Studies on Difficult Intramolecular Hydroaminations in the Context of Four Syntheses of Alkaloid Natural Products

Abstract

Examples of intramolecular alkene hydroaminations forming six-membered ring systems are rare, especially for systems in which the double bond is disubstituted. Such cyclizations have important synthetic relevance. Herein we report a systematic study of these cyclizations using recently developed Cope-type hydroamination methodologies. Difficult intramolecular alkene hydroaminations were used as key steps in syntheses of 2-epi-pumiliotoxin C, coniine, N-norreticuline and desbromoarborescidine A. This effort required the development of optimized hydroamination conditions to improve the efficiency of the cyclizations. Collectively, our results show that Cope-type cyclizations can be achieved on a variety of challenging substrates and proceed under similar conditions for both N-H and N-substituted hydroxylamines.

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit

“…The key step was the construction of the b-carboline core by the hydroamination of hydroxylamine 811 (Scheme 167). 259 The synthesis of rac-807 was reported. Tetracyclic intermediate 812 was prepared through the one-pot In-promoted allylation of in situ-generated iminium, followed by RCM with Grubbs' catalyst (Scheme 168).…”

Intramolecular Alkene Aminocarbonylation Using Concerted Cycloadditions of Amino‐Isocyanates

“…[5] In our efforts to develop metal-free alkene amination reactions, we have demonstrated the utility of bifunctionalr eagentsf or the formation of CÀNb onds from alkenes, alkynes and allenesu nder metal-free, thermal conditions. [6,7] In particular,h ydroxylamines provedt ob ee ffective reagents for intraand intermolecularC ope-type (concerted) alkene hydroaminations. [6] However,t he instability of hydroxylamines upon heating at approximately 100 8Cl ed to the development of related reactivityw ith otherb ifunctionalr eagents possessing increasedt hermals tability.…”

“…[6,7] In particular,h ydroxylamines provedt ob ee ffective reagents for intraand intermolecularC ope-type (concerted) alkene hydroaminations. [6] However,t he instability of hydroxylamines upon heating at approximately 100 8Cl ed to the development of related reactivityw ith otherb ifunctionalr eagents possessing increasedt hermals tability. This led to the discovery that hydrazine derivatives also engage in concerted, Cope-type hydroaminationr eactions of alkenes and alkynes.…”

Toward the Asymmetric Synthesis of Cardenolides and Related Steroidal Systems: syn-SN2′ of Organometallics with C14–C17 Vinylepoxides

“…Notably, cyanocuprates were conceived as potentially useful in this regard, albeit it was understood that related S N 2′ reactions of such nucleophiles with vinylepoxides are known to proceed in an anti-S N 2′ fashion (Figure 4A). 8,17 While we were aware of a report by Marino that formal syn-S N 2′ addition has been observed with reagents originally derived from alkyl iodides (Figure 4B), this observation was reasoned to result from a reaction mechanism proceeding by way of initial S N 2 addition of iodide to the electrophilic epoxide, followed by anti-S N 2′ addition of the organocopper species to the resulting allylic iodide. 18 Despite a lack of precedent to support generality for the desired regio-and stereoselective syn-S N 2′ reaction of cyanocuprate reagents with vinylepoxides like 13 and 14, effort was directed at investigating the viability of this type of functionalization reaction.…”

“…While we were delighted to observe the desired regio- and stereoselective functionalization of 13 by reaction with an organolithium reagent, we aimed to identify less reactive/basic nucleophiles as potentially more functional group tolerant alternatives. Notably, cyanocuprates were conceived as potentially useful in this regard, albeit it was understood that related S N 2′ reactions of such nucleophiles with vinylepoxides are known to proceed in an anti -S N 2′ fashion (Figure A). , While we were aware of a report by Marino that formal syn -S N 2′ addition has been observed with reagents originally derived from alkyl iodides (Figure B), this observation was reasoned to result from a reaction mechanism proceeding by way of initial S N 2 addition of iodide to the electrophilic epoxide, followed by anti -S N 2′ addition of the organocopper species to the resulting allylic iodide …”