Stereoselective Addition to N-Activated Pyridines James A. Bull,‡ James J. Mousseau, Guillaume Pelletier,† and Andre ́ B. Charette*,† †Department of Chemistry, Universite ́ de Montreál, P.O. Box 6128, Station Downtown, Montreál, Queb́ec, Canada H3C 3J7 ‡Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K. Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition to N-Activated Pyridines

Computational studies on carboxylate-assisted C–H activation and functionalization at group 8–10 transition metal centers are reviewed This Review is organized by metal and will cover work published from late 2009 until mid-2016 A brief overview of computational work prior to 2010 is also provided, and this outlines the understanding of carboxylate-assisted C–H activation in terms of the “ambiphilic metal–ligand assistance” (AMLA) and “concerted metalation deprotonation” (CMD) concepts Computational studies are then surveyed in terms of the nature of the C–H bond being activated (C(sp2)–H or C(sp3)–H), the nature of the process involved (intramolecular with a directing group or intermolecular), and the context (stoichiometric C–H activation or within a variety of catalytic processes) This Review aims to emphasize the connection between computation and experiment and to highlight the contribution of computational chemistry to our understanding of catalytic C–H functionalization based on carboxylate-ass

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Computational Studies of Carboxylate-Assisted C-H Activation and Functionalization at Group 8-10 Transition Metal Centers

Camptothecin: current perspectives.

Recent developments in the chemistry of dihydropyridines

The Pummerer Reaction: Methodology and Strategy for the Synthesis of Heterocyclic Compounds

An indole-templated ring-closing metathesis or a 2-indolylacyl radical cyclization constitute the central steps of two alternative approaches developed to assemble the tricyclic ABC substructure of the indole alkaloid apparicine. From this key intermediate, an intramolecular vinyl halide Heck reaction accomplished the closure of the strained 1-azabicyclo[4.2.2]decane framework of the alkaloid with concomitant incorporation of the exocyclic alkylidene substituents.

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Total synthesis of the bridged indole alkaloid apparicine.

Several 4-substituted dihydropyridones or 2-pyridones have been prepared by nucleophilic addition of alpha-(methylsulfanyl)ester enolates to N-alkyl-2-fluoropyridinium salts, followed by acid hydrolysis or oxidation with concomitant hydrolysis, of the intermediate 2-fluoro-1,4-dihydropyridine adducts, respectively Addition of the enolate derived from isopropyl alpha-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoropyridinium triflate 21 followed by DDQ treatment gave pyridone 29, from which (+/-)-20-deoxycamptothecin (31), a known precursor of camptothecin, was synthesized by a radical cyclization-desulfurization, with subsequent elaboration of the lactone E ring by chemoselective reduction A similar sequence starting from the enolate of a chiral 2-hydroxybutyric acid derivative (33) provides access to natural (+)-camptothecin (37)

Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: total synthesis of (+/-)-20-deoxycamptothecin and (+)-camptothecin.

The addition of enolates derived from indole-3-acetic esters 1−3 to pyridinium salts 4, 23, and 24, followed by acid cyclization of the resulting 1,4-dihydropyridines, leads to tetrahydro-1,5-methanoazocino[3,4-b]indoles 5−7, 25−27, which have been subsequently elaborated into 4E-ethylidene(or 4α-ethyl)-hexahydro-1,5-methanoazocino[3,4-b]indoles. Closure of the six-membered C ring of akuammiline alkaloids by formation of C-6/C-7 bond from appropriately N(b)-substituted derivatives of these tetracyclic ABDE substructures has been extensively investigated. In the N-unsubstituted indole series, both cyclization of thionium ions generated either by Pummerer reaction from sulfoxide 16 or by DMTSF treatment of dithioacetal 36 and photocyclization of chloroacetamide 47 occur upon the indole nitrogen to give pentacycles 18, 38, and 49, respectively. When the indole nitrogen is blocked by a substituent, the thionium ions derived from sulfoxides 17 and 43 and dithioacetals 37 and 44 do not cyclize and lead to diffe...

Synthetic Efforts toward Akuammiline Alkaloids from Tetracyclic 6,7-Seco Derivatives

The first total synthesis of (±)-apparicine

A short route to tetracyclic ring substructures of C-mavacurine, Strychnos, and akuammiline-type alkaloids, based on the addition of methyl 1-, 2-, or 3-indoleacetate anions to N-alkylpyridinium salts followed by acid cyclization of the resultant 1,4-dihydropyridines, is reported. Further stereoselective elaboration of the C-20 (E)-ethylidene substituent results in the synthesis of the indole alkaloid vinoxine and of 4-ethylidene-hexahydro-1,5-methanoazocino [4,3-b]- and -[3,4-b] indoles

Ester Zulaica

Papers

Total synthesis of the bridged indole alkaloid apparicine.

Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: total synthesis of (+/-)-20-deoxycamptothecin and (+)-camptothecin.

Synthetic Efforts toward Akuammiline Alkaloids from Tetracyclic 6,7-Seco Derivatives

The first total synthesis of (±)-apparicine

General method for the synthesis of bridged indole alkaloids. Nucleophilic addition of indoleacetic ester enolates to N-alkylpyridinium salts