Acylammonium Salts as Dienophiles in Diels–Alder/Lactonization Organocascades

Abstract

α,β-Unsaturated acylammonium salts, generated in situ from commodity acid chlorides and a chiral isothiourea organocatalyst, comprise a new and versatile family of chiral dienophiles for the venerable Diels–Alder (DA) cycloaddition. Their reactivity is unveiled through a highly diastereo- and enantioselective Diels–Alder/lactonization organocascade that generates cis- and trans-fused bicyclic γ- and δ-lactones bearing up to four contiguous stereocenters. Moreover, the first examples of DA-initiated, stereodivergent organocascades are described delivering complex scaffolds found in bioactive compounds. The origins of stereoselectivity are rationalized through computational studies. In addition, the utility of this methodology is demonstrated through a concise approach to the core structure of glaciolide and formal syntheses of fraxinellone, trisporic acids, and trisporols.

Asymmetric Organocatalysis: The Emerging Utility of α,β‐Unsaturated Acylammonium Salts

“…21 Use of O -silylated dienes bearing pendant alcohols ( e.g. 60 ) with commodity acid chlorides ( e.g.…”

Stereodivergent, Diels–Alder-initiated organocascades employing α,β-unsaturated acylammonium salts: scope, mechanism, and application

“…24 Importantly, this was the first example of a DA-initiated, stereodivergent organocascade (Fig. 1b) delivering complex and stereochemically diverse scaffolds found in bioactive compounds with excellent relative and absolute stereocontrol.…”

Utility and NMR studies of α,β-unsaturated acylammonium salts: synthesis of polycyclic dihydropyranones and a dihydropyridone

“…7 These N-heterocyclic carbene (NHC) catalyzed reactions require either a stoichiometric amount of oxidant or functionalized aldehydes or esters as starting materials and have focused primarily on acyclic 1,3-dicarbonyl compounds. 8 These limitations, coupled to our recent studies of chiral α ,β -unsaturated acylammonium salts enabling Michael-aldol-β -lactonization, 9 Michael-proton transfer-lactamization, 10 and Diels-Alder-lactonization 11 organocascades, prompted us to reinvestigate the original idea of making cyclic enol lactones from unsaturated acid derivatives through organocatalysis with achiral and chiral Lewis bases under mild conditions. 12 In particular, the use of mono-and bicyclic 1,3-dicarbonyls in these reactions have not been described and thus we focused on these substrates.…”

“…Furthermore, we also demonstrated the full potential of α,β-unsaturated acylammonium salts in enabling formation of three new bonds through Michael-aldol-lactonization 9 and Diels-Alder-lactonization organocascades. 11 Building on these studies, we sought to explore the use of cyclic 1,3-dicarbonyls and enamino ketones to access polycyclic dihydropyranones and dihydropyridinones using unsaturated acylammonium salts.…”