Enantioselective total Synthesis of the agelastatin and trigonoliimine alkaloids

Thesis (Ph. D. in Organic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2012.Vita. Cataloged from PDF version of thesis.Includes bibliographical references.I. Total Synthesis of the (-)-Agelastatin Alkaloids The pyrrole-imidazole family of marine alkaloids, derived from linear clathrodin-like precursors, constitutes a diverse array of structurally complex natural products. The bioactive agelastatins are members of this family that possess a tetracyclic molecular framework incorporating C4-C8 and C7-N12 bond connectivities. We provide a hypothesis for the formation of the unique agelastatin architecture that maximally exploits the intrinsic chemistry of plausible biosynthetic precursors. We report the concise enantioselective total syntheses of all known agelastatin alkaloids including the first total syntheses of agelastatins C, D, E, and F. Our gram-scale chemical synthesis of agelastatin A was inspired by our hypothesis for the biogenesis of the cyclopentane C-ring and required the development of new transformations including an imidazolone-forming annulation reaction and a carbohydroxylative trapping of imidazolones. II. Total Synthesis of the (-)-Trigonoliimine Alkaloids The concise and enantioselective total syntheses of (-)-trigonoliimines A, B, and C are described. Our unified strategy to all three natural products is based on asymmetric oxidation and reorganization of a single bistryptamine, a sequence of transformations with possible biogenetic relevance. We revise the absolute stereochemistry of (-)-trigonoliimines A, B, and C.by Sunkyu Han.Ph.D.in Organic Chemistr

Lithiation and electrophilic substitution of dimethyl triazones

The lithiation and electrophilic substitution of dimethyl triazones is described. Directed lithiation or tin–lithium exchange of dimethyl triazones afforded the corresponding dipole stabilized nucleophiles that were trapped with various electrophiles. Keto-triazone derivatives accessed by acylation of such nucleophiles were readily converted into the corresponding imidazolone heterocycles.National Institutes of Health (U.S.) (National Institute of General Medical Sciences (U.S.) GM074825

Transformation of (allo)securinine to (allo)norsecurinine via a molecular editing strategy

Securinega alkaloids have intrigued chemists since the isolation of securinine in 1956. This family of natural products comprises a securinane subfamily with a piperidine substructure and norsecurinane alkaloids featuring a pyrrolidine core. From a biosynthetic perspective, the piperidine moiety in securinane alkaloids derives from lysine, whereas the pyrrolidine moiety in norsecurinane natural products originates from ornithine, marking an early biogenetic divergence. Herein, we introduce a single-atom deletion strategy that enables the late-stage conversion of securinane to norsecurinane alkaloids. Notably, for the first time, this method enabled the transformation of piperidine-based (allo)securinine into pyrrolidine-based (allo)norsecurinine. Straightforward access to norsecurinine from securinine, which can be readily extracted from the plant Flueggea suffruticosa, abundant across the Korean peninsula, holds promise for synthetic studies of norsecurinine-based oligomeric securinega alkaloids

Crowdsourced mapping of unexplored target space of kinase inhibitors

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound-kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome. The IDG-DREAM Challenge carried out crowdsourced benchmarking of predictive algorithms for kinase inhibitor activities on unpublished data. This study provides a resource to compare emerging algorithms and prioritize new kinase activities to accelerate drug discovery and repurposing efforts

Concise Total Synthesis and Stereochemical Revision of all (−)-Trigonoliimines

The concise and enantioselective total syntheses of (−)-trigonoliimines A, B, and C are described. Our unified strategy to all three natural products is based on asymmetric oxidation and reorganization of a single bistryptamine, a sequence of transformations with possible biogenetic relevance. We revise the absolute stereochemistry of (−)-trigonoliimines A, B, and C.National Institute of General Medical Sciences (U.S.) (GM074825)National Science Foundation (U.S.) (CHE-0946721)Amgen Inc.DuPont (Firm

Biomimetic total synthesis of (±)-berkeleyamide D

We describe the total synthesis of (±)-berkeleyamide D using a biosynthetically inspired strategy. The spirocyclic core of berkeleyamide D was constructed via sequential epoxidations and a late-stage base-mediated cyclization of a biosynthetically relevant precursor. Our synthetic solution might be applicable to access other fungal natural products of this family. © the Partner Organisations 20171221sciescopu

An Accelerated Intermolecular Rauhut–Currier Reaction Enables the Total Synthesis of (−)-Flueggenine C

The first total synthesis of dimeric securinega alkaloid (−)-flueggenine C is completed via an accelerated intermolecular Rauhut–Currier (RC) reaction. Despite the numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas whose monomeric units are connected by a putative enzymatic RC reaction has not been reported to date. We have found that installation of a nucleophilic functional group at the γ-position of an enone greatly accelerates the rate of the diastereoselective intermolecular RC reaction. This discovery enabled an efficient and selective formation of the dimeric intermediate which was further transformed to (−)-flueggenine C

Syntheses of Dimeric Securinega Alkaloids

The isolation of flueggenines A and B by Yue and co-workers in 2006 has triggered a burst of isolation reports of dimeric and oligomeric securinega alkaloid natural products. The compelling molecular structures of these compounds with various modes of connection between monomeric securinega units have posed intriguing challenges to the synthetic organic community. Herein, we have categorized high-order securinega alkaloids based on their biosynthetic mode of dimerization or oligomerization. We then have compiled all reported syntheses of dimeric securinega alkaloids based on our classification. 1 Introduction 2 Categorization of High-Order Securinega Alkaloid Natural Products 3 Syntheses of Type I Dimeric Securinega Alkaloids 4 Syntheses of Type II Dimeric Securinega Alkaloids 5 Synthesis of Type III Dimeric Securinega Alkaloid 6 Conclusio © Georg Thieme Verlag Stuttgart101sciescopu

Academic research inspired design of an expository organic chemistry lab course

In this paper, we present fortified instructional methods that contributed in improving students' interest toward the expository organic chemistry laboratory course. Reformed TA (Teaching assistant) training and allocation method, a thorough course orientation session, text-light/graphics-heavy results PPT reports, and journal article templated-term papers have improved students' satisfaction in the organic chemistry laboratory course. These methods could be implemented while maintaining the traditional organic chemistry laboratory instruction styles and hence could be broadly applicable. © 2018 Korean Chemical Society. All rights reserved11scopuskc

Asymmetric Catalysis at a Distance: Catalytic, Site-Selective Phosphorylation of Teicoplanin

We report three distinct, peptide-based catalysts that enable site-selective phosphorylation of three distinct hydroxyl groups within the complex glycopeptide antibiotic teicoplanin A₂-2. Two of the catalysts are based on a design that capitalizes on a catalyst–substrate interaction that mimics the biological mechanism of action for teicoplanin. These catalysts are based on a dXaa–dXaa peptide motif that is known to target the teicoplanin structure in a specific manner. The third was identified through evaluation of a set of catalysts that had been developed for historically distinct projects. Each catalyst contains additional functionality designed to dispose a catalytic moiety (a nucleophilic alkylimidazole) at a different region of the glycopeptide structure. A combination of mass spectrometry and 2D-NMR spectroscopy allowed structural assignment of the distinct phosphorylated teicoplanin derivatives. Mechanistic studies are also reported that support the hypotheses that led to the discovery of the catalysts. In this manner, small molecule catalysts have been achieved that allow rational, catalytic control over reactions at sites that are separated by 11.6, 16.5, and nearly 17.7 Å, based on the X-ray crystal structure of teicoplanin A₂-2. Finally, we report the biological activity of the new phosphorylated teicoplanin analogs and compare the results to the natural product itself