TETRAHEDRON: ASYMMETRY Tetrahedron: Asymmetry 14 (2003) 2839–2844 Pergamon One-pot synthesis and resolution of chiral allylic alcohols Ahmed Kamal,* Mahendra Sandbhor, Ahmad Ali Shaik and V. Sravanthi Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India Received 11 July 2003; accepted 24 July 2003 Abstract—Substituted ,-unsaturated ketones were selectively reduced to the corresponding allylic alcohols under mild reaction conditions. The allylic alcohols thus obtained were kinetically resolved by lipase catalyzed transesterification in the same pot to afford chiral allylic alcohols in excellent enantioselectivity. Various lipases were screened for this one-pot transesterification of allylic alcohols. Effects of different solvent have also been studied under these conditions. Pseudomonas cepacia lipase immobilized on ceramic particles (PS-C) and on diatomaceous earth (PS-D) catalyzes this transesterification in diisopropyl ether in a highly efficient manner. © 2003 Elsevier Ltd. All rights reserved. 1. Introduction Chiral allylic alcohols represent an important structural motif and have attracted synthetic chemists for their wide range of applications. 1 They are useful chiral synthons in sigmatropic reactions 2a as well as for the synthesis of natural products viz. octalactin A, (-)- and (+)-cis --irone. 2b,c They have been used as chiral pre- cursors for the synthesis of (S )- and (R )-verapamil, 3 a calcium channel blocker used for the treatment of classical angina pectoris and superventricular tachycar- dia. Allylic alcohols are synthesized in enantiomerically pure form from prochiral ketones by microbial reduc- tion, and chemically by stereoselective reduction or hydrogenation processes. 4 Among the methods cur- rently available for the synthesis of enantiopure allylic alcohols, two of the most practical are the dynamic kinetic resolution of racemic allylic alcohols, 5a asym- metric epoxidation 5b and enzymatic acylation 6 in organic solvents and in ionic liquids. 6d These methods have some limitations which make them unsuitable for the practical synthesis of chiral allylic alcohols. Whole cell reductions of ,-unsaturated ketones are less applicable because of low yields and poor enantioselec- tivities and needs the complementary approaches of metal catalyzed asymmetric hydrogenation. 4a Whereas chemical hydrogenation methods afford poor chemose- lectivity in reducing ,-unsaturated ketone and give saturated alcohols, saturated ketones and -hydroxy ketones as side products. 6b Moreover, these methods need high pressure, longer reaction time and expensive metal catalysts. In lipase catalyzed transesterification of (RS )-trans -4-phenyl-3-butene-2-ol 2 using dimethyl- malonate as the acyl donor the enantiomeric excess did not exceed 93% for the unsaturated alcohol and the condition applied such as reaction under reduced pres- sure and use of KHCO 3 limit its application at a large scale. 2a In continuation of our earlier work on the one-pot synthesis and lipase catalyzed resolution of enantiopure secondary alcohols 7a and their applications for the synthesis of biologically important intermediates 7b and chiral - and -lactones, 7c herein we report stereoselective syntheses of chiral allylic alcohols using one-pot reduction and lipase resolution protocols. 2. Result and discussion In the selective reduction of carbonyls considerable progress has been made in the development of reducing agents derived from NaBH 4 . 8 We report NaBH 4 /acti- vated alumina 9 mediated selective reduction of carbonyl group of ,-unsaturated ketone quantitatively under mild conditions. The racemic alcohol thus obtained was subjected to lipase catalyzed transesterification in the same pot. Both the enantiomers of the chiral allylic alcohol were obtained in good enantioselectivity by using this one-pot lipase resolution process. * Corresponding author. Fax: 91-40-27193189; e-mail: ahmedkamal@iict.ap.nic.in 0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0957-4166(03)00598-6