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Synlett 2005(12): 1936-1938  
DOI: 10.1055/s-2005-871577
LETTER
© Georg Thieme Verlag Stuttgart · New York

Chemo-Enzymatic Synthesis of (R)- and (S)-2-Hydroxy-4-phenylbutanoic Acid via Enantio-Complementary Deracemization of (±)-2-Hydroxy-4-phenyl-3-butenoic Acid Using a Racemase-Lipase Two-Enzyme System

Barbara Larissegger-Schnell, Wolfgang Kroutil, Kurt Faber*
Department of Chemistry, Organic & Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Fax: +43(316)3809840; e-Mail: Kurt.Faber@uni-graz.at;
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Publikationsverlauf

Received 4 May 2005
Publikationsdatum:
07. Juli 2005 (online)

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Abstract

Deracemization of (±)-2-hydroxy-4-phenylbut-3-enoic acid was accomplished by lipase-catalyzed kinetic resolution ­coupled to mandelate racemase-mediated racemization of the non-reacting substrate enantiomer. Stepwise cyclic repetition of this ­sequence led to a single enantiomeric product, the stereochemical outcome of which could be controlled by switching between lipase-catalyzed acyl-transfer/ester hydrolysis reactions. Both enantio­meric products were easily transformed into (R)- and (S)-2-­hydroxy-4-phenylbutanoic acid, important building blocks for ACE-inhibitors.

Key words

deracemization - lipase - mandelate racemase - biocatalysis - enzyme catalysis

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Although several processes producing enantiomeric products were reported depending on the choice of biocatalyst, the search for e.g. ‘anti-Kazlauskas’ carboxyl ester hydrolyses and ‘anti-Prelog’ alcohol dehydrogenases still represents a major challenge in biocatalysis.

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( S )-2-Acetoxy-4-phenyl-3-butenoic Acid [( S )-2] via Deracemization of [ rac -1].
Kinetic resolution step (a): to a solution of rac-1 (0.25 g, 1.4 mmol) in diisopropyl ether (25 mL), vinyl acetate (2.5 mL) and lipase PS-C ‘Amano’ II (0.25 g) were added and the mixture was shaken for 48 h at 25 °C and 150 rpm. The enzyme was filtered and dried for reuse; the filtrate was evaporated to dryness. HPLC analysis showed a conversion of 50% [Chiralpak AD column, Daicel, heptane-2-PrOH-CF3COOH, 90:10:0.1; 0.4 mL/min, 18 °C, (S)-2: τ = 29.3 min, (R)-1: τ = 42.6 min].
Racemization step (b): to a solution of (S)-2 and (R)-1 obtained from step (a) in Hepes buffer (10 mL, 50 mmol, pH 7.5, 10 mM MgCl2), mandelate racemase [EC 5.1.2.2] (1.5 g, prepared as described in ref. 14) rehydrated in 15 mL Hepes buffer was added. The mixture was shaken for 24 h at 30 °C and 150 rpm. After centrifugation the solution was acidified to pH 1-2 and extracted with EtOAc, dried (Na2SO4) and evaporated. HPLC analyses showed complete racemization of (R)-1; (S)-1: τ = 36.2 min. After repeating step (a) for three times and step (b) for two times, the residue was purified by flash chromatography to yield (S)-2 as the sole product (0.21g, 68% overall yield from rac-1); mp 80-82 °C; mp lit. 82 °C; [α]D 20 +100.3 (c 0.47, EtOH, >99% ee); lit. [α]D 25 +108.0 (c 0.36, EtOH).
( S )-2-Hydroxy-4-phenyl-3-butenoic Acid [( S )-1].
A mixture of (S)-2 (110 mg, 0.5 mmol), MeOH (4 mL) and K2CO3 (0.5 g) was stirred at 0 °C. After 3-4 h the mixture was acidified with HCl (3 M) to pH 1-2 and then extracted three times with EtOAc. The organic layer was dried (Na2SO4), evaporated and the residue was purified by flash chromatography to yield (S)-1 (56 mg; 63%); mp 132-133 °C; lit. mp 104 °C; [α]D 20 +96.5 (c 0.27, MeOH, >99% ee); lit. [α]D 25 +85.2 (c 0.55, MeOH, 94% ee).
( S )-2-Hydroxy-4-phenylbutanoic Acid [( S )-3].
(S)-1 (50 mg, 0.28 mmol) was hydrogenated employing a rubber balloon using a catalytic amount of Pd on C (10%, 5 mg) in MeOH for 10 min. Then the catalyst was filtered off and the solvent was evaporated to yield (S)-3 (42 mg, 83%); mp 115-117 °C; lit. mp 114 °C; [α]D 20 +8.1 (c 1.0, EtOH, >99% ee); lit. [α]D 25 +7.5 (c 0.5, EtOH, 84% ee); chiral HPLC analysis using the method described above showed a single peak at τ = 26.8 min.