High‐Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates

Abstract

Cyclobutane rings are important in medicinal chemistry, yet few enantioselective methods exist to access this scaffold. In particular, cyclobutylboronates are receiving increasing attention in the literature due to the synthetic versatility of alkylboronic esters and the increasing role of boronic acids in drug discovery. Herein, a conjugate borylation of α‐alkyl,β‐aryl/alkyl cyclobutenones is reported leading to the first synthesis of enantioenriched tertiary cyclobutylboronates. Cyclobutanones with two stereogenic centers are obtained in good to high yield, with high enantioselectivity and diastereoselectivity. Vital to this advance are the development of a novel approach to α,β unsymmetrically disubstituted cyclobutenone substrates and the use of a high‐throughput chiral ligand screening platform. The synthetic utility of both the boronic ester and ketone functionalities is displayed, with remarkable chemoselectivity for either group being possible in this small ring scaffold.

Enantioselective Functionalization of Prochiral Cyclobutanones and Cyclobutenones

“…Hall and co-workers also reported an enantioselective conjugate borylation of cyclobutenones, enabled by highthrough ligand screening (Scheme 14). 33 Under the catalysis of Cu(MeCN) 4 PF 6 and S-BDPP, the reaction of cyclobutenones 24 and B 2 Pin 2 afforded tertiary cyclobutylboronates 25 in high diastereoselectivities and enantioselectivities. Further synthetic utilities were pursued based on boronic ester and ketone functionalities.…”

Enantioselective Synthesis of 3‐Substituted Cyclobutenes by Catalytic Conjugate Addition/Trapping Strategies

“…Recently, enantioselective syntheses of cyclobutene derivatives have been reported by [2+2] cycloaddition approaches –. To the best of our knowledge, the functionalization of cyclobutenones is a far less studied strategy . In line with our continued interest in the desymmetrization of cyclobutanones, we planned to access chiral cyclobutene derivatives with higher stability and efficiency in a catalytic process.…”

Iridium‐Catalyzed Enantioselective C(sp3)–H Borylation of Cyclobutanes

“…[ 13 ] Mediated by an excessive amount of a chiral hydrogen bonding template, Bach and coworkers developed an enantioselective intermolecular [2+2] photocycloadditon of isoquionolone with alkenes. [ 14 ] Chiral phosphine/Cu enabled Catalytic asymmetric hydroboration of meso ‐cyclobutuenes [ 15 ] and conjugate borylation of cyclobutenones [ 16 ] also provide efficient methods to access these frameworks (Schemes 1A and 1B). It should be noted that the carbon atoms for the aforementioned C—B bond forming reactions need to be pre‐functionalized.…”