New route to 1-formylalkylphosphonates using diethyl trichloromethylphosphonate as a precursor

The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C- nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.

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“…44 The same method applied to 2-(bromomethyl)-1,3-dioxolane afforded title compound 29, n=1 with the same NMR data as reported. 45 …”

Section: Methodsmentioning

confidence: 99%

Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

Clinch¹,

Crump²,

Evans³

et al. 2013

Bioorganic & Medicinal Chemistry

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“…32 α-Alkyl-α-silyl-chloromethylphosphonates obtained from the silylated carbanion can be involved in subsequent reactions with ethyl formate to afford 1-formylalkylphosphonates in good yields (eq 13). 33 Finally, the stabilized carbanion can be quenched with deuterium oxide. Subsequent treatment of the silylated derivative with LiOD allow incorporation of a second deuterium atom, by cleavage of the C-Si bond, to afford α,α-dideuterio-chloromethylphosphonate (eq 14).…”

Section: Synthesis Of α-Substitutedmentioning

confidence: 99%

Diethyl Trichloromethylphosphonate

Marinetti

Betzer

2014

Encyclopedia of Reagents for Organic Synthesis

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“…Hydrolysis with 2M HCl to diethyl 1-formyl-alkylphosphonates 19 usually as a mixture of aldehyde and enol in a good overall yield (70%). 41 (R Formylation of methylene group with orthoformic esters is a more limited reaction. In the presence of sodium in Et 2 O at room temperature, orthoformic esters effect a formylation reaction with a number of relatively acidic (Z=Cl, 33a Br, 33a Ph 33a,42 ) or very acidic phosphonates 25 (Z=CN, 33b CO 2 R, 33b COR 29,33a,43 ).…”

Section: Fig 5 Synthesis Of Oxazine Phosphonates 25mentioning

confidence: 99%