Total synthesis of AI-77-B: stereoselective hydroxylation of 4-alkenylazetidinones

A stereoselective synthesis of the anti-ulcer compound AI-77-B 1 is described. The 4-formylazetidinone 6 was converted into the 4-(Z)-alkene 23 using a phosphonate condensation, and dihydroxylation using osmium tetroxide and N-methylmorpholine N-oxide gave a mixture of the diols 24 and 25 in an 80:20, ratio. After protection of the diol 24 as its acetonide, hydrogenolysis gave the acid 27. The oxazoline 45 was deprotonated using butyllithium, and the lithiated oxazoline added to Cbz-protected leucinal 29, which had previously been deprotonated by tertbutylmagnesium chloride, to give the lactones 30 and 31, ratio 85: 15, after treatment with silica in dichloromethane. Hydrogenolysis gave the aminolactone hydrochloride 52 which was condensed with the acid 27 to give the protected dipeptide 54. Deprotection under acidic conditions gave the dihydroxyazetidinone 55. Treatment with sodium hydroxide followed by acidification then gave the aminolactone hydrochloride 56 which on further treatment with sodium hydroxide followed by acid gave AI-77-B methyl ether 58. Demethylation of the phenolic methyl ether 30 followed by hydrogenolysis of the Cbz-protecting group gave the aminophenol 60 which was coupled with the acid 27 and the product taken through to AI-77-R 1 following the sequence used to prepare the methyl ether 58.