Chemoenzymatic Total Synthesis of Hydromorphone by an Oxidative Dearomatization/Intramolecular [4 + 2] Cycloaddition Sequence: A Second-Generation Approach

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.

本研究针对氧化去芳构化/狄尔斯-阿尔德环加成（oxidative dearomatization/Diels–Alder cycloaddition）路径构建第二代氢吗啡酮（hydromorphone）合成方法展开系统探究。首先，率先针对截短模型体系及制备对映氢吗啡酮（ent-hydromorphone）的原料，对[4+2]环加成反应的立体化学结果开展详细分析。立体化学构型通过核磁共振（NMR）与X射线衍射法完成指认。两类对映异构体路线均完成了氢吗啡酮的第二代合成。采用高价碘试剂替代四乙酸铅（Pb(OAc)4），实现了去芳构化反应条件的优化。同时探究了电化学氧化去芳构化方法。开发了可由甲氧基缩酮实现A环再芳构化的新型反应条件，并完成了天然对映体氢吗啡酮的形式合成。所有新化合物均提供了实验与光谱表征数据。