Science of Synthesis

Whitehead, A.; Sieck, S. R.; Mukherjee, S.; Hanson, P. R., Science of Synthesis, (2005) 21, 913.

Fluorination of acylphosphonates has been used for the study of biological phosphate mimics and other therapeutic applications.[‌21‌,‌22‌] Generation of such (fluoroalkyl)phosphonates is shown in ‌Scheme 7‌. α,α-Difluorination of an acylphosphonate is achieved through the use of a large excess of N,N-diethylaminosulfur trifluoride en route to 4-[(dihydroxyphosphoryl)difluoromethyl]-Nα-(9-fluorenylmethoxycarbonyl)-l-phenylalanine as analogues of nonhydrolyzable O-(dihydroxyphosphoryl)tyrosine for use in peptide synthesis.[‌23‌] Starting with a carboxylic acid such as ‌20‌, treatment with phosphorus tribromide provides an acid bromide which is converted into the α-oxo phosphonate ‌21‌ via the Arbuzov reaction (see Section ‌21.14.1.1.1‌). Due to the unstable nature of the phosphonate, it is immediately treated with a large excess of N,N-diethylaminosulfur trifluoride to give the desired difluorinated phosphonate ‌22‌. Subsequent alkylation at the benzyl bromide position with an imino lactone produces a 4-[(dihydroxyphosphoryl)difluoromethyl]-Nα-(9-fluorenylmethoxycarbonyl)-l-phenylalanine analogue. α-Fluorinated propargylphosphonates can be generated in a similar manner using N,N-diethylaminosulfur trifluoride.[‌24‌]

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