Synthesis of bioactive marine natural products using intramolecular ene reaction of acylnitroso compounds

卤化氯和品甲酸是Uemura和他的同事在1996年分离的结构上相关的海洋生物碱。这些生物碱的不同寻常的结构，加上有价值的生物活性，激发了大量的合成研究，最终导致了几条通往核心氮杂环十二烷系统的路线。我们以氮杂双环酮为原料，通过酰基亚硝基化合物的分子内烯化反应，合成了丹尼舍夫斯基关键中间体。异羟肟酸被Pr4NiO4氧化后，原位生成的酰基亚硝基化合物的分子内烯反应顺利进行，生成单一的非对映异构体螺环内酰胺。随后的氢化和高立体选择性的乙炔基化得到了氮杂环酮，它被转化为1，7-二取代的6-氮杂螺[4.5]正十一烷键中间体，通过烯烃氢化、三环内酰胺的C-甲基化以及随后的使用三氟酸甲酯开环的过程建立了适当的立体化学。通过五步Horner-Wadsworth-Emmons同源反应，将得到的螺环化合物转化为TBDPS保护的Danishefsky中间体。在此基础上，以氮杂双环醛为原料，通过二烯在第二代格拉布斯催化剂上的开环歧化反应，得到了合成卤代氯的关键中间体丹尼舍夫斯基的乙酯类似物。

Halichlorine and pinnaic acid are structurally related marine alkaloids isolated by Uemura and co-workers in 1996. The unusual structures of these alkaloids, coupled with the valuable biological activities, have inspired numerous synthetic investigations, culminating in several routes to the core azaspirodecane system. We have developed the synthesis of the Danishefsky key intermediates starting with the azaspirobicyclic ketone as a common precursor, which was obtained using intramolecular ene reaction of acylnitroso compounds and achieved. Upon oxidation of the hydroxamic acid with Pr_4NIO_4, intramolecular ene reaction of the in situ generated acylnitroso compound proceeded smoothly to yield the spirocyclic lactam as a single diastereomer. Subsequent hydrogenation and highly stereoselective ethynylation led to the azaspirocyclic ketone, which was converted to the 1,7-disubstituted 6-azaspiro[4.5]decane key intemediate with the proper stereochemistry established by olefin hydrogenation followed by C-methylation of the tricyclic lactam and the subsequent processes involving lactam ring-opening using methyl triflate. The spirobicyclic compound thus obtained was converted to the TBDPS-protected Danishefsky intermediate in the total synthesis of pinnaic acid via five steps involving Horner-Wadsworth-Emmons homologation. Furthermore, the ethyl ester analog of the Danishefsky key intermediate in the total synthesis of halichlorine was achieved from the azaspirobicyclic aldehyde via ring-closing metathesis of the diene with the second-generation Grubbs'catalyst.