Unified Strategy to Amphenicol Antibiotics: Asymmetric Synthesis of (−)-Chloramphenicol, (−)-Azidamphenicol, and (+)-Thiamphenicol and Its (+)-3-Floride

The asymmetric synthesis of (−)-chloramphenicol, (−)-azidamphenicol, and (+)-thiamphenicol and its (+)-3-floride, (+)-florfenicol, is reported. This approach toward the amphenicol antibiotic family features two key steps: (1) a cinchona alkaloid derived urea-catalyzed aldol reaction allows highly enantioselective access to oxazolidinone gem-diesters and (2) a continuous flow diastereoselective decarboxylation of thermally stable oxazolidinone gem-diesters to form the desired trans-oxazolidinone monoesters with two adjacent stereocenters that provide the desired privileged scaffolds of syn-vicinal amino alcohols in the amphenicol family.本文报道了(-)-氯霉素((-)-chloramphenicol)、(-)-叠氮氯霉素((-)-azidamphenicol)以及(+)-甲砜霉素((+)-thiamphenicol)及其(+)-3-氟代物、(+)-氟甲砜霉素((+)-florfenicol)的不对称合成方法。该针对酰胺醇类抗生素家族(amphenicol antibiotic family)的合成策略包含两个关键步骤：(1) 以金鸡纳生物碱(cinchona alkaloid)衍生的脲为催化剂的羟醛缩合反应(aldol reaction)，可高对映选择性地获得恶唑烷酮偕二酯(oxazolidinone gem-diesters)；(2) 对热稳定的恶唑烷酮偕二酯进行连续流非对映选择性脱羧反应，得到目标反式恶唑烷酮单酯，该产物含有两个相邻手性中心，可构建氯霉素类抗生素家族所需的顺式邻位氨基醇优势骨架(privileged scaffolds)。