Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids

Lomaiviticin A (1) and B (2) are natural products with remarkably complex C2-symmetric structures and potent antiproliferative properties. Achieving total syntheses of 1 and 2 has been a long-standing project in the Shair group and part one of this thesis describes our first successful synthesis of...

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Main Author:	Lee, Amy S
Other Authors:	Shair, Matthew David
Language:	en_US
Published:	Harvard University 2014
Subjects:	Organic chemistry lomaiviticin lycopodium natural product total synthesis
Online Access:	http://dissertations.umi.com/gsas.harvard.inactive:11724 http://nrs.harvard.edu/urn-3:HUL.InstRepos:13065032

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spelling	ndltd-harvard.edu-oai-dash.harvard.edu-1-130650322017-07-27T15:51:30ZProgress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium AlkaloidsLee, Amy SOrganic chemistrylomaiviticinlycopodiumnatural producttotal synthesisLomaiviticin A (1) and B (2) are natural products with remarkably complex C2-symmetric structures and potent antiproliferative properties. Achieving total syntheses of 1 and 2 has been a long-standing project in the Shair group and part one of this thesis describes our first successful synthesis of the C4-epi-lomaiviticin A and B core structures. A key stereoselective oxidative enolate dimerization of an oxanorbornanone system was employed to establish the highly hindered C2-C2' bond. Crucial to our completion of the lomaiviticin core structures was the discovery of subtle yet far-reaching stereoelectronic effects imparted by the C4/C4'-stereocenters. The Lycopodium alkaloids are a family of complex polycyclic alkaloid natural products that have long served as popular targets for developing synthetic chemistry. More recently, select members have been reported to exhibit neurological effects. Part two of this thesis presents the development of a biomimetic, unified strategy for the synthesis of 7-membered ring-containing Lycopodium alkaloids and its successful application toward the first total syntheses of the proposed structure of (-)-himeradine A (38), (-)-lycopecurine (39), and (-)-dehydrolycopecurine (199), and the syntheses of (+)-lyconadin A (31) and (-)-lyconadin B (32). A biosynthetically inspired one-pot cascade reaction sequence was developed to construct the strained polycyclic core structure shared amongst these alkaloids. Additionally, the syntheses of 38, 39, and 199 featured a biomimetic intramolecular Mannich reaction to furnish the tetracyclic ring system. The successful application of our unifying strategy toward the synthesis of a diverse set of alkaloids lends support to our biosynthetic hypothesis that 7-membered ring-containing Lycopodium alkaloids arise from a common precursor. Our synthetic approach can potentially provide access to all such natural products.Chemistry and Chemical BiologyShair, Matthew David2014-10-21T17:47:12Z2014-10-2120142016-01-01T08:30:54ZThesis or DissertationLee, Amy S. 2014. Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids. Doctoral dissertation, Harvard University.http://dissertations.umi.com/gsas.harvard.inactive:11724http://nrs.harvard.edu/urn-3:HUL.InstRepos:13065032en_USopenhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAHarvard University
collection	NDLTD
language	en_US
sources	NDLTD
topic	Organic chemistry lomaiviticin lycopodium natural product total synthesis
spellingShingle	Organic chemistry lomaiviticin lycopodium natural product total synthesis Lee, Amy S Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids
description	Lomaiviticin A (1) and B (2) are natural products with remarkably complex C2-symmetric structures and potent antiproliferative properties. Achieving total syntheses of 1 and 2 has been a long-standing project in the Shair group and part one of this thesis describes our first successful synthesis of the C4-epi-lomaiviticin A and B core structures. A key stereoselective oxidative enolate dimerization of an oxanorbornanone system was employed to establish the highly hindered C2-C2' bond. Crucial to our completion of the lomaiviticin core structures was the discovery of subtle yet far-reaching stereoelectronic effects imparted by the C4/C4'-stereocenters. The Lycopodium alkaloids are a family of complex polycyclic alkaloid natural products that have long served as popular targets for developing synthetic chemistry. More recently, select members have been reported to exhibit neurological effects. Part two of this thesis presents the development of a biomimetic, unified strategy for the synthesis of 7-membered ring-containing Lycopodium alkaloids and its successful application toward the first total syntheses of the proposed structure of (-)-himeradine A (38), (-)-lycopecurine (39), and (-)-dehydrolycopecurine (199), and the syntheses of (+)-lyconadin A (31) and (-)-lyconadin B (32). A biosynthetically inspired one-pot cascade reaction sequence was developed to construct the strained polycyclic core structure shared amongst these alkaloids. Additionally, the syntheses of 38, 39, and 199 featured a biomimetic intramolecular Mannich reaction to furnish the tetracyclic ring system. The successful application of our unifying strategy toward the synthesis of a diverse set of alkaloids lends support to our biosynthetic hypothesis that 7-membered ring-containing Lycopodium alkaloids arise from a common precursor. Our synthetic approach can potentially provide access to all such natural products. === Chemistry and Chemical Biology
author2	Shair, Matthew David
author_facet	Shair, Matthew David Lee, Amy S
author	Lee, Amy S
author_sort	Lee, Amy S
title	Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids
title_short	Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids
title_full	Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids
title_fullStr	Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids
title_full_unstemmed	Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids
title_sort	progress toward the total synthesis of the lomaiviticins and a biomimetic unified strategy for the synthesis of 7-membered ring-containing lycopodium alkaloids
publisher	Harvard University
publishDate	2014
url	http://dissertations.umi.com/gsas.harvard.inactive:11724 http://nrs.harvard.edu/urn-3:HUL.InstRepos:13065032
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Progress Toward the Total Synthesis of the Lomaiviticins and a Biomimetic Unified Strategy for the Synthesis of 7-Membered Ring-Containing Lycopodium Alkaloids

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