Under the influence of a chiral bidentate diphosphine ligand, the Pd-catalyzed asymmetric cross-coupling of allylboron reagents and allylic electrophiles establishes 1,5-dienes with adjacent stereocenters in high regio- and stereoselectivity. . A mechanistic study of the coupling utilizing reaction calorimetry and density functional theory analysis suggests that the reaction operates through an inner-sphere 3,3'-reductive elimination pathway, which is both rate- and stereodefining. Coupled with optimized reaction conditions, this mechanistic detail is used to expand the scope of allyl-allyl couplings to allow the generation of 1,5-dienes with tertiary centers adjacent to quaternary centers as well as a unique set of cyclic structures.

The palladium catalyzed allyl-allyl cross-coupling was investigated with substituted prochiral allylic boronates. These reactions deliver products bearing adjacent stereocenters and the issue of diastereocontrol is therefore paramount. Under appropriately modified conditions, this allyl-allyl coupling strategy was found to apply to a range of substrates, generally occurring with high enantioselectivity (92:8 – >99:1 er) and good diastereoselection (4:1 – 14:1 dr).

Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SNAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson’s disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

The palladium-catalyzed cross-coupling of chiral propargyl acetates and allyl boronates delivers chiral 1,5-enynes with excellent levels of chirality transfer and applied across a broad range of substrates.1,5-Enynes are important and versatile synthetic intermediates. In addition to offering differentiated π-systems for selective functionalization, 1,5-enynes can be transformed into a diverse array of cyclic structures. 1 A current challenge to reaction methodology surrounding 1,5-enynes lies in the preparation of these structures in an enantiomerically enriched fashion. Synthesis of 1,5-enynes is commonly accomplished by allylation of propargylic electrophiles, employing either stoichiometric or catalytic Lewis acid activation. 2 While high levels of regiocontrol have been observed in these processes, they appear to proceed through an achiral carbocation intermediate and this feature precludes the transfer of chirality from enantiomerically-enriched starting materials to 1,5-enyne products (Scheme 1, eq. 1). 3,4 Transition metal catalysis could provide a solution to this limitation: palladium undergoes stereospecific anti S N 2´ oxidative addition with propargylic electrophiles. 5 This reaction delivers an η 1 -(allenyl)palladium complex (A, Scheme 1) whose configuration reflects that of the starting material. While (allenyl)palladium complexes can undergo isomerization to η 1 -(propargyl)palladium species (A→B), this transformation is also stereospecific. 5,6 With appropriately substituted substrates, both the propargyl (B) and the allenyl (A) palladium complexes are chiral and the fact that they are configurationally stable enables stereospecific cross-couplings. 7 However, the Pd-catalyzed cross-coupling of organometallic reagents and branched propargylic electrophiles generally favors the allene as opposed to the 1,5 enyne product. 7,8 This regioselectivity likely arises from steric effects; complex A is less hindered than complex B and this leads to allene products on reductive elimination. This reaction manifold renders traditional palladium catalysis ineffective for construction of chiral alkyne-containing compounds from chiral propargylic electrophiles.In contrast to the cross-coupling of alkyl, aryl and vinyl metal reagents, cross-couplings of allyl metal reagents may occur with allyl migration. To exploit this feature, our lab has studied cross-couplings of allyl metal reagents and allylic electrophiles and has found that these reactions appear to occur by an inner sphere 3,3'-reductive elimination. 9,10,11 In the presence of appropriately selected ligands (bidentate, small bite-angle diphosphines), allylallyl cross-couplings occur with excellent levels of regio-and stereocontrol. Along these * Corresponding Authormorken@bc.edu. Supporting Information. Procedures, characterization and spectral data. This material is available free of charge via the Internet at http://pubs.acs.org.The authors declare no competing financial interest. lines, we considered that allyl-propargyl cross-couplings mi...

The application of bicyclo[1.1.1]pentanes (BCPs) as phenyl bioisosteres has garnered significant attention, as these structural motifs can improve the physiochemical profiles of drug candidates. Despite the potential of using 1-bicyclo[1.1.1]pentylpyrazoles (BCPPs) as 1-phenylpyrazole bioisosteres, this area remains underexplored because of the relative lack of reliable synthetic methods for the preparation of BCPPs. Herein we address this synthetic gap and report the development of novel and scalable routes to generate a host of BCPPs.

α-Arylations of cyclopropyl and related nitriles provide access to important synthetic intermediates and pharmacophores for biologically active molecules. However, robust methods for coupling of sterically encumbered partners have remained elusive. Through optimization using high-throughput experimentation (HTE), the NiXantphos ligand was found to be effective in the coupling of sterically hindered β-substituted cyclopropyl nitriles with a number of aryl groups and heterocycles, including those containing acidic N–H and O–H bonds.

The evolution of picolinamide derived LRRK2 inhibitors with improved kinase off target selectivity and de-risked for AMES mutagenicity.