Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany.
Chemistry. 2010 Oct 25;16(40):12133-40. doi: 10.1002/chem.201001133.
A productive total synthesis of both enantiomers of berkelic acid (1) is outlined that takes the structure revision of this bioactive fungal metabolite previously proposed by our group into account. The successful route relies on a fully optimized triple-deprotection/1,4-addition/spiroacetalization cascade reaction sequence, which delivers the tetracyclic core 32 of the target as a single isomer in excellent yield. The required cyclization precursor 31 is assembled from the polysubstituted benzaldehyde derivative 20 and methyl ketone 25 by an aldol condensation, in which the acetyl residue in 20 transforms from a passive protecting group into an active participant. Access to fragment 25 takes advantage of the Collum-Godenschwager variant of the ester enolate Claisen rearrangement, which clearly surpasses the classical Ireland-Claisen procedure in terms of diastereoselectivity. Although it is possible to elaborate 32 into the target without any additional manipulations of protecting groups, a short detour consisting in the conversion of the phenolic -OH into the corresponding TBS-ether is beneficial. It tempers the sensitivity of the compound toward oxidation and hence improves the efficiency and reliability of the final stages. Orthogonal ester groups for the benzoate and the aliphatic carboxylate terminus of the side chain secure an efficient liberation of free berkelic acid in the final step of the route.
本文概述了 Berkeli 酸（1）对映异构体的高效全合成，该合成考虑了我们小组之前提出的该生物活性真菌代谢物的结构修订。成功的路线依赖于完全优化的三重脱保护/1,4-加成/螺缩酮化级联反应序列，该序列以优异的收率提供了目标的四环核心 32 作为单一异构体。所需的环化前体 31 由多取代苯甲醛衍生物 20 和甲基酮 25 通过羟醛缩合组装而成，其中 20 中的乙酰基残基从被动保护基团转变为活性参与者。片段 25 的获得利用了 Collum-Godenschwager 酯烯醇化物 Claisen 重排变体，该变体在非对映选择性方面明显优于经典的 Ireland-Claisen 方法。尽管可以在不进行任何额外的保护基操作的情况下将 32 精心设计为目标化合物，但包含将酚羟基转化为相应的 TBS-醚的简短迂回是有益的。它可以调节化合物对氧化的敏感性，从而提高最后阶段的效率和可靠性。苯甲酸酯和侧链脂肪羧酸末端的正交酯基确保了在路线的最后一步能够有效地释放出游离的 Berkeli 酸。
