In the present article, we describe SAR studies within a series of N-hydroxy-dihydronaphthyridinone HIV integrase inhibitors that led to a candidate compound, PF-4776548, of high potency and with an excellent resistance profile. Uncertainties around the human pharmacokinetic predictions for PF-4776548 led to the compound being taken into a human microdose study to confirm its human pharmacokinetics, the results of which are described herein.
A library of 4,6-diaryl-1,4-dihydropyridines was synthesized using a CAN-catalyzed, Hantzsch-related three component reaction starting from ammonium acetate, β-dicarbonyl compounds and a variety of α,β-unsaturated ketones including chalcones, their vinylogs and heteroanalogues. These compounds lack the structural features needed for vascular activity and were found to prevent calcium overload and behave as neuroprotective agents. One of the compounds, bearing a 2-thienyl substituent at C-4, showed the highest neuroprotective activity and was also a moderate antioxidant, being a good lead compound for further studies in this area.
A Direct and Stereoretentive Synthesis of Amides from Cyclic Alcohols
D. Mondal, L. Bellucci, S. D. Lepore,
Eur. J. Org. Chem. 2011.
Salvatore Lepore and colleagues, Florida Atlantic University, USA, report a one-pot amidation reaction for cyclic alcohols that gives complete retention of configuration. They use a chlorosulfite leaving group formed in situ by reaction of the alcohol and thionyl chloride. The leaving group is chelated by a TiIV nitrile complex that is also generated in situ by reaction of TiF4 and alkyl or aryl nitrile.
The Ti nitrile complex is thought to chelate the chlorosulfite in the transition state to create a carbocation that is rapidly captured by the nitrile nucleophile through a front-side attack mechanism. This is the first experimental verification of secondary hyperconjomers, a theory of non-planar carbocations developed by Sorensen and Schleyer.
Most stereoselective approaches to amides from chiral alcohols require multistep procedures.
DR ANTHONY CRASTO
The carbocation intermediate formed in the reaction’s rate limiting step is an sp2 hybridized carbon with trigonal planar molecular geometry. This allows two different avenues for the nucleophilic attack, one on either side of the planar molecule. If neither avenue is preferentially favored, these two avenues occur equally, yielding a racemic mix of enantiomers if the reaction takes place at a stereocenter.This is illustrated below in the SN1 reaction of S-3-chloro-3-methylhexane with an iodide ion, which yields a racemic mixture of 3-iodo-3-methylhexane:
However, an excess of one stereoisomer can be observed, as the leaving group can remain in proximity to the carbocation intermediate for a short time and block nucleophilic attack. This stands in contrast to the SN2 mechanism, which is a stereospecific mechanism where stereochemistry is always inverted.