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Solid‐phase Total Synthesis of (−)‐Apratoxin A and Its Analogues and Their Biological Evaluation
Author(s) -
Doi Takayuki,
Numajiri Yoshitaka,
Takahashi Takashi,
Takagi Motoki,
Shinya Kazuo
Publication year - 2011
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.201000549
Subject(s) - thiazoline , chemistry , total synthesis , phenylacetylene , yield (engineering) , solid phase synthesis , chemoselectivity , epimer , stereochemistry , peptide synthesis , amino acid , peptide , cycloaddition , tyrosine , combinatorial chemistry , chloride , organic chemistry , catalysis , materials science , biochemistry , metallurgy
Abstract Two approaches for the solid‐phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer‐support, macrolactamization of 10 , followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid‐phase peptide synthesis by using amino acids 13 – 15 and 18 . The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O ‐methyl tyrosine can be replaced by 7‐azidoheptyl tyrosine without loss of activity. The 1,3‐dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.