Synthesis of the First Stable Phosphonamide Transition State Analogue

Abstract

Three methods were selected for the one-pot synthesis of the fully protected beta-fluoroaminophosphonic acids, using the readily accessible N-protected beta-fluoroaminals. These were activated by acylation leading, by beta-elimination, to a transient N-acylimine immediately trapped by reactive forms of dialkyl phosphites. Avoiding basic conditions, the complete or partial deprotection of these N-protected beta-fluoroaminophosphonic esters allowed the synthesis of the free amino acids, their esters, and a racemic beta-trifluorophosphonamidic acid. The latter, which represents a transition state analogue formed by the bacterial transpeptidase, is perfectly stable at pH 4.7, contrary to the nonfluorinated compounds.

Synthesis of functionalized α-CF3-α-aminophosphonates via Cu(I)-catalyzed 1,3-dipolar cycloaddition

“…1 O 7 P: C,48.96;H,5.67;N,9.93. Found: C,48.81;H,5.59;N,9. (5) To a solution of Cbz-protected aminophosphonate 3b (1.6 mmol) in methanol (20 ml) 10% Pd/C (5 mol%) was added and slow stream of hydrogen was bubbled at room temperature. When TLC indicated no starting material (about 3 h), mixture was filtered and the solvent was removed under reduced pressure.…”

“…Therefore, such approach is very popular in construction of new biologically active molecules. However, in contrast to the rather well developed aminophosphonic and aminophosphinic acids area, only limited representatives of fluorine containing a-aminophosphonates are currently known [6][7][8][9][10][11][12][13]. Thus, the synthesis of new fluorinated aaminophosphonates as potential drug candidates is of current interest.…”

Asymmetric synthesis of fluorine-containing amines, amino alcohols, α- and β-amino acids mediated by chiral sulfinyl group

“…However, partial slow hydrolysis was observed at pH 2.18 (half life was 36 h). Difluorophosphonamides, hydrolytically stable at physiological pH, may find biochemical applications as potent inhibitors of metallo-proteases [48]. …”

Facile synthesis of cyclic α-perfluoroalkyl-α-aminophosphonates

“…That is why fluorine is more and more popular in the construction of new pharmaceutical and biochemical tools. However, in contrast to the rather well developed aminophosphonic and aminophosphinic acids area, only limited representatives of fluorine containing a-aminophosphonates are currently known [24][25][26][27][28][29][30][31][32]. The compounds with linear scaffold were obtained in few steps starting from fluorinated acetic acid [25], generated in situ fluorinated aldehydes [26] or fluorinated N-acyl hemiaminals [27] or aluminum iminoderivates obtained in turn by reduction of dehydropipecolinic and tetrahydroazepin-2-carboxylic acids 3 [32], were obtained via the ring closing metathesis strategy starting from a-CF 3 -substituted a-amino phosphonates with two alkene chains, 1,7-dienes and 1,8-dienes, obtained in turn by nucleophilic addition of dialkyl phosphites to highly electrophilic imines Cbz-N = C(CF 3 )P(O)(OR) 2 [31].…”