1,2-Asymmetric induction in the aldol addition reaction of malonate ester enolate to a-alkoxy aldehyde

The stereoselective aldol reaction represents one of the major challenges of modern synthetic organic chemistry.1 Many useful methodologies have been reported during the last few decades. For instance, 1,2-asymmetric induction in the aldol reaction of a-alkoxy aldehydes with silyl enol ethers or ketene silyl acetals is well-established.2 The aldol reaction between a-alkoxy aldehydes and a malonate ester is especially useful for the synthesis of biologically active compounds.3 For example, our recent synthesis of the neuritogenic agent epolactaene4 relied exclusively on this operation for the formation of the 1,2-diol. However, Saba et al.5 have been the only ones to report this type of aldol reaction, and the examples are limited. According to their report, when optically active dimenthyl malonate was added to chiral a-alkoxy aldehydes, the anti aldol adduct was obtained in ratios from 3:1 to 5:1, even in matched cases. Here we demonstrate simpler and more general methodologies for these aldol reactions which give higher anti product stereoselectively. Initially, we attempted an 1,2-asymmetric aldol reaction between the lithium enolate of tert-butyl malonate and 2-benzyloxypropanal 1a,6 derived from methyl lactate, at 278 °C (Table 1). When this reaction was carried out without Lewis acid, aldol adduct 4a was obtained with low diastereoselectivity (60:40, entry 1). However, when we added MgBr2 to coordinate to the carbonyl group, the diastereoselectivity was slightly increased (68:32, entry 2). The reaction was further examined in the presence of various Lewis acids under various conditions.‡ The results are shown in Table 1. High anti-selectivity was observed using ZnCl2 (82:18) or BF3·OEt2 (91:9) (entries 4, 5). Moreover, when the reaction was carried out at 298 °C in the presence of ZnCl2, the anti aldol adduct was obtained in excellent yield with high stereoselectivity (87:13). In order to further evaluate the effect of the addition process on stereoselectivity, various a-alkoxy aldehydes were examined in this aldol reaction in the presence of ZnCl2 at 278 °C. The results are summarized in Table 2. The stereoselectivity decreased somewhat when a bulky silyl group was used in place of the benzyl group as the protective group (entries 1–3). In contrast, when the alkyl group was changed from methyl to a more bulky isopropyl group (2a–d) high anti-selectivity was obtained using any aldehyde, although the chemical yield was affected by the size of the protective group (entries 4–7). The aldehyde 3a, derived from mandelic acid, also gave a good result (entry 8).