CsF-Mediated in Situ Desilylation of TMS-Alkynes for Sonogashira Reaction.

A practical and mild set of conditions for the Sonogashira reaction utilizing CsF-mediated in situ TMS-alkyne desilylation followed by Sonogashira coupling has been developed for the synthesis of a variety of alkynyl benzenes and heteroarenes in good to excellent yields. This methodology demonstrates excellent functional group tolerance and simple purification, which allows large-scale industrial applications. This one-pot protocol enables a high-yielding Sonogashira coupling with volatile alkynes by avoiding challenging isolation of free alkynes.

Ketoreductase-Catalyzed Access to Axially Chiral 2,6-Disubstituted Spiro[3.3]heptane Derivatives.

The desymmetrization of a prochiral 6-oxaspiro[3.3]heptane-2-carboxylic acid derivative via biocatalytic ketoreductase-mediated reduction has provided access to both enantiomers in high ee. The axially chiral alcohol was converted to the corresponding ester alcohol, amino acid, and amino alcohol building blocks while high enantiopurity was maintained.

Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1.

In our efforts to identify novel small molecule inhibitors for the treatment of adrenoleukodystrophy (ALD), we conducted a high-throughput radiometric screen for inhibitors of elongation of very long chain fatty acid 1 (ELOVL1) enzyme. We developed a series of highly potent, central nervous system (CNS)-penetrant pyrimidine ether-based compounds with favorable pharmacokinetics culminating in compound 22. Compound 22 is a selective inhibitor of ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts and lymphocytes in vitro. Compound 22 reduced C26:0 lysophosphatidyl choline (LPC), a subtype of VLCFA, in the blood of ATP binding cassette transporter D1 (ABCD1) KO mice, a murine model of ALD to near wild-type levels. Compound 22 is a low-molecular-weight, potent ELOVL1 inhibitor that may serve as a useful tool for exploring therapeutic approaches to the treatment of ALD.

Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.

While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.

Tandem Pummerer-Diels-Alder Reaction Sequence. A Novel Cascade Process for the Preparation of 1-Arylnaphthalene Lignans.

The alpha-thiocarbocation generated from the Pummerer reaction of an o-benzoyl-substituted sulfoxide is intercepted by the adjacent keto group to produce an alpha-thio isobenzofuran as a transient intermediate which undergoes a subsequent Diels-Alder cycloaddition with added dienophiles. Acid-catalyzed ring-opening of the cycloadduct followed by aromatization gave an arylnaphthalene derivative. With acetylenic dienophiles, the tandem cyclization-cycloaddition sequence provided tetralones which result from a pinacol-type rearrangement of the primary cycloadducts. The versatility of the approach is highlighted through the synthesis of taiwanin C and E and justicidin E. The alpha-thiocarbocation generated from the Pummerer reaction of benzo[1,3]dioxol-5-yl-[6-[(ethylsulfinyl)methyl]benzo[1,3]dioxol-5-yl)methanone is intercepted by the adjacent keto group to produce an alpha-thioisobenzofuran as a transient intermediate which undergoes a subsequent Diels-Alder cycloaddition with dimethyl maleate. The initially formed Diels-Alder cycloadduct was readily converted to 5-benzo[1,3]dioxol-5-yl-8-(ethylthio)naphtho[2,3-d][1,3]dioxole-6,7-dicarboxylic acid dimethyl ester by loss of water on treatment with p-toluenesulfonic acid. Desulfurization of the thionaphthalene with Ra/Ni followed by hydrolysis of the less hindered methyl ester afforded 5-benzo[1,3]dioxol-5-ylnaphtho[2,3-d][1,3]dioxole-6,7-dicarboxylic acid 6-methyl ester which was further transformed into taiwanin C and justicidin E in good yield. Oxidation of the initial Diels-Alder cycloadduct with NaIO(4) in the presence of RuCl(3) followed by extrusion of ethyl sulfinate gave a naphthol derivative which can be converted into taiwanin E.

Studies Dealing with the Cycloaddition/Ring Opening/Elimination Sequence of 2-Amino-Substituted Isobenzofurans.

The alpha-thiocarbocation generated from the Pummerer reaction of an o-amido-substituted sulfoxide is intercepted by the adjacent amido carbonyl group to produce a 2-amino-substituted isobenzofuran as a transient intermediate. In the presence of an electron-deficient dienophile, the reactive isobenzofuran undergoes a Diels-Alder cycloaddition followed by ring opening to furnish a vinylogous C-acyliminium ion that readily aromatizes. The one-pot intramolecular cascade process only occurs either if the olefinic tether is activated by an ester or if a carbonyl group is located adjacent to the nitrogen atom of the 2-amino-substituted isobenzofuran. To examine the amine vs amide influence on the course of intramolecular cycloaddition, density functional theory (DFT) calculations have been carried out for both ground and transition states. The results strongly suggest that the amide-substituted isobenzofurans are destabilized by steric effects between the aromatic ring and the nitrogen-containing side chain. Raising of the ground-state amide energies thereby reduces the activation energy for internal cycloaddition and leads to Diels-Alder adducts more rapidly than for the corresponding amines. Amide tethers emerge as remote-site promoters of intramolecular cycloaddition for tandem processes yielding products with multiple fused rings.

The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor.

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38α inhibitors is described. Application of structural information from enzyme-ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38α inhibitors containing a previously unreported bicyclic heterocycle core. Advancing the SAR of this series led to the eventual discovery of 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one (VX-745). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.

Occupant dynamics in rollover crashes: influence of roof deformation and seat belt performance on probable spinal column injury.

Motor vehicle crashes are the leading cause of death in the United States for people ages 3-33, and rollover crashes have a higher fatality rate than any other crash mode. At the request and under the sponsorship of Ford Motor Company, Autoliv conducted a series of dynamic rollover tests on Ford Explorer sport utility vehicles (SUV) during 1998 and 1999. Data from those tests were made available to the public and were analyzed in this study to investigate the magnitude of and the temporal relationship between roof deformation, lap-shoulder seat belt loads, and restrained anthropometric test dummy (ATD) neck loads. During each of the three FMVSS 208 dolly rollover tests of Ford Explorer SUVs, the far-side, passenger ATDs exhibited peak neck compression and flexion loads, which indicated a probable spinal column injury in all three tests. In those same tests, the near-side, driver ATD neck loads never predicted a potential injury. In all three tests, objective roof/pillar deformation occurred prior to the occurrence of peak neck loads (F ( z ), M ( y )) for far-side, passenger ATDs, and peak neck loads were predictive of probable spinal column injury. The production lap and shoulder seat belts in the SUVs, which restrained both driver and passenger ATDs, consistently allowed ATD head contact with the roof while the roof was contacting the ground during this 1000 ms test series. Local peak neck forces and moments were noted each time the far-side, passenger ATD head contacted ("dived into") the roof while the roof was in contact with the ground; however, the magnitude of these local peaks was only 2-13% of peak neck loads in all three tests. "Diving-type" neck loads were not predictive of injury for either driver or passenger ATD in any of the three tests.