A formal synthesis of (-)-aphanorphine and studies on the synthesis of (+) clauslactone S and enantiomerically enriched α-hydroxy acid derivatives

Kulkarni, Kaivalya G. (2014) A formal synthesis of (-)-aphanorphine and studies on the synthesis of (+) clauslactone S and enantiomerically enriched α-hydroxy acid derivatives. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

(−)-Aphanorphine is an alkaloid isolated from the fresh water algae Aphanizomenon flos-aquae. The 3-benzazepine scaffold in aphanorphine resembles the benzomorphan analgesics such as pentazocine, eptazocine and morphine. The complex 3-benzazepine scaffold and a quaternary stereocenter has made (−)-aphanorphine an interesting synthetic target. The synthesis of (−)-aphanorphine from an enantiomerically enriched α-hydroxy acid derivative is described in Chapter 1 of this thesis. This hydroxy acid is readily available from an ephedrine-derived morpholinone via a highly diastereoselective allylation followed by removal of the ephedrine portion. The methodology developed for the synthesis of (−)-aphanorphine is potentially useful for the synthesis of other N-methylpyrrolidine-based natural products and related structural motifs. Clauslactone S is a terpenoid which was extracted from the leaves and stems of Clausena excavate in 2008. There has been no synthesis of clauslactone S reported to date. We envisaged that the substituted δ-lactone in clauslactone S can be synthesized using an enantiomerically enriched α-hydroxy acid derivative. Studies on the development of a modular synthetic strategy for clauslactone S and the details of the synthesis of a potential intermediate to clauslactone S are described in Chapter 2 of the thesis. The α-hydroxy acid derivative employed as starting material in the aphanorphine and clauslctone S studies is readily obtained by a highly diastereoselective double alkylation of an ephedrine-derived morpholinedione. However, the limitation of the methodology is that ephedrine is no longer commercially available. Hence, studies were conducted on several morpholinediones, that were derived from enantiomerically enriched amino alcohols, with the objective of finding an alternative to ephedrine. Details of these investigations are presented in Chapter 3 of this thesis.

Item Type: Thesis (Doctoral (PhD))
URI: http://research.library.mun.ca/id/eprint/8180
Item ID: 8180
Additional Information: Includes bibliographical references.
Department(s): Science, Faculty of > Chemistry
Date: October 2014
Date Type: Submission
Library of Congress Subject Heading: Alkaloids--Synthesis; Hydroxy acids--Derivatives; Terpenes--Synthesis; Alkylation

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