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New stereocontrolled routes into functionalized fluorinated phosphonates: Discovery of an exceptionally facile thiono-claisen rearrangement

Kaushik Panigrahi, University of Nebraska - Lincoln


Fluorinated phosphonates are phosphatase-resistant mimics of biological phosphates. The potential of this class of "teflon phosphonates" has long been recognized in areas such as medicinal chemistry and chemical biology where these analogues can be used to mimic a "constitutive phosphorylation" phenotype to study cell signaling pathways, for example. For years, the Berkowitz group and others have been developing methodology for the synthesis of fluorinated phosphonates. The major part of this thesis work will focus on a new chemoenzymatic approach for the facile and stereoselective synthesis of densely functionalized δ-thio-β,γ-unsaturated-&agr;,&agr;-difluorophosphonate building blocks. The precursor enantioenriched (L)-β-hydroxy-&agr;,&agr;-difluorophosphonate is synthesized by the stereoselective reduction of the corresponding β-keto substrate using an alcohol dehydrogenase enzyme from Clostridium acetobutylicum (CaADH). The resultant alcohol, upon conversion to a pentafluorophenyl thionocarbonate, undergoes a rapid [3,3]-sigmatropic thiono-Claisen rearrangement with a half-time (t1/2) of 3 min @ RT. Pleasingly, the one step β-C-O to δ-C-S transformation proceeds with conservation of enantiopurity and in high yield. An Eyring analysis of the temperature dependence of this transformation reveals an unusually positive entropy of activation (ΔS = +14.5 e.u.), suggesting a partially dissociative T.S, which is further supported by studies on solvent dependence. In related work, methodology for the efficient synthesis for allyl ester bearing &agr;,&agr;-difluorinated phosphonates has been developed. Diallyl &agr;,&agr; –difluoromethyllithium is added into aldehyde substrates, followed by a modified Barton deoxygenation, under conditions compatible with the allyl ester protecting groups. Finally, a relatively unexploited Ru(II)-deallylation catalyst (Kitamura catalyst) is used to deblock the allyl phosphonate ester protecting groups, in essentially quantitative yield. Mild conditions are employed, with methanol formally serving as the allyl cation scavenger. This methodology was applied to the synthesis and evaluation of a set of bis-( &agr;,&agr;-difluoro)phosphonate PTP1B (Protein Tyrosine Phosphatase 1B) inhibitors.

Subject Area

Cellular biology|Biochemistry|Physical chemistry

Recommended Citation

Panigrahi, Kaushik, "New stereocontrolled routes into functionalized fluorinated phosphonates: Discovery of an exceptionally facile thiono-claisen rearrangement" (2014). ETD collection for University of Nebraska - Lincoln. AAI3667146.