Dehydrative Annulation Strategy for the Construction of Octahydroindolizine Framework: A Diastereoselective Synthesis of (6R,8aS)-Octahydroindolizin-6-ol

Abstract

A dehydrative annulation strategy involving an intramolecular ring closure under a Mitsunobu-type reaction condition has been used for the construction of octahydroindolizine framework successfully. This strategy that was reported to be unsuccessful when applied to a similar system allowed us to perform a diastereoselective synthesis of (6R,8aS)-octahydroindolizin-6-ol [a precursor of (–)-8a-epidesacetoxyslaframine] starting from commercially available chiral (S)-epichlorohydrin via a piperidine intermediate, i.e., (3R,6S)-6-(3-hydroxypropyl)piperidin-3-ol. The methodology has potential to afford a library of optically pure small molecules of pharmacological importance based on the related indolizine framework.

GRAPHICAL ABSTRACT

Keywords:

• Diastereoselectivity
• Mitsunobu reaction
• octahydroindolizine
• (S)-epichlorohydrin

ACKNOWLEDGMENTS

The authors thank Dr. Vilas Dahanukar and Dr. H. Rammohan of Dr. Reddy’s Laboratories Limited for useful discussions and the Analytical Department of Dr. Reddy’s Laboratories Limited for spectra.

SUPPLEMENTAL MATERIAL

Full experimental details, spectral data, ¹H and ¹³C NMR spectra, and HPLC traces for this article can be accessed on the publisher’s website.