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Total synthesis of piperazimycin A: a cytotoxic cyclic hexadepsipeptide.

screened using the National Cancer Institute s panel of 60 cancer cell lines, piperazimycin A exhibited in vitro cytotoxicity toward multiple tumor cell lines with a mean GI50 value of 100 nm. Additional analysis revealed that this compound had a nearly three-fold more potent activity against solid tumors than against the leukemia cell lines tested. This selectivity is not enough to support the development piperazimycin A for the treatment of cancer because of the general cytotoxicity. Structure-activity relationship (SAR) studies of this natural product would not only be able to overcome this drawback, but also open a new avenue for exploring the possible mode of action of this compound. However, before comprehensive SAR studies can become a reality, an efficient total synthesis of piperazimycin A is required. Herein, we disclose the first total synthesis of this natural product. Structurally, piperazimycin A is an 18-membered macrocycle which is composed of a hydroxyacetic acid and five rare amino acids. These amino acid residues include an (S)-amethylserine, a novel (S)-2-amino-8-methyl-4,6-nonadienoic acid (S-AMNA), two g-hydroxypiperazic acids ((S,S)gOHPip and (R,R)-gOHPip), and one g-chloropiperazic acid ((R,S)-gClPip). The g-substituted piperazic acid residues have also been found in other antitumor cyclodepsipeptides such as polyoxypeptins, and antibiotic cyclodepsipeptides such as monamycins, himastatin, lydiamycins, and dentigerumycin. The total synthesis of piperazic acid containing natural products has received much attention during the past decades. Although some cyclodepsipeptides with the g-substituted piperazic acid residues have been synthesized successfully, none of them contain a dipeptide unit having two piperazic acid residues (such as (R,S)-gClPip-(S,S)gOHPip in piperazimycin A). This difficult-to-install dipeptide presents a new synthetic challenge. Indeed, we have prepared both the protected (R,S)-gClPip and (S,S)-gOHPip units, but failed in installing them under various conditions, especially using acid chlorides as coupling reagents. Accordingly, we planned to assemble this section of the molecule by forming two piperazine rings only after the connection of their precursors, as indicated in Figure 1. Since the ester part of this molecule is the only less sterically hindered site, we decided to carry out the macrocyclization through an ester bond formation. The synthetic routes to requisite fragments 6 and 8 are illustrated in Scheme 1. Treatment of the known lactone 2 with LiHMDS and subsequent trapping of the resulting anion with MoOPH gave the desired trans-alcohol 3 in 73 % yield (79 % brsm) with a 6:1 diastereoselectivity. The trans-alcohol 3 was reacted with triflic anhydride, and then exposed to benzyl carbazate to afford hydrazide 4 in 81% yield. Protection of 4 with TrocCl led to formation of 5, which upon saponification and subsequent methylation provided a methyl ester, which was chlorinated using Ph3P and CCl4 to deliver 6. In a parallel procedure, the enantiomer of trans-alcohol 3 (ent-3) was reacted with Tf2O and then treated with tert-butyl carbazate to give hydrazide 7 in 88% yield. Removal of the TBDPS ether in 7 by reaction with TBAF and AcOH provided alcohol 8 in quantitative yield. These fragments could then used to assemble the required (R,S)-gClPip/(S,S)gOHPip fragments (see below). Notably, 6 and 8 could be easily converted into protected g-hydroxypiperazic acid and g-chloropiperazic acid, respectively. Although several groups have reported their efforts for assembling these g-substituted piperazic acids, our method apparently represents one of the simplest procedures. Figure 1. Structure of piperazimycin A and its bond disconnection analysis.