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Development of new methods for the synthesis of indolines and quinolizidines / by Hui Li

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Author	Li, Hui
Title	Development of new methods for the synthesis of indolines and quinolizidines / by Hui Li
Date	2015
Abstract	I. (3 + 2) Cycloaddition Reactions of Oxyallyl Cationic Intermediates with Indoles Cyclopenta- and cyclohexa[b]indolines are ubiquitous molecular skeletons in natural products and pharmaceutical agents. We have developed (3 + 2) cycloaddition reactions of 3-substituted indoles with α-haloketones to access those scaffolds. Significant diastereo- and regiochemical control were observed. The reactions were found to proceed via an O-bound intermediate. Kinetic studies of the cycloaddition reactions and DFT calculations (B3LYP-D3/6-311++G**/MeOH) on cyclization mechanisms involving the 2-hydroxyallyl cation and its deprotonated oxyallyl cation have been performed. Both oxyallyl cationic intermediates were predicted to be viable reactive species. The synthetic potential of these reactions were demonstrated in the concise syntheses of structural cores of vincorine, isocorymine, and aspidophylline A. II. Vinylogous Mukaiyama-Michael Reactions of Dihydropyridinones 2,3-Dihydro-4-pyridinones are versatile building blocks in constructing nitrogencontaining heterocyclic compounds. We have developed In(III)-catalyzed vinylogous Mukaiyama-Michael (vM-Michael) addition of O-silyl vinylketene acetals to dihydropyridinones. The reactions featured the employment of supersilyl groups to control the α-vs-γ regioselectivity when γ-substituted O-silyl vinylketene acetals were used. These transformations can allow easy access to quinolizidine-based alkaloids. This potential was demonstrated by formal synthesis of deoxynupharidine, lasubine I and II, as well as construction of the structural core of hupermine A. III. Discovery of the First Known Apoptotic Monomeric Nuphar Analogs and Enantioselective Formal Syntheses of 11 Nuphar Alkaloids (+)-6-Hydroxythiobinupharidine induces apoptosis of U937 human leukemia cells in a speed faster than any known small organic molecules. In order to obtain useful SAR information, we have designed and synthesized a stereochemically diverse collection of monomeric nuphar analogs bearing C6 hemiaminal hydroxyl groups. We have also achieved the concise enantioselective formal syntheses of eight dimeric and three monomeric nuphar alkaloids. The above syntheses involved the development of highly enantioselective chiral phosphoric acid-catalyzed vinylogous Mukaiyama-Mannich (vM-Mannich) reactions. The vM-Mannich reactions employed the supersilyl groups as a key element in controlling regio-, enantio- and diastereoselectivity. Biological evaluation of the monomeric nuphar quinolizidines identified analogs that are even more potent than the parent natural product (+)-6-Hydroxythiobinupharidine.
Description	1 online resource (xii, 598 leaves) : illustrations (some color)
Format	application/pdf
College	Dartmouth College -- Department of Chemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	Made available by the author under a Creative Commons Attribution-NonCommercial License.; Made available by the Trustees of Dartmouth College under a Creative Commons Attribution-NonCommercial License. https://creativecommons.org/licenses/by-nc/4.0/
DOI	https://doi.org/10.1349/ddlp.2283

Title	li2016 1
Full Text	DEVELOPMENT OF NEW METHODS FOR THE SYNTHESIS OF INDOLINES AND QUINOLIZIDINES A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry by Hui Li DARTMOUTH COLLEGE Hanover, New Hampshire Dec. 2015 Examining Committee: (chair) Peter A. Jacobi Jimmy Wu Gordon W. Gribble Yimon Aye F. Jon Kull, Ph.D. Dean of Graduate Studies

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Development of new methods for the synthesis of indolines and quinolizidines / by Hui Li

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