# Stereoselective Transition Metal Catalysis Enabled by Hydrogen-Bond Donor Mediated Electrophile Activation

> **NIH NIH F32** · HARVARD UNIVERSITY · 2024 · $73,828

## Abstract

Project Summary
 Enantioenriched amines are prevalent functional groups found in various bioactive compounds and
pharmaceuticals. Current methods for accessing them come with limitations, such as poor atom-economy, poor
selectivity, poor reactivity, or requirement for high-pressure gases. Transition metal catalyzed cross-coupling
reactions represent a powerful approach towards accessing enantioenriched amine compounds, which could
overcome some of the inherent issues with current state-of-the-art. However, the discovery of new asymmetric
transition metal catalyzed processes often requires exhaustive ligand screening and search for an optimal set of
conditions that enable satisfactory activity, chemoselectivity, and stereoselectivity. In some processes, the best
metal catalysts employed are those without any added ligands or with ligands to which no chiral equivalents
exist, presenting challenging scenarios for enantioinduction. This proposal outlines an alternative approach
towards the development of new transition metal catalyzed methodology, utilizing hydrogen-bond donor (HBD)
catalysis to activate C(sp3)–O bonds towards a Ni-catalyzed cross-coupling reaction. This dual catalytic platform
is a conceptually unexplored approach towards cross-coupling chemistry, wherein the role of the HBD is to
accelerate the oxidative addition while simultaneously imparting stereoselectivity to the step through ion pairing.
These roles have traditionally been assigned to ligand properties as the driver of reaction development, however
this proposed research will demonstrate the feasibility of leveraging both catalytic modes to cooperatively engage
mild electrophiles in an enantioconvergent C(sp3)–C(sp2) cross-coupling to generate amine compounds. Suzuki-
Miyaura and Mizoroki-Heck type couplings of readily-accessible hemiaminal substrates will be explored by
leveraging HBD-mediated substrate ionization for the generation of iminium ions. HBDs have been demonstrated
to be effective catalysts for the generation of iminium ions, and their subsequent engagement in enantioselective
trapping by standard nucleophiles. Unlike these traditional reaction profiles, the trapping of iminium ions by a
metal is proposed here. Interestingly, various stereoselective Ni-catalyzed couplings of C(sp3)–O bonds have
been reported to perform the best under “ligandless” conditions or with olefinic ligands that are not easily
converted to chiral equivalents, thus highlighting the strategy of this approach. Successful execution of this
proposal will reveal a new method for accessing enantioenriched amines and establish a proof-of-concept for
the synergistic cooperation of HBD-catalysis with transition metal catalysis.

## Key facts

- **NIH application ID:** 10995259
- **Project number:** 5F32GM149151-02
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Sepand K Nistanaki
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995259

## Citation

> US National Institutes of Health, RePORTER application 10995259, Stereoselective Transition Metal Catalysis Enabled by Hydrogen-Bond Donor Mediated Electrophile Activation (5F32GM149151-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10995259. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*