Synthesis of 2,3,4,4A,9,10-hexahydro-7-methoxy-4A-methylphenanthren-2-one by aryl radical cyclization. Studies directed toward the asymmetric total synthesis of (+)-cepharamine. Asymmetric and racemic syntheses, opioid receptor affinities, and antinociceptive effects of a new class of structural analogues of the morphine alkaloids.

摘要

2,3,4,4a,9,10-Hexahydro-7-methoxy-4a-methylphenanthren-2-one was synthesized in 47% overall yield by Birch reduction-alkylation of methyl 3-methoxy-6-methylbenzoate with 2-(2-bromo-5-methoxyphenyl)-1-iodoethane followed by saponification, acid catalyzed lactonization, intramolecular radical cyclization, and finally oxidative decarboxylation.; An enantioselective synthesis of the hasubanan alkaloid ring system has been developed. Highlights of the synthesis include Birch reduction-alkylation of a L-prolinol derived 5-methoxy-2-(2-(4-methoxyphenoxy) ethyl) benzamide with 2-(2-bromophenyl)-1-iodoethane to give a 1,4-cyclohexadiene; acid-catalyzed lactonizations of cis- and trans-hydroxyl amides and to release the chiral auxiliary; intramolecular radical cyclization to form a quaternary carbon-aryl bond in 85% yield to construct the B-ring; and pyrrolidine ring formation involving oxidative decarboxylation followed by spontaneous or acid catalyzed Michael addition of a tosyl amide group to the {dollar}alpha ,beta{dollar}-unsaturated enone to furnish the 7-oxo-hasubanan ring skeleton.; Enantiomers of the 8-amino-3-hydroxy-5,9-methano-5-methylbenzo cyclooctenes, new ligands for the opioid receptors, have been prepared. The key steps in the reaction sequence involved Birch reduction of the L- or D-proline derived 7-methylpyrrolobenzodiazepine-5,11-dione and alkylation with 4-methoxybenzyl bromide. Subsequent acid catalyzed cyclization provided the bicyclo(3.3.1) benzononane ring system. A modified synthetic approach has provided short and efficient syntheses of the racemic ligands and an example of the C(8) diastereomeric series. Opioid receptor binding studies have shown that several compounds bind with excellent efficiency to the {dollar}mu{dollar}-receptor {dollar}rm (Ksb{lcub}1{rcub}simeq 2 nM).{dollar} Inversion of configuration at the nitrogen-bearing carbon atom C(8) ((+)-237a vs (dl)-260) resulted in a greater than ten-fold increase in {dollar}kappa{dollar}-receptor affinity while retaining Cl-receptor affinity. Opioid receptor affinity studies have also revealed the virtual absence of enantioselectivity for receptor binding, particularly at the {dollar}mu{dollar}-receptor, for the (+)-37a-f and the (-)-237a-f series. Antinociceptive studies demonstrated that (dl)-260 was a full {dollar}kappa{dollar}+-agonist.