# Chiral Complexes Designed to Catalyzed Organic Reactions

> **NIH NIH R01** · HARVARD UNIVERSITY · 2022 · $728,271

## Abstract

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 Brønsted 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.

## Key facts

- **NIH application ID:** 10320847
- **Project number:** 5R01GM043214-32
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** ERIC N JACOBSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $728,271
- **Award type:** 5
- **Project period:** 1991-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320847

## Citation

> US National Institutes of Health, RePORTER application 10320847, Chiral Complexes Designed to Catalyzed Organic Reactions (5R01GM043214-32). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320847. Licensed CC0.

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