# Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2024 · $382,556

## Abstract

PROJECT SUMMARY/ABSTRACT
Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions
 Our MIRA-supported research program encompasses synthetic, mechanistic, and structural organic chem-
istry. We address unresolved contemporary problems through studies that lead to i) new ways of deducing the
structures of novel chemical entities, often through innovative use of NMR methodologies, ii) new insights
about how chemical reactions, including spontaneous biosynthetic transformations, proceed, and iii) new ways
to make molecules that have structural features of interest to researchers pursuing targets with promising bio-
logical properties. We will capitalize on recent accomplishments and launch new efforts as follows.
 I. Natural Products Chemistry
 A. We remain interested in unraveling key steps in the biosynthesis of natural products that proceed in
the absence of enzymatic catalysis—that is, spontaneously. Two specific hypotheses related to the origin of
the unique skeleton of ottelione A drive current work: i) an unprecedented, low-barrier Cope rearrangement
fashions the strange, dearomatized 4-methylenecyclohexenone present in this secondary metabolite and ii) a
simple, achiral diarylheptanoid is oxidatively transformed into the strained and preorganized Cope substrate.
The engagement of an outstanding collaborator to use genome mapping approaches will be of great benefit.
 B. We frequently engage in natural product structure determination studies and the development of
methodologies of value to those who do the same. These studies have had impact extending well beyond the
specific questions that we address. Our record in doing this is strong. One notable example teaches methodol-
ogy for calculation of chemical shifts to the experimentalist who may be a novice computationalist. Our ap-
proach was the same as that used in the newest developments of probabilistic methods for comparison of
computed vs. experimental NMR chemical shifts to validate structure assignments (DP4, DP4+, DP4-AI, DP5).
We find a gap in that some communities have yet to embrace these approaches. We propose to evaluate the
effectiveness (and limitations) of these methods for structural assessment of various cyclic peptides and then
to communicate, advertise if you will, these outcomes to benefit future structural studies by peptide chemists.
 II. HDDA-Benzyne Chemistry
 Our discovery of the broad scope of the hexadehydro-Diels–Alder (HDDA) reaction is both exciting and en-
abling. This work has advanced significantly since the onset of our MIRA funding four years ago. The opportu-
nities in this arena show no sign of abating. To the contrary, it seems that every month or so a coworker arrives
at my doorstep with yet another new result that elicits from me something to the effect of “Wow, HDDA-
benzynes will also do that!” Myriad new directions are presented in pages 4–6 of the Research Strategy. Many
will lead to products containing a greater preponderance of h...

## Key facts

- **NIH application ID:** 10893321
- **Project number:** 5R35GM127097-07
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** THOMAS R. HOYE
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $382,556
- **Award type:** 5
- **Project period:** 2018-04-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893321

## Citation

> US National Institutes of Health, RePORTER application 10893321, Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions (5R35GM127097-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10893321. Licensed CC0.

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