Development of a novel method for synthesis of β-lactams by the use of diazoacetamides

Abstract

Due to the increase in antibacterial resistance, the world is in need of new, powerful antibacterial agents and synthetic methods to halter this trend. This study focused on broadening the scope of a new synthesis of β-lactams developed by Kaupang and Konradsen. The method uses carbenes generated from α-bromodiazoacetamides in an intramolecular C-H insertion reaction to generate the β-lactam moiety. With this new method, it could be possible to synthesize new β-lactam molecules. This creates an opportunity of discovering molecules with novel antibacterial properties beyond what is known today. The method was successfully applied in the syntheses of the diazoacetamides with a methyl, ethyl or isopropyl ester. Only the β-lactam with the ethyl ester was successfully synthesized from the diazoacetamides. Consequently, not enough data was available to determine how the product distribution in this synthetic step was affected by the ester. Additional focus of this thesis was on improving the synthesis of the diazoacetamides, due to a difficult purification and moderate yields. Several test reactions were conducted in order to develop a one-step synthesis of the diazoacetamides. A one-step reaction could avoid the problems in the original procedure, in addition to making the β-lactam formation more effective. The test reaction using 2,5-dioxypyrrolidin-1-yl 2-diazoacetate and methyl D-prolinate as reactants seems promising, but more work is necessary to develop the procedure further.