Application of diazene-directed fragment assembly to the total synthesis and stereochemical assignment of (+)-desmethyl-meso-chimonanthine and related heterodimeric alkaloids

We describe the first application of our methodology for heterodimerization via diazene fragmentation towards the total synthesis of (−)-calycanthidine, meso-chimonanthine, and (+)-desmethyl-meso-chimonanthine. Our syntheses of these alkaloids feature an improved route to C3a-aminocyclotryptamines, an enhanced method for sulfamide synthesis and oxidation, in addition to a late-stage diversification leading to the first enantioselective total synthesis of (+)-desmethyl-meso-chimonanthine and its unambiguous stereochemical assignment. This versatile strategy for directed assembly of heterodimeric cyclotryptamine alkaloids has broad implications for the controlled synthesis of higher order derivatives with related substructures.National Institute of General Medical Sciences (U.S.) (Grant GM089732)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (Postdoctoral Fellowship F32GM097776)National Science Foundation (U.S.). Center for Chemical Innovation (CHE-1205646

Electrophilic carbonyl activation: competing condensative cyclizations of tryptamine derivatives

A series of tryptamine derived bisindole substrates were subjected to electrophilic activation of the func-tional grouping at their [alpha]-nitrogen in the form of iminium ions to enable cyclization onto the sterically hindered indole substructure. Our observations regarding divergent cyclization outcomes using electronically distinct bisindole substrates are described. Surprising preference for the Friedel–Crafts alkylation reaction and evidence for an intriguing reversible spirocyclization are discussed.National Institute of General Medical Sciences (U.S.) (GM074825)National Institute of General Medical Sciences (U.S.) (GM089732)Massachusetts Institute of Technology. Undergraduate Research Opportunities ProgramHoward Hughes Medical Institute (Summer Fellowship in Chemical Biology)Novartis Undergraduate Summer Fellowshi

Dimerization of (+)-myrmicarin 215B. A potential biomimetic approach to complex myrmicarin alkaloids

The acid promoted diastereoselective dimerization of myrmicarin 215B is described. The reactivity of these sensitive alkaloids, structural assignment, and a possible mechanism for the observed dimerization is discussed. These finding raise the intriguing possibility of the synthesis of the highly sensitive myrmicarin alkaloids based on a strategy involving the direct dimerization of functional tricyclic myrmicarin derivatives

Total synthesis and study of myrmicarin alkaloids

The myrmicarins are a family of air- and temperature-sensitive alkaloids that possess unique structural features. Our concise enantioselective synthesis of the tricyclic myrmicarins enabled evaluation of a potentially biomimetic assembly of the complex members via direct dimerization of simpler structures. These studies revealed that myrmicarin 215B undergoes efficient and highly diastereoselective Brønsted acid-induced dimerization to generate a new heptacyclic structure, isomyrmicarin 430A. Mechanistic analysis demonstrated that heterodimerization between myrmicarin 215B and a conformationally restricted azafulvenium ion precursor afforded a functionalized isomyrmicarin 430A structure in a manner that was consistent with a highly efficient, non-concerted ionic process. Recent advancement in heterodimerization between tricyclic derivatives has enabled the preparation of strategically functionalized hexacyclic structures. The design and synthesis of structurally versatile dimeric compounds has greatly facilitated manipulation of these structures en route to more complex myrmicarin derivatives.Novartis (Firm) (Graduate Fellowship)National Institute of General Medical Sciences (U.S.) (GM074825

Enantioselective Total Synthesis of Tricyclic Myrmicarin Alkaloids

An enantioselective gram-scale synthesis of a key dihydroindolizine intermediate for the preparation of myrmicarin alkaloids is described. Key transformations in this convergent approach include a stereospecific palladium-catalyzed N-vinylation of a pyrrole with a vinyl triflate, a copper-catalyzed enantioselective conjugate reduction of a β-pyrrolyl enoate, and a regioselective Friedel−Crafts reaction. The synthesis of optically active and isomerically pure samples of (4aR)-myrmicarins 215A, 215B, and 217 in addition to their respective C4a-epimers is presented

Palladium-Catalyzed Synthesis of N-Vinyl Pyrroles and Indoles

A stereospecific palladium-catalyzed N-vinylation of azaheterocycles with vinyl triflates is described. Cyclic and acyclic vinyl triflates along with nonnucleophilic azaheterocycles were found to be substrates for this palladium-catalyzed synthesis of N-vinyl pyrrole and indole derivatives

Radical-mediated Dimerization and Oxidation Reactions for the Synthesis of Complex Alkaloids

The doi doesn't seem to work, but it is the correct one.Concise and general strategies for radical-based dimerization of cyclotryptamine and cyclotryptophan derivatives in addition to radical-based oxidation of structurally complex diketopiperazines are discussed. The impact of these radical-based chemistries on the rapid generation of molecular complexity is highlighted using representative examples from recent complex homodimeric alkaloid total syntheses. Additionally, a new and general strategy for radical-based directed heterodimerization of cyclotryptamine substructures via solvent-caged unsymmetrical diazene fragmentation is discussed.National Institute of General Medical Sciences (U.S.) (GM089732)Amgen Inc.Camille & Henry Dreyfus Foundatio

Total synthesis of (+)-11,11′-dideoxyverticillin A

The alkaloid (+)-11,11′-dideoxyverticillin A [(+)-1] isolated from a marine fungal species has attracted considerable attention because of its highly functionalized and stereochemically complex molecular structure. This ornate dimeric natural product is a member of a large family of epidithiodiketopiperazine alkaloids (Fig. 1), which have been known for (Chemical Equation Presented) their rich biological activity and intricate molecular architecture. The intimidating task of constructing the sterically crowded stereogenic centers and highly sensitive functionalities make these compounds elusive for total synthesis. This study, however, describes a biosynthetically inspired enantioselective first total synthesis of (+)-1 that features stereoselective and chemoselective advanced-stage tetrahydroxylation and tetrathiolation reactions. The retrosynthetic analysis of (+)-1 (Fig. 2) mimics a biosynthesis pathway connecting dimeric epidithiodiketopiperazines to common α-amino acid precursors. The total synthesis of (+)-11,11′-dideoxyverticillin A is detailed in Figure 3. A multigram amount of the dimeric diketopiperazine intermediate (+)-13 was obtained in several steps from commercially available amino acid derivative 9. The hydroxylation of (+)-13 proved to be onerous. After extensive experimentation, Py 2 AgMnO 4 was found to efficiently oxidize (+)-13 to afford tetraol (+)-14 as a single diastereomer in multigram scale. Subsequent derivatization and reduction steps yielded (+)-16, a surrogate of intermediate 6 (Fig. 2). Treatment with trithiocarbonate followed by ethanolamine furnished the desired tetrathiolation product 5, which upon KI 3 treatment finally produced the title compound (+)-1 in 62% yield as a colorless solid. The structure of (+)-1 was unambiguously established by spectroscopic and crystallographic analyses. (Chemical Equation Presented) © 2010 Data Trace Publishing Company.American Society for Engineering Education. National Defense Science and Engineering Graduate FellowshipFonds québécois de la recherche sur la nature et les technologies (Fellowship

Direct C7 Functionalization of Tryptophan. Synthesis of Methyl ( S )-2-(( tert -Butoxycarbonyl)amino)-3-(7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1 H -indol-3-yl)propanoate

National Institute of General Medical Sciences (U.S.) (GM089732)National Institute of General Medical Sciences (U.S.) (GM074825)National Science Foundation (U.S.) (CHE-1205646

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