Enantioselective reduction and deracemisation using the non-conventional yeast Pichia glucozyma in water/organic solvent biphasic systems: preparation of (S)-1,2-diaryl-2-hydroxyethanones (benzoins) Maria Caterina Fragnelli a, b , Pilar Hoyos b , Diego Romano a , Raffaela Gandolfi c , Andr  es R. Alc  antara b, * , Francesco Molinari a, * a Dipartimento di Scienze e Tecnologie Alimentari e Microbiologiche, Universit a degli Studi di Milano, Via Mangiagalli 25, Milano 20133, Italy b Departamento de Química Org anica y Farmac eutica, Universidad Complutense de Madrid, Plaza de Ram on y Cajal s/n, Madrid 28040, Spain c Dipartimento di Scienze Molecolari Applicate ai Biosistemi, Universit a degli Studi di Milano, Via Venezian 21, Milan 20133, Italy article info Article history: Received 18 July 2011 Received in revised form 17 October 2011 Accepted 7 November 2011 Available online 13 November 2011 Keywords: Benzoin Deracemisation Pichia glucozyma Benzil Dehydrogenase Stereoselective reduction Two-liquid-phase system abstract Water/organic solvent two-liquid-phase systems have been successfully applied in the synthesis of enantiomerically pure (S)-benzoin through two different methodologies catalysed by whole cells from the non-conventional yeast Pichia glucozyma: the stereoselective monoreduction of benzil and the de- racemisation of benzoin. The presence of the organic solvent influences the redox systems implied in the reactions, avoiding the formation of the corresponding diols, increasing the enantioselectivity and al- lowing the easy isolation of the products in high yields and excellent enantiomeric excesses. The use of both strategies has been extended to the preparation of different chiral benzoin derivatives. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Homochiral benzoins (1,2-diaryl-2-hydroxyethanone struc- tures) can be chemically obtained through benzoin condensation, one of the most traditional CeC bond forming reactions, catalysed by chiral thiazolium and triazolium salts 1,2 or chiral metal- lophosphites. 3 Alternatively, biocatalytic methods can offer an at- tractive platform by exploiting different enzymatic reactions, 4 such as benzoin condensation catalysed by thiamine-diphosphate- dependent enzymes, 5e8 dynamic kinetic resolution of racemic benzoins, 9,10 enantioselective reduction of a-diketones, 11e16 or deracemisation of racemic benzoins using redox processes cata- lysed by whole cells. 17 Optically pure benzoin is considered a useful building block in the synthesis of different drugs and fine chemicals due to its functional nature. 4,18e20 More concretely, benzoin can be used for the preparation of 2-amino-1,2-diphenylethanol which, in its op- tically pure form, has recently received widespread attention due to the use of these amino alcohols as chiral auxiliaries in asymmetric synthesis, 21 chiral stationary phases for HPLC applications 22 and as ligands in asymmetric catalysis. 23 Microbial dehydrogenases bound to whole cells have been used for the stereoselective reductions of aromatic a-diketones, with formation of the desired chiral a-hydroxyketone as major product, and in some cases to a full reduction to the corresponding diol, most likely because the whole cell contains other competing ketoreductases. In fact, the reduction of benzil (1) was firstly re- ported with the most classical bio-reduction biocatalyst (baker’s yeast, whole cells from Saccharomyces cerevisiae), although the reaction proceeded with no enantioselectivity. 24 More recent studies with this same biocatalyst show the production of (R)- benzoin ((R)-2) with 50% enantiomeric excess, while the use of organic co-solvents led to higher enantiopurity values. 13 Other microorganisms have also been described for this same process with more success, 11,12,14,15 but often these biotransformations are hampered by the low rates reported. The monoreduction of dif- ferent 1,2-diarylethanediones (including benzil) with lyophilised * Corresponding authors. Tel.: þ39 (0)2 5031 9148; fax: þ39 (0)2 5031 6694 (F.M.); tel.: þ34 91 394 1820; fax: þ34 91 394 1822 (A.R.A.); e-mail addresses: andresrf@farm.ucm.es (A.R. Alc antara), francesco.molinari@unimi.it (F. Molinari). Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.11.014 Tetrahedron 68 (2012) 523e528