Abstract

A second-generation approach to the synthesis of hydromorphone by oxidative dearomatization/Diels-Alder cycloaddition was investigated. Detailed analysis of the stereochemical outcome of the [4 + 2] cycloaddition was performed first on a truncated model system as well as on the material leading to ent-hydromorphone. The stereochemical assignments were made by NMR and X-ray methods. The second-generation synthesis of hydromorphone was completed in both enantiomeric series. Improvements in the dearomatization conditions were attained using hypervalent iodine reagents instead of Pb(OAc). Electrochemical methods of oxidative dearomatization were also investigated. New conditions enabling the rearomatization of ring A from the methoxyketal were developed, and a formal synthesis of the natural enantiomer of hydromorphone was completed. Experimental and spectral data are provided for all new compounds.

Mechanistic studies with 5-ethyl-3-methyllumiflavinium (Fl + )p erchlorate, ab iomimetic model for flavoenzyme monoamine oxidase B( MAO-B) catalysis, and the tertiary, allyl amine 1-methyl-4-(1-methyl-1 H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP) revealt hat proton-coupled electron transfer (PCET) may be an important pathway for MAO catalysis. The first step involves as ingle-electron transfer (SET) leading to the free radicals FlC and MMTPC,t he latter produced by deprotonation of the initially formed and highly acidic MMTPC + .M olecular oxygen (O 2 )i sf ound to play a hitherto unrecognized role in the early steps of the oxidation. MMTP and severals tructurally similar tertiarya mines are the only tertiary amines oxidized by MAO, and their structural/electronic properties provide the key to understanding this behavior.Ageneral hypothesis about the role of SET in MAO catalysis, and the recognition that PCET occurs with appropriatelys ubstituted substrates is presented.

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