Formal syntheses of (−)- and (+)-aphanorphine from (2S,4R)-4-hydroxyproline

We describe the efficient formal syntheses of both natural (−)-aphanorphine and unnatural (+)-aphanorphine from the same commercially available amino acid, (2S,4R)-4-hydroxyproline. The tricyclic framework was constructed by intramolecular Friedel-Crafts reaction. (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine (8) was synthesized in six steps from sulfonamide 3; (−)-aphanorphine methyl ether 24 was obtained in seven steps from lactone 10. Intramolecular etherification of 18 proceeded with excellent stereoselectivity in the presence of BF3·OEt2, which has paved an efficient synthetic route to a series of medicinally attractive heterocycles.

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