Formal synthesis of piperazinomycin, a novel antifungal antibiotic

An alternative synthesis of piperazinomycin is disclosed. The approach is based on an intramolecular O -arylation of arylboronic acid with phenol for formation of the macrocyclic biaryl ether.


Introduction
Piperazinomycin 1, constitutes the simplest naturally occurring agent possessing the parent 14membered para-and metacyclophane diary1 ether structural subunit found in bouvardin, 1 deoxybouvardin, 1 RA-I-X, 2 OF4949-I-OF494-IV, 3 and K-13. 4 This has renewed the interest in the synthesis and evaluation of piperazinomycin and structurally related agents since 1 and notably 2. However, efforts to critically examine the importance of the cycloisodityrosine subunit have been hampered by the synthetic inaccessibility of such systems.

Results and Discussion
In the present paper, we describe a practical and short synthetic route to compound 2 from commercially available L-tyrosine by a coupling reaction of arylboronic acid with phenol originally developed by Chan, 5 Evans, 6 and Lam.Commercially obtained L-tyrosine 3 was brominated at 3-position with bromine in acetic acid and hydrobromic acid in acetic acid at room temperature to afford 3-bromo-L-tyrosine hydrobromide 4 9 in 95 % yield from 3. Compound 4 was N-protected with a Boc group and methylated with dimethyl sulphate (2.5 eq.) in presence of potassium carbonate (3 eq.) in acetone to afford protected bromotyrosine 5 in 96% yield from 4. Compound 5 was treated with bis (pinacolato) diboron (1.3 eq.), potassium acetate (3 eq.) and PdCl 2 (dppf) (0.05 eq.), as a catalyst, in 1, 2-dimethoxy ethane (DME) at 110 0 C for 18 h to afford compound 6 in 90 % yield.Compound 10 was N-deprotected using 2N HCl in ethyl acetate to yield the corresponding hydrochloride salt which was then treated with 0.1M acetic acid in isopropyl alcohol in presence of N-methylmorpholine to afford compound 11 in 90 % yield.Key ring closure of 11 to 2 11 via the intramolecular O-arylation of phenol with arylboronic acid 11 smoothly proceeded using cupric acetate (1.3 eq.) and triethyl amine (5 eq.) in N,N-dimethyl formamide in presence of powered 4 A 0 molecular sieves for 72 h at room temperature in 33% yield.The conversion of compound 2 to compound 1 has already been reported in the literature. 12

Conclusions
Our methods described above provide new and shorter routes for the synthesis of piperazinomycin from commercially available L-tyrosine.

Experimental Section
General Procedures.All solvents and reagents were purchased from the suppliers and used without further purification.All non-aqueous reactions were performed in dry glassware under dry nitrogen atmosphere.Organic solutions were concentrated under reduced pressure.Thin layer chromatography was performed on Merck precoated Silica-gel 60F 254 plates. 1 H and 13 C NMR spectra were recorded on a Varian Gemini 400 MHz FT NMR spectrometer using DMSOd 6 and CDCl 3 as a solvent.The chemical shifts were reported in δ ppm relative to TMS.The mass spectra were recorded on Shimadzu LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS/MS.Melting points were obtained by using the open capillary method and are uncorrected.
The arylboronate 6 was easily converted into arylboronic acid 7 10 using sodium metaperiodate (3 eq.) in acetone (20 Vol) in presence of 0.1M NH 4 OAc aq.solution at room temperature for 16 h.in 90 % yield.Compound 7 was hydrolyzed with lithium hydroxide in methanol and water at room temperature for 30 min to afford compound 8 in 96 % yield.