(alpha-monofluoroalkyl)phosphonates: a class of isoacidic and "tunable" mimics of biological phosphates

In the early 1980s, Blackburn and McKenna suggested that a-fluorination mig ht lead to phosphonates that better mimic natural phosphates. Although alph a -monofluorination produces phosphonates with "matching" second pK(a) valu es, the alpha,alpha -difluorinated phosphonates have received more attentio n in the past decade or so. Recently, reported enzyme kinetic data on the a -monofluorinated phosphonates from the O'Hagan lab and from our lab suggest that the CHF stereochemistry does affect enzyme-binding, thereby providing an additional variable that may be tuned to achieve optimal binding to an active site of interest. This asymmetry also appears in structural data fro m the groups of Barford/Burke and Tracey on PTP1B complexes with bound a,a- difluorinated phosphonate inhibitors. In those complexes, only one of two p rochiral fluorine atoms appears to interact appreciably with the enzyme. Na mely, it is thought that the pro-R (F-si) fluorine is engaged in an importa nt hydrogen bond with the Phe-182 amide NH. Available methods for the synthesis of this class of alpha -monofluorinated phosphonates are reviewed. A new convergent approach, developed at Nebrask a, in which the potassium anion of (alpha -fluoro-alpha -phenylsulfonylmeth yl)phosphonate is used to displace primary triflates is also described. Thi s method is particularly convenient as it allows one to perform a "fluorina ted phosphonate scan" of an active site of interest (in what follows, we us e this expression to designate the synthesis and evaluation of a complete s et of the CH2-, CF2- and both stereoisomeric CHF-phosphonates in an active site of interest) from a single primary triflate. The properties of the tit le compounds in enzyme active sites are discussed, as are possible interact ions of these fluorine-containing bioisosteres with active site residues. ( C) 2001 Elsevier Science B.V. All rights reserved.