Halichondrin B: Synthesis of the C1−C22 Subunit

Two efficient routes to the C1−C22 subunit of halichondrin B are described. The cage ketal 7,
which contains 11 asymmetric centers embedded within the ABCDEF-ring framework, was
assembled from (+)-conduritol E (27) in 18 steps and 4% overall yield. In a separate route, 7 was
also synthesized in 18 steps and 2% overall yield from a derivative of α-d-glucoheptonic acid γ-lactone
(62). While the former route installs the fully elaborated C-ring endowed with the correct C12
stereochemistry early in the synthesis, the latter features a late-stage introduction of the C12
stereocenter during the ultimate one-pot Michael addition/ketalization cascade to form the CDE-ring system of the cage. The importance of the C12 stereocenter to the crucial ketalization event
is discussed through comparison of these two strategies.

本文报道了两条合成软海绵素B（halichondrin B）C1−C22亚基的高效路线。笼状缩酮7（cage ketal 7）含有嵌入ABCDEF环骨架中的11个手性中心，可由(+)-康多利醇E（(+)-conduritol E, 27）经18步反应合成，总收率为4%。在另一合成路线中，化合物7亦可由α-D-葡萄庚糖酸γ-内酯（α-d-glucoheptonic acid γ-lactone, 62）的衍生物经18步反应合成，总收率为2%。前一条路线在合成早期即构建了带有正确C12立体化学构型的完整C环，而后一条路线则在合成后期，通过最终的一锅法迈克尔加成/缩酮化级联反应构建笼状结构的CDE环体系时引入C12手性中心。本文通过对比这两种合成策略，探讨了C12手性中心对关键缩酮化反应的重要性。