Development of a 2-Aza-Cope-[3 + 2] Dipolar Cycloaddition Strategy for the Synthesis of Quaternary Proline Scaffolds

Abstract

A one-pot multicomponent procedure for the synthesis of highly functionalized pyrrolidine rings through a domino 2-aza-Cope-[3+2] dipolar cycloaddition sequence has been demonstrated. This protocol was found to be both high yielding and stereoselective for the endo-cycloadduct.The pyrrolidine ring represents a prevalent scaffold for many compounds of pharmaceutical interest as well as a structural element common to the Amaryllidaceae and Erythrina alkaloids. 1 The development of mild, efficient, and operationally simple methods for their construction continues to warrant interest. As chemical synthesis places an ever-increasing emphasis on concise molecular assembly, processes that rapidly assemble complex structures in a stereocontrolled fashion are highly desirable. Toward these ends, multicomponent reactions have played an important role. 2 The orchestration of two or more distinct chemical events involving multiple components permits a magnification of structural complexity in a minimal number of synthetic steps. 3 In the context of heterocyclic chemistry, strategic extensions of the 2-aza-Cope rearrangement could potentially meet these criteria. Specifically, the merging of the 2-aza-Cope rearrangement with a [3+2] dipolar cycloaddition reaction could provide new and more concise routes to a variety of pyrrolidine-containing targets.The 2-aza-Cope rearrangement affords imine or iminium products which could in principle be used directly for additional carbon-carbon bond forming events. A classic example of this strategy is well illustrated by Overman's aza-Cope-Mannich reaction (Scheme 1). 4 In this powerful variant, a charge-accelerated cationic 2-aza-Cope rearrangement affords an iminium ion having an enol moiety correctly positioned for Mannich cyclization. The utility of this process has been amply demonstrated by Overman 5 and others 6 in many elegant total syntheses. Bennett and others have used a 2-aza-Cope-iminium ion solvolysis protocol to prepare allylglycine derivatives. 7 * stephen.waters@uvm.edu . Supporting Information Available:Experimental procedures, characterization data, and NMR spectra for all new compounds. X-ray crystallographic information for 2-allyl proline 4a. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 September 3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptInspired by these advancements, we took interest in developing conceptually new unions of the 2-aza-Cope rearrangement with other carbon-carbon bond forming reactions. We first envisioned that the 2-aza-Cope rearrangement could be used to prepare azomethine ylide precursors for direct use in [3+2] dipolar cycloadditions. Such a strategy would capitalize on the considerable bond-reorganization properties of the Cope rearrangement as well as the diversity and facility of azomethine ylide cycloaddition. Condensation of a homoallylic amine with a glyoxylate ester would ...

Toward a Symphony of Reactivity: Cascades Involving Catalysis and Sigmatropic Rearrangements

“…Waters and co-workers combined a similar condensation/aza-Cope reaction with silver-mediated [3+2] cyclo-addition in a consecutive reaction trio. [102] …”

A Cascade Aza‐Cope/Aza‐Prins Cyclization Leading to Piperidine Derivatives

“…workers synthesized allylglycine derivatives from α-substituted homoallylamines through a cationic aza-Cope rearrangement and iminium ion solvolysis. [14] Waters et al prepared scaffolds of indolizidines through an aza-Cope-[3+2] dipolar cycloaddition followed by an aza-Prins cyclization using trifluoroacetic acid (TFA) and water as attacking nucleophiles to trap the intermediate carbocation [15] (Scheme 1).…”

Synthesis of Functionalized Indolizidines through Pauson–Khand Cycloaddition of 2-Allylpyrrolidines

“…Although our original experimental conditions for ylide formation employed a molar excess of AgOAc, 8 we have now observed that the process can be conducted catalytically (10 mol%) with no deleterious effect on the overall yield. Indeed, the use of Et 3 N (2.0 equiv) and AgOAc (0.1 equiv) furnished an N –metalated azomethine ylide intermediate that underwent endo -selective [3+2] dipolar cycloaddition in the presence of dipolarophiles 5a–b , providing the highly functionalized 2-allylpyrrolidines 6a–f (Table 1) as single diastereomers in good overall yields.…”

“…8 Condensation of a homoallylic amine (cf. 4 , Scheme 1) with ethyl glyoxylate affords an imine ( I ), which is positioned to undergo 2-aza-Cope rearrangement 9 to furnish an azomethine ylide precursor ( II ).…”