Chemoenzymatic Total Synthesis of Hydromorphone by an Oxidative Dearomatization/Intramolecular [4 + 2] Cycloaddition
Lukas Rycek1, John J Hayward1, Marwa Abdel Latif2
1Department of Chemistry and Centre for Biotechnology, Brock University , 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada.
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)4. 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.
Related Concept Videos
Oxidation of Alkenes: Syn Dihydroxylation with Osmium Tetraoxide
Cycloaddition Reactions: Overview
Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation
Oxidation of Alkenes: Anti Dihydroxylation with Peroxy Acids
[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction
Preparation of Epoxides
Epoxides result from alkene oxidation, which can be achieved by a) air, b) peroxy acids, c) hypochlorous acids, and d) halohydrin cyclization.
Epoxidation with Peroxy Acids
Epoxidation of alkenes via oxidation with peroxy acids involves the conversion of a carbon–carbon double bond to an epoxide using the oxidizing agent meta-chloroperoxybenzoic acid, commonly known as MCPBA. Since the O–O bond of peroxy acids is very weak, the addition of electrophilic oxygen of peroxy acids to...

![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
