Unified divergent strategy towards the total synthesis of the three sub-classes of hasubanan alkaloids

Abstract

Elegant asymmetric synthesis of hasubanan alkaloids have been developed over the past decades. However, a divergent approach leading to all three sub-classes of this family of natural products remains unknown. We report herein the realization of such an endeavor by accomplishing enantioselective total syntheses of four representative members. The synthesis is characterized by catalytic enantioselective construction of the tricyclic compounds from which three different intramolecular C-N bond forming processes leading to three topologically different hasubanan alkaloids are developed. An aza-Michael addition is used for the construction of the aza-[4.4.3]-propellane structure of (-)-cepharamine, whereas an oxidation/double deprotection/intramolecular hemiaminal forming sequence is developed to forge the bridged 6/6/6/6 tetracycle of (-)-cepharatines A and C and a domino bromination/double deprotection/cyclization sequence allows the build-up of the 6/6/5/5 fused tetracyclic structure of (−)-sinoracutine.

Total Syntheses of (+)-Waixenicin A, (+)-9-Deacetoxy-14,15-deepoxyxeniculin, and (−)-Xeniafaraunol A

“…Iodide 13 (three steps from ethyl 2-butynoate) represents a previously unknown but valuable alternative to the classical Stork–Jung vinylsilane . Treating a mixture of 14 and phenyl bistriflimide (PhNTf 2 ) with potassium hexamethyldisilazide (KHMDS) gave the corresponding enol triflate in excellent yield (85%).…”

Enantioselective Total Synthesis of (+)-Stephadiamine

“…Structurally, this class of natural products, sharing a common aza[4.4.3]­propellane core, differs mainly on the oxidation level of the polycyclic structure and the presence of an additional oxa-heterocycle. While the total synthesis campaign started in the late 1960s, asymmetric syntheses have been accomplished only recently. − …”

Enantioselective Total Synthesis of (+)-Stephadiamine through Bioinspired Aza-Benzilic Acid Type Rearrangement

“…More than 40 congeners of these alkaloids have been identified to date, and they show a wide range of biological activities, including antiviral, antimicrobial, and cytotoxic activities . Hasubanan alkaloids, exemplified by compounds 2 – 5 , commonly possess a characteristic tetracyclic aza­[4,4,3]­propellane core 1 (Figure a). , Owing to the synthetically challenging structures of these alkaloids as well as their important biological activities, numerous synthetic studies have been reported. − …”