CYCLOPENTENES

Abstract: The individual enantiomers of the compounds (Ia), (Ib), (IIa) or (IIb), optionally substituted by non-interfering substituent(s). The novel enantiomers can be obtained by biotransformation. The (Ia) or (IIa) compounds can be used for the synthesis of chiral carbocyclic nucleosides.

Description: CYCLOPENTENES Field of the Invention This invention relates to cyclopentene derivatives and also to their preparation and use. Background of the Invention Carbocyclic nucleosides such as Carbovir are of therapeutic value. Their stereospecific synthesis is important. EP-A-0424064 describes the enantioselective hydrolysis of the γ-lactam 2-azabicyclo[2.2.l]hept-5-en-3-one, utilising enzymatic activity available in deposits NCIMB 40213 and 40249. See also Taylor et al, J. Chem. Soc. Chem. Com . (1990) 1120. Summary of the Invention This application concerns the enantiomers of cyclopentene derivatives of structures la, lb, Ila and lib wherein X (at the 1-position) represents hydrogen or an acyl group, and Y (on the CH 2 0Y group which is at the 4 or 5-position) represents hydrogen or a group that can be readily replaced by hydrogen, i.e. a protecting group, such as an acyl, triaryl ethyl or trialkylsilyl group. These novel compounds may each be provided substantially free of other enantiomers. Description of the Invention An aspect of the invention is the means to introduce a heterocyclic base such as adenine in a single step to form a protected or unprotected carbocyclic nucleoside of formula III. Thus, for example, treatment of cyclopentene la (X=Ac, Y=H) with adenine in the presence of, say, a catalyst such as tetrakis(triphenylphosphine)palladium(0) and sodium hydride gives an unprotected nucleoside (III) ; similarly, treatment of cyclopentene la (X=Ac, Y=CPh 3 ) with 6-chloropurine gives a protected nucleoside (III) • Alternatively, direct reaction of Ila (X=H, Y=CPh 3 ) with chloropurine in the presence of triphenylphosphine and diethyl azodicarboxylate (Mitsunobu conditions) also gives III. Similarly, lb and lib give an enantiomer of III. The key individual enantiomeric synthons of this invention, la, lb, Ila and lib may be prepared from racemic mixtures la + lb and Ila + lib, wherein X=Ac or H by either lipase-catalysed enantioselective deacylation (X=Ac → X=H) or lipase-catalysed enantioselective acylation with vinyl acetate (X=H → X=Ac) . A suitable lipase for the purpose is Pseudomonas fluorescens lipase, in which case the enantiomers lb and lib are substrates for the enzyme and la and Ila are not. The absolute configurations of the products may be determined by correlation with the tetraol of formula IV for which the assignment is known (see Tadano et al, J. Org. Chem. 54. (1989) 276) , after dihydroxylation with osmium tetroxide. The racemic compounds used as substrates for the biocatalytic resolution may be made by known methods. For example, the compounds in which CH 2 0Y is at the 4-position may be prepared by the Prins reaction onto cyclopentadiene. Such methods are described by Bajorek et al, J. Chem. Soc. Perkin Trans. 1 (1947) 1243, and Pawson et al, Chem. Ber. 114 (1981) 346. The reaction affords a mixture of diastereoisomers la/lb + Ila/lib, wherein X=Y=H. The diastereoisomers are separated conveniently as the trityl derivative (X=H, Y=CPh 3 ) , for instance by chromatography on silica gel. The group Y may be left as trityl in the biotransformation or altered to a different suitable protecting group such as tert-butyldi ethylsilyl. Compounds of formula I in which the CH 2 0Y group is at the 5-position may be prepared from the cycloadduct of formula V that is obtained by reaction between cyclopentene and glyoxylic acid. The Chart (below) shows an illustrative synthetic sequence to a compound of formula III: Step 1 involves, e.g. reduction with LiAlH A , treatment with NaI0 4 and then NaBH 4 , and selective protection, e.g. with Ph 3 CCl or t-BuMe 2 SiCl; Step 2 comprises biotransformation, e.g. using a lipase, and vinyl acetate; Steo 3 comprises treatment with Pd(PPh 3 ) 4 , adenine and NaH. The key biotransformation step is carried out by treatment of the secondary alcohol with an acyl donor such as vinyl acetate or butyric anhydride in an organic solvent such as tetrahydrofuran. Alternatively, the racemic secondary alcohol is acylated chemically and the racemic acyl derivative subjected to biotransformation under hydrolytic conditions: either a lipase in a two-phase system of aqueous buffer and organic solvent such as toluene or by a microbial biocatalyst in an aqueous suspension of the acyl derivative. The palladium complex-catalysed coupling reaction that enables direct incorporation of the heterocyclic base unit (possibly in protected form) proceeds via an η π-allyl palladium complex that is common with that obtained from the isomeric cyclopentene derivatives of formula I. The compounds of the invention may be substituted, if desired, by non-interfering substituents, i.e. substituents that do not affect the biotransformation. Examples of substituents (if present) are methyl, ethyl, n-butyl, OH, Cl, Br, F, CF 3 and N 3 . The total number of C atoms in the substituent(s) will not usually exceed 8 or, more usually, 4. The following Examples illustrate the invention specifically for the cyclopentenes having a 4-(CH 2 OY) group. Example 1 la (X = Ac, Y = SiMe 2 fiu) [ (-)-1(R)-acetoxy-4(S)- (tert-butyldi ethylsilyloxymethyl)-cyclopent-2-ene] and lb (X = H, Y = SiMe 2 tBU) [ (+)-4(R)-tert-butyldimethylsilyloxy- ethyl)cyclopent-2-en-l ( S)-ol] To a solution of (±)-I (X = Ac, Y = -SiMe 2 Bu; 203.5 mg, 0.75 mmol) in acetone (2.5 ml), pH 7 phosphate buffer (12.5 ml) waε added with stirring. To this, Pseudomonas fluorescens lipase (PFL) (96.2 mg) was added and the mixture stirred for 15 h when another aliquot of fresh enzyme was added. After a further 5 h of stirring TLC indicated approx. 50% hydrolysis. The enzyme was removed by filtration and the filtrate extracted with ether (4 x 40 ml) . The combined organic phases were dried (MgS0 4 ) , filtered, and the filtrate concentrated in vacuo. The residue (180 mg) was chromatographed on silica (9:1 petrol:ethyl acetate) to give first la (X = Ac, Y = SiMe 2 tBu) (88 mg, 43%) followed by lb (X = H, Y = SiMe 2 Bu) (72 mg, 42%), both as oils. Data: la: [α] 25 D -4.2° (c = 1.78, CHC1 3 ) (>95% ee) γmax (neat) 2934, 2860, 1736 (C = O str) , 1242, 1082 cm "1 SE (CDC1 3 ) 0.03 (S, 6H, SiMe 2 ) , 0.87 (S, 9H, + Bu) , 1.50 (ddd, IH, H-6) 2.00 (S, 3H, Ac), 2.40 (ddd, IH, H-6) , 2.79 (M, IH, H-4), 3.53 (d, 2H, CH 2 OSi) , 5.61 (M, IH, H-l) , 5.82 (ddd, IH, H-3), 6.03 (ddd, IH, H-2) . lb: [α] 5 D +49.6° (c = 1.42, CHC1 3 ) (>95% ee) γ ax (neat) 3394 (OH str), 2957, 2933, 2859, 1466, 1385, 1254, 1084, 1040, 1008 cm "1 , SE (CDC1 3 ) 0.04 (S, 6H, SiMe 2 ) , 0.87 (S, 9H, + Bu) , 1.49 (ddd, IH, H-6), 2.26 (ddd, IH, H-6), 2.76 (M, 2H, H-4 and OH), 3.56-3.62 (x dd CH 2 OSi) , 4.57 (M, IH, H-l), 5.73 (dd, IH, H-3) and 5.90 (ddd, IH, H-2) . Example 2 la (X = H, Y = Ph 3 C) and lb (X = Ac, Y = Ph 3 C) A solution of (±)-I (X = H, Y = -Ph 3 C; 55.4 mg, 0.16 mmol) in vinyl acetate (4 ml), was stirred with PFL (22.9 mg) for 46h. The enzyme was removed by filtration and the filtrate concentrated i vacuo. The residue (75 mg) was chromatographed on silica (6:1 petrol:ethyl acetate) to give first lb (X = Ac, Y = Ph 3 C) as an oil (13.6 mg, 22%) followed by lb (X = H, Y = Ph 3 C) as a white solid (mp 111- 112°C) (27.7 mg, 50%) . Data: lb: [ ] 27 D +16.2° (c = 0.68, CHC1 3 ) (>95% ee) γmax (neat) 3062, 3030, 2916, 2868, 1732 (C=0 str), 1490, 1445, 1366, 1240, 1067, 1021 cm "1 , SE (CDC1 3 ) 1.60 (ddd, IH, H-6), 2.00 (S, 3H, Ac) , 2.51 (ddd, H-5),2.96 (M, IH, H-4), 3.06-3.18 (m, 2H, CH 2 OCPh 3 ) , 5.67 (M, IH, H-l), 5.89 (dd, IH, H-3), 6.13 (ddd, IH, H-2), 7.03-7.50 (M, 15H, CP la: [ ] 27 D -52.1° (c = 1.39, CHCl 3 ) (82% ee) γmax (KBr) 3382 (OH str), 3059, 2935, 1488, 1445, 1388, 1314, 1218, 1179, 1153, 1091, 1053 and 1033 cm '1 SE (CDC1 3 ) 1.42 (ddd, IH, H-6) 2.13 (br.d, IH, OH) , 2.37 (ddd, IH, H-6) , 2.84 (M, IH, H-4), 3.08 (dd, 2H, CH 2 OCPh 3 ) , 3.29 (dd, IH, OH), 4.71 (br.s, IH, H-l), 5.97 (S, 2H, H-2 and H- 3), 7.29-745 (M, 15H, CPh 3 ) . Example 3 Ila (X = H, Y = Ph 3 C) and lib (X = Ac, Y = Ph 3 C) A solution of (±)-II (X = H, Y = -Ph 3 C; 53.7 mg, 0.15 mmol) in vinyl acetate (3.5 ml), was stirred with PFL (32.9 mg) for 48 h until TLC indicated approx. 50% acetylation. The enzyme was removed by filtration and the filtrate concentrated in vacuo. The residue (62.4 mg) was chromatographed on silica to give first lib (X = Ac, Y = Ph 3 C) as an oil (31.1 mg, 52%) followed by Ila (X = H, Y = Ph 3 C) as a white solid, mp 101-104° (25.7 mg, 48%). Data: lib: [α] 6 D -87.9° (c = 1.06, CHC1 3 ) (74% ee) γmax (neat) 3062, 3030 (OH str), 2914, 2867, 1733 (C=0 str) , 1491, 1446, 1367, 1241, 1184, 1069 and 1022 cm '1 , < SH (CDC1 3 ) 2.08 (m, 5H, 2 X H-6 + CH 3 C0) , 3.04-3.16 (M, 2H, CH 2 OCPh 3 ) , 3.20-3.28 (M, IH, H-4), 5.72-5.76 ( , IH, H-l), 5.91-5.98 (ddd, IH, H-3) , 6.20 (ddd, IH, H-2), 7.24-7.47 (M, 15H, CPh 3 ) Ila: [α] 26 D -85.2° (c = 0.99, CHC1 3 ) (74% ee) γmax (neat) 3247 (OH str) , 3060, 2912, 2885, 1488, 1445, 1382, 1319, 1215, 1181, 1154, 1112, 1075 and 1047 cm "1 SE (CDC1 3 ) 1.63 (S, IH, OH) 1.80-1.99 (M, H-6), 2.99 (dd, IH, CH 2 OCPh 3 ) , 3.08 (dd, IH, CH 2 OCPh 3 ) , 3.15-3.26 (M, IH, H- 4) , 4.85-492 (M, IH, H-l) , 5.89-5.94 (M, IH, H-3), 6.06- 6.12 (M, IH, H-2) , 7.22-732 (M, 9H, Ph) and 7.47-755 (M, 6H, Ph) Example 4 III (base = adenine, Y = H) A suspension of adenine (91 mg, 0.7 mmol) and sodium hydride (26.3 mg, 60% dispersion) was stirred in N,N- dimethylformamide (DMF) (1.7 ml) until deprotection was complete (4h at ambient temperature) . This was added dropwise to a solution of tetrakis(triphenylphosphine) palladium(O) (460 mg) and la (X = Ac, Y = H; 68.6 mg, 0.4 mmol) in tetrahydrofuran (0.95 ml) with stirring under argon. When no more reaction was evident by TLC (24 h) , the solids were removed by filtration through a celite/silica/magnesium sulphate plug. The filtrate and washing were concentrated in vacuo and the residue chromatographed on silica (15:1 in dichloro ethane- methanol) to give III (base = adenin-9-yl; Y = H) as a white solid, mp 188-191°C (21.8 mg, 22%) SE (CDC1 3 ) 1.75 (ddd, IH, H-6 1 ), 2.83 (ddd, IH, H-6 1 ) 2.98-3.08 (M, IH, H- 4 1 ), 3.58, 3.67 (each dd, 2H, CH 2 OH) , 5.66-5.73 (M, IH, H- 1 « ), 5.95 (ddd, IH, H-2'), 6.22 (ddd, IH, H-3 1 ), 8.13 (S, IH, H-2) and 8.20 (S, IH, H-8) , high resolution mass .+ spectrum; Found (Cl) 232-1198; calculated for M + H (C H 13 N 5 0) = 232-1198. Example 5 III (base = 6-chloropurine, Y = Ph 3 C) By the method of Example 4, reaction of 6-chloropurine in DMF with sodium hydride, then with la (X = Ac, Y = Ph 3 C) in the presence of Pd(PPh 3 ) 4 gave a 21% yield of III (base = 6-chloropurinyl, Y = Ph 3 C) as a white foam; high resolution mass spectrum; Found (Cl) 493.1795; calculated for M+H + (C 30 H 25 N 4 OC1) = 493.1795. Example 6 III (base = 6-chloropurine, Y = Ph 3 C) Diethyl azodicarboxylate (0.4 ml) was added dropwise to a solution of triphenylphosphine (670 mg, 2.6 mmol) and 6-chloropurine (391 mg) in tetrahydrofuran (THF) (8 ml) with stirring at room temperature under argon. After 5 min a solution of Ila (X = H, Y = Ph 3 C; 323 mg, 0.91 mmol) in THF (1 ml) was added dropwise, and then the mixture was stirred overnight when TLC showed that reaction was complete. The solvent was removed in vacuo and the residual orange oil was chromatographed on silica (3:1 to 2:1 petrol-ethyl acetate) to give III as a white foam (212 mg, 47%) identical to that prepared by the method of Example 5. IV (i) III

Claims: CLAIMS 1. An individual enantiomer of a cyclopentene of formula (la) , (lb) , (Ila) or (lib) , wherein X (at the 1-position) represents hydrogen or an acyl group, and Y (on the CH 2 OY group which is at the 4 or 5-position) represents hydrogen or a group that can be readily replaced by hydrogen, optionally substituted by non-interfering substituent(s) . 2. A process of preparing an enantiomer of claim 1 by biocatalyst-mediated esterification of the racemic secondary alcohols or deesterification of acyl derivatives of the racemic alcohols. 3. A process for the preparation of an optionally- protected carbocyclic nucleoside, which comprises the reaction of a heterocyclic base with an enantiomer (la) or (lb) as defined in claim 1 by displacement of an acyloxy group. 4. A process for the preparation of an optionally- protected carbocyclic nucleoside, which comprises the reaction of a heterocyclic base with an enantiomer (Ila) or (lib) as defined in claim 1 wherein OX is a good leaving group, by direct S N 2 displacement. 5. A process according to claim 3, wherein the displacement is palladium-catalysed.

Inventors: EVANS CHRISTOPHER THOMAS, MACKEITH ROSEMARY, ROBERTS STANLEY MICHAEL, SHOBERU KAROLINE, EVANS, CHRISTOPHER, THOMAS, MACKEITH, ROSEMARY, ROBERTS, STANLEY, MICHAEL, SHOBERU, KAROLINE
Applicants: CHIROS LTD, CHIROS LIMITED
Application year: 1992
Main classification: C07C
IPC codes: C07C35, C07C69, C07D307, C12P17, C12P41