Electrochemistry has recently gained increased attention as a versatile strategy for achieving challenging transformations at the forefront of synthetic organic chemistry.

Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific protein targets in a proteasome-dependent manner.However, a major limitation to broader TPD applications is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent ligand for the E3 ligase RNF114. When linked to the BET family inhibitor JQ1, the resulting heterobifunctional PROTAC molecule was capable of selectively degrading BRD4 in cancer cells. Here, we show the broader utility of nimbolide as an E3 ligase recruiter for TPD applications. We demonstrate that a PROTAC linking nimbolide to the kinase and BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades BCR-ABL over c-ABL in leukemia cancer cells, compared to previously reported cereblon or VHL-recruiting BCR-ABL degraders that show opposite selectivity or in some cases inactivity. Further contrasting from cereblon or VHL-recruiting degradation, we show that BT1 treatment not only leads to BCR-ABL degradation, but also stabilizes the endogenous RNF114 substrate and tumor suppressor substrate p21. This leads to additional anti-proliferative effects in leukemia cancer cells beyond those observed with cereblon or VHL-recruiting BCR-ABL PROTACs. Thus, we further establish nimbolide as an additional general E3 ligase recruiter for PROTACs with unique additional benefits for oncology applications. We also further demonstrate the importance of expanding upon the arsenal of E3 ligase recruiters, as such molecules confer differing and unpredictable selectivity for the degradation of neo-substrate proteins.

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. Insight gathered during these studies, however, ultimately led to a synthesis of the pseudoanisatinoids along with the allo-cedrane natural product 11-O-debenzoyltashironin.A second-generation strategy was then developed to access the more highly oxidized majucinoid compounds including jiadifenolide and majucin itself. Overall, one dozen natural products can be accessed from an abundant and inexpensive terpene feedstock. A multitude of general observations regarding site-selective C(sp 3 )-H bond functionalization reactions in complex polycyclic architectures are reported.

Hydrogen-atom transfer mediated by earth-abundant transition-metal hydrides (M-Hs) has emerged as a powerful tool in organic synthesis. Current methods to generate M-Hs most frequently rely on oxidatively initiated hydride transfer. Herein, we report a reductive approach to generate Co–H, which allows for canonical hydrogen evolution reactions to be intercepted by hydrogen-atom transfer to an alkene. Electroanalytical and spectroscopic studies provided mechanistic insights into the formation and reactivity of Co–H, which enabled the development of two new alkene hydrofunctionalization reactions.

The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp 3 )−H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C−C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl" effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

A successful combination of computational chemistry and total synthesis was explored to tentatively elucidate the absolute configuration of cryptomoscatone E3, a polyketide isolated from the Brazilian tree Cryptocarya mandiocanna. Two independent synthetic approaches are discussed based on asymmetric allylation, ring closing metathesis, and aldol reactions.

An enantioselective total synthesis of cryptolatifolione and its C-8 epimer is presented in a protecting-group-free fashion. The synthesis relied on the use of a catalytic double Krische allylation, catalytic olefin metathesis and a C-H oxidation. Comparison of spectroscopic data of the synthetic isomers and natural product made possible the unequivocally elucidation of the absolute configuration of cryptolatifolione.

Since the elucidation of the structure of anisatin in the late 1960’s, 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 both desirable structural and medicinal attributes. This synopsis will focus on recently developed synthetic strategies to access these compact, highly oxidized terpenoids.