Asymmetric Transfer Hydrogenation of Cyclobutenediones

Abstract

Four-membered carbocycles are fundamental substructures in bioactive molecules and approved drugs and serve as irreplaceable building blocks in organic synthesis. However, developing efficient protocols furnishing diversified four-membered ring compounds in a highly regio-, diastereo-, and enantioselective fashion remains challenging but very desirable. Here, we report the unprecedented asymmetric transfer hydrogenation of cyclobutenediones. The reaction can selectively afford three types of four-membered products in high yields with high stereoselectivities, and the highly functionalized products enable a series of further transformations to form more diversified four-membered compounds. Asymmetric synthesis of di-, tri-, and tetrasubstituted bioactive molecules has also been achieved. Systematic mechanistic studies and theoretical calculations have revealed the origin of the regioselectivity, the key hydrogenation transition state models, and the sequence of the double and triple hydrogenation processes. The work provides a new choice for the catalytic asymmetric synthesis of cyclobutanes and related structures and demonstrates the robustness of asymmetric transfer hydrogenation in the accurate selectivity control of highly functionalized substrates.

Catalytic Asymmetric Transfer Hydrogenation of Acylboronates: BMIDA as the Privileged Directing Group

“…As our continued interest in addressing challenging research topics in the field of ATH and disclosing the hidden secrets associated with these studies, herein, we report for the first time the ATH of N -methyliminodiacetyl (MIDA) acylboronates (Scheme d). The reaction proceeds efficiently under mild conditions to afford a large variety of α-hydroxyboronates with excellent enantioselectivities.…”

Regio- and Stereoselective Transfer Hydrogenation of Aryloxy Group-Substituted Unsymmetrical 1,2-Diketones: Synthetic Applications and Mechanistic Studies

“…On the other hand, asymmetric transfer hydrogenation (ATH) of ketones has been a longstanding research focus in both academic communities and the pharmaceutical industry, , but the ATH of unsymmetrical 1,2-diketones is still an underdeveloped territory, and its huge potential remains to be released . To address all the above issues, we initiated a program offering a systematic solution to the asymmetric synthesis of all three of the above types of bioactive molecules using the protocol of ATH on unsymmetrical 1,2-diketones (Scheme b, eqs 5 and 6).…”