Total Synthesis of an Antitumor Agent RA-VII via an Efficient Preparation of Cycloisodityrosine
Details of efficient syntheses of cycloisodityrosine I (R = OMe, R1 = H, R2 = R3= Me, R4 = H) and a concise total synthesis of RA-VII were described. An intramol. SNAr-based cycloetherification reaction was employed as the key ring-closure step for construction of the illusive 14-membered m,p-cyclophane. Treatment of dipeptide II (R5 = OMe) with potassium carbonate in DMSO at room temp. provided a mixt. of two atropdiastereomers I [R = OMe, R1 = NO2, R2 = Boc (Me3CO2C), R3 = R4 = H] in 75% yield that were transformed into cycloisodityrosine I (R = OMe, R1 = H, R2 = R3= Me, R4 = H) in good overall yield. Furthermore, a size-selective ring-forming process was established for II (R5 = OH). Thus, cyclization of II (R5 = OH) (K2CO3, DMSO, rt), followed by in situ methylation, gave exclusively a mixt. of two atropdiastereomers of 14-membered m,p-cyclophane I (R = OMe, R1 = NO2, R2 = Boc, R3 = R4 = H) 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 addn., step that detd. the ring-size selectivity obsd. in the cyclization of substrate II (R5 = OH). Coupling of I (R = OMe, R1 = H, R2 = R3= Me, R4 = H) with Boc-L-Ala-OH proceeded efficiently to provide the corresponding tripeptide that, after removal of the N-Boc function, was allowed to react with another tripeptide, Boc-D-Ala-L-Ala-L-NMeCH(CH2C6H4-4-OMe)CO2H, to afford the hexapeptide I [R = OMe, R1 = H, R2 = R3 = Me, R4 = Boc-D-Ala-L-Ala-L-NMeCH(CH2C6H4-4-OMe)CO] in good overall yield. Sapon. followed by liberation of amino function from the hexapeptide gave the seco-acid, whose cyclization (DPPA, DMF, NaHCO3) afforded the natural product RA-VII. [on SciFinder (R)]
1999
64
17
6283
6296
CAN 131:257846
34-3
Amino Acids, Peptides, and Proteins
Institut de Chimie des Substances Naturelles,CNRS,Gif-sur-Yvette,Fr.
Journal
written in English.
203311-01-7P; 203311-07-3P Role: PRP (Properties), RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (total synthesis of RA-VII via an efficient prepn. of cycloisodityrosine); 13139-17-8; 15761-38-3; 90719-32-7; 160877-40-7; 173775-54-7; 188624-33-1; 193073-38-0; 203310-96-7; 203311-03-9; 221123-53-1; 244769-40-2; 244769-41-3; 244769-43-5 Role: RCT (Reactant), RACT (Reactant or reagent) (total synthesis of RA-VII via an efficient prepn. of cycloisodityrosine); 109011-07-6P; 109011-08-7P; 135226-90-3P; 135226-91-4P; 138605-22-8P; 152429-89-5P; 203310-99-0P; 203450-65-1P; 203526-43-6P; 244769-31-1P; 244769-32-2P; 244769-33-3P; 244769-34-4P; 244769-35-5P; 244769-36-6P; 244769-37-7P; 244769-38-8P; 244769-42-4P; 244769-44-6P; 244769-46-8P; 244769-47-9P; 244790-35-0P; 244790-36-1P; 244790-38-3P; 244790-39-4P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (total synthesis of RA-VII via an efficient prepn. of cycloisodityrosine); 86229-97-2P (RA-VII); 132539-23-2P; 203311-08-4P; 244769-39-9P; 244790-37-2P; 244790-40-7P Role: SPN (Synthetic preparation), PREP (Preparation) (total synthesis of RA-VII via an efficient prepn. of cycloisodityrosine)
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