Biphenyl‐Derived Phosphepines as Chiral Nucleophilic Catalysts: Enantioselective [4+1] Annulations To Form Functionalized Cyclopentenes

Abstract

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.

Catalyst-controlled regioselectivity in phosphine catalysis: the synthesis of spirocyclic benzofuranones via regiodivergent [3 + 2] annulations of aurones and an allenoate

“…The past decade has witnessed the blossoming of enantioselective nucleophilic phosphine catalysis. 1 Among the wide range of phosphine-mediated asymmetric processes, phosphine-catalyzed annulations 2 – 4 are arguably the most important reactions in synthetic organic chemistry. Ever since Lu’s seminal discovery of the phosphine-catalyzed [3 + 2] annulation of electron-deficient allenes with activated olefins in 1995, 2 a this powerful mode of cyclization has attracted enormous attention from synthetic organic chemists and has now become a common method for the construction of 5-membered ring systems.…”

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

“…Shortly after our report, the Fu group reported another enantioselective [4+1] annulation of β′‐acetate allenoate . They chose α‐cyanocarbonyl compounds 46 as the dinucleophilic partner for the reaction and the carbonyl components could be ketones, amides, or esters.…”

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

“… 1 Allenes are the most commonly investigated substrates in phosphine catalysis, due to their high and versatile reactivities, as well as their ready synthetic accessibility. 2 Since Lu’s pioneering report on phosphine-catalyzed [3 + 2] cyclization of allenoates with activated alkenes in 1995, 3 a wide variety of asymmetric intermolecular annulation processes between allenes and activated alkenes have been developed, such as [3 + 2], 4 [4 + 2], 5 and [4 + 1] 6 annulations, among others. 7 However, phosphine-catalyzed intramolecular annulations are very rare.…”