Dissertation/Thesis Abstract

Part I. Asymmetric α-Alkylation of Aldehydes with Simple Olefins, And Part II. Enantioselective Total Synthesis of Polypyrroloindoline Natural Products
by Comito, Robert J., Ph.D., Princeton University, 2014, 286; 3642075
Abstract (Summary)

The direct asymmetric α-alkylation of carbonyls using simple olefins has been accomplished using organocatalysis. This method relies upon transient open shell activation of carbonyl substrates with chiral amine catalysts as enamine radical cations, an activation mode termed singly occupied molecular orbital (SOMO) catalysis. The stereoselective radical addition across unactivated alkenes by this catalytic intermediate provides a general asymmetric strategy for carbon-carbon bond formation from very simple starting materials. Conceptually, this novel transformation provides access to “homo-ene” type products. Stereoselective cyclization of simple aldehyde-olefin substrates affords enantioenriched complex small ring adducts, bearing vicinal stereocenters with carbon substitution. Predictable catalyst-directed cyclic conformational control provides high selectivity for the formation of enantioenriched heterocycles with multiple stereocenters. Intermolecularly, the asymmetric oxidative coupling of aldehydes and feedstock olefins using this method demonstrates a new concept for asymmetric synthesis from simple precursors. In an extension of the SOMO organocatalysis paradigm, rearrangements of reactive intermediates are induced under catalyst control, providing topologically complex adducts.

Polypyrroloindolines natural products are currently targets of intense synthetic interest due to their complicated structure and intriguing biological potency. This effort has culminated in several elegant total syntheses and creative new strategies for asymmetric synthesis. Despite these achievements, a general strategy is lacking that would provide efficient access to the more complex members of this family. Composed as oligomers of a repeating cyclotryptamine unit, polypyrroloindolines can be readily assembled conceptually by controlled polymerization of tryptamine-derived precursors. Herein, a novel arylation/cyclization transformation has been developed using asymmetric copper catalysis that accomplishes this strategy. Oligomerization to multi-pyrroloindoline motifs has been demonstrated through iterative application of this method. In this way, concise enantioselective total syntheses of the trimeric natural products hodgkinsine and hodgkinsine B have been accomplished. Ongoing studies will be discussed toward the tetrameric natural products such as quadrigemine H that have not previously been prepared by total synthesis.

Indexing (document details)
Advisor: MacMillan, David W. C.
Commitee: Chirik, Paul, Doyle, Abigail G., Schwartz, Jeffrey
School: Princeton University
Department: Chemistry
School Location: United States -- New Jersey
Source: DAI-B 76/03(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Organic chemistry
Keywords: Aldehydes, Alkylation, Asymmetric catalysis, Enantioselective, Olefins, Polypyrroloindoline, SOMO, Singly occupied molecular orbital catalysis, Total synthesis
Publication Number: 3642075
ISBN: 9781321287288
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