, 0.54 mmol) and 4-dimethylaminopyridine (DMAP) (8 mg, 0.053 mmol) in dichloromethane (10 mL) at 0 ° C. The resulting white slurry was stirred at room temperature for 3 hours during which time methanol (0.1 mL) and glacial acetic acid (0.1 mL) were added. After stirring for 10 minutes, the mixture was diluted with hexane (15 mL), filtered through • ♦ *** Celite, and concentrated. The resulting crude product was dissolved in hexane (15 mL), filtered through Celite and concentrated to give 170 mg (100%) of (1'R, 2'S, 5'R) -menthyl -: ... · 5R-acetoxy-1,3-oxathiolane-2S-carboxylate and (1'R, 2'S, 5'R) -menthyl 5S-acetoxy-1,3-oxathiolane-2S-carboxylate:

1 H NMR

(CDCl 3) δ 0.75 (d, 3H, J <7 Hz), 0.78 (d, 3H, J <7 Hz), 0.88-0.94 (in, 12H), 0.97-2.03 (m, 18H), 2.10 (s, 3H), 2.13 (s, 3H), 3.23-3.30 (m, 4H), 4.65-4.75 (m, 2H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 2H).

44 102279

The above mixture of two diastereomers was recrystallized from petroleum ether (40-60 ° C) and a minimum amount of diethyl ether at room temperature. The white crystalline material formed (95 mg) was collected by filtration. This material was recrystallized again from diethyl ether-petroleum ether to give 74 mg (78% based on one enantiomer) of (1'R, 2'S, 5'R) -menthyl 5R-acetoxy-1,3-oxathiolane-2S-carboxylate. .

Example 11

r ^ 'S' R.S'Sl-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate-methacrylate

Λ · X "^ \ ° T0Ae <X1

A solution of dicyclohexylcarbodiimide (1.588 g, 7.7 mmol) in dichloromethane (7 mL) was added to a 50 mL round bottom flask containing cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (1.36 g, 7 mmol), (1S, 2R, 5S) - (+) - menthol (1.216 g, 7.7 mmol) and 4-dimethylaminopyridine (85 mg, 0.7 mmol) in dichloromethane (16 mL) at 0 ° C. The resulting thick slurry was stirred at room temperature for 3 hours. The reaction was quenched with methanol (0.4 mL) and • ♦ **. with glacial acetic acid (0.4 ml), and the mixture was stirred for 10 minutes. The resulting mixture was diluted with hexanes (25 mL), filtered through a pad of Celite and concentrated. The crude material thus obtained was redissolved in hexane (25 mL) and filtered through Celite. Removal of the solvent under reduced pressure gave 2.3 g of a white solid (100%) consisting of (1'S, 2'R, 5'S) -menyl 5S-acetoxy-1,3-oxathiolane-2R-carboxylate and (1'S From 2'R, 5'S) -menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate: 1R (CDCl 3) δ 0.75 (d, 3H, J-7 Hz), 0.78 (d, 3H, J = 7 Hz), 0.88-0.94 (m, 12H), 0.97-2.03 (m, 18H), 2.10 (s, 3H), 2.13 (s, 3H), 3.23-3.30 (m, 4H), 4.65-4.74 ( m, 2H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 2H).

45 1 0 2 2 7 9

The above mixture of diastereomers was recrystallized from petroleum ether (40-60 ° C) and a small amount of diethyl ether at room temperature to give 1.3 g of a white solid.

This material was recrystallized again from diethyl ether-petroleum ether (40-60 ° C) to give 900 mg (78% based on one enantiomer) of (1'S, 2'R, 5'S) -menthyl-5S-acetoxy-1,3- oxathiolane-2R carboxylate m.p. 110.2 ° C; [α] D +177 · (c, 1.10, CHCl3); 1 H NMR (CDCl 3) δ 0.75 (d, 3H, J = 7 Hz), 0.89 (d, 3H, J = 7Hz), 0.92 (d, 3H, J = 7Hz), 0.98-2.02 (m, 9H), 2.12 (s, 3H), 3.22 (d, 1H, J = 11 Hz), 3.29 (dd, 1H, J * 4, 11 Hz), 4.74 (dt, 1H, J = 11 Hz), 5.63 (s , 1H), 6.65 (d, 1H, J <3 Hz); 13 C NMR (CDCl 3) δ 16.9, 20.69, 21.19, 21.95, 23.29, 26.10, 31.34, 34.09, 37.62, 40.32, 46.82, 75.79, 80.20, 99.36, 168.55, 170.23.

Example 12

f 1 * R. 2 'S. 5 'R1-MENTHYL-5S- (CYTOSIN-1 "-YL> -1,3-OXATHIOLANE-2R-CARBOXYLATE

NHj Λ. £> '.

s 9: T-Butyldimethylsilyl trifluoromethanesulfonate (1.1 mL, 4.79 mmol) was added cytosine (0.27 g, 2.5 mmol). to a suspension in CH 2 Cl 2 (2 mL) containing 2,4,6-collidine (0.65 mL, 4.92 mmol) at room temperature. The resulting mixture was stirred for 15 minutes to give a clear solution. A solution of (1'R, 2'S, 5'R) -menthyl-5S-acetoxy-1,3-46,10 2 277 oxathiolane-2R-carboxylate (0.66 g, 1.99 mmol) in methyl in chlorene chloride (1.5 ml) was added to the mixture and stirring was continued for 5 minutes. Iodotrimethylsilane (0.31 mL, 2.18 mmol) was added dropwise and a white precipitate formed upon addition. The reaction mixture was allowed to stir for 18 hours. The reaction was quenched by the addition of saturated aqueous Na 2 S 2 O 3 (10 mL) and CH 2 Cl 2 (30 mL). The organic layer was separated and washed with brine (2 x 10 mL). The solvent was removed in vacuo to give a viscous oil which was suspended in diethyl ether (30 mL). To this suspension was added saturated aqueous NaHCO 3 (20 mL) with vigorous stirring.

A white precipitate formed and the resulting suspension was diluted with hexane (10 mL). The precipitate was collected by filtration to give 0.57 g (75%) of a white solid. The 1 H NMR spectrum of this material showed that it was a mixture of the cis and trans diastereomers of the expected nucleoside in a ratio of 23: 1.

This product was further purified by recrystallization from EtOAc-hexane-MeOH: [c *] D-144e (c, 1.02, CHCl 3); mp: 219 ° C (dec.);

1 H NMR

(COCl 3) δ 0.76 (d, 3H, J <7 Hz), 0.85-0.94 (m, 6H), 1.02-1.10 (m, 2H), 1.42-2.06 (m, 7H), 3.14 (dd, 1H, J -6.6, 12.1 Hz), 3.54 (dd, 1H, J = 4.7, 12.1 Hz), 4.72-4.78 (m, 1H), 5.46 (s, 1H), 5.99 (d, 1H, J = 7.5 Hz),. ·. 8.43 (d, 1H, J = 7.6 Hz); 13C (CDCl 3) δ 16.1, 20.7, 21.9, 23.2, 26.4, 31.4, 34.0, 36.3, 40.7, 47.1, 76.7, 78.4, f **. 90.3, 94.6, 141.8, 155.4, 165.6, 169.8.

• · • * • · · • · · • • • • • • • Example 13

(L'S, 2'R, 5'S) -MENTHYL-5S- (CYTOSIN-1 "-YL \ -1,3-OXATHIOLANE-2R-CARBOXYLATE

47 102279 NH 2 - · 2 - 2,4,6-Collidine (0.317 mL, 2.4 mmol) and t-butyl dimethylsilyl trifluoromethanesulfonate (0.551 mL, 2.4 mmol) were added sequentially to cytosine (133.3 mg, 1 , 2 mmol) in CH 2 Cl 2 (1 mL) at room temperature under argon. The resulting mixture was stirred for 15 minutes to form a clear solution. A solution of (1'S, 2'R, 5'S) -menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (330 mg, 1 mmol) in CH 2 Cl 2 (0.5 mL) was added, followed by iodotrimethylsilane. (0.156 mL, 1.1 mmol). The resulting mixture was stirred for 3 hours. The mixture was diluted with CH 2 Cl 2 (20 mL) and washed sequentially with saturated aqueous NaHSO 3, water, and brine. The solvent was evaporated and the residue was taken up in ether-hexane (1: 1, 10 ml) and saturated aqueous NaHCO 3 (2 ml). Stirring was continued for 15 minutes. The aqueous layer was removed and the organic phase was centrifuged to give a white solid which was washed with hexane (3 x 5 mL) and dried in vacuo. This substance, namely (1'S, 2'R, 5'S) -menthyl 5S- (cytosin-1 "-yl) -1,3-oxathiolane-2R-carboxylate (380 mg, 100%), was contaminated. · About 3% of (1'S, 2'R, 5'S) -menthyl-5R- (cytosin-1 "-yl) -1,3-« · *

Example 14 fl'R ^ 'S.S'RI-MENTYL-5R- (SYTQSIN-1 "-HYL--1,3-QXATHIOLANE-2S-

CARBOXYLATE

48 102279 NH 2 O --2,4,6-Collidine (0.317 mL, 2.4 mmol.) And t-butyldimethylsilyl trifluoromethanesulfonate (0.551 mL, 2.4 mL) were added sequentially to cytosine (133.3 mg, 1, 2 mmol) in CH 2 Cl 2 (1 mL) at room temperature under argon, the resulting mixture was stirred for 15 minutes to give a clear solution, and (1'R, 2'S, 5'R) -menthyl-5R-acetoxy-1,3-oxathiolane was added. A solution of 2S-carboxylate (330 mg, 1 mmol) in CH 2 Cl 2 (0.5 mL) followed by iodotrimethylsilane (0.156 mL, 1.1 mmol) and stirring was continued for 3 h.The mixture was diluted with CH 2 Cl 2 (20 mL). ) and washed successively with saturated aqueous NaHSO 3, water, brine and then concentrated, the residue was taken up in a mixture of ether and hexane (li, 10 mL) and saturated aqueous NaHCO 3 (2 mL) and stirred at room temperature. ** For 4 minutes, the aqueous layer was removed and the organic phase was centrifuged to give a white solid. those which were washed with hexane (3 x 5 mL) and then dried in vacuo.

... * Product (1'R, 2'S, 5'R) -menthyl 5R- (cytosin-1 "-yl) -1,3-oxa-thiolan-2S-carboxylate (336.3 mg, 88%) contained about 6% · (1'R, 2'S, 5'R) -menthyl-SS-isytosine-4-yl-4-yl-oxathiol-β-carboxylate (NMR) This material was recrystallized from MeOH to give the desired product * [Α] D + 56β (c, 1.08, CHCl 3), mp 235 ° C (decomposed), NMR (CDCl 3) δ 0.80 (3H) 0.91 (6H), 1.00 (2H), 1.37-2.10 (7H), 3.11 (1H), 3.55 (1H), 4.77 (1H), 5.47 (1H), · · 5.79 (1H), 6.49 (1H), 8.37 (1H), 13 C NMR (CDCl 3) δ 16.8, 21.3, 22.5, 23.9 , 26.8, 32.0, 34.6, 36.8, 40.7, 47.4, 77.1, 78.8, 90.9, 95.6, 141.9, 156.3, 166.6, 170.2.

49 102279

Example 15

(1'S ^ 'R ^' S) -MENTHYL-5R- (CYTOSIN-1 "-YL) -1,3-OXATHIOLANE-2S-CARBOXYLATE

NHj Λ ...

2,4,6-Collidine (0.106 mL, 0.8 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate were added sequentially to a suspension of cytosine (44 mg, 0.4 mmol) in CH 2 Cl 2 (0.5 mL) at room temperature under argon. Stirring was continued at room temperature for 15 minutes to give a clear solution. A solution of (1'S, 2'R, 5'S) -menthyl 5S-acetoxy-1,3-oxathiolane-2S-carboxylate (110 mg, 0.33 mmol) in CH 2 Cl 2 (0.3 mL) was added, and then iodotrimethylsilane (0.052 mL, 0.36 mmol). The resulting mixture was stirred at room temperature overnight and diluted with CH 2 Cl 2 (10 mL). The mixture was washed successively with saturated aqueous NaHSO 3, water, brine and concentrated under reduced pressure. The residue was taken up in a mixture of ether and hexane (1: 1, 5 mL) and saturated aqueous NaHCO 3 (1 mL) and. ; stirring was continued at room temperature for 20 minutes. The water · * /. the ros was removed and the white solid suspended or-I *. the organic phase was collected by centrifugation. This solid was washed with hexane (3 x 5 mL) and then dried in vacuo to give 65 mg (51.2%) of (1'S, 2'R, 5'S) -menthyl-5R- (cytosin-1 "- yl) -1,3-oxathiolane-2S-carboxylate concentrated with about 5% (1'S, 2'R, 5'S) -menthyl-5S- (cytosin-1 "-yl) -1, 3-Oxathiolane-2S-carboxylate as determined by 1 H NMR spectroscopy. Recrystallization of the crude material from MeOH-Et 2 O gave the desired product: mp: 210-211 ° C; (e) D + 179 · (C, 0.66, CHCl 3); 1 H NMR 1 (CDCl 3) δ 0.77 (3H) 0.92 (6H), 1.00 (2H), 1.37-2.10 (6H), 3.14 (1H), 3.55 (1H), 4.76 (1H), 5.46 (1H), 5.88 mp 102279 (1H), 6.46 (1H), 8.38 (1H); 13 C NMR (CDCl 3) δ 16.8, 21.3. 21.8, 22.5, 23.9, 26.7, 31.9, 34.7, 38.7, 40.9, 47.4, 76.4, 80.8, 100.0, 169.1, 170.8

The washings and supernatant were combined and washed with 1N HCl, water, brine and then dried over Na 2 SO 4. Evaporation of the solvent gave 53 mg (48%) of unreacted (1'S, 2'R, 5'S) -menthyl 5S-acetoxy-1,3-oxathiolane-2S-carboxylate.

Example 16

2R-HYDROXYMETHYL-5S- (CYTOSIN-l * -YYLIϊ-1,3-OXATHIOLANE

NHj Λ λ Jj (XII) s

Solution of (1'R, 2'S, 5'R) -menthyl 5S- (cytosin-1 "-yl) -1,3-oxathiolane-2R-carboxylate (67 mg, 0.18 mmol) in THP (1 mL) was slowly added to a stirred suspension of lithium aluminum hydride (19 mg, 0.5 mmol) in THF (2 mL) at ambient temperature under argon and stirring was continued for 30 minutes.

The reaction was then quenched with methanol (3 mL) followed by the addition of silica gel (5 g). The resulting slurry was stirred for 30 minutes and then applied to a short column packed with Celite and silica gel and eluted with 1: 1: 1 → 1 * EtOAc-hexane-methanol (50 mL). The eluate was concentrated and subjected to silica gel column chromatography (EtOAc-hexane-methanol 1: 1: 1) to give a gummy solid.

This solid was azeotroped with toluene to give 38 mg (94%) of the desired product: [α] D-122 ° (c, 1.01, MeOH); mp: 128-130 ° C? si 102279

1H NKR

(CD3OD) δ 3.05 (dd, 1H, J = 4.3, 11.9 Hz) 3.42 (dd, 1H, J ~ 5.3, 11.9 Hz), 3.76-3.89 (m, 2H), 5.19-5.21 (m, 1H), 5.81 (d, 1H, J = 7.6Hz), 6.20-6.23 (m, 1H), 7.01-7.16 (bra, 2H, exchangeable), 7.98 (d, 1H, J = 7.5 Hz); 13 C (CD 3 OD) δ 38.5, 64.1, 88.0, 88.9, 95.7, 142.8, 157.9, 167.7.

Example 17

2S-HYDRQKSIMETYYLI-5R- (CYTOSIN-1-YL * \ -1,3-OXATHIOLANE

NH 2

rS

(Xii)

Solution of (1'R, 2'S, 5'R) -menthyl 5R- (cytosin-1 "-yl) -1,3-oxathiolane-2S-carboxylate (102 mg, 0.27 mmol) in THF (3 mL) was slowly added to a stirred suspension of lithium aluminum hydride (20 mg, 0.54 mmol) in THF (2 mL) at ambient temperature under argon, stirring was continued for 30 minutes, and the reaction was then quenched with methanol (5 mL) followed by · * Silica gel (7 g) was added and the resulting slurry was stirred for 30 minutes and then applied to a short column packed with Celite and silica gel and eluted with 1: 1: 1 EtOAc-hexane-methanol. (50 mL) The eluate was concentrated and subjected to silica gel column chromatography (EtOAc-hexane-11N-MeOH 1: 1: 1) to give a gummy solid which was azeotroped with toluene to give 50 mg (82%). ) as a white solid: t ^] „+ 125e (c, 1.01,

MeOH); mp: 130-132eC; 1 H HRR (CD 3 OD) δ

3.05 (dd, 1H, J = 4.3, 11.9 Hz), 3.42 (dd, 1H, J * 5.3, 11.9 Hz), 3.76-3.89 (m, 2H), 5.19-5.21 (m, 1H), 5.81 (d, 1H, J = 7.6 Hz), 6.20-6.23 (m, 1H), 7.01-7.16 (brm, 2H, exchangeable), 7.98 (d, 1H, J = 7.5 Hz); 13 C (CD3OD) δ 38.5, 64.1, 88.0, 88.9, 95.7, 142.8, 157.9, 167.7.

52 102279

Example 18

/1*11.2*8.5*1 »-MENTHYL-5R-15 * -FLUOROCYTOSIN-1 * -YL) -1,3-OXA-THIOLANE-2S-CARBOXYLATE

To a suspension of 5-fluorocytosine (155 mg, 1.2 mmol) in CH 2 Cl 2 (1 mL) at room temperature under argon was added sequentially 2,4,6-collidine (0.317 mL, 2.4 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate (0.551 ml, 2.4 mmol). The resulting mixture was stirred for 15 minutes to give a clear solution. (1'R, 2'S, 5 * R) -menthyl 5R-acetoxy-1,3-oxathiolane-2S-carboxylate (330 mg, 1 mmol) in CH 2 Cl 2 (0.5 mL) was added followed by iodotrimethylsilane (0.156 mL, 1.1 mmol) was added. Stirring was continued for 3 hours. The mixture was diluted with CH 2 Cl 2 (20 mL) and washed sequentially with saturated aqueous NaHSO 3, water, brine and then concentrated. The residue was taken up in ether-hexane (1: 1, 10 mL) and saturated aqueous NaHCO 3 (2 mL) and stirred at room temperature for 15 minutes. The aqueous layer was removed and the organic phase was centrifuged. . to give a white solid which was washed with hexane (2 x 5 mL) and then dried in vacuo. The product thus obtained (1'R, 2'S, 5'R) -menthyl 5R- (5 "- fluorocytosin-1" -yl) -1,3-oxa-thiolane-2S-carboxylate (350 mg , 88%) contained about 6% * · * * (1 * R, 2'S, 5 * R) -menthyl-5S- (5 "-fluorocytosin-1" -yl) -1,3-oxathiolane-2S- carboxylate (NMR). This material was recrystallized from MeOH / CH 2 Cl 2 / benzene to give a crystalline product: i: [ot] D + 22e (c, 0.19, MeOH); mp: 216-218 ° C, 1 H NMR (CDCl 3) δ 0.78 (d, 3H, J = 7Hz), 0.91 (t, 6H, J = 7.3 Hz), 1.00 (m, 2H), 1.39-2.04 (m, 7H), 3.12 (dd, 1H, J * = 6.6 Hz, 6.1 Hz), 3.52 (dd, 1H, J = 4.7 Hz, 6.1 Hz), 4.79 (dt, 1H, J <4.4 Hz, 4.3 Hz), 5.46 (S, 1H), 5.75 (bs, 1H, exchangeable), 6.42 (5t, 1H, J = 5.0 53 102279

Hz), 8.10 (bs, 1H, exchangeable), 8.48 (d, 1H, J <6.6 Hz); 13 C NMR (CDCl 3 -DMSO-d 6): δ 16.7, 21.2, 22.4, 23.7, 26.6, 31.8, 34.4, 36.6, 40.5, 47.2, 77.1, 79.1, 90.8, 126.3 (d, J <33 Hz), 137.1 (d , J «= 244 Hz), 154.2, 158.3 (d, J« 15 Hz), 170.1.

Example 19

flfS.2 * R.5'S1-MENTHYL-5S- (5 "-FLUOROCYTOSIN-1" -YL) -1,3-OXA-THILALAN-2R-CARBOXYATE

f o N

To a suspension of 5-fluorocytosine (180 mg, 1.4 mmol) in CH 2 Cl 2 (1 mL) at room temperature under argon was added sequentially 2,4,6-collidine (0.46 mL, 3.5 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate (0 mL). , 67 mL, 2.9 mmol). The resulting mixture was stirred for 15 minutes to give a clear solution. (1'S, 2'R, 5'S) -menthyl-5S-acetoxy-1,3-oxathiolane-2R-carbol was added. ; carboxylate (414 mg, 1.25 mmol) in CH 2 Cl 2 (0.6 mL) to which was added iodotrimethylsilane (0.18 mL, 1.27 mmol). The resulting mixture was stirred for 1 hour. The mixture was diluted with CH 2 Cl 2 (20 μL mL) and washed sequentially with saturated aqueous NaHSO 3, water, brine. The solvent was evaporated and the residue was taken up in ether-hexane (1: 1, 10 ml) and saturated aqueous MaHCO 3 (2 ml) and stirred at room temperature for 15 minutes. The aqueous layer was removed and the organic phase was centrifuged to give a white solid which was washed with hexane (3 x 5 mL) and then dried in vacuo. The product thus obtained (1'S, 2'R, 5'S) -menthyl 5S- (5M-fluorocytosin-1 "-yl) -1,3-oxathiolane-2R-carboxylate (454, 91%) containing about 7% (1'S, 2'R, 5, S) -menthyl 5R- (5 "-fluorocytosin-1" -yl) -1,3-oxa-54 102279 thiolane-2R-carboxylate (shown by 1 H NMR) , recrystallized from benzene-CH 2 Cl 2 -MeOH to give the title compound: [α] D 26-20 ° (c, 0.072, MeOH), mp 220-222 ° C (decomposed), 1 H NMR (CDCl 3) δ 0.80 (d , 3H, J «= 7 Hz), 0.90 (t, 6H, J« 7 Hz), 1.0 (a, 2H) »1.39-2.04 (m, 7H), 3.12 (dd, 1H, J« 6.6 and 6 Hz ), 3.52 (dd, 1H, J <5 and 6 Hz), 4.8 (dt, 1H, J = 4.4 and 4.3

Hz), 5.46 (s, 1H), 5.78 (bs, 1H, exchangeable), 6.42 (t, 1H, J = 5 Hz), 8.1 (bs, 1H exchangeable), 8.5 d, 1H, J-6.6 Hz); 13 C (CDCl 3) δ 16.2, 20.7, 21.9, 23.3, 26.2, 31.4, 34.0, 36.3, 40.1, 46.8, 76.7, 78.7, 90.5, 125.9 (d. J * 33 Hz), 136.5 (d, J = 242 Hz) , 153.7, 158.2 (d, J «14 Hz), 169.6.

Example 20

2S-HYDROXIMETHYL-5R- (5 * -FLUOROCYTOSIN-1 * -YL1-1,3-OXATHIOLAA-NI

O nh2 ΥΎ

H0 ^ y ^ F

To a suspension of lithium aluminum hydride (10 mg, 0.54 mmol) in THF (1 mL) at ambient temperature under an argon atmosphere was slowly added a solution of (1'R, 2'S, 5'R) -menthyl-5R- (5 "-fluorocytosine). "-yl) -1,3-oxathiolane-2S-carboxylate (54 mg, 0.135 mmol) • · ***. In THF (2 mL). The reaction mixture was allowed to stir for 30 minutes, then quenched with excess methanol (2 mL), followed by the addition of silica gel (3 g). The resulting slurry was subjected to silica gel column chromatography (EtOAc-hexane-MeOH, 9: 1: 1: 1) to give a gummy solid which was dried. ; : azeotropically with toluene to give 20.7 mg (63%) of a white solid as the product: [<X] D26 + 114e (c, 0.12,

MeOH) 1 H NMR (DMSO-d 6) δ 3.14 (dd, 1H, J δ 4.3, 11.9 Hz), 3.42 (dd, 1H J-5.3, 11.9 Hz), 3.76 (m, 2H), 5.18 (o, 1H), 5.42 (t, 1H, J <4.8 Hz), 6.14 (m, 1H), 7.59 (br m, 1H, exchangeable), 7.83 (br m, 1H exchangeable), 8.20 (d, 1H, J = 7.66 Hz).

55 1 0 2 2 7 9

Example 21

2R-HYDROXIMETHYL-5S- (5 1-FLUOROCYTOSIN-11-YL) -1,3-OXATHIOLA-NI

° vs N yNHj

Y Y

Η0 \ γΝΑ s- '

To a stirred suspension of lithium aluminum hydride (22 mg, 1.13 iranol) in THF (2 mL) was slowly added at ambient temperature under argon (1'R, 2'S, 5'R) -menthyl-5S- (5 "-fluorocytosine-1 "-yl) -1,3-oxathiolane-2R-carboxylate (91 mg, 0.23 mmol) in THF (8 mL). The reaction mixture was allowed to stir for 2 hours, and quenched with methanol (3 mL), followed by the addition of silica gel (5 g). The resulting slurry was stirred for 30 minutes. The mixture was then passed through a short pad of Celite and silica gel and eluted with Is 1: 1 EtOAc-hexane-methanol (10x5 mL). The eluate was concentrated and subjected to silica gel column chromatography (EtOAc-hexane-methanol, 1: 1: 1) to give a gummy solid.

This solid was azeotroped with toluene to give 45 mg (80%) of the desired product: [α] D 26-119 ° (c, 1.01, MeOH), 1 H NMR (DMSO-d 6) δ 3.14 (dd, 1H , J = 4.3, 11.9 Hz), 3.42 (dd, 1H, J = 5.3, 11.9 '2 · Hz), 3.76 (m, 2H), 5.18 (m, 1H), 5.42 (t, 1H, J = 4.8 • · ·: ... · Hz), 6.14 (m, 1H), 7.59 (br m, 1H, exchangeable), 7.83 (br n, 1H exchangeable), 8.20 (d, 1H J = 7.66 Hz).

♦ · ♦ • · · • · · • · · · · · · · · · · • • • •

Example 22 CIS-2 (N-METHYL-N-METORSIAMINOCARBONYL1-5-FURASIL-1'-YL1-

1.3-OKSATIQLAANI

L \ J

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (107 μΐ, 0.552 mmol) was added to a stirred suspension of uracil (31 mg, 0.276 mmol) in dichloromethane (1.5 mL) containing collidine (73 μΐ, 0.552 mmol) under argon. The resulting mixture was stirred for 15 minutes to obtain a homogeneous solution. A solution of trans-2- (N-methyl-N-methoxyaminocarbonyl) -5-acetoxy-1,3-oxathiolane (50 mg, 0.23 mmol) in dichloromethane (1 mL) was added, followed by iodotrimethylsilane (TMSI) ( 33 μΐ, 0.23 mmol). The reaction was allowed to proceed for 2.5 h and then quenched with saturated NaHCO 3 and Na 2 S 2 O 3 solution (1: 1). The resulting mixture was stirred for 5 minutes and then transferred to a separatory funnel using additional dichloromethane. The aqueous phase was removed and the organic layer was washed with saturated Na 2 S 2 O 3, water, brine and then dried (Na 2 SO 4). Evaporation of the solvent under reduced pressure gave the crude product which was triturated with EtOAc-hexane (1: 1) to give 54 mg (87%). the title compound as a white solid; • · • · · t * · ti *. 1 H NMR (CDCl 3): δ 3.14 (d of d, 1H, J = 8.0, 11.8 *** 1 H 2), 3.23 (S, 3H), 3.38 (d of d, 1H, J = 4.7, 11.8 Hz) , 3.74 (s, 3H), 5.80 (d, 1H, J = 8.2 Hz), 5.82 (S, 1H), * * 6.44 (d of d, 1H, J = 4.7, 8.0 Hz), 8.64 (d, 1H, J = 8.2 Hz), 9.64 (br s, 1H).

57 102279

Example 23

CIS AND TRANS-2-BENZQYL-5-ACETQXY-1,3-QUAXATIAN

Phenylglyoxal monohydrate (608 mg, 4.0 mmol) and 2,5-dihydroxy-1,4-dithiane (304 mg, 2.0 mmol) were heated at 65 ° C for about 5 minutes until the reagents melted. The reaction mixture was diluted with dichloromethane (40 mL). Pyridine (1.32 mL, 16.0 mmol), 4-dimethylaminopyridine (DMAP) (48 mg) and acetyl chloride (0.85 mL, 12.0 mmol) were added to the stirred solution at 0 ° C. The reaction mixture was stirred at room temperature for 4.5 hours and diluted with brine (15 mL). The organic layer was separated, washed with sodium bicarbonate and brine, dried (sodium sulfate), and evaporated to a brown liquid (1.80 g). The residue was purified by silica gel chromatography eluting with hexane-EtOAc (3: 1) to give the trans and cis isomers (2.4: 1) (714 mg, 71%); NMR (CDCl 3) δ 2.0 (s, 3H), 2.14 (s, 3H), 3.15-3.25 (m, 1H), 3.35-3.45 (m, 1H), 6.42 (s, 1H), 6.51 (S, 1H) , 6.7 (m, 1H), 6.9 (m, 1H), 7.4-7.5. (m, 2H), 7.55-7.65 (m, 1H), 7.9-8.0 (m, 2H).

• · · • · · • t · • · · • · Example: 24

CIS-2- <1 * -PYRROLIDINECARBONYL11-5-ACETOXY-1,3-OXATHIOLANE

C-Vr se 102279 5-Acetoxyoxathiolane-2-carboxylic acid (576 mg, 3.0 mmol), pyridine (0.533 mL, 6.60 mmol) and to a solution of dichloromethane (20 mL) at 0 ° C was added oxalyl chloride (0.314 mL, 3.6 mmol). The reaction was stirred at 0 ° C for 30 minutes and then cooled to -70 ° C during which time pyrrolidine (0.5 mL, 6.0 mmol) was added in one portion. The reaction was stirred at room temperature for 2 hours, after which 1N HCl (5 mL) was added. The organic layer was separated, washed with sodium bicarbonate and brine, dried (sodium sulfate), and concentrated to give 0.851 g of crude product. This residue was purified by silica gel chromatography eluting with EtOAc / hexane (9: 1) to give 616 mg (84%) of the desired product.

1 NMR (CDCl 3) δ 1.80-2.00 (m, 4H), 2.11 (s, 3H), 3.20-3.35 (m, 2H), 3.40-3.55 (m, 4H), 5.76 (s, 1H), 6.60 (m, 1H).

Example 25

CIS-2-CARBOMETHOXY-5- (5 * -BROMMIURASIL-1H-YYL-1,3-OXATHIOLANE

xY

Y y ... s-f::: • · · • · · f * * I · <•

Bis-trimethylsilylacetamide (4 mL, 16.2 mmol) was added to a suspension of 5-9 bromouracil (1.5 g, 7.9 mmol) in dichloromethane (10 mL). The reaction was stirred for 30 minutes to give a clear solution. A solution of 2-carbomethoxy-5-acetoxy-1,3-oxathiolane (1.6 g, 7.8 mmol, cis: trans 1: 2) in dichloromethane (5 mL) was then added, followed by TMSI (1.1 mL). , 7.7 mmol).

59 102279

The reaction was stirred at ambient temperature for 18 hours and treated slightly with saturated Na 2 S 2 O 3 and NaHCO 3 solutions to give a white suspension. The suspension was filtered to remove a solid (unreacted base). The filtrate was concentrated and triturated with EtOAc-hexane (1: 1) to give a white solid which was filtered, washed and dried to give 0.98 g (38%) of product.

1 H NMR (CDCl 3) δ 3.2 (dd, 1H, J = 7 and 12 Hz), 3.47 (dd, 1H, J * 5 and 12 Hz), 3.87 (s, 1H), 5.50 (s, 1H), 6.42 ( dd, 1H, J * = 5 and 7 Hz), 8.72 (s, 1H), 9.19 (br s, 1H).

Example 26

CIS-2-HYDRQKSIMETYYLI-5 <6'-KLQORIURASIL-1 * YL \ -1.3-OXA-thiolane

TMSOTf (4.5 mL, 27.3 mmol) was added to bis-O-silyl-6-chlorouracil (9.5 g, 32.6 mmol) and 2-carbethoxy-5-acetoxyoxathiolane (6.3 g). , 27.4 mmol) in 1,2-dichloroethane (40 mL). The resulting clear solution was slowly heated to 60 ° C and maintained at this temperature for 1 hour during which time a thick precipitate formed. The reaction was cooled to ambient temperature and the white precipitate was collected after filtration, washed and dried to give 3.5 g (42%) of the cis-nucleoside ester product only (1 H NMR) To a suspension of the nucleoside ester product (2.6 g, 8.5 mmol) in tetrahydrofuran (THF) (50 mL) under argon was slowly added LiBH 4 ( 0.4 g, 18.6 mmol) The reaction was stirred for 5 h, then quenched with methanol, and the solvent was removed and the resulting fibrous material was subjected to column chromatography (2: 2: 1, EtOAc-hexane-MeOH, v / v) to give 1.9 g (85%) of the title nucleoside were obtained The total yield of the two transformations was 64%, HPLC purity (96%), mp 202-204 ° C, 1 H NMR (DMSO-d 6) Δ 3-09-3.30 (1H), 3.38-3.47 (1H), 3.60-3.72 (2H), 4.45 (1H), 5.05-5.09 (1H), 5.27 (1H), 5.5 9-5.62 (1H), 6.71-6.76 (1H); 13 C NMR (DMSO-d 6) δ 32.6, 63.2, 64.2, 84.7, 87.9, 94.4, 106.6, 128.6, 164.4.

Example 27

(L S.2'R.5'S -MENTHYL-5S- (N-4 "-ACETYLCYTOSIN-1" -YYLIΪ-1.3-0KSATI0LAANI-2R-KARBQKSYLAATTI

O. M NHCOMe To a stirred suspension of N-4-acetylcytosine (68 mg, 0.4 mmol) in dichloromethane (0.5 mL) containing 2,4,6-collidine (105 μΐ, 0.8 mmol) under argon was added trimethylsilyl. -litrifluoromethanesulfonate (155 μΐ, 0.8 mmol). The resulting mixture. . stirred for 15 minutes to give a homogeneous solution.

• ·

The substrate, (1'S, 2'R, 5'S) -menthyl 5S-acetoxy-1,3-oxathiolane-2R-carboxylate (110 mg, 0.333 mmol) was introduced into the above It! ‘I * solution in one batch. In a separate flask equipped with a condenser, a solution of hexamethyldisilazane (34 μΐ, 0.167 mmol) and iodine (42 mg, 0.167 mmol) in dichloromethane (0.5 mL) under argon was refluxed. 30 minutes. After cooling to room temperature, the resulting purple solution was transferred via syringe to a mixture containing substrate and silylated base.

The reaction mixture was kept at room temperature for 7 hours and then quenched with a 1: 1 mixture of saturated NaHCO 3 and 61 102279

Na2S203: a. The resulting mixture was stirred for 5 minutes and then transferred to a separatory funnel with the addition of additional dichloromethane. The aqueous phase was removed and the organic layer was washed with saturated Na 2 S 2 O 3, water, brine and then dried (Na 2 SO 4). The solvent was removed under reduced pressure to give 153 mg of crude product. cis - [(1 / S, 2rR, 5, S) -menthyl 5S- (N-4 "-acetylcytosin-1" -yl) -1,3-oxathiolane-2R-carboxylate] and trans - [(1'S To determine the ratio of, 2'R, 5'S) -menthyl-5R- (N-4 "-acetylcytosin-1M-yl) -1,3-oxathiolane-2R-carboxylate] to the crude product, 1 H NMR analysis was performed on CDCl 3. By evaluating the signals of the C6 protons of the cytosine moiety, the ratio of the cis isomer [S 8.70 (d, J = 7.6 Hz)] to the trans isomer [<f 7.79 (d, J = 7.6 Hz)] was determined to be 7: 1. .

Example 28

CIS-2-CARBOXYL-5-OJRASIL-1 * -YL \ -1,3-OXATHIOLANE

h °,

Iodotrimethylsilane (118 μΐ, 0.832 mmol) was added to a stirred mixture of bis-trimethylsilyluracil (122 mg, 0.475 mmol) and trans-2-carboxyl-5-acetoxy-1,3-oxathiolane (76 mg, 0.396 mmol). .. * to a suspension in dichloromethane (2.5 mL) containing collidine (53 μΐ, 0.396 mmol). The resulting mixture was stirred for 18 hours · »* J;‘ at room temperature under argon and then quenched by the addition of 5 ml of 0.5 M sodium carbonate solution. The aqueous phase was acidified with 1 M HCl to pH 4, followed by extraction with tetrahydrofuran (3 x 6 mL). The combined extract was dried over MgSO 4 and the solvent was removed under reduced pressure. The resulting crude product was triturated with dichloromethane to give a white suspension. The white solid was separated by centrifugation and dried in vacuo to give 27 mg of the desired product, the 1 H NMR spectrum of which indicated the presence of a small amount of uracil (ca. 10%) and that the isomeric purity was> 95%.

62 102279

The title compound had the following spectral data: 1 H NMR (DMSO d 6) δ: 2.26 (d of d, 1H, J ** 4.9, 12.3 Hz), 3.49 (d of d, 1H, J-5.2, 12.4 Hz), 5.57 (ε, 1H), 5.71 (d Of d, 1H, J = 2.2, 8.0 Hz; this signal collapsed to a Doublet on treatment with D20 (J «= 8.2 Hz)), 6.29 (t, 1H, J = 5.2 Hz ), 8.07, (d, 1H, J = 8.2 Hz), 11.41 (br s, 1H, exchanged with D 2 O).

Example 29

CIS-2- (1 · -PYRROLIDINECARBONYL) -5-FURASIL-1 * -YL) -1,3-OXYL OIL I

Λ VV

A \ ^ y

Iodotrimethylsilane (37 μΐ, 1 equivalent) was added to cis-2- (1'-pyrrolidinecarbonyl) -5-acetoxy-1,3-oxathiolane (64 mg, 0.26 mmol) and bis-trimethylsilyluracil (80 mg, 1.2 equivalents). ) to a stirred solution in dichloromethane (1.5 ml) under argon. The reaction mixture was kept for 1 hour 20 minutes at room temperature. The reaction was quenched with a 1: 1 mixture of saturated Na 2 S 2 O 3 and NaHCO 3 (2 mL), then diluted with dichloromethane (4 mL). The resulting mixture was stirred for 5 minutes and then transferred to a separatory funnel with the addition of dichloromethane. The aqueous phase was removed and the organic phase was washed with water, brine and dried over anhydrous Na 2 SO 4. Removal of the solvent under reduced pressure and treatment of the crude product thus obtained by column chromatography (7%, MeOH-EtOAc) gave 74 mg (95%) of the title compound; } T: 1 H NMR (CDCl 3): δ 1.85-2.00 (m, 2H), 2.00-2.15 (m, 2H), 3.25-3.70 (m, 6H), 5.61 (s, 1H), 5.80 (d of d, 1H, J = 2.3, 8.2 Hz), 6.44 (d of d, 1H, J = 4.8, 7.0 Hz), 8.29 (br s, 1H), 8.88 (d, 1H, J = 8.1 Hz).

63 102279

Example 30

CIS-2-benzoyl-5-lURASIL-1> YL \ -1.3-OXATHIOLANE

p-F

Trimethylsilyl trifluoromethanesulfonate (92 μΐ, 0.475 mmol) was added to a stirred suspension of uracil (50 mg, 0.238 mmol) in dichloromethane (1.5 mL) containing collidine (63 μΐ, 0.475 mmol) under argon. The resulting mixture was stirred for 15 minutes to obtain a homogeneous solution. A mixture of 2-benzoyl-5-acetoxy-1,3-oxathiolane (50 mg, 0.198 mmol) (2.4: 1, trans: cis) was added as a solution in dichloromethane (1.5 mL) followed by iodotrimethylsilane (28 μL, 0.198 mmol). The reaction was allowed to proceed for 22 hours and then quenched with a 1: 1 mixture of saturated NaHCO 3 and Na 2 S 2 O 3. The resulting mixture was stirred for 5 minutes and then transferred to a separatory funnel with the addition of dichloromethane. The aqueous phase was removed and the organic layer was washed with saturated Na 2 S 2 O 3, water, brine and then dried (Na 2 SO 4). Thin layer chromatographic analysis of the impure product showed that a small amount of · .; the starting material had not reacted. Impure product tritu-. ···. was treated with EtOAc to give 26 mg (43%) of the title compound. distillate as a white solid; 1 H NMR (DMSO): δ 3.19 (d of d, 1H, d of d, J * 6.8, 12.1 Hz), 3.60 (d of d, 1H, J (5.1, 12.2 Hz), 5.77 (d, 1H, J — 8.2 Hz), 6.38 (d of d, 1H »J = 5.2, 6.9 Hz), 6.81 (s, 1H), 7.52-7.64 (m, 2H) , 7.66-7.76 (tt, 1H), 7.94-8.04 (m, 2H), 8.22 (d, 1H, J = 8.1 Hz), 11.44 (br S, 1H).

64 102279

Example 31

M1'R, 2'S, 5'm -MENTHYL-5S- {CYTOSIN-1 "-YL \ -1,3-OXATIQUEAN-2R-CARBOXYLATE

A mixture of (1'R, 2'S, 5'R) -menthyl 5S- (N-4 "-acetylcytosin-1" -yl) -oxathiolane-2R-oxathiolanecarboxylate (cis- isomer) and (1R, 2'S, 5'R) -menthyl 5S- (N-4 "-acetylcytosin-1" -yl) -oxathiolane-2R-oxathiolanecarboxylate (trans isomer) (47 mg, 0.11 mmol) was dissolved in dichloromethane (0.5 ml) and 2-propanol (1 ml). Trifluoroacetic acid (0.2 ml) was added to this solution, and the resulting mixture was heated at 60 ° C for 2 hours and then kept at room temperature for 14.5 hours. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO 3 solution, water, brine and then dried (anhydrous Na 2 SO 4). The solvent was removed under reduced pressure and the resulting product was dried in vacuo to give 40 mg (95%) of the title compounds. The Ή NMR spectrum of the above material showed> 97% purity. Based on the cytosine moiety in both isomers. · ,. The signals from C6 hydrogen were found to be. ** ·. that the ratio of isomers of cis- [(8.38 (d, J = 7.3 Hz)] and trans- [(7.48 (d, J = 7.3 • · ·.. ·. Hz)] was 12; 1. The title compound was obtained

I I I

with methanol and its physical properties were • · · * identical to those given in this example.

»• · ·

Example 32 • · ·::: fl'S.2'R.5'Sl-MENTHYL-5S-fN-4 "-acetylcytosine-1" -yl] -1,3-oxathiolane-2R-carboxylate = A _ O. k. NHAc 102279 (1'S, 2'R, 5'S) -Mentyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate (55 mg, 0.166 mmol) in dichloromethane (0.5 mL) and iodotrimethylsilane (0.026 mL, 0.166 mmol) was added to monosilylated N-4-acetylcytosine (59 mg, 0.198 mmol) obtained by refluxing N-4-acetylcytosine in 1,1,1,3,3,3-hexamethyldisilazane (HMDS) overnight with a catalytic amount of ammonium sulfate. and then removing HMDS, in dichloromethane (0.5 mL) under argon at room temperature. Stirring was continued for 19 hours, and thin layer chromatography showed that the starting oxathiolane was almost completely consumed. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, aqueous sodium thiosulfate solution and brine, dried over sodium sulfate, concentrated and dried to give 70 mg (100%) of crude products. 1 H NMR showed a cis: trans ratio of 15: 1 and the presence of about 4.6% unreacted oxathiolane.

1 H NMR (CDCl 3): 0.78 (d, 3H), 0.80-2.10 (m, 15H), 2.27 (s, 3H), 3.12-3.30 (a, 1H) 3.52-3.78 (m, 1H), 4.78 (m, 1H), 5.51 (S, 0896H), 5.60 (S, 0.046H), 5.82 (s, 0.058H), S 6.42 (t, 0.896H), 6.63 (dd, 0.046H), 6.68 (d, 0.058H) , 7.47 (d, 0.954H), 7.77 (d, 0.058H), 8.70 (d, 0.896H).

The main compound was isolated by crystallization from methanol or a trituration pad with ethyl acetate-ether.

• · · • · • 1 '** Example 33 i:: - ::: n 1 S. 2- [5-1-MENTHYL-5S- {N-4 "-AACYLTHYCOSIN-1" -YL] -1 -1-

** '1 0XATHIOLLAX-2R-CARBOXYLATE

• · «• · · M 2 2? - NHAc 66 1 0 2 2 7 9 2,6-Lutidine (0.023 mL, 0.199 mmol) and trimethylsilyl trifluoromethanesulfonate (0.038 mL, 0.199 mmol) were added to N-4-acetylcytosine (30.5 mg, 0.199 mmol) in dichloromethane (0 , 2 ml) at room temperature under argon. The mixture was stirred for 20 minutes and (1'S, 2'R, 5'S) -menthyl 5S-acetoxy-1,3-oxathiolane-2R-carboxylate (55 mg, 0.166 mmol) in dichloromethane (0.3 mL) and iodotrimethylsilane (0.026 mL) were added sequentially. ml, 0.166 mmol). Stirring was continued for 2.5 hours and thin layer chromatography showed complete consumption of the starting oxathiolane. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate, aqueous sodium thiosulfate and brine, photographed with sodium sulfate, concentrated and dried to give 70 mg (100%) of crude products. NMR showed a cisstrans ratio of 10: 1 and no other detectable impurities in the spectrum.

NMR (CDCl 3): 0.78 (d, 3H), 0.80-2.10 (m, 15H), 2.27 (S, 3H), 3.16 (dd, 0.91H), 3.25 (d, 0.09H), 3.63 (dd, 0.91H) ), 3.74 (dd, 0.09H), 4.78 (m, 1H), 5.51 (s, 0.91H), 5.82 (s, 0.09H); S 6.42 (t, 0.91H), 6.68 (d, 0.09H), 7.47 (d, 1H), 7.77 (d, 0.09H), 8.70 (d, 0.91H).

Example 34 CIS- and TRANS-ISOPROPYLI-5-ACETQSI-1. 3-OXATTOLANE-2-CARBQK CYLATE • · · 1 • · · • «**: l-PrOjC .0.

1 c · and trans-acetoxy-1,3-oxathiolane-2-carboxylic acid (260 mg, 1.3528 mmol) and isopropanol (0.11 mL, 1.3528 mmol) in dichloromethane (4 mL) at 0 ° C was treated with dicyclohexylcarbodiimide (DCC) (279 mg, 1.3528 mmol) in dichloromethane (1 mL) and 4-dimethylaminopyridine (DMAP) (14 mg, 0.135 mmol). The mixture was stirred at room temperature overnight, then diluted with ether and filtered through a pad of Celite®. The filtrate was concentrated and the residue was chromatographed on silica gel with ethyl acetate-hexane to give the products as a colorless oil (263 mgf 83%).

S 1.26 (6 H, d); 2.10, 2.11 (3 H, s); 3.13-3.46 (2 H, m); 5.05 (1 H, m); 5.60, 5.61 (1 H, s); 6.63 (0.54 H, m); 6.78 (0.46 H, d).

Example 35

CIS-ISOPROPYL-5- (SYTQSIN-1'-yls-1,3-OKSATTOLAANI-2-carboxylate-methacrylate

2,4,6-Collidine (0.23 mL, 1.74 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate (0.4 mL, 1.74 mmol) were added to cytosine (96.7 mg, 0.87 mmol). suspension in dichloromethane (0.8 ml) at room temperature under argon. The mixture was stirred for 25 minutes and a solution of cis: trans (1.2: 1) isopropyl 5-acetoxy-1,3-oxathiolane-2-carboxylate (168 mg, 0.717 mmol) in dichloromethane (0.8 mL) and iodotrimethylsilane. *. (0.114 mL, 0.788 mmol) was added sequentially. Stirring was continued for one hour and the reaction mixture was diluted with dichloromethane, treated with saturated sodium thiosulfate, water and brine, dried over sodium sulfate and concentrated. The residue was triturated with ether-hexane (1: 1, 7 mL) and saturated aqueous sodium bicarbonate (1.5 mL). The Ve - ::: success layer was removed and the remaining mixture was centrifuged.

The solid was washed twice with hexane and the washings were combined with the liquid obtained by centrifugation, washed with 1N HCl, water and brine, dried and concentrated to give the unreacted starting material as essentially 68-102279 pure (64 mg, 38%, cis: trans = 1: 9). ). The white solid was dried to give the products as a 12: 1 mixture of cisstrans (122.6 mg, 60%).

1 H NMR (CDCl 3): δ 1.30 (t, 6H), 3.11 (dd, 1H), 3.52 (dd, 1H), 5.11 (m, 1H), 5.45 (e, 1H), 5.82 (d, 1H), 6.47 (dd, 0.92H), 6.72 (m, 0.08H), 7.49 (d, 0.08H), 8.32 (d, 0.92H).

Example 36

CIS AND TRANS — T — BUTYL — 5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLATE

t-BuOjC .0. .OAc A solution of S- 'cis- and trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (176 mg, 0.915 mmol) and t-butanol (0.095 mL, 0.915 mmol) in dichloromethane (4 mL) at 0 ° C. was treated with DCC (207 mg, 1 mmol) in dichloromethane (1 mL) and DMAP (11 mg, 0.09 mmol). The mixture was stirred at room temperature overnight, then diluted with ether and filtered through a pad of Celite®. Soda. . concentrated and the residue was chromatographed on silica gel with ethyl acetate-hexane to give the products as a colorless oil (175 mg, 77%).

NMR (CDCl 3): δ 1.46 (9H, d); 2.07, 2.09 (3 H, s); 3.10-3.44 (2 H, m); 5.50, 5.52 (1 H, s); 6.60 (0.42 H, n); 6.74 (0.58 H, d).

• · · • · ·

Example 37

CIS-T-BUTYL-5- (CYTOSIN-YL # l \ -1,3-OXATHIOLANE-2-carboxylate-methacrylate

69 102279 υύ * "BUOfi \ ° yN ^ 2,4,6-Collidine (0.187 mL, 1.4 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate (0.325 mL, 1.4 mmol) were added cytosine (78.6 mg, 0 mmol). , 7 mmol) in dichloromethane (0.6 ml) at room temperature under argon, the mixture was stirred for 25 minutes and a solution of cis: trans (1: 1.4) in t-butyl 5-acetoxy-1,3-oxathiolane-2-carboxylate (146.5 mg, 0.59 mmol) in dichloromethane (0.6 mL) and a solution of iodotrimethylsilane (0.092 mL, 0.65 mmol) were added sequentially Stirring was continued for one hour and the reaction mixture was diluted with dichloromethane, washed with saturated sodium thiosulfate, water and The residue was triturated with ether-hexane (1: 1, 7 mL) and saturated aqueous sodium bicarbonate (1.5 mL), the aqueous layer was removed and the remaining mixture was centrifuged.

The solid was washed twice with hexane and the washings were combined with the liquid obtained by centrifugation, washed with 1N HCl, water and brine, dried and concentrated to give the unreacted starting material as substantially pure (77 mg, 52.6%, cis: trans = 1: 1). ). The white solid was dried to give the products as a 16: 1 cis: trans mixture (82.6 mg, 46.4%).

• «·· * \ i .: * Η NMR (CDCl 3): δ 1.50, 1.52 · *. ·· * (s, 9H), 3.12 (dd, 0.94H), 3.20 (dd, 0.06H), 3.52 ( dd, 0.94H), 3.72 (dd, 0.06H), 5.37 (s, 0.94H), 5.75 (s, 0.06H), 5.82 (d, 1H), 6.44 (dd, 0.94H), 6.71 (d, 0.06H), 7.49 (d, 0.06H), 8.38 (d, 0.98H).

• · · 70 102279

Example 38

CIS- AND TRANS-2-N.N-DIETHYLAMINO CARBOXYL-5-ACETOXY-I.3-OXY--OLAF I

O

Solution of cis- and trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (119 mg, 0.62 mmol) and diethylamine (0.07 mL, 0.68 mmol) in dichloromethane (2 mL) at 0 ° C: was treated with DCC (140 mg, 0.68 mmol) in dichloromethane (1 mL) and DMAP (7.6 mg, 0.06 mmol). The mixture was stirred at room temperature overnight, then diluted with ether and filtered through a pad of Celite®. The filtrate was concentrated and the residue was chromatographed on silica gel with ethyl acetate-hexane to give the products as a colorless oil (84.5 mg, 55%).

NMR (CDCl 3): δ 1.10, 1.40 (6H, t); 2.07, 2.10 (3 H, s); 3.15-3.56 (6 H, n); 5.80, 5.87 (1 H, s); 6.58 (0.53H, m); 6.83 (0.47H, d).

Example 39 CIS-2-N.N-DIETHYLAMINO CARBONYL-5- (CYTOSIN-1'-YL) -1.3-OXSA-. - TIOLAANI • · '··· • · • · • ·

=; = · J V V

··· S— '• · · 2,4,6-Collidine (0.108 mL, 0.82 mmol) and t-butyldimethylsilyl trifluoromethanesulfonate (0.188 mL, 0.82 mmol) were added to cytosine (45.5 mg, 0, 41 mmol) in dichloromethane 102279 (0.4 mL) at room temperature under argon. The mixture was stirred for 25 minutes and a solution of cisttrans (1.12: 1) in 2-N, N-diethylaminocarbonyl-5-acetoxy-1,3-oxathiolane (84 mg, 0.34 mmol) in dichloromethane (0.4 mL) and a solution of iodotrimethylsilane (0.053 mL, 0.375 mmol) was added sequentially. Stirring was continued for one hour and the reaction mixture was diluted with dichloromethane, washed with saturated sodium thiosulfate, water and brine, dried over sodium sulfate and concentrated. The residue was triturated with ether-hexane (1: 1, 7 mL) and saturated aqueous sodium bicarbonate (1.5 mL). The aqueous layer was removed and the remaining mixture was centrifuged.

The solid was washed twice with hexane and the washings were combined with the liquid obtained by centrifugation, washed with 1N HCl, water and brine, dried and concentrated to give the unreacted starting material as substantially pure (17 mg, 20%, trans alone). The white solid was dried to give the products as a 24: 1 cis: trans mixture (47.5 mg, 47.5%).

1 H NMR (DMSO-d 6): δ 1.04 (t, 3H, J-7 Hz), 1.12 (t, 3H, J-7 Hz), 3.17 (dd, 1H, J-5 Hz, 9 Hz), 3.30 ( m, 4H), 3.53 (dd, 1H, J-5 Hz, 9 Hz), 5.74 (d, 1H, J-7 Hz), 5.96 (S, 1H), 6.28 (t, 0.96H, J-5 Hz) ), 6.62 (in, 0.04H), 7.16 (bS, NH), 7.22 (bs, NH), 7.60 (d, 0.04H), 8.46 (d, 0.96H, J = 7 Hz).

. . Example 40 ·· -

(S.2'R.5'S1 l-menthyl-1,3-OXATHIOLANE-2R-CARBOXYLATE

• · • · · ** A **

To a mixture of (1'S, 2'R, 5'S) -menthyl-5R-acetoxy-1,3-oxa-thiolane-2R-carboxylate (2.01 g, 6.08 mmol) and triethylsilane (9.67 mL, 60.05 mmol) at room temperature under argon, 72 102279, trimethylsilyl trifluoromethanesulfonate (1.17 mL, 6.04 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give the crude product. Chromatography on silica gel using hexane-ethyl acetate as eluent gave the product as a colorless oil.

1 H NMR (CDCl 3): δ 0.75-2.10 (m, 15H), 2.97-3.20 (m, 2H), 4.20-4.40 (m, 2H), 4.72 (dt, 1H), 5.45 (S, 1H) [α] ) D + 104 ° (c 1.16, CHCl 3).

Example 41 (1'S, 2'R, 5'S-MENTHYL-4R-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE AND S.2'5.5'SI-ENTHYL-4S-HYDROXY-1,3-OXYL-TOLANO-

2R-CARBOXYLATE

'OH

. . A mixture of (1'S, 2'R, 5'S) -menthyl-1,3-oxathiolane-2R-t ···] carboxylate (0.500 g, 1.84 mmol) and benzoyl peroxide • · '*! (0.489 g, 97%, 1.96 mmol) in 20 mL of benzene, heated to 1 * - 9% i **; at reflux for 6 hours. The organic solvent was removed in vacuo and the residue was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give the crude benzoate product. Subsequent chromatography using hexane-ethyl acetate as eluent gave the benzoate as a solid (0.21 g, 30.3%). A mixture of benzoate (0.200 g, 0.531 mmol) and potassium carbonate (0.073 g, 0.532 mmol) in THF-MeOH-H 2 O solution (4 mL / 5 mL / 2 mL) was stirred at 0 ° C for 7 h and the organic solvent was removed in vacuo. - 73 102279 where. The residue was diluted with H 2 O (7 mL) r extracted with ether (10 mL), acidified with HCl, and extracted with dichloromethane. The dichloromethane layer was dried over sodium sulfate and evaporated to dryness in vacuo to give the crude product.

Subsequent chromatography using hexane-ether as eluent gave the product as a solid (67 mg, 43.7%). 1 H NMR (CDCl 3): δ 0.75-2.10 (m, 15H), 4.03-4.83 (m # 2H), 5.52-5.75 ( m, 2H).

Example 42 tl · S.2 'R, 5' SI-MENTHYL-4R-CHLORO-1,3-OXATIQULAAN-2R-CARBOXYLATE AND IL'S (1'R.S'S1-MENTHYL-4S-KLCX) RI-1,3-OXATHIOLANE -2R-

CARBOXYLATE

AA,

To a mixture of (1'S, 2'R, 5'S) -menthyl 4R-hydroxy-1,3-oxa-thiolane-2R-carboxylate and (1'S, 2'R, 5'S) -menthyl-4S-hydroxylate 1,3-oxathiolane-2R-carboxylate (40 mg, 0.138 mmol) and. . methyl trifluoromethanesulfonyl chloride (18.24 μΐ, 0.239 mmol)% in dichloromethane (5 mL) at room temperature under argon, triethylamine (57.99 mL, 0.416 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give the crude product. Subsequent chromatography using hexane-ether as eluent gave the product as two diastereomers (18 mg, 42.3%, 14.6 mg, 34.2%) that were epimeric at C4.

2 H NHR CDCl 3): δ 0.75-2.05 (m, 15H), 4.55 (m, 1H) t 4.69 (m, 1H), 5.75 (o, 1H), 5.80 (m, 1H); S 0.75-2.10 (m, 15H), 4.33 (m, 1H), 4.78 (m, 1H), 5.56 (s, 1H), 5.68 (m, 1H).

74 102279

Example 43

CIS 2-CARBOETHOXY-4-ACETOXY-1,3-DIOXOLANE

O

Jv O JOAc »Ay o— 2 # 5: 1 mixture of cis- and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 mg, 2.16 mmol), 85% meta-chloroperbenzoic acid ( mCPBA) (68 mg, 3.81 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane (10 mL) were stirred under argon for 16 hours at room temperature. The resulting suspension was diluted with dichloromethane and water and stirred for 10 minutes. The aqueous phase was removed and the organic phase was washed successively with saturated sodium thiosulfate, water, brine and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product thus obtained was subjected to flash column chromatography (30% EtOAc-hexane) to give the title compound (yield 11%) having the following spectral data; 1 H NMR (CDCl 3) δ 1.31 (t, 3H, J = 7.2 Hz), 2.07 (s, 1H), 4.15 (d of d, 1H, J-4.5, 9.1 Hz), 4.21-4.29 (m, 3H) , 5.42 (S, 1H), 6.39 (d of d, 1H, ·, · J = 2.4, 4.5 Hz); 13 C NMR (CDCl 3): δ 14.05, 20.97, 29.69, 71.34, 94.04, 99.80, 167.19, 170.11.

IM

*; * • · «•« t * · '' Example 44

TRANS 2-CARBOETHOXY-4-ACETOXY-1,3-DIOXOLANE

i · · • ·

IM

»M« · »

. f. Q

JL o nOAc

At 75 102279 2.5 μl mixture of cis- and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 mg, 2.16 mmol) 85% mCPBA (68 mg, 3.81 mmol) and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane (10 mL) was stirred under argon for 16 hours at room temperature. The resulting suspension was diluted with dichloromethane and water and stirred for 10 minutes. The aqueous phase was removed and the organic phase was washed successively with saturated sodium thiosulfate, water, brine and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the crude product thus obtained was subjected to flash column chromatography (30% EtOAc-hexane) to give the title compound (yield 49%) having the following spectral data; 1 H NMR (CDCl 3): δ 1.29 (t, 3H, J-7.2 Hz), 2.09 (s, 1H), 4.12 (d of d, 1H, J-0.9, 9.1 Hz), 4.19-4.31 (m, 3H ), 5.53 (s, 1H), 6.48 (d of d, 1H, J-0.9, 3.9 Hz).

Example 45

CIS- AND TRANS-2-CARBOETHXY-4- (THYMIN-1'-YYL-1,3-DIOXOLANE

_ H n

s YY

To a stirred suspension of thymine (44.5 mg, 0.353 mmol) in dichloro-::: rimethane (1 mL) containing 2 , 6-lutidine (82 μΐ, 0.706 mmol) under argon, trimethylsilyl trifluoromethanesulfonate (136 μΐ, 0.706 mmol) was added. The resulting mixture was stirred for 15 minutes to obtain a homogeneous solution. A solution of the substrate, ethyl 4-acetoxy-1,3-dioxolane-2-carboxylate (60 mg, 0.294 mmol) in dichloromethane (1 mL) and iodotrimethylsilane 76 102279 (42 μΐ, 0.294 mmol) was added briefly to the above solution. The reaction mixture was stirred at room temperature for 5 hours and quenched with half-saturated Na 2 S 2 O 3 solution (2 mL), then diluted with dichloromethane (5 mL). The resulting mixture was stirred for 5 minutes and then transferred to a separatory funnel with the addition of additional dichloromethane. The aqueous phase was removed and the organic layer was washed with saturated Na 2 S 2 O 3, water, 1 M HCl, brine and then dried (Na 2 SO 4). The solvent was removed under reduced pressure to give an impure product. This material was suspended in dichloromethane (ca. 1.5 mL), and then triturated with a 1: 1 mixture of EtOAc-hexane (ca. 6 mL) to give 25 mg of cis nucleoside as a white solid; 1 H NMR (DMSO dr): δ

O

1.23 (t, 3H, J-7.1 Hz), 1.78 (d, 3H, J1 Hz), 4.15-4.30 (m, 4H), 4.38 (d of d, 1H, J = 2.3, 9.8 Hz), 5.33 (S , 1H), 6.33 (d of d, 1H, J12.3, 5.8 Hz), 7.52 (d, 1H, J1.1, Hz), 11.42 (br s, 1H).

The trituration result was concentrated and subjected to column chromatography (70% EtOAc-hexane) to give 26 mg of two nucleosides as a 1: 1 mixture; 1 H NMR (CDCl 3): δ 1.33 (t, 1.5H, J-7.2 Hz), 1.35 (t, 1.5H, J-7.2 Hz), 1.91-1.99 (two overlapping d, 3H), 4.16 (d of d 0.5H, J = 1.9, 9.7 Hz), 4.20-4.38 (m, 3H), 4.53 (d of d, 0.5H, J <5.8, 9.7 Hz), 5.30 (S, 0.5H), 5.72 (S , 0.5H), 6.44 (d of d, • · 0.5H, J-3.3, 5.4 Hz), 6.60 (d of d, 0.5H, J «2.0, 5.8 * ::: 'HZ), 7.10 (d, O.SH, J = 1.3 Hz), 7.75 (d, O.SH, J-1.3 v 1 Hz), 9.40 (br s, 0.5H), 9.43 (br S, 0.5H).

• · «• · · • · · · · · · ·

Example 46

CIS AND TRANS-2-CARBOXETOXY-4- (N-4'-ACETYLCYTOSIN-1'-YL--1,3-DIOXOLAN

77 1 0 2 2 7 9 Ο. N NHAc i vy To a stirred suspension of N-acetylcytosine (66 mg, 0.430 mmol) in dry CH 2 Cl 2 (1.5 mL) under argon was added sequentially 2,6-lutidine (100 μΐ, 0.859 mmol) and trimethylsilyl trifluoromethanesulfonate (166 μΐ, 0.859). mmol). The resulting mixture was stirred for 25 minutes to obtain a homogeneous solution. A 4: 1 mixture of cis- and trans-2-carboethoxy-4-acetoxy-1,3-dioxolane (73 mg, 0.358 mmol) in CH 2 Cl 2 (1 mL) was added followed by iodotrimethylsilane (51 μΐ, 0.358 mmol). The reaction was allowed to proceed for 16 hours and then quenched with saturated sodium thiosulfate. The resulting mixture was diluted with CH 2 Cl 2 and washed successively with saturated sodium thiosulfate, water, brine and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the crude product which was purified by flash column chromatography (2% MeOH-EtOAc) to give 44% of the title compounds as a 3: 1 mixture of cis and trans isomers.

1 H NMR (CDCl 3): δ 1.34 (t, 3H, J-7.0 HS), 2.28 (s, 0.75H), 2.29 (s, 0.25H), 4.21-4.35 (a, 3H), 4.36 (d of d , 0.75 H, J-5.2, 9.9 Hz), 4.59 (d of d, 0.25H, J-5.2, 9.9 Hz), 5.39 (s, 0.75H), 5.77 (s, 0.25H), 6.24 (d of d , 0.75H, J-2.8, 5.1 Hz), «··,. ·. 6.39 (d Of d, 0.25H, J-1.7, 5.1 Hz), 7.49 (2 ... overlapping doublets, 1H), 7.79 (d, 0.25H, J-7.6 Hz), • · «* 8.40 (d, 0.75H, J-7.6 Hz), 9.95 (br s, 1H).

«•» · • · · • · 1 • 4 4 4 4 • · ·

Example 47

(± λ-CIS AND TRANS-5-ACETQXY-1,3-OXATIOANAN-2-CARBOXYLIC ACID

78 1 0 2 2 7 9 £ OCOCHj o m \ y

Trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid (250 g, 1.67 mol) was added in small portions to a stirred solution of acetic anhydride (0.625 L, 6.62 mol) and methanesulfonic acid (5 mL, 77 mmol) at room temperature. The resulting clear solution was stirred at room temperature for 60 minutes, slowly added to stirred 0.03 M aqueous sodium bicarbonate solution (2.5 L), and then the mixture was stirred for an additional 60 minutes. Sodium chloride (750 g, 12.83 mol) was added and the mixture was stirred for a further 30 minutes, clarified and then extracted with isopropyl acetate (1 x 1.25 L, 3 x 0.625 L). The combined extracts were concentrated to 1.25 liters under reduced pressure. Xylene (2.5 L) was added and the mixture was reconcentrated to 1.25 liters under reduced pressure. The addition / reconcentration of xylene was repeated and the resulting suspension was cooled to room temperature and stirred for 18 hours. The solid was collected by vacuum filtration, washed with xylene (2 x 0.25 L) and dried in vacuo at 40-45 ° C to give the title compound (265 g, 83%), which was shown by 1 H NMR spectra to be 65:35. a mixture of the compounds of Examples 3 and 4.

Example 48

5R-acetoxy-1,3-oxathiolane-2R-carboxylic acid. SALT

# ... IS. 2R-CK - f 1-AMINOETHYL ^ WITH BENZENE METHANOL {1: 1) • * · • · • ti i

Ph OH

HOjC, ^ OCOCH,: T: A S- H, cr NH; 79 102279 a) A solution of 1S, 2R-thi (- (1-aminoethyl) -benzenemethanol (125.9 g, 0.83 mol) in isopropyl acetate (0.5 L) was added (±) -cis- / trans To a stirred solution of -5-acetoxy-1,3-oxathiolane-2-carboxylic acid (Example 47; 400 g, 2.08 mol) in isopropyl acetate (4.2 L) at room temperature under nitrogen, the resulting solution was stirred for 10 minutes, seeded with authentic product ( 0.4 g) and stirred for a further 4 hours at room temperature The suspension was stirred at 15-18 ° C for 17 hours and the solid was collected by vacuum filtration, washed with isopropyl acetate (1 x 0.4 L, 1 x 0.2 L) and dried in vacuo at 45 ° C to give the title compound (205.9 g, 28%). [α] D +34 ° (MeOH), mp 151-2 ° (dec.), S (DMSO-D 6 ) 0.91 (d, UH, J = 6.8 Hz), 2.05 (S, 3H), 3.04 (d, 1H, J = 11 Hz), 3.32 (dd, 1H, J = 4.2 Hz), 3.40 (dq, 1H, J * 6.8, 2.4 Hz), 4.97 (d, 1H, J = 2.4 Hz), 5.34 (s, 1H), ca 6.4 (br, 1H), 7.2-7.4 (η, 5H), ca 8.3 (br , 3H).

b) A solution of 1S, 2R-6 - (- (1-aminoethyl) -benzenethanol (177 mg, 1.17 mmol) in isopropyl acetate (1 mL) was added to (+) - trans-5-acetoxy-1,3-oxathiolane-2 to a stirred solution of carboxylic acid (500 mg, 2.60 mmol) in isopropyl acetate (6 mL) at 25-30 ° C, and more isopropyl acetate (0.5 mL) was added, crystallization occurred after 5 minutes, and the suspension was stirred at 25-30 ° C. for 18 hours and the solid was collected by vacuum filtration, washed with isopropyl acetate (1 ml) and dried in vacuo at 40 ° C to give the title compound (353 mg, 40%), which was shown by comparison with 1 H NMR spectrum with 1 (t) part (a).

I «·

Example 49 t 1

(-1-TRANS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC ACID

'XT

(·) 80 102279 5 M aqueous hydrochloric acid (126 ml, 0.63 mol) was added to a stirred suspension of Example 48 (180 g, 0.52 mol) in saturated aqueous sodium chloride solution (414 ml) at room temperature. The mixture was stirred at room temperature for 30 minutes, cooled to 10 ° C and stirred at this temperature for a further 30 minutes. The solid was collected by vacuum filtration, washed with chilled water (2 x 90 mL) and dried in vacuo at 33 ° C to give the title compound (81.3 g, 81%).

Example 50

f 1 * R.2 * S.5'm-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE

a) A solution of oxalyl chloride (66.5 g, 0.52 mol) in dichloromethane (120 ml) was added over 30 minutes to a stirred cold (-5 ° C) mixture of N, N-dimethylformamide (32 ml) with dichloromethane (240 ml). , and the resulting suspension was stirred at -5-0 ° C for 30 minutes. The compound of Example 49 (80 g, 0.42 • mol) was added in small portions and the resulting yellow solution was stirred. was stirred at 0 ° C for 45 minutes. This solution was added over 60 minutes to a solution of (1R, 2S, 5R) - (-) - menthol (65.2 g, 0.425 mol) (-5 °) in dichloromethane (200 mL) and in pyridine (84 ml, 1.04 mol), and the resulting suspension was stirred at 0-5 ° C for a further 2 hours.

The reaction mixture was washed with 2M aqueous hydrochloric acid (1 x 240 ml, 1 x 160 ml) and the combined acidic aqueous washings were back-extracted with dichloromethane (160 ml). The organic phases were combined, clarified and concentrated in vacuo to about 240 ml, 2,2,4-trimethylpentane (400 ml) was added and the solution was concentrated in vacuo to a volume of 240 ml. Crystallization of the product occurred during distillation. Additional 2,2,4-trimethylpentane (400 mL) was added and the mixture was concentrated to about 700 mL. The stirred suspension was then cooled to 5 ° and allowed to stand for 60 minutes. The solid was collected by vacuum filtration, washed with 2,2,4-trimethylpentane (2 x 80 mL) and dried in vacuo at 33 ° to give the title compound (93.2 g, 68%) as shown by comparison with Example 8. Η with NMR spectrum.

b) Oxalyl chloride (102 g, 0.80 mol) was added over 20 minutes to a stirred cold (-10 °) mixture of N, N-dimethylformamide (63 ml) with dichloromethane (840 ml) and the resulting suspension was stirred at -10 to -6 ° 15 minutes. The compound of Example B (140 g, 0.728 mol) was added and the resulting pale yellow solution was stirred at -8 ° for 20 minutes. (1R, 2S, 5R) - (-) - Menthol (126 g, 0.80 mol) was added followed by pyridine (140 mL, 1.73 mol) over 50 minutes. The resulting suspension was stirred at -9 ° for 18 hours and then 1M aqueous hydrochloric acid (280 ml) was added. The separated aqueous phase was extracted with dichloromethane (140 ml) and the combined organic phases were washed with 1M aqueous hydrochloric acid (280 ml). The aqueous phase was back-extracted with dichloromethane (140 ml) and the combined organic phases were washed with a solution of sodium hydrogen carbonate (5.6 g) and sodium chloride (28 g) in water (266 ml). The aqueous phase was back-extracted with dichloromethane (140 ml) and the combined organic phases were clarified and concentrated to 560 ml by distillation at atmospheric pressure. 2,2,4-Trimethylpentane (700 ml) was added and the solution was concentrated in vacuo to 700 ml. The addition / reconcentration of 2,2,4-trimethylpentane was repeated and the resulting solution was cooled to 17 ° (seeded with authentic product (0.7 g) at 34 ° and 23 °). ). The suspension was stirred at 17 ° for 2 hours. The solid was collected by vacuum filtration, washed with 2,2,4-trimethylpentane (2 x 70 mL) and dried in vacuo at 43 ° to give the title compound (332 g, 14%). which was demonstrated by comparing the Ή NMR spectrum with that of the product of Example 8.

Claims (5)

82 1 0 2 2 7 9 Since we have presented numerous embodiments, many alternatives, modifications, and variations of these embodiments will be apparent to those skilled in the art. Intermediate compounds of formula (II) W 1 -L R 3ww / j (II) wherein W is S, S = O, SO 2 or O; X is S, S = O, SO 2 or O; R 3 is a substituted carbonyl or carbonyl derivative; and L is a leaving group. Intermediate compounds of formula (VI) wherein W is S, S = O, SO 2 or O; X is S, S = O, SO 2 or O; R 1 is a substituted carbonyl or carbonyl derivative; R4 is a chiral auxiliary group; and / L is a leaving group. • · ··· • · · An intermediate of formula (XIII) wherein W is S, S = O, SO 2 or O; : X is S, S = o, SO 2 or O; R 3 is a substituted carbonyl or carbonyl derivative; 83 102279 And R4 is a chiral auxiliary group. An intermediate according to claim 2 or 3, wherein R 4 is derived from (d) -menthol or (1) -mentol. An intermediate of formula (XIV) "" "<y (XIV) wherein W is S, S = O, SO 2 or O; X is S, SssO, SO 2 or O; R 3 is a substituted carbonyl or carbonyl derivative.