Enantioselective synthesis of functionalized g-butyrolactones Ali Samarat, a Hassen Amri a, * and Yannick Landais b, * a Laboratoire de Chimie Organique and Organome ´tallique, Faculte ´ des Sciences, Campus Universitaire, 1060-Tunis, Tunisia b Laboratoire de Chimie Organique and Organome ´tallique, Universite ´ Bordeaux-I, 351 cours de la Libe ´ration, 33405 Talence, Cedex, France Received 1 April 2004; revised 1 July 2004; accepted 6 July 2004 Available online 14 August 2004 Abstract—Sharpless asymmetric dihydroxylation and aminohydroxylation of (E)-dimethyl-2-alkylidene glutarates 2 were shown to afford enantio-enriched or enantiopure highly functionalized g-butyrolactones 3 and 7. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction Functionalized g-lactones have attracted considerable attention in recent years due to their importance as building blocks in the synthesis of a number of natural products and biologically relevant compounds, 1 , for example, precursors of inhibitors of HIV-1 protease. 2,3 We wish to propose here a rapid access to these attractive intermediates using a straightforward approach based on the utilization of Sharpless asymmetric dihydroxylation (AD) and amino- hydroxylation (AA) of diesters 2(a-e). 4,5 2. Stereoselective synthesis of dimethyl (E)-2-alkylidene glutarates 2 We have previously described a highly stereoselective synthesis of dialkyl 2-alkylidene glutarates by nucleophilic substitution of the vinylic bromine atom in 1 by magnesium dialkyl cuprates generated in situ at low temperature. 6 The dimethyl (E)-2-bromomethylene glutarate 1 was prepared through a simple tandem-process: bromination–dehydro- bromination of dimethyl-2-methylene glutarate 2a accord- ing to the Ref. 7. We report herein, our results on the conjugated addition of dialkyl organocuprates to the dimethyl (E)-2-bromomethyl- ene glutarate 1, leading to the corresponding dimethyl-2- alkylidene glutarates 2 in excellent yields with total E-stereoselectivity (Scheme 1, Table 1). 3. Results and discussion The catalytic asymmetric dihydroxylation of these olefins was then examined. The intermediate diols were not detected but spontaneously lactonized to give the corre- sponding functionalized g-butyrolactones 3(a-e), posses- sing a quaternary centre in modest to good yields. It is interesting to notice that spontaneous cyclization of the resulting diols under the AD reaction conditions was completely regioselective in the examined cases, only g-butyrolactones being obtained. Prediction of the absolute configuration of the major enantiomer for chiral g-lactones 3(a-e) was based on Sharpless’mnemonic device 5a,b (Scheme 2). As shown in Table 2, several commercially available Sharpless ligands were tested as chiral ligands and the best results were obtained using (DHQ) 2 AQN. In each case, the reaction was also carried out in racemic series using quinuclidine as ligand. The absence of a suitable chromophore on the lactone 3(a-c) and 3e prevented us to determine the enantiomeric excesses of these compounds through HPLC on chiral column. We thus protected first the hydroxyl function of alcohols 3(a-c) as their benzoate 4(a-c). However, all attempts to convert sterically hindered 3e into the corresponding benzoate failed. The silylated ether 4e was prepared instead but finally proved to be unsuitable for the determination of the enantiomeric excess through HPLC (Scheme 3). The ee values of 4(a-c) were eventually determined through HPLC using Chiracel OD w column. Enantiomeric excesses are moderate to excellent depending on the nature of the R group on the olefin. Sharpless ligands used in this study are usually known to provide moderate enantioselectivities with 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.07.012 Tetrahedron 60 (2004) 8949–8956 Keywords:(E)-2-Alkylidene glutarates; Asymmetric dihydroxylation; Asymmetric amino-hydroxylation; g-Butyrolactones. * Corresponding authors. Tel.: C216-71-872-600; fax: C216-71-885-008 (H.A.); fax: C33-5-40006286 (Y.L.); e-mail: hassen.amri@fst.rnu.tn