Diastereoselective One-Pot Synthesis of 7- and 8-Substituted 5-PhenylmorphansProbes for Narcotic Receptor Mediated Phenomena. 45.

Abstract

Novel 7- and 8-alkyl and aryl substituted 5-phenylmorphans were synthesized from substituted allyl halides and N-benzyl-4-aryl-1,2,3,6-tetrahydropyridine by a highly efficient and diastereoselective reaction series, “one-pot” alkylation and ene-imine cyclization followed by sodium borohydride reduction. Mild cyclization conditions gave the desired substituted 5-phenylmorphans in good yield as a single diastereomer.

Probes for narcotic receptor mediated phenomena. 48. C7- and C8-substituted 5-phenylmorphan opioids from diastereoselective alkylation

“…Thus, the cyclohexane annulated compound 7d and 8d also were formed as a single product with the same stereochemistry. As we noted previously, [9] a possible mechanism that explained the obtained data suggested 6-membered Re -face C-C bond formation and an intramolecular hydride shift as key aspects of the highly diastereoselective cyclization that gave trans selectivity at C7 and cis selectivity at C8.…”

“…[9] The reported cyclization protocol always gave C7- trans and C8- cis isomers (relative to the piperidine ring) as a single product without any minor isomers. Thus, the cyclohexane annulated compound 7d and 8d also were formed as a single product with the same stereochemistry.…”

“…Acid-catalyzed ene-imine cyclization of the alkylated intermediate 3 , followed by in-situ reduction of resulting cyclized imine 4 , gave the desired N -benzyl-5-phenylmorphans 5a-d [9] in good yields (Scheme 1). The N -Bn compounds 5a-d were converted into their secondary amines 6 by Pd/C catalyzed hydrogenolysis (Scheme 2).…”

“…1). [9] With a C7α-methyl substituent the relative stereochemistry of the C7 moiety in racemic 7b and the piperidine ring, as shown in Fig. 1, was trans (C1 R* , C5 S *and C7 S* ), and with the C7β-hydroxyl it was cis (C1 S* , C5 R* , and C7 S* ).…”

“…We have previously reported this “one pot” diastereoselective synthesis that provided C7-oxo, hydroxy and alkyl substituents, as well as C8-alkyl substituted 5-phenylmorphans, as well as compounds that had a new cyclohexane ring that includes the C7 and C8 carbon atoms of the 5-phenylmorphan. [9] The use of this synthetic pathway has allowed us to prepare N-derivatives other than the N -methyl and N -benzyl compounds that were noted in our initial paper. We now report on compounds that have been synthesized and evaluated in opioid receptor binding assays.…”