203310-99-0Relevant articles and documents
Synthesis of cycloisodityrosine revisited: A selective ring forming process
Bigot, Antony,Zhu, Jieping
, p. 551 - 554 (1998)
Cycloetherification of dipeptide (L,L) N-Boc-(4-fluoro-3-nitro)Phe-Dopa methyl ester (11) gave exclusively the (m,p)-cyclophane (14) at the expenseof the 15-membered (p,p)cyclophane (16). An efficient synthesis of cycloisodityrosine was consequently developed.
Total synthesis of an antitumor agent RA-VII via an efficient preparation of cycloisodityrosine
Bigot, Antony,Tran Huu Dau, Marie Elise,Zhu, Jieping
, p. 6283 - 6296 (2007/10/03)
Details of efficient syntheses of (9S, 12S)-cycloisodityrosine (6) and a concise total synthesis of RAVII (1) were described. An intramolecular S(N)Ar-based cycloetherification reaction was employed as the key ring- closure step for construction of the illusive 14-membered m,p-cyclophane. Treatment of methyl N-[N-(tert-butyloxycarbonyl)-L-(3-hydroxy-4- methoxyphenylalanyl]-L-4-fluoro-3-nitrophenylalaninate ((9S,12S)-10) with potassium carbonate in DMSO at room temperature provided a mixture of two atropdiastereomers 20a and 20b in 75% yield that were transformed into cycloisodityrosine 6 in good overall yield. Furthermore, a size-selective ring-forming process was established for methyl N-[N-(tert-butyloxycarbonyl)- L-(3,4-dihydroxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate ((9S,12S)- 11). Thus, cyclization of 11 (K2CO3, DMSO, rt), followed by in situ methylation, gave exclusively the 14-membered m,p-cyclphane 20a and 20b without competitive formation of the alternative 15-membered p,p-cyclophane. The selective ring-forming process allowed us to develop one of the shortest and the most efficient synthesis of cycloisodityrosine to date. Computational studies have shown that it was the elimination, but not the addition, step that determined the ring-size selectivity observed in the cyclization of substrate 11. Coupling of 6 with L-N-Boc-Ala (51) proceeded efficiently to provide the corresponding tripeptide 52 that, after removal of the N-Boc function, was allowed to react with another tripeptide 53 to afford the hexapeptide 50 in good overall yield. Saponification followed by liberation of amino function from 50 gave the seco-acid, whose cyclization (DPPA, DMF, NaHCO3) afforded the natural product RA-VII (1).
