Cyclization of acyl radical onto N[dbnd]C bond: Application in the synthesis of β-lactam

Abstract

Cyclization of acyl radical onto NC bond represents an appealing method for the synthesis of β-lactam. In this paper, we have conducted the systematic theoretical study on the regioselectivity in the cyclizations of various 4-azahexenoyl radical series by using DFT method. Firstly, it is found that cyclization of the linear unsubstituted 4-azahexenoyl radical mainly produces 5-endo product, while introduction of substituent with π-system at the C-terminal position (such as NO2, Ph) makes the cyclization yield 4-exo product (i.e. β-lactam) almost exclusively. Secondly, the feasibility of this radical cyclization method on the syntheses of β-lactam-fused bicyclic compounds has been examined, where the NC bond is placed in a ring and accepts the attack of extraannular (outside of the ring) acyl radical. It is found that the size of ring, hetero-atom on the ring and substituent have great influence over the syntheses of the bicyclic compounds. Finally, we have especially focused on the substituent effect of the radical cyclization when the NC bond is included in a five-membered sulfur-containing heterocycle, for the possible bicyclic product is the core structure of the penicillin. Calculations show that electron-withdrawing group is generally favorable to the final objective product.