Through the design and synthesis of a new chiral phosphepine, the first catalytic asymmetric method for the [3+2] cycloaddition of allenes with olefins has been developed that generates cyclopentenes that bear nitrogen-, phosphorus-, oxygen-, and sulfur-substituted quaternary stereocenters. A wide array of racemic γ-substituted allenes can be employed in this stereoconvergent process, which occurs with good enantioselectivity, diastereoselectivity, regioselectivity, and yield. Mechanistic studies, including a unique observation of a (modest) kinetic resolution of a racemic allene, are consistent with addition of the phosphepine to the allene being the turnover-limiting step of the catalytic cycle.
Due to the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. In this report, we introduce a new family of chiral nucleophilic catalysts, biphenyl-derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation first described by Tong. A range of one-carbon coupling partners can be employed, thereby generating cyclopentenes that bear a fully substituted stereocenter (either all-carbon or heteroatom-substituted (sulfur and phosphorus)). Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four-carbon coupling partner is not the turnover-limiting step of the catalytic cycle.
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.
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