Boyer Zachary W, Kwon Na Yeon, Ellman Jonathan A
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
J Am Chem Soc. 2025 May 7;147(18):14954-14959. doi: 10.1021/jacs.5c03841. Epub 2025 Apr 28.
Sulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an -methyl or an -cyclopropyl substituent. Here, we report on a general and efficient sequence for the asymmetric synthesis of both of these sulfoximine substitution patterns. The asymmetric synthesis of sulfilimine intermediates by the first Ru-catalyzed enantioselective alkylation of sulfenamides enables the first examples of enantioselective -alkylation with monosubstituted diazo compounds. The reaction proceeds at ≤1 mol % Ru-catalyst loading, and for -butyl diazoacetate, high yields and ≥98:2 er are achieved for an exceedingly broad range of sulfenamides, including with -(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl, and --butyl substituents and for sterically and electronically diverse -acyl groups. Sulfenamides derived from densely functionalized advanced drug intermediates also alkylated with 99:1 er. After oxidation of an -pivaloyl --butyl acetate substituted sulfilimine to the corresponding sulfoximine, treatment with trifluoracetic acid in an aprotic solvent resulted in decarboxylation to the -methyl -pivaloyl sulfoximine, while aqueous HCl resulted in both decarboxylation and cleavage of the -acyl group to give the -methyl NH sulfoximine. Alternatively, sulfoximine alkylation with dibromoethane followed by acid-mediated decarboxylation provided the -cyclopropyl sulfoximine. The efficient asymmetric synthesis of the preclinical candidate LTGO-33 and the formal asymmetric synthesis of the phase II clinical candidate ART0380 demonstrate the utility of the disclosed approach.
磺胺氧化合物越来越多地应用于制药和农用化学品中,所有磺胺氧化合物临床候选物都含有α-甲基或α-环丙基取代基。在此,我们报道了一种通用且高效的方法,用于不对称合成这两种磺胺氧化合物取代模式。通过钌催化的亚磺酰胺的首次对映选择性烷基化反应不对称合成亚磺酰亚胺中间体,实现了单取代重氮化合物对映选择性α-烷基化的首例。该反应在钌催化剂负载量≤1 mol%的条件下进行,对于乙酸叔丁酯重氮,对于范围极广的亚磺酰胺,包括含有α-(杂)芳基、α-烯基、α-甲基、α-苄基、α-支链烷基和α-叔丁基取代基以及空间和电子性质多样的α-酰基的亚磺酰胺,都能实现高产率和≥98:2的对映体过量。源自功能密集的先进药物中间体的亚磺酰胺也能以99:1的对映体过量进行烷基化反应。将α-新戊酰基-α-乙酸叔丁酯取代的亚磺酰亚胺氧化为相应的磺胺氧化合物后,在非质子溶剂中用三氟乙酸处理会脱羧生成α-甲基-α-新戊酰基磺胺氧化合物,而用盐酸水溶液处理则会导致脱羧并裂解α-酰基,生成α-甲基-NH-磺胺氧化合物。或者,磺胺氧化合物与二溴乙烷进行烷基化反应,随后经酸介导脱羧,可得到α-环丙基磺胺氧化合物。临床前候选药物LTGO-33的高效不对称合成以及II期临床候选药物ART0380的形式不对称合成证明了所公开方法的实用性。