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A mild and nonreversible tert-butylation of alcohols and phenols can be achieved in high yields using the noncoordinating acid–base catalyst [bis(trifluoromethane)sulfonimide and 2,6-lutidine] with...

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.

The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.

A mild and nonreversible

An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive S

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

A copper-catalyzed site-selective propargylation/allenylation reaction toward carbonyl compounds has been mechanistically investigated using a computational approach. Different reaction pathways and catalytic cycles were investigated. Control of the site selectivity arises from a destabilizing interaction introduced by the phenyl-substituted ligand.

A practical and efficient synthesis of the FLAP inhibitor 1 was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of 1: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling.

Through a computer-guided approach, new series of monophosphine ligands were designed and developed for asymmetric Suzuki–Miyaura couplings of challenging heterocyclic substrates. Computer modeling pointed to a tunable, yet unexplored quadrant in BI-DIME, leading to the discovery of the 3′,5′-dimethyl-substituted ligand which improved the atropisomeric selectivity of the Suzuki–Miyaura reaction from the previously reported 5:1 dr to 15:1 dr for the synthesis of a challenging HIV integrase intermediate, and up to 24:1 dr with various other quinoline substrates.

A practical and cost-effective synthesis of (2-aminopyrimidin-5-yl) boronic acid 1b has been developed. Key features of the synthesis include the inexpensive in situ protection of the amine via bis-silylation using TMSCl followed by metal–halogen exchange using n-BuLi and trapping with B(Oi-Pr)3. The water-soluble boronic acid is isolated by a well-designed acid–base sequence providing the target in 80% yield and high purity for the two-step process. The large-scale (15 kg) implementation of a Suzuki–Miyaura borylation to form the pinacol boronic ester is also described.

A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.

A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of sec-BuLi combined with an in situ trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale.

A practical, safe, and efficient synthesis of anti-inflammatory cytokine inhibitors was developed and implemented for a number of analogues. A key aspect of the process is an efficient, one-pot, tandem copper-catalyzed azidonation and Huisgen 1,3-dipolar cycloaddition using silyl protected alkynes.

A highly electron-rich P-chiral bis(trialkylphosphane) ligand MeO-BIBOP (1) was efficiently synthesized on large scale. The MeO-BIBOP–rhodium complex exhibited remarkably high reactivities (up to 200,000 TON) for the hydrogenation of N-acetyl enamides to provide chiral acetamides on kilogram scale. In the meantime, a high-yielding, cost-effective, and practical preparation of N-acetyl enamide by reductive acylation of oxime was developed employing an in situ formation of Fe(II) acetate from Fe/AcOH/Ac2O.

Reported herein is a safe and economical synthesis of methyl 6-chloro-5-(trifluoromethyl)nicotinate, an intermediate in the synthesis of novel anti-infective agents. The key to this process is the trifluoromethylation of an aryl iodide using an inexpensive methyl chlorodifluoroacetate (MCDFA)/KF/CuI system, with an emphasis on the development work which led to this effective process.

A facile and economical five-step process for the synthesis of a sodium–hydrogen exchange type I inhibitor (NHE-1) was developed from readily available starting materials in 43% overall yield. Key transformations included a highly efficient copper-catalyzed conjugate addition of 2-trifluoromethylphenyl Grignard reagents to acetyl pyridinium salts, a facile hydrogenation of 4-aryl dihydropyridines, a regioselective aromatic bromination, an efficient palladium-catalyzed carbonylation of aryl bromides, and a high-yielding acyl guanidine formation. A safe and scalable protocol for preparation of 2-trifluoromethyl phenyl Grignard reagent was developed, and a facile method for controlling the palladium content with N-acetyl-L-cysteine as the scavenger was demonstrated. Process issues in controlling the formation of a key diacylation side product during acyl guanidine formation are also addressed.

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C–H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

An efficient synthesis of the enantiomerically pure 3,3'-bis-arylated BINOL derivatives is accomplished through the palladium-catalyzed Suzuki-Miyaura coupling of the unprotected 3,3'-dibromo-BINOL with complete retention of enantiopurity. The active catalyst system Pd(OAc)2/BI-DIME has enabled mild reaction conditions at palladium loads as low as 500 ppm.

A novel asymmetric synthesis of isopropyl (1R,2S)-dehydrocoronamate is described from (S)-1,2,4-butanetriol as the starting material in 28% overall yield. Highlights of this synthetic route include selective cyclopropanation between chiral cyclic sulfate 5 and diisopropyl malonate (8c), formation of vinylcyclopropane 3c via elimination of halide 4c, selective monohydrolysis of diisopropyl ester 3c, and Curtius rearrangement of acid 10 to form isopropyl (1R,2S)-dehydrocoronamate TsOH salt 13 in >99% ee. With the involvement of only three isolations, this chromatography-free process provides a rapid and practical access to (1R,2S)-1-amino-2-vinylcyclopropane-1-carboxylic acid derivatives.

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.

A unique solvent effect encountered in the Barton–Zard pyrrole synthesis was exploited to develop an efficient synthesis of pyrrole-2-esters. The chemistry was extended to a one-pot synthesis of pyrrole-2,4-dicarboxylates.

1-(4-Bromophenyl)ethanone Hydroxylamine hydrochloride Ethanol Pyridine 1-(4-Bromophenyl)ethanone oxime N-(1-(4-Bromophenyl)vinyl)acetamide Tetrahydrofuran Acetic anhydride Acetic acid Iron(II) acetate Keywords: N-acetyl enamides; Reductive acetylation; Oximes; Iron(II) acetate; N-(1-(4-bromophenyl)vinyl)acetamide; Acyclic N-acetyl α-arylenamides

Herein we describe the optimization and application of a copper(I) chloride-mediated protocol for the multikilogram synthesis of 5-bromo-2-cyclopropyl-1-methyl-1H-imidazole hydrochloride (1), a key...

A practical, one-step process for the synthesis of 2,5-disubstituted pyrimidines is presented. The protocol proved to be general for the synthesis of a variety of pyrimidine-containing compounds bearing an assortment of functional groups.

A practical, one-step process for the synthesis of 2,5-disubstituted pyrimidines is presented. The protocol proved to be general for the synthesis of a variety of pyrimidine-containing compounds bearing an assortment of functional groups.

A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A model is proposed that explains the origin of the site selectivity.

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1–0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.

A series of novel P-chiral monophosphorus ligands exhibit efficiency in asymmetric Suzuki–Miyaura coupling reactions, enabling the construction of an array of chiral biaryl products in high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. The carbonyl-benzooxazolidinone moiety in these chiral biaryl products allows facile derivatization for further synthetic applications. A computational study has revealed that a π–π interaction between the two coupling partners can enhance the enantioselectivity of the coupling reaction.

Sterically hindered aryl bromides and chlorides are converted with very low catalyst loadings using the new monophosphorus ligand (Ia) and Bedford′s Pd precursor (II).

In combination with the Bedford Pd precursor, the new biaryl monophosphorus ligand 5 was efficient for palladium-catalyzed Miyaura borylation of sterically hindered aryl bromides at low catalyst loadings.

A series of structurally novel, operationally convenient, and efficient chiral 2-phosphino-2,3-dihydrobenzo[d][1,3]oxaphosphole ligands was developed. Applications of ligands 3a and 3b in rhodium-catalyzed asymmetric hydrogenation of alpha-(acylamino)acrylates and beta-(acylamino)acrylates provided excellent enantioselectivities (up to99% ee) and reactivities (up to 10,000 TON).