新加坡南洋理工大学Tan, Choon-Hong团队开发了手性亚磺酸酯不对称缩合合成策略。相关研究成果于2022年2月14日发表在《自然》。
非手性硫官能团如磺酰胺、砜、硫醇和硫醚在药物和天然产品中很常见。然而，手性硫官能团作为药效集团通常被忽略；但亚砜肟具有独特的物理化学和药代动力学特性，最近已被纳入若干临床候选药物中。因此，其他硫立体生成中心，如亚硫酸酯、亚硫酸酰胺、磺酰胺酯和磺酰胺，也开始引起人们的注意。这些硫立体基因中心的多样性和复杂性有可能扩大药物发现的化学空间。然而，将这些结构对映选择性地安装到药物分子中是极具挑战性的。
该文中，研究人员报道了通过前手性亚磺酸酯和醇的不对称缩合，以戊胺为有机催化剂，直接获得富含对映体的亚磺酸酯。研究人员成功地将多种亚硫酸酯和生物活性醇立体选择性地偶联。最初的亚磺酸酯可以从现有的砜和磺酰胺类药物中制备，得到的亚磺酸酯可用于转化为多种手性硫药效集团。通过塞来昔布和其他药物衍生物的后期多样化研究，研究人员证明了这种针对硫立体基因中心的统一方法的可行性。
附：英文原文
Title: Synthesis of chiral sulfinate esters by asymmetric condensation
Author: Zhang, Xin, Ang, Esther Cai Xia, Yang, Ziqi, Kee, Choon Wee, Tan, Choon-Hong
Issue&Volume: 2022-02-14
Abstract: Achiral sulfur functional groups such as sulfonamide, sulfone, thiols and thioethers are common in drugs and natural products. However, chiral sulfur functional groups are often neglected as pharmacophores1–3; but sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centers, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide have started to attract attention. The diversity and complexity of these sulfur stereogenic centers have the potential to expand chemical space for drug discovery6–10. However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here, we report the straightforward access to enantioenriched sulfinate esters via asymmetric condensation of pro-chiral sulfinates and alcohols using pentanidium as an organocatalyst. We successfully coupled a wide range of sulfinates and bioactive alcohols stereoselectively. The initial sulfinates can be prepared from existing sulfone and sulfonamide drugs, and the resulting sulfinate esters are versatile for transformations to diverse chiral sulfur pharmacophores. Through late-stage diversification11,12 of Celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centers.
DOI: 10.1038/s41586-022-04524-4
Source: https://www.nature.com/articles/s41586-022-04524-4