Heterocycl. Commun. 2015; aop
Preliminary Communication
Kyriakos G. Varnava and Jonathan Sperry*
Synthesis of colletotrichumine A
DOI 10.1515/hc-2015-0154
In summary, a straightforward synthesis of the oxin-
dole-pyrazine alkaloid colletotrichumine A is reported.
Biological evaluation of colletotrichumine A is in pro-
gress, the results of which will hopefully determine if this
heteroaromatic compound plays a role in the pathogenic-
ity of C. capsici.
Received July 23, 2015; accepted July 31, 2015
Abstract: A short synthesis of colletotrichumine A, an
oxindole-pyrazine alkaloid isolated from the pathogenic
fungus Colletotrichum capsici, is described.
Keywords: alkaloid; colletotrichumine A; indole; natural
product; pyrazine.
Experimental
The fungus Colletotrichum capsici is an economically
damaging plant pathogen with a range of hosts includ-
ing vegetables, legumes, cereals and various tree fruits [1].
The fungus causes the often devastating anthracnose in
chili, one of the most important crops in the tropics [2].
The ethyl acetate extract of C. capsici was recently
shown to contain colletotrichumine A (1), a structurally
unique alkaloid comprising an oxindole fused to trimeth-
ylpyrazine moiety (Figure 1) [3]. Glume blotch in wheat
is caused by Septoria nodorum, a pathogenic fungus that
produces septorine (2), which is a pyrazine that causes
Commercially available reagents were used throughout without puri-
fication. Anhydrous solvents were used as supplied. All reactions
were routinely carried out in oven-dried glassware under a nitrogen
atmosphere. Analytical thin layer chromatography was performed
using silica plates and compounds were visualized at 254 nm and/
or 360 nm ultraviolet irradiation followed by staining with either
alkaline permanganate or ethanolic vanillin solution. Melting points
were recorded on an electrothermal melting point apparatus and are
1
uncorrected. NMR spectra were recorded at 400 MHz for H nuclei
and 100 MHz for 13C nuclei. Assignments were made with the aid of
NOESY and HMBC experiments. High resolution mass spectra were
obtained by electrospray ionization in positive ion mode at a nominal
a decoupling action on wheat mitochondria and likely accelerating voltage of 70 eV on a microTOF mass spectrometer.
contributes to the pathogenicity of the fungus [4]. Thus,
we set out to determine if colletotrichumine A (1) plays a
role in the pathogenicity of C. capsici and as such, set out 3,5,6-Trimethylpyrazine-2-carbaldehyde (4)
to synthesize this natural product to provide a sufficient
quantity for biological evaluation.
To a solution of 2-hydroxymethyl-3,5,6-trimethylpyrazine (3) [6]
(40 mg 0.26 mmol) in ethanol (3 mL) was added manganese dioxide
(1 g, 11.5 mmol) and the mixture was stirred for 1 h at room tempera-
ture, filtered and the solid washed with ethanol. The filtrate was con-
centrated in vacuo to yield compound 4 (39 mg, 0.26 mmol, 98%) as
a colorless solid; mp 75–77°C; 1H NMR: (CDCl3): δH 10.16 (1 H, s, CHO),
2.80 (3 H, s, Me), 2.60 (3 H, s, Me), 2.46 (3 H, s, Me); 13C NMR (CDCl3):
δC 194.6 (Cꢀ=ꢀO), 155.5 (C), 151.8 (C), 150.2 (C), 141.9 (C), 22.4 (Me),
21.5 (Me), 18.5 (Me); 1H NMR data consistent with the literature [6].
A classic Knoevenagel approach [5] was used to con-
struct colletotrichumine A (1 in Figure 1 and Scheme 1).
Oxidation of the known alcohol 3 [6] with manganese
dioxide gave 3,5,6-trimethylpyrazine-2-carbaldehyde (4)
using the literature protocol [7]. The Knoevenagel conden-
sation of 4 with 2-oxindole gave exclusively the desired
regioisomer 1, as determined by NOE studies (Scheme 1).
The spectroscopic data of synthetic 1 were identical in all
aspects to the natural product (Table 1).
Colletotrichumine A (1)
A solution of 3,5,6-trimethylpyrazine-2-carbaldehyde (4) (40 mg,
0.26 mmol), 2-oxindole (35 mg, 0.26 mmol) and piperidine (0.02 mL)
in EtOH (3 mL) was heated to reflux for 3 h. Upon cooling to room tem-
perature, the mixture was concentrated in vacuo, diluted in ethyl ace-
tate (30 mL), washed with brine (20 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The crude solid was purified by flash chro-
matography on silica gel (30:70 EtOAc/CH2Cl2) to yield compound 1
*Corresponding author: Jonathan Sperry, School of Chemical
Sciences, University of Auckland, 23 Symonds St., Auckland,
Kyriakos G. Varnava: School of Chemical Sciences, University of
Auckland, 23 Symonds St., Auckland, New Zealand
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