121(P66) 1β-メチルカルバペネムの効率的合成手法の開発(ポスター発表の部)

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Carbapenems have received considerable attention in the β-lactam antibiotics due to high antibacterial activity and broad therapeutic spectram. Among them, 1β-methylcarbapenem 3 possesses chemical and metabolic stability, and the synthetic study of 3 has revealed several non-trivial problems because of the four consecutive chiral centers. Control of the stereochemistry of the methyl group at the 1-position is the most important and difficult step. Stereoselective hydrogenation of cyclic intermediate has offered one of the main methods for the control of C-1 methyl group. In the present study, the use of acyclic substrate possessing a stationary conformation gave the desired 1β-methyl derivative with high stereoselectivity. The starting material 5 was obtained as a single diastereomer from a chiral imine 4. Hydroxyethyl side chain of the 3-position was introduced by acetylation followed by stereoselective reduction. Propargyl acetate derivative 11 was prepared in high yield. Hydrogenolysis of the acetate 11 with palladium catalyst was carried out with 4 eq of formic acid in 1,4-dioxane to give directly α,β-unsaturated ester 12 with complete β-selectivity in a single step procedure. Deprotection of 12 was carried out with CAN to give α,β-unsaturated ester 15, which was transformed into the β-ketoester derivative 17. On the other hand, Cyclization of α,β-unsaturated ester 15 was effected by methanesulfenyl chloride to give carbapenam derivative 18. In summary, a new efficient method for the synthesis of 1β-methylcarbapenem has been achieved using ready hydrogenolysis of propargyl acetate 11 and simple cyclization of α,β-unsaturated ester with β-lactam ring 15 by the use of methanesulfenyl chloride as key steps.
天然有機化合物討論会の論文
1996-09-02

121(P66) 1β-メチルカルバペネムの効率的合成手法の開発(ポスター発表の部)

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