Benzyl amino acid synthesis

Oxazol-5(2H)-one, 2-benzylidene-4-methyl-tautomerism, 6, 186 Oxazol-5(2ff)-one, 2-methylene-isomerization, 6, 226 Oxazol-5(2H)-one, 2-trifluoromethyl-acylation, 6, 201 Oxazol-5(4ff)-one, 4-allyl-thermal rearrangements, 6, 199 Oxazol-5(4H)-one, 4(arylmethylene)-Friedel-Crafts reactions, 6, 205 geometrical isomerism, 6, 185 Oxazol-5(4ff)-one, 4-benzylidene-2-phenyl-configuration, 6, 185 photorearrangement, 6, 201 Oxazol-5(4ff)-one, 4-benzyl-2-methyl-Friedel-Crafts reactions, 6, 205 Oxazol-5(4ff)-one, 4-methylene-in amino acid synthesis, 6, 203 Oxazol-5(4ff) -one. 2-trifluoromethyl-hydrolysis, 6, 206 Oxazolones... 

Amino acid synthesis.1 Optically pure amino acids can be prepared in two steps from serine, readily available as either the d- or L-enantiomer. Reaction of N-benzylserine (or of N-benzyl-N-Boc-serine) with the preformed Mitsunobu reagent in CH3CN at -55° provides the protected serine (J-lactone (2) in almost quantitative yield. The lactone reacts with lithium organocuprates (R2CuLi) to... 

Scheme 5. Asymmetric variants of the amino acid synthesis according to Strecker (Bn = Benzyl).

Lactim benzyl ethers. Cyclodipeptides are converted to the bislactim ethers, which are valuable intermediates for stereoselective a-amino acid synthesis. 

Kawase described a direct and general synthesis of 2,4-disubstituted 5-(trifluoromethyl)oxazoles 500 from reaction of an A -acyl-A-benzyl amino acid 499 with trifluoroacetic anhydride in pyridine (Scheme 1.136). In general, the best... 

A key point to note in the synthesis of the N,0-bis(Fmoc)-N-(2-hydroxy-4-methoxy benzyl)amino acid derivatives is the balance of water to dioxane in the reaction mixture. Improved yields are obtained if the sodium salt of the desired product precipitates in the reaction mixture on its formation, since the Fmoc group present on the 2-hydroxyl as a carbonate is removed slowly by aq. Na2C03. Thus, if the proportion of dioxane present in the reaction mixture is sufficient to keep the desired product is solution, then pre-... 

Amino Acids. Chloroformates play a most important role for the protection of the amino group of amino acids (qv) during peptide synthesis (32). The protective carbamate formed by the reaction of benzyl chloroformate and amino acid (33) can be cleaved by hydrogenolysis to free the amine after the carboxyl group has reacted further. The selectivity of the amino groups toward chloroformates results in amino-protected amino acids with the other reactive groups unprotected (34,35). Methods for the preparation of protected amino acids on an industrial scale have been developed (36,37). A wide variety of chloroformates have been used that give various carbamates that are stable or cleaved under different conditions. 

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

A similar series of reactions was performed by Paulsen and Hdlck141 for the preparation of the T-antigenic, unprotected, amino acid-disaccha-rides 200 and 201, starting from the 4,6-0-benzylidene-N-(benzyloxy-carbonyl) benzyl esters 198 and 199, respectively, by condensation with 110 in the presence of mercury dicyanide-mercury dichloride and molecular sieves 4A, and deprotection of the product. Sinay and co-workers148 also reported the synthesis of hexa-O-acetyl derivatives of 200 and 201 by application of the sequence of azido-nitration-bromination. 

Cooke and coworkers reported on the synthesis of the amino acid N-benzyl-4-acetylproline (2-889) (Scheme 2.198) [453], as this might represent an interesting synthon for the preparation of bioactive compounds. These authors also used a domino iminium ion formation/aza-Cope/Mannich protocol. Thus, treatment of the secondary amine 2-885 with glyoxylic acid (2-888) primarily provided the corresponding iminium ion, which led to 2-889 in 64% yield as a mixture of diastereom-ers. 

In the search of new methodologies for the asymmetric synthesis of nonproteinogenic amino acids, 8-methyl-4,8a-diphenyltetrahydro-17/-pyrrolo[2.1 -r l, 4 oxazinc-l, 6(7//)-dionc 62, obtained as described in Scheme 24 (Section 11.11.7.3), was selectively reduced at the lactam carbonyl with BH3 and further opened by hydrogenolysis to give syn-disubstituted proline derivative 64 in 95% yield <1997SL935> (Scheme 6). It is noteworthy that hydrogenolysis did not affect the benzylic position of bicyclic compound 63. 

The efficient addition-cyclization sequence described above could be successfully applied to the preparation of the polyhydroxylated y-amino acid (-)-detoxinine [73], The crucial key step in this fairly short synthesis is the chelate-controlled addition of lithiated benzyloxyallene 120 (R = Bn) to the chiral N-benzyl-substituted imine 121 as shown in Scheme 8.31. The required skeleton of the natural product was generated in good overall yield. 

The next residues were attached successively by dicyclohexylcarbodiimide-mediated coupling of Boc-amino acids with the free amino groups. The use of excess Boc-amino acid eliminated the need for capping after coupling. The last Boc-group and the benzyl-based side chain and carboxy-terminal protectors were removed at the end of the synthesis by acidolysis with hydrogen bromide in trifluoroacetic acid the latter was used instead of acetic acid to avoid acetylation of hydroxymethyl side chains (see Section 6.6). Catalytic hydrogenolysis of the peptide removed the nitro... 

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. 

FIGURE 5.17 Resins and linkers for synthesis of peptides using Fmoc/tBu chemistry. The linkers are secured to supports by reaction with aminomethyl resins. A protected amino acid is anchored to the support as an ester by reaction with a hydroxyl or chloro group (italicized). The alkoxy and phenyl substituents render the benzyl esters sensitive to the cleavage reagents. 

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