Activating Imides with Triflic Acid: A General Intramolecular Aldol Condensation Strategy Toward Indolizidine, Quinolizidine, and Valmerin Alkaloids

Abstract

A simple, inexpensive, step economic, and highly modular synthetic strategy to access izidine alkaloids is described. The key step is a TfOH-promoted intramolecular aldol condensation between enol and cyclic imide moieties. This cyclization strategy can be employed within an aza-Robinson annulation framework and represents a general tool to build fused bicyclic amines. To illustrate the power of this method, we describe the preparation of (±)-coniceine, (±)-quinolizidine, (±)-tashiromine, (±)-epilupinine, and the core of (±)-valmerins Letter pubs.acs.org/OrgLett

C–H/C–C Functionalization Approach to N-Fused Heterocycles from Saturated Azacycles

“…As a part of a broad program aimed at the general preparation of N-fused bicycles, we questioned whether the seemingly straightforward addition of α-acyl saturated azacycles (e.g., 1 , Table ) to activated, electron-deficient alkenes (i.e., 2 ) could be employed for this purpose. We anticipated that under an optimal set of conditions, amphoteric molecules such as 1 could be preferentially engaged in a conjugate addition (aza-Michael addition) with 2 followed by an aldol reaction of the resulting enolate with the ketone moiety (see proposed intermediate 3 ).…”

Cyclization Strategies Using Imide Derivatives for the Synthesis of Polycyclic Nitrogen‐Containing Compounds

“…In 2020, the cyclization of enols with protonated imides was described by Jurberg, Gamba‐Sánchez, and co‐worker [56] using TfOH as a stoichiometric promoter serving presumably for both the activation of the imide carbonyl, as well as assisting in the tautomerization event unlocking the enol fragment. In this context, ketones, acetals and ketals could successfully generate enol intermediates.…”

“…A representative example of cyclization involved the TfOH‐promoted conversion of intermediate 76 to bicyclic 78 in 90 % yield (Scheme 17a). This synthetic strategy and derivations thereof could be used in the preparation of the alkaloids (±)‐coniceine, (±)‐quinolizidine, (±)‐tashiromine and (±)‐epilupinine [56] (Scheme 17b).…”

5-Aryloxazolidines as Reagents for Double Alkylation of Arenes: A Novel Synthesis of 4-Aryltetrahydroisoquinolines

“…The search and development of effective methods for the construction of hydrogenated azaheterocycles, one of the most widespread fragments of alkaloids and pharmaceuticals, is a particularly engaging research area and remains a relevant topic in organic synthesis . Recently, a large number of reports have been devoted to atom-economical approaches for the preparation of previously difficult-to-obtain nitrogen-containing heterocycles, methods for a direct CH-functionalization of the heterocyclic ring, as well as the design of new and improved known catalysts for carrying out such reactions .…”