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

盐氯和羽叶酸是由Uemura及其同事在1996年分离的结构相关的海洋生物碱。这些生物碱的不寻常的结构，加上有价值的生物活性，激发了许多合成研究，最终在几个路线的核心氮杂螺癸烷系统。我们已经开发了Danishefsky关键中间体的合成与氮杂螺双环酮作为一个共同的前体，这是使用分子内烯反应的酰基亚硝基化合物，并实现。在异羟肟酸与Pr_4NIO_4的氧化反应中，原位生成的酰基亚硝基化合物发生分子内烯化反应，生成单一的非对映体螺环内酰胺。随后的氢化和高度立体选择性的乙炔化产生氮杂螺环酮，其转化为1，7-二取代的6-氮杂螺[4.5]癸烷关键中间体，其中通过烯烃氢化建立适当的立体化学，然后通过三环内酰胺的C-甲基化和随后的涉及使用三氟甲磺酸甲酯的内酰胺开环的过程。由此获得的螺双环化合物通过涉及Horner-Wadsworth-Emmons同系化的五个步骤在羽酸的全合成中转化为TBDPS保护的Danishefsky中间体。此外，在第二代Grubbs催化剂的作用下，通过二烯的闭环复分解反应，由氮杂螺双环醛合成了卤氯全合成中Danishefsky关键中间体的乙酯类似物。

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.