Benzyl phosphate, hydrogenolysis

Benzyl phosphates are less readily attacked by nucleophiles than methyl phosphates and they are more stable towards acidolysis than rm-butyl phosphates Benzyl phosphates are often used in complex polyfunctional targets because they are easily removed by hydrogenolysis. An indication of the reduced reactivity of benzyl phosphates is given in Scheme 7.17.32 Reaction of the phospho-nate diester 17.1 with one equivalent of 1 4-diazabicyclo[2 2 2]octane (DABCO) in refluxing toluene afforded the mono-deprotected derivative 17.2 in quantitative yield. Quinuclidine can also be used as the nucleophile. Assisted cleavage of benzyl phosphates is exemplified by the deprotection of the Shikimic Acid derivative in Scheme 7.18 using bromotrimethylsilane.33 34... 

TFA, FDT, TIS, H2O. These conditions readily cleave the benzyl phosphate but also result in some methyl ester hydrolysis of a cyclic peptide. The problem was avoided by using hydrogenolysis to affect cleavage, but this also reduced an olefin in the molecule. 

Scheme 6 illustrates the use of these protecting groups in the phosphorylation of 2 -deoxynucleosides by Michelson and Todd. 5 -0-Trityl-thymidine (110) was phosphorylated with dibenzyl phosphorochloridate (44) to (111), which, after treatment with 80% acetic acid, afforded thymidine 3-(benzyl phosphate) (112). Catalytic hydrogenolysis of (112) gave thymidine 3 -phosphate. Acetylation of (110) yielded the 3 -acetate (114) which, on detritylation to (115), followed by phosphorylation, catalytic reduction, and deacetylation, gave thymidine 5 -phosphate (116), identical with the thymidylic acid obtained by enzymic hydrolysis of 2 -deoxyribonueleic acid. A rather similar sequence was applied to the preparation of the 2 -deoxycytidine analogs of (113) and (116). 

Mild acid-catalyzed hydrolysis removes the acetonide group, and hydrogenolysis cleaves the benzyl phosphate bonds. 

Pd-C, EtOH, NaHC03, H2." Hydrogenolysis in the presence of NH4OAC cleaves only one benzyl group of a dibenzyl phosphate. ... 

Debenzylation of the benzyl esters of phosphoric acid has been employed in the synthesis of phosphorylated alcohols. Examples are shown in eqs. 13.2348 and 13.24.49 Tener and Khorana synthesized a-D-ribofuranose 1,5-diphosphate (36) by hydrogenolysis of the benzyl phenyl phosphate 35, first, in the presence of 5% Pd-C, and then in the presence of Adams platinum to remove, respectively, the benzyl and the phenyl groups (eq. 13.25).50... 

Myoinositol bis (trichloroethyl)phosphates were not as stable to pyridine at 20°C as were the related benzyl analogs. This group is not compatible with Fmoc chemistry because of its instability to piperidine. The trichloroethyl phosphates are compatible with TFA, and with hydrogenolysis under acidic conditions. Neutral conditions result in cleavage. ... 

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