Synthesis of (.alpha.,.alpha.-difluoroalkyl)phosphonates by displacement of primary triflates

Synthesis and Anti‐Retroviral Activity of Novel 5′‐Deoxy‐5′,5′‐difluoro‐threosyl Nucleoside Phosphonic Acid Analogs

“…Hence, methoxylation of the anomeric position furnished glycoside 10 in 83% yield. Removal of the benzyl group of glycoside 10 under routine dissolving metal reduction for a prolonged time (~30 min) furnished alcohol 11 with 78% yield, which was converted to 13 using triflation followed by a triflate displacement according to the procedure of Berkowitz et al 16 Finally, the preparation of a suitable glycosylating agent was achieved by acetolysis of 13 under mild acidic conditions (Ac 2 O, AcOH, H 2 SO 4 , EtOAc, 0 C) to afford an anomeric mixture of 1-O-acetylfuranoside 14 in high yield (Scheme 2). 17 The synthesis of adenine nucleoside was performed using a Vorbrüggen condensation 18 of compound 14 with silylated 6-chloropurine and trimethylsilyltriflate (TMSOTf ) as a catalyst in DCE to yield the protected 6-chloropurine derivatives 15α and 15β, respectively.…”

The α,α-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase- Dependent Signal Transduction

“…This has spurred a great effort in methodology development in this area (Benayoud et al, 1996; Blackburn et al, 1985a; Blackburn et al, 1994; Blades et al, 1997; Caplan et al, 2000; Cockerill et al, 2000; Diab et al, 2008; Gautier et al, 2004; Herpin et al, 1996; Hikishima et al, 2006; Lopin et al, 2003; Murano et al, 2005; Nair and Burton, 1997; Ozouf et al, 2004; Pajkert et al, 2008; Pfund et al, 2005; Pignard et al, 2006; Roeschenthaler et al, 2006; Xu et al, 2005; Yokomatsu et al, 2003). The phosphate mimics program in this laboratory was initiated around the goal of establishing methods to access fluorinated phosphonate analogues of sugar phosphates (Berkowitz et al, 2001; Berkowitz et al, 2000a; Berkowitz et al, 1993; Shen et al, 1994), and continues in this direction, with a particular interest, of late, in bivalent sugar phosphonates as ligands for the mannose 6-phosphate-insulin-like growth factor II receptor (M6P/IGF2R) (Berkowitz et al, 2004; Fei et al, 2008). …”

“…Namely, in early work by Blackburn and coworkers, it was observed that the LiCF 2 P(O)(OEt) 2 anion is unstable to α-elimination to difluorocarbene, at temperatures of approximately −40 °C or higher (Bla ckburn et al, 1987). Therefore, we sought to develop especially efficient ways of capturing this nucleophile, at low T. Indeed, it was found that displacements of primary sugar triflates generally proceed at −78 °C with this rea gent, in a matter of minutes (Berkowitz et al, 1993). This behavior contrasted sharply with the markedly lower reactivity of alkyl halides.…”

“…Unfortunately, that ring opening proceeds in modest yield and limits the efficiency of this route. So, the phosphonate team in the lab set about on a parallel route, in which triflate displacement would still be employed for fluorinated phosphonate installation, but upon a glyceryl acetonide scaffold, rather similar to the sugar scaffolds originally employed (Berkowitz et al, 1993). This worked smoothly and allowed for late introduction of nitrogen, via azide displacement upon a secondary triflate (Scheme 2).…”

Nucleophilic difluoromethylation and difluoromethylenation of aldehydes and ketones using diethyl difluoromethylphosphonate

“…Diethyl difluoromethylphosphonate ( 1 ) has been used for nucleophilic introduction of difluoromethyl phosphonate moiety by a base deprotonation and reaction with various electrophiles including carbonyl compounds,15,16 imines,17 carboxylic acid esters,18,19 and chlorides,20 unsaturated compounds21 and triflates 22…”