The stereoselective synthesis of methyllycaconitine analogues

Abstract

This thesis describes the synthetic studies made toward enantio-enriched AE and ABE ring analogues of methyllycaconitine (MLA) 1. MLA is a norditerpenoid isolated from a large family of structurally-related alkaloids of the Delphinium and Aconitum species. It is a highly selective antagonist of α7 nictotinic acetylcholine receptors that are thought to play an important role in neurodegenerative diseases. Structure-activity relationship studies have identified the amine and anthranilate ester located on the E ring as crucial for biological activity. Initial efforts focused on the synthesis of AE ring analogues formed by a double-Mannich reaction of preformed bis(aminol)ether 67 with chiral auxiliaries incorporated into p-ketoacid 106. A series of chiral amides and esters were tested, affording low diastereoselectivities. Separation of diastereomeric products was possible with some substrates. The next approach involved separating the double-Mannich reaction into two discrete mono-Mannich reactions. The use of chiral A,O-acetals 122 and 150 afforded low diastereoselectivities A new, more-efficient double-Mannich reaction utilising 3-alkyl-l,5,3-dioxazepanes 156, 158 - 163 was developed with a number of β-ketoesters (23, 173, 175, 185) and ketones (172 and 180). The stereodirecting ability of chiral dioxazepanes 163 and 170 was investigated, but no stereoinduction was observed in their reaction with β-ketoester 23. An diastereoselective synthesis of ABE ring analogues was developed using the Diels-Alder reaction of 1-azadiene 247 with enal 234 to construct B ring 262. Intramolecular cyclization aldehyde 262 to afford p-hydroxyester 263 was followed by oxidation to β-ketoester 264 to form the A ring. The amine in β-ketoester 264 was Boc-deprotected and the resulting amine condensed with formalin in an intramolecular Mannich cyclization to form E ring 221. An enatioselective synthesis of ABE ring analogues was developed with chiral cobalt (III) salen complex 272. The key Diels-Alder reaction afforded B ring 281 in high yield and enatiomeric excess (95%). The enantioenriched B ring 282 was subjected to the same transformations as the racemic mixture to afford enantioenriched ABE ring analogue 286.