This research proposal seeks to establish the capacity of our newly introduced paradigm of organocascade catalysis to accomplish, with unprecedented levels of efficiency, the total synthesis of an array of complex, natural product-based molecules. The current prevailing approach to complex molecule synthesis, generally adopted by both academic and pharmaceutical practitioners of the field, entails a 'stop-and-go'strategy, wherein each individual chemical transformation is executed as a separate process. Because of the requirement for isolation and purification of intermediates at each stage along the synthetic route, this classical approach to multi-step synthesis suffers from a number of serious limitations with regard to efficiency and product selectivity. As an alternative approach, we recently introduced a novel synthetic concept, termed organocascade catalysis, which seeks to translate some of the advantages offered by natural product biosynthesis to the realm of laboratory synthesis. Organocascade catalysis emulates the conceptual blueprint of biosynthesis through the merger of multiple sequential transformations, each governed by an orthogonal mode of organocatalytic activation, into a single cascade sequence. Toward this end, we have demonstrated, in a variety of settings, the remarkable ability of organocascade catalysis to enable the rapid conversion of simple achiral substrates to complex, stereochemically rich, single-enantiomer adducts. This research proposal seeks to demonstrate the unprecedented synthetic capabilities of organocascade catalysis through the total synthesis of a range of high-profile natural products. Due to their complexity, as well as their historical and medical significance, the natural products targeted herein serve as valuable total synthetic benchmark compounds, by which to assess the current state of the field of organic synthesis. It is of note that each of the synthetic routes to the targets proposed herein, if realizable, would represent a significant improvement, in terms of efficiency and selectivity, over previously reported total syntheses. Specifically, Project I outlines the development of an enantioselective triple organocatalytic cascade sequence. The common intermediate arising from this transformation will be rapidly advanced to key members of the Aspidosperma, Kopsia, and Strychnos families of natural products - namely, strychnine, akuammicine, kopsinine, kopsanone, aspidospermidine, and vincadifformine. Projects II and IV envision the development of second generation, quadruple cascade routes to kopsanone and strychnine, respectively. In Project III, we will pursue a rapid organocascade approach to a common intermediate en route to a number of members of the Aspidosperma and Strychnos families. The key organocascade adduct will be advanced to ochrosamine B. Project V will entail the investigation of a new cascade-based strategy toward cytotoxic teleocidin natural products, such as indolactam V, and analogs thereof. Finally, the focus of Project VI will be on the development of a SOMO-catalysis based organocascade platform, as well as the subsequent application of this novel approach to the total syntheses of the natural products, phyllantidine and bruceol.

Public Health Relevance

The objective of this research is to establish a new strategy for chemical synthesis whereby natural products, bioactive compounds and medicinal agents can be generated in a highly accelerated fashion from cheap, inexpensive and readily available starting materials.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078201-08
Application #
8518371
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (03))
Program Officer
Lees, Robert G
Project Start
2006-07-07
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2013
Total Cost
$302,762
Indirect Cost
$102,138
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
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Jeffrey, Jenna L; Petronijević, Filip R; MacMillan, David W C (2015) Selective Radical-Radical Cross-Couplings: Design of a Formal β-Mannich Reaction. J Am Chem Soc 137:8404-7
Jeffrey, Jenna L; Terrett, Jack A; MacMillan, David W C (2015) O-H hydrogen bonding promotes H-atom transfer from α C-H bonds for C-alkylation of alcohols. Science 349:1532-6
Le, Chi Chip; MacMillan, David W C (2015) Fragment Couplings via CO2 Extrusion-Recombination: Expansion of a Classic Bond-Forming Strategy via Metallaphotoredox. J Am Chem Soc 137:11938-41

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