This talk will highlight key developments in a program directed at the synthesis and application of biologically relevant a,a-difluorinated phosphonates.  a-Fluorinated phosphonates are of interest because they act as isopolar/isoacidic analogues of the corresponding biological phosphate esters, yet are resistant to cleavage by phosphatase enzymes.  Most of the synthetic routes developed at Nebraska to access these phosphate mimics emanate from LiCF2P(O)(OR)2 reagents and include: (A) triflate displacement; (B) addition into (activated) esters, and (C) addition into aldehydes with the corresponding diallyl-protected reagent, followed by especially mild deoxygenation and Ru(II)-catalyst mediated phosphonate ester deprotection.  A recently discovered variant on Method B involves nucleophilic difluoromethyl phosphonate anion 1,2-addition into activated a,�-unsaturated carboxylates.  The resultant �-keto a,a-difluorophosphonate esters may be enzymatically reduced to enantiomerically enriched secondary allylic alcohols, and subjected to a remarkably facile thia-Claisen rearrangement, following installation of an appropriate thiono-ester.  Using this suite of methods, alpha-di-, mono- and non-fluorinated sugar phosphonates have been assembled and shown to serve as artificial substrates of sugar phosphate-processing enzymes or competitive inhibitors for sugar-phosphate-binding receptors.  Finally, these methods have collectively allowed the a,a-difluorinated phosphonate analogues of phosphoserine or phospho-threonine to be accessed in these laboratories.  These chemical biological tools have been deployed in the community to induce an artificial �constitutive� phosphorylation phenotype (i) to more efficiently produce antibodies to native phosphoproteins or (ii) to illuminate the regulatory roles of specific protein phosphorylation events.

New stereocontrolled routes into fluorinated phosphonates as surrogates of biologically relevant phosphates

244th National Meeting (2012)

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