Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride.

In our drug discovery campaigns to target the oncogenic drivers of cancers, the demand for a chemoselective, stereoselective and economical synthesis of chiral benzylamines drove the development of a catalytic zirconium hydride reduction. This methodology uses the inexpensive, bench stable zirconocene dichloride, and a novel tetrabutylammonium fluoride activation tactic to catalytically generate a metal hydride under ambient conditions. The diastereo- and chemoselectivity of this reaction was tested with the preparation of key intermediates from our discovery programs and in the scope of sulfinyl ketimines and carbonyls relevant to medicinal chemistry and natural product synthesis. A preliminary mechanistic investigation conducted into the role of tetrabutylammonium fluoride indicates that formation of a zirconocene fluoride occurs to initiate catalysis. The implications of this convenient activation approach may provide expanded roles for zirconium hydrides in catalytic transformations.

Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3Kα Mutant Protein.

The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047R over PI3KαWT is crucial due to the role that PI3KαWT plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3KαH1047R with high selectivity over PI3KαWT, resulting in the discovery of compound 17. When dosed in the HCC1954 tumor model in mice, 17 provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3KαH1047R including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program.

Chiral amine synthesis remains a significant challenge in accelerating the design cycle of drug discovery programs. A zirconium hydride, due to its high oxophilicity and lower reactivity, gave highly chemo- and stereoselective reductions of sulfinyl ketimines. The development of this zirconocene-mediated reduction helped to accelerate our drug discovery efforts and is applicable to several motifs commonly used in medicinal chemistry. Computational investigation supported a cyclic half-chair transition state to rationalize the high selectivity in benzyl systems.

Selected Approaches to Disrupting Protein-Protein Interactions within the MAPK/RAS Pathway.

Within the MAPK/RAS pathway, there exists a plethora of protein-protein interactions (PPIs). For many years, scientists have focused efforts on drugging KRAS and its effectors in hopes to provide much needed therapies for patients with KRAS-mutant driven cancers. In this review, we focus on recent strategies to inhibit RAS-signaling via disrupting PPIs associated with SOS1, RAF, PDEδ, Grb2, and RAS.

Modular terpene synthesis enabled by mild electrochemical couplings.

The synthesis of terpenes is a large field of research that is woven deeply into the history of chemistry. Terpene biosynthesis is a case study of how the logic of a modular design can lead to diverse structures with unparalleled efficiency. This work leverages modern nickel-catalyzed electrochemical sp2-sp3 decarboxylative coupling reactions, enabled by silver nanoparticle-modified electrodes, to intuitively assemble terpene natural products and complex polyenes by using simple modular building blocks. The step change in efficiency of this approach is exemplified through the scalable preparation of 13 complex terpenes, which minimized protecting group manipulations, functional group interconversions, and redox fluctuations. The mechanistic aspects of the essential functionalized electrodes are studied in depth through a variety of spectroscopic and analytical techniques.

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. 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(sp3)-H bond functionalization reactions in complex polycyclic architectures are reported.

Radical Retrosynthesis.

In The Logic of Chemical Synthesis, E. J. Corey stated that the key to retrosynthetic analysis was a "wise choice of appropriate simplifying transforms" ( Corey , E. J. ; Cheng , X.-M. The Logic of Chemical Synthesis ; John Wiley : New York , 1989 ). Through the lens of "ideality", chemists can identify opportunities that can lead to more practical, scalable, and sustainable synthesis. The percent ideality of a synthesis is defined as [(no. of construction rxns) + (no. of strategic redox rxns)]/(total no. of steps) × 100. A direct consequence of designing "wise" or "ideal" plans is that new transformations often need invention. For example, if functional group interconversions are to be avoided, one is faced with the prospect of directly functionalizing C-H bonds ( Gutekunst , W. R. ; Baran , P. S. Chem. Soc. Rev. 2011 , 40 , 1976 ; Brückl , T. ; et al. Acc. Chem. Res. 2012 , 45 , 826 ). If protecting groups are minimized, methods testing the limits of chemoselectivity require invention ( Baran , P. S. ; et al. Nature 2007 , 446 , 404 ; Young , I. S. ; Baran , P. S. Nat. Chem. 2009 , 1 , 193 ). Finally, if extraneous redox manipulations are to be eliminated, methods directly generating key skeletal bonds result ( Burns , N. Z. ; et al. Angew. Chem., Int. Ed. 2009 , 48 , 2854 ). Such analyses applied to total synthesis have seen an explosion of interest in recent years. Thus, it is the interplay of aspirational strategic demands with the limits of available methods that can influence and inspire ingenuity. E. J. Corey's sage advice holds true when endeavoring in complex molecule synthesis, but together with the tenets of the "ideal" synthesis, avoiding concession steps leads to the most strategically and tactically optimal route ( Hendrickson , J. B. J. Am. Chem. Soc. 1975 , 97 , 5784 ; Gaich , T. ; Baran , P. S. J. Org. Chem. 2010 , 75 , 4657 ). Polar disconnections are intuitive and underlie much of retrosynthetic logic. Undergraduates exposed to multistep synthesis are often taught to assemble organic molecules through the combination of positively and negatively charged synthons because, after all, opposites attract. Indeed, the most employed two-electron C-C bond forming reactions today are those based upon either classical cross-coupling reactions (e.g., Suzuki, Negishi, or Heck) or polar additions (aldol, Michael, or Grignard). These reactions are the mainstay of modern synthesis and have revolutionized the way molecules are constructed due to their robust and predictable nature. In contrast, radical chemistry is sparsely covered beyond the basic principles of radical chain processes (i.e., radical halogenation). The historical perception of radicals as somewhat uncontrollable species does not help the situation. As a result, synthetic chemists are not prone to make radical-based strategic bond disconnections during first-pass retrosynthetic analyses. Recent interest in the use of one-electron radical cross-coupling (RCC) methods has been fueled by the realization of their uniquely chemoselective profiles and the opportunities they uncover for dramatically simplifying synthesis. In general, such couplings can proceed by relying on the innate preferences of a substrate (innate RCC) or through interception with a mediator (usually a transition metal) to achieve programmed RCC. This Account presents a series of case studies illustrating the inherent strategic and tactical advantages of employing both types of radical-based cross-couplings in a variety of disparate settings. Thematically, it is clear that one-electron disconnections, while not considered to be intuitive, can serve to enable syntheses that are more direct and feature a minimal use of protecting group chemistry, functional group interconversions, and nonstrategic redox fluctuations.

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(sp3)-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.