Nickel-Catalyzed Cross-Electrophile Reductive Couplings of Neopentyl Bromides with Aryl Bromides.

5-Cyanoimidazole was identified as an inexpensive ligand for nickel-catalyzed cross-electrophile couplings by screening a diverse set of pharmaceutical compound library. A strategic screening approach led to the discovery of this novel ligand, which was successfully applied in the preparation of various alkylated arene products with good to high yields. Furthermore, the properties of this ligand allowed expanding the scope of reductive couplings to challenging substrates, such as sterically hindered neopentyl halides, which are known to generate motifs that are prevalent in biologically active molecules.

Sulfone-Mediated SNAr Reaction as a Powerful Tool for the Synthesis of 4-Quinolinyl Ethers and More-Application to the Synthesis of HCV NS3/4a Protease Inhibitor BI 201420.

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.

Synthesis of stable isotope-labelled firocoxib.

Firocoxib (ML-1,785,713) is a nonsteroidal, potent, and selective COX-2 inhibitor, approved for the control of pain and inflammation associated with osteoarthritis in dogs and horses, as well as to control postoperative pain and inflammation in dogs. We employed a six-step synthesis to prepare firocoxib-[13 C6 ] in an overall yield of 35% from the commercially available bromobenzene-[13 C6 ]. The synthetic route involved the preparation of the key intermediate phenyl-13 C6 -methyl sulfide using cesium carbonate and S-methylthiourea sulfate under transition-metal free conditions. A two-step preparation of firocoxib-[13 C,2 H3 ] via the sulfinic acid derivative of firocoxib and methyl iodide-[13 C,2 H3 ] using the procedure of Gauthier and Yoshikawa was first undertaken. However, the deuterium atoms of the methyl sulfone undergo extensive exchange in aqueous media even at neutral pH. The isotope-labelled firocoxib is intended as an internal standard for bioanalyses of firocoxib from biological matrices.

Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura Cross-Coupling Reaction in Flow.

The application of a Buchwald's third generation palladacycle containing a dihydrobenzooxaphosphole-based ligand (e.g., BIDIME) was reported in the Suzuki cross-coupling reaction. Using flow technology, high yield and reproducible Suzuki cross-coupling reaction for one of our key intermediates was achieved with Pd loadings as low as 0.5 mol %. This continuous flow approach overcomes catalyst deactivation and scale dependence issues that can be a problem in some traditional batch-mode operations and responds to the challenge of improving process greenness.

Development of a Scalable, Chromatography-Free Synthesis of t-Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF3-Alcohol Derivative with High Enantioselectivity Using Rh-Catalyzed Asymmetric Hydrogenation.

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

Synthesis of P-Chiral Dihydrobenzooxaphosphole Core for BI Ligands in Asymmetric Transformations.

An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the undesired (R,R)-diastereomeric phosphine oxide 19 through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (R,S)-diastereomer 12.

Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11ß-HSD-1 Inhibitor.

A concise asymmetric synthesis of an 11ß-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.

Synthesis of P-Chiral Dihydrobenzooxaphospholes Through Negishi Cross-Coupling.

An efficient Negishi cross-coupling was developed for the synthesis of the biaryl axes present in useful P-chiral dihydrobenzooxaphosphole ligands. This approach has allowed for the synthesis of new derivatives of these ligands that were not accessible by the previous route employing Suzuki-Miyaura cross-coupling. The use of Pd2(dba)3/BI-DIME as the catalyst system affords the desired biaryl compounds in good yields with excellent rates and with catalyst loadings as low as 0.25 mol %.

Ligand-Accelerated Stereoretentive Suzuki-Miyaura Coupling of Unprotected 3,3'-Dibromo-BINOL.

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.

Construction of Quaternary Stereocenters by Nickel-Catalyzed Heck Cyclization Reactions.

A nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters is reported. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in numerous biologically active molecules. The method shows broad scope, proceeds in synthetically useful yields, and provides a rare means to construct stereochemically complex frameworks by nonprecious-metal catalysis.

Development of an asymmetric synthesis of a chiral quaternary FLAP inhibitor.

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.

Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor.

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.

Efficient asymmetric synthesis of structurally diverse P-stereogenic phosphinamides for catalyst design.

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.

ß(2) integrins inhibit TLR responses by regulating NF-κB pathway and p38 MAPK activation.

Outside-in signals from ß(2) integrins require immunoreceptor tyrosine-based activation motif adapters in myeloid cells that are known to dampen TLR responses. However, the relationship between ß(2) integrins and TLR regulation is unclear. Here we show that deficiency in ß(2) integrins (Itgb2(-/-) ) causes hyperresponsiveness to TLR stimulation, demonstrating that ß(2) integrins inhibit signals downstream of TLR ligation. Itgb2(-/-) macrophages and dendritic cells produced more IL-12 and IL-6 than WT cells when stimulated with TLR agonists and Itgb2(-/-) mice produced more inflammatory cytokines than WT mice when injected with LPS. TLR hypersensitivity was not the result of insufficient ABIN-3, A20, Hes-1, or IRAK-M expression, nor to changes in IL-10 production or sensitivity, though Itgb2(-/-) macrophages had reduced p38 MAPK phosphorylation after LPS treatment. Furthermore, a Cbl-b-MyD88 regulatory axis is not required for TLR inhibition in macrophages. Instead, Itgb2(-/-) macrophages presented with enhanced IκBα degradation, leading to changes in NF-κB recruitment to target promoters and elevated cytokine, chemokine, and anti-apoptotic gene transcription. Thus, ß(2) integrins limit TLR signaling by inhibiting NF-κB pathway activation and promoting p38 MAPK activation, thereby fine-tuning TLR-induced inflammatory responses.

Synthesis of pyridyl-dihydrobenzooxaphosphole ligands and their application in asymmetric hydrogenation of unfunctionalized alkenes.

Synthesis of the electron-rich 2-substituted-6-(phenylsulfonyl)pyridines is presented. A series of air-stable, tunable, P-chiral pyridyl-dihydrobenzooxaphosphole ligands were designed and synthesized by a diastereoselective S(N)Ar substitution of the corresponding sulfonyl pyridines. The ligands were successfully applied in the Ir-catalyzed asymmetric hydrogenation of unfunctionalized alkenes with good enantioselectivities.

Remarkable enhancement of enantioselectivity in the asymmetric conjugate addition of dimethylzinc to (Z)-nitroalkenes with a catalytic [(MeCN)4Cu]PF6-Hoveyda ligand complex.

An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.

Copper catalyzed asymmetric propargylation of aldehydes.

The highly enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes with a propargyl borolane reagent is reported. The methodology demonstrated broad functional group tolerance and provided high enantioselectivities for aliphatic, vinyl, and aryl aldehydes. The utility of the TMS homopropargylic alcohols was demonstrated by the facile conversion to a chiral dihydropyranone.

Copper-catalyzed annulation of 2-formylazoles with o-aminoiodoarenes.

In the presence of catalytic CuI and sparteine, 2-formylpyrroles can be annulated with o-aminoiodoarenes to give substituted pyrrolo[1,2-a]quinoxalines and related heterocycles. The reaction also works for annulation of 2-formylindoles, 2-formylimidazole, 2-formylbenzimidazole, and a 3-formylpyrazole.

Rational Design of New Dihydrobenzooxophosphole-Based Lewis Base Organocatalysts.

A series of new dihydrobenzooxophosphole-based Lewis Base organocatalysts were designed and synthesized. They are demonstrated effective in trichlorosilane-mediated stereoselective conjugate reductions of C=C bonds. DFT calculations reveal that the strong hydrogen bond between the amide linker and the chloride on silicon in the transition state contributes to the high reactivity of the catalyst 3a.

A facile and practical synthesis of N-acetyl enamides.

A facile and practical method for the synthesis of N-acetyl alpha-arylenamides has been developed from corresponding ketoximes as the starting materials with ferrous acetate as the reducing reagent. This methodology offers mild reaction conditions, simple purification procedures, and high yields for a variety of N-acetyl enamides.