-Piperidinoethylsulfides are oxidized by
m-chloroperbenzoic acid to intermediates containing both
N-oxide and sulfone functions. These undergo a Cope-type elimination to a vinylsulfone that can be captured by amines to afford
-aminoethylsulfones. When a
-aminoethylsulfone group is linked to the 4-position of a phenyl group attached at N-2 of
O6-cyclohexylmethylguanine, the resulting derivatives are inhibitors of the cyclin-dependent kinase CDK2. One of the most potent inhibitors (IC
50 = 45 nM) contained a
N-3-hydroxypropyl group on the aminoethylsulfonyl substituent. The crystal structure of this inhibitor bound to CDK2/cyclin A was determined and shows an unusual network of hydrogen bonds. The synthetic methodology developed can be utilized in multiple-parallel format and has numerous potential applications in medicinal chemistry.