Our laboratory has a longstanding interest in the development of generic organocatalytic activation modes that may be parlayed into a wide range of new asymmetric transformations. Along these lines, we have introduced a menu of powerful asymmetric methods based upon organocatalytic iminium catalysis, enamine activation, and SOMO (singly occupied molecular orbital) catalysis. A more recent focus has been on the invention of new asymmetric methods based on the powerful multicatalytic strategies of organocascade catalysis and synergistic catalysis. The synergistic concept envisions the productive merger of two simultaneous catalytic cycles, which operate in concert to separately activate each reactant, culminating in a single bond-forming event. Because of its enormous potential to enable the development of previously inconceivable chemical transformations, synergistic catalysis has emerged as a transformative synthetic paradigm. In this research proposal, we outline new directions for our wide-ranging organocatalysis-based research program. In the six aims proposed herein, we employ a variety of organocatalytic strategies en route to challenging asymmetric bond constructions. The successful completion of these aims will result in the facile, direct, and highly selective synthesis of privileged functionl motifs, including ?-aryl, ?-alkyl, and ?-amino aldehydes; ?-alkyl aldehydes; and ?-functionalied ketones.
In Aim 1, we propose to develop a direct ?-amination of simple aldehyde precursors through synergistic SOMO-based organocatalysis and Lewis acid catalysis.
Aim 2 envisions the direct coupling of aldehydes and aryl boronic acids via the synergistic merger of chiral enamine organocatalysis and copper catalysis, en route to valuable ?-aryl aldehyde motifs.
In Aim 3, we explore the direct ?-alkylation of aldehydes through synergistic chiral amine organocatalysis, thiol-based organocatalysis, and photoredox catalysis.
In Aim 4, we propose to accomplish the asymmetric ?-alkylation of enal precursors through the intermediacy of a catalytically generated iminium species; key to the successful implementation of this goal will be the development of an effective Hantzsch ester-derived alkylating reagent.
Aim 5 outlines our plans to establish a generic new mode of asymmetric activation, whereby ketones are transiently converted to activated chiral oxyallyl cation species. The trapping of these electrophilic intermediates with nucleophilic coupling partners should lead to the formation of a wide menu of ?-substituted ketone synthons. Finally, in Aim 6 we propose to complete an asymmetric total synthesis of ochrosamine B through a rapid organocascade catalysis pathway.

Public Health Relevance

The development of improved strategies for the synthesis of medicinally useful compounds is a fundamental goal of organic chemistry. Using powerful organocatalytic technologies developed in our lab, we aim to develop a series of useful new chemical reactions that will provide access to a menu of complex, high- value structural motifs that are not readily accessible through currently available methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078201-12
Application #
9391683
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2006-07-07
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08543
Welin, Eric R; Le, Chip; Arias-Rotondo, Daniela M et al. (2017) Photosensitized, energy transfer-mediated organometallic catalysis through electronically excited nickel(II). Science 355:380-385
Le, Chip; Liang, Yufan; Evans, Ryan W et al. (2017) Selective sp3 C-H alkylation via polarity-match-based cross-coupling. Nature 547:79-83
Capacci, Andrew G; Malinowski, Justin T; McAlpine, Neil J et al. (2017) Direct, enantioselective ?-alkylation of aldehydes using simple olefins. Nat Chem 9:1073-1077
McCarver, Stefan J; Qiao, Jennifer X; Carpenter, Joseph et al. (2017) Decarboxylative Peptide Macrocyclization through Photoredox Catalysis. Angew Chem Int Ed Engl 56:728-732
Corcoran, Emily B; Pirnot, Michael T; Lin, Shishi et al. (2016) Aryl amination using ligand-free Ni(II) salts and photoredox catalysis. Science 353:279-83
Liu, Chun; Oblak, E Zachary; Vander Wal, Mark N et al. (2016) Oxy-Allyl Cation Catalysis: An Enantioselective Electrophilic Activation Mode. J Am Chem Soc 138:2134-7
Shaw, Megan H; Twilton, Jack; MacMillan, David W C (2016) Photoredox Catalysis in Organic Chemistry. J Org Chem 81:6898-926
Shaw, Megan H; Shurtleff, Valerie W; Terrett, Jack A et al. (2016) Native functionality in triple catalytic cross-coupling: spĀ³ C-H bonds as latent nucleophiles. Science 352:1304-8
Zhang, Patricia; Le, Chi Chip; MacMillan, David W C (2016) Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling. J Am Chem Soc 138:8084-7
Jeffrey, Jenna L; Petronijevi?, Filip R; MacMillan, David W C (2015) Selective Radical-Radical Cross-Couplings: Design of a Formal ?-Mannich Reaction. J Am Chem Soc 137:8404-7

Showing the most recent 10 out of 43 publications