A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn (CO) , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by Mn(CO) . The rate-limiting step is the iodine abstraction from an alkyl iodide by Mn(CO) .

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.

Cyclobutane rings are important in medicinal chemistry, yet few enantioselective methods exist to access this scaffold. In particular, cyclobutylboronates are receiving increasing attention in the literature due to the synthetic versatility of alkylboronic esters and the increasing role of boronic acids in drug discovery. Herein, a conjugate borylation of α‐alkyl,β‐aryl/alkyl cyclobutenones is reported leading to the first synthesis of enantioenriched tertiary cyclobutylboronates. Cyclobutanones with two stereogenic centers are obtained in good to high yield, with high enantioselectivity and diastereoselectivity. Vital to this advance are the development of a novel approach to α,β unsymmetrically disubstituted cyclobutenone substrates and the use of a high‐throughput chiral ligand screening platform. The synthetic utility of both the boronic ester and ketone functionalities is displayed, with remarkable chemoselectivity for either group being possible in this small ring scaffold.

Avisible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn 2 (CO) 10 ,t og enerate alkylr adicals from alkyl iodides has been developed. This Minisci protocol is compatible with awide arrayofsensitive functional groups,including oxetanes,s ugar moieties,a zetidines,t ert-butyl carbamates (Boc-group), cyclobutanes,a nd spirocycles.T he robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs.P hotophysical and DFT studies indicate al ight-initiated chain reaction mechanism propagated by CMn(CO) 5 .T he rate-limiting step is the iodine abstraction from an alkyl iodide by CMn(CO) 5 . Scheme 1. Photomediated Minisci CÀHalkylation of N-heteroarenes.

Chiral cyclobutanes are components of numerous bioactive natural products, and consequently, they have also gained significant attention in medicinal chemistry. Optically enriched cyclobutylboronates can serve as valuable synthetic intermediates for the synthesis of a broad variety of chiral cyclobutanes through exploiting the versatility of the boronyl functionality. Herein, by using a high-throughput ligand screening approach, an efficient method for the asymmetric conjugate borylation of a cyclobutene 1-carboxyester was optimized, leading to a highly enantioenriched cis-β-boronyl cyclobutylcarboxyester scaffold (99% ee, >20:1 dr). Of the 118 ligands screened, the Naud family of phosphine–oxazoline ligands was found to be the most effective. Computational modeling of the possible preinsertion complexes shows a large preference for the π-bound Cu­(I)–alkene complex where the substrate’s large benzhydryl ester occupies a relatively unhindered quadrant of the chiral ligand in a spatially tight environment that is highly specific for the cyclobutenoate substrate and imparts much lower selectivity with larger ring substrates. The cis diastereoselectivity is proposed to arise from a sterically controlled, irreversible protodecupration step. A highly diastereoselective nickel/photoredox dual-catalyzed Csp3–Csp2 cross-coupling of the corresponding trifluoroborate salt with aryl/heteroaryl bromides and cycloalkenyl nonaflates was developed, providing access to a wide diversity of trans-β-aryl/heteroaryl and cycloalkenyl cyclobutylcarboxyesters with an excellent diastereoselectivity and high retention of optical purity (91–99% ee, >20:1 dr). Azaheterocyclic halides, which are notoriously challenging substrates in Pd-catalyzed cross-coupling, are successful with this Ni/photoredox manifold. A stereoconvergent model based on steric factors is proposed for the key carbon–carbon bond forming step, leading to a high diastereoselectivity. Despite the radical nature of the cross-coupling conditions, the flanking carboxyester proved to be a reliable chirality relay group to maintain the stereochemical integrity of the organoboron intermediate. Furthermore, mild oxidation of the carbon–boron bond and extension of the catalytic asymmetric conjugate borylation reaction to a three-component aldol reaction with an aldehyde afford valuable enantioenriched cyclobutane products.