Stereocontrolled synthesis of antitumor alkaloids based on intramolecular hetero-Diels-Alder reaction of acylnitroso compounds

首次全合成了三环海洋生物碱（±）-马齿苋素和（±）-左二福明。合成的关键共同策略元素是分子内立体控制的n-酰基亚硝基部分与有或没有溴取代的外环二烯的杂diols - alder反应，分别控制顺面或反面选择性，从而产生反式或顺式融合的十氢喹啉环体系，其中包括在一个步骤中同时引入氮化的季中心。在六元环或五元环的进一步细化中，输合的加合物提供（±）-筋环素或（±）-左二福明。合成的（±）-左二福尔明的盐酸盐与分离的天然左二福尔明样品相同，然而，通过光谱比较发现，由顺式融合加合物衍生的具有左二福尔明结构的三环氨基醇与左二福尔明不同。这些结果明确地确定了左二甲双胍的相对立体化学，以前被错误地分配为3R^*，5S^*,7aR^*, 11aR^*。

The first total synthesis of tricyclic marine alkaloids (±)-fasicularin and (±)-lepadiformine was accomplished. The key common strategic element for the synthesis is the stereocontrolled intramolecular hetero-Diels-Alder reaction of an N-acylnitroso moiety to an exocyclic diene with or without bromine substitution to control the syn-facial or anti-facial selectivity, respectively, leading to the trans- or cis-fused decahydroquinoline ring systems involving the simultaneous introduction of the nitrogenated quarternary center in a single step. On further elaboration of the six-membered or five membered ring, the trans-fused adduct provided either (±)-fasicularin or (±)-lepadiformine. The hydrochloride salt of synthetic (±)-lepadiformine was found to be identical with the isolated natural sample of lepadiformine, however, the tricyclic amino alcohol having proposed structure of lepadiformine, derived from the cis-fused adduct, was found to be different from lepadiformine by spectral comparison. These results unambiguously established the relative stereochemistry of lepadiformine, formerly assigned incorrectly, to be 3R^*,5S^*,7aR^*, 11aR^*.