# Development of Enantioselective Sm-Catalyzed Transformations

> **NIH NIH F32** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2022 · $24,828

## Abstract

Project Summary
Reductive SmIII2-mediated transformations are ubiquitous in the synthesis of biologically active natural products,
however, they require a stoichiometric quantity of SmIII2, which prohibits their utility on large-scale and impedes
the design of enantioselective variants. In principle, strategies to perform reductive SmIII2-mediated processes
with catalytic quantities of Sm could lay the foundation to overcome these limitations, but efforts have been
inhibited by a paucity of mechanistic understanding. In this project, these challenges will be addressed through
the mechanistically-guided development of asymmetric reductive Sm-catalyzed reactions. Initially, we will
translate the conditions we developed for the Sm-catalyzed reduction of ketones, which uses Mg0 as an
exogenous reductant, to electrochemical conditions. Electroanalytical techniques will provide insight into the
mechanism of the reaction and will provide a platform reaction scouting. This information will be used to develop
an electrocatalytic system for Sm-catalyzed reduction of ketones on preparative-scale. The strategies discovered
through this work will be leveraged to develop other electrochemically-driven reductive Sm-catalyzed
transformations, such as the coupling of ketones with ethyl acrylate to produce g-lactones. This scalability of this
reaction will be demonstrated using a continuous flow reactor. Next, we will introduce a diverse series of chiral
ligands into the coupling reaction between ketones with ethyl acrylate to promote the enantioselective formation
of g-lactones. Once a lead hit is identified in ligand screening, a family of analogues of this ligand will be
judiciously prepared featuring systematically altered steric, electronic, and hydrogen bonding properties. This
family of ligands will be screened in catalysis, and the resulting product enantiomeric enrichment will be
correlated to various physical organic molecular descriptors of the ligands using multivariate linear regression
analysis. This will provide unprecedented insight into what factors are important for the design of asymmetric
reductive Sm-catalyzed reactions, which will be used to guide reaction optimization and result in one of the first
reported enantioselective reductive Sm-catalyzed reactions. The practical utility of this transformation will be
demonstrated through a concise synthesis of (-)-bipinnatin J, which is a biosynthetic intermediate towards
several natural products with potent cytotoxicity properties. Overall, this work will contribute to the fundamental
understanding of reductive Sm catalysis, which will provide a robust foundation for the development of future
systems and, more broadly, facilitate the discovery and manufacturing of new drugs.

## Key facts

- **NIH application ID:** 10538344
- **Project number:** 1F32GM146439-01A1
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** David Charboneau
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $24,828
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-01-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538344

## Citation

> US National Institutes of Health, RePORTER application 10538344, Development of Enantioselective Sm-Catalyzed Transformations (1F32GM146439-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10538344. Licensed CC0.

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