Piperazinomycin

An efficient four-step synthetic strategy for cis-2,5-disubstituted chiral piperazines derived from amino-acid-based aziridines is described. The key steps in this strategy are the highly regioselective boron trifluoride diethyl etherate (BF(3)·OEt(2))-mediated ring-opening of less-reactive N-Ts chiral aziridines by α-amino acid methyl ester hydrochloride followed by Mitsunobu cyclization. This protocol has been used in an attempt to construct the piperazine core framework of natural product (+)-piperazinomycin.

A new antifungal antibiotic, named piperazinomycin, was isolated from the cultured broth of Streptoverticillium olivoreticuli subsp. neoenacticus. The antibiotic was obtained from the mycelial cake by extraction with methanol and also from the broth filtrate by adsorption on Amberlite XAD-2 and subsequent elution with aqueous acetone. The antibitoic is of basic and lipophilic nature and can be extracted with methyl isobutyl ketone at alkaline pH. Its purification was carried out by column chromatography on Sephadex LH-20 and then on Sephadex G-15 followed by preparative thin-layer chromatography on silica gel. The molecular formula of piperazinomycin was determined to be C125H20NsO2 by high resolution mass spectrum and the spectroscopic and chemical properties were examined. Piperazinomycin showed inhibitory activity against fungi and yeasts, especially against Trichophyton.

The endo aryl-aryl and aryl-alkyl ether bonds exist in a number of biologically important macrocyclic natural products, such as vancomycin family glycopeptide antibiotics (1-3), antitumor series RA I-XIV (4), K-13 (5), OF4949 (6), piperazinomycin (7), cyclopeptide alkaloids (8,9), nonpeptidic diarylheptanoids (10), and so on. Peptidomimetics incorporating, such structural features, have also been designed and synthesized as potential inhibitors of ACE (11), anti-HIV agents (12) and so on. From the view point of synthesis design (15), macrocyclization via formation of aryl-aryl or aryl-alkyl ether bond is unique, since it tackles two difficult synthetic problems, i.e., formation of ether bond and ring closure by a single operation. Intramolecular Ullmann ether synthesis (16), oxidative coupling reaction (17), and so forth, have been employed for the synthesis of type A (Fig. 1) compounds. Ring closure via the formation of aryl-aryl (type A) (18) and aryl-alkyl ether bonds (type B, Fig. 1) (19) by way of intramolecualr S(N)Ar reaction (20) will be the focus of this chapter. Figure 1.