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WO1992018477A1 - Azabicycloheptanone - Google Patents

Azabicycloheptanone Download PDF

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Publication number
WO1992018477A1
WO1992018477A1 PCT/GB1992/000731 GB9200731W WO9218477A1 WO 1992018477 A1 WO1992018477 A1 WO 1992018477A1 GB 9200731 W GB9200731 W GB 9200731W WO 9218477 A1 WO9218477 A1 WO 9218477A1
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Prior art keywords
lactam
iia
iib
enantiomers
pentacin
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PCT/GB1992/000731
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French (fr)
Inventor
Christopher Thomas Evans
Stanley Michael Roberts
Alan Gordon Sutherland
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Chiros Ltd
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Chiros Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures

Definitions

  • This invention relates to bicycloheptanes, their preparation, and their use as chiral synthons.
  • This compound can be prepared by hydrolysis of the ß-lactam (IIa) which may in turn be made by catalytic hydrogenation of the unsaturated ß-lactam (Ia).
  • EP-A-0424064 describes the enantioselective hydrolysis of the ⁇ -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. As described by Evans et al, J. Chem. Soc. Perkin Trans. I (1991) 656, the cells used for that ⁇ -lactam are apparently intolerant of structural variation.
  • This invention concerns the enantiomers of azabicycloheptane derivatives of formulae Ia, Ib, IIa and lib which, in optically pure form, are novel compounds.
  • novel compounds are useful as intermediates to optically-pure biologically-active compounds; in particular, preparation of cis-pentacin from an opticallypure ß-lactam precursor (Ia) or (IIa) is advantageous.
  • Suitable activities for the enantioselective transformation are described in EP-A-0424064, e.g. those present in certain novel wild-type isolates of the genera Pseudomonas, Alcalicrenes, Arthrobacter, Brevibacterium, Nocardia, Rhodococcus and Corynebacterium, whilst not being limited to isolates of these genera. Selection for these activities may be conducted in the presence of compounds containing one or more N-acyl substituents. If necessary, elevated levels of activity may be produced by growth of cells in the presence of such compounds. Particular examples of suitable activity are those produced maximally active in cells of the unique strains ENZA-20 and Rhodococcus sp. ENZA-1, the latter when cultivated in a suitable medium in the presence of N-acetyl-L-phenylalanine or N-acetyl-D,L-phenylalanine.
  • Rhodococcus sp. ENZA-1 was isolated from soil samples by enrichment culture in mineral salts medium containing N-acetyl-L-phenylalanine as the sole source of carbon and energy. The isolate has been deposited at the NCIMB in Aberdeen, on 17.10.89. The accession number is NCIMB 40213.
  • the racemic unsaturated ß-lactam (Ia + Ib) is made by the known method of [2+2]cycloaddition of chlorosulphonyl isocyanate onto cyclopentadiene, followed by hydrolytic removal of the chlorosulphonyl function with sodium sulphate. This synthesis is described by Malpass et al, J. Chem. Soc. Perkins Trans. I (1977) 874. For the preparation of cis-pentacin it can be advantageous to proceed via the racemic saturated ß-lactam (IIa + IIb), for this can be made in an efficient cycloaddition between cyclopentene and chlorosulphonyl isocyanate.
  • the enantiomers of formulae Ib and IIb are useful synthons in the preparation of ß-lactams, cis-pentacin analogues and amino-acid isosteres.
  • the compounds of the invention may be substituted, if desired, by non-interfering substituents, i.e. substituents that do not affect the biotransformation.
  • 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.
  • Rhodococcus equi NCIB 40213 (ENZA-1; 700 mg paste) was suspended in phosphate buffer (0.05 M; pH 7) and racemic 6-azabicyclo[3.2.0]hept-3-en-7-one (340 mg, 3.12 mmol) was added. The mixture was stirred at ambient temperature for 142 h after which the cells were removed by centrifugation. The supernatant was extracted with dichloromethane (4 ⁇ 100 ml) and the combined organic layers were dried (MgSO 4 ) and concentrated. The recovered lactam (197 mg) was reincubated with ENZA-1 (280 mg) in buffer (36 ml) for a further 170 h, then recovered as above.
  • the strain ENZA-1 thus gave, from the racemic ß-lactam (Ia + Ib), the [1R,5S]-(+)-lactam (Ia) in >99% ee and 40% yield together with an amino-acid of opposite configuration which was isolated as its methyl ester, acetamide, in 96% ee.
  • the recovered lactam (Ia) was of the correct stereochemistry for conversion into (-)-cis-pentacin.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The individual enantiomers of the bicyclic β-lactam 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 cis-pentacin.

Description

AZABICYCLOHEPTANOME
Field of the Invention
This invention relates to bicycloheptanes, their preparation, and their use as chiral synthons.
Background of the Invention
Oki et al, J. Antibiotics 42 (1989) 1756, disclose the anti-fungal microbial antibiotic cis-pentacin, of formula III (see below).
This compound can be prepared by hydrolysis of the ß-lactam (IIa) which may in turn be made by catalytic hydrogenation of the unsaturated ß-lactam (Ia).
A preparation of III in optically-active form is described by Korushi et al, J. Antibiotics 42 (1989) 1749, involving repeated crystallisation of the (+)-dehydro abietylamine salt formed from the racemate. It is not expected that this represents an economic method of making more than gram quantities of the optically-active antibiotic.
EP-A-0424064 describes the enantioselective hydrolysis of the γ-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. As described by Evans et al, J. Chem. Soc. Perkin Trans. I (1991) 656, the cells used for that γ-lactam are apparently intolerant of structural variation.
Summary of the Invention
This invention concerns the enantiomers of azabicycloheptane derivatives of formulae Ia, Ib, IIa and lib which, in optically pure form, are novel compounds.
They may each be provided substantially free of other enantiomers.
The novel compounds are useful as intermediates to optically-pure biologically-active compounds; in particular, preparation of cis-pentacin from an opticallypure ß-lactam precursor (Ia) or (IIa) is advantageous. Description of the Invention
An important discovery behind the present invention is that material of biological origin will react selectively on racemates of the ß-lactam (Ia + Ib) or (IIa + IIb) to give one enantiomer as untransformed lactam recoverable by solvent extraction, and the other as hydrolysis product, i.e. the amino-acid; the amino-acid is retained in aqueous solution upon extraction with solvent, but may be isolated, if required, for instance by adsorption on an ion-exchange resin.
Suitable activities for the enantioselective transformation are described in EP-A-0424064, e.g. those present in certain novel wild-type isolates of the genera Pseudomonas, Alcalicrenes, Arthrobacter, Brevibacterium, Nocardia, Rhodococcus and Corynebacterium, whilst not being limited to isolates of these genera. Selection for these activities may be conducted in the presence of compounds containing one or more N-acyl substituents. If necessary, elevated levels of activity may be produced by growth of cells in the presence of such compounds. Particular examples of suitable activity are those produced maximally active in cells of the unique strains ENZA-20 and Rhodococcus sp. ENZA-1, the latter when cultivated in a suitable medium in the presence of N-acetyl-L-phenylalanine or N-acetyl-D,L-phenylalanine.
Rhodococcus sp. ENZA-1 was isolated from soil samples by enrichment culture in mineral salts medium containing N-acetyl-L-phenylalanine as the sole source of carbon and energy. The isolate has been deposited at the NCIMB in Aberdeen, on 17.10.89. The accession number is NCIMB 40213.
Although the novel biotransformation is analogous to that described previously, and in EP-A-0424064, the enantioselective hydrolysis of the γ-lactam 2-azabicyclo[2.2.1]hept-5-en-3-one, efficient transformation of the ß-lactam (Ia + Ib) was unexpected, considering that the cells used for the γ-lactam seemed intolerant of structural variation.
The racemic unsaturated ß-lactam (Ia + Ib) is made by the known method of [2+2]cycloaddition of chlorosulphonyl isocyanate onto cyclopentadiene, followed by hydrolytic removal of the chlorosulphonyl function with sodium sulphate. This synthesis is described by Malpass et al, J. Chem. Soc. Perkins Trans. I (1977) 874. For the preparation of cis-pentacin it can be advantageous to proceed via the racemic saturated ß-lactam (IIa + IIb), for this can be made in an efficient cycloaddition between cyclopentene and chlorosulphonyl isocyanate.
The enantiomers of formulae Ib and IIb are useful synthons in the preparation of ß-lactams, cis-pentacin analogues and amino-acid isosteres.
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. In each case, the ee value obtained exceeds 99%.
Example 1 Whole cell resolution of 6-azabicyclo[3.2.0]hept- 3-en-7-one
Rhodococcus equi NCIB 40213 (ENZA-1; 700 mg paste) was suspended in phosphate buffer (0.05 M; pH 7) and racemic 6-azabicyclo[3.2.0]hept-3-en-7-one (340 mg, 3.12 mmol) was added. The mixture was stirred at ambient temperature for 142 h after which the cells were removed by centrifugation. The supernatant was extracted with dichloromethane (4 × 100 ml) and the combined organic layers were dried (MgSO4) and concentrated. The recovered lactam (197 mg) was reincubated with ENZA-1 (280 mg) in buffer (36 ml) for a further 170 h, then recovered as above. Column chromatography over silica using acetate as eluent gave (1R,2S)-(+)-6-azabicyclo[3.2.0]hept-3-en-7-one (137 mg, 40%) as a white solid; m.p. 76-77°C; [α]20 D 37 (c = 0.4, CHCl3); vmax (CHCl3) 3414 and 1754 cm-1; δH (CDCl3) 6.25 (1 H, brs, NH), 6.12-5.85 (2 H, m, 3-H and 4-H), 4.59-4.42 (1 H, m, 5-H), 3.85 (1 H, ddd, J 9.8, 3.5, 3.5 Hz, 1-H) and 2.90-2.25 (2 H,m, 2-H2).
The strain ENZA-1 thus gave, from the racemic ß-lactam (Ia + Ib), the [1R,5S]-(+)-lactam (Ia) in >99% ee and 40% yield together with an amino-acid of opposite configuration which was isolated as its methyl ester, acetamide, in 96% ee. The recovered lactam (Ia) was of the correct stereochemistry for conversion into (-)-cis-pentacin.
Example 2 Hydrogenation of (1R,2S)-(+)-6-azabicyclo[3.2.0]- hept-3-en-7-one
The title lactam (57 mg, 0.52 mmol) in ethyl acetate (3 ml) was added to a suspension of 10% palladium on charcoal (8 mg) in ethyl acetate (2 ml). The mixture was stirred under hydrogen at ambient temperature for 1½ h. when Hc indicated complete reaction (on silica , eluent ethyl acetate, KMnO4 development, product has RF 0.38, starting material has RF 0.45). The mixture was filtered through Celite and the filtrate concentrated to a colourless oil (55 mg 95%) which solidifies below room temperature. It was pure by GC and 1H NMR; [α]D -38 (c = 1.1, CHCl3 ).
Example 3 cis-pentacin
The reduced lactam from Example 2 (53 mg, 0.48 mmol) was stirred in 2 M hydrochloric acid (6 ml) at ambient temperature for 1 h when He indicated complete reaction (silica, ethyl acetate:methanol 4:1, KMnO4 development). The mixture was loaded onto a Dowex (H+) column and eluted with water followed by 1 M aqueous ammonia. Fractions containing product were concentrated to give cis-pentacin [(1R,2S)-2-aminocyclopentane-1-carboxylic acid] (60 mg. 97%) as an off-white solid [α]D -8 (c = 1, H2O).
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
Figure imgf000007_0004
Figure imgf000007_0005

Claims

1. The individual enantiomers of the bicyclic ß-lactam compounds (Ia), (Ib), (IIa) or (IIb),
Figure imgf000008_0001
optionally substituted by non-interfering substituent(s).
2. A process for the resolution of a mixture enantiomers of bicyclic ß-lactams (Ia + Ib) or (IIa + IIb) as defined in claim 1, by means of a biocatalyst derived from bacterial whole cells and characterised by its ability to hydrolyse only one enantiomer of the mixture, to give the corresponding ring-opened amino-acid.
3. Use of an enantiomer (Ia) or (IIa) as defined in claim 1, for the synthesis of the anti-fungal antibiotic cispentacin.
PCT/GB1992/000731 1991-04-19 1992-04-21 Azabicycloheptanone Ceased WO1992018477A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919108384A GB9108384D0 (en) 1991-04-19 1991-04-19 Bicycloheptanes
GB9108384.0 1991-04-19

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0571870A1 (en) * 1992-05-29 1993-12-01 Bayer Ag Cyclopentane- and -pentene-beta-amino-acids
WO1999010519A1 (en) * 1997-08-22 1999-03-04 Glaxo Group Limited Process for preparing enantiomerically enriched n-derivatised lactams
WO2000058283A1 (en) * 1999-03-31 2000-10-05 Chirotech Technology Limited Biocatalyst and its use in enzymatic resolution of racemic beta-lactams

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0424064A1 (en) * 1989-10-16 1991-04-24 Chiroscience Limited Chiral azabicyloheptanone and a process for their preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0424064A1 (en) * 1989-10-16 1991-04-24 Chiroscience Limited Chiral azabicyloheptanone and a process for their preparation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF THE CHEMICAL SOCIETY PERKIN TRANSACTIONS 1 no. 3, March 1991, pages 656 - 657; C. EVANS ET AL: 'SYNTHESIS OF EITHER ENANTIOMER DF CIS-3-AMINOCYCLOPENTANECARBOXYLIC ACID FROM BOTH ENANTIOMERS OF RACEMIC 2-AZABICYCLO (2.2.1) HEPT-5-EN-3 ONE.' cited in the application *
JOURNAL OF THE CHEMICAL SOCIETY,PERKIN TRANSACTIONS 1 no. 9, September 1991, pages 2276 - 2277; C. EVANS ET AL.: 'WHOLE CELL CATALYSED KINETIC RESOLUTION OF 6-AZABICYCLO(3.2.0)HEP-3-EN-7-ONE: SYNTHESIS OF (-)-CISPENTACIN (FR 109615).' *
TETRAHEDRON LETTERS no. 27, 1972, pages 2793 - 2796; H. REHLING ET AL.: 'CIRCULARDICHROISMUS UND ABSOLUTE KONFIGURATION VON BETA-LACTAMEN' *
THE JOURNAL OF ANTIBIOTICS vol. 42, no. 12, 1989, pages 1749 - 1755; KONISHI ET AL.: 'CISPENTACIN, A NEW ANTIFUNGAL ANTIBIOTIC.' cited in the application *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0571870A1 (en) * 1992-05-29 1993-12-01 Bayer Ag Cyclopentane- and -pentene-beta-amino-acids
WO1999010519A1 (en) * 1997-08-22 1999-03-04 Glaxo Group Limited Process for preparing enantiomerically enriched n-derivatised lactams
US6340587B1 (en) 1997-08-22 2002-01-22 Smithkline Beecham Corporation Process for preparing enantiomerically enriched N-derivatized lactams
AP1104A (en) * 1997-08-22 2002-09-04 Glaxo Group Ltd Process for preparing enantiomerically enriched N-derivatised lactams.
CN1133749C (en) * 1997-08-22 2004-01-07 葛兰素集团有限公司 Process for the preparation of enantiomerically enriched N-derivatized lactams
WO2000058283A1 (en) * 1999-03-31 2000-10-05 Chirotech Technology Limited Biocatalyst and its use in enzymatic resolution of racemic beta-lactams

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AU1669792A (en) 1992-11-17

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