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Dokumentenidentifikation EP0580667 26.10.2000
EP-Veröffentlichungsnummer 0580667
Titel ENANTIOMERE VON CYCLOPENTEN-DERIVATEN
Anmelder Chirotech Technology Ltd., Cambridge, GB
Erfinder EVANS, Christopher Thomas, Heydon, Hertfordshire SG8 8PU, GB;
ROBERTS, Stanley Michael, Kenton, Devon EX6 8NH, GB;
SHOBERU, Karoline, Springfield, Chelmsford CM1 5LJ, GB;
MACKEITH, Rosemary, Stocker Road, Exeter EX4 4QD, GB
Vertreter Barz, P., Dipl.-Chem. Dr.rer.nat., Pat.-Anw., 80803 München
DE-Aktenzeichen 69231466
Vertragsstaaten AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE
Sprache des Dokument EN
EP-Anmeldetag 21.04.1992
EP-Aktenzeichen 929082352
WO-Anmeldetag 21.04.1992
PCT-Aktenzeichen GB9200730
WO-Veröffentlichungsnummer 9218444
WO-Veröffentlichungsdatum 29.10.1992
EP-Offenlegungsdatum 02.02.1994
EP date of grant 20.09.2000
Veröffentlichungstag im Patentblatt 26.10.2000
IPC-Hauptklasse C12P 7/00

Beschreibung[en]
Field of the Invention

This invention relates to the preparation and use of cyclopentene derivatives, some of which are novel.

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 y-lactam 2-azabicyclo[2. 2.1]hept-5-en-3-one, utilising enzymatic activity available in deposits NCIMB 40213 and 40249. See also Taylor et al, J. Chem. Soc. Chem. Comm. (1990) 1120.

US-A-4950758 discloses racemic 4-hydroxymethyl-2-cyclopenten-1-ol. EP-A-0267878 discloses racemic 1-hydroxymethyl-2-hydroxy-3-cyclopentene. WO-A-9115447, a reference under Art. 54(3) EPC, discloses enantiomers of 4-hydroxymethyl-2-cyclopenten-1-ol. All these compounds are used in the preparation of carbocyclic nucleosides.

Summary of the Invention

This invention concerns the preparation of enantiomers of cyclopentene derivatives of structures Ia, Ib, IIa and IIb wherein X represents hydrogen or an acyl group, and Y represents hydrogen or a group that can be readily replaced by hydrogen, i.e. a protecting group, such as an acyl, triarylmethyl or trialkylsilyl group. These compounds may each be provided substantially free of other enantiomers. The enantiomers wherein the CH2OY group is at the 5-position are novel.

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 Ia (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 (IIIa); similarly, treatment of cyclopentene Ia (X=Ac, Y=CPh3) with 6-chloropurine gives a protected nucleoside (IIIa). Alternatively, direct reaction of IIa (X = H, Y = CPh3) with chloropurine in the presence of triphenylphosphine and diethyl azodicarboxylate (Mitsunobu conditions) also gives III. Similarly, Ib and IIb give an enantiomer of III.

The key individual enantiomeric synthons of this invention, Ia, Ib, IIa and IIb may be prepared from racemic mixtures Ia + Ib and IIa + IIb, 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 Ib and IIb are substrates for the enzyme and Ia and IIa 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 CH2OY 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 Ia/Ib + IIa/IIb, wherein X=Y=H. The diastereoisomers are separated conveniently as the trityl derivative (X=H, Y=CPh3), 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-butyldimethylsilyl.

Compounds of formula I in which the CH2OY 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 IIIb: Step 1 involves, e.g. reduction with LiAlH4, treatment with NaIO4 and then NaBH4, and selective protection, e.g. with Ph3CCl or t-BuMe2SiCl; Step 2 comprises biotransformation, e.g. using a lipase, and vinyl acetate; Step 3 preferably comprises treatment with Pd(PPh3)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 η3 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, CF3 and N3. 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-(CH2OY) group.

Example 1 Ia (X = Ac, Y = SiMe2tBu) [(-)-1(R)-acetoxy-4(S)-(tert-butyldimethylsilyloxymethyl)-cyclopent-2-ene] and Ib (X = H, Y = SiMe2tBu)[(+)-4(R)-tert-butyldimethylsilyloxymethyl)cyclopent-2-en-1(S)-ol]

To a solution of (±)-I (X = Ac, Y = -SiMe2 Bu; 203.5 mg, 0.75 mmol) in acetone (2.5 ml), pH 7 phosphate buffer (12.5 ml) was 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 (MgSO4), filtered, and the filtrate concentrated in vacuo. The residue (180 mg) was chromatographed on silica (9:1 petrol:ethyl acetate) to give first Ia (X = Ac, Y = SiMe2tBu) (88 mg, 43%) followed by Ib (X = H, Y = SiMe2tBu) (72 mg, 42%), both as oils.

Data:

  • Ia: [α]25D-4.2° (c = 1.78, CHCl3) (>95% ee)

    γmax (neat) 2934, 2860, 1736 (C = 0 str) , 1242, 1082 cm-1 δH (CDCl3) 0.03 (S, 6H, SiMe2), 0.87 (S, 9H, +Bu), 1.50 (ddd, 1H, H-6) 2.00 (S, 3H, Ac), 2.40 (ddd, 1H, H-6), 2.79 (M, 1H, H-4), 3.53 (d, 2H, CH2OSi), 5.61 (M, 1H, H-1), 5.82 (ddd, 1H, H-3), 6.03 (ddd, 1H, H-2).

  • Ib: [α]25D+49.6° (c = 1.42, CHCl3) (>95% ee)

    γmax (neat) 3394 (OH str), 2957, 2933, 2859, 1466, 1385, 1254, 1084, 1040, 1008 cm-1 , δH (CDCl3) 0.04 (S, 6H, SiMe2), 0.87 (S, 9H, +Bu), 1.49 (ddd, 1H, H-6), 2.26 (ddd, 1H, H-6), 2.76 (M, 2H, H-4 and OH), 3.56-3.62 (x dd CH2OSi), 4.57 (M, 1H, H-1), 5.73 (dd, 1H, H-3) and 5.90 (ddd, 1H, H-2).

Example 2 Ia (X = H, Y = Ph3C) and Ib (X = Ac, Y = Ph3C)

A solution of (±)-I (X = H, Y = -Ph3C; 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 in vacuo. The residue (75 mg) was chromatographed on silica (6:1 petrol:ethyl acetate) to give first Ib (X = Ac, Y = Ph3C) as an oil (13.6 mg, 22%) followed by Ib (X = H, Y = Ph3C) as a white solid (mp 111-112°C) (27.7 mg, 50%).

Data:

  • Ib: [a]27D+16.2° (c = 0.68, CHCl3) (>95% ee)

    γmax (neat) 3062, 3030, 2916, 2868, 1732 (C=O str), 1490, 1445, 1366, 1240, 1067, 1021 cm-1 , δH (CDCl3) 1.60 (ddd, 1H, H-6), 2.00 (S, 3H, Ac), 2.51 (ddd, H-5), 2.96 (M, 1H, H-4), 3.06-3.18 (m, 2H, CH2OCPh3), 5.67 (M, 1H, H-1), 5.89 (dd, 1H, H-3), 6.13 (ddd, 1H, H-2), 7.03-7.50 (M, 15H, CPh3)

  • Ia: [α]27D-52.1° (c = 1.39, CHCl3) (82% ee)

    γmax (KBr) 3382 (OH str), 3059, 2935, 1488, 1445, 1388, 1314, 1218, 1179, 1153, 1091, 1053 and 1033 cm-1 δH (CDCl3) 1.42 (ddd, 1H, H-6) 2.13 (br.d, 1H, OH), 2.37 (ddd, 1H, H-6), 2.84 (M, 1H, H-4), 3.08 (dd, 2H, CH2OCPh3), 3.29 (dd, 1H, OH), 4.71 (br.s, 1H, H-1), 5.97 (S, 2H, H-2 and H-3), 7.29-745 (M, 15H, CPh3).

Example 3 IIa (X = H, Y = Ph3C) and IIb (X = Ac, Y = Ph3C)

A solution of (±)-II (X = H, Y = -Ph3C; 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 IIb (X = Ac, Y = Ph3C) as an oil (31.1 mg, 52%) followed by IIa (X = H, Y = Ph3C) as a white solid, mp 101-104° (25.7 mg, 48%).

Data:

  • IIb: [α]26D-87.9° (c = 1.06, CHCl3) (74% ee)

    γmax (neat) 3062, 3030 (OH str), 2914, 2867, 1733 (C=O str), 1491, 1446, 1367, 1241, 1184, 1069 and 1022 cm-1, δH (CDCl3) 2.08 (m, 5H, 2 x H-6 + CH3CO), 3.04-3.16 (M, 2H, CH2OCPh3), 3.20-3.28 (M, 1H, H-4), 5.72-5.76 (m, 1H, H-1), 5.91-5.98 (ddd, 1H, H-3), 6.20 (ddd, 1H, H-2), 7.24-7.47 (M, 15H, CPh3)

  • IIa: [α]26D-85.2° (c = 0.99, CHCl3) (74% ee)

    γmax (neat) 3247 (OH str), 3060, 2912, 2885, 1488, 1445, 1382, 1319, 1215, 1181, 1154, 1112, 1075 and 1047 cm-1 δH (CDCl3) 1.63 (S, 1H, OH) 1.80-1.99 (M, H-6), 2.99 (dd, 1H, CH2OCPh3), 3.08 (dd, 1H, CH2OCPh3), 3.15-3.26 (M, 1H, H-4), 4.85-492 (M, 1H, H-1), 5.89-5.94 (M, 1H, H-3), 6.06-6.12 (M, 1H, 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(0) (460 mg) and Ia (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 dichloromethanemethanol) to give III (base = adenin-9-yl; Y = H) as a white solid, mp 188-191°C (21.8 mg, 22%) δH (CDCl3) 1.75 (ddd, 1H, H-6'), 2.83 (ddd, 1H, H-6') 2.98-3.08 (M, 1H, H-4'), 3.58, 3.67 (each dd, 2H, CH2OH), 5.66-5.73 (M, 1H, H-1'), 5.95 (ddd, 1H, H-2'), 6.22 (ddd, 1H, H-3'), 8.13 (S, 1H, H-2) and 8.20 (S, 1H, H-8), high resolution mass spectrum; Found (CI) 232-1198; calculated for M + H+ (C11H13N5O) = 232-1198.

Example 5 III (base = 6-chloropurine, Y = Ph3C)

By the method of Example 4, reaction of 6-chloropurine in DMF with sodium hydride, then with Ia (X = Ac, Y = Ph3C) in the presence of Pd(PPh3)4 gave a 21% yield of III (base = 6-chloropurinyl, Y = Ph3C) as a white foam; high resolution mass spectrum; Found (CI) 493.1795; calculated for M+H+ (C30H25N4OCl) = 493.1795.

Example 6 III (base = 6-chloropurine, Y = Ph3C)

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 IIa (X = H, Y = Ph3C; 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.


Anspruch[de]
  1. Verfahren zur Herstellung eines einzelnen Enantiomers eines Cyclopentens irgendeiner der Formeln
    worin X Wasserstoff oder eine Acylgruppe darstellt, die CH2OY-Gruppe an der 4- oder 5-Position vorliegt und Y Wasserstoff darstellt oder eine Gruppe, die leicht durch Wasserstoff ersetzt werden kann, gegebenenfalls mit einem oder mehreren nicht-störenden Substituenten substituiert, welches Verfahren die Biokatalysator-vermittelte Veresterung des entsprechenden racemischen sekundären Alkohols oder Entesterung eines Acyl-Derivats des racemischen Alkohols umfaßt.
  2. Verfahren nach Anspruch 1, worin CH2OY an der 4-Position vorliegt.
  3. Enantiomer wie in Anspruch 1 definiert, worin CH2OY an der 5-Position vorliegt.
  4. Verfahren zur Herstellung eines gegebenenfalls geschützten carbocyclischen Nukleosids, welches das Verfahren von Anspruch 1 oder Anspruch 2 umfaßt und den zusätzlichen Schritt der Umsetzung einer heterocyclischen Base mit einem Enantiomer (Ia) oder (Ib) mit einer heterocyclischen Base durch Verdrängung einer Acyloxygruppe.
  5. Verfahren zur Herstellung eines gegebenenfalls geschützten carbocyclischen Nukleosids, welches umfaßt die Reaktion einer heterocyclischen Base mit einem Enantiomer (IIa) oder (IIb) wie in Anspruch 1 oder Anspruch 2 definiert, worin OX eine gute Austrittsgruppe ist, durch direkte SN2-Verdrängung.
  6. Verfahren nach Anspruch 4, worin die Verdrängung Palladium-katalysiert ist.
Anspruch[en]
  1. A process for preparing an individual enantiomer of a cyclopentene of any of the formulae
    wherein X represents hydrogen or an acyl group, the CH2OY group is at the 4 or 5-position, and Y represents hydrogen or a group that can be readily replaced by hydrogen, optionally substituted by non-interfering substituent(s), which comprises biocatalyst-mediated esterification of the corresponding racemic secondary alcohol or deesterification of an acyl derivative of the racemic alcohol.
  2. A process according to claim 1, wherein CH2OY is at the 4-position.
  3. An enantiomer as defined in claim 1, wherein CH2OY is at the 5-position.
  4. A process for the preparation of an optionally-protected carbocyclic nucleoside, which comprises the process of claim 1 or claim 2 and the additional step of reaction of a heterocyclic base with an enantiomer (Ia) or (Ib) with a heterocyclic base, by displacement of an acyloxy group.
  5. A process for the preparation of an optionally-protected carbocyclic nucleoside, which comprises the reaction of a heterocyclic base with an enantiomer (IIa) or (IIb) as defined in claim 1 or claim 2 wherein OX is a good leaving group, by direct SN2 displacement.
  6. A process according to claim 4, wherein the displacement is palladium-catalysed.
Anspruch[fr]
  1. Procédé de préparation d'un énantiomère individuel d'un cyclopentène selon l'une quelconque des formules
    dans lesquelles X représente l'hydrogène ou un groupe acyle, le radical CH2OY se trouve en position 4 ou 5, et Y représente l'hydrogène ou un groupe qui peut facilement être remplacé par l'hydrogène, facultativement substitué par un ou des substituants non-intervenants, qui comprend une estérification médiée par biocatalyseur de l'alcool secondaire, racémique, correspondant, ou une désestérification d'un dérivé acyle de l'alcool racémique.
  2. Procédé selon la revendication 1, dans lequel CH2OY se trouve en position 4.
  3. Enantiomère selon la revendication 1, dans lequel CH2OY se trouve en position 5.
  4. Procédé de préparation d'un nucléoside carbocyclique facultativement protégé, qui comprend le procédé de la revendication 1 ou de la revendication 2 et l'étape supplémentaire de réaction d'une base hétérocyclique avec un énantiomère (Ia) ou (Ib) avec une base hétérocyclique, par déplacement d'un groupe acyloxy.
  5. Procédé de préparation d'un nucléoside carbocyclique facultativement protégé, qui comprend la réaction d'une base hétérocyclique avec un énantiomère (IIa) ou (IIb) tel que défini dans la revendication 1 ou la revendication 2, dans lequel OX est un groupe qui se sépare facilement, par déplacement direct par SN2.
  6. Procédé selon la revendication 4, dans lequel le déplacement est catalysé par palladium.






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