Synthesis and Reactivity of Alkyl-1,1,1-trisphosphonate Esters

Abstract

The α–trisphosphonic acid esters provide a unique spatial arrangement of three phosphonate groups, and may represent an attractive motif for inhibitors of enzymes that utilize di- or triphosphate substrates. To advance studies of this unique functionality, a general route to alkyl derivatives of the parent system (R = H) has been developed. A set of new α-alkyl-1,1,1-trisphosphonate esters has been prepared through phosphinylation and subsequent oxidation of tetraethyl alkylbisphosphonates, and the reactivity of these new compounds has been studied in representative reactions that afford additional examples of this functionality.

Methylidynetrisphosphonates: Promising C1 building block for the design of phosphate mimetics

“…An improved version of this method includes oxidation of the phosphinate intermediate with hydrogen peroxide in tetrahydrofuran [26]. Mixed ethyl/isopropyl trisphosphonate ester 9 has been prepared by treatment of the bisphosphonate 7 with diethyl chlorophosphite and sodium hexamethyldisilazane, and subsequent oxidation of the phosphinate intermediate 8 with iodine in pyridine–THF–H 2 O (Scheme 5) [7,27].…”

“…For the synthesis of alkylidyne-1,1,1-trisphosphonate esters 12a – f a three-step protocol including synthesis of alkylidene-1,1-bisphosphonates 11 from tetraethyl methylenebisphosphonate ( 10 ), phosphinylation and oxidation has been developed (Scheme 6) [26]. Propargyl-substituted trisphosphonate 15 was prepared by conjugate addition of sodium acetylide to ethenylidenebisphosphonate 13 and the subsequent phosphinylation and oxidation (Scheme 7).…”

“…Propargyl-substituted trisphosphonate 15 was prepared by conjugate addition of sodium acetylide to ethenylidenebisphosphonate 13 and the subsequent phosphinylation and oxidation (Scheme 7). This compound has been used in an elegant construction (“click” chemistry) of triazole derivatives (see Scheme 17) [26,28]. …”

“…Upon treatment of hexaethyl methylidynetrisphosphonate ( 6 ) with NaH in THF, formation of the sodium salt was suggested by a downfield shift in the 31 P NMR spectrum (from 14 to 32 ppm). However, no further alkylation reaction could be observed with benzyl bromide and allyl bromide, presumably because of high stabilization and strong steric shielding of the carbanionic center [26]. In fact, the importance of steric factors in the reactivity of trisphosphonate esters manifested in many reactions of α-alkyl-substituted trisphosphonates.…”

“…Thus, attempted cross metathesis of allyl derivative 12b with 2-methyl-2-butene and the Grubbs second-generation catalyst afforded the unexpected cis and trans- 1,2-disubstituted olefins 30 as the major product and only a small amount of the expected trisubstituted olefin 31 . However, under similar conditions sterically less congested analogue 12e smoothly undergoes cross metathesis to give the desired trisubstituted olefin 32 in high yield (Scheme 15) [26]. …”