Stereoselective Total Synthesis of (±)-Peribysin E

Radical cyclization of iodoketone 3 afforded cis-hydrindanone 8. Compound 8 was converted into key intermediate 5 via conventional
transformations. Annulation of a spiro-lactal unit to 5 was pursued with three different approaches. In the first approach,
radical cyclization of propargyl ester 17 provided spiro-lactone 18 with an undesired stereochemistry. Attempts to invert the
stereochemistry at the spiro-center via retro-aldol and aldol condensation
of compound 20 failed. In the second approach, key intermediate 5 was transformed into 23. Acylation of compound 23 gave 24 as a single diastereomer with the
desired stereochemistry but in low yield. NBS bromination of 24 followed by lactone formation gave 26 in low
yield. Alternatively, allylic oxidation of 24 with SeO2 followed by lactonization gave 26 also in low
yield. Finally, a third approach employing a semipinacol-type rearrangement
of epoxy-alcohol 33 gave aldehyde 34 with
the desired stereochemistry. Treatment of compound 34 with HCl in MeOH effected spiro-lactal formation and provided (±)-peribysin
E. The overall yield of our synthesis is 3.2% from 2-methylcyclohenen-1-one.

碘酮3经历自由基环化反应后得到顺式-水合茚满8。化合物8经过常规转化步骤转化为关键中间体5。针对5的环化反应，我们采用了三种不同的策略。在第一种策略中，丙炔酯17的自由基环化反应生成了具有不期望立体化学的螺环内酯18。尝试通过逆式醛缩合和醛缩合反应反转化合物20的螺环中心的立体化学未能成功。在第二种策略中，关键中间体5被转化为化合物23。化合物23的酰化反应生成了一种具有期望立体化学的单对映异构体24，但产率较低。随后，NBS溴化24并形成内酯，产率低，得到了化合物26。另一种方法是将24与SeO2进行烯丙基氧化，随后进行内酯化，也以低产率得到了化合物26。最后，采用第三种策略，通过环氧醇33的半呋喃型重排，得到了具有期望立体化学的醛34。用MeOH中的HCl处理化合物34，实现了螺环内酯的形成，并提供了(±)-peribysin E。整个合成过程的产率为3.2%，起始原料为2-甲基环己烯-1-酮。