WO1993010129A1

WO1993010129A1 - Intermediates and process for the preparation of mevinic acids

Info

Publication number: WO1993010129A1
Application number: PCT/GB1992/002004
Authority: WO
Inventors: Christopher Norman Lewis; Richard Simon Todd; Christopher Mark Blackwell
Original assignee: British Bio Technology Ltd
Current assignee: Vernalis R&D Ltd
Priority date: 1991-11-11
Filing date: 1992-11-02
Publication date: 1993-05-27
Anticipated expiration: 1994-05-11
Also published as: GB9123933D0; ZA928451B; AU2883792A

Abstract

Compounds of general formula (I) wherein R1 represents a hydrogen atom, or a COC¿1-8? alkyl, COC3-8 cycloalkyl, COC3-8 cycloalkyl (C1-8 alkyl), COC2-8 alkenyl, COC1-6 alkylphenyl, COC1-6 alkyl (substituted phenyl), an Si(R?6R7R8¿) group or a suitable protecting group; R2 represents a hydrogen atom, C¿1-8? alkyl, C2-8 alkenyl, C2-8 alkynyl group, or a C1-5 alkyl, C2-5 alkenyl or C2-5 alkynyl group substituted with a phenyl or substituted phenyl group, or an OSi(R?6R7R8¿) group, C¿1-8?alkyl-OSi(R?6R7R8¿), hydroxy group protected by a suitable protecting group or a hydroxy(C¿1-8?) alkyl group protected by a suitable protecting group; R?3¿ represents a hydrogen atom or a C¿1-8? alkyl group; R?4¿ represents a hydrogen atom, or a methyl or ethyl group; R5 represents a C¿1-5? alkyl group; R?6, R7, and R8¿ each independently represents a C¿1-8? alkyl group or a phenyl group; each of a, b, and c is independently a single or double bond except that when a and c are double bonds then b is a single bond; are useful intermediates in the preparation of HMG-CoA reductase inhibitors derived from mevinic acid.

Description

INTERMEDIATES AND PROCESS FOR THE PREPARATION OF MEVINIC ACIDS

This invention relates primarily to novel compounds which are useful intermediates in the synthesis of a range of mevinic acids and novel synthetic procedures relating thereto.

A number of mevinic acids have been reported to be p ot ent inh ib i t o rs o f the en z yme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase) , the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidamia.

Thus W F Hoffman et al (J. Med. Chem., 29, 849-852 (1986)) have reported the synthesis and testing of a compound now known as simvastatin (1)

EP-A-0251625 (Inamine) discloses compounds of structure

where R is similar to the corresponding group in the compound described above, R¹ is a group of formula CH₂OH, CH₂OCOR³, CO₂R⁴or CONR⁶R⁷ wherein R³, R⁴, R⁶, and R⁷ can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.

The compounds disclosed have been generally obtained by fermentation of a suitable microorganism, or derived chemically from compounds obtained from such fermentations. However, a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost.

Accordingly, Heathcock and Rosen disclosed in US-A-4950775 the total synthesis of compactin (3), which also possesses HMG-CoA reductase inhibitory activity

Similarly, WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids. In particular the document describes the synthesis of (1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]-6-[(E)-prop-1-enyl]-1-napthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one (4)

It is known in the art (for a review, see TIPS, 8, 442 (1987)) that the stereochemistry of the substituted tetrahydropyran ring must be as indicated for compounds of general formula 1 to possess anti-HMG-CoA reductase activity.

The stereochemistry of the two chiral centres a and b in the lactone ring is usually established during the synthesis of precursors of compounds such as (3) and (4). Thus WO-A-9100280 discloses the synthesis of a precursor of (4) via a reagent (5) containing chiral centre (a) thus

Following specific reduction of the thus introduced olefinic bridge and subsequent desilylation to give (8), WO-A-9100280 further describes a procedure for the introduction of the second chiral centre, b, via chiral reduction of the keto function in the introduced side chain to give (9) thus

and the target compound (4) is achieved by lactonisation of the resulting dihydroxy ester (9) .

Similarly, our copending British patent application No 9100174.3 discloses the synthesis of a C-6 disubstituted analogue of (4) prepared from (5) and the appropriate aldehyde.

However, this approach has certain drawbacks. Firstly, chiral reagents such as (5) always contain at least trace amounts of the other enantiomer. Indeed,

US-A-4950775 discloses that (5) is prepared with a purity of approximately 98%, with 2% comprising the undesired enantiomer. Similarly, the chiral reduction step of (8) to (9) described in WO-A-9100280 also produces undesired isomers as impurities, with up to 5% of the thus introduced hydroxy function being of the undesired configuration. The dihydroxy compound (9) produced by the procedures disclosed and described in WO-A-9100280 is thus contaminated with up 10% impurities consisting of undesired diastereoisomers. Secondly, it is very difficult to remove the contaminating diastereoisomers and thereby purify the product as both product and contaminants have very similar mobilities in a wide range of chromatographic systems. High Performance Chromatography has to be used and it is usually only possible to separate pairs of diastereoisomers. This problem is well known in the art - for a review see Tetrahedron. 42, No 18, 4909-4951 (1986). Therefore, although the prior art and the work disclosed in US-A-4950775 and WO-A-9100280 are pioneering, there is still room for further improvement in the synthetic methodology used, in particular to expedite removal of undesired diastereoisomers in order to optimise the purity and to facilitate recovery of products. There is now herein disclosed a novel and useful class of derivatives of dihydroxy compounds such as (9) which are valuable intermediates in the synthesis of inter alia mevinic acids, and which enable the synthetic production of mevinic acids in high purity. According to a first aspect of the invention there is provided a compound of general formula I

wherein

R¹ represents a hydrogen atom, or a COC_1-8 alkyl, COC_3-8 cycloalkyl, COC_3-8 cycloalkyl (C_1-8 alkyl), COC_2-8 alkenyl, COC_1-6 alkylphenyl, COC_1-6 alkyl (substituted phenyl), an Si(R⁶R⁷R⁸) group or a suitable protecting group;

R² represents a hydrogen atom, C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl group, or a C_1-5 alkyl, C_2-5 alkenyl or C_2-5 alkynyl group substituted with a phenyl or substituted phenyl group, or an osi(R⁶R⁷R⁸) group, C_1-8alkyl-OSi(R⁶ R⁷ R⁸), hydroxy group protected by a suitable protecting group or a hydroxy (C_1-8 alkyl) group protected by a suitable protecting group;

R³ represents a hydrogen atom or a C_1-8 alkyl group;

R⁴ represents a hydrogen atom, or a methyl or ethyl group; R⁵ represents a C_1-5 alkyl group R⁶, R⁷, and R⁸ each independently represents a C_1-8 alkyl group or a phenyl group; each of a, b,and c is independently a single or double bond except that when a and c are double bonds then b is a single bond. As used herein the term "C_1-8 alkyl" refers to straight chain or branched chain hydrocarbon groups having from one to eight carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. The terms "C_1-5 alkyl" and "C _{1- 6} alkyl" refer to similar groups having from one to five and one to six carbon atoms respectively. As used herein the term "C_2-8 alkenyl" refers to straight chain or branched chain hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl. The term "C_2-5 alkenyl" refers to similar groups having from two to five atoms. As used herein the term "C_2-8 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, propynyl, butynyl and pentynyl. The term "C_2-5 alkynyl" refers to similar groups having from two to five carbon atoms. As used herein the term "hydroxy C_1-8 alkyl" refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group. Illustrative of such alkoxy groups are hydroxyethyl and hydroxy-propyl. As used herein , the term "C_{3 -8} cycloalkyl " refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo. As used herein, the term "substituted phenyl" means a phenyl group substituted with up to four substituents, each of which may be C_1-6 alkyl, C_1-6 alkoxy, hydroxy, thiol, amino, halo, trifluoromethyl or nitro. As used herein the term "suitable protecting group" refers to a group temporarily attached to a reactive centre in a multifunctional molecule. The protecting group should ideally be able to be introduced specifically at the group to be protected, should be stable throughout all subsequent reaction conditions involving manipulations at other reactive sites, and be able to be removed under conditions that do not affect other reactive sites. For a good review of protecting groups, see "Protective Groups in Organic Synthesis", Greene, T W Ed., John Wiley and Sons, 1981. Preferred compounds include those in which, independently or in any compatible combination R¹ represents a COC_1-8 alkyl, an Si(R⁶R⁷R⁸) group, or a suitable protecting group; R² represents a hydrogen atom , C_1-8 alkyl , C_{2 -8} alkenyl, an OSi(R⁶R⁷R⁸) group, a C_1-8 alkyl-OSi(R⁶R⁷ R⁸) group, a hydroxy group protected by a suitable protecting group or a hydroxy (C_1-8) alkyl group protected by a suitable protecting group; R³ represents a hydrogen atom or a methyl group; R⁴ represents a methyl group; R⁵ represents a methyl group; R⁶ represents a methyl group; R⁷ represents a methyl group; R⁸ represents a t-butyl group; a is optionally a single or double bond, b is a single bond and c is a double bond; and the two carbon atoms substituted with OSi(R⁶R⁷R⁸) groups are both of the R configuration. Particularly preferred compounds include: 1. Methyl(1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7^,-{2-(1,2,4a, 5,6,7,8, 8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"- oxobutyl)-oxy]-6-[(E)-prop-1-enyl]-1-napthalenyl))- 3',5'-bis(t-butyldimethylsiloxy)heptanoate. 2. Methyl(1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-{2-(1,2,4a,5, 6,7,8,8a- octahydro-2,6-dimethyl-8-[(2",2"-dimethyl-1"- oxobutyl)-oxy]-6-[(E)-prop-1-enyl]-1-napthalenyl)}-3', 5'-bis(t-butyldimethylsiloxy) heptanoate. According to a second aspect of the invention there is provided a process for the preparation of a compound of general formula I as defined above, the process comprising: reacting a compound of general formula II

wherein R³, R⁴ and R⁵ are as defined as in general formula I; R⁹ represents a hydrogen atom, a COC_1-8 alkyl, COC_3-8 cycloalkyl, COC_3-8 cycloalkylC_1-8 alkyl, COC_2-8 alkenyl, COC_1-6 alkylphenyl, COC_1-6 alkyl (substituted phenyl) group or a suitable protecting group; and R¹⁰ represents a hydrogen atom, C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl group, or a C_1-5 alkyl, C_2-5 alkenyl or C_2-5 alkynyl group substituted with a phenyl or substituted phenyl group, a hydroxy group, a hydroxy (C_1-8 alkyl) group, or a hydroxy group protected by a suitable protecting group or a hydroxy (C_1-8 alkyl) group protected by a suitable protecting group; (a) with a compound of general formula III (R⁶R⁷R⁸)SiCl III wherein R⁶, R⁷, and R⁸ are as defined in general formula I in the presence of a base, particularly a nitrogenous base; at a temperature between 20°C and 100°C; or (b) alternatively with a compound of general formula IV (R⁶R⁷R⁸)SiOSO₂CF₃ IV wherein R⁶, R⁷,and R⁸ are as defined in general formula I in the presence of a suitable base and in a suitable solvent; and (c) optionally after step (a) or (b) converting, in one or a plurality of steps , a compound of general formula I into another compound of general formula I. Suitable nitrogenous bases for use in step (a) are hexamethyldisilazane , imidazole or pyridine and suitable solvents are polar solvents such as dichlorome thane, acetonitrile or dimethyl formamide. It may also be advantageous to employ a catalyst such as dimethylaminopyridine. A suitable base for use in step (b) is 2,6-lutidine although other bases could be used and a suitable solvent is a polar solvent such as dichloromethane or chloroform. The reaction takes place at a temperature of -10 to 40°C, preferably 0 to 25°C. Compounds of general formula I in which R¹ is a protecting group and/or R² is a protected hydroxy or hydroxy ( C_{1 - 8} alkyl) group can be converted to compounds of general formula I in which R is H and/or R² is OH or hydroxy C_1-8 alkyl respectively by deprotection using any suitable deprotecting agent for the protecting group used. Compounds of general formula II are known in the art or can be prepared by methods analogous to those in the art. Compounds of general formula I are valuable intermediates in the synthesis of, inter alia, mevinic acids . As mentioned above , diastereoisomers of compounds of general formula II have very similar mobilities in a variety of chromatographic systems and consequently it has proved very difficult to prepare compounds of general formula II in high purity. Multiple recrystallisation steps have had to be employed with concomitant loss of material . In marked contrast, diastereoisomers of compounds of general formula I have marked differences in mobility in a range of chromatographic systems and can therefore be separated easily. It is therefore possible to use compounds of formula I in place of compounds of formula II in syntheses where separate isomers are required. An additional valuable property of compounds of general formula I is that treatment with a desilylating agent leads to desilylation followed by rapid lactonisation to the corresponding mevinic acid. According to a third aspect of the invention there is provided a process for the preparation of compounds of general formula V

wherein R³, R⁴, R⁹, R¹⁰, a, b and c are as defined above the process comprising treating a compound of general formula I as defined above with an acidic desilylating agent. An acidic solution of fluoride ions will act as a desilylating agent and a suitable reagent for use in this case is a solution of hydrofluoric acid in acetonitrile. The reaction should preferably be carried out at a temperature between 0°C and 50°C. In a further aspect of the invention there is provided a process for the conversion of a mixture of isomers of general formula II to a selected isomer of general formula V, the process comprising converting the mixture of isomers of general formula II to a mixture of isomers of general formula I; separating out the required isomer of general formula I and converting that isomer to a compound of general formula V. The following examples, which are for the purposes of illustration only, show the synthesis of a compound of general formula I from a compound of general formula II and a compound of general formula III, the separation of diastereoisomers of a compound of general formula I, and the preparation of an diastereoisomerically pure compound of general formula V.

Experimental details for silylation of alcohols and transformation to lactones Organic solutions were dried over anhydrous magnesium sulphate. Ether refers to diethyl ether. NMR spectra were acquired at 250MHz (proton) or 62.9MHz (carbon) in deuteriochloroform unless noted otherwise. Coupling constants are given in Hertz. EXAMPLE 1 Methyl (1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-(1,2,4a, 5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"- oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1- naphthalenyl)-3', 5'-bis(t-butyldimethyl-silyloxy)heptanoate, and Methyl (1S,2S,4aR,6S,8S,8aS,3'S,5'S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3',5'-bis(t-butyldimethyl-silyloxy)

heptanoate.

An approximately equal mixture of the (3'R,5'R) and (3'S,5'S) isomers of methyl (1S,2S,4aR,6S,8S, 8aS)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2", 2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1- naphthalenyl)-3',5'-dihydroxy-heptanoate which could not be separated by silica chromatography (methanol/dichloromethane, hexane/ethyl acetate, acetone/hexane, and ether/hexane systems all gave one spot on TLC) (46 mg; 0.10 mmole), imidazole (36 mg; 0.52 mmole), tert-butyldimethyl silylchloride (63 mg; 0.42 mmole) and a crystal of DMAP were stirred together in dry dimethylformamide (1 mL) at room temperature for 3 hours. Hydrochloric acid (2M; 3 mL) was added and the mixture extracted with ethyl acetate. The combined organic layers were washed with hydrochloric acid (2M), dried and evaporated to an oil. The last traces of DMF were removed by azeotroping with hexane. Chromatography on silica eluting with hexane: ethyl acetate 98:2 gave the (3^,S, 5'S) isomer followed by the (3^,R, 5'R) isomer. (3'S, 5'S) isomer Rf (19:1 hexane: ethyl acetate) 0.29 delta H 5.75 (1H, ddq, J = 15, 7.7 and 2.5), 5.66 (1H, dq, J = 10.5 and 2.5), 5.38 (2H, m), 5.12 (1H, m), 4.29 (1H, m), 3.66 (3H, s), 3.59 (1H, m), 2.56 (1H, dd, J = 15 and 5), 2.5 (1H, dd, J = 15 and 5), 2.37 (1H, dd, J = 15.5 and 7.5), 2.32 (1H, m), 2.05 (1H, m), 1.95 - 0.7 (25H, m), 1.15 (3H, s), 1.14 (3H, s), 0.89 (9H, s), 0.86 (9H, s), 0.06 (3H, s), 0.05 (3H, s), 0.02 (6H, s) delta C 175.6, 170.8, 134.8, 131.3, 129.4, 121.4, 68.6, 68.1, 65.7, 49.9, 43.1, 41.4, 40.9, 40.6, 36.4, 36.0, 34.6, 33.9, 33.7, 31.4, 30.2, 29.8, 24.5, 24.3, 23.2, 21.6, 16.5, 13.5, 7.8, -5.4, -5.7, -6.2, - 6.4 (3'R, 5'R) isomer Rf (19:1 hexane: ethyl acetate) 0.22 delta H 5.88 (1H, ddq, J = 15, 7.7 and 2.5), 5.66 (1H, dq, J = 10.5 and 2.5), 5.4 (2H, m), 5.15 (1H, m), 4.28 (1H, m), 3.67 (3H, s), 3.54 (1H, m), 2.6 - 2.2 (4H, m), 2.01 (1H, m), 1.85 - 0.7 (23H, m), 1.17 (3H, s), 1.16 (3H, s), 0.90 (9H, s), 0.86 (9H, s), 0.08 (3H, s), 0.07 (3H, s), 0.06 (3H, s), 0.02 (3H, s) delta C 175.7, 170.7, 134.8, 131.3, 129.4, 121.4,

69.0, 68.0, 65.5, 49.9, 44.4, 41.4, 40.9, 40.6, 36.15,

36.1, 34.7, 34.0, 33.9, 31.5, 30.2, 29.9, 24.5, 24.3, 23.3, 22.7, 16.5, 16.4, 13.8, 13.4, 7.8, -5.4, -5.5, -5.6, -5.7

EXAMPLE 2

Derivatisation with triethylsilyl group

A similar mixture of the same diols (27 mg; 0.06 mmol) was dissolved in a mixture of DMF (1 mL) and pyridine (24 microL; 0.3 mM). A crystal of DMAP and triethylsilylchloride (40 microL; 0.24 mmol) were added and the reaction stirred for 3 hours at room temperature. Copper sulphate solution was added and the mixture extracted with ethyl acetate. The organic layer was dried and evaporated, then remaining DMF removed by azetroping with hexane to leave a pale yellow oil. TLC showed two spots (19:1 hexane: ethyl acetate) with Rf 0.26 and 0.24.

EXAMPLE 3

Derivatisation using the silyl-triflate; (3'S, 5'R) isomer.

Tert-butyldimethylsilyl trifluoromethylsulphonate (0.11 mL; 0.49 mmole) was added to a solution of 2,6-lutidine (0.1 mL; 0.8 mmole) and a mixture of anti-diols (78 mg; 0.16 mmole) in dry dichloromethane (5 mL) under argon at 00C. The mixture was stirred at room temperature for 25 minutes, when TLC showed no remaining starting material, then poured into ether and washed with phosphoric acid (IM) and brine. The organic solution was evaporated and traces of solvent removed by azeotroping with hexane to give the crude disilylated compounds (72 mg). Chromatography on silica eluting with hexane then hexane: ethyl acetate (50:1) gave the (3'S, 5'R) isomer as the fastest running compound.

delta H 5.77 (1H, ddd, J = 15.2, 8.1 and 1.6), 5.68 (1H, dq, J = 9.7 and 2.5), 5.39 (2H, m), 5.11 (1H, m), 4.13 (1H, m), 3.65 (3H, s), 3.54 (1H, m), 2.48 (4H, m), 2.32 (1H, m), 2.01 (1H, m), 1.90 - 1.43 (12H, m), 1.42 - 1.0 (5H, m), 1.15 (3H, s), 1.14 (3H, s), 0.99 - 0.75 (5H, m), 0.88 (9H, s), 0.86 (9H,s), 0.08 (3H,s), 0.07 (3H, s), 0.065 (3H, s), 0.037 (3H,s). delta C 175.6, 170.3, 134.8, 131.4, 129.5, 121.5, 69.5, 68.1, 66.1, 49.9, 45.1, 41.8, 41.5, 40.6, 36.3, 36.1, 34.7, 33.9, 33.7, 31.6, 30.3, 29.9, 24.5, 24.3, 23.3, 22.9, 16.6, 16.5, 13.4, 7.8, 5.5, -5.5, -6.0. EXAMPLE 4 A mixture of the (3'R, 5'R) and the (3'S, 5'R) tert-butyldimethylsilyl ethers (prepared similarly to above; 7.5 mg) was separated by chromatography on silica eluting with hexane then hexane: ethyl acetate 40:1 to give pure (3'S, 5'R) compound (6.2 mg) followed by pure (3'R, 5'R) isomer (1.3 mg). On another occasion, TLC of all the compounds on one plate using 15:1 hexane: ethyl acetate gave the following Rf values (3'R, 5'R) 0.14; (3'S, 5'S) 0.18; (3'R, 5'S) 0.20; (3'S, 5'R) 0.22 EXAMPLE 5

(1S,2S,4aR,6S,8S,8aS,4'S,6'S)-6'-{2-(1,2,4a,5,6,7,8, 8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl) oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}- tetrahydro-4'-hydroxy-2H-pyran-2'-one.

The (3'S, 5'S) isomer (8.3 mg; 0.012 mmol) produced above was stirred in a mixture of 48% hydrofluoric acid and acetonitrile (1:9) at room temperature for 90 minutes. Solid sodium hydrogen carbonate was added carefully, then the reaction diluted with water and extracted with ethyl acetate (3 x). The organic layers were dried and evaporated to give the lactone as a white solid. delta H 5.73 (1H, ddq, 15, 8 and 1.5), 5.63 (1H, dq, 8 and 2.5), 5.3 - 5.45 (2H, m), 5.14 (1H, m), 4.66 (1H, m), 4.36 (1H, m), 2.70 (1H, dd, J = 15 and 5), 2.60 (IH, dd, J = 15 and 2), 2.48 (2H, m), 2.39 (2H, m), 2.0 - 1.87 (2H, m), 1.88 -1.0 (10H, m), 1.6 (3H, d, J = 7.5), 1.55 (2H, q, J = 7.5), 1.14 (6H, s), 0.95 - 0.7 (6H, m) delta C 176.41, 66.9, 134.6, 131.0, 129.5, 121.6, 74.5, 66.2, 61.2, 41.6, 40.4, 37.1, 36.2, 35.9, 34.7, 33.8, 33.6, 31.5, 30.9, 30.2, 29.8, 23.2, 20.7, 16.4, 13.4, 7.8

EXAMPLE 6

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl)tetrahydro-4'-hydroxy-2H-pyran-2'-one.

The (3'R, 5'R) isomer (6.35 g; 9.0. mmol) produced in a manner similar to that described above was stirred in a mixture of 48% hydrofluoric acid and acetonitrile (1:19, 120 mL) at room temperature for 90 minutes. Saturated aqueous sodium hydrogen carbonate solution was added carefully until effervescence ceased, then the reaction mixture extracted with ethyl acetate (4 × 50 mL). The organic layers were washed with brine (50 mL), dried and evaporated to give a white solid. Column chromatography eluting with hexane:ethyl acetate (3:2) gave the pure product (3.05 g; 76%) delta H 5.78 (1H, ddq, J = 15, 8, 1.5), 5.67 (1H, dq, J = 10 and 3), 5.3 - 5.45 (2H, m), 5.18 (1H, m), 4.60 (1H, m), 4.36 (1H, m), 2.74 (1H, dd, J = 17 and 5), 2.62 (1H, ddd, J = 17, 4, and 1), 2.50 (2H, m), 2.31 (IH, m), 2.2 - 1.85 (3H, m), 1.8 - 1.65 (6H, m), 1.63 (3H, d, J = 5), 1.6 (2H, q, J = 7),1.45 - 1.05 (6H, m), 1.16 (3H, S), 1.15 (3H, s), 0.98 - 0.75 (6H, m) delta C 176.4, 169.5, 134.6, 131.1, 129.4, 121.5,75.0, 68.3, 60.9, 41.5, 40.4, 37.1, 35.9, 35.8, 34.7, 34.4, 33.8, 31.5, 31.0, 29.8, 23.2, 21.7, 16.5, 13.4, 7.8 The (4'S, 6 'S) and (4'R, 6'R) lactones were inseparable on silica TLC plates.

Claims

1. A compound of general formula I

wherein

R² represents a hydrogen atom, C_1-8 alkyl, C_2-8 alkenyl , C_{2 -8} alkynyl group , or a C_1-5 alkyl , C_{2 -5} alkenyl or C_2-5 alkynyl group substituted with a phenyl or substituted phenyl group, or an 0Si(R⁶R R⁸) group, C_1-8alkyl-OSi (R⁶ R⁷ R³), hydroxy group protected by a suitable protecting group or a hydroxy(C_1-8) alkyl group protected by a suitable protecting group; represents a hydrogen atom or a C_1-8 alkyl group; R⁴ represents a hydrogen atom, or a methyl or ethyl group; R⁵ represents a C_1-5 alkyl group; R⁶, R⁷, and R⁸ each independently represents a C_1-8 alkyl group or a phenyl group; each of a, b,and c is independently a single or double bond except that when a and c are double bonds then b is a single bond.

2. A compound as claimed in claim 1 wherein R¹ represents a COC_1-8 alkyl, Si(R⁶R⁷R⁸) or a suitable protecting group.

3. A compound as claimed in Claim 1 or Claim 2 , wherein R² represents a hydrogen atom, C_1-8 alkyl, C_2-8 alkenyl, an OSi(R⁶R⁷R⁸) group, a C_1-8 alkyl-OSi(R⁶R⁷ R⁸) group, a hydroxy group protected by a suitable protecting group or a hydroxy(C_1-8) alkyl group protected by a suitable protecting group.

4. A compound as claimed in any one of claims 1 to 3 wherein R³ is a hydrogen atom or a methyl group.

5. A compound as claimed in any one of claims 1 to 4 wherein R⁴ is a methyl group.

6. A compound as claimed in any one of claims 1 to 5 wherein R⁵ is methyl group.

7. A compound as claimed in any one of claims 1 to 6 wherein R⁶ is a methyl group.

8. A compound as claimed in any one of claims 1 to 7 wherein R⁷ is a methyl group.

9. A compound as claimed in any one of claims 1 to 8 wherein R⁸ is a t-butyl group.

10. A compound as claimed in any one of claims 1 to 9 wherein both of the carbon atoms substituted with OSi(R⁶R⁷R ) are of the R configuration.

11. A compound as claimed in any one of claims 1 to 10 wherein a is either a single or a double bond, b is a single bond and c is a double bond.

12. Methyl(1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-{2-(1,2,4a, 5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl-1"- oxobutyl)-oxy]-6-[(E)-prop-l-enyl]-1-napthalenyl)}- 3',5'-bis(t-butyldimethylsiloxy) heptanoate; or Methyl(1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]-6-[(E)-prop-1-enyl]-1-napthalenyl))-3',5'-bis(t-butyldimethylsiloxy) heptanoate.

13. A process for the preparation of a compound of general formula I, the process comprising reacting a compound of general formula II

wherein R³, R⁴ and R⁵ are as defined as in general formula I; R⁹ represents a hydrogen atom, a COC_1-8 alkyl, COC_3-8 cycloalkyl, COC_3-8 cycloalkylC_1-8 alkyl, COC_2-8 alkenyl, COC_1-6 alkylphenyl, COC_1-6 alkyl (substituted phenyl) group or a suitable protecting group; and R¹⁰ represents a hydrogen atom, C_1-8 alkyl, C_2-8 alkenyl, C_2-8 alkynyl group, or a C_1-5 alkyl, C_2-5 alkenyl or C_2-5 alkynyl group substituted with a phenyl or substituted phenyl group, a hydroxy group, a hydroxy (C_1-8 alkyl) group, or a hydroxy group protected by a suitable protecting group or a hydroxy (C_1-8 alkyl) group protected by a suitable protecting group; (a) with a compound of general formula III (R⁶R⁷R⁸)SiCl III wherein R⁶, R⁷,and R⁸ are as defined in general formula I in the presence of a base; at a temperature between 20°C and 100°C; or (b) alternatively with a compound cf general formula IV (R⁶R⁷R⁸)SiOSO₂CF₃ IV wherein R⁶, R⁷, and R⁸ are as defined in general formula I in the presence of a suitable base; and (c) optionally after step (a) or (b) converting, in one or a plurality of steps, a compound of general formula I into another compound of general formula I.

14. A process as claimed in claim 13, wherein, in step (a) the base is hexamethyldisilazane, imidazole or pyridine.

15. A process as claimed in claim 13, wherein, in step (b), the base is 2,6-lutidine.

16. A process for the preparation of a compound of general formula V

wherein R³, R⁴, R⁹, R¹⁰, a, b and c are as defined above; the process comprising treating a compound of general formula I with a desilylating agent.

17. A process as claimed in claim 16 wherein the desilylating agent comprises a solution of hydrofluoric acid in acetonitrile.

18. A process as claimed in claim 16 or claim 17 wherein the reaction temperature is on 0 to 50°C.

19. A process for the conversion of a mixture of isomers of general formula II to a selected isomer of general formula V, the process comprising; converting the mixture of isomers of general formula II to a mixture of isomers of general formual I by a process as claimed in any one of claims 12 to 14; separating out the required isomer of general formula I; and converting the separated isomer to a compound of general formula V by a process as claimed in any one of claims 16 to 18.