UC Riverside

Norcrassin A is a C16 tetranorditerpenoid characterized by a unique 5/5/5/6 tetracyclic framework – a structural feature not previously reported in natural products. Further evaluation of norcrassin A also showed its exciting promise as an anti-Alzheimer’s disease (AD) compound. Given its novel molecular structure and reported biological profile, a concise and convergent synthesis to this structurally and functionally important molecule was envisioned from cost-effective starting materials through straightforward chemical transformations. The salient features of the developed route include a multi-gram, eight-step synthesis of an advanced bicyclic lactone intermediate and a one-pot aldol/aldol/lactonization sequence to gain rapid entry to the tetracyclic skeleton.

Berbamine is a cyclic bisbenzylisoquinoline alkaloid (bisBIA) with a well-documented history of usage in clinical practice for treating inflammation, cancer, and autoimmune diseases. Despite its exciting biology, only limited hit-to-lead optimizations are possible due to the lack of functional group handles for derivatizations and the absence of a total synthesis for modifications in the core scaffold. While current access relies on isolation from natural sources, commercial samples acquired by us and our collaborator Dr. Wendong Huang at City of Hope National Medical Center between 2018–2021 revealed compromised authenticities by NMR analysis. Hence, a practical synthesis would provide indisputable access to berbamine and its diverse analogs. An array of scalable, multi-step synthetic strategies were designed and progressed en route to berbamine. The intention is to explore opportunities for derivatization, substrate- versus catalyst-controlled hydrogenation, as well as atropisomerism of the hindered diaryl ether linkage.

The Friedel–Crafts alkylation provides an intuitive bond disconnection for C(sp2)–C(sp3) bond retrosynthesis. Prior investigations in the Kou laboratory reported conditions for setting quaternary carbon centers in site-selective Friedel–Crafts reactions using unactivated tertiary alcohols and catalytic combinations of FeX3/HX. Encouraged by this previous work, a new combination of catalytic ZnCl2 and catalytic camphorsulfonic acid (CSA) led to the first site-selective Friedel–Crafts alkylation of phenols with unactivated secondary alcohols, affording the desired products in up to 85% yield. This dual catalytic system favored ortho-selectivity in the absence of steric influence while starting from minimally prefunctionalized reaction precursors, serving as a departure from conventional transition-metal-catalyzed cross-coupling methods.