Synthesis of aryl pyrrolizidines from endocyclic enecarbamates. Novelapplications of the Heck arylation of 3-pyrrolines using diazonium salts

Abstract

The novel aryl platynecines 3a/3b were synthesized from endocyclic 4-aryl enecarbamates 8a/8b by a concise and practical route. The synthesis was based on an efficient preparation of 4-aryl enecarbamates 8a/8b from 3-pyrrolines by means of a Heck arylation using aryldiazonium tetrafluoroborates, followed by a highly stereoselective cycloaddition of the 4-aryl enecarbamates 8a/8b to 2-chloroethyl ketene to afford exclusively the 7-endo-(2-chloroethyl) cyclobutanones 12a/12b in good yields (67% and 65%). Baeyer-Villiger oxidation of the cyclobutanones 12a/12b occurred with high regioselectivity to furnish the aza-lactones 13a/13b in 96% and 90% yields. Reduction of lactones 13a and 13b with LiAlH4 gave the desired aryl platynecines 3a/3b. The total synthetic sequence involved 6 steps and provided the aryl platynecines 3a/3b in an overall yield of 41% and 38%, respectively. These compounds are the first examples of necine bases bearing an aromatic substituent on the azabicyclo[3.3.0]octane framework and incorporate some of the key structural element of the pharmacologically active 1,3,4-trisubstituted pyrrolines which act as antagonists of the chemokine receptor CC5.