Thermodynamic Understanding of an Aza-Michael Reaction Enables Five-Step Synthesis of the Potent Integrin Inhibitor MK-0429.

We describe a general strategy for the aza-Michael addition of nucleophilic heterocycles into β-substituted acrylates using potassium -butoxide as catalyst. Demonstrating that the reaction is under thermodynamic control underpins optimization efforts and enables rapid exploration of the substrate scope, with yields ranging from 55% to 94%. We further leverage these lessons in a significantly shortened synthesis of MK-0429, a potent pan-integrin inhibitor previously taken into human clinical trials for the treatment of prostate cancer and osteoporosis.

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes.

The Illicium sesquiterpenes are a family of natural products containing over 100 highly oxidized and structurally complex members, many of which display interesting biological activities. This comprehensive account chronicles the evolution of a semisynthetic strategy toward these molecules from (+)-cedrol, seeking to emulate key aspects of their presumed biosynthesis. An initial route generated lower oxidation state analogs but failed in delivering a crucial hydroxy group in the final step.

Contemporary Synthetic Strategies toward seco-Prezizaane Sesquiterpenes from Illicium Species.

Since the elucidation of the structure of anisatin in the late 1960s, sesquiterpene lactones from various Illicium species of plants have captivated synthetic chemists worldwide, resulting in a large body of synthetic work. In particular, Illicium sesquiterpenes containing the seco-prezizaane carbon framework have seen immense interest in recent years owing to desirable structural and medicinal attributes. This synopsis will focus on recently developed synthetic strategies to access these compact, highly oxidized terpenoids.

Total Syntheses of (-)-Majucin and (-)-Jiadifenoxolane A, Complex Majucin-Type Illicium Sesquiterpenes.

We report the first chemical syntheses of both (-)-majucin and (-)-jiadifenoxolane A via 10 net oxidations from the ubiquitous terpene (+)-cedrol. Additionally, this approach allows for access to other majucin-type sesquiterpenes, like (-)-jiadifenolide, (-)-jiadifenin, and (-)-(1R,10S)-2-oxo-3,4-dehydroxyneomajucin (ODNM) along the synthetic pathway. Site-selective aliphatic C(sp)-H bond oxidation reactions serve as the cornerstone of this work which offers access to highly oxidized natural products from an abundant and renewable terpene feedstock.

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products.

The pool of abundant chiral terpene building blocks (i.e., "chiral pool terpenes") has long served as a starting point for the chemical synthesis of complex natural products, including many terpenes themselves.

Oxidative Entry into the Illicium Sesquiterpenes: Enantiospecific Synthesis of (+)-Pseudoanisatin.

Illicium sesquiterpenes have been the subject of numerous synthetic efforts due to their ornate and highly oxidized structures as well as significant biological activities. Herein we report the first chemical synthesis of (+)-pseudoanisatin from the abundant feedstock chemical cedrol (∼$50 USD/kg) in 12 steps using extensive site-selective C(sp)-H bond functionalization. Significantly, this work represents a novel oxidative strategic template for future approaches to these natural products and their analogs.

A platform for the discovery of new macrolide antibiotics.

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches.