Synthetic approach toward cis-disubstituted g- and d-lactones through enantioselective dialkylzinc addition to aldehydes: application to the synthesis of optically active flavors and fragrances Laura Pisani, Stefano Superchi * , Alessandra D’Elia, Patrizia Scafato, Carlo Rosini y Dipartimento di Chimica, Universit a della Basilicata, via dell’Ateneo Lucano 10, 85100 Potenza, Italy article info Article history: Received 13 February 2012 Received in revised form 19 April 2012 Accepted 8 May 2012 Available online 15 May 2012 Keywords: Asymmetric catalysis Enantioselective alkylation Alkylzinc Optically active lactones Whisky lactone abstract A versatile and straightforward approach to optically active cis-4,5-disubstituted g- and d-lactones by catalytic enantioselective addition of dialkyzincs to cinnamic aldehydes and RCM ring closure has been reported. The synthetic importance of the enantioselective dialkylzinc alkylation of aldehydes has been thus widened. Such an approach has then been employed for the enantioselective synthesis of naturally occurring g-lactone flavors like (S)-5-ethyl-butanolide (6a) and (4S,5S)-cis-whisky lactone (6b) and ex- tended to the preparation of d-lactones like (5S,6S)-5-methyl-6-ethylpentanolide (9a), precursor of the pheromone serricornin. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction The enantioselective alkylation of aldehydes by dialkylzinc re- agents is by far one of the most studied asymmetric trans- formations. 1 This reaction was described for the first time in 1984 by Oguni and Omi, employing (S)-leucinol as a chiral catalyst. 2 Since then a very large amount of different chiral catalytic pre- cursors have been developed, often leading to high levels of enantioinduction. Moreover, contrary to other popular enantiose- lective reactions, in this case deep experimental and theoretical investigations have defined with a good degree of certainty the mechanism determining the asymmetric induction. 3 The knowl- edge of the reaction mechanism, joined to the ease of the operating conditions made this reaction a popular benchmark to test the ef- ficiency of new chiral ligands as chirality inducers. 4 Surprisingly, despite the vast number of reactivity studies undertaken over a couple of decades, this reaction has found, until now, very few synthetic applications. 5 The only synthetic studies reported so far concern the employment of such reaction in the preparation of chiral methyl carbinol synthons, precursors of natural products, 6 and the preparation of optically active 3-alkylphthalides. 7 We recently developed a new family of chiral aminoalcohols, endowed with C 2 symmetric 1,1 0 -binaphthylazepine structure, which efficiently catalyze the enantioselective addition of dialkyl, diphenyl, and dialkynyl zinc reagents to aldehydes, providing good to excellent enantioselectivity. 8 Such results prompted us to ex- plore the synthetic potential of these reactions in order to dem- onstrate that they can provide not only a feasible test of the catalysts activity, but also a reliable tool for the asymmetric syn- thesis of complex intermediates. Generally speaking, the asymmetric alkylation of aldehydes af- fords high ee’s with aryl and a,b-unsaturated aldehydes. Therefore, in principle, it can provide access to optically active benzylic and allylic alcohols. In particular, the latter compounds are potentially valuable chiral intermediates and precursors of important natural products. Interestingly, some recent works point out the role of allylic alcohols as precursors of racemic g-lactones 9 and b,g-un- saturated d-lactones 10 through esterification with, respectively, acrylic or 3-butenoic acid followed by a ring closing metathesis (RCM) reaction. 11 We then envisaged that the catalytic enantiose- lective dialkylzinc addition to aldehydes could be employed as a key step for a new general approach to the synthesis of optically active cis-4,5-disubstituted g-lactones and cis-5,6-disubstituted d- lactones as showed in Scheme 1 . The approach described herein then has the double aim of showing the underexplored synthetic utility of the enantioselective dialkylzinc addition and to provide a straightforward and versatile * Corresponding author. Tel.: þ39 0971 206098; fax: þ39 0971 205678; e-mail address: stefano.superchi@unibas.it (S. Superchi). y Deceased, February 18, 2010. Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2012.05.028 Tetrahedron 68 (2012) 5779e5784