1
078
Chem. Pharm. Bull. 65, 1078–1080 (2017)
Vol. 65, No. 11
Note
Improved Synthesis of Nigricanin
Hitoshi Abe,* Takanori Nagai, Haruka Imai, and Yoshikazu Horino
Graduate School of Science and Engineering, University of Toyama; Toyama 930–8555, Japan.
Received June 4, 2017; accepted August 14, 2017
An ellagic acid-related natural product, nigricanin (1), was synthesized via the Ullmann coupling reac-
tion of 2-bromo-3,4-dialkoxybenzaldehyde (4) followed by the Cannizzaro reaction for desymmetrization
of the symmetric biaryl compound (5). Compared to our previously reported study, the presented synthesis
improved the sequence step number.
Key words Ullmann coupling; Cannizzaro reaction; ellagic acid; Russula nigricans
Nigricanin (1) was isolated from fruiting bodies of Rus- (seven steps), and the synthesis without using of an expensive
sula nigricans (Russulaceae), and its chemical structure was palladium reagent was accomplished, compared to our previ-
1)
determined by Liu and colleagues in 2004. The structural ous work.
feature of 1 is possessing a highly oxygenated tetracyclic
skeleton which is an ellagic acid-like heterocyclic system with Experimental
partially-reduced aromatic rings. This class of compounds
General Melting points (mp) were measured using a
2
–7)
often exhibits interesting biological activities,
thus their Yanagimoto micro-melting point hot-plate apparatus and are
total synthesis would be an attractive subject. Recently, we uncorrected. The IR spectra were recorded using a Shimadzu
achieved the synthesis of 1, in which a palladium-mediated FTIR-8400 spectrophotometer. The NMR spectra were ob-
8)
biaryl coupling reaction of the phenyl benzoate derivative
was used in the key step (Chart 1).
tained using a JEOL α-400 instrument with the chemical
shifts being reported as δ ppm and the couplings expressed
9)
In Chart 1, nine steps were necessary for completion of the in Hertz (Hz). The elemental analysis was performed using a
synthesis of 1, and the expensive palladium reagent was es- Thermo Scientific FlashEA1112 analyzer. Electron ionization
sential for the key coupling process. In order to improve the mass spectra (EI-MS) was obtained using a JEOL JMS-700
efficiency of the synthesis, we planned an alternative synthetic instrument. Silica gel column chromatography was carried out
route as shown in Chart 2, involving the Ullmann coupling using Wako-gel C-200. Copper was treated by the reported
1
0,11)
12)
19)
reaction
method for forming non-symmetrical biaryl compounds via
the Ullmann coupling and the Cannizzaro reaction has been a solution of isovanillin (2) (5.0g, 32.9mmol) in CHCl3
and the Cannizzaro reaction. This sequential method before use.
2
0)
2-Bromo-3-hydroxy-4-methoxybenzaldehyde (3)
To
13)
14)
reported by Kobayashi et al., Moore et al., Bringmann (1000mL), DBDMH (5.2g, 18.2mmol) was portionwise added,
et al., and Seitz and colleagues.
15)
16)
and the mixture was stirred for 9h at ambient temperature.
According to the retrosynthesis scheme, we selected isovan- After the addition of water (300mL), the organic layer was
illin (2) as the starting material for the synthesis of nigricanin separated, washed with brine, and dried over MgSO . The
4
(
1), which was transformed into 3 by the ortho-selective bro- organic solvent was removed in vacuo to give a crude mate-
mination with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) rial which was purified by recrystallization from AcOEt. The
Chart 3). The phenolic hydroxyl group of 3 was protected title compound (3, 5.8g, 25.1mmol, 77%) was obtained as a
(
17)
15)
with the benzyl group to afford 4, then the coupling precur- pale orange powder, mp 200.2–201.0°C (AcOEt) [lit. mp
sor 4 was subjected to the Ullmann conditions using an excess 206–207°C (EtOH)]. H-NMR (400MHz, CDCl ) δ: 10.26 (d,
1
3
amount of copper dust to perform the dimerization reaction 1H, CHO), 7.58 (d, J=8.8Hz, 1H, ArH), 6.93 (d, J=8.8Hz,
for producing 5. The intramolecular Cannizzaro reaction was 1H, ArH), 6.07 (s, 1H, OH), 4.01 (s, 3H, OMe).
2
0)
effective for desymmetrization of the symmetric structure of
5
3-Benzyloxy-2-bromo-4-methoxybenzaldehyde (4)
To
18)
under alkaline conditions. Transformation of the gener- a solution of 3 (7.65g, 33.1mmol) and K CO (13.7g,
2
3
ated carboxylic acid into a methyl ester 6 using trimethylsilyl 99.4mmol) in N,N-dimethylformamide (DMF) (100mL),
TMS) diazomethane was necessary, otherwise, the oxidation BnBr (3.7mL, 33.6mmol) was added at room temperature
(
reaction in the next step did not cleanly proceed. The pyri- (r.t.), and the mixture was stirred for 1h at 75°C. After cool-
dinium dichromate (PDC) oxidation of the benzylic alcohol ing, the mixture was acidified to pH 1, then extracted with
of 6 was conducted to form the aldehyde 7. Finally, treatment AcOEt. The organic layer was washed with brine, dried over
of 7 with BBr followed by the addition of methanol was suc- MgSO , and evaporated to give the title compound (4, 9.94g,
3
4
2
0)
cessful for forming the target nigricanin (1) in a one-pot op- 30.9mmol, 94%) as a pale orange solid, mp 78.1–78.9°C [lit.
eration. The obtained material was identical to the sample in mp 79–81°C]. H-NMR (400MHz, CDCl ) δ: 10.27 (s, 1H,
1
3
hand which we previously prepared.
CHO), 7.76 (d, J=8.8Hz, 1H, ArH), 7.35–7.54 (m, 5H, ArH),
Consequently, we completed the synthesis of nigricanin (1) 6.98 (d, J=8.8Hz, 1H, ArH), 5.05 (s, 2H, ArCH ), 3.96 (s,
2
via a different route from the previously reported way. In the 3H, OMe). This material was used for the next step without
presented scheme, the sequence step number was improved further purification.
*
©
2017 The Pharmaceutical Society of Japan