Enantioselective Synthesis of Chiral Cyclobutenes Enabled by Brønsted Acid-Catalyzed Isomerization of BCBs

Abstract

Chiral cyclobutene units are commonly found in natural products and biologically active molecules. Transition-metal-catalysis has been extensively used in asymmetric synthesis of such structures, while organocatalytic approaches remain elusive. In this study, bicyclo[1.1.0]butanes are involved in enantioselective transformation for the first time to offer a highly efficient route toward cyclobutenes with good regio- and enantiocontrol. The utilization of N-triflyl phosphoramide as a chiral Brønsted acid promoter enables this isomerization process to proceed under mild conditions with low catalyst loading as well as good functional group compatibility. The resulting chiral cyclobutenes could serve as platform molecules for downstream manipulations with excellent reservation of stereochemical integrity, demonstrating the synthetic practicality of the developed method. Control experiments have also been performed to verify the formation of a key carbocation intermediate at the benzylic position.

Stereoselective Alder-Ene Reactions of Bicyclo[1.1.0]butanes: Facile Synthesis of Cyclopropyl- and Aryl-Substituted Cyclobutenes

“…In terms of further chemistry, related cyclobutenes have recently been shown to be suitable substrates for (3 + 2) and (2 + 1) cycloaddition reactions to form rigid cyclobutane-fused ring systems. 27 As an alternative to additional ring formation, we were able to demonstrate successful cyclobutene ring cleavage via ozonolysis of the double bond in 3e (Figure 5), which afforded the complex cyclopropane-containing product 7 in 74% yield. Featuring three different carbonyl environments, this ketoaldehyde would be expected to undergo a variety of other chemistries toward stereochemically rich carbon backbones.…”

“…The products of these ene reactions are rich in functionality and could be of use in other settings such as medicinal chemistry research, where highly substituted small ring systems are of importance. In terms of further chemistry, related cyclobutenes have recently been shown to be suitable substrates for (3 + 2) and (2 + 1) cycloaddition reactions to form rigid cyclobutane-fused ring systems . As an alternative to additional ring formation, we were able to demonstrate successful cyclobutene ring cleavage via ozonolysis of the double bond in 3e (Figure ), which afforded the complex cyclopropane-containing product 7 in 74% yield.…”

Recent Advances in Asymmetric Synthesis of Chiral Cyclobutenes

“…More recently, Tan, Chen and coworkers reported a chiral Brønsted acid-catalyzed isomerization of bicyclo[1.1.0]butanes 211 for the enantioselective synthesis of chiral cyclobutenes 212 (Scheme 37, top). [50] A bunch of bicyclo[1.1.0]butanes embedding with various functional entities could be smoothly transformed into the desired products. Nonetheless, the strong electron-withdrawing substituents are not compatible under the standard reaction conditions.…”

Substituent Effects on the Equilibria between Cyclopropylcarbinyl, Bicyclobutonium, Homoallyl, and Cyclobutyl Cations

“…Recently, Anderson and Duarte reported on the acid-mediated rearrangement of bicyclobutane amides IX , forming cyclopropylcarbinyl or cyclobutane products X or XI , both in good diastereoselectivity, depending on slight changes in substitution on the cation XII . The electrophilic opening of strained bicyclobutanes, which generate BCB/CPC/CB cations, , have recently garnered a lot of attention for the formation of cyclobutanes and cyclobutenes. − …”