This program is dedicated to the development and elucidation of new principles for stereoselective catalysis, and in the application of those principles to the invention of practical synthetic methods for the preparation of chiral, bioactive compounds. This renewal application is focused on two distinct approaches to the generation and stereocontrolled reaction of highly electrophilic intermediates. Each of the proposed reaction manifolds is based on firm mechanistic hypotheses gleaned from extensive preliminary investigations. The first involves the application of precisely designed chiral ureas, thioureas, and squaramides to catalyze enantioselective reactions via ion-pair intermediates. These dual hydrogen-bond donors can abstract or bind weakly basic anions, such as halides, sulfonates, and carboxylates, to generate chiral ion pairs that remain tightly associated during subsequent selectivity-determining reactions of the prochiral cations. We discovered that the combination of hydrogen-bond donors with achiral Lewis or Brnsted acids generates highly reactive complexes that can promote activation and enantioselective reactions of weakly electrophilic substrates. This new principle is directed to creative new applications including the enantioselective multi-component synthesis of amines from carbonyl compounds and to the asymmetric ring opening of oxetanes. The principle of anion-abstraction catalysis is also applied in a new way to the promotion of enantioselective boronate rearrangements, through a novel chiral recognition mechanism involving discrimination of enantiotopic leaving groups. The boronate rearrangement methodology provides a general approach to the systematic construction of trisubstituted stereocenters from readily available organoboron derivatives. The second distinct approach involves the oxidative fluorofunctionalization of alkenes using hypervalent iodine catalysis. We have discovered that simple C2-symmetric aryl iodides catalyze enantioselective difluorination of simple alkenes via a multistep mechanism involving a highly reactive fluoroalkyl iodane intermediate. That intermediate can be intercepted in a variety of intra- or intermolecular reactions, leading to novel, 1,1-, 1,2-, and 1,3-fluorofunctionalized products in highly enantioenriched form. Efforts are directed toward the mechanistic elucidation of the new reactions, and to their practical enablement through the use of practical fluoride sources.

Public Health Relevance

We seek to discover new principles for selective catalysis, and to apply those principles to the discovery of valuable organic reactions. The fruit of this effort will be new classes of small- molecule, chiral organic catalysts that generate highly electrophilic intermediates and control their reactivity through networks of attractive non-covalent interactions. These catalysts form the basis for conceptually novel and efficient methods for preparing to chiral frameworks of known or potential utility in the preparation of bioactive structures.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043214-31
Application #
10070617
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Brown, Patrick
Project Start
1991-01-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
31
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Wendlandt, Alison E; Vangal, Prithvi; Jacobsen, Eric N (2018) Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556:447-451
Zhou, Biying; Haj, Moriana K; Jacobsen, Eric N et al. (2018) Mechanism and Origins of Chemo- and Stereoselectivities of Aryl Iodide-Catalyzed Asymmetric Difluorinations of ?-Substituted Styrenes. J Am Chem Soc 140:15206-15218
Kwan, Eugene E; Zeng, Yuwen; Besser, Harrison A et al. (2018) Concerted nucleophilic aromatic substitutions. Nat Chem 10:917-923
Mennie, Katrina M; Banik, Steven M; Reichert, Elaine C et al. (2018) Catalytic Diastereo- and Enantioselective Fluoroamination of Alkenes. J Am Chem Soc 140:4797-4802
Kwan, Eugene E; Park, Yongho; Besser, Harrison A et al. (2017) Sensitive and Accurate 13C Kinetic Isotope Effect Measurements Enabled by Polarization Transfer. J Am Chem Soc 139:43-46
Banik, Steven M; Levina, Anna; Hyde, Alan M et al. (2017) Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis. Science 358:761-764
Klausen, Rebekka S; Kennedy, C Rose; Hyde, Alan M et al. (2017) Chiral Thioureas Promote Enantioselective Pictet-Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction. J Am Chem Soc 139:12299-12309
Banik, Steven M; Mennie, Katrina M; Jacobsen, Eric N (2017) Catalytic 1,3-Difunctionalization via Oxidative C-C Bond Activation. J Am Chem Soc 139:9152-9155
Park, Yongho; Harper, Kaid C; Kuhl, Nadine et al. (2017) Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions. Science 355:162-166
Park, Yongho; Schindler, Corinna S; Jacobsen, Eric N (2016) Enantioselective Aza-Sakurai Cyclizations: Dual Role of Thiourea as H-Bond Donor and Lewis Base. J Am Chem Soc 138:14848-14851

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