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We provide an account of synthetic strategies aimed at the efficient preparation of 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (3), an important cyclic sulfone building block for medicinal chemistry. A practical and scalable protocol has been developed that readily gives access to the title compound from commercially available and inexpensive starting materials. In addition, this novel approach has enabled the synthesis of various related 4,4-disubstituted cyclic sulfone derivatives that serve as valuable structural motifs for drug discovery.

A novel class of 13 and 16 membered steroidal macrocycles were synthesized by using ring closing metathesis reaction from the readily available anti-inflammatory steroids such as prednisolone, 6-methyl prednisolone, and 16-methyl prednisolone.

Intramolecular [2+3] cycloaddition reaction of trimethylenemethane diyls that were generated successfully from the reaction of malonate anions containing diene units with propynyl iodonium salts via alkylidene carbene intermediates produced linearly fused triquinanes.

Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile.

[reaction: see text] A tandem electrocyclic closure, perceived as the key step in a biomimetic approach to SNF 4435C and D, was tested with 1,1,8-trisubstituted tetraene substrates. The ratio of endo:exo products could be controlled by the choice of the RZ substituent at C-1. On the basis of these results, a short stereoselective route to an advanced SNF 4435 intermediate was devised.

The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.

Tris(2-benzimidazolylmethyl)amines have been found to be superior accelerating ligands for the copper(I)-catalyzed azide−alkyne cycloaddition reaction. Candidates bearing different benzimidazole N-substituents as well as benzothiazole and pyridyl ligand arms were evaluated by absolute rate measurements under relatively dilute conditions by aliquot quenching kinetics and by relative rate measurements under concentrated conditions by reaction calorimetry. Benzimidazole-based ligands with pendant alkylcarboxylate arms proved to be advantageous in the latter case. The catalyst system was shown to involve more than one active species, providing a complex response to changes in pH and buffer salts and the persistence of high catalytic rate in the presence of high concentrations of coordinating ligands. The water-soluble ligand (BimC4A)3 was found to be especially convenient for the rapid and high-yielding synthesis of several functionalized triazoles with 0.01−0.5 mol % Cu.

[reaction: see text] Halogenation of achiral trans-2-pyridone photodimers results in 1,3-migration of an amide nitrogen and formation of a chiral structure with six stereogenic centers and well-differentiated functionality. The reactivity of this product toward nucleophiles, including the allylic halide, is dominated by participation by the amide nitrogen.

A bicyclo[3.1.0]hexane, with one cyclopropane carbon flanked by a ketone and an ester or an aldehyde, undergoes methanolysis with cleavage of one of the two activated cyclopropane bonds, depending on the reaction conditions. Acidic conditions yield primarily or exclusively a 4-methoxycyclohexane, while basic conditions yield a 3-methoxymethylcyclopentanone.

[reaction: see text] Photocycloaddition of 2-pyridones yields a rigid polycyclic product containing a 1,5-cyclooctadiene. The cis isomer, with the alkenes in close proximity, undergoes a transannular reaction when treated with chlorine to give a polyquinane product. The chlorination reaction involves migration of an amide nitrogen and forms a single isomer, generating eight stereogenic centers in two steps.