Chemo- and biocatalytic strategies to obtain phenylisoserine, a lateral chain of Taxol by asymmetric reduction Isabella Rimoldi a,⇑ , Michela Pellizzoni c , Giorgio Facchetti a , Francesco Molinari b , Daniele Zerla a , Raffaella Gandolfi c a Università degli Studi di Milano, Facoltà di Farmacia, Dipartimento di Chimica Inorganica, Metallorganica e Analitica ‘L. Malatesta’ e Istituto CNR-ISTM, Via Venezian 21, 20133 Milano, Italy b Università degli Studi di Milano, Facoltà di Agraria, DISTAM-Sez. Microbiologia Industriale, Via Celoria 2, 20133 Milano, Italy c Università degli Studi di Milano, Facoltà di Farmacia, Dipartimento di Scienze Molecolari Applicate ai Biosistemi, Sez. Chimica Organica ‘A. Marchesini’, Via Venezian 21, 20133 Milano, Italy article info Article history: Received 26 October 2011 Accepted 30 November 2011 Available online 4 January 2012 abstract Enriched ethyl 3-benzamido-2-hydroxy-3-phenylpropanoate (protected phenylisoserine), the chiral side chain of Taxol, was obtained via asymmetric reduction with transition metal–diphoshine complexes or with whole cells of non-conventional yeasts. Asymmetric hydrogenation was carried out using different approaches: hydrogenation of the tetra-substituted double bond of (E)-1-benzamido-3-ethoxy-3-oxo-1- phenylprop-1-en-2-yl ethyl oxalate 1 with Ir(I)–diphosphine complexes in the presence of TEA, hydroge- nation of the carbonyl group of racemic ethyl 3-benzamido-2-oxo-3-phenylpropanoate 2 with Ru(II)–diphoshine complexes in the presence of a Lewis acid and finally a two-step enzymatic transforma- tion of (E)-1-benzamido-3-ethoxy-3-oxo-1-phenylprop-1-en-2-yl ethyl oxalate 1 catalyzed by whole cells of yeasts bearing cell-bound esterases and dehydrogenases. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Drugs that come from plants have always had an important role in the treatment of an enormous array of pathologies, including Cancer. Today the most used antineoplastic drug in therapy is Paclitaxel (Fig. 1), particularly in breast and ovary Cancer and ad- vanced forms of Kaposi’s sarcoma. 1,2 The major differences between the Taxol skeleton and the other 200 members of its family are the presence of a side chain at the C- 13 position, esterified by an N-benzoyl-phenyl-isoserine group and an oxetanic ring attached to C 4–5 of the cyclohexane ring. Both groups are necessary for the biological activity. Taxol can be isolated from the bark of Taxus brevifolia, a tree that grows slowly, making Taxol production insufficient for world demand. Thus there is a need to develop new strategies for the large-scale synthesis of this drug. Different approaches have been studied: total synthesis, 3–5 production by vegetable crops, 6 prepa- ration from mushrooms, 7 extraction from the leaves of the Taxus species, 8 the semi-synthesis from 10-deacetyl baccatine III, 9 and the stereoselective synthesis of the Taxol side chain. 10–14 From these methods, only the last three approaches have become indus- trially applied, one of which has been patented by Bristol-Myers Squibb. 15,16 This synthesis provides the esterification of modified 10-deacetyl baccatine III, a tetra substituted diterpene extract from T. brevifolia leaves, with the lateral chain (2R,3S)-N-benzoyl-O-(1-ethoxyeth- yl)-3-phenylisoserine. Different strategies have been developed for the synthesis of the lateral chain in an enantiomerically pure form. The first asymmetric synthesis of the lateral chain was realised by Greene 9 in 1986, utilising a Sharpless epoxidation. Other strat- egies have been developed by Ojima et al. using b-lactam, 11 and by Sharpless using methyl cinnamate. 12 Another example includes the chemo-enzymatic Kayser approach, 13 which combined a chemical synthesis with biocatalysis reactions using yeasts. 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.11.017 ⇑ Corresponding author. Tel.: +39 02 503 14609; fax: +39 02 503 14615. E-mail address: isabella.rimoldi@unimi.it (I. Rimoldi). O HO HO O OAc H O O OH O NH O OH O Figure 1. Paclitaxel. Tetrahedron: Asymmetry 22 (2011) 2110–2116 Contents lists available at SciVerse ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy