Biocatalytic Racemization of Aliphatic, Arylaliphatic, and Aromatic α-Hydroxycarboxylic Acids

Abstract

[reaction: see text] Biocatalytic racemization of a range of aliphatic, (aryl)aliphatic, and aromatic alpha-hydroxycarboxylic acids was accomplished by using whole resting cells of a range of Lactobacillus spp. The mild (physiological) reaction conditions ensured an essentially "clean" isomerization in the absence of side reactions, such as elimination or decomposition. Whereas straight-chain aliphatic 2-hydroxycarboxylic acids were racemized with excellent rates (up to 85% relative to lactate), steric hindrance was observed for branched-chain analogues. Good rates were observed for aryl-alkyl derivatives, such as 3-phenyllactic acid (up to 59%) and 4-phenyl-2-hydroxybutanoic acid (up to 47%). In addition, also mandelate and its o-chloro analogue were accepted at a fair rate (45%). This biocatalytic racemization represents an important tool for the deracemization of a number of pharmaceutically important building blocks.

Antineoplastic Agents. 600. From the South Pacific Ocean to the Silstatins

“…9 The strategy and the series of reactions were the same as for the preparation of 7a, 8a, and 8b, obtaining similar yields in each step.…”

“…6 Hz,7.2 Hz), 3.89 (2H, dd, J = 10 Hz, 6.0 Hz), 3.10 (2H, m), 2.23 (5H, m), 1.74 (7H, m), 1.55 (2H, t, J = 6.8 Hz), 1.42 (6H, d, J = 6.8 Hz), 1.36 (3H, d, J = 6.8 Hz), 1.30 (9H, s), 1.05 (18H, m), 0.92 (24H, m), 0.75 (3H, d, J = 6.8 Hz), and 0.71 (3H, d, J = 6.4 Hz); 13 C NMR (CDCl 3 , 101 MHz) δ 172. 49, 172.37, 172.10, 172.00, 171.71, 171.69, 171.53, 171.43, 170.59, 170.52, 170.27, 170.03, 154.31, 131.01, 129.66, 123.91, 78.11, 73.61, 73.18, 70.71, 70.50, 70.07, 60.41, 60.37, 59.39, 59.28, 58.39, 54.57, 40.73, 40.63, 40.61, 40.48, 35.27, 30.32, 29.65, 28.80, 28.58, 28.53, 28.46, 28.40, 24.45, 24.16, 23.71, 23.31, 22.88, 21.80, 21.24, 21.08, 19.73, 19.46, 19.35, 19.33, 19.17, 19.14, 19.11, 19.06, 19.04, 18.84, 17.19, 17.09, and 16.81 51, 172.82, 172.39, 172.32, 172.20, 171.92, 171.53, 171.20, 171.00, 170.92, 170.29, 169.97, 74.49, 73.29, 73.16, 70.76, 70.70, 70.42, 66.19, 60.84, 60.47, 60.14, 59.89, 59.60, 58.52, 40.84, 40.70, 40.62, 28.72, 28.67, 28.55, 28.49, 28.21, 24.67, 24.57, 23.49, 23.37, 23.35, 23.33, 21.53, 21.36, 21.35, 19.70, 19.60, 19.53, 19.48, 19.47, 19.46, 19.45, 19.41, 19.37, 19.35, 18.98, 17.53, 17.10, and 17 50, 172.38, 172.23, 172.04, 171.98, 171.94, 171.81, 171.53, 171.43, 170.36, 170.28, 170.20, 155.19, 130.57, 127.82, 115.78, 73.90, 73.58, 73.43, 70.73, 70.64, 60.57, 60.22, 59.01, 58.81, 58.80, 55.29, 40.94, 40.80, 40.68, 35.44, 29.85, 29.81, 29.08, 28.79, 28.73, 28.63, 24.68, 24.64, 24.28, 23.49, 23.20, 22.84, 21.66, 21.41, 21.31, 19.83, 19.71, 19.59, 19.55, 19.47, 19.38, 19.37, 19.12, 18.98, 18.83, 17.42, 17.18, and 17 D-Hcha-D-Val-Lac-OBn (9). Using the strategy followed for the preparation and purification of 2, unit 1 (2.52 g, 6.64 mmol) was deprotected with TFA (7.5 mL) in 30 mL of anhydrous DCM and then coupled to (2R)-2-hydroxy-3-cyclohexylpropionic acid (1.23 g, 7.14 mmol) using HOBt (1.35 g, 9.96 mmol), TEA (1.38 mL, 1.10 g, 9.96 mmol), and EDCI hydrochloride (1.91 g, 9.96 mmol) in 30 mL of anhydrous DCM.…”

Novel Developments Employing Redox Enzymes: Old Enzymes in New Clothes

“…To circumvent this limitation and to broaden the portfolio of biocatalytic racemization, resting cells of a range of Lactobacillus spp. were employed for the biocatalytic racemization of a variety of different substrate classes, such as aliphathic and (hetero)aryl-aliphatic α-hydroxycarboxylic acids [124][125][126] and α-hydroxyketones (acyloins) [127]. Based on racemization using Lactobacillus spp., stereocomplementary stepwise deracemization processes for (±)-3-phenyllactic acid (4.13a) and (±)-2-hydroxy-4-phenylbutanoic acid (4.13b) have been developed [128] (Scheme 16).…”

Biocatalytic Racemization of (Hetero)Aryl‐aliphatic α‐Hydroxycarboxylic Acids by Lactobacillus spp. Proceeds via an Oxidation–Reduction Sequence

“…Approximately half of the strains investigated showed excellent racemization rates with unfunctionalized aryl-alkyl derivatives 1 and 10, with the former substrate being slightly superior. [9] 3-Phenyllactic acid (1) and several arylsubstituted derivatives thereof are frequently used chiral components of pharmaceuticals, such as rhinovirus protease inhibitors [11] and natural antibiotic agents. [10] The latter compounds are particularly difficult to racemize using conventional methods due to the ease of elimination of H 2 O to form cinnamic acid.…”

“…Based on early reports on the lactate racemase activity of halophilic Archaea, anaerobic rumen bacteria and Lactobacillus spp., a screening recently provided a set of lactic acid bacteria that are able to racemize a broad spectrum of aliphatic and aryl-aliphatic α-hydroxycarboxylic acids at fair rates. [9] Whereas the racemization of aliphatic α-hydroxycarboxylic acids bearing structurally demanding branched side-chains proceeded at moderate rates, straightchain analogues and aryl-aliphatic derivatives, such as 3-phenyllactic acid and 2-hydroxy-4-phenylbutyric acid, proved to be excellent substrates. The latter compounds possess interesting bioactivity themselves or serve as chiral building blocks for the synthesis of numerous pharmaceutical products, such as viral protease and ACE inhibitors.…”