Asymmetric total syntheses of sarglamides A, C, D, E, and F

Abstract

Sarglamides A–E were identified as a structurally new class of alkaloids with potential application for inflammation-associated diseases. Reported is the first asymmetric total synthesis of sarglamides A, C, D, E, and F within 7 steps, featuring an intermolecular Diels–Alder cycloaddition of (S)-phellandrene and 1,4-benzoquinone and intramolecular (aza-)Michael addition to construct the tetracyclic core of sarglamides. Importantly, our work demonstrated that the hypothetic Diels–Alder reaction of α-phellandrene with dienophile toussaintine C (or analogues) originally proposed as a biosynthetic pathway was not viable under non-enzymatic conditions. Additionally, we discovered novel and efficient double cyclization (cycloetherification and oxa-Michael cyclization) to construct the core framework of sarglamides E and D. Our concise synthetic strategy might allow rapid access to a library of sarglamide analogues for further evaluation of their bioactivity and mode of action.