A Concise Enantioselective Total Synthesis of (−)‐Virosaine A

• Published in: Angewandte Chemie International Edition Vol. 56; no. 36; pp. 10830 - 10834
• Main Authors: Hughes, Jonathan M. E., Gleason, James L.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 28.08.2017
• Subjects: alkaloids; cascade reactions; Chemistry; Chemistry, Multidisciplinary; directed lithiation; Physical Sciences; Science & Technology; total synthesis; virosaine A; ORGANIC-SYNTHESIS; INSERTION; directed lithiation; NATURAL-PRODUCTS; alkaloids; BOND FUNCTIONALIZATION; ABSOLUTE STEREOCHEMISTRY; POLYGALOLIDE-B; cascade reactions; virosaine A; BIOMIMETIC TOTAL-SYNTHESIS; C-H OXIDATION; SITE-SELECTIVITY; total synthesis; virosaine A
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201706273

The total synthesis of (−)‐virosaine A (1) was achieved in ten steps starting from furan and 2‐bromoacrolein. A one‐pot Diels–Alder cycloaddition/organolithium addition initiated an efficient sequence to access a key oxime/epoxide intermediate. Heating this intermediate in acetic acid resulted in an intramolecular epoxide opening/nitrone [3+2] cycloaddition cascade to construct the caged core of 1 in a single step. Several methods of C−H functionalization were assessed on the cascade product, and ultimately, a directed lithiation/bromination effected selective C14 functionalization, enabling the synthesis of 1. Not too late: The core of virosaine A was prepared in five short steps by a cycloaddition/organolithium addition and a nitrone formation/cycloaddition cascade. Late‐stage selective functionalization of an unactivated C−H group by directed lithiation enabled conversion of the shown key intermediate into the natural product.