CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticides & Chemical Biology Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China.
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
J Am Chem Soc. 2022 Apr 6;144(13):6040-6049. doi: 10.1021/jacs.2c01116. Epub 2022 Mar 24.
Axially chiral biaryls and heterobiaryls constitute the most represented subclass of atropisomers with prevalence in natural products, bioactive compounds, privileged chiral ligand/catalysts, and optically pure materials. Despite many ionic protocols for their construction, radical-based variants represent another highly desirable and intriguing strategy but are far less developed. Moreover, efficient synthesis of axially chiral heterobiaryl molecules, especially ones having multiple heteroatoms and other types of chiral elements, through radical routes remains extremely limited. We herein disclose the first catalytic asymmetric, metal-free construction of axially and centrally chiral heterobiaryls by Minisci reaction of 5-arylpyrimidines and α-amino acid-derived redox-active esters. This is enabled by the use of 4CzIPN as an organic photoredox catalyst in conjunction with a chiral phosphoric acid catalyst. The reaction achieved a variety of interesting 5-arylpyrimidines featuring the union of an axially chiral heterobiaryl and a centrally chiral α-branched amine with generally excellent regio-, diastereo-, and enantioselectivity (up to 82% yield; >19:1 dr; >99% ee). This finding also builds up a new platform for the development of desymmetrization methods via radical-involved atroposelective functionalization at heteroarene of prochiral heterobiaryls.
轴手性联芳基和杂联芳基是最具代表性的阻转异构体亚类之一，广泛存在于天然产物、生物活性化合物、手性配体/催化剂和光学纯材料中。尽管有许多用于构建它们的离子型方案，但基于自由基的变体代表了另一种高度理想和有趣的策略，但开发得要少得多。此外，通过自由基途径高效合成轴手性杂联芳基分子，特别是具有多个杂原子和其他类型手性元素的杂联芳基分子，仍然极其有限。我们在此通过 5-芳基嘧啶和α-氨基酸衍生的氧化还原活性酯的 Minisci 反应，公开了第一个通过 Minisci 反应催化不对称、无金属构建轴手性和中心手性杂联芳基的方法。这是通过使用 4CzIPN 作为有机光氧化还原催化剂与手性磷酸催化剂结合来实现的。该反应实现了多种有趣的 5-芳基嘧啶，它们具有轴手性杂联芳基和中心手性α-支链胺的联合，通常具有优异的区域选择性、非对映选择性和对映选择性（高达 82%的产率；>19:1 dr；>99%ee）。这一发现还为通过涉及自由基的前手性芳杂环的对映选择性官能化来开发轴不对称去对称方法建立了一个新的平台。
