High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates
High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates
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DOI：
10.1002/anie.201909308
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发表时间：
2019-12-16
影响因子：
16.6
通讯作者：
Hall, Dennis G.
中科院分区：
文献类型：
--
作者：
Clement, Helen A.;Boghi, Michele;Hall, Dennis G.
环丁烷环在药物化学中是重要的，但很少有对映选择性方法存在，以获得这种支架。特别地，由于烷基硼酸酯的合成多功能性和硼酸在药物发现中的作用越来越大，环丁基硼酸酯在文献中受到越来越多的关注。本文报道了a-烷基、b-芳基/烷基环丁烯酮的共轭硼基化反应，首次合成了对映体富集的叔环丁基硼酸酯。具有两个立体中心的环丁酮以良好至高产率获得，具有高的对映选择性和非对映选择性。这一进展至关重要的是发展一种新的方法，a，B不对称二取代环丁烯酮底物和使用的高通量手性配体筛选平台。硼酸酯和酮官能团的合成效用被显示出来，在这个小环支架中，对任何一个基团都有可能具有显着的化学选择性。
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 a-alkyl,b-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 a,b 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.