# Mechanistic Investigations of Doubly Axially Chiral Phosphoric Acid Catalysts for the Synthesis of Enantioenriched Heterocycles

> **NIH NIH F32** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $28,650

## Abstract

Project Summary
Pharmaceutical production is driven by the development of novel chemical transformations as they can allow for
the expedient synthesis of drug molecules. Reactions that proceed through simple disconnections and which set
important stereochemical information in the presence of a chiral catalyst are particularly valuable. A plethora of
BINOL-derived phosphoric acid catalyzed reactions to form carbon-carbon bonds have been developed and
used in these contexts, however identifying the best chiral catalyst can be challenging as the optimal choice is
often substrate dependent. Since the underlying mechanisms that result in the transfer of chiral information from
the catalyst to the product are poorly understood, making informed decisions regarding catalyst design in the
development of new reactions is difficult. One particular phosphoric acid class that has received little mechanistic
study, partially due to its increased complexity, are doubly axially chiral phosphoric acids (DAP). These catalysts,
which contain a second chiral axis, have been shown to effectively catalyze intramolecular allylic substitution
reactions for the synthesis of enantioenriched heterocycles, however the optimized reaction conditions are
difficult to translate to other heterocyclic systems. The primary objective of this project is to develop a combined
experimental and computational model that explains how substitution on the DAP catalyst affects the observed
selectivity of allylic substitution reactions for the synthesis of enantioenriched heterocycles. To address this
objective, two specific aims are proposed: 1) investigate the mechanism of chiral DAP-catalyzed allylic
substitution reactions, and 2) probe DAP catalyst flexibility across a broad set of reaction classes. The DAP
catalysts will be parameterized by analyzing linear free energy relationships from correlated experimental data
and computed molecular fragments that probe for the presence of non-covalent interactions. This model will then
be used to predict a more selective catalyst that will expand the targeted reaction scope through the inclusion of
previously inaccessible substrates. A comprehensive model that can predict chiral DAP catalysts for novel
transformations will then be developed. This meta-analytical approach will incorporate the study of numerous
transformations previously reported with BINOL-derived phosphoric acids in order to effectively parameterize
the DAP scaffold to achieve better catalyst predictions. In summary, these studies determine how catalyst
flexibility and the resulting non-covalent interactions affect the stability of reaction transition states affording
highly enantioselective products, particularly those for chiral heterocycle formation. The optimization and
development of these methods will ultimately allow synthetic access to a broad range of pharmaceutical agents.

## Key facts

- **NIH application ID:** 10217207
- **Project number:** 5F32GM134613-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Julie Lyn Hofstra Wahlman
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $28,650
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217207

## Citation

> US National Institutes of Health, RePORTER application 10217207, Mechanistic Investigations of Doubly Axially Chiral Phosphoric Acid Catalysts for the Synthesis of Enantioenriched Heterocycles (5F32GM134613-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10217207. Licensed CC0.

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