Part A. Asymmetric Total Synthesis of (–)-Penibruguieramine A Using Memory of Chirality and Dynamic Kinetic Resolution. Part B. Biphasic CuAAC Reaction Using a Phase Transfer Agent.

Abstract

Part A. Asymmetric Total Synthesis of (–)-Penibruguieramine A Using Memory of Chirality and Dynamic Kinetic Resolution.

(–)-Penibruguieramine A is a novel marine pyrrolizidine alkaloid, which was recently identified by Guo from the endophytic fungus Penicillium sp. GD6 associated with Chinese mangroves. This natural product has an unprecedented 1-hydroxyl-2-methyl pyrrolizidin-3-one skeleton. We have achieved the first total synthesis of this marine alkaloid using the principles of memory of chirality (MOC) and dynamic kinetic resolution (DKR) for the asymmetric synthesis from proline as the only chiral source. MOC and DKR are attractive strategies for asymmetric synthesis. However, although there have been reports of DKR being utilized, there are only few reports of MOC being applied in total synthesis of natural products. Moreover, the combination of these two concepts has not been previously reported for asymmetric synthesis. Our synthesis follows the proposed biosynthetic pathway and features an asymmetric construction of stereocenters with essentially complete diastereo- and enantioselectivity in the absence of external chiral sources. Noteworthy is the excellent level of memory of chirality in a protic solvent environment. To understand this, we performed some experiments and provided a mechanistic rationale.

Part B. Biphasic CuAAC Reaction Using a Phase Transfer Agent.

A phase transfer agent assisted biphasic Cu(I) catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction system was developed. A biphasic reaction media consisting of water and an organic solvent ensures a dissolution of reagents and substrates. Tris(triazolylmethyl)amine ligands with an appropriate hydrophilic-lipophilic balance are able to extract copper from the aqueous phase to the organic phase, accelerating the CuAAC reaction rate. The present system is widely applicable to substrates with various functionalities, including a free amino group and especially to lipophilic substrates.