benoiton - chemistry of peptide synthesis (crc, 2006)

[...]... a Boc-Xff-OH + H-Xee-OR Boc-Xff-Xee-OR Boc-Xff-Xee-OH + H-Xdd-OR Boc-Xff-Xee-Xdd-OR Boc-Xbb-OH + H-Xaa-OR Boc-Xbb-Xaa-OR Boc-Xcc-OH + H-Xbb-Xaa-OR Boc-Xcc-Xbb-Xaa-OR Boc-Xff-Xee-Xdd-OH H-Xcc-Xbb-Xaa-OR + Gly by segment coupling Pro Boc-Xff-Xee-Xdd-Xcc-Xbb-Xaa-OR FIGURE 1.19 Strategies for the synthesis of enantiomerically pure peptides Peptides are always synthesized starting from the carboxy-terminal... feature of the synthesis It is ideally achieved by use of a chemical mechanism 6 Chemistry of Peptide Synthesis NH2-AA2-CO2H NH2-AA3-CO2H Protection Pg2 Pg5NH-AA2-CO Coupling Selective deprotection Coupling Final deprotection NH2-AA1-CO2H Pg1 NH2-AA1-CO2Pg4 2H Pg2 Pg5NH-AA2-CO Pg1 NH-AA1-CO2Pg4 Pg1 Pg3 Pg2 Pg6NH-AA3-CO2H NH2-AA2-CO NH-AA1-CO2Pg4 Pg3 Pg6NH-AA3-CO Pg1 Pg2 2-CO NH-AA1-CO Pg4 NH-AA 2 NH2-AA3-CO... 2-tert-butoxy-4-isopropyl-5(4H)-oxazolone — the oxazolone from Boc-valine The same compound was isolated in 7% yield from an EDC-mediated reaction of Boc-valine with an amino-acid ester that had been terminated after 3 minutes This was the first demonstration of the formation of a 2-alkoxy-5(4H)-oxazolone during the coupling of an N-alkoxycarbonylamino acid The existence of 2-alkoxy-5(4H)-oxazolones... Resin for Synthesis of Peptides Using Boc/Bzl Chemistry 143 Phenylacetamidomethyl Resin for Synthesis of Peptides Using Boc/Bzl Chemistry .144 Benzhydrylamine Resin for Synthesis of Peptide Amides Using Boc/Bzl Chemistry .145 Resins and Linkers for Synthesis of Peptides Using Fmoc/tBu Chemistry 146 Resins and Linkers for Synthesis of Peptide Amides Using Fmoc/tBu Chemistry. .. functional groups in peptides (Figure 1.3) Other ionizable groups are found on the side chains of peptides These include the β-CO2H of aspartic acid (Asp), the γ-CO2H of glutamic acid (Glu), the ε-NH2 of lysine (Lys), and the δ-guanidino of arginine (Arg) The β-CO2H group is more acidic than the γ-CO2H group because of its proximity to the peptide chain, but both 4 Chemistry of Peptide Synthesis R2 R2 R2... 1.45 ppm doublets O IR: 1770 cm-1 (O C N) IR: 1700, 1845 cm-1 (oxazolone) 3000 cm-1 (N H) 2-tert-Butoxy-4-isopropylBoc-Valine derivatives 5(4H)-oxazolone FIGURE 1.18 2-Alkoxy-5(4H)-oxazolones as intermediates in reactions of N-alkoxycarbonylamino acids.22 After removal of the symmetrical anhydride from a reaction mixture containing Boc-valine and ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride,... ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride is the only general method of synthesis that gives enantiomerically pure 2-alkyl-5(4H)-oxazolones The slight acidity of the soluble carbodiimide is sufficient to prevent the oxazolone from tautomerizing 18 IZ Siemion, K Nowak New method of synthesis of 2-phenyl-4-alkyl-oxazolones-5 Rocz Chem 43, 1479, 1960 19 FMF Chen, K Kuroda, NL Benoiton A simple preparation of 5-oxo-4,5-dihydro-1,3oxazoles... H O R5 Peptide D E H 2 Peptide H 2 2 R R R N C L N C D N C C O G C OH G C O C C C C C C 2 O 2 O 2 O 2-Alkyl-5(4H)-oxazolone 2-Alkyl-5(4H)-oxazolone achiral O R2 O H H B R C N C C N C C H H R5 L O E R R2 C FIGURE 1.9 Coupling, 2-alkyl-5(4H)-oxazolone formation and generation of diastereoisomers from activated peptides 10 Chemistry of Peptide Synthesis an achiral molecule that has lost its α-proton... Witty The formation of 2-benzyloxyoxazol-5(4H)-ones from benzyloxycarbonylamino-acids J Chem Soc Perkin Trans 1 3203, 1979 22 NL Benoiton, FMF Chen 2-Alkoxy-5(4H)-oxazolones from N-alkoxycarbonylamino acids and their implication in carbodiimide-mediated reactions in peptide synthesis Can J Chem 59, 384, 1981 1.19 REVISION OF THE CENTRAL TENET OF PEPTIDE SYNTHESIS Experience with synthesis over several... Young, ed Peptides 1962 Proceedings of the 5th European Peptide Symposium, Pergamon, Oxford, 1963, pp 11 9-1 21 8 I Antanovics, GT Young Amino-acids and peptides Part XXV The mechanism of the base-catalysed racemisation of the p-nitrophenyl esters of acylpeptides J Chem Soc C 595, 1967 1.10 COUPLING OF N-ALKOXYCARBONYLAMINO ACIDS WITHOUT GENERATION OF DIASTEREOISOMERS: CHIRALLY STABLE 2-ALKOXY-5(4H)-OXAZOLONES . it. NH-AA 2 -CO NH-AA 1 -CO 2 HNH 2 -AA 3 -CO NH 2 -AA 2 -CO Pg 2 NH-AA 1 -CO 2 Pg 4 Pg 1 Pg 6 NH-AA 3 -CO 2 H Pg 3 Protection Pg 5 NH-AA 2 -CO Pg 2 NH-AA 1 -CO 2 Pg 4 Pg 1 NH 2 -AA 3 -CO 2 H NH 2 -AA 2 -CO 2 H NH 2 -AA 1 -CO 2 H Coupling Coupling Pg 5 NH-AA 2 -CO 2 H Pg 2 . 7. 7-8 .3 CH 2 H 2 C H 2 C CH 2 NH 3 CO 2 Amino terminus pK 3. 0-3 .4 pK 7. 7-8 .3 Fundamentals of Peptide Synthesis 5 to a peptide chain. This is evident from reversed-phase, high-performance liquid chromatography of L-alanyl-L-alanine and L-alanyl-L-alanyl-L-alanine,. infringe. Library of Congress Cataloging-in-Publication Data Benoiton, N. Leo. Chemistry of peptide synthesis / N. Leo Benoiton. p. ; cm. Includes bibliographical references. ISBN-13: 97 8-1 -5 744 4-4 5 4-4 (hardcover