The development of new synthetic strategies and methodologies for complex alkaloid total synthesis : a concise synthesis of (+)-chimonanthine, (+)-WIN 64821, (-)-ditryptophenaline and related alkaloids
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260457144-MIT.pdf
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Author(s)
Schmidt, Michael Anthony, 1980-
Advisor(s)
Mohammad Movassaghi.
Alternative Title
Concise synthesis of (+)-chimonanthine, (+)-WIN 64821, (-)-ditryptophenaline and related alkaloids
Date Issued
2008
Publisher
Massachusetts Institute of Technology
Abstract
I. The Development of a General Strategy Towards Dimeric Hexahydropyrroloindole Alkaloids. A Concise Total Synthesis of (+)-Chimonanthine, (+)-Folicanthine and (-)Calycanthine. An efficient and convergent strategy for the synthesis of dimeric hexahydropyrroloindole alkaloids is described. The simultaneous formation of the vicinal quaternary stereocenters using a reductive dimerization reaction provides gram-scale access to an optically active key intermediate employed in the synthesis of (+)-chimonanthine, (+)-folicanthine, and (-)calycanthine. II. The Development of a General Strategy Towards Dimeric Hexahydropyrroloindole Alkaloids. A Concise Total Synthesis of (+)-WIN 64821, (-)-Ditryptophenaline and (-)-1'(2-Phenylethylene)-ditryptophenaline. The concise enantioselective total synthesis of (+)-WIN 64821 and (-)-ditryptophenaline in six and seven steps, respectively, from commercially available amino acid derivatives is described. The gram-scale synthesis of key intermediates and simultaneous introduction of the vicinal quaternary stereocenters provides a highly effective and preparative synthesis of these natural alkaloids. Additionally, the synthesis and structural confirmation of the natural alkaloid (-)-1 '-(2-phenylethylene)-ditryptophenaline is described. III. N-Heterocyclic Carbene-Alcohol Hydrogen Bonds. Studies and Application in the Amidation of Unactivated Esters. A single-step and catalytic amidation of unactivated esters with amino alcohols is described. Treatment of equimolar quantities of amino alcohols and unactivated esters with N,Nbismestiylimidazolylidene (5 mol%) affords the desired amides in high yield under mild reaction conditions.
(cont.) The compatibility of the present methodology with a wide range of functional groups, heterocycles, and optically active substrates in addition to both aromatic and aliphatic esters is noteworthy. Preliminary data regarding an unprecedented hydrogen-bonded carbene-alcohol complex is reported. Further investigation of this hydrogen bond revealed steric and electronic influences on the nature of this bond, cumulating in discovery of a practical metal free method for the stabilization and storage of these nitrogen heterocyclic carbenes. Also described is a method for the synthesis of optically active imidazo-[1,5-a]-pyridinium salts as precursors to optically active nitrogen heterocyclic carbenes.
Description
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2008.
Vita.
Includes bibliographical references.
Subjects
Chemistry.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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