Stereoselective synthesis of the spirocyclic core of 13-desmethyl spirolide C using an aza-Claisen rearrangement and an exo-selective Diels-Alder cycloaddition.

Abstract

13-Desmethyl spirolide C is a marine natural product of the cyclic imine class that demonstrates remarkable bioactivity against several biomarkers of Alzheimer's Disease, which renders its [7,6]-spirocyclic imine pharmacophore of significant synthetic interest. This work describes a facile and efficient synthesis of the [7,6]-spirocyclic core of 13-desmethyl spirolide C from inexpensive starting materials, featuring an aza-Claisen rearrangement to simultaneously set both stereocentres of the dimethyl moiety with complete atom economy, and a highly exo-selective Diels-Alder cycloaddition to construct the challenging contiguous tertiary and quaternary stereocentres of the spirocyclic core of 13-desmethyl spirolide C. A comprehensive study of the key Diels-Alder reaction was also performed to evaluate the stereoselectivity and reactivity of various functionalised dienes and protected lactam dienophiles, wherein the first successful exo-selective Diels-Alder cycloaddition to construct spirocyclic structures using a bromodiene and α-exo-methylene dienophiles is reported. This strategy not only establishes a more efficient stereoselective access to the spirocyclic core that can be used for the total synthesis of 13-desmethyl spirolide C, but also serves as a sound platform for convenient preparations of a range of spirocyclic analogues required for a comprehensive biological evaluation of this desirable pharmacophore.

• Authors: Andrew D W Earl, Freda F Li, Chao Ma, Daniel P Furkert, Margaret A Brimble
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 21 Issue 6 Pg. 1222-1234 (02 08 2023) ISSN: 1477-0539 [Electronic] England
• PMID: 36633001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 13-desmethylspirolide C
• Spiro Compounds
• Polyenes
• Imines

Topics

• Cycloaddition Reaction
• Spiro Compounds (chemistry)
• Polyenes
• Imines (chemistry)