736 RESEARCH PAPER
DECEMBER, 736–737
JOURNAL OF CHEMICAL RESEARCH 2012
The first total synthesis of fuscain
Yuan-wei Liang, Xiao-jian Liao, Chang-jun Wang, Jin-zhi Guo, Shuo Li and Shi-hai Xu*
Department of Chemistry, Jinan University, Guangzhou 510632, P. R. China
The first total synthesis of the furanolactam fuscain is reported. The key step in the synthesis was the formation of
seven-membered lactam by acylation of a furan ring using the mild Lewis acid CuSO4·5H2O.
Keyword: fuscain, furanolactam, total synthesis, seven-membered ring, mild Lewis acid
Fuscain, a new furanolactam which was originally isolated
from the sponge Phacellis fusca collected in South China Sea,
showed a moderate cytotoxicity toward P388 and L1210 cell
lines.1 The same sponge yielded three pyrrololactam alkaloids:
saldisin,2-bromoaldisinanddebromohymenialdisin.2 Recently,
furan analogues isolated from marine organisms have shown
anticancer,3–5 antibacterial,6 anticoagulant,7 antifungal,8 anti-
malarial,9 antiplatelet,10 antituberculosis and antiviral activi-
ties11. Aldisin-based derivatives can be easily synthesised.12
However, it is still a challenge to synthesise fuscain. Hence the
biological effects of fuscain and its derivatives on cell cycle
progression and antitumour activities have rarely been reported.
The synthetic route to fuscain is shown in Scheme 1. The
key step is an intramolecular Friedel–Crafts cyclisation to
form the seven-membered ring. Various Lewis acids (poly-
phosphoric acid, POCl3, polyphosphoric acid–acetic acid,
POCl3–P2O5, TFA or MSA) have been reported for Friedel–
Crafts cyclisation.13,14. Initially, we selected PPA and P2O5 as
catalysts but no product was obtained. Because of the struc-
tural difference between Alidisin and fuscain, the aromaticity
of furan ring is less than a pyrrole ring, and a furan ring usually
polymerised under acidic conditions, we selected a relatively
mild Lewis acid CuSO4·5H2O to complete the intramolecular
cyclisation to form fuscain.
In conclusion, the first total synthesis of fuscain has been
accomplished. The key step in the synthetic pathway is the
seven-membered lactam ring formation by using the mild
Lewis acid CuSO4·5H2O.
Experimental
Melting points were determined in open capillaries without further
correction, NMR data were recorded on a Bruker Avance 400 spec-
trometer equipped with two RF channels, indirect detection, and
pulsed-field gradients (z-axis only) using TMS as an internal standard.
IR spectra were determined on a Bruker Equinox 55 spectrometer
with KBr discs pallet. ESI-MS spectra were recorded on 4000Q mass
spectrometer. TLC was performed on precoated sheets of Silica
60 F254 (Merck Art. 5719).
Furan-2-carbonyl chloride: 2-Furoic acid (12.5 g, 110 mmol) and
SOCl2 (28.8 g, 240 mmol) were mixed in a three-necked flask
(150 mL) at 80 °C to reflux for 1 h, and vacuum distillation afforded
furan-2-carbonyl chloride (11.48 g, 80.0% yield).
Methyl 3-(furan-2-carboxamido)propanoate: β-Alanine methyl ester
(2.79 g, 20 mmol) and CH2Cl2 (20 mL) were added in a three-necked
flask (50 mL) with a CaCl2 drying tube. The mixture was stirred for
0.5 h and cooled in ice bath, then (2.65 g, 20 mmol) of furan-2-
carbonyl chloride (2 mL) in CH2Cl2 (10 mL) was added dropwise.
After 2 h at room temperature, TLC indicated complete consumption
of the starting material. The reaction mixture was poured onto ice and
extracted with CH2Cl2 (4 × 25 mL). The organic extracts were washed
with brine, dried over MgSO4, filtered, concentrated and recrystallised
to provide methyl 3-(furan-2-carboxamido)propanoate (3.28 g, 83.5%
Starting from commercially available furoic acid which
gave the furan-2-carbonyl chloride, the synthesis was rela-
tively easy following the literature.15–17 Furan-2-carbonyl chlor-
ide condensed with the ethyl ester of β-alanine to provide the
corresponding amides. This was followed by hydrolysis of
the ester to give the acid. Intramolecular cyclisation gave the
desired compound.
1
yield); m.p. 31–32 °C. H NMR(400 MHz, CDCl3): δ 7.42 (s, 1H),
7.09 (d, J = 3.4 Hz, 1H), 6.98 (1H, CONH), 6.47 (q, J = 1.75 Hz, 1H),
3.70 (s, 3H, OCH3), 3.67 (t, J = 6 Hz, 2H), 2.63 (t, J = 6 Hz, 2H).
ESI-MS: m/z 198(MH+).
3-(Furan-2-carboxamido)propanoic acid: Methyl 3-(furan-2-carb-
oxamido)propanoate (2.96 g, 15 mmol) and NaOH solution (100 mL)
were added in round bottom flask. The solution was neutralised
(pH 8) by slow addition of 10% aqueous NaOH (30 mL) and ethanol
(6 mL) and the mixture was stirred for 12 h at room temperature.
Concentrated HCl was used to adjust to pH 3–4, and the resulting
mixture was extracted with EtOAc (3×15 mL). The combined organic
phases were dried (Na2SO4), filtered, and concentrated then recrystal-
lised with ethanol to provide 3-(furan-2-carboxamido)propanoic acid
(2.50 g, 91.1% yield); m.p. 148–149 °C. 1H NMR (400 MHz, DMSO-
d6): δ 12.13 (brs, 1H), 8.25 (brs, 1H, CONH), 7.80 (dd, J = 1.64 Hz,
J = 0.64 Hz, 1H), 7.06 (dd, J = 3.44 Hz, J = 0.68 Hz, 1H), 6.60 (q,
J = 1.68 Hz, 1H), 3.45–3.40 (m, 2H, CH2), 2.51–2.47 (m, 2H, CH2).
ESI-MS: m/z 184(MH+).
Fuscain: 3-(Furan-2-carboxamido)propanoic acid (183 mg, 2 mmol),
CuSO4·5H2O (0.05 g, 0.2 mmol) toluene solution (20 mL) were mixed
Fig. 1 Structures of fuscain and aldisin.
Scheme 1
* Correspondent. E-mail: txush@jnu.edu.com
Liang, Yuan-Wei
