Total Synthesis of (−)-Galbonolide B and the Determination of Its Absolute Stereochemistry

Through a trans-lactonization reaction, galbonolide B
(1) was converted to 3 with the chiral
secondary
alcohol at C13 exposed for derivatization. Two independent methods
were employed to determine the absolute
chirality at C13. Both of these methods established S
chirality at C13. Since the relative stereochemistry of
galbonolide
B had been determined from the X-ray structure, the absolute
stereochemistry of galbonolide B was therefore formally
established to be structure 1, which contradicted earlier
speculations in the literature. A total synthesis of
galbonolide
B has been completed. A highly selective method was developed for
the assembly of the peculiar diene unit using
Martin's sulfurane reagent for the dehydration of the preceding
tertiary alcohol 20. The chiral center at C4
was
installed by “contra-steric” enolate chemistry. A novel
macro-Dieckmann cyclization was employed to generate the
macrocycle. The desired configuration at C2 was obtained from the
kinetic protonation of the corresponding enolate.
Finally, a seldom used protecting group,
2,4,6-trimethylbenzylidene acetal, was employed for the glycol unit.
It
exhibited extremely facile hydrolysis under mildly acidic conditions
without causing any decomposition of synthetic
intermediates.

通过转内酯化反应，galbonolide B（化合物1）被转化为化合物3，其C13位的手性仲醇暴露以用于衍生化。本研究采用两种独立方法测定C13位的绝对手性，两种方法均确定C13位为S构型。由于galbonolide B的相对立体化学已通过X射线晶体结构确定，因此其绝对立体化学正式确定为化合物1的结构，这与此前文献中的推测相悖。本研究完成了galbonolide B的全合成：开发了一种高选择性方法用于构建特殊的二烯单元，以Martin硫烷试剂对前体叔醇20进行脱水反应；通过“逆空间”烯醇盐化学策略构建C4位的手性中心；采用新型大环狄克曼环化反应构建大环骨架；通过对应烯醇盐的动力学质子化得到C2位所需的构型。最后，针对乙二醇单元使用了一种极少使用的保护基——2,4,6-三甲基亚苄基缩醛，该保护基在弱酸性条件下水解极为便捷，且不会导致合成中间体发生任何分解。