Benzyl Phosphates

From a tributylstannyl phosphate BnBr, Et4NBr, CH3CN, reflux. Phenacyl, 4-nitrobenzyl and simple alkyl derivatives were similarly prepared. Yields are substrate and alkylating-agent dependent.  

Diphenyl phosphates are converted by transesteriflcation to dibenzyl phosphates upon treatment with BnONa in THF at 25°C in 83% yield.  

NaHCOs, H2. Hydrogenolysis in the presence of NH4OAC cleaves only one benzyl group of a dibenzyl phosphate.  

ammonia. Cyanoethyl and trichloroethyl phosphates are also deprotected. 

1 M TFMSA in TFA, thioanisole. Dibenzyl phosphates are only partially labile to TFA alone.  

---

The following table compares the cleavage rates for a variety of benzyl phosphates using thiols or pyridine for the reaction" " ... 

The above section already introduced the influence of leaving groups at the benzylic position that eliminate to form and regenerate QM3, and the trend extends beyond adducts formed by the deoxynucleosides as expected. The standard benzylic acetate of QMP4 eliminates completely from the deprotected phenol under neutral aqueous conditions and ambient temperature within approximately 20 h, while an equivalent benzyl bromide eliminates completely within 5 min.48 Benzylic phosphates are also extremely labile, and, if the phosphate backbone of DNA is able to trap QM, the resulting products are likely to be too labile for standard detection.53,54 In contrast, amines and thiols are much less susceptible to elimination from the benzylic position and require forcing conditions to regenerate the parent QM.26,30 The benzylic alcohol derivative also appears stable under almost all thermal conditions and only eliminates routinely to form a QM after photochemical excitation.55... 

Scheme 3) [30]. The pY + 3 diversity alcohols (Ri)-OI I (Fig. 15) were attached to the template through a Mitsunobu coupling to provide ether derivatives of 16. Palladium-mediated Alloc deprotection followed by amide formation using the phosphate-ester-containing diversity acids (R2)-C02H provided the fully coupled resin-bound products of 17. Cleavage from the resin with 95% TFA/H20, which also afforded benzyl phosphate deprotection, followed by reversed-phase (RP) semipreparative... 

The deprotection procedure is based on transesterification of benzyl phosphate into the corresponding silyl ester followed by hydrolysis or alcoholysis. 

Another beautiful example of multiple recognition by the use of multi-functionalized cyclodextrin is symmetrical triamino-O-permethyl-a-cyclo-dextrin (16), which is designed for the specific recognition for the phosphate group (Fig. 23) (55). As is expected, 16 shows a higher affinity toward benzyl phosphate (Kass = 3.2 x 104) than does the corresponding monoammonium derivative (Kaas = 3.3 x 101). 

Hammerschmidt, F. Schmidt, S. Deprotonation of secondary benzylic phosphates. Configurationally stable benzylic carbanions with a diethoxyphosphoryloxy substituent and their rearrangement to optically active tertiary a-hydroxyphosphonates. Chem. Ber. 1996, 329, 1503-1508. 

Hammerschmidt, F. Hanninger, A. Enantioselective deproto nation of benzyl phosphates by homochiral lithium amide bases. Configurational stability of benzyl carbanions with a dialkoxyphosphoryloxy substituent and their rearrangement to optically active a-hydroxy phosphonates. Chem. Ber. 1995, 328, 823-830. Avolio, S. Malan, C. Marek, I. Knochel, P. Preparation and reactions of functionalized magnesium carbenoids. Synlett 1999, 1820-1822. 

The parallelism in reactions with HMPT and mixtures of phosphorus pentoxide and amines can best be realized by looking at the mechanism of HMPT reactions [1 5 ]. In the reaction of p-methoxy-benzylalcohol with HMPT which produce the corresponding N,N-dimethylbenzyl amine--p-methoxybenzyl phosphate was identified in the XP NMR spectrum of the reaction mixture. Since pyrophosphate was also observed during the reaction of the benzyl alcohol with HMPT, the intermediate formation of the metaphosphate anion can be assumed. Addition of the benzyl alcohol to that anion then produce the benzyl phosphate. Phosphate ions are known to be good leaving groups so that a benzylamine can easily be produced from the phosphate by reaction with di-methylamine released from the dimethylammonium ion. The phosphoric acid produced during the reaction is believed to react with HMPT, so that more dihydro-gen-bis(dimethylammonium) pyrophosphate is formed. 

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... 

A trenchant example of the utility of benzyl phosphates is found in the synthesis of 5-PP-D-myo-InsP5 (19.7) outlined in Scheme 7 19,35 which illustrates how a... 

SYNS 2-CHLORO-l-(2,4,5-TRICHLOROPHENYI.)VINYL DIMETHYL PHOSPHATE 2-CHLORO-l-(2,4,5-TRICHLOROPHENYL)VINYL PHOSPHORIC ACID DIMETHYL ESTER 0,0-DIMETHYL-0-2-CHL0R-l-(2,4,5-TRICHLORPHENYL)-VINYDPHOSPHAT (GERMAN) IPO 8 NCI-C00168 PHOSPHORIC ACID, 2-CHLORO-1 -(2,4,5-TRICHLOROPHENYL)ETHENYL DIMETHYL ESTER 2,4,5-TRICHLORO-a-(CHLOROMETHYLENE)-BENZYL PHOSPHATE... 

Mild treatment of periodate-oxidized adenosine 5-phosphate or adenosine 5-(benzyl hydrogen phosphate) with alkali gave adenine and inorganic phosphate or benzyl phosphate. " " Periodate oxidation followed by alkali treatment would, therefore, be a means of degrading polynucleotides step-wise. " " A dinucleotide has been degraded in this way. " ... 

Preparation. Under the catalytic action of 2,6-lutidine, the reagent reacts with a free hydroxyl group of a sugar (1) to form a benzyl phosphate (2), which can be chlorinated with N-chlorosuccinimide (3). Hydrolysis then gives the benzyl hydrogen phosphate (4), and the benzyl group is removed by hydrogenation. ... 

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. 

Phosphate derivatives 168 (Fig. 1) were also prepared starting from racemic 4-z-propyl-2-bromomethyl-isothiazolidin-3-one S,S-dioxide and di -butyl- and benzyl phosphate in the presence of DBU [55]. 

The photochemistry of phosphate esters, including benzylic phosphates, has recently been reviewed by Givens and Kueper [121]. Much of this research has... 

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). 

Phosphodiesters and phosphotriesters cannot undergo substitution reactions by dissociative mechanisms. Thus, the dibenzyl phosphate monoanion is much less reactive in hydrolysis than the benzyl phosphate monoanion (107). 

On investigating the relationship between the action and structure of the compounds, Kado (1969) established that S-benzyl-0,0-dialkyl derivatives are more effective than the respective O-benzyl-phosphate, phosphorothioate and phosphorodithioate derivatives. The 0,0-diisopropyl derivative is more stable than the diethyl derivative and at the same time less toxic to warm-blooded organism (Yamamoto et al., 1973). Recently, 15000 tons of the diisopropyl derivative (IBP), marketed under the name Kitazin P , has been used in Japan for prevention of rice blast (Searle et al., 1973). 

---