Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies

Abstract

Chiral molecules with multiple stereocenters are widely present in natural products and pharmaceuticals, whose absolute and relative configurations are both critically important for their physiological activities. In spite of the fact that a series of ingenious strategies have been developed for asymmetric diastereodivergent catalysis, most of these methods are limited to the divergent construction of point chirality. Here we report an enantioselective and diastereodivergent synthesis of trisubstituted allenes by asymmetric additions of oxazolones to activated 1,3-enynes enabled by chiral phosphoric acid (CPA) catalysis, where the divergence of the allenic axial stereogenicity is realized by modifications of CPA catalysts. Density functional theory (DFT) calculations are performed to elucidate the origin of diastereodivergence by the stacking- and stagger-form in the transition state (TS) of allene formation step, as well as to disclose a Münchnone-type activation mode of oxazolones under Brønsted acid catalysis.

Mechanism and Origin of Enantioselectivity in Bifunctional Squaramide‐Catalyzed α‐Thiolation of Azlactones

“…[16][17][18] This kind of activation mode has been proposed as the most plausible mechanism in recent studies involving azlactone ring transformations and has been attracting great interest in the literature. [19,20] Secondary interactions between the squaramide and the succinimide groups are also present in this proposal.…”

Recent Advances in Organocatalytic Enantioselective Synthesis of Axially Chiral Allenes

“…With the aid of chiral phosphoric acid, Yang and co‐works reported an asymmetric additions of oxazolones 36 to 1,3‐enynes 35 for enantioselective and diastereodivergent synthesis of trisubstituted allenes 37 / 38 (Scheme 12). [21] The divergence of the allenic axial stereogenicity was controlled by organocatalysts, which was elucidated by density functional theory (DFT) calculations.…”

Asymmetric Organocatalysis of Activated Alkynes and Enynes

“…Yang, Peng, and co-workers developed an organocatalyzed strategy to provide trisubstituted axially chiral allenes 120 through conjugate addition of oxazolones 118 to the activated 1,3-enynes (Scheme 35). [60] Interestingly, a stereodivergent pro Jørgensen and co-workers developed a protocol to furnish axially chiral functionalized tri-substituted allenes 123 by employing α-alkynyl-α,β-enones 117 via chiral enamine or dienamine intermediates (Scheme 36). [61] The delivered enantioenriched products 123 contain two additional stereogenic centers in addition to the axial chirality.…”

“…Yang, Peng, and co‐workers developed an organocatalyzed strategy to provide trisubstituted axially chiral allenes 120 through conjugate addition of oxazolones 118 to the activated 1,3‐enynes (Scheme 35). [60] Interestingly, a stereodivergent protocol was established by employing two different chiral phosphoric acid catalysts ( 46 d and 46 e ) via Münchnone‐type transition state. The diastereodivergent allenic products were obtained in good yields and excellent stereoselectivity (38–78% yield, 89–99% ee, and 3 : 1–>25 : 1 dr).…”