抄録
Sandramycin (1), which was isolated from the culture broth of Norcardioides sp. (ATCC 39419), constitutes one of the members of class of C2-symmetric cyclic decadepsipeptide. It binds to the minor groove of double-strand DNA (dsDNA) with bisintercalation. Sandramycin (1) has exceptionally potent activity against L1210 cell in vitro with IC_<50> values of 0.02 nM. Total synthesis of 1 has accomplished by Boger's group via a sequential peptide coupling approach. The macrocycle moiety of 1 binds to the minor groove of dsDNA and greatly contributes to the sequence selectivity. We planned to synthesize 1 and its analogues of the macrocycle moiety considering to develop more convergent synthesic route, which can be applicable to study the structure-activity relationship of the macrocycle moiety. Our retro-synthetic analysis of sandramycin (1) is depicted in Scheme 1. First, the cyclic imine 6 was obtained by the Staudinger/aza-Wittig reaction sequence, and it was subsequently reacted with the isonitrile 5 and the carboxylic acid 7 in toluene at 70℃ as the Ugi three component reaction. As a result, the desired pentadepsipeptide 4 was obtained in 59% yield in a diastereoselective manner. This synthesis allows us to construct the pentapeptide 4 with simultaneous construction of the unnatural L-Pip residue and its linking to the two dipeptides at both C- and N- terminus. Next, deprotection of either the Boc group or the Tce group of 4 gave the amine 19 and the carboxylic acid 20, respectively. The [5+5] assemblage of 19 and 20 was conducted by the peptide coupling with the formation of the additional N-methylamide moiety to afford the liner decapeptide 21 (DEPBT, NaHCO_3, CH_2C1_2-DMF, 74%). Deprotection of the Boc and the Tce group of 21 with the same conditions used for the preparation of 19 and 20 gave the free liner peptide 3, which was then cyclized by DPPA in CH_2Cl_2-DMF to afford the cyclic decadepsipeptide 2 in 46% yield over three steps from 21. This synthetic approach is advantageous because sarcosine has no substituent at the a-position and the peptide coupling is free from a racemization, which is usually problematic in the peptide coupling chemistry.
