Benzyl ester, hydrogenolysis

Benzyl ester, hydrogenolysis of, 1034 Benzyl group, 518 Benzylic, 377... 

Carboxyl groups of ammo acids and peptides are normally protected as esters Methyl and ethyl esters are prepared by Fischer esterification Deprotection of methyl and ethyl esters is accomplished by hydrolysis m base Benzyl esters are a popular choice because they can also be removed by hydrogenolysis Thus a synthetic peptide protected at both... 

Catalytic transfer hydrogenation (entries 2 and 3 below) can be used to cleave benzyl esters in some compounds that contain sulfur, a poison for hydrogenolysis catalysts. 

Catalytic hydrogenolysis of an O-benzyl protective group is a mild, selective method introduced by Bergmann and Zervas to cleave a benzyl carbamate (>NC0-0CH2C6H5 —> >NH) prepared to protect an amino group during peptide syntheses. The method has also been used to cleave alkyl benzyl ethers, stable compounds prepared to protect alkyl alcohols benzyl esters are cleaved by catalytic hydrogenolysis under neutral conditions. 

In a penicillin synthesis, the carboxyl group was protected as a / -bromophenacyl ester that was cleaved by nucleophilic displacement (PhSK, DMF, 20°, 30 min, 64% yield). Hydrogenolysis of a benzyl ester was difficult (perhaps because of catalyst poisoning by sulfur) basic hydrolysis of methyl or ethyl esters led to attack at the /3-lactam ring. ... 

Formation of this ester proceeds under standard DCC coupling conditions (DMAP, THF, 28-93%). The ester is cleaved with 1% TFA or dichloroacetic acid in CH2CI2 by DDQ (reflux, CH2CI2, H2O, 5-15 h, 47-92% yield). Hydrogenolysis (Pd/C, EtOAc, MeOH) cleaves the ester in 23 h, whereas a benzyl ester is cleaved in 10 min under these conditions. ... 

The most useful property of benzyl esters is that they are readily cleaved by hydrogenolysis. 

Tertiary amines are effective promoters in hydrogenolysis of hindered benzyl esters that otherwise may undergo cleavage only with difficulty (187). 

In subsequent studies,22 Sheehan et al. demonstrated that the action of diisopropylcarbodiimide on penicilloate 24, prepared by protection of the free primary amino group in 23 with trityl chloride (see Scheme 6b), results in the formation of the desired -lactam 25 in a very respectable yield of 67 %. In this most successful transformation, the competing azlactonization reaction is prevented by the use of a trityl group (Ph3C) to protect the C-6 amino function. Hydrogenolysis of the benzyl ester function in 25, followed by removal of the trityl protecting group with dilute aqueous HC1, furnishes 6-aminopenicillanic acid (26), a versatile intermediate for the synthesis of natural and unnatural penicillins. 

Benzyl esters of carboxylic acids are frequently used in organic synthesis for the protection of carboxyl groups. The C-O bond in benzyl esters can be cleaved more easily than the corresponding benzyl ether bond. The hydrogenolysis of an ester leads to carboxylic acid and toluene. Examples of debenzylation of benzyl esters of carboxylic acids on Pd/C catalysts are summarized in Table 4.4. 

Concomitant hydrogenolysis of a benzyl ester and hydrogenation of a diene were performed in one step over Pt02 in AcOEt.207 In contrast, 10% Pd(OH)2/C in AcOEt or EtOH at room temperature for 1 hour under hydrogen was used for the hydrogenolysis of a benzyl group without the saturation of a cyclic carbon-carbon double bond.208... 

During the preparation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, the benzyl ester protecting group was removed by catalytic hydrogenolysis (Scheme 4.42). 

The a-carbonyl function of a lactam was removed by transfer hydrogenolysis. Its benzyl ester was dissolved in MeOH under argon ammonium formate and 5% Pd/C were added and the reaction mixture was stirred for 1.5 hours.271,272... 

The Pyoc group is stable to acids and bases, but may be selectively removed after conversion into the jV-methylpyridinium form and subsequent treatment with morpholine, to give 146. Treatment of 146 with acetic anhydride in pyridine gave 147. Hydrogenolysis of the benzyl ester group of 147 followed by methanolysis catalyzed by hydrazine afforded (44,73) the de-protected derivative 148. 

---