Cleavage of phosphonate esters

In Situ Generation of lodotrimethylsilane. Of the published methods used to form TMSI in situ, the most convenient involves the use of TMSCl with Nal in acetonitrile. This method has been used for a variety of synthetic transformations, including cleavage of phosphonate esters (eq 23), conversion of vicinal diols to alkenes (eq 2A), and reductive removal of epoxides (eq 25). ... 

Cleavage of Phosphonate Esters. Compared to the reactivity of TMS-I with phosphonate and phosphate esters, TMS-Br is more selective and will cleave phosphonate esters even in the presence of carboxylic esters and carbamates. Benzyl ester protecting groups on aryl phosphates are selectively removed with TMS-Br. The reaction of phosphonate esters with TMS-Br proceeds through a mechanism similar to ester cleavage, providing a silyl ester which is subsequently hydrolyzed with MeOH or H2O (eq 14). 

In the instances of phosphorous and phosphonous acid systems, the generation of a new C-P bond via the classical Michaelis-Arbuzov reactions as noted above leads to products that are esters themselves. Isolation of the free acid product requires cleavage of the ester linkage in a separate reaction step, generally after isolation and purification of the initial product. The advent of silyl phosphorus reagents for the Michaelis-Arbuzov reaction allowed free acid products to be isolated simply by water workup of the reaction system. Further, since the byproduct was a silyl-halide, the general concern that the by-product halide would participate in an extraneous Michaelis-Arbuzov reaction was obviated. 

Scheme 29 Cleavage of Phosphonate, Phosphonamidate, and Carboxylate Methyl Esters Using Lithium Propanethiolate 67 71 73 103 ...

However, the 1-(substituted phenoxyacetoxy(alkylphosphonic acids were not stable, because these compounds themselves were strong acids which would lead to the cleavage of carboxylate ester group. Alternatively, mono alkali metal salts of 1-(substituted phenoxyacetoxy)alkylphosphonic acids were designed including monolithium salts (IIF-l-IIF-13), monosodium salts (IIG-l-IIG-13), and monopotassium salts (IIH-l-IIH-13). These compounds were almost neutral salts with higher stabihty than the corresponding phosphonic acids (Scheme 3.9). 

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

Other types of ester have been studied (Fendler and Fendler, 1975 Bender and Komiyama, 1978 Szejtli, 1982), though in much less detail. Brass and Bender (1973) studied the cleavage of two diaryl carbonates and three diaryl methylphosphonates in basic buffers (Table A5.ll). For the carbonates, reacting with /1-CD, introduction of p-nitro groups increases the acceleration ratio and worsens substrate binding, so that KTs barely alters. More interesting are the results for the phosphonates in that the effects of nitro groups depend on their position and on the CD. 

Quite recently it was shown that phosphonic esters, trimethylsilyl [124, 143] and alkyl esters [124,143, 145] could also be used to modify the surface of titanium or aluminum oxide in organic solvents at moderate temperatures. Unlike Si-O-C bonds, P-O-C bonds are not easily hydrolyzed, and their cleavage on an oxide surface was unexpected. Most probably, coordination of the phosphoryl oxygen to the surface assists the condensation by increasing the electrophilicity of the P atom, thus facilitating the condensation of P-0-R groups with surface hydroxyls (Scheme 7) [124]. The chemisorption of... 

Cleavage of the phosphonate allyl esters from Abu[PO(OAl)2]-peptide-resins is accomplished by treatment with Pd(PPh3)4 (50 °C, 5 h)[103l followed by acidolytic deprotection of the Abu[PO(OH)2]-peptide from the resin support. The viability of employing allyl phosphonate protection for phosphopeptide synthesis has been demonstrated by the Fmoc solid-phase synthesis (DIC/HOBt couplings) of several 6-9-mer Abu[PO(OH)2]-containing peptides and has been extended to the synthesis of a 19-mer caldneurin-related Abu[PO(OH)2]-peptide.[104 ... 

Demethylation of, POCH3. Phosphate and phosphonate esters are partially dealkylated by tertiary amines. r-Butylamine is superior Tor this cleavage, and it is very selective. Only O—Cl I3 bonds are affected ethyl esters are stable to the amine for several weeks. A benzyl group can be cleaved under forcing conditions.1 [Examples ... 

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