開催日: 2017/09/20 - 2017/09/22
Aflastatin A was isolated from the culture broth of Streptomyces sp. MRI142 by Sakuda and co-workers in 1996 (Figure 1). This natural product exhibits an inhibitory activity against the biosynthesis of carcinogen aflatoxin produced by a part of Aspergillus sp. The highly oxygenated structure of aflastatin A contains various typical polyketide structures including polyacetate, polypropionate, deoxypropionate and contiguous polyol motifs. We selected aflastatin A as a synthetic target in order to develop the efficient synthesis of these various polyketide motifs. In the synthesis of the C22-C48 polyol segment, the contiguous polyol motif such as C27-C31 moiety would be efficiently synthesized by the aldol reaction. We examined the aldol reaction between aldehyde 7 derived from D-mannose and ketone 18 derived from L-tartric acid (Figure 4). In consequence, addition of SnCl2 gave the desired aldol adduct 19 in high stereoselectivity and we achieved the efficient synthesis of C22-C48 segment 21. In the synthesis of the C3-C21 segment including deoxypropionate and propionate structures, we constructed these compounds by transformation of olefins of products 22, 29 and 33 synthesized from vinylketene silyl N,O-acetal 22 and ent-22 according to our previous studies on the remote asymmetric introduction-type alkylation and the aldol reaction (Figure 6 to 8). Streoselective Birch reduction with a compound 23 was achieved by using 2-methyl -benzimidazole as a bulky proton to give the C4-C7 deoxypropionate 24 in only 2 steps. Appropriate oxidations of olefins of compound 29 such as regioselective epoxidation following hydroboration gave propionate 32, the C9-C15 moiety of aflastatin A. Coupling reactions including the Julia-Kocienski reaction between C3-C8 and C9-C15 segment and the aldol reaction between C3-C15 and C16-C21 segment gave C3-C21 segment 40 (Figure 9).