SYNTHESIS OF THE STEREOISOMERS OF A NOVEL ANTIBACTERIAL AGENT AND INTERPRETATION OF THEIR RELATIVE ACTIVITIES IN TERMS OF A THEORETICAL-MODEL OF THE PENICILLIN RECEPTOR

(2'-hydroxypropyl)-5-carboxy-Delta(3)-1,4-thiazine (1) is a designed a ntibacterial agent. Based on an analysis of how penicillin complexes t o and reacts with a model of a penicillin-binding protein, 1 contains a functional group (C=N) that can react with a serine hydroxyl group o f the receptor according to the putative reaction Enz-OH + C=N --> Enz -O-C-NH. Compound 1 also contains additional substituents that are des igned to position the O-H and C=N groups relative to one another in th e enzyme-substrate complex in a geometry that attempts to reproduce th e optimum geometry of approach of two such reactants. A most important assumption is that this optimum geometry can be computed ab initio. I n a first preparation of 1, (+/-)-5 methyl-4-hexene-2-ol (2) was conve rted to the lithium salt pto-2-methyl-5-tert-butyldimethylsiloxy-3-hex anone (7), which was condensed with the N-tert-butoxycarbonyl-D- and L -serine-beta-lactones (3). The synthesis was completed by deprotection with formic acid and cyclization in water. The R and S enantiomers of 2 have now been obtained, and the absolute configuration of the alcoh ol established, by reaction of the R- and S-propylene oxides with an o rganometallic reagent prepared from beta,beta-dimethylvinyl bromide. T he R alcohol has also been secured by lipase-catalyzed transesterifica tion with trifluoroethyl butyrate, and chemical hydrolysis of the trif luoroethyl ester. The R and 5 enantiomers of 2 were converted to the R and S enantiomers of 7, and these were condensed with the R and S ena ntiomers of 3 to yield each of the stereoisomers of the chemically uns table 1 in ca. 95% optically pure form. Antibacterial activity resides in the 5S,8R and 5S,8S isomers. These findings are shown to be consis tent with the theoretical model. It is hoped that the stability of the lead structure 1 can be improved, to allow binding experiments with p enicillin recognizing enzymes to proceed.