Total synthesis of dimeric securinega alkaloids

Abstract

This thesis is divided into three chapters. Each chapter describes a review of high-order securinega alkaloids and the total synthesis of dimeric securinega alkaloids flueggenine C, D, and I.

Chapter 1 provides a detailed review of high-order securinega alkaloids. The isolation of flueggenines A and B by Yue and coworkers in 2006 has triggered a burst of isolation reports of dimeric and oligomeric securinega alkaloid natural products. Their compelling molecular structures with various modes of connection between monomeric securinega units have posed intriguing challenges to the synthetic organic community. Herein, we have categorized high-order securinega alkaloids based on their biosynthetic mode of dimerization or oligomerization. We then have compiled all reported syntheses of dimeric securinega alkaloids based on our classification.

Chapter 2 reports the first total synthesis of dimeric securinega alkaloid (–)-flueggenine C. The total synthesis of (–)-flueggenine C is completed via an accelerated intermolecular Rauhut–Currier (RC) reaction. Despite the numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas whose monomeric units are connected by a putative enzymatic RC reaction has not been reported to date. We have found that an installation of a nucleophilic functional group at the γ-position of an enone greatly accelerates the rate of the diastereoselective intermolecular RC reaction. This discovery enabled an efficient and selective formation of the dimeric intermediate which was further transformed to (–)-flueggenine C.

Chapter 3 reports the first total synthesis of dimeric securinega alkaloid (–)-flueggenines D and I. This features the first total synthesis of dimeric securinega alkaloids with a C(α)–C(δ’) connectivity between two monomeric units. The key dimerization was enabled by a sequence that involves Stille reaction and conjugate reduction. The high chemofidelity of the Stille reaction enabled us to assemble two structurally complex fragments that could not be connected by other methods. Stereochemical flexibility and controllability at the δ’-junction of the dimeric intermediate render our synthetic strategy broadly applicable to the synthesis of other high-order securinega alkaloids.