Studies On Asymmetric Synthesis Of Amino Alchol Antibiotics: Thiamphenicol And Florfenicol

Thiamphenicol (1) and florfenicol (2) are a class of broad-spectrum antibiotics possessingβ-amino alcohol structure with two stereocenters. Continuous synthetic efforts have been made in developing novel and practical asymmetric approaches towards 1 and 2. In this thesis, two novel and asymmetric synthetic routes to 1 and 2 are described.In chapter 1, the research progresses in the synthesis of 1 and 2 since their discovery in 1952 and 1979 have been reviewed. The current industrial synthesis of 1 and 2 is based upon the established chemical resolution process starting from p-(methylsulfonyl)benzaldehyde. The aim of our studies is to develop new asymmetric synthesis of 1 and 2 by utilizing asymmetric aziridination reaction (routeⅠ) and Sharpless AD reaction (routeⅡ) as key reactions.In chapter 2, an efficient and asymmetric synthesis of 1 and 2 was developed in routeⅠvia (2S,3S)-aziridinol 8 starting from commercial available p-(methylsulfonyl)-benzaldehyde in 47% and 46% total yield respectively. The key reaction of this soute is the asymmetric aziridination reaction of imine (9) and EDA to 8 with excellent yield and high enantioselectivity (increased to >99% ee after recrystallization), mediated by the Wulff's catalyst in situ derived from (R)-VANOL. Another feature of this synthesis is the PTSA-catalyzed stereospecific ring-opening reaction of (2S,3S)-aziridinol 12 and (2S,3S)-fluoroaziridine 13 with high yields. The Meddleton fluorination of 12 with DAST introduced fluorine at C-3 site for 2.In addition, the absolute configuration of 8 was unambiguously confirmed by X-ray single crystal diffraction and NOESY spectrum.In chapter 3, another asymmetric approach towards 1 and 2 was accomplished in routeⅡstarting from commercial available p-(methylsulfonyl)benzaldehyde in 27% and 23% total yield respectively. The key reaction of this synthesis is the Sharpless AD reaction of cinnamic esters 68 to (2S,3S)-α,β-dihydroxy esters 67 with excellent yield and enantioselectivity under mild condition. Theβ-amino alcohol structure of target molecules was constructed by utilizing selective sulfonation/NaN3 substitution strategy. The introduction of fluorine atoms at C-3 site for 2 was achieved via the fluorination of (4S,5S)-oxazolines 65 with Ishikawa reagent.In addition, the absolute configuration of 70 was unambiguously determined by X-ray single crystal diffraction. The spatial configuration of 73 and 80 was assigned on the basis of NOESY spectrum.