Department of Chemistry, 4-010 CCIS, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada.
Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA, 92121, USA.
Angew Chem Int Ed Engl. 2019 Dec 16;58(51):18405-18409. doi: 10.1002/anie.201909308. Epub 2019 Oct 31.
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.
环丁烷环在药物化学中很重要，但很少有对映选择性的方法可以获得这种支架。特别是，由于烷基硼酸酯的合成多功能性以及硼酸在药物发现中的作用不断增加，环丁基硼酸酯在文献中受到越来越多的关注。在此，报道了α-烷基，β-芳基/烷基环丁烯酮的共轭硼化反应，首次合成了对映体富集的叔环丁基硼酸酯。具有两个手性中心的环丁酮以良好到高产率获得，具有高对映选择性和非对映选择性。这一进展的关键是开发了一种新的方法来制备α，β不对称取代的环丁烯酮底物，并使用高通量手性配体筛选平台。展示了硼酸酯和酮官能团的合成实用性，在这个小环支架中，对于这两个基团都有可能具有显著的化学选择性。
