From C-Glycosides to Pyranopyrans: An Approach to Thyrsiferol Using Titanium(III)-Promoted Redox Couplings

An approach to the pyranopyran ring system that is found in many natural products, including
thyrsiferol, is described. The route entails the assembly of an α,β-unsaturated ketone (11) from
geraniol and dihydropyran (23) from acetyl acetaldehyde dimethyl acetal (19) and their titanium(III)-promoted coupling to afford a respectable 60% yield of keto alcohol 26. The σ-bond formed in
this process corresponds to the pro-C9−C10 bond of thyrsiferol (4). Attempts to invert the
stereochemistry at the pro-C11 center were thwarted by the congestion imparted by the presence of
the vicinal TBS-ether. Consequently, cyclization of the coupling adduct under conditions developed
by Olah and Prakash and co-workers led to the cis-fused pyranopyran 27. X-ray analysis of this
crystalline material confirmed each of the stereochemical assignments. After much effort, it was
determined that the hydroxyl group at C12 could be removed by treating the derived methyl xanthate
with a tri-n-butylphosphine−borane complex under radical-forming conditions. The reaction
sequence worked well, despite the hindered working environment and the presence of a potentially
labile C−Br bond.

本文报道了一种可用于构建众多天然产物中存在的吡喃并吡喃环系（pyranopyran ring system）的合成策略，目标天然产物包括瑟西弗醇（thyrsiferol）。该合成路线首先分别从香叶醇（geraniol）制备α,β-不饱和酮（11），从乙酰乙醛二甲缩醛（acetyl acetaldehyde dimethyl acetal，19）制备二氢吡喃（dihydropyran，23）；随后通过三价钛（titanium(III)）介导的偶联反应，以可观的60%收率得到酮醇化合物26。本过程中形成的σ键（σ-bond）对应于瑟西弗醇（4）的前C9−C10键。尝试翻转前C11位中心的立体化学构型时，因邻位叔丁基二甲基硅基醚（TBS-ether）带来的空间位阻而受阻。因此，利用奥拉（Olah）与普拉卡什（Prakash）等课题组开发的环化条件对该偶联加合物进行环化，得到顺式稠合的吡喃并吡喃环化合物27。对该结晶产物进行X射线衍射分析，确认了所有立体化学构型的指认。经过大量优化尝试后，我们发现可通过在自由基引发条件下，使该偶联产物衍生得到的甲基黄原酸酯与三正丁基膦-硼烷复合物反应，脱去C12位的羟基。尽管该反应环境位阻较大且存在潜在易断裂的C−Br键，整个反应序列仍表现出优异的反应性。