About

Tom R. Pettus is a professor in the Department of Chemistry & Biochemistry at the University of California, Santa Barbara. His specialization includes Organic & Bioorganic Molecular Design & Synthesis, Biomedical Sciences, and Biology-Inspired Chemistry & Physics. Dr. Pettus obtained his Ph.D. in 1996 from the University of Rochester, working with Professor R. H. Schlessinger, after completing his undergraduate research with Professor Tomás Hudlicky at VPI. He conducted postdoctoral research as an NSF Postdoctoral Fellow at Columbia University with Professor S. J. Danishefsky before joining UCSB in 1998. His research group focuses on developing new methods and strategies for constructing architecturally complex tetramic acid derivatives, which are significant due to their presence in natural products with diverse biological activities, including antimicrobial, antiviral, and antifungal properties. His work aims to improve the efficiency of synthesizing these compounds, especially in enantioselective manners, with ongoing projects involving the total synthesis of natural products like tetrapetalone A. Dr. Pettus has been recognized with awards such as the Research Innovation Award from Research Corporation and an NSF-Career Grant. His research contributes to the understanding and development of synthetic methods for complex heterocyclic architectures, with implications for pharmaceutical and biological applications.

Research topics

• Chemistry
• Combinatorial chemistry
• Stereochemistry
• Organic chemistry
• Materials science

Selected publications

• Allosteric Inhibitors of Cell-Cycle-Regulated Methyltransferase for Novel Antibiotic Development

  ACS Omega · 2025-04-09

  articleOpen accessCorresponding

  Cell-cycle-regulated methyltransferase (CcrM) plays a crucial role in regulating important cellular processes that are essential for proper cell division and growth; disruptions of these processes can attenuate the bacteria's viability. Notably, CcrM homologs are present across a set of diverse human pathogens, suggesting that selective inhibition of CcrM over human DNA methyltransferases (DNMT's) could offer a new strategy for combating human bacterial pathogens, leading to the development of novel antibiotics. Herein, we report the screening of two open-access chemical libraries-the National Cancer Institute Developmental Therapeutic Program Diversity Set VII and Medicines for Malaria Venture Global Health Priority Box-and identified four structurally diverse inhibitors of CcrM. Among these, two inhibitors displayed both micromolar affinity and high selectivity for CcrM over human DNA methyltransferase 3A, highlighting their potential as leads for a new class of antibiotics.

  PublisherDOI

• Structural Investigations of Phthalazinone Derivatives as Allosteric Inhibitors of Human DNA Methyltransferase 3A

  ACS Medicinal Chemistry Letters · 2024-04-08 · 3 citations

  articleOpen accessCorresponding

  The development of new therapeutics targeting enzymes involved in epigenetic pathways such as histone modification and DNA methylation has received a lot of attention, particularly for targeting diverse cancers. Unfortunately, irreversible nucleoside inhibitors (azacytidine and decitabine) have proven highly cytotoxic, and competitive inhibitors are also problematic. This work describes synthetic and structural investigations of a new class of allosteric DNA methyltransferase 3A (DNMT3A) inhibitors, leading to the identification of several critical pharmacophores in the lead structure. Specifically, we find that the tetrazole and phthalazinone moieties are indispensable for the inhibitory activity of DNMT3A and elucidate other modifiable regions in the lead compound.

  PublisherOA PDFDOI

• Synthesis of Naturally Racemic Marilines B & C through Multicomponent Reactions Involving ortho-Quinone Methides and Various Nitrogen Nucleophiles

  Synthesis · 2023-06-28 · 1 citations

  articleOpen access1st authorCorresponding

  Abstract Herein, we report the first total synthesis of (±)-marilines B and C, as well as a failed approach to (±)-mariline A, by using our recently developed multicomponent reaction method, which involves the interception of ortho-quinone methides with various nitrogen nucleophiles to allow easy assembly of various benzylic amine cores with diverse substituents.

  PublisherOA PDFDOI

• Nucleophilic Addition of 4,5-Dihydrooxazole Derivatives to Base Generated <i>o</i>-Quinone Methides: A Four-Component Reaction

  The Journal of Organic Chemistry · 2023-01-31 · 2 citations

  articleOpen accessSenior authorCorresponding

  A novel method for joining four components together in a single pot leading to an assortment of N-amino-benzylated phenols is described. The method involves the addition of different Grignard reagents to various o-OBoc salicylaldehydes in the presence of assorted 4,5-dihydrooxazoles, followed by aqueous workup. Seventeen examples are presented with varied (-R, -R′ -R″, -R‴, -R⁗, and Cn) substituents.

  PublisherOA PDFDOI

• Strategies for ortho-tert-Butylation of Phenols and their Analogues

  Synlett · 2022-01-28

  articleOpen access1st authorCorresponding

  Abstract A new general process for constructing ortho-tert-butyl phenols is presented within the context of other known methods. All are briefly evaluated with regards to regioselectivity, efficiency, and functional group tolerance. In addition, we present an assortment of tert-butyl substrates accessed through o-QM chemistry. Our conclusion is that the o-QM process provides greater yields, flexibility, and generality than most other known methods for delivering ortho-tert-buytlated phenols and their derivatives. 1 Introduction 2 Friedel–Crafts Alkylation 3 Addition of t-Bu– or t-Bu• to Carbonyl Compounds 4 ipso-SNAr Reactions of Aryl Methoxy and tert-Butylsulfoxide Moieties 5 Metal-Mediated Coupling of Aryl Bromides 6 Applications of o-Quinone Methides (o-QMs) 7 Conclusion

  PublisherOA PDFDOI

• Tetrapetalones ruminations, trials and tribulations

  Strategies and tactics in organic synthesis · 2021-01-01

  book-chapterSenior authorCorresponding
  PublisherDOI

• Nucleophilic Imines and Electrophilic <i>o</i>-Quinone Methides, a Three-Component Assembly of Assorted 3,4-Dihydro-2<i>H</i>-1,3-benzoxazines

  Organic Letters · 2019-09-18 · 8 citations

  articleSenior authorCorresponding

  A one-pot method for joining three separate components leading to an assortment of N-substituted 3,4-dihydro-2H-1,3-benzoxazines is described. The method involves the addition of a Grignard reagent to an o-OBoc salicylaldehyde in the presence of an imine. With a variety of components, 15 examples are presented, including the diastereoselective incorporation of chiral imines.

  PublisherDOI

• A Biomimetic Synthesis of des-Hydroxy Paecilospirone

  Synlett · 2018-05-09 · 7 citations

  articleOpen access1st authorCorresponding

  The carbon framework of des-hydroxy paecilospirone was rapidly synthesized using a biomimetic approach whereby an enol ether and an ortho-quinone methide (o-QM), each derived from the same lactone, were combined to arrive at the complete carbon skeleton of paecilospirone.

  PublisherOA PDFDOI

• Synthetic Studies toward the Tetrapetalones: Diastereoselective Construction of a Putative Intermediate

  Organic Letters · 2018-01-30 · 14 citations

  articleSenior author

  A strategy toward tetrapetalones was explored including a site-selective ethylenation of the silyl enol ether A to afford a quaternary stereocenter that serves in a stereogenic capacity. Regio- and diastereoselective reactions were observed in conjunction with the oxidative formation of cation B, which included subsequent selective formation of either carbon-oxygen or carbon-carbon bonds at the δ or ζ position on the seven-membered ring. The fourth ring was formed using a Stetter reaction.

  PublisherDOI

• ChemInform Abstract: A General Diastereoselective Catalytic Vinylogous Aldol Reaction Among Tetramic Acid‐Derived Pyrroles.

  ChemInform · 2015-02-19

  articleSenior author

  Abstract The title process proceeds with good to excellent syn selectivity to provide the corresponding aldol products.

  PublisherDOI

Recent grants

• NIH Grant R01GM064831

  NIH · $2.4M · 2015

• CAREER: New Applications for Ortho-Quinone Methides in Organic Synthesis

  NSF · $463k · 2002–2007

• Organic Synthesis with Quinone Methides and their Adducts

  NSF · $396k · 2008–2012

Frequent coauthors

• C. Selenski

  28 shared

• Xiaotao Chen

  University of Science and Technology of China

  20 shared

• Samuel J. Danishefsky

  Kettering University

  19 shared

• Wen‐Ju Bai

  AbbVie (United States)

  17 shared

• Clare E. Gutteridge

  United States Naval Academy

  13 shared

• Samit K. Bhattacharya

  Pfizer (United States)

  12 shared

• Ryan W. Van De Water

  University of California, Santa Barbara

  12 shared

• Yaodong Huang

  Shenzhen University

  11 shared

Labs

• Pettus GroupPI

Education

• Ph.D., Chemistry

  University of Rochester

  1996

Awards & honors

• Research Innovation Award from Research Corporation
• NSF CAREER Grant