ORGANIC
LETTERS
2
012
Vol. 14, No. 1
–5
Total Synthesis of (()-Cephalosol
3
†
Yuanzhen Xie, Ning Wang, Bin Cheng, and Hongbin Zhai*
‡
‡
,†,‡
Department of Chemistry, University of Science and Technology of China, Hefei 230026,
China, and State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
Received October 29, 2011
ABSTRACT
A concise and efficient total synthesis of (()-cephalosol has been completed (5 steps from known ester 5, 39% overall yield), featuring a Cu(II)-
promoted haloisocoumarin formation and sequential Suzuki cross-coupling/intramolecular oxo-Michael addition.
(
À)-Cephalosol was isolated as a potent antimicrobial
metabolite by Tan and co-workers from Cephalosporium
1
acremonium IFB-E007, an endophytic fungal strain. The
host plant, Trachelospermun jasminoides (Lindl.) Lem.
Scheme 1. Retrosynthetic Analysis of (()-Cephalosol (1)
(
medicine (TCM) to treat arthritis and other inflammatory
Apocynaceae), has long been used in traditional Chinese
1
diseases. The natural product possesses a novel tricyclic
backbone featuring a conjugated unsaturated γ-lactone
fused to an isocoumarin at C-5a and C-11b. Attached to
the sole quaternary center [C-3, of (S) configuration] are
methyl and methoxycarbonylmethyl groups. Moreover,
this metabolite showed prominent antimicrobial bioactiv-
ities as confirmed with human pathogenic microbes
including Escherichia coli, Pseudomonas fluorescens,
Trichophyton rubrum, and Candida albicans; the MIC
values ranged from 1.95 to 7.8 μg/mL. As a result, this
molecule should be a superb target for the synthetic
communities. Indeed, the first total synthesis of (()-
cephalosol (1, Scheme 1) has already been reported by
selective ether cleavage. Tricycle 2 should be accessible via
Suzuki coupling of bromoisocoumarin 3a with boronate 4
followed by an intramolecular oxo-Michael addition. Bro-
moisocoumarin 3a in turn could be generated from the
known ester 5 by Sonogashira coupling and Cu(II)-
promoted haloisocoumarin formation.
2
Arlt and Koert.
3
Herein, we wish to disclose our studies in developing a
new convergent total synthesis. We envisioned that 1 could
be constructed from 2 by allylic oxidation followed by a
†
University of Science and Technology of China.
(
5) For representative examples, see: (a) Mehta, S.; Larock, R. C. J.
‡
Lanzhou University.
1) Zhang, H. W.; Huang, W. Y.; Chen, J. R.; Yan, W. Z.; Xie, D. Q.;
Org. Chem. 2010, 75, 1652. (b) Roy, S.; Roy, S.; Neuenswander, B.; Hill,
D.; Larock, R. C. J. Comb. Chem. 2009, 11, 1128. (c) Mehta, S.; Waldo,
J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141. (d) Chin, L. Y.; Lee,
C. Y.; Lo, Y. H.; Wu, M. J. J. Chin. Chem. Soc. 2008, 55, 643. (e) Liang,
Y.; Xie, Y. X.; Li, J. H. Synthesis 2007, 400. (f) Yao, T.; Larock, R. C. J.
Org. Chem. 2003, 68, 5936. (g) Yao, T.; Larock, R. C. Tetrahedron Lett.
2002, 43, 7401. (h) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.;
Rossi, R. Tetrahedron 2002, 58, 5023.
(
Tan, R. X. Chem.;Eur. J. 2008, 14, 10670.
(2) Arlt, A.; Koert, U. Synthesis 2010, 917 (requiring 10 steps).
(3) Barros, M. T.; Maycock, C. D.; Madureira, M. I.; Ventura, M. R.
Chem. Commun. 2001, 37, 1662.
4) Takano, S.; Sugihara, T.; Samizu, K.; Akiyama, M.; Ogasawara,
K. Chem. Lett. 1989, 10, 1781.
(
1
0.1021/ol202923u r 2011 American Chemical Society
Published on Web 11/21/2011