The detailed study of the chemistry and biology of complex natural products at a fundamental level provides critical insight to understanding their mode of action and enables development of new approaches for treatment of various human ailments. This research program focuses on the development of efficient and concise total chemical syntheses of structurally complex and biologically active natural products through the systematic discovery, development, and application of new synthetic strategies and methodologies. The targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, abundance of opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological studies. This program will focus on synthetic studies of the rich family of cyclotryptamine and diketopiperazine alkaloids. Of central interest is the directed, regioselective, stereoselective, and efficient union of cyclotryptamine substructures providing late-stage couplings to secure challenging linkages, including complete stereocontrol at quaternary stereogenic centers. Convergent and guided assembly of advanced fragments is complemented by application of new highly selective transformations for the rapid generation of molecular complexity. These include stereoretentive diketopiperazine hydroxylation followed by stereocontrolled sulfidation, employing a variety of new reagents and conditions developed in this program, to access the corresponding epipolythiodiketopiperazines. With this program's access to potently bioactive families of complex alkaloids and derivatives, we look for opportunities for extensive comparative analysis of groups of compounds to gain valuable insight concerning structure-activity relationships that can inform synthesis of designed derivatives to facilitate further biochemical collaborative investigations. This program will continue to provide synthetic samples of rare and precious compounds for structure validation and detailed examination of their chemistry and biology. The well recognized biological activity of this rich family of alkaloids ensure that the many related intermediates and derivatives accessed through these efforts will also behold great promise both as mechanistic tools and as new bioactive compounds, and thus they will be subject to continuous evaluation through our multidisciplinary and collaborative engagements.

Public Health Relevance

The detailed study of the fundamental chemistry and biological mechanism of action of natural products plays an important role in the development of new treatments for a variety of human ailments. This program aims to discover, develop, and apply new chemical synthesis strategies and methodologies for preparation of, and efficient access to, bioactive and complex naturally occurring molecules and designed derivatives. Whereas the immediate impact of this program is access to precious and rare samples of complex alkaloids for structure validation, collaborative biological evaluation, and mechanistic studies, the long-term and broader impact of this program is the establishment of precedence for the application of new chemistries in synthesis of other complex molecules, natural or designed, with therapeutic potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM089732-09
Application #
9660230
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-01-01
Project End
2022-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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

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