CA2180963C

CA2180963C - Novel high enantio-selective process for producing pure enantiomeric cyclopentane and cyclopentene-.beta.-amino acids

Info

Publication number: CA2180963C
Application number: CA002180963A
Authority: CA
Inventors: Joachim Mittendorf; Hermann Arold; Peter Fey; Michael Matzke; Hans-Christian Militzer; Klaus-Helmut Mohrs
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1994-01-13
Filing date: 1995-01-09
Publication date: 2006-03-14
Anticipated expiration: 2015-01-09
Also published as: CA2180963A1

Abstract

The present invention relates to a highly enantio-selective process for the preparation of enantiomerically pure cyclopentane- and -pentene .beta.-amino acids of the general formula (I) (see formula I) in which A and L, A and D or E and L, D and E, R2, R3, T and R1 have the meaning given in the description.

Description

y 218963 The present invention relates to a highly enantioselec-tive process for the preparation of enantiomerically pure cyclopentane- and -pentene ~-amino acids.
The principle of an asyamnetric ring opening of prochiral acid anhydrides with methanol and catalytic amounts of cinchona alkaloids is known from the publications J.
Chem. Soc. Perkia Trans. I, 1987, 1053; Tetrahedron Asymm. 1990, 517 and J. Chem. Soc. Chem. Common. 1985, 1717-1719. The corresponding half-esters are obtained with moderate enantiomeric excesses of from 35 to 67% of theory.
The invention relates to a highly enantioselective pro cess for the preparation of enantiomerically pure cyclo pentane- and -pentene ~-amino acids of the general for mula (I).
D E
A L
cn ~R2N CO-T-R~
in which A and L denote hydrogen Le A 29 957 - 1 -2lgo~~s or A and D or E and L in each case together form a double bond, D and E are identical or different and represent hydro-gen, halogen or hydroxyl or represent straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- to disubstituted by identical or different substituents consisting of halogen, hydroxyl, phenyl, benzyloxy or carboxyl or of straight-chain or branched alkoxy, acyl or alkoxycarbonyl haviag in each case up to 6 carbon atoms or of a group of the formula -NR''R5, in which R'' and RS are identical or different and denote hydrogen, phenyl or straight-chain or _ branched alkyl having up to 6 carbon atoms, or D and E together represent a radical of the formula Rs CwR~
Le A 29 957 - 2 -2~~~963 or =N-OH, in which R6 and R' are identical or different and denote hydrogen or halogen or straight-chain or branched alkyl, alkoxy or oxyacyl having in each case up to 8 carbon atoms, or denote benzyl or phenyl, or D and E together represent the radical of the formula =O
or =S, Rs represents hydrogen or represents an amino-protecting group, or represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- to disubstituted by identical or different substi-tuents consisting of hydroxyl or formyl or of straight-chain or breached acyl having up to 6 carbon atoms or of phenyl or beazoyl, which are optionally substituted up to 2 times by identical or different substituents consisting of halogen, vitro or cyano or of straight-chain or branched alkyl having up to 6 carbon atoms, or represents straight-chain or branched acyl having up to 8 carbon atoms, Le A 29 957 - 3 -2 ~ a~~~s or represents benzoyl which is optionally substituted as described above, or represents a group of the formula -SOsR°, in which RB denotes straight-chain or branched alkyl having up to 8 carbon atoms or denotes benzyl or phenyl, the latter radicals being optionally substituted up to 3 times by identical or different substituents consisting of halogen, hydroxyl, nitro, cyano. trifluoromethyl or trifluoromethvxy or of straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, or carboxyl or of the above-indicated group -NR'R5, in which R'~ and RS have the meaning given above, or represents phenyl which is optionally substituted up to 3 times by identical or different substi-tuents consisting of halogen, hydroxyl, vitro, tri-fluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl Le A 29 957 - 4 -haviag in each case up to 6 carbon atoms or of a group of the formula -NR~RS or -SOsRe~
in which R'', RS and Re have the meaning given above or represent an amino acid residue of the formula R9 _ -CO NHR'°
in which R' denotes cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or hydrogen or denotes straight-chain or branched alkyl having up to 8 carbon atoms the alkyl being optionally substituted by cyano, methylthio~ hydroxyl, mercapto or guani dyl or by a group of the formula -NRllRlz or Rl'-OC
in which R11 and Rlz independently of one another Le A 29 957 - 5 -21 ~Q~b3 represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, and R1' denotes hydroxyl, benzyloxy or alkoxy having up to 6 carbon atoms or denotes the above-indicated group -~mRia ~
or the alkyl is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms which is substituted in turn by hydroxyl, halogen, vitro or alkoxy having up to 8 carbon atoms or by the group -NRlRiz in which R11 and R1' have the meaning given above, and Rl° denotes hydrogen or an amino-protecting group, R' represents hydrogen or represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by phenyl, Le A 29 957 - 6 -or R' and R' together represent the radical of the formula =CHR14 , in which Rl'' denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by halogen, hydroxyl, phenyl _or carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, T represents an oxygen or sulphur atom or represents the -NH group, R1 represents hydrogen or represents straight-chaia or branched alkyl having up to 8 carbon atoms or phenyl, the latter radicals being optionally sub-stituted up to 3 times by identical or different substituents consisting of hydroxyl, halogen, nitro, cyano, carboxyl, trifluoromethyl or trifluoromethoxy, of straight-chain or branched alkoxy, and in the case of phenyl also of straight-chain or branched alkyl, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, or of a group of the formula -NR4R5 or -SORB, Le A 29 957 - 7 -._ 21 X0963 in which R4, RS and R8 have the meaning given above, or, if T represents the -NH group, R1 represents the group of the formula -SOsRB, in which R8 has the meaning given above, characterized in that meso-dicarboxylic acid anhydrides of the general formula (II) D
A L
v - v in which A, D, E and L have the meaning given above are converted by an asyamnetric alcoholysis with alcohols of the general formula (III) Le A 29 957 - 8 -__ 2 i 8096:
Rls-off (III) in which R15 represents straight-chain or branched alkyl or represents alkenyl haviag in each case up to 5 carbon atoms, which are optionally substituted by cyano, trimethylsilyl, phenyl or trichloromethyl, and in the presence of equimolar amounts of a chiral amine base which is present in_ enantiomerically pure form, in inert solvents and initially via the inter-mediate, enantiomerically pure salt stage of the general formula (IV) D E
A L C+),~_) VOOO2C COZ R;$
in which A, D, E, L and R15 have the meaning given above and V represents the chiral amine base, to the enantiomerically pure compounds of the general formula (IVa) Le A 29 957 - 9 -2~~09~3 D E- .
A ~ (+).(-) H02C C02 R~s in which A, D, E, L and R15 have the meaning given above, subsequently, following activation of the free carboxylic acid function by reaction with liquid NH3, the enantio-merically pure amides of the general formula (V) D E
A L (+),(_) H2N-OC C02 R~~
in which A, D, E, L and R15 have the meaning given above, are prepared, in a further step the products are converted, by elimina-tion of the radical R15 in inert solvents, enzymatically Le A 29 957 - 10 -218i~963 or in the presence of a Pd catalyst, and is each case depending oa a nucleophilic auxiliary, into the compounds of the general formula (VI) or (VIa) D E D E
A L A L
. (~')~(-) (VI) (+).(-) (Vla) H2N-OC C024 X~ ~ HZN-OC C02H
in which A, D, E and L have the meaning given above, and X represents an alkali metal or alkaline earth metal atom, preferably sodium, and finally a Hofmann rearrangement is carried out using alkali metal hypochlorites or alkaline earth metal hypo-chlorites in aqueous alkali metal hydroxide or alkaline earth metal hydroxide solution, the free amine function is initially blocked in solutioa with a typical amino-protecting group, which is eliminated by conventional methods after isolation of the protected compounds in accordance with conventional conditions, to obtain the respective pure enantiomer.
The process according to the invention can be illustrated Le A 29 957 - 11 -by way of example by means of the following equation:
~H
HO
.~~~~i H

' NJ
O o O
OOH , Et~O, -20'C _ HO O
O O
83.5 (e.e. = 97 %) 1.) C1C02tBu, N-ethylmorpholine -5°C
2 . ) NH3 (aq. ) 3.) cat.Pd(PPh3)1 Sodium 2-ethylhexanoate HZN ~--ONa O O
Le A 29 957 - 12 -_ 2 ~ t~;~9u3 1.) KOCI,~KOH, -5'C (Hofmann-rearrangement) 2.) Fmoc.OSu 3.) Piperidine 4.) HCI
HCI x HzN COzH
63 %
(-)-enaati0mer (e.e.> 98 %) ~H
'N
.,~~~i H
H3C0 ~
.' J
0 O. O N
OOH , EtzO, -20'C HO O

(e.e. = 97 %) 1.) CIC02t Bu, N-ethyimorpholine, -5'C
2.) NH3(a~ .
3.) cat. Pd (PPh~4 Sodium 2-ethylhexanoate HZN ONa 62 °~o O 0 Le A 29 957 - 13 -2 ~ ~ia~~~
1.) KOCI, KOH, -5'C (Hofmann-rearrangement) 2.) (BOC)20 3.) HCI
HCI x HzN C02H

(-)-enaatiomer (e.e.> 98 %) Surprisingly, when carrying out the process according to the invention, the chiral compounds of the general for-.
mula (I) are obtained in an elegant manner with a very high enantiomeric purity combined. with very good yields.
In contrast to the above-cited prior art, the process according to the invention makes possible a highly enantioselective route to the opening of prochiral anhydrides in the presence of equimolar quantities of a chiral amine base, an additionally enantiomeric enrich-went being brought about by crystallization of the inter-mediate salts of the corresponding dicarboxylic acid monoesters (formula IVa) with the chiral amine base. Even the dicarboxylic acid monoesters (foraaula IVa) are obtained in a good yield and in highly pure form.
Furthermore, the process according to the invention is distinguished, in contrast to the prior art, by the fact that not only can the chiral amine base be recovered completely simply by extraction with dilute acids but also the dicarboxylic acid monoester (foraaula IVa) , which is contained in the mother liquor at a somewhat lower enantiomeric purity, can be converted back in an elegant manner into the corresponding anhydride.
Le A 29 957 - 14 -A further advantage of the process according to the invention, especially is view of the cost factor as well, is that the overall reaction sequence is very short and of low complexity, and that even the various inter-s mediates are obtained and/or can be recovered in very good yields and with high enantiomeric purity.
Suitable solvents for the reaction of the dicarboxylic acid anhydrides of the general formula (II) are all inert organic solvents which are not changed under the reaction conditions. These include preferably ethers such as diethyl ether., dioxane, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuraa or glycol dimethyl ether, or hydrocarbons such as toluene, benzene, xylene, hexane, cyclohexane or petroleum fractions, or chlorinated hydro-carbons such as chloroform or methyleae chloride, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or glacial acetic acid, dimethyl sulphoxide, acetonitrile or pyridine. Diiso-_ propyl ether, diethyl ether, dioxane, tert-butyl methyl ether and toluene are preferred for the individual steps.
The reaction temperatures can be varied over a relatively wide range. The reactions are in general carried out between -60°C and +20°C, preferably between -20°C and +25°C.
The reactions can be carried out at atmospheric pressure but also at elevated or reduced pressure (e.g. from 0.5 to 80 bar) . They are generally carried out at atmospheric Le A 29 957 - 15 -_ - 2i~n963 pressure.
Suitable alcohols (formula III) for the process according to the invention are preferably primary alcohols such as, for example, propanol, butaaol, isopropanol, ethanol, allyl alcohol or cinaamyl alcohol.
Suitable chiral amiae bases for the process according to the invention are preferably alkaloids and cinchona alkaloids. Particular preference is given to cinchona alkaloids such as, for example, (+),(-)-quinine, (+),(-)-hydroquinine, (+),(-)-cinchonidine, (+),(-)-epiquinidine, (+) , (-) -epicinchonidine, ~ (+) , (-) -cinchoniae, (+) , (-) -epicinchoniae, (+),(-)-epiquiaine, (+),(-)-hydroquini-dine, (+),(-)-4-chlorobenzoate-epiquinine or (+),(-)-4-chlorobenzoate-epicinchonine. (+),(-)-Quinine and (+),(-)-quinidine are particularly preferred.
The chiral amine base is employed in equivalent quan-tities based on 1 mol of the dicarboxylic acid anhydrides of the general formula (II).
Examples of suitable acids for the recovery of the free chiral amine base are mineral acids such as HCl, HBr or sulphuric acid.
The acid is generally employed in a quantity of from 1 mol to 10 mol, preferably from 1.5 mol to 4 mol, based on 1 mol of the compounds of the general formula (IV).
Le A 29 957 - 16 -21~0~63 The recovery is generally carried out in a temperature range from 0°C to +50°C, preferably from 20°C to 30°C at atmospheric pressure.
The amidation is generally carried out in inert solvents is the presence of a base and an activating reagent.
Suitable solvents in this context are inert organic solvents which are not changed under the reaction conditions indicated. These include esters such as methyl, ethyl, isopropyl or n-butyl acetate or ethers such as diethyl ether, dioxane, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuraa or glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethaae, tetrachloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, di-methylformamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to employ mixtures of the solvents. Methyl acetate is particularly preferred.
Suitable bases for the amidation are organic amines such as N-ethylmorpholine, N-methylmorpholine, pyridine, triethylamine or N-methylpiperidine.
The amidation is generally carried out in a temperature range from -30°C to +20°C, preferably at from -20°C to 0°C.
Le A 29 957 - 17 -The amidation is generally carried out at atmospheric pressure. However, it is also possible to carry out the process at subatmospheric pressure or at superatmospheric pressure (e. g. in a range from 0.5 to 5 bar).
Suitable activating reagents are carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexyl-carbodiimide or N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-~ulphonate or propane-phosphoric anhydride, or alkyl chloroformates such as ethyl or isobutyl chloroformate, or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, or N,N-diphenylphosphonamide, or methanesulphoayl chloride, optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine.
The base is generally employed in a quantity of from 1 mol to 3 mol, preferably from 1 mol to 1.5 mol, based on 1 mol of the compounds of the general formula (IVa).
The radical R15 is generally eliminated in inert solvents such as, for example, in the above-listed hydrocarbons, esters or ethers, in particular in tetrahydrofuran, acetonitrile, dimethylformamide or ethyl acetate. Ethyl acetate is preferred.
Examples of suitable nucleophilic auxiliaries for the elimination of the radical R15 are carboxylic acids and Le A 29 957 - 18 -their alkali metal salts (e. g. formic acid, acetic acid, 2-ethylhexanoic acid, sodium 2-ethyl-hexanoate), organic amines such as, for example, morpholine, triethylamine, pyrrolidine, dimethyltrimethylsilylamine, trimethylsilyl-morpholine, n-butylamine, dimedone, sodium diethylmalonate, tributyltin hydride, N,N-dimethyl-barbituric acid or ammonium formate. 2-Ethylhexanoic acid and sodium 2-ethyl-hexanoate are preferred.
The auxiliary is generally employed in a quantity of from 1 mol to 20 mol, preferably from 1.1 mol to 2 mol, based on 1 mol of the compounds of the general formula (V).
Examples of Pd catalysts which are suitable in the con-text of the process according to the invention are tetra-kistriphenylphosphiaepalladium (O) (Pd(PPh3)~/PPh3, palladium dibenzylideneacetoae (Pd=(dba)3), Pd,(dba)3 x CHC13, Pd (dba) z, PdCl2, Pd (OAc) s, PdClz (PhCN) z, PdClz (CH3CN) z or PdClz (PPh3),. Palladium dibenzylideneacetone and tetra-kistriphenylphosphinepalladium are preferred.
The catalyst is generally employed in a quantity of from 0.0001 mol to 0.2 mol, preferably from 0.001 mol to 0.05 mol, based on 1 mol of the compounds of the general formula (V).
The elimination of the radical R15 is generally carried out in a temperature range from 0°C to 60°C, preferably from 20°C to 30°C.
Le A 29 957 - 19 -2 I ~09~3 The elimination is generally carried out at atmospheric pressure. However, it is also possible to work at sub-atmospheric pressure or superatmospheric pressure (e. g.
from 0.5 to 5 bar) .
Amino-protecting groups in the context of the invention are the conventional amino-protecting groups used in peptide chemistry.
These include preferably: benzyloxycarbonyl, 3,4-di methoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,' 2,4-dimethoxybenzyloxycarbonyl, . 4-methoxybeazyloxy carbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxy-carbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarboayl, tert-butoxycarboayl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxy-carbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, 4-nitrophenoxy-carbonyl, N-fluorenyl-9-methoxycarbonyl (Fmoc), formyl, _. acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromo acetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, benzyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxy methylene, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4-nitro phenyl or 2-aitrophenylsulphenyl. Fbnoc is particularly preferred.
The Hofmann rearrangement of the compounds of the general formula (VI) or (VIa) is in general carried out using alkali metal hypochlorites or alkaline earth metal Le A 29 957 - 20 -- 2~~09~3 hypochlorites in aqueous alkali metal hydroxide or alka-line earth metal hydroxide solution. Potassium hypochlorite in aqueous,potassium hydroxide solution is preferred.
The Hofmann rearrangement is generally carried out in a temperature range from -15°C to +50°C, preferably from -10°C to +30°C at atmospheric pressure.
The amino-protecting group is introduced by conventional methods in one of the above-listed solvents, preferably dioxane, in the presence of a base and in a temperature range from 0°C to 60°C, preferably at room temperature and atmospheric pressure.
Suitable bases are the conventional basic compounds.
These include preferably alkali metal hydroxides and alkaline earth metal hydroxides such as lithium hydro-xide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrogen carbonates and alkaline earth metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or barium hydrogen carbonate, and alkali metal carbonates or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, or alkali metal alcoholates. Sodium hydrogen carbonate is particularly preferred.
The base is generally employed is a quantity of from 1 mol to 20 mol, preferably from 5 mol to 10 mol, based Le A 29 957 - 21 -on 1 mol of the compounds of the general formula (VI).
The amino-protecting group is generally eliminated using the above-listed organic amines. Piperidine is preferred.
The base is generally employed in a quantity of from 1 mol to 100 mol, preferably from 20 mol to 60 mol, based on 1 mol of the protected compound.
The elimination is generally carried out in a temperature range from 0°C to 60°C, preferably from 20°C to 30°C at atmospheric pressure.
The compounds of the general formula (II) are known per se or can be prepared according to published methods.
The'alcohols of the general formula (III) are known.
The compounds of the general formulae (IV), (IVa) and (V) are novel and can be prepared, for example, as described above.
Some of the compounds of the general formulae (VI) and (VIa) are known, in which case they can be prepared as described above.
The process according to the invention is preferably used to prepare enantiomerically pure compounds of the general formula (I) Le A 29 957 - 22 -21~~~~~
in which A and L denote hydrogen, D and E are identical or different and represent hydro-gen, fluorine, chlorine, bromine, benzyl or hydroxyl or represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by halogen, benzyloxy or hydroxyl, by straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 4 carbon atoms or by a group of the formula -NR''R5, in which R~ and RS are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or D and E together represent a radical of the formula R~
C~R~
or =N-OH, Le A 29 957 - 23 -~~~09~
in which R6 and R' are identical or different and denote hydrogen, fluorine, chlorine, bromine, or straight-chain or branched alkyl having up to 6 carbon atoms, or denote benzyl or phenyl, or D and E together represent the radical of the formula =O
or =S, Rs represents hydrogen or represents Boc, benzyl, benzyloxycarbonyl, allyloxycarbonyl or 9-fluorenyl methyloxycarbonyl (Fmoc), or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substi tuted by hydroxyl or formyl or by straight-chain or branched acyl having up to 4 carbon atoms or by phenyl or benzoyl, which are optionally substituted by halogen, vitro or cyano or by straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 6 carbon atoms, or represents benzoyl which is optionally substituted as described above, Le A 29 957 - 24 -2 ~ sof~~~
or represents a group of the formula -SO,R°, in which RB denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, the latter radicals being optionally substituted up to 2 times by identical or different substi-tuents consisting of halogen, hydroxyl, vitro, cyano, trifluoromethyl_or trifluoromethoxy or of straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms or of the above-listed group of the formula -NR'R5, in which R' and RS have the meaning given above, represents phenyl which is optionally substi-tuted up to 2 times by identical or different substituents consisting of halogen, hydroxyl, vitro, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or of a group of the formula -NR6R' or -SOzRe, in which Le A 29 957 - 25 -R6 and R' have the meaning given above, or represents an amino acid residue of the formula Rs -CO ~NHR~°
in which R9 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, and R1° denotes hydrogen, benzyloxy, Fmoc or tert-butoxycarbonyl, R' represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, or RZ and R' together represent the radical of the formula =CFiRl! , Le A 29 957 - 26 -in which R1' denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by halogen or hydroxyl or by straight-chain or branched alkoxy or alkoxycarboayl having in each case up to 4 carbon atoms, T represents an oxygen or sulphur atom or represents the -NH group, _ Rl represents hydrogen or represents straight-chain or branched alkyl having up to 6 carbon atoms or phenyl, the latter radicals being optionally sub-stituted up to 2 times by identical or different substituents consisting of hydroxyl, halogen, nitro, cyano, trifluoromethyl or trifluoromethoxy, of straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 4 carbon atoms, or of a group of the formula -NR'~RS or -S02R8, in which R', RS and R8 have the meaning given above, or, if T represents the -NH group, R1 represents the group of the formula -S02R8, he A 29 957 - 27 -2180~a3 in which R8 has the meaning given above.
The process according to the invention is used with particular preference to prepare enantiomerically pure compounds of the generah formula (I) in which A and L denote hydrogen, or D and E are identical or different and represent hydro-gen, fluorine, chlorine, bromine, benzyl or hydroxyl or represent straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl or benzyloxy, or D and E together represent a radical of the formula RE
C~R7 Le A 29 957 - 28 -~~ ~~'~~3 or =N-OH, in which R6 and R' are identical or different and deaote hydrogen, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 4 carbon atoms or denote phenyl, or D and E together represent the radical of the formula =O
or =S, R2 represents hydrogen, allyloxycarbonyl, benzyl, Boc or Fmoc, or represents straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 4 carbon atoms or represents a group of the formula -SOzRa, in which R8 denotes straight-chain or branched alkyl having up to 4 carbon atoms, or denotes phenyl or benzyl, the latter radicals being optionally substituted by hydroxyl, fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl or -methoxy, or Le A 29 957 - 29 -2i8~~~3 represents an amino acid residue of the formula -CO NHR~°
in which R' denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, and R1° deaotes hydrogen, tert-butoxycarboayl or Fmoc, R' represents hydrogen or represents straight-chain or branched alkyl having up to 4 carbon atoms, or R~ and R3 together represent the radical of the formula =CHRl'~ , in which R14 denotes hydrogen or straight-chaia or branched alkyl having up to 4 carbon Le A 29 957 - 30 -~1~Q9~3 atoms, T represents an oxygen or sulphur atom or the -NH
group, R1 represents hydrogen or represents straight-chain or braached alkyl haviag up to 4 carbon atoms or phenyl, the latter radicals being optionally sub-stituted by fluorine, chlorine, bromine, vitro, cyano, methoxy or ethoxy or by a group of the formula -NR'RS or -SOzR°, in which R' and RS are identical or different and denote hydrogen, methyl or ethyl and R8 has the meaning given above, or, if T represents the -NH group, R1 represents the group of the formula -SORB, in which R8 has the meaning given above.
The process according to the invention is used with very Le A 29 957 - 31 -21~0~63 particular preference to prepare enantiomerically pure compounds of the general formula (I) in which A, D, E and L represent hydrogen, or A and L represent hydrogen and D and E together form a double bond.
The process according to the iavention enables access, in a highly enantioselective manner combined with quantita-tive yields, to enantiomerically pure cyclopentane- and -pentene ~-amino acids of the general formula (I), which constitute valuable antimycotic aad antibacterial medica-ments.
Example 1 4-Methylene-cyclopentane-1,2-dicarboxylic acid Ize A 29 957 - 32 -:,,, 2.2245 kg (40 mol) of potassium hydroxide are dissolved is 15.7 1 of water and the solution is cooled to room temperature. 2.2263 kg (10 mol) of diethyl 4-methylene-1,2-cyclopentane-dicarboxylate are dissolved in 15.7 1 of ethaaol, and the solution is run at room temperature into the potassium hydroxide solution.- After stirring for 30 minutes at RT.the ethanol is distilled off at 55°C on a rotary evaporator. The aqueous solution which remains is washed with twice 5 1 of diethyl ether, the ether phase is discarded, and the aqueous phase is cooled and adjusted to a pH of 2 using 3 1 of concentrated hydro-chloric acid. The mixture is then extracted 3 times with 9 1 of ethyl acetate each time, and the ethyl acetate phase is dried over sodium sulphate and concentrated at 60°C on a rotary evaporator.
Yield: 1.66 kg; 97.5% of theory M.p.: 165-172°C
4-Methylene-cyclopentane-1,2-dicarboxylic anhydride Le A 29 957 - 33 -~~8~~~3 ~

O ~ O

1325.6 g (7.79 mol) of 4-methylene-1,2-cyclopentane-dicarboxylic acid and 6 1 of propionic anhydride are heated under reflux (160°C) for 7 h. A portion of the propionic anhydride is distilled off at 80°C on a rotary evaporator and the residue (2.165 kg) is distilled under a high vacuum.
Yield: 1014.9 g; 80.2% of theory GC: 93.7% pure B.pt.: 97-100°C (0.5 mm Hg) Example 3 Cyclopentane-1,2-dicarboxylic anhydride o~o The preparation is carried out by analogy with that described for Example 2, starting from 29.9 g (189 a~ol) of 1,2-cyclopentane-dicarboxylic acid.
Yield: 17.8 g (77%) Le A 29 957 - 34 -w~ 2180963 B.pt.: 140°C (0.1 mbar, bulb tube distillation) Monoallyl (-)-1,2-cis-4-methylene-cyclopentane-1,2-di-carboxylate, quinine salt x quinine HO ~'- O

Monoallyl (-)-1,2-cis-4-methylene-cyclopentane-1,2-dicarboxylate Ho o~

750 g (4.93 mol) of 4-methylene-1,2-cyclopentane-dicar-boxylic anhydride are dissolved in 34 1 of diethyl ether and the solution is cooled to 0°C. 1.6 kg (4.9 mol) of (-)-quinine are added, the mixture is cooled to -10°C, 504.6 ml (7.4 mol) of allyl alcohol are added, and the mixture is stirred at from -10°C to -5°C for 4 h, with precipitation of Example 4. The product is filtered off Le A 29 957 - 35 -,.

._- ~ 1 X0963 with suction, washed with a total of 10 1 of diethyl ether and dried in vacuo. 2217.7 g of the compound of Example 4 are suspended in 30 1 of ethyl acetate and washed with 10 1 of 1N hydrochloric acid. The combined hydrochloric acid phases are washed twice with ethyl acetate, aad the combined ethyl acetate phases are washed with saturated sodium chloride solutioa, dried over sodium sulphate and concentrated at 50°C on a rotary evaporator to give 859.2 g .(83.5% of theory).
Enantiomeric excess: Z 99% (HPLC, Chiracel OD) 1H-NMR (CDC13) : 8 - 2.59 - 2 . 91 (4H) , 3 .11 - 3 .28 (2H) , 4 .58 (2H) , 4. 94 (2H) ; 5.18 - 5.37 (2H) ; 5 . 80 - 5 . 97 (1H) .
The aqueous hydrochloric acid phase is adjusted to a pH
of 9.4 using 2.5 M sodium hydroxide solution, and the quinine which precipitates is filtered off with suction, washed with water and dried at 50°C in a circulating-air drying cabinet.
Yield:
M.p.. 160-162°C
Example 6 Monoallyl (-)-cis-cyclopentane-1,2-dicarboxylate H0~0 Le A 29 957 - 36 -w- 218~9b~
The preparation is carried out by analogy with that described for Example 4 aad 5, starting from 13.8 g (98.6 mmol) of the compouad of Example 3.
Yield: 13.0 g (67%) 1H-NMR (CDC13) : 1.56 - 2 .20 (6H) ; 3 .03 - 3 .16 (2H) ; 4.08 (2H); 5.69 - 5.90 (2H); 5.82 - 6.00 (1H).
Enantiomeric excess e.e.: Z 98% (determined by HPLC after coupling of the carboxylic acid function with L-phenyl-glycinol) The compounds listed is Table 1 are prepared in analogy to the procedure of Examples 4, 5 and 6:
H02C C02 R~5 Le A 29 957 - 37 -Ex.No. Rls Yield (% of th. e. e. (%) ) 7 - (CHs) z-CN' 41 78 8 - (CHs) z-Si (CH3)87 64 3' 9 -CH (CH3) i' 76 17 10 -CZHS' 74 88 11 -CH3' 81 75 12 - (CH=) 2CH, 72 98 13 - (CHZ) 3CH3 67 . 97 . 5 14 -CH=CH-C6H5 82 94 15 -CHs-CH (CH3) s 69 95 - in toluene at 0°C
A11y1 (-)-1,2-cis-2-aminocarbonyl-4-methylene-cyclopea-tane-1-carboxylate HZN ~-0--~

1.145 kg (5.447 mol) of monoallyl (-)-1,2-cis-4-I~e A 29 957 - 38 -~ ~ ~~~b.3 methylene-1,2-cyclopentane-dicarboxylate are dissolved in 25 1 of ethyl acetate, 729 ml (5.73 mol) of N-ethyl-morpholine are added, and 743.5 ml (5.73 mol) of isobutyl chloroformate are rua in at -6°C over the course of 20 minutes. The mixture is stirred at from -6°C to -10°C for 1 h and, at this temperature, 1276 ml (17.07 mol) of a precooled dilute aqueous ammonia solution are run in. The mixture is stirred at this temperature for 1 h, adjusted to a pH of 5 with dilute hydrochloric acid, the phases are separated, the aqueous phase is washed with 4 1 of ethyl acetate, and the combined ethyl acetate phases are washed with twice 3 1 of saturated sodium chloride sol-ution, dried over sodium sulphate and concentrated on a rotary evaporator. The product crystallizes out by addi-tion of 4 1 of petroleum ether and is filtered off with suction, stirred with 4 1 of petroleum ether, filtered off with suctioa, washed with 2 1 of petroleum ether and dried in vacuo.
Yield: 996 g, 87.4% of theory M.p.. 62°C
Allyl (-)-cis-2-aminocarbonyl-cyclopentane-1-carboxylate HzN-~-O

Le A 29 957 - 39 -'- 218~9~3 The preparation is carried out by analogy with that described for Example 17, starting from 12.7 g (64 a~ol) of the compound of Example 6.
Yield: 9.9 g (78%) M.p.. 35°C
fa] D° _ -10 .4 (c=1. 05, CHC13) (-)-1,2-cis-2-Aminocarbonyl-4-methylene-cyclopentane-1-carboxylic acid, sodium salt _ HzN ONa 258 g (1.233 mol) of allyl (-)-1,2-cis-2-aminocarbonyl-4-methylene-1,2-cyclopentanecarboxylate are dissolved in 5 1 of ethyl acetate under an argon atmosphere. A solu-tion of 1.749 mol of 2-ethylhexanoic acid, sodium salt in 3.15 1 ethyl acetate, 32.5 g (0.123 mol) of triphenyl-phosphine and 7.1 g (6.15 mmol) of tetrakis(triphenyl phosphine)palladium are added, and the solution is stirred at RT for 2 h, with the product precipitating.
The suspension is stirred to extract the product in 10 1 of acetone, and the product is filtered off with suction and dried in vacuo.
Crude yield: 281.1 g; contaminated with ethylhexanoic Le A 29 957 - 40 -2 ~ 80~~~
acid, sodium salt 1H-Nl~t (Ds0) : b = 2 . 54 - 2 . 82 (4H) ; 3 . 08 - 3 .25 (2H) ; 5. O1 (2H) (-)-1,2-cis-2-Aminocarbonyl-cyclopentane-1-carboxylic acid, sodium salt H2N-~ONa The preparation is carried out analogously with that described for Example 19, starting from 9.85 g (50.0 a~ol) of the compound of Example 18.
Yield: 7.1 g (79~) 1H-NI~t (CDC13) : 8 = 1.52 - 2 .14 (6H) ; 2.95 - 3 .18 (2H) .
(-)-1,2-cis-2-Aminocarbonyl-4-methylene-cyclopentane-1-carboxylic acid Le A 29 957 - 41 -., . ~18d~63 104.5 g (0.5 mol) of allyl (-)-1,2-cis-2-aminocarbonyl-4-methylene-1,2-cyclopentanecarboxylate are dissolved under a nitrogen atmosphere in 1, 1 of acetic acid and 119 ml (0.75 mol) of 2-ethylhexanoic acid. After addition of 13.1 g (0.05 mol) of triphenylphosphine and 3 g (0.005 mol) of bis(dibenzylideneacetone)palladium(0) the reactioa solution is stirred at RT for 5 h, the product crystallizing out. The product is filtered off with suction, washed with 50 ml o.f ethyl acetate and dried in vacuo.
Yield: 63.4 g (75% of theory) Aqueous solution of (-)-1,2-cis-2-amino-4-methylene-cyclopentanecarboxylic acid x H20 H2N ~C02H
817 g (4.27 mol) of (-)-1,2-cis-2-aminocarbonyl-4-methylene-1,2-cyclopentanecarboxylic acid, sodium salt, are added at 0°C to a solution of 478.45 g (8.54 mol) of potassium hydroxide in 9 1 of water. 3.12 1 of a 2.5 molar potassium hypochlorite solution are added, and the mixture is stirred overnight at this temperature. The solution is adjusted to a pH of 2 with 5N hydrochloric acid, washed 4 times with diethyl ether, and the aqueous Le A 29 957 - 42 -21~09~3 phase is adjusted to a pH of 6.9 with 5N sodium hydroxide solution and filtered off with suction over kieselguhr.
Aqueous solution of (-)-1,2-cis-2-amino-cyclopentane-1-carboxylic acid x H20 H2N C02H.
The preparation is carried out analogously to that described for Example 22, starting from 7.0 g (39.0 mmol) of the compound of Example 20.
(-)-1,2-cis-2-N-(9-Fluorenylmethoxycarbonyl)-amino-4-methylene-1-cyclopentane-carboxylic acid Fmoc-HN COZH
2.21 kg (26.34 mol) of sodium hydrogen carbonate are added to 21.18 1 (about 3.7 mol) of the aqueous solution of (-)-1,2-cis-2-amino-4-methylene-cyclopentanecarboxylic acid, and the mixture is stirred at RT for 15 minutes. A
Le A 29 957 - 43 -~ ~ ~ ~9b.3 solution of 1.02 kg (3.01 mol) of N-(9-fluorenylmethoxy-carbonyloxy)-succinimide in 5.4 1 of dioxaae is run in, and the mixture is stirred at RT for 5 h. The solution is filtered and washed with 20 1 of diethyl ether, the organic phase is washed with dilute sodium carbonate solution and the aqueous basic product phases are adjusted to a pH of 2 at RT using dilute hydrochloric acid. The mixture is washed several times with diethyl ether, and the combined organic phases are dried over sodium sulphate and concentrated oa a rotary evaporator to give an oil.
Yield: 1.47 kg; 104.6% of theory Lad D° _ -18 . 8 (c=1, MeOH) M.p.. 137°C
Enantiomeric excess e.e.: >99% (HPLC, Chiralpak AS) (-)-1,2-cis-2-(tert-Butyloxycarbonyl)amino-cyclopentane-1-carboxylic acid (CH3)3C-02C-HN ~C02H
To the neutralized aqueous solution of the compound of Example 23 are added 15 g of sodium carbonate (pH = 9.8) and 200 ml of dioxane. 9.2 g (42 mmol) of di-tert-butyl dicarbonate are added at 0°C, and the mixture is stirred Le A 29 957 - 44 -~ ~ ~~96 at 0°C for 10 min and at room temperature for 20 h. The reaction mixture is adjusted to a pH of 2 with dilute hydrochloric acid and _is extracted with three times 200 ml of ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over NazSO,, and concentrated on a rotary evaporator. The residue is chromatographed over silica gel with dichloromethane/
methanol (20:1) as eluent (Rf = 0.35) .
Yield: 7.34 g (82%) [a] D° _ -35 . 0 (c=1.2, CHC13) (-)-1,2-cis-2-Amino-4-methylene-cyclopentane carboxylic acid A suspension of 1.47 kg (3.76 mol) of (-)-1,2-cis-2-N-(9-fluorenylmethoxycarbonyl)-amino-4-methylene-1-cyclo-pentane carboxylic acid in 13 1 of piperidine is stirred at room temperature for 3 h until a clear solution is formed, after which 8 1 of piperidine are distilled off under a steam jet vacuum (60°C bath temperature), 10 1 of diethyl ether are added, and the mixture is stirred overnight in a rotary evaporator. The suspension is transferred to a full-aperture drum, 10 1 of diethyl Le A 29 957 - 45 -ether are added, the mixture is stirred for 2 h and the product is filtered off with suction. On the suction filter, the solid is stirred three times with 3 1 of diethyl ether each time and sucked dry, and is dried over phosphorus pentoxide under a high vacuum at room temperature for 3 h to give 377 g of the free amino acid.
The product is dissolved is 6.6 1 of ethanol/water (9:1) to give a clear solution and left to crystallize out overnight. The product is filtered off, washed with 0.2 1 of 95% ethanol and dried over phosphorus pentoxide in vacuo.
Yield: 214.5 g The filtrate is concentrated on a rotary evaporator and crystallized as described above from ethanol/water (9:1) .
Total yield: 333.2 g; 63% of theory M.p.: 222°C
tat D° _ -31. 6 (c--1, HZO) (-)-1,2-cis-2-Amino-4-methylene-cyclopentane-carboxylic acid hydrochloride HCI x H2N C02H
341.7 g (2.42 mol) of (-)-1,2-cis-2-amino-4-methylene-cyclopentane-carboxylic acid are dissolved in 8 1 of Le A 29 957 - 46 -~ ~ ~n9b double-distilled water, the solution is filtered with suction through a sintered glass suction filter, and the suction filter is washed with 0.2 1 of double-distilled water. 2.42 ml of 1 N hydrochloric acid are added to the solution in a rotary evaporator flask, and the solution is concentrated to remove the residual solvents until crystallization commences (bath 65°C), whea twice 2 1 of double-distilled water are added; the mixture is concen-trated to dryness and the residue is dried subsequently at 40°C for 30 minutes. It is then dried over phosphorus pentoxide under a high vacuum for.84 h and over potassium hydroxide for 24 h.
Yield: 421.1 g; 97.7% of theory Lal D° _ -11. 6 (c=1, H20) Le A 29 957 - 47 -2~8Q965 (-)-1,2-cis-2-Amino-cyclopeatane-1-carboxylic acid hydro-chloride HC1 x , H2N ~C02H
A solution of the compound of Example 25 (3.90 g, 17.0 mmol) in 30 ml of 4 N HC1 is dioxane is stirred at room temperature for 2 h. The precipitated product is filtered off with suction, washed with dioxane and ether and dried under a high vacuum for 15 h.
Yield: 2.39 g (84%) [a] D = -5.7 (c=0 . 99, Hz0) Enantiomeric excess e.e.: Z 95% (HPLC, Chiralpak AS after conversion to the N-Fmoc-protected compound) Le A 29 957 - 48 -

Claims

CLAIMS:

1. A process for the preparation of enantiomerically pure cyclopentane- and -pentene .beta.-amino acids of the general formula (I):
wherein:
A and L represent H; or A and D or E and L in each case together form a double bond;
D and E, independently of one another, represent: (i) H, a halogen atom or hydroxyl, or (ii) straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono-to disubstituted by identical or different substituents consisting of (a): a halogen atom, hydroxyl, phenyl, benzyloxy or carboxyl, (b) straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, or (c) a group of the general formula:
-NR4R5, wherein R4 and R5, independently, represent H, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms; or D and E together represent =O, =S, =N-OH or a radical of the general formula:
wherein:

R6 and R7, independently of one another, represent: (i) H or a halogen atom, (ii) straight-chain or branched alkyl, alkoxy or oxyacyl having in each case up to 8 carbon atoms, or (iii) benzyl or phenyl;
R2 represents:
(I) H or an amino-protecting group, (II) straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- to disubstituted by identical or different substituents consisting of: (a) hydroxyl or formyl, (b) straight-chain or branched acyl having up to 6 carbon atoms, (c) phenyl or benzoyl, which are optionally substituted up to 2 times by identical or different substituents consisting of a halogen atom, nitro or cyano, or (d) straight-chain or branched alkyl having up to 6 carbon atoms, (III) straight-chain or branched acyl having up to 8 carbon atoms, (IV) benzoyl which is optionally substituted as defined in (II)(c), (V) a group of the general formula: -SO2R8, wherein R8 represents: (i) straight-chain or branched alkyl having up to 8 carbon atoms or (ii) benzyl or phenyl, which are optionally substituted up to 3 times by identical or different substituents consisting of: (a) a halogen atom, hydroxyl, nitro, cyano, trifluoromethyl or trifluoromethoxy, (b) straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, or (c) carboxyl or a group of the general formula: -NR4R5, wherein R4 and R5 are as defined above, (VI) phenyl which is optionally substituted up to 3 times by identical or different substituents consisting of: (a) a halogen atom, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, (b) straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, (c) a group of the general formula:
-NR4R5 or -SO2R8, wherein R4, R5 and R8 are as defined above, or (VII) an amino acid residue of the general formula:
wherein:
R9 represents: (i) cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or H, or (ii) straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by: (a) cyano, methylthio, hydroxyl, mercapto or guanidyl, or (b) a group of the general formula: -NR11R12 or R13-OC-, wherein:
R11 and R12, independently of one another, represent H, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, and R13 represents: (i) hydroxyl, benzyloxy or alkoxy having up to 6 carbon atoms, (ii) the group of general formula:
-NR11R12, wherein R11 and R12 are as defined above and wherein the alkyl is optionally substituted by: (a) cycloalkyl having 3 to 8 carbon atoms or (b) aryl having 6 to 10 carbon atoms which is optionally substituted by hydroxyl, a halogen atom, nitro, alkoxy having up to 8 carbon atoms or by the group of general formula: -NR11R12, wherein R11 and R12 as defined above, and R10 represents H or an amino-protecting group;
R3 represents H or straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by phenyl;
or R2 and R3 together represent a radical of the general formula: =CHR14, wherein R14 represents: (a) H or straight-chain or branched alkyl having up to 8 carbon atoms which is optionally substituted by: (a) a halogen atom, hydroxyl, phenyl or carboxyl, or (b) straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms;
T represents -O-, -S- or -NH-; and R1 represents: (i) H or (ii) straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, which are optionally substituted up to 3 times by identical or different substituents consisting of: (a) hydroxyl, a halogen atom, nitro, cyano, carboxyl, trifluoromethyl, trifluoromethoxy, or straight-chain or branched alkoxy, and in the case of phenyl also of (b1) straight-chain or branched alkyl, acyl or akoxycarbonyl having in each case up to 6 carbon atoms, or (b2) a group of the general formula:
-NR4R5 or -SO2R8, where in R4, R5 and R8 are as defined above;
or if T represents -NH-, R1 represents the group of the general formula: -SO2R8, wherein R8 is as defined above;
the process comprising:
(A) converting a meso-dicarboxylic acid anhydride of the general formula (II):

wherein A, D, E and L are as defined above, by an asymmetric alcoholysis with an alcohol of the general formula (III):

R15-OH (III) wherein R15 represents straight-chain or branched alkyl or alkenyl having in each case up to 5 carbon atoms, which are optionally substituted by cyano, trimethylsilyl, phenyl or trichloromethyl, and in the presence of equimolar amounts of a chiral amine base which is present in enantiomerically pure form, in an inert solvent and initially via the intermediate, enantiomerically pure salt stage of the general formula (IV):
wherein A, D, E, L and R15 are as defined above, and V
represents the chiral amine base, to an enantiomerically pure compound of the general formula (IVa):
wherein A, D, E, L and R15 are as defined above;

(B) subsequently, following activation of the free carboxylic acid function of the compound of general formula (IVa) by reaction with liquid NH3, an enantiomerically pure amide of the general formula (V):
wherein A, D, E, L and R15 are as defined above, is prepared;
(C) in a further step a product of step (b) is converted, by elimination of the radical R15 in an inert solvent, enzymatically or in the presence of a Pd catalyst, and in each case depending on a nucleophilic auxiliary, into a compound of the general formula (VI) or (VIa):
wherein A, D, E and L are as defined above, and X represents an alkali metal or alkaline earth metal atom; and (D) finally, a Hofmann rearrangement is carried out using an alkali metal hypochlorite or alkaline earth metal hypochlorite in an aqueous alkali metal hydroxide or alkaline earth metal hydroxide solution, the free amine function is initially blocked in solution with an amino-protecting group, which is eliminated after isolation of the protected compound to obtain the respective pure enantiomer.

2. A process according to claim 1, wherein a compound of the general formula (V):
wherein A, D, E, L and R15 are as defined in claim 1, is converted, by elimination of the radical R15 in an inert solvent, enzymatically or in the presence of a Pd catalyst, and in each case in the absence of a nucleophilic auxiliary, to a compound of the general formula (VI) or (VIa):
wherein A, D, E, L and X are as defined in claim 1.

3. An enantiomerically pure compound of the general formula (IVa):
wherein A, D, E, L and R15 are as defined in claim 1, with the exception of a compound wherein R15 represents methyl.

4. An enantiomerically pure compound of the general formula (IV):
wherein A, D, E, L, R15 and V are as defined in claim 1.

5. An enantiomerically pure compound according to claim 4, wherein V represents an alkaloid or cinchona alkaloid.

6. An enantiomerically pure compound according to claim 5, wherein V represents quinine, hydroquinine, cinchonidine, epiquinidine, epicinchonidine, cinchonine, epicinchonine, epiquinine, hydroquinidine, 4-chlorobenzoate-epiquinine or 4-chlorobenzoate-epicinchonine.

7. An enantiomerically pure compound of the general formula (V):
wherein A, D, E, L and R15 are as defined in claim 1.

8. The compound:

9. The compound:

10. The compound:

11. The compound: