LETTER
Synthetic Studies towards Stachybotrin C
2921
Me
Me
OEt
OEt
1) (COCl)2, DMSO, Et3N
CH2Cl2, –78 °C, 1 h, 99%
Me
Me
trans,trans-farnesol
19
2) HC(OEt)3, NH4NO3 (cat.)
EtOH, r.t., 12 h, 99%
18
O
HO
AcCl, MeOH
r.t., 12 h
OH
12, 3-picoline (cat.)
xylene, reflux, 24–48 h
N
17
O
82%
75%
Me
Me
Me
Me
20
Scheme 4 Intermolecular cyclization
(2) (a) Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006,
39, 53. (b) Joyner, P. M.; Cichewicz, R. H. Nat. Prod. Rep.
2011, 28, 26. (c) Williams, P.; Sorribas, A.; Howes, M.-J. R.
Nat. Prod. Rep. 2011, 28, 48.
(3) Xu, X.; de Guzman, F. S.; Gloer, J. B. J. Org. Chem. 1992,
57, 6700.
(4) Inoue, S.; Kim, R.; Hoshino, Y.; Honda, K. Chem. Commun.
2006, 1974.
(5) (a) Menon, R. S.; Findlay, A. D.; Bissember, A. C.; Banwell,
M. G. J. Org. Chem. 2009, 74, 8901. (b) Jean, M.; van de
Weghe, P. Tetrahedron Lett. 2011, 52, 3509.
Encouraged by this result, we decided to focus on a
straightforward approach involving an intermolecular cy-
clization, as rationalized by North and co-workers.10 After
conversion of trans,trans-farnesol 18 into diethyl acetal
19 in two efficient steps, heating the latter in xylene under
reflux with phenol 12 and a catalytic amount of 3-picoline
led, after two days, to the pyrano-isoindolinone derivative
17 in 75% yield (Scheme 4).11 The MOM protecting
group was cleanly removed by exposure of 17 to HCl
(generated in situ by adding AcCl to methanol), affording
20 in good yield.12
(6) Katoh, T.; Ohmori, O.; Iwasaki, K.; Inoue, M. Tetrahedron
2002, 58, 1289; and references cited therein..
(7) For the preparation of 11 and 13, see the Supporting
Information.
(8) For a significant and recent review on gold-catalyzed
additions to C–C multiple bonds, see: Huang, H.; Zhou, Y.;
Liu, H. Beilstein J. Org. Chem. 2011, 7, 897.
(9) The gold-catalyzed biscyclopropanation of dienynes has
been already reported, see: Nieto-Oberhuber, C.; López, S.;
Paz Muñoz, M.; Jiménez-Núñez, E.; Buñuel, E.; Cárdenas,
D. J.; Echavarren, A. M. Chem.–Eur. J. 2006, 12, 1694.
(10) North, J. T.; Kronenthal, D. R.; Pullockaran, A. J.; Real, S.
D.; Chen, H. Y. J. Org. Chem. 1995, 60, 3397.
(11) To a solution of 12 (500 mg, 1.34 mmol, 1.0 equiv) in
anhydrous o-xylene (8 mL), 19 (790 mg, 2.68 mmol,
2.0 equiv) and 3-picoline (33 μL, 0.34 mmol, 0.25 equiv)
were added. The reaction mixture was heated to reflux for
48 h, then the solvent was removed under reduced pressure
and the residue was purified by column chromatography on
silica gel (CH2Cl2–EtOAc, 9:1→4:1) to afford 17 (775 mg,
75%) as a brown oil. 1H NMR (500 MHz, CDCl3): δ = 1.40
(s, 3 H), 1.56 (s, 3 H), 1.59 (s, 3 H), 1.66–1.76 (m, 5 H),
1.92–1.97 (m, 2 H), 2.01–2.15 (m, 4 H), 2.92 (t, J = 7.5 Hz,
2 H), 3.47 (s, 3 H), 3.48 (s, 3 H), 3.74–3.84 (m, 2 H), 4.16 (s,
2 H), 5.05–5.14 (m, 2 H), 5.15 (s, 2 H), 5.22 (s, 2 H), 5.61 (d,
J = 10.2 Hz, 1 H), 6.76 (d, J = 10.2 Hz, 1 H), 6.96 (d, J = 8.7
Hz, 2 H), 7.07 (s, 1 H), 7.16 (d, J = 8.7 Hz, 2 H). 13C NMR
(125 MHz, CDCl3): δ = 15.9, 17.7, 22.5, 25.7, 26.6, 34.0,
39.6, 41.2, 44.3, 47.7, 55.9, 56.3, 78.9, 94.5, 95.0, 101.2,
113.6, 116.4, 117.5, 121.4, 123.6, 124.2, 129.4, 129.7,
131.4, 132.1, 133.9, 135.5, 148.2, 153.2, 155.9, 168.3.
HRMS (ESI): m/z [M + Na]+ calcd for C35H45NO6Na:
598.3139; found: 598.3139.
In conclusion, the preparation of pyrano-isoindolinone
derivative 20 (30% overall yield in 11 steps) from 3,5-di-
hydroxybenzoic acid (7) has been achieved. Compound
20 can be considered as an analogue of stachybotrin C and
its biological activity will be evaluated later. Whereas the
approach involving intramolecular gold-catalyzed hy-
droarylation reaction of alkyne failed, intermolecular cy-
clization to form the benzopyran moiety proved to be
effective. To date, despite our continuous efforts, conver-
sion of intermediate 17 or compound 20 into racemic
stachybotrin C has been unsuccessful. A revised strategy
is in progress and will be reported in due course.
Acknowledgment
This research has been performed as part of the Indo-French ‘Joint
Laboratory for Sustainable Chemistry at Interfaces’. We thank the
CNRS, France, and CSIR, India, for support. We also thank the Mi-
nistère de la Recherche, France, for a fellowship to M.J. and the
PRISM platform for NMR analysis (Université de Rennes 1, UFR
Sciences Biologiques et Pharmaceutiques, 2 avenue du Prof Léon
Bernard, 35043 Rennes Cedex, France).
Supporting Information for this article is available online at
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References and Notes
(12) To a solution of 17 (200 mg, 0.35 mmol, 1.0 equiv) in
anhydrous MeOH (4 mL) was added at 0 °C, acetyl chloride
(100 μL, 1.39 mmol, 4.0 equiv). The solution was stirred at
room temperature for 20 h then concentrated under reduced
(1) (a) Nozawa, Y.; Yamamoto, K.; Ito, M.; Sakai, N.; Mizoue,
K.; Mizobe, F.; Hanada, K. J. Antibiot. 1997, 50, 635.
(b) Nozawa, Y.; Ito, M.; Sugawara, K.; Hanada, K.; Mizoue,
K. J. Antibiot. 1997, 50, 641.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2919–2922