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

首次完成了三环海洋生物碱（±）-fasicularin和（±）-lepadiformine的全合成。合成的关键共同战略要素是立体控制的分子内杂Diels-桤木反应的N-酰基亚硝基部分的环外二烯与或不与溴取代，以控制顺式或反面选择性，分别导致反式或顺式稠合的十氢喹啉环系统，涉及在一个单一的步骤中同时引入氮化的季中心。在进一步加工六元或五元环时，输注加合物提供（±）-fasicularin或（±）-lepadiformine。合成的（±）-lepadiformine盐酸盐与分离的天然lepadiformine样品一致，但通过光谱比较发现，由顺式稠合物衍生的具有lepadiformine结构的三环氨基醇与lepadiformine不同。这些结果毫不含糊地确定了lepadiformine的相对立体化学，以前错误地指定为3R^*，5S ^*，7aR ^*，11 aR ^*。

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^*.