Copper(I)-catalyzed diastereo- and enantio-selective construction of optically pure exocyclic allenes

Abstract

Among about 150 identified allenic natural products, the exocyclic allenes constitute a major subclass. Substantial efforts are devoted to the construction of axially chiral allenes, however, the strategies to prepare chiral exocyclic allenes are still rare. Herein, we show an efficient strategy for the asymmetric synthesis of chiral exocyclic allenes with the simultaneous control of axial and central chirality through copper(I)-catalyzed asymmetric intramolecular reductive coupling of 1,3-enynes to cyclohexadienones. This tandem reaction exhibits good functional group compatibility and the corresponding optically pure exocyclic allenes bearing cis-hydrobenzofuran, cis-hydroindole, and cis-hydroindene frameworks, are obtained with high yields (up to 99% yield), excellent diastereoselectivities (generally >20:1 dr) and enantioselectivities (mostly >99% ee). Furthermore, a gram-scale experiment and several synthetic transformations of the chiral exocyclic allenes are also presented.

Recent advances in the metal-catalyzed asymmetric synthesis of chiral allenes

“…This transformation provided a practical and general protocol for the enantioselective construction of chiral heteroaromatic allenes, which exist widely in biologically active natural products and synthetic drugs. Later, Lin and coworkers developed a similar Cu–H catalyzed reaction to rapidly construct chiral exocyclic allenes (Scheme 3B), 13 in which the allenyl copper species 6 inserted into α,β-unsaturated ketone instead of quinoline N -oxide. The corresponding chiral exocyclic allenes possessing cis -hydrobenzofuran and cis -hydroindene moieties were obtained in high yields with excellent stereoselectivities.…”

Pd/Xu-Phos-catalyzed asymmetric elimination of fully substituted enol triflates into axially chiral trisubstituted allenes

“…1A). Great efforts have been made to develop new methodologies for the preparation of optically active allenes (15)(16)(17)(18), such as the organocatalytic (19,20), enzyme-catalytic (21,22) and metal-catalytic (23)(24)(25)(26)(27) transformations. In 2013, after an extensive screening of ∼110 chiral phosphine ligands, Frantz and co-workers (28) demonstrated the first example of synthesis of disubstituted chiral allenoates via the Pd-catalyzed asymmetric β-H elimination of vinyl palladium species with the use of the homemade chiral ligand (Fig.…”

Synthesis of tetrasubstituted allenes via a 1,4-palladium migration/carbene insertion/β-H elimination sequence

“…Allenes are ubiquitous in natural products, 1 pharmaceuticals, 2 and molecular materials. 3 Although numerous methods for the preparation of allenes have been extensively explored, 4,5 they still lag far behind the growing demand in application. 6 For instance, the synthesis of tetrasubstituted allenes remains a challenge.…”