Enantioselective synthesis with an ephedrine-derived morpholine-dione - new methods and applications in target-oriented synthesis

Adsool, Vikrant A. (Vikrant Arun) (2009) Enantioselective synthesis with an ephedrine-derived morpholine-dione - new methods and applications in target-oriented synthesis. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Enantiomerically pure α-hydroxy acids and their derivatives are an important class of organic compounds due to their utility as building blocks for the asymmetric synthesis of natural products and biologically active molecules. As a result, several synthetic strategies towards these targets have been reported in recent years. This thesis describes the applications of an ephedrine-based morpholine-dione as a chiral controller for the asymmetric synthesis of α-hydroxy acid derivatives. The methodology has been applied in enantioselective synthetic approaches to functionalized oxacycles as well as selected natural products such as (-)-quinic acid (R)-homocitric acid lactone and (+)-laurencin. -- A formal, enantioselective synthesis of (-)-quinic acid was achieved from a (1S,2R)-ephedrine-derived morpholine-dione which was converted to a dialkyl morpholinone via a highly diastereoselective allylation reaction. Using a similar strategy and by employing the enantiomeric (1R,2S)-ephedrine-derived dione, a concise and highly enantioselective synthesis of (R)-homocitric acid lactone was achieved. -- Enantioselective routes to functionalized, seven-, eight-, and nine-membered oxacycles that are amenable to further elaboration have been developed. Salient features of the methodology include highly diastereoselective and regioselective transformations of an ephedrine-derived epoxy-morpholinone to functionalized precursors of the oxacycles. The ephedrine scaffold exerts remote stereocontrol in the functionalization of the appended oxacycle. -- An application of the strategy for the enantioselective synthesis of medium-sized oxacycles has been demonstrated in a convergent, enantioselective route to an advanced intermediate for the synthesis of the marine natural product (+)-laurencin. The methodology employs ring-opening of an ephedrine-based spiro-epoxide with a chiral secondary alcohol, hemiacetal allylation and ring closing metathesis as the key steps for elaboration of the functionalized medium-ring ether moiety in laurencin. -- Studies on applications of the epoxy-morpholinone in the synthesis of funtionalized pyrrolidines were also conducted. The methodology, which is currently under development, employs ring-opening of an ephedrine-based spiroepoxide with a primary amine. Ring-closing of the amine side-chain on the resulting hemiacetal should provide functionalized pyrrolidines. -- In the investigations described above, removal of the ephedrine portion has been achieved by reductive cleavage (dissolving metal reduction), which results in destruction of the ephedrine portion. Hence, potentially recoverable chiral amino alcohols were examined as alternatives to ephedrine. This study has identified diphenyl alaninol as a potential substitute for ephedrine and has also provided some insights into the morpholinone structural elements that are necessary for good diastereoselection.

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