| An enantioselective total synthesis of (-)-strychnine (1) was achieved from easily accessible, optically pure Michael adduct 63, which was synthesized by the catalytic asymmetric Michael reaction on a greater than kilogram scale. Another key step in this entry was a novel tandem cyclization promoted by zinc reduction for the simultaneous construction of B- and D-rings (Figure ab-1).(1) Practical large-scale synthesis of enantiomerically pure Michael adductThe multifunctional asymmetric catalyst AlLibis(binaphthoxide) complex (ALB), which was developed by Prof. Shibasaki and co-workers in the University of Tokyo in 1996, is very effective for the catalytic Michael reaction of cyclic enones with malonates. Although several new catalysts including the LaNa3tris(binaphthoxide) complex, GaNabis(binaphthoxide) complex, and La-linked-BINOL complex have been developed in the above group, ALB is the most effective catalysts for the present Michael reaction in terms of catalyst efficiency and catalyst cost. Even improved procedure being used, however, 1 mol % of the catalyst was still required to obtain the product in excellent yield and high enentiomeric excess. In order to apply this chemistry to the synthesis of (-)-strychnine and a manufacturing scale synthesis, it was definitely necessary to further improve not only catalyst efficiency, such as catalyst loading and reaction time, but also the work-up procedure to eliminate the need for chromatographic separation. Thus, the effects of additive, solvent and ligand tuning were examined in this thesis and it was eventually discovered that the reaction was effectively accelerated under highly concentrated condition without lowering chemical yield or the high enantiomeric excess. Therefore, the catalyst loading was able to be decreased from 1.0 to 0.1 mol %. The reaction completed within 24 h at ambient temperature (Scheme ab-1) and was finally performed in pre-manufacturing scale (more than kilogram) synthesis, which was possible to be carried out in a two-literred flask due to the highly concentrated reaction condition. Followed an ordinary quenching procedure, theorganic layer was concentrated, and successively crystallized(total three times) from AcOEt/hexane to afford the Michael adduct 63 as a white crystal in 91% yield (1.24 kg) and morethan 99% ee. In addition, (R)-BINOL was recovered from the mother liquor by subsequent fractional extraction in about 80% yield without any loss of enantiomeric purity. To the best of our knowledge, the described method is one of the most practical and efficient catalytic asymmetric carbon-carbon bond formations in excellent enantioselectivity.(2) Enantioselective total synthesis of (-)-strychnineWith a large amount of the optically pure Michael adduct 63 in hand, our attention was then turned to the enantioselective total synthesis of (-)-strychnme, a flagship compound of strychnos alkaloids, ranking as one of themost complex natural products of its size: six contiguous asymmetric centers (five in the core cyclohexane ring) and a mere 24 skeletal atoms compactly arranged in its seven rings.The research proved to be challenging so that the synthetic strategies were modified for several times. In the first-generation strategy, the synthesis was directed to the key tricyclic intermediate 54 (similar to Bosch's intermediate) (Scheme ab-2). The first challenging step was the (E)-selective introduction of the hydroxyethylidene moiety at C-20. Starting from 62, several methodologies were tried. For example, syn-aldol/anti-elimination proved to be fruitless due to their low selectivity. It was eventually found that the anti-aldol, obtained from the selectively chelatingreduction of the corresponding (3-ketoester 61 with NaBH3CN/TiCl4, and the following syn-elimination with DCC/CuCl under neutral condition, could tackle the problem. The reduction was carried out in THF using CH2C12 as a co-solvent for dissolving TiCl4 (ratio: ca. 5/1). Although it was moderate (5.7:1) under the original condition (-78℃),... |
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