Enabling, Decagram-Scale Synthesis of Macrocyclic MCL-1 Inhibitor ABBV-467.

ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization.

Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson's Disease.

Foslevodopa (FLD, levodopa 4'-monophosphate, ) and foscarbidopa (FCD, carbidopa 4'-monophosphate, ) were identified as water-soluble prodrugs of levodopa (LD, ) and carbidopa (CD, ), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD () and FCD () drug substances and their manufacture at pilot scale. The synthesis of FLD () employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry.

Cu-Catalyzed C-N Coupling with Sterically Hindered Partners.

Copper, an earth-abundant metal, has reemerged as a viable alternative to the versatile Pd-catalyzed C-N coupling. Coupling sterically hindered reaction partners, however, remains challenging. Herein, we disclose the discovery and development of a pyrrole-ol ligand to facilitate the coupling of -substituted aryl iodides with sterically hindered amines.

Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor.

Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered.

Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor.

The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality.

Copper-Catalyzed Aerobic Oxidative Amidation of Benzyl Alcohols.

A Cu-catalyzed synthesis of amides from alcohols and secondary amines using the oxygen in air as the terminal oxidant has been developed. The methodology is operationally simple requiring no high pressure equipment or handling of pure oxygen. The commercially available, nonprecious metal catalyst, Cu(phen)Cl, in conjunction with di-tert-butyl hydrazine dicarboxylate and an inorganic base provides a variety of benzamides in moderate to excellent yields.

Ligand-Controlled Synthesis of Azoles via Ir-Catalyzed Reactions of Sulfoxonium Ylides with 2-Amino Heterocycles.

An iridium-catalyzed method was developed for the synthesis of imidazo-fused pyrrolopyrazines. The presence or absence of a nitrogenated ligand controlled the outcome of the reaction, leading to simple β-keto amine products in the absence of added ligand and the cyclized 7- and 8-substituted-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine products in the presence of ligand. This catalyst control was conserved across a variety of ylide and amine coupling partners.

Pd-Catalyzed Synthesis of Aryl and Heteroaryl Triflones from Reactions of Sodium Triflinate with Aryl (Heteroaryl) Triflates.

A novel method for Pd-catalyzed triflination of aryl and heteroaryl triflates using NaSO2CF3 as the nucleophile is described. The combination of Pd2(dba)3 and RockPhos formed the most effective catalyst. A broad range of functional groups and heteroaromatic compounds were tolerated under the neutral reaction conditions.

Development of Zn-ProPhenol-catalyzed asymmetric alkyne addition: synthesis of chiral propargylic alcohols.

The development of a general and practical zinc-catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand (1) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and α,β-unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc.

Enantioselective ProPhenol-catalyzed addition of 1,3-diynes to aldehydes to generate synthetically versatile building blocks and diyne natural products.

A highly enantioselective method for the catalytic addition of terminal 1,3-diynes to aldehydes was developed using our dinuclear zinc ProPhenol (1) system. Furthermore, triphenylphosphine oxide was found to interact synergistically with the catalyst to substantially enhance the chiral recognition. The generality of this catalytic transformation was demonstrated with aryl, alpha,beta-unsaturated and saturated aldehydes, of which the latter were previously limited in alkynyl zinc additions.

Development of ruthenium catalysts for the enantioselective synthesis of P-stereogenic phosphines via nucleophilic phosphido intermediates.

This work details the development of ruthenium(II) catalysts for the enantioselective alkylation of chiral racemic secondary phosphines. The reactions proceed through the intermediacy of nucleophilic phosphido species, which have low barriers to pyramidal inversion; this allows for a dynamic kinetic asymmetric alkylation. The initially discovered [((R)-iPr-PHOX)(2)Ru(H)][BPh(4)] (6) catalyst was found to be effective in the reaction with benzylic chlorides; moreover, the alkylation displayed an unusual temperature dependence.

Asymmetric catalytic synthesis of P-stereogenic phosphines via a nucleophilic ruthenium phosphido complex.

Ruthenium phosphido complexes have been shown to be excellent nucleophiles, reacting via two-electron processes with a variety of electrophiles. A catalytic alkylation reaction was developed using an achiral ruthenium complex, which was then elaborated into a catalytic enantioselective synthesis of P-stereogenic phosphines. These useful and synthetically challenging phosphines can now be accessed in a single step from simple secondary phosphines and alkyl halides.