Stereoselective Formal Synthesis of (-)-mesembrane via Asymmetric Allylation and Resoluting Condensation Reactions

Abstract

The enantioselective synthesis of quaternary carbon stereocenters and application to natural products has been a formidable challenge to synthetic organic chemists. Ways to quaternary stereocenters are demanded very much given the prevalence of the centers in various attractive natural products. One of the most promising methods for the purpose is the Pd-catalyzed alkylation of prochiral stabilized enolates. Although these methods have been useful, regioselectivity can be meet only in the case of single acidic site or a large pKa difference between two acidic sites to prevent the mixture formation. Instead, Tsuji allylation pathway from allyl enol carbonates which would be formed regioselectively by controlled methods prevented the production of mixtures of allylated products and allowed the neutral reaction conditions to yield good to excellent selectivity. Recently, we published the stereoselective synthesis of (-)mesembrane 1 which contains a quarternary center. Mesembrane 1 is a well known member of the Sceletium alkaloids, which has the basic structural element of cis-3a-aryloctahydroindole skeleton 2 (Figure 1). In the previous synthesis, we have applied desymmetrization of 1,3-dicarbonyl groups of cyclohexadione by intramolecular condensation with chiral amides. The maximum selectivity was moderately 3:1. So, we wanted to find out the strategy which would afford enhanced selectivity, and decided to combine Tsuji asymmetric allylation and the resoluting condensation step using a proper chiral auxilary. In the condensation step, it is anticipated that the energy difference of the diastereomeric aminol intermediates formed from attack of chiral amide to carbonyl group presumably would cause the difference of formation rates and the final production yields. We should find out the matching chiral auxiliary which would result in optimum resolution in the cyclization process to afford the desired isomer with better selectivity (Scheme 1). First, in the condensation reaction of chiral amide and carbonyl group of 7, we wanted to see how much resoluting selectivity would be generated through diastereomeric aminol intermediate (Table 1). The inseparable amide ketone diastereomers 7 could be prepared by employing the known procedure from 3. Cyclization has been found to proceed best in toluene at 65 C in the presence of TsOH. Among four chiral auxiliaries selected for the preparation of 7, two (Entry 1 and 2) provided 2:1 selectivity in 50 and 70% yields. Although the selectivity was moderate, we expected that this step would be helpful to increase the selectivity as an ancillary step and provide a known chiral intermediate. We have tried asymmetric allylation of allyl enol carbonate 9 to find out the optimum condition including the best chiral ligand. The required intermediate 9 was prepared from 3 by the reaction with allyl chloroformate in 67% yield as a single isomer. Various reaction conditions have been adopted in the allylation reaction using several known chiral ligands. And we found that (R,R)-ANDEN-phenyl Trost ligand 11 (5.5 mol %) afforded the best selectivity 83:17 in 58% yield in toluene at −78 C in the presence of Pd2(dba)3 (2.5 mol %). The isomeric ratio was determined by chiral HPLC column chromatography (Scheme 2). At this stage the absolute configuration of the quarternary center could not be determined,