Asymmetric total synthesis of yuzurimine-type Daphniphyllum alkaloid (+)-caldaphnidine J

Lian-Dong Guo,Jing Xu,Chengqing Ning,Yan Zhang,Heyifei Fu,Yuye Chen,Jingping Hu

doi:10.1038/s41467-020-17350-x

Lian-Dong Guo, Jing Xu + Show 5 more

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https://doi.org/10.1038/s41467-020-17350-x

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Abstract

Ever since Hirata’s report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. Despite extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine-type Daphniphyllum alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol coupling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Our approach paves the way for the synthesis of other yuzurimine-type alkaloids and related natural products.

Highlights

Ever since Hirata’s report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids
Our group has recently accomplished the asymmetric total syntheses of himalensine A31, dapholdhamine B32, and caldaphnidine O33
It was further envisioned that a ketene dithioacetal Prins reaction[54,55,56,57] would form the cyclopentene moiety in 1, while compound 2 might be produced from the enyne acetal 3 via a carbocyclization cascade[58]

Summary

Introduction

Ever since Hirata’s report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. The first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzuriminetype Daphniphyllum alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol coupling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Despite extensive synthetic studies[34,35,36,37,38,39,40,41,42,43,44,45,46,47,48], total synthesis of yuzurimine-type alkaloids—the largest subfamily of the Daphniphyllum alkaloids—has not been achieved so far. Other notable attempts toward the 7/5 bicycle in our target molecule are discussed

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