# Chiral Complexes Designed to Catalyzed Organic Reactions

> **NIH NIH R01** · HARVARD UNIVERSITY · 2021 · $9,021

## Abstract

PROJECT SUMMARY/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 (HBDs) 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
HBDs 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 developed here specifically in
the context of cooperative reactions between achiral transition metal complexes and chiral HBDs. 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:** 10393975
- **Project number:** 3R01GM043214-31S1
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** ERIC N JACOBSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $9,021
- **Award type:** 3
- **Project period:** 1991-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393975

## Citation

> US National Institutes of Health, RePORTER application 10393975, Chiral Complexes Designed to Catalyzed Organic Reactions (3R01GM043214-31S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10393975. Licensed CC0.

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