The detailed study of the chemistry and biology of complex natural products at a fundamental level provides insight that is key to understanding their mode of action and development of new therapeutics for treatment of various human ailments. This research program aims to develop efficient and concise total syntheses of structurally complex and biologically active natural products through the discovery, development, and application of new strategies and methodologies. In this program, biogenetic considerations provide inspiration for development of new generalizable strategies to rapidly build molecular complexity. A key feature of the planned syntheses is the development of new highly chemoselective and stereoselective transformations. Of particular interest is development of new methodologies allowing advanced stage functionalization using the inherent reactivity of intermediates. Targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, ample opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological mechanistic studies. This program will focus on synthetic studies of the rich family of dimeric diketopiperazine alkaloids. The core structures of these alkaloids are adjoined by either Csp3-alkyl (sp3-sp3) or Csp3-aryl (sp3-sp2) bond connectivity at quaternary stereocenters. The program will focus on potently bioactive epidithiodiketopiperazines, including the verticillin alkaloids, and will develop generalizable methodologies for rapid assembly and functionalization of dimeric diketopiperazines containing vicinal quaternary stereocenters connected via a Csp3-Csp3 bond. We will also study a late stage highly stereoselective oxidation-migration sequence using bisindole structures to access the Csp3-aryl (sp3-sp2) bond connectivity found in a variety of alkaloids. This program will result in synthetic samples of rare and precious compounds for structure validation and exploration of their chemistry and biology. Given the rich biological activity of diketopiperazines and epidithiodiketopiperazines under investigation, related intermediates and derivatives also hold great promise as mechanistic tools and new bioactive compounds, and thus will be subject to various tests through our collaborative activities.

Public Health Relevance

The study of the fundamental chemical and biological mechanism of action of natural products continues to play an important role in the development of new treatments for a variety of human ailments. This program aims to discover, develop, and apply new and unique strategies and methodologies for preparation of bioactive and complex natural molecules and related designed derivatives. While the immediate result is direct access to samples of extremely rare and precious compounds for structure validation, collaborative biological evaluation, and mechanistic studies, the longer term and broader impact of this program is the establishment of precedence for the application of these new chemistries to other targets and potential therapeutics both natural or rationally designed.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
Zip Code
Nelson, Brandon M; Loach, Richard P; Schiesser, Stefan et al. (2018) Concise total synthesis of (+)-asperazine A and (+)-pestalazine B. Org Biomol Chem 16:202-207
Haines, Brandon E; Nelson, Brandon M; Grandner, Jessica M et al. (2018) Mechanism of Permanganate-Promoted Dihydroxylation of Complex Diketopiperazines: Critical Roles of Counter-cation and Ion-Pairing. J Am Chem Soc 140:13375-13386
Lindovska, Petra; Movassaghi, Mohammad (2017) Concise Synthesis of (-)-Hodgkinsine, (-)-Calycosidine, (-)-Hodgkinsine B, (-)-Quadrigemine C, and (-)-Psycholeine via Convergent and Directed Modular Assembly of Cyclotryptamines. J Am Chem Soc 139:17590-17596
Bischoff, Amanda J; Nelson, Brandon M; Niemeyer, Zachary L et al. (2017) Quantitative Modeling of Bis(pyridine)silver(I) Permanganate Oxidation of Hydantoin Derivatives: Guidelines for Predicting the Site of Oxidation in Complex Substrates. J Am Chem Soc 139:15539-15547
Loach, Richard P; Fenton, Owen S; Movassaghi, Mohammad (2016) Concise Total Synthesis of (+)-Asperazine, (+)-Pestalazine A, and (+)-iso-Pestalazine A. Structure Revision of (+)-Pestalazine A. J Am Chem Soc 138:1057-64
White, Kolby L; Movassaghi, Mohammad (2016) Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives. J Am Chem Soc 138:11383-9
Lathrop, Stephen P; Pompeo, Matthew; Chang, Wen-Tau T et al. (2016) Convergent and Biomimetic Enantioselective Total Synthesis of (-)-Communesin F. J Am Chem Soc 138:7763-9
Kim, Justin; Movassaghi, Mohammad (2015) Biogenetically-inspired total synthesis of epidithiodiketopiperazines and related alkaloids. Acc Chem Res 48:1159-71
Adams, Timothy C; Payette, Joshua N; Cheah, Jaime H et al. (2015) Concise Total Synthesis of (+)-Luteoalbusins A and B. Org Lett 17:4268-71
Liu, Fan; Movassaghi, Mohammad (2015) Electrophilic Carbonyl Activation: Competing Condensative Cyclizations of Tryptamine Derivatives. Tetrahedron Lett 56:2995-3000

Showing the most recent 10 out of 22 publications