Phosphine-Catalyzed Enantioselective Intramolecular [3+2] Annulations To Generate Fused Ring Systems

Abstract

Substantial progress has been described in the development of asymmetric variants of the phosphine-catalyzed intermolecular [3+2] annulation of allenes with alkenes; however, there have not been corresponding advances for the intramolecular process, which can generate a higher level of complexity (an additional ring and stereocenter(s)). In this study, we describe the application of chiral phosphepine catalysts to address this challenge, thereby providing access to useful scaffolds that are found in bioactive compounds, including diquinane and quinolin-2-one derivatives, with very good stereoselectivity. The products of the [3+2] annulation can be readily transformed into structures that are even more stereochemically rich. Mechanistic studies are consistent with β addition of the phosphepine to the allene being the turnover-limiting step of the catalytic cycle, followed by a concerted [3+2] cycloaddition to the pendant olefin.

Asymmetric Reactions Catalyzed by Chiral Tertiary Phosphines

“…Until 2015, Fu and co‐workers achieved highly enantioselective intramolecular phosphine‐catalyzed [3+2] cycloaddition reactions, delivering functionalized, fused bicyclic ring systems that bear multiple contiguous stereocenters. [ 37 ] Using chiral phosphine 120 as a catalyst, a wide range of substrates 121 underwent the intramolecular phosphine‐catalyzed [3+2] cycloaddition reaction smoothly, affording a series of diquinanes 122 in good yields with high enantioselectivies (Scheme 25), which provided an access to useful scaffolds that are found in bioactive compounds.…”

Enantioselective Construction of All‐Carbon Quaternary Stereogenic Centers by Using Phosphine Catalysis

“…Racemic examples of intramolecular [3+2] annulations of electron‐poor alkynoates or allenoates with alkenes have been reported by the groups of Krische– and Kwon, respectively. Very recently, Fu and co‐workers reported an enantioselective intramolecular [3+2] cycloaddition reaction between allenes and alkenes to create fused chiral ring scaffolds . By using BINOL‐derived phosphine catalysts P1 , P2 , or P3 , allene–alkenes 40 were smoothly transformed into compounds 41 in excellent yields and good diastereo‐ and enantioselectivities (Scheme a).…”

Chiral phosphine-mediated intramolecular [3 + 2] annulation: enhanced enantioselectivity by achiral Brønsted acid

“… 9 Very recently, Fu developed an enantioselective intramolecular [3 + 2] cycloaddition of allenes and alkenes to create fused chiral ring scaffolds. 10 In the past few years, our group has developed amino acid-based bifunctional phosphine catalysts, and demonstrated their applications in a wide range of enantioselective intermolecular annulation processes. 11 Attracted by the great potential of phosphine-catalyzed intramolecular processes for quick access to challenging chiral skeletons, we became interested in such valuable transformations.…”

“…In phosphine catalysis, however, while phosphine-mediated asymmetric intermolecular cyclizations are very common, there is only one reported enantioselective intramolecular annulation to date. 10 The paucity of this important reaction type may be due to the crowdedness of the advanced intermediates formed upon phosphine activation. This results in an inherent challenge to distinguish different transition states in a rather crowded and constrained environment.…”