Synthetic procedures have been developed to provide 2,3-disubstituted-3,4-dihydro-1(2H)-isoquinolinones 6, 10, and 15 from (1R,2S)-ephedrine, (1R,2R)-pseudoephedrine, and l-phenylalanine. Birch
reduction of 6 and 10 gave enantiomerically related lactam enolates that were alkylated with methyl
iodide, allyl bromide, benzyl bromide, p-benzyloxybenzyl bromide, and p-methoxybenzyl bromide
to give 7a−7e, 11a, and 11b with diastereoselectivities > 20:1. Birch reduction−methylation of
15 gave 19 with a diastereoselectivity of >35:1. Selective reduction of the disubstituted double
bond in 19 with diimide and cleavage of the tert-butyldimethylsilyl ether gave 20b, from which
iodoetherification under thermodynamic control gave the iodopyran 21a; iodoetherification of 20b
under kinetic control gave the iodotetrahydrofuran 22. Enantiospecific syntheses of analogues of
24 (Schultz, A. G.; Kirincich, S. J.; Rahm, R. Tetrahedron Lett. 1995, 36, 4551−4554) have been
developed. Tetracycle 24 is isomeric with the potent analgesic agent levorphanol, but the bridging
of the hydroisoquinoline ring by the hydroxybenzyl unit in 24 is at C(7, isoquinoline numbering)
and C(8a) rather than at C(1) and C(4a) as in levorphanol. The key step in the transformation of
7d and 7e to tetracyclic phenolic amines (−)-26 and (+)-28 is the Grewe-type cyclization of 7d to
25b and 7e to 25c. K
i values for the inhibition of binding to the μ-, δ-, and κ-opioid receptors by
(−)-26, (+)-26, (+)-28, (−)-28, and (+)-32 are reported.
