Amidation Benzyl ester

Acid B.P. M.P. 1 Anilide /hToIuI- dlde Amide phcnacyl Ester Nltro- benzyl Ester /)-Phenyl- phenacyl Ester S-Benzyl> Mo-thlu- ronlum Salt -Bromo- anlUde Hydrazlde ... 

Add B.P. H.P Anilide Amide phenacyl Ester benzyl Ester phenacyl Ester uronlum Salt ... 

Acid B.P. H.P. AnlUde p-Tolu4- dide 1 Amide p-Bromo- phenacyl ter p-Nitro- benzyl Ester p-Phenyl phenacyl Ester S-Benzyl- uo-thi- uronium Salt Other Derivatives... 

The carboxamidomethyl ester was prepared for use in peptide synthesis. It is formed from the cesium salt of an A-protected amino acid and o -chloroacet-amide (60-85% yield). It is cleaved with 0.5 M NaOH or NaHC03 in DMF/H2O. It is stable to the conditions required to remove BOC, Cbz, Fmoc, and t-butyl esters. It cannot be selectively cleaved in the presence of a benzyl ester of aspartic acid. ... 

The chemistry of indium metal is the subject of current investigation, especially since the reactions induced by it can be performed in aqueous solution.15 The selective reductions of ethyl 4-nitrobenzoate (entry 1), 2-nitrobenzyl alcohol (entry 2), l-bromo-4-nitrobenzene (entry 3), 4-nitrocinnamyl alcohol (entry 4), 4-nitrobenzonitrile (entry 5), 4-nitrobenzamide (entry 6), 4-nitroanisole (entry 7), and 2-nitrofluorenone (entry 8) with indium metal in the presence of ammonium chloride using aqueous ethanol were performed and the corresponding amines were produced in good yield. These results indicate a useful selectivity in the reduction procedure. For example, ester, nitrile, bromo, amide, benzylic ketone, benzylic alcohol, aromatic ether, and unsaturated bonds remained unaffected during this transformation. Many of the previous methods produce a mixture of compounds. Other metals like zinc, tin, and iron usually require acid-catalysts for the activation process, with resultant problems of waste disposal. 

Acid B.P. M.P Anilide Tolul- dlde Amide Bromo- pbenacyl Ester Nltro- benzyl Ester Pbenyl- pbenacyl Ester S-Benzyl- wo-tbi- uronlum Salt Other Oeilvatlves... 

L-alanylglycyl-L-cysteinyl-L-lysyl-L-asparaginyl-L-phenylalanyl-L-phenylalanyl-L-tryptophanyl-L-lysyl-L-threonyl-L-threonyl-L-cysteine 6-0-benzoyl-N-(benzyloxycarbonyl) methylamide 4,6-0-benzylidene-N-benzylidene-N-(benzyloxycarbonyl) methylamide N- (benzyloxy carbonyl) -N-(benzyloxycarbonyl)-, amide N-(benzyloxycarbonyl)-, hydrazide N-(benzyloxycarbonyl)-, methylamide N-(benzyloxycarbonyl)-, methyl ester N-(benzyloxycarbonyl)-L-alanyl-L-alanine methyl ester N-(benzyloxycarbonyl)-L-alanylglycine ethyl ester N-(benzyloxycarbonyl)glycyl-L-alanine methyl ester 3,4,6-tri-0-acetyl-2-amino-2-deoxy-N-(benzyloxycarbonyl)-, benzyl ester, hydrochloride... 

Reaction of iV-[(benzotriazol-l-yl)methyl]amide 707 with PCI5 gives chloroimine 708, which upon treatment with Bu OK is converted to nitrile ylide 709. Benzyl esters of ot,(3-unsaturated acids used as dipolarophiles trap species 709 to generate pyrroles 712 (Scheme 110) <2002JHC759>. When no trapping agent is added, the N-2 atom of benzotriazole act as a nucleophile, and tricyclic system 711 is formed <2001TL9109>. Addition of benzyl bromide... 

There are dozens of linkers available for synthesis, and nearly all of them, once acylated by a protected amino acid, provide a benzyl ester or a benzyl amide that has been sensitized to cleavage by acid by the presence of electron-donating moieties such as alkoxy, phenyl, or substituted phenyl. There are cases in which a peptide chain is bound to a support through two different linkers in series. This allows for versatility in synthesis. The distinction between designation of a moiety affixed to a support as a handle or linker is sometimes arbitrary. 

The first peptide amides prepared by solid-phase synthesis were obtained by ammonolysis of resin-bound benzyl esters of peptides in solvents containing methanol (Figure 5.16, A). The method was occasionally employed but was not popular because it was inefficient, producing some ester in addition to the amide. A new variant employing gaseous ammonia will likely rekindle this approach (see Section 8.3). During the early developments of solid-phase synthesis, it was known that the... 

FIGURE 5.16 Production of amides by cleavage of benzhydryl amides. Recognition that removal by acidolysis of benzhydryl protectors from carboxamides gave the amides (B) led to development of benzhydrylamine (BHA) resin (C).33 Treatment with HF of a peptide amide that has been assembled on a BHA resin using Boc/Bzl chemistry gives the peptide amide (D). Peptide amide is also obtainable by ammonolysis of the resin-bound benzyl ester (A), a reaction that is more efficient if gaseous NH3 is employed (see Section 8.3). 

Completion of the synthesis of quinapril involves amide bond formation between 26 and a tetrahydroisoquinoline fragment. Two complementary protected 1,2,3,4-tetrahydro-3-isoquinoline subunits 27 and 28, each available in a single step from commercially available (6)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, were utilized (Scheme 10.7). Coupling with 26 using DCC and HOBt in dichloromethane afforded the penultimate compounds 29 and 30 as maleate salts. Cleavage of the f-butyl ester of 29 and treatment with HCl provided quinapril. Alternatively, hydrogenation of 30 under standard conditions cleanly removed the benzyl ester, and quinapril (3) was isolated after formation of the hydrochloride salt. 

The carbodiimide method has been employed in several syntheses of depsipeptides. However, direct application of DCC for the formation of the ester bond between the amino acid and hydroxy acid components under the usual conditions of amide coupling affords the desired depsipeptides in acceptable yields only in the case of unhindered co-hydroxy units [54] or an active hydroxy group, such as in TV-benzoyl-u-hydroxyglycine benzyl ester. For example, Ravdel et al.[55 have performed the esterification of various benzyloxycarbonyl- and phthalylamino acids with /V-benzoyl-a-hydroxyglycine benzyl ester with DCC in 50-65% yield. On the other hand, Shemyakin et all21 failed to obtain the expected depsipeptide products on condensation of bulky benzyloxycarbonyl- or phthalylvaline with a-hydroxy-isovaleric acid benzyl ester. The main product was acylurea in the first case and phthalylvaline anhydride in the second. Thus, the classical carbodiimide procedure could not be applied in practical depsipeptide preparation. 

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. 

Coupling of the two amino acids is achieved by N, N -dicyclohexyIcarbodiimide (DCCI)-promoted amide bond formation between the free amino group of leucine benzyl ester and the free carboxyl group of Z-protected alanine. 

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