# New eras of catalysis: Towards the development of pseudotransition metal organocatalysts for metal-free cross-coupling transformations

> **NIH NIH F32** · HARVARD UNIVERSITY · 2024 · $22,922

## Abstract

Transition-metal catalyzed cross-coupling transformations are indispensable to pharmaceutical development
and medicinal chemistry, allowing access to innumerable bond connections in extremely complex molecular
settings. Despite its power, continued reliance on transition-metal catalysis poses many challenges. For
example, a most pressing challenge in pharmaceutical synthesis is the extreme cost associated with the noble
metals that form these precious, high-powered catalysts (e.g., Ru, Rh, Pd, Pt, and Ir). Furthermore, transition-
metals are treated with strict regulation due to their elemental toxicity, imparting significant cost in the upstream
synthetic stages of delivering a drug to the marketplace. Finally, continued reliance on transition-metal catalysis
is unsustainable, threatened by the rapid depletion of raw materials at known global deposits and consistent
supply-chain disruptions. Thus, the development of alternative strategies for mild and general bond formation is
necessary for continued productivity in pharmaceutical and medicinal chemistry.
 Organocatalysis is an attractive surrogate to traditional transition-metal catalysis, leveraging readily
accessible, inexpensive, and practical small molecules as catalysts. The identification of an organocatalyst with
the ability to mimic the behavior of a transition-metal catalyst forms an ideal approach; a priori, such a strategy
would be “plug and play,” invoking only a change in catalyst identity while preserving the nature of cross-coupling
partners traditionally utilized in cross-coupling chemistry. If successful, this approach would address each of the
challenges previously enumerated.
 The goal of this proposal is to design, synthesize, and develop a series of “pseudometal” organocatalysts
to facilitate a vast array of catalytic cross-coupling transformations. These catalysts are termed pseudometal to
reflect their ability to mimic the classical bond-breaking and bond-forming behavior of transition-metal catalysts.
Specifically, this research plan details the development of ortho-dithioquinones as pseudometal organocatalysts,
guided by principles of rational design, structure-activity-relationships, computational modeling, and hypothesis-
driven experimentation. Our preliminary computational results direct us to ortho-dithioquinones due to the neutral
Gibbs free energies predicted for oxidative insertion of these scaffolds into several s-bond types. In this research,
rigorous mechanistic and characterization studies will profile the key principles inherent to organocatalyst
speciation and the associated elementary steps, featuring stoichiometric studies, linear free-energy relationship
analyses, and catalytic intermediate characterization. Guided by a rich mechanistic understanding, we will
examine the synthetic capabilities of these organocatalysts through a series of cross-coupling transformations,
including examples of C–N, C–O, C–SF5, and N–CF3 bond formation. Overall, this resear...

## Key facts

- **NIH application ID:** 10888906
- **Project number:** 5F32GM151794-02
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Isabelle Leibler
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $22,922
- **Award type:** 5
- **Project period:** 2023-08-01 → 2024-11-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888906

## Citation

> US National Institutes of Health, RePORTER application 10888906, New eras of catalysis: Towards the development of pseudotransition metal organocatalysts for metal-free cross-coupling transformations (5F32GM151794-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10888906. Licensed CC0.

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