Hydrogenolysis benzyl amides

Benzyl amides are more resistant to hydrogenolysis than are secondary benzyl amines (Eqn. 20.47). Higher temperatures and pressures are required to debenzylate these amides. 

Na or Li and ammonia, excellent yields. This is a very good method to remove a benzyl group from an amide and will usually work when hydrogenolysis does not. A dissolving metal reduction can be effected without cleavage of a sulfur-carbon bond. Note also the unusual selectivity in the cleavage illustrated below. This was attributed to steric compression. Primary benzyl amides are not cleaved under these conditions. ... 

Esters and amides are quite resistant to hydrogenation under almost all conditions so their presence is not expected to cause difficulties. Alkyl ethers and ketals are generally resistant to hydrogenolysis but benzyl ethers are readily cleaved, particularly over palladium or Raney nickel catalysts. ... 

Dibenzopyrrocolines have been prepared by intramolecular addition of benzyne intermediates and by nucleophilic substitutions, as shown in Scheme 6 with the synthesis of ( )-cryptowoline (2) and the related dehydro base 39 by Bennington and Morin (7). ( )-6 -Bromotetrahydroisoquinoline 37, prepared by standard procedures, when heated with copper powder in dimethylformamide afforded dibenzopyrrocoline 38 in low yield, and 39 was formed when 37 was allowed to react with potassium amide in liquid ammonia. Compound 39 was converted to ( )-cryptowoline iodide (2) by hydrogenolysis of O-benzyl ether 39 and quartemization with methyl iodide. 

Benzyl alcohol linkers, such as those described in Section 3.1.1.1, can also be cleaved by palladium-catalyzed hydrogenolysis. Carboxylic acids have, for example, been obtained by hydrogenolysis of insoluble benzyl esters with Pd(OAc)2/DMF/H2 [89,161]. Resin-bound benzylic carbamates [162,163] and amides [164] can also be released by treatment with Pd(OAc)2 in DMF in the presence of a hydrogen source, such as 1,4-cyclohexadiene or ammonium formate. These reactions are quite surprising, because they require the formation of metallic palladium within the gelated beads. 

The 5-methyl ether of V-acetylmannosamine cannot be prepared by this route. The D-glucofuranose 42 was obtained from the 5,6-diol by selective benzylation by way of the dibutyltin derivative, followed by conventional methylation. It was converted into the benzyl glycoside 43 with benzyl alcohol under acidic conditions. Conversion into the amine 44 and amide 45 followed the same path as in the pyranose series. Hydrogenolysis gave20 28 (see Scheme 12). 

The amino group of the A-benzyloxycarbonyl derivative is protected as the amide half of a carbamate ester (a urethane, Section 21-16), which is more easily hydrolyzed than most other amides. In addition, the ester half of this urethane is a benzyl ester that undergoes hydrogenolysis. Catalytic hydrogenolysis of the A-benzyloxy carbonyl amino acid gives an unstable carbamic acid that quickly decarboxylates to give the deprotected amino acid. 

The final step in the solution-phase synthesis is to deprotect the N terminus of the completed peptide. The N-terminal amide bond must be cleaved without breaking any of the peptide bonds in the product. Fortunately, the benzyloxycarbonyl group is partly an amide and partly a benzyl ester, and hydrogenolysis of the benzyl ester takes place under mild conditions that do not cleave the peptide bonds. This mild cleavage is the reason for using the benzyloxycarbonyl group (as opposed to some other acyl group) to protect the N terminus. 

Cbz-protected amines behave like amides—they are no longer nucleophilic, because the nitrogen s lone pair is tied up in conjugation with the carbonyl group. They are resistant to both aqueous acid and aqueous base, but they have, to use the analogy we developed in the last chapter, an Achilles heel or safety catch—the benzyl ester. The same conditions that removed benzyl ethers in Chapter 24 will remove Cbz HBr or hydrogenolysis. cleavage of Cbz (Z) in HBr/AcOH... 

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