James R. McCarthy

Stereospecific synthesis of 1-fluoro olefins via (fluorovinyl)stannanes and an unequivocal NMR method for the assignment of fluoro olefin geometry

Abstract (E)- and (Z)-Fluorovinyl sulfones (II) form (fluorovinyl)stannanes (III) on treatment with two equivalents of tributyltin hydride and a catalytic amount of AIBN; the free radical catalyzed reaction proceeds with retention of configuration for 2,2-disubstituted fluorovinyl sulfones (IIa and IIb). Conversion of III to 1-fluoro olefins (IV) is a stereospecific reaction and provides a general method to (E) and (Z) fluoro olefins. The utility of this method is exemplified by the synthesis of the deutero fluoro olefin 27, nucleosides 32 and 34, and the amino acids 43 and 47. Proton observe, 19F irradiated (1H-19F) NOE difference specroscopy was used for the first time as an unequivocal method for the assignment of olefin geometry for fluorovinyl sulfones, (fluorovinyl)stannanes and fluoro olefins.

A new method for the electrophilic fluorination of vinyl stannanes

Abstract A new method for the electrophilic fluorination of vinyl stannanes using commercially available 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate) (1) has been developed.

A new route to 1,1-difluoro olefins: Application to the synthesis of 2′-deoxy-2′-difluoromethylene nucleosides.

Abstract Methodology has been developed for the difluoromethylenation of ketone 2 , resulting in the synthesis of cytidine derivative 1c .

The synthesis of (1-fluorovinyl)tributyltin: A synthetic equivalent for the 1-fluoroethene anion

Abstract The synthesis of (1-fluorovinyl)tributyltin ( 1b ) is reported, and the utility of 1b as a synthetic equivalent for the 1-fluoroethene anion 2 through palladium-catalyzed couplings is demonstrated.

A Stereoselective method to (E)- and (Z)-fluorovinyl phosphonates Utilizing Palladium(0) coupling methodology

Abstract The first stereoselective method to both (E)- and (Z)-fluorovinyl phosphonates from fluorovinyl iodides was developed utilizing palladium(O) based coupling protocol. This method allowed the preparation of (E)- and (Z)-fluorovinyl phosphonic acid analogs of glucose-6-phosphate that were designed to be machanism-based inhibitors of inositol synthase.

A new route to 2-fluoro-1-olefins utilizing a synthetic equivalent for the 1-fluoroethene anion

Abstract The preparation of (E)-tributyl(1-fluoro-2-trimethylsilyl)vinylstannane ( 10 ), a synthetic equivalent for the 1-fluoroethene anion, and its utility for the synthesis of nucleoside 20 , and other 2-fluoro-1-olefins is described.

Improved Synthesis of (E)-2′-Deoxy-2′-(fluoromethylene)cytidine - A Potent Inhibitor Of Ribonucleotide Diphosphate Reductase

Abstract An improved synthesis of 1 is reported that utilizes cytidine as starting material and incorporates the stereospecific method to fluoro olefins as in the original process. The new route is five steps, compared to the seven step original procedure, with an overall yield of 29%. Several intermediates are crystalline and readily purified.

Use of the Mitsunobu reaction in the synthesis of polyamines

Abstract The Mitsunobu reaction has been used in the synthesis of polyamine analogues. The synthesis of the (R,R), (S,S) and meso- isomers of a tetraamine are described. The chemistry was used to synthesize a fluorinated polyamine analog and a hexaamine.

The ribonucleotide reductase inhibitor (E)-2′-fluoromethylene-2′-deoxycytidine (MDL 101,731): a potential topical therapy for herpes simplex virus infection

The ribonucleotide reductase inhibitor MDL 101,731 was examined for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro and in combination with acyclovir in the murine zosteriform model of HSV-1 infection. The in vitro antiviral activity (IC50) for both serotypes of HSV was similar and in the range 23-98 nM for Vero cells. Comparable activities were obtained against acyclovir-resistant viruses. In the zosteriform model, topical combination therapy of MDL 101,731 with acyclovir (5%:5% w/w) applied 48 h after infection was more effective than acyclovir alone and even appeared to promote lesion resolution.

(E) and (Z)5′-fluoro olefin carbocyclic nucleosides: effect of olefin geometry on inhibition of s-adenosyl-l-homocysteine hydrolase

Abstract (E) and (Z) 4′,5′-Didehydro-5′-deoxy-5′-fluoroaristeromycin ( 9a and 9b ) were synthesized utilizing the fluoro-Pummerer reaction . Fluoro olefin 9a was a time-dependent inhibitor of S-adenosyl-L- homocysteine hydrolase whereas 9b was a competitive inhibitor. The effects of 9a and 9b on T cell proliferation are presented.