CA2076580A1 - Process for the production of optically-active 4-amino-3-hydroxycarboxylic acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A process is disclosed for the production of optically-active 4-amino-3-hydroxy-carboxylic acids in the (rel-3R,4R) configuration, especially statine, starting from 5-alkylidene or 5-benzylidenetetramic acid. The synthesis process includes the 0-acylation of the tetramic acid to form the corresponding 4-acyloxy-3-pyrrolin-2-one, a stereoselective hydrogenation to produce (rel-4R,5R)-4-acyloxy-5-alkyl or 5-benzylpyrrolidin-2-one and an enantioselective enzymatic hydrolysis of the (4R,5R)-enantiomer to form the corresponding 4-hydroxypyrrolidin-2-one. The nonhydrolyzed enantiomer is separated and converted into the target compound with (3S,4S) configuration by hydrolytic cleavage of the lactam ring and the ester function and optional introduction of an amino protecting group. Analogously, the (3R,4R)-enantiomer can be obtained from the 4-hydroxypyrrolidin-2-one from the enzymatic hydrolysis. The 4-amino-3-hydroxycarboxylic acids produced by the process of the invention are the structural elements of enzyme inhibitors.

Description

' J~ 3 This invention relates to a process for the production of optically-active 4-amino-3-hydroxycarboxylic acids and their N-protected derivatives.
The products of the process according to the invention have the general formula:

OE~

1 * *l -CH -COOH (I) NHX

wherein Rl is an optionally branched and/or substituted alkyl group with 1 to 10 C atoms or an optionally substituted aryl, arylalkyl or cycloalkyl group and X is a - hydrogen or an amino protecting group. These compounds have two chiral centers and, therefore, can each occur in four stereoisomeric forms.
The process according to the invention allows production alternatively of the (3R,4R) or (3S,4S) enantiomer. These two enantiomers are comprised by the stereochemical designations (rel-3R,4R) or (3R*,4R*). The first of-the two designations is used below.
Some of these compounds, especially those with Rl = isopropyl or cyclohexyl, are of interest as the structural element of peptides which have enzyme inhibiting effects. But only the (3S,4S~-stereoisomer is effective in this connection. In particular, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (which is known by the trivial name statine and which is contained in the renin inhibitor pepstatine) has already been the aim of numerous different synthesis processes [see, for example, European Patent No.
0210896; H.J. Altenbach, Nachr. Chem. Tech. Lab., 36, (1988), pages 756 to 758; M. Saiah et al., Tetrahedron Asymmetry, 2, (1991), payes 111 and 112, as well as the literature cited therein~. ~owever, these syntheses are only poorly suitable or unsuitable for the economical production of large amounts of different substituted 4-amino-3-hydroxycarboxylic acids, because they require, in part, expensive starting materials, they are suitable, in part, only on a laboratory scale and the necessary starting materials are available at all in some cases only for specific radicals Rl of general formula I.
The main object of the invention, therefore, is to provide a process for the production of optically-active (rel-3R,4R)-4-amino-3-hydroxycarboxylic acids, that requires only reasonably priced starting materials and that can be performed on a large scale.
Accordingly, the invention involves a process for the production of optically-active (rel-3R,4R)-4-amino-3-hydroxycarboxylic acids of the general formula:

0~
R1-CH - CH- CH-CH2-COOH (I) NHX

wherein Rl is an optionally branched and/or substituted alkyl group with 1 to 10 C atoms or an optionally substituted aryl, arylalkyl or cycloalkyl group and X is hydrogen or an amino protecting group, which process comprises acylating a substituted tetramic acid of the general formula:

R1~ ~ (II) Jr-f ~j~r~

wherein Rl has the above-mentioned meaniny, with a carboxylic acid or a carboxylic acid derivative of the general formula:

2 ~ (III) R ~::--Y

wherein R2 is an optionally branched and/or substituted alkyl group with 1 to 10 C atoms or an aryl group and Y is halogen, OH or OC(=O)R2, to form a compound of the general formula:
R2 3 o ~ ' (IV) and then stereoselectively hydrogenating the compound (IV) to form the corresponding enantiomeric pyrrolidin-2-ones of the general formulae:

O O
R2_C_o R2-C-O

R1-CHz-- ~ O Va and R1-cH2 ~ Vb The (4R,5R) enantiomer (Va) is hydrolyzed enantioselectively with a lipase to form th~ corresponding (4R,5R)-4-hydroxypyrrolidin-2 one o~ the general formula:

HC
~ (VI) ~ ~0 R1_cH2 H

and separating from the nonhydrolyzed (4S,5S)-enantiomer (Vb). Then, the acyloxy compound (Vb~ or the hydroxy compound VI i9 hydrolyzed with cleavage of the lactam riny to produce the target compound I (X = H), which may be optionally converted (e.g., according to known processes) into tha corresponding N-protected form.
Preferably butyric acid or a derivative of butyric acid is used as the carboxylic acid or carboxylic acid derivative (III), respectively. Butyryl chloride is the preferred butyric acid derivative. Preferably the stereoselective hydrogenation is performed with a palladium or rhodium catalyst or a palladium/rhodium mixed catalyst.
A supported palladium catalyst is preferably used as catalyst. Preferably a lipase from Candida cylindracea is used as the lipase. After the enantioselective hydrolysis, the nonhydrolyzed (4S,5S)-enantiomer (Vb) is preferably reacted to form the target compound. Preferably, after the cleavage of the lactam ring, a tert-b~toxycarbonyl group is introduced as the amino protective group X. A 5-isobutylidene- (Rl = isopropyl) or 5-benzylidenetetramic acid-(RI = phenyl) is preferably used as the substituted tetramic acid (II).
The invention also includes (4S,5S)-4-acyloxypyrrolidin-2-ones of the general formula:
o R2 -C -0~

35 R -C;~2 ~ (Vb) K

;r-~ .r~

wherein R1 is an optionally branched and/or substituted alkyl group with l to lO c atoms or an optionally substituted aryl, arylalkyl or cycloalkyl group and p~2 is an optionally branched and/or substituted alkyl group with l to lO C atoms or an optionally substituted aryl group.
Preferably R1 is isopropyl, phenyl or cyclohexyl. R2 is preferably propyl.
~ hus, starting from 5-alkylidene tetramic acids of the general formula:

o ~ ~ O (II) or the tautomeric form:

~
= ~ ~ = 0 (II') in which R1 has the above-mentioned meaning, and carboxylic acids or carboxylic acid derivatives of the general formula:

2 11 (III) R -C-Y

in which R2 is an optionally branched and/or substituted alkyl group with l to lO C atoms or an aryl group and Y is sJ~

halogen, OH or OC(=O)R~, 4-O-acyl-5-alkylidene tetramic acids of the general formula:
o (IV) =
R

wherein Rl and R2 have the above-mentioned meanings, can be obtained and then hydrogenated with good stereoselectivity to form a mixture, which consists basically of the (4RS,5RS)-racemate of the corresponding 4-acyloxy-pyrrolidin-2-ones of the general formulae:

O O
R2_c_o R2_C_o R1-CHz-- ~ O and Rl-CH ~N~
H H

wherein R1 and R2 have the above-mentioned meanings and of small amounts of the corresponding (4RS,5SR)-racemate. The undesirable (4RS,5SR)-racemate can be easily separated.
Further it was found that the enantiomer with the (4R,5R)-configuration (Va) can be selectively deacylated in the presence of lipases. Because of the great difference in polarity, (4R,5R)-4-hydroxypyrrolidin-2-one of the general formula:

HO

~ O (VI) R1-CH~
H

~ ~ w ,r~

wherein ~I has the above-mentioned meaning, can be easily separated.
The unreacted (4S,5S)-4-acyloxypyrrolidin-2-one (Vb) can finally be conver~ed, analogously to known processes with cleavage of the acyl group and opening of the lactam ring, to form the corresponding (3S,4S)-4-amino-3-hydroxycarboxylic acid (I).
As an alternative to the above, the corresponding (3R,4R)-4-amino-3-hydroxycarboxylic acid (I) can be obtained from (4R,5R)-4-hydroxypyrrolidin-2-one (VI), formed in the enzymatic deacylation, after isolation thereof, by hydrolytic opening of the lactam ring.
The 5-alkylidenetetramic acids (II) employed in the process according to the invention can be produced according to known processes from 4-alkoxy-3-pyrrolin-2-ones and aldehydes (European Published Patent Application No. 035gl28).
It has been found that their synthesis can be simplified significantly by the production of 4-alkoxy-3-pyrrolin-2-one and the reaction with aldehyde being performed in one pot without isolation of the intermediate products. For this purpose an (E)-3-alkoxy-4-chlorobut-2-enoic acid alkyl ester, which is easily available from 4-chloroacetoacetyl chloxide (European Published Patent Application No. 0346852), is cyclized with aqueous ammonia in a manner known in the art (European Patent No. 0216324) to form the corresponding 4-alkoxy-3-pyrrolin-2-one and the latter is condensed with the aldehyde without isolation and in the presence of a strong base, to form the corresponding 4-alkoxy-5-alkylidene-3-pyrrolin-2-one. Preferably (E)-4-chloro-3-methoxybut-2-ene methyl ester i5 used as the initial material and sodium hydroxide as the strong base.
The thus-obtained 4-alkoxy-5-alkylidene-3-pyrrolin-2-one can be converted by acid hydrolysis without isolation in a manner known in the art into 5-alkylidenetetramic acid (I~).

For acylation of a 5-alkylidenetekramic acid (IIJ
to a 4-acyloxy compound (IV), which can be regarded as a mixed anhydride of the corresponding carboxylic acid and tetramic acid or as enolic ester, basically any process for the production o~ mixed carboxylic acid anhydrides or carboxylic acid-enolic esters from the corresponding carboxylic acids or carboxylic acid derivatives can be used. These include, for example, reaction with the carboxylic acid in the presence of a carbodiimides or 1-acylimidazole, and reaction with a carboxylic acidanhydride or with a carboxylic acid halide [see, H.
Pielatzik et al. in "Methoden der ~rganischen Chemie"
(Methods of Organic Chemistry), (Houben-Weyl), 4th ed., Vol. E5, Stuttgart (1985), pages 633 to 656, and G. Hesse in "Methoden der Organischen Chemie", (Houben-Weyl), 4th ed., Vol. VI/ld, Stuttgart, (1978), pages 108 to 115].
A preferred embodiment uses a carboxylic acid halide, especially a carboxylic acid chloride, in the presence of a tertiary amine, such as triethylamine or pyridine. Instead of the free tetramic acid (II), the enolate, for example the sodium salt, can also be used.
As carboxylic acid or carboxylic acid derivative (III), aliphatic or aromatic carboxylic acids, especially C2-CIl-alkanoic acids or benzoic acids, or their derivatives, can be used ~or the acylation. Especially preferred is butyric acid or butyryl chloride.
The 4-acyloxy compounds (IV) were hydrogenated according to the invention and two asymmetric centers were formed. The hydrogenation takes place largely stereoselectively so that, aside from a little (4RS,5SR)-diastereomer, mainly the (racemic) (4RS,5RS)-pyrrolidin-2-one (Va/Vb) results.
As the catalyst for the hydrogenation, preferably a supported palladium catalyst is used, ~or example 5 percent palladium on activated carbon. Instead of palladium, a rhodium catalyst, for example rhodium on ..~f ~'1~

aluminum oxide, or a Pd/Rh-catalyst, can also be used. As the solvent for the hydrogenation, advantayeously nonpolar or polar aprotic solvents are used, for example toluene, ethyl acetate or tetrahydrofuran. Protic solvents, such as alcohols, can also be used, but such lead to poorer yields.
The hydrogenation is preferably performed at about room temperature and under a medium pressure of, for example 2 MPa (20 bar).
(4RS,5SR)-pyrrolidin-2-ones as well as hydrogenolysis products occasionally resulting as by-products in the hydrogenation can easily be separated during working up, for example by simple recrystallization in which they remain in the mother liquor.
The racemate from the (4R,5R)- and the t4S,5S)-pyrrolidin-2-one (Va/Vb) is enantioselectively deacylated according to the invention with an esterase. As the esterase, a lipase is suitably used, preferably a lipase from Candida cylindracea. This lipase enantioselectively hydrolyzes the (4R,5R)-4-acyloxypyrrolidin-2-one (Va) to form the corresponding 4-hydroxy compound. This deacylation is advantageously performed in an aqueous medium at a pH near neutral, preferably at pH 6 to 8, so as to suppress non-enzymatic deacylation or hydrolysis. The reaction temperature is suitably from 0 to 40C, preferably from 0 to 25C. During the reaction the pH is maintained substantially constant, preferably by a suitable control unit ("pH-Stat") by addition of a strong base. As the strong base, sodium hydroxide solution is preferably used.
The reaction conversion can be determined by the amount of base added. Suitably the reaction is ~erminated after a conversion of about 50 percent of the total amount used (Va+Vb). Depending on whether the nonhydrolized or the hydrolized enantiomer is to be processed further, the reaction is advantageously performed up to a conversion o~
somewhat more than 50 percent or somewhat less than 50 percent to obtain a product with the highest possible optical purity.
The separation of the hydroxy compound (VI) from the acyloxy compound (Vb) is advantageously performed by 5 extraction with a solvent of low polarity, for example toluene. The hydroxy compound in this case remains in the aqueous phase, while the acyloxy compound passes into the organic phase.
The optically active acyloxy compound or hydroxy compound produced according to the invention is finally converted analogously to known processes (European Patent No. 0210896) by hydrolysis of the lactam ring and optionally of the ester function into the target compound (I). An acid is preferably used as the catalyst for the acid hydrolysis, with hydrobromic acid being especially preferred.
The unprotected 4-amino-3-hydroxycarboxylic acids tend toward spontaneous lactam formation and therefore advantageously are provided with a protecting group on the amino group. Such protecting groups and the methods for their introduction and removal are known to those skilled in the art. The tert-butoxycarbonyl group is mentioned as an example of a suitable protecting group. Instead of the amino group, the carboxyl group can also be protected, for example by esterification.
The following Examples illustrate the process according to the invention.
Example 1 tZ)-S-isobutylidene-4-methoxy-3-pyrrolin-2-one 30120 g of (E)-2-chloro-3-methoxybut-2-enoic acid methyl ester was instilled in 200 ml of concentrated aqueous ammonia solution at 65 to 70C over 3 hours with constant passage of ammonia gas. The reaction mixture was stirred for another 1.5 hours at this temperature and then refluxed for another 0.5 hour. After cooling to room temperature, 450 ml of 1 M sodium hydroxide solution was ll added and the pH was increased to a value greater than 13 by the further addition of 33 percent sodium hydroxide solution. Then 50 g of isobutyraldehyde was added and the reaction mixture was heated to 60C with stirring for 6 5 hours. After cooling to room temperature, the precipitated product was filtered off, washed with cold water and dried in a vacuum drying cabinet. The yield of the title compound was 93.2 g (80 percent of theory). The product had a melting point of 140.5 to 141.1C (from diethyl 10 ether).
Example 2 (Z~-S-Isobutylidenepyrrolidine-2,4-dione (II, Rl =
isopropyl) 50 g of finely powdered (Z)-5-isobutylidene-4-15 methoxy-3-pyrroline-2-one was stirred with 500 ml of concentrated hydrochloric acid for 5 hours at room temperature. The mixture was then stirred for 5 hours at room temperature and slowly mixed with 1 liter of 14 percent sodium hydroxide solution. The precipitated yellow 20 product was filtered off, washed with cold water and dried in a vacuum drying cabinet. The yield of the title compound was 42.0 g (92 percent of theory). The product had a melting point of 134 to 136C (THF/hexane~.
Example 3 25 (Z~-4-Butyryloxv-5-isobutylidene-3-~Yrrolin-2-one (IV. Rl =
isopropyl, R2 = propyl) 31.8 g of (Z)-5-isobutylidenepyrrolidine-2,4-dione was suspended in 318 ml of dichloromethane and cooled to -5C. 23.22 g of butyryl chloride was first added and 30 then 27.32 g of triethylamine was added. After the addition, the mixture was stirred for another 10 minutes at 0C, then diluted with 100 ml of dichloromethane, and washed twice with 100 ml of 5 percent NaHC03 solution each and twice with 100 ml of 0.4 M hydrochloric acid each. The 35 aqueous phases were extracted separately with dichloromethane and the combined organic phases were dried on magnesium sulfate. After distilliny off the solvent, the crude product (46 g) was recrystallized from hexane.
The yield of the title compound was 38.8 g (84 percent of theory). The product had a melting point of 111 to 112~C.
Other data concerning the product were:
H-NMR (CDC13; 400 MHz): 1.03 (t, J=7.5, 3H) 1.12 (d, J=6.6, 6H) 1.77 (m, 2H) 2.56 (t, J-7.5, 2H) 2.78-2.83 (m, lH) 5.35 (d, J=10, lH) 6.15 (br.s, lH) 9.91 (br.s, lH) Exàmple 4 15 (4RS,5RS)~4-Butyryloxy-5-isobutylpyrrolidin-2-one (Va/Vb R~ = isoProPvll R2 = propyl 30.0 g of (Z)-4-butyryloxy-5-isobutylidene-3-pyrrolin-2-one (produced according to Example 3) was dissolved in 300 ml of toluene, mixed with 3.0 g of palladium/activated carbon (5 percent Pd) and hydrogenated for 24 hours in an autoclave at 2 MPa (20 bar). Then the catalyst was filtered off, the filtrate was concentrated by evaporation and the residue was recrystallized from hexane.
The yield of the title compound was 23.50 g (77 percent of theory). The product had a melting point of 101.5 to 102.7C. Other data concerning the product were:
H-NMR (CDC13; 400 MHz): 0.91-0.98 (m, 9H) 1.35-1.71 (m, 5H) 2.29-2.36 (m, 3H) Z.71 (dd, J=6.4, 17.6, lH) 3.88-3.93 (m, lH) 5.40-5.43 (m, lH) 7.49 (br.s, lH) 2 ~ 3 Example 5 (4S.5S)-4-Butyry]oxy-5-isobutylpyrrolidin-2-one (Vb, Rl --isopropyl R2 = propyl) g of (4RS,5RS)-4-butyryloxy-5-isobutylpyrrolidin-2-one (produced according to Example 4) and 2 g of Candida ~Yl~n~ lipase (Biocatalysts) were stirred in 100 ml of water at room temperature. The pH of the suspension was held constant at 7 by the addition of 1 M sodium hydroxide solution. After 70 hours and a consumption of 47.36 ml of 1 M sodium hydroxide solution (corresponding to 53.8 percent conversion), the reaction was terminated. The reaction mixture was diluted with 200 ml of water and extracted once with 400 ml and another two times with 200 ml of toluene each. The combined toluene phases were concentrated by evaporation in a vacuum and the residue was dried under high vacuum. The yield of the title compound was 8.55 g (85.5 percent, relative to one enantiomer). The product had a melting point of 94.9 to 95.3C. Other data concerning the product were:

[~] :-3.9 (c = 1.0; CHC13) D

ee-value (GC, LipodexR D-column) > 99 percent Exam~le 6 (3S 4S)-4-(tert-Butoxycarbonylamino-3-hydroxy-6-meth~l heptanoic acid (boc-Statine) (I Rl = iso~ropyl, X = tert-butoxy-carbonyl) 3.0 g of (4S,5S)-4-butyryloxy-5-isobutylpyrrolidin-2-one (produced accordiny to Example 5) was stirred for 24 hours in 30 ml of 48 percent aqueous hydrobromic acid at 75C. After cooling to room temperature, the mixture was diluted with 30 ml of water and was extracted three ti,nes with 20 ml of diethyl ether each time to remove the butyric acid. The aqueous phase was cooled to -10C and adjusted to p~ 10 with 33 percent sodium hydroxide solution. Then 20 ml of tetrahydrofuran ~ 1S,~ ~31r~

and 2.~ g of di-tert-butyl dicarbonate were added. The mixture was allowed to react for 94 hours at room temperature and the pH was held substantially constant by the addition of lM NaOH. Then the mixture was acidified to pH 1.4 with 16 percent hydrochloric acid and quickly extracted three times with 100 ml of diethyl ether each~
The ether phase was dried on magnesi.um sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate/acetic acid 6:4:0.1). The yield of the title compound was 2.09 g (58 percent of theory). The product had a melting point of 120.2 to 120.9C
(acetone/hexane). Other data concerning the product were:

[~] : -40.3 (c = 1.0; CH30H) H-NMR (d6-DMSO; 400 MHz): 0.83-0.88 (m, 6H) 1.22-1.29 (m, 2H) 1.38 (s, 9H) 1.53-1.57 (m, lH) 2.12 (dd, J=15.5, 9.1, lH) 2.34 (dd, J-15.5, 3.8, lH) 3.49-3.53 (m, lH) 3.79-3.82 (m, lH) 6.24 (d, J=9.1, lH) Example 7 (Z)-5-Benzylidene pyrrolidin-2.4-dione tII Rl =~henYl) 133 g of concentrated aqueous ammonia solution was heated to 65 to 70OC. 75 g of (E)-2-chloro-3-methoxybut-2-enoic acid methyl ester was instilled over 3 hours with constant passage of ammonia gas. The mixture was stirred for another 45 minutes at this temperature, heated for 30 minutes to reflux temperature and then cooled to room temperature. After the addition of 300 ml of water and 50 ml of 33 percent sodium hydroxide solution, 46.4 g of benzaldehyde was added. The mixture was heated for 6 .

hours at 60C with stirring and then cooled to roo~
temperature. 688 ml of concentraked hydrochloric acid was then added and the reaction mixture was stirred for 22 hours at 40C. After cooling to room temperature, the yellow product was filtered off, washed with cold water and dried in a vacuum drying cabinet. The yield of the title compound was 74.66 g (88 percent of theory). I'he product had a melting point of 186 to 187C (THF/hexane).
Example 8 (Z)-5-BenzYlidene-4-butyryloxy-3-pyrrolin-2-one (IV Rl =
phenyl, R2 = propYl~
To a suspension of 67.0 g of (Z)-5-benzylidene pyrrolidin-2,4-dione cooled to 0C in ~70 ml of dichloromethane, 40.0 g of butyryl chloride and then 47.1 g of triethyl amine were added and the mixture was stirred for another 5 minutes at 0C. Then the mixture washed twice with 200 ml of 5 percent NaHCO3 solution each time and then twice with 200 ml of 0.5 M hydrochloric acid each time.
The aqueous phases were extracted separately with dichloromethane. The combined organic phases were dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue was recrystallized from 230 ml of toluene. The yleld of the title compound was 67.25 g (73 percent of theory). The product had a melting point of 25 139.8 to 141.5C. Other data concerning the product were:
H-NMR (CDC13; 400 MHz): 1.03 (t, J=7.4, 3H) 1.78 (m, 2H) 2.58 (t, J=6.7, 2H) 6.20 (s, lH) 6.30 (s, lH) 7.28-7.50 (m, 5H) 9.20 (br.s, lH) .7 "J ~.G ~ ?~

Example 9 ~4RS 5RS)-5-Benzyl-4-butYrYloxypyrrolidin-2-one (Va/Vb, R
= phenyl, R2 = propyl) 46.6~ y of (Z)-5-benzylidene-4-butyryloxy-3-pyrrolin-2-one (produced according to Example 8) was suspended in ~67 ml of toluene and hydrogenated for 28 hours with 4.67 g of palladium/activated carbon (5 percent Pd) in an autoclave at room temperature and 2 MPa (20 bar).
Then the catalyst was filtered off and the filtrate was concentrated by evaporation in a vacuum. The residue was recrystallized from diisopropyl ether. The yield of the title compound was 32.88 percent (69 percent of theory).
The product had a melting point of 85.6 to 87C. Other data concerning the product wexe:
15 IH-NMR (CDCl3, 400 MHz): 0.98 (t, J=7.3, 3H) 1.69 (sext., J=7.3, 2H) 2.34-2.41 (m, 3H) 2.68-2.77 (m, 2H) 2.92 (dd, J=14.0, 5.1, lH) 4.07-4.18 (m, lH) 5.40-5.48 (m, lH) 6.04 (br.s, lH) 7.16-7.34 (m, 5H) Example 10 25 (4S 5S)-5-Benzyl-4-butvrvloxYpyrrolidin-2-one (Vb, R
phenyl. R2 = propyl) In a two phase system of 145 ml of water and 36 ml of toluene, 21.14 g of (4RS,5RS)-5-benzyl-4-butyryloxypyrrolidin-2-one (produced according to Example 9) and 4.22 g of Candida cvlindracea lipase (Biocatalysts) were reacted analogously to Example 5. After 116 hours and the consumption of 47.01 ml of 1 M sodium hydroxide solution (corresponding to 58 percent conversion), the reaction was terminated. The reaction mixture was diluted with 600 ml of toluene and 250 ml of water and stirred vigorously for 30 minutes. The phases were separated and the aqueous phase was extracted with 300 ml of toluene.
The combined toluene phases were concentrated by evaporation in a vacuum, the residue was taken up in 170 ml of toluene, washed three times with 40 ml o~ water each time and again concentrated by evaporation in a vacuum.
The thus-obtained crude product was recrystallized from diisopropyl ether. The yield of the title compound was 7.80 g (74 percent relative to one enantiomer). The product had a melting point of 78.9 to 79.2C. Other data concerning the product were:

[~]D : -89.0 (c = 1.0; CHC13) Example 11 (3S ,4St-4-(tert-Butoxycarbonylamino)-3-hydrox~-5-phenYlpentanoic acid (I Rl = phen~l X = tert-butoxycarbonyl) 1.0 g of (4S,5S)-5-benzyl-4-butyryloxypyrrolidin-2-one (produced according to Example 10) was stirred for 20 hours at 80C in 10 ml of 48 percent a~ueous hydrobromic acid. The mixture was then cooled to room temperature, diluted with 10 ml of water and extracted three times with 20 ml of diethyl ether each time for removal of the butyric acid. The ether phase was discarded. The aqueous phase was cooled to -5~ and adjusted to pH 10 with 33 percent sodium hydroxide solution. Then, 20 ml of tetrahydrofuran and 0.86 g of di-tert-butyl dicarbonate were added and the mixture was reacted for 24 hours at room temperature and a constant pH of 10. Then the mixture was acidified with 1 M of hydrochloric acid to pH 1 and extracted three times with 50 ml of diethyl ether each time. The combined ether phases were dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate/acetic acid 10:10:0.25). The yield of the title compound was 0.64 g (54 percent of theory). The product 18 ~.~? ~
had a melting point of 153.2 to 153.~C (CHC13/hexane).
Other data concerning the product were:

D : ~37 7 (c = 1.1; CH3OH) H-NMR (CDC13, 60C;
400 MHz): 1.40 (s, 9H) 2.40-2.66 (m, 2H) 2.86-1.96 (m, 2H) 3.66-3.82 (m, lH) 3.96-4.07 (m, lH) 4.82-5.00 (br.s, lH) 7.12-7.35 (m, 5H) Example 12 (4S,5S)-4-Butyryloxy-5-(cyclohexylmethyl)pyrrolidin-2-one (VB. Rl = cYclohexyl L R2 = ~roPVl 1.0 g of (4S,5S)-5-benzyl-4-butyryloxypyrrolidin-2-one (produced according to Example 10) was dissolved in ml of ethylacetate, mixed with 100 mg of rhodium/activated carbon (5 percent of Rh, Johnson Matthey Type 20A) and hydrogenatad for 20 hours in an autoclave at room temperature at 2 MPa (20 bar). Then the catalyst was filtered off and the filtrate was concentratad by evaporation in a vacuum. The yield of the title compound was 1.0 g of viscous oil (about 98 percent). Other data concerning the product were:
~H-NMR (CDC13, 300 MHz): 0.8-1.35 (m, 9H) 1.45 (t, 2H) 1.58-1.80 (m, 7H) 2.22-2.40 (m, 3H) 2.70 (dd, lH) 3.85-3.g8 (m, lH) 5.35-5.45 (m, lH) 6.35 (br.s, lH)

Claims (12)

1. A process for the production of an optically-active (rel-3R,4R)-4-amino-3-hydroxycarboxylic acid of the general formula:

(I) wherein R1 is an optionally branched and/or substituted alkyl group with 1 to 10 C atoms or an optionally substituted aryl, arylalkyl or cycloalkyl group and X is hydrogen or an amino protecting group, which comprises acylating a substituted tetramic acid of the general formula:

(II) wherein R1 has the above-mentioned meaning, with a carboxylic acid or a carboxylic acid derivative of the general formula:

(III) wherein R2 is an optionally branched and/or substituted alkyl group with 1 to 10 C atoms or an aryl group and Y is halogen, OH or OC(=0)R2, to form a compound of the general formula:

(IV) then stereoselectively hydrogenating the compound (IV) to form the corresponding enantiomeric pyrrolidin-2-ones of the general formulae:

Va and Vb enantioselectively hydrolyzing the (4R,5R)-enantiomer (Va) with a lipase to form the corresponding (4R,5R)-4-hydroxypyrrolidin-2-one of the general formula:

(VI) and separating the nonhydrolyzed (4S,5S)-enantiomer (Vb) and then alternatively hydrolyzing the acyloxy compound Vb or the hydroxy compound VI with cleavage of the lactam ring to form a compound I (in which X = H) and optionally converting same into the corresponding N-protected form.

2. A process according to claim 1, wherein the carboxylic acid or carboxylic acid derivative (III) is butyric acid or a derivative of butyric acid, respectively.

3. A process according to claim 2, wherein the butyric acid derivative is butyryl chloride.

4. A process according to claim 1, 2 or 3, wherein the stereoselective hydrogenation is performed with a palladium or rhodium catalyst or a palladium/rhodium mixed catalyst.

5. A process according to claim 4, wherein a supported palladium catalyst is used as the catalyst.

6. A process according to claim 1, 2 or 3, wherein the lipase is a lipase from Candida cylindracea.

7. A process according to claim 1, 2 or 3, wherein, after the enantioselective hydrolysis, the nonhydrolyzed (4S,5S)-enantiomer (Vb) is reacted to form the end compound (I).

8. A process according to claim 7, wherein, after the cleavage of the lactam ring a tert-butoxycarbonyl group is introduced as an amino protecting group X.

9. A process according to claim 1, 2 or 3, wherein the substituted tetramic acid (II) is a 5-isobutylidene-(R1= isopropyl) or 5-benzylidenetetramic acid (R1 = phenyl) derivative.

10. A (4S,5S)-4-acyloxypyrrolidin-2-one of the general formula:

(Vb) wherein R1 is an optionally branched and/or substituted alkyl group with 1 to 10 c atoms or an optionally substituted aryl, arylalkyl or cycloalkyl group and R2 is an optionally branched and/or substituted alkyl group with 1 to 10 C atoms or an optionally substituted aryl group.

11. A compound according to claim 10, wherein R1 is isopropyl, phenyl or cyclohexyl.

12. A compound according to claim 10 or 11, wherein R2 is propyl.