Chemoenzymatic synthesis of both enantiomers of 3-hydroxy- and 3-amino-3-phenylpropanoic acid Annamaria Varga a , Valentin Zaharia a , Mihály Nógrádi b , László Poppe b,⇑ a Department of Pharmacy 1, Iuliu Hat ßieganu University of Medicine and Pharmacy, Str. Creanga ˘ Ion 12, RO-400010 Cluj-Napoca, Romania b Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1111 Budapest, M} uegyetem rkp. 3-9, Hungary article info Article history: Received 8 July 2013 Accepted 9 September 2013 Available online xxxx abstract Ethyl (S)-3-hydroxy-3-phenylpropionate (S)-2 was obtained by the asymmetric reduction of ethyl 3-phenyl-3-oxopropionate 1 with the yeast Saccharomyces cerevisiae (ATCC 9080). The kinetic resolution of racemic ethyl 2-acetoxy-3-phenyl-propionate rac-3 with the same microorganism, gave after hydrolysis ethyl (R)- and (S)-3-hydroxy-3-phenylpropionates (R)-2 and (S)-2 which were converted by a straightfor- ward series of reactions to the enantiomers of 3-amino-3-phenyl-propionic acids (S)-6 and (R)-6. The asymmetric reduction and hydrolytic kinetic resolution were also tested with several other whole cell systems under a variety of conditions. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Enantiomerically pure b-hydroxy esters are important chiral building blocks for the synthesis of various pharmaceuticals such as fluoxetine, 1 b-lactam antibiotics, 2 Tuckolide (an HMGCoA reductase-inhibitor), 3 and dihydrokawain (a narcotic). 4 The amino derivative obtained from (S)-b-hydroxy ester is a building block of Taxol. 5 Ethyl 4-chloro-3-hydroxy butanoate is used in the prepara- tion of L-carnitine, which is known as nutraceutical. 6 Chiral b-hydroxy esters are also used as starting materials for the preparation of enantiomerically pure b-blockers, that is, propranolol, alpreno- lol, and 1-(isopropylamino)-3-para-methoxyphenoxy-2-propanol. 7 The utility of sodium (R)-b-hydroxy butanoate as a cerebral func- tion improving agent on cerebral hypoxia, anoxia, and ischemia in mice and rats has also been reported. 8 Both enantiomers of ethyl 3-hydroxy butanoate and ethyl 3-hydroxy pentanoate are important in the synthesis of pheromones. 9 b-Hydroxy esters also play an important role in many biological reactions inside the human body. 10 The most commonly used methods for obtaining enantiomeri- cally pure b-hydroxy esters are: (i) the reduction of the corre- sponding ketones; and (ii) the kinetic resolution of racemic b-hydroxy esters. (i) The enantioselective reduction of b-keto esters with organo- metallics and by chemo-enzymatic procedures are known methods. Various microbial whole cells 11 and plant cells 12 are used for the chemoenzymatic synthesis of various chiral molecules. Engineered whole cells of baker’s yeast have been reported to carry out a highly stereoselective synthesis of a-unsubstituted and a-alkyl-b-hydroxy esters. 13 The microbial reduction of aliphatic b-keto esters using most of- ten baker’s yeast, a readily available and inexpensive reducing agent, was reported. 14 Depending on the reaction conditions, a wide range of yields and enantiomeric excesses of the product was observed. 15 For baker’s yeast mediated bioreductions, the use of water miscible organic co-solvents is advantageous, while in water immiscible organic solvents, such as petroleum ether, the efficiency can even be further enhanced. 15 Employing a wide range of microorganisms, such as yeasts (ba- ker’s yeast and Rhodotorula sp.), fungi (Aspergillus, Geotrichum and Mortierella sp.), or bacteria (Lactobacillus sp.) Bartod et al. 16 studied the reduction of b-keto esters. Freeze dried baker’s yeast was used under fermenting and non-fermenting conditions. Bioconversions with other microorganisms were carried out using washed resting cells. Only two microorganisms (baker’s yeast and Mortierella isa- bellina) were able to reduce b-keto esters to yield hydroxy esters. The addition of sucrose (fermenting conditions) was found to accelerate the baker’s yeast mediated reaction. 17 With other micro- organisms, low conversions and poor selectivities were observed and significantly more by-products were formed. Secondary reac- tions can appear at any stage, even from the beginning of the reac- tion. 18 A possible explanation could be that concurrent hydrolysis and decarboxylation of the ketoester occur. Side reactions can be suppressed by certain additives, but this may be at the expense of stereoselectivity. 19 For example ethyl chloroacetate is known to inhibit (R)-selective enzymes by allowing the expression of the 0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2013.09.007 ⇑ Corresponding author. Tel.: +36 1 4633299; fax: +36 1 463 3697. E-mail address: poppe@mail.bme.hu (L. Poppe). Tetrahedron: Asymmetry xxx (2013) xxx–xxx Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy Please cite this article in press as: Varga, A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.09.007