Project Summary/Abstract
Natural products and derivatives are a significant potential source of new drug candidates due to their
high complexity and biological activity. However, chemical synthesis is often too time and resource-intensive to
enable timely development of natural product derivatives as drugs. In contrast, nature has an incredible
proficiency for the synthesis of complex chemical structures. Many organisms have evolved powerful enzymes
that have been used by chemists to produce natural products cost-effectively and in large quantities via
fermentation. However, it remains a significant challenge to modify the structure of natural products to improve
pharmacokinetic properties and increase efficacy. This proposal seeks to develop multifunctional catalysts that
mimic the synthetic efficiency of enzymes and benefit from the versatility of chemical synthesis. To accomplish
this, we will use structurally well-defined helical peptides to scaffold multiple catalysts (e.g. organocatalysts,
transition metals, Lewis acids) in close proximity to enable enzyme-like catalysis. Preliminary data from our
laboratory confirm that helical peptides can preorganize multiple catalysts in such a way to facilitate proximity-
accelerated reactivity and selectivity based on the binding of multiple substrates. In this proposal, we will first
optimize the efficiency of our enzyme-like catalysts to maximize the enhanced reactivity and selectivity already
observed to levels that approach the efficiency of natural enzymes. These efforts will be guided by predictive
computational models developed in our group. We will then capitalize on these proximity effects to rationally
design multifunctional catalysts and multi-catalyst systems that achieve unprecedented reactivity and enable
bond constructions that cannot be performed with traditional catalysts. We will also develop multifunctional
catalysts that overcome inherent reaction selectivity by preorganizing reacting partners to achieve novel
selectivity (regioselectivity, enantioselectivity). These efforts will enable new reactions that streamline the
synthetic process, improve access to complex molecules for drug discovery, and enable cost-effective
development of new medicines. The use of helix-templated catalysts will enable new synthetic strategies based
on the ability of the catalysts to bind and activate intermediates in close proximity, leading to lower step counts
in synthesis. By doing so, this project has the potential to greatly affect overall human health by advancing drug
discovery and enabling cost-effective production of new pharmaceuticals. The interdisciplinary research
proposed herein will enable significant innovation in synthetic chemistry, de novo enzyme design, and drug
discovery, and when successful, will have a broad impact in the areas of catalysis, synthetic design, and
medicine.