1938
J. Nat. Prod. 2010, 73, 1938–1939
A Short Synthesis of the Triazolopyrimidine Antibiotic Essramycin
Ugo Battaglia and Christopher J. Moody*
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham, NG7 2RD, United Kingdom
ReceiVed May 5, 2010
A short synthesis of the 1,2,4-triazolo[1,5-a]pyrimidine antibiotic essramycin is described involving condensation of
aminoguanidine with ethyl benzoylacetate to give an amino-1,2,4-triazole, followed by condensation with ethyl acetoacetate
to form the pyrimidone ring.
Compounds containing the N-N bond are relatively rare
among natural products. Examples include the hydrazine peptide
negamycin,1 the pyrazolopyridazine nigellicine,2 pyridazinomy-
cin,3 and the piperazic acid-containing cyclodepsipeptides.4 In
addition there are a number of naturally occurring diazo
compounds such as cremeomycin.5 Recently a new antibiotic
substance was isolated from the fermentation broth of a marine
organism (Streptomyces sp. Isolate Merv8102) collected from
sediments in the Mediterranean Sea off the Egyptian coast.6 The
compound named essramycin was assigned as the 1,2,4-
triazolo[1,5-a]pyrimidine 1, an extremely unusual structure for
a naturally occurring substance. We now report a short synthesis
of essramycin, the first (and only) triazolopyrimidine natural
product.
Figure 1. Some natural products with N-N bonds.
Although not isolated as natural products previously, 1,2,4-
triazolo[1,5-a]pyrimidines are nevertheless quite well-known
compounds, being previously investigated, for example, as
vasodilators and herbicides.7 In planning a synthesis of essra-
mycin (1) we considered routes based on the known triazolopy-
rimidine acetic acid derivative 28 or on the amino-1,2,4-triazole
39 (Scheme 1). In the event, we elected to use the latter precursor,
and therefore our synthesis started with the condensation of
aminoguanidine bicarbonate with ethyl benzoylacetate in n-
butanol to give the amino-1,2,4-triazole 3 in 32% yield. Although
this compound has been described previously,9 few data were
reported, and therefore we fully characterized the compound.
With amino-1,2,4-triazole 3 available, it remained to construct
the pyrimidone ring by condensation with ethyl acetoacetate.
Although in principle this condensation could result in the
formation of isomers of the desired structure 1, according to
which carbonyl of the acetoacetic ester reacts first, and which
nitrogen of the triazole ring participates in the subsequent
cyclization, we were confident that under acidic reaction
conditions the desired isomer 1 would result. Thus it has been
reported that the condensation of 5-substituted 3-amino-1,2,4-
triazoles proceeds through reaction at the acetoacetate ketone
with formation of an aminocrotonate intermediate that cyclizes
at N-2 of the triazole ring.10,11 In the event this proved correct,
and condensation of the 3-amino-1,2,4-triazole 3 with ethyl
acetoacetate in acetic acid gave essramycin (1) in excellent yield
Scheme 1. Structure of Essramycin (1) and Its Retrosynthetic
Analysis
silica gel 60 GF254 and visualized under UV light at 254 and/or
360 nm and/or by chemical staining. Flash chromatography was
carried out using silica 60A, with the eluent specified. Infrared
spectra were recorded in the range 4000-600 cm-1 in solution in
the solvent specified or as solids in attenuated total reflectance
(ATR) mode. NMR spectra were recorded at 400 MHz (100 MHz
13C frequency). Chemical shifts are quoted in parts per million
(ppm) and are referenced to residual H in the deuterated solvent as
the internal standard. Coupling constants, J, are quoted in Hz. Mass
spectra were recorded on a time-of-flight mass spectrometer using
electrospray ionization (ESI).
2-(5-Amino-4H-1,2,4-triazol-3-yl)-1-phenylethanone, 3. A suspen-
sion of aminoguanidine bicarbonate (4.73 g, 35 mmol) and ethyl
benzoylacetate (6.72 g, 35 mmol) in n-butanol (20 mL) was heated
under reflux at 125 °C for 6 h. During this time all solids went into
solution. The mixture was cooled and kept in a refrigerator overnight.
The suspension was filtered and the solid was washed with n-butanol
(10 mL) and water (10 mL). The colorless solid thus obtained was
resuspended in DMF (25 mL) and stirred for 30 min. The suspension
was finally filtrated and washed with DMF (10 mL) to give the title
compound 3 as a colorless solid (2.26 g, 11.2 mmol, 32%): mp
208-209 °C (lit.9 mp 195-198 °C); (found: M + H+, 203.0930;
C10H10N4O+H+ requires 203.0927); νmax (CHCl3)/cm-1 3391, 3328,
2985, 1731, 1375, 1251, 1046; δH (400 MHz; DMSO-d6) 11.79 (1H,
br s, NH), 7.98 (2H, m, ArH), 7.59 (3H, m, ArH), 5.81 (2H, br s,
1
(Scheme 2). The H and 13C NMR spectroscopic data closely
matched those of the natural product, and therefore we conclude
that essramycin does indeed have the unusual triazolopyrimidine
structure 1.
Experimental Section
Commercially available reagents were used throughout without
purification unless otherwise stated. Analytical thin-layer chroma-
tography was carried out on aluminum-backed plates coated with
* To whom correspondence should be addressed. Tel: +44 115 846 8500.
Fax: +44 115 951 3564. E-mail: c.j.moody@nottingham.ac.uk.
10.1021/np100298m 2010 American Chemical Society and American Society of Pharmacognosy
Published on Web 09/13/2010
Battaglia, Ugo
