ORGANIC
LETTERS
2012
Vol. 14, No. 8
2002–2005
TiCl4-Promoted Tandem Carbonyl or Imine
Addition and FriedelÀCrafts Cyclization:
Synthesis of Benzo-Fused
Oxabicyclooctanes and Nonanes
Arun K. Ghosh,* Cuthbert D. Martyr, and Chun-Xiao Xu
Department of Chemistry and Department of Medicinal Chemistry, Purdue University,
560 Oval Drive, West Lafayette, Indiana 47907, United States
Received February 27, 2012
ABSTRACT
A new and convenient synthesis of benzo-fused 8-oxabicyclo[3.2.1]octane and 9-oxabicyclo[4.2.1]nonane derivatives are described. The reaction
involved a TiCl4-mediated tandem carbonyl or imine addition followed by a FriedelÀCrafts cyclization to provide these functionalized derivatives
in good to excellent yields and high diastereoselectivity.
Functionalized benzo-fused oxabicyclooctanes and
nonanes are unique heterocyclic frameworks, and their
use in molecular design is rather limited. In connec-
tion with our work in probing the enzyme active site
using designed ligands, we have been particularly inter-
ested in stereochemically defined oxabicyclic hetero-
cyclic scaffolds.1 The benzannulated 8-oxabicyclo-
[3.2.1]octane ring system is also inherent to bioactive
natural products, bruguierol AÀC.2,3 Several syntheses
of benzo-fused 8-oxabicyclo[3.2.1]octanes have been
previously described.4 The structural novelty and antibac-
terial activity of bruguierol C also led to several recent
reports of the synthesis of the 8-oxabicyclo[3.2.1]octane
core in the literature.5
We have previously developed TiCl4-mediated multi-
component reactions of vinyl ethers, carbonyl, or imine
electrophiles with various nucleophiles (TMS-Nu, alcohols,
or amines).6 These reactions provided rapid access to a
range of functionalized tetrahydrofuran and tetrahydropy-
ran derivatives with multiple chiral centers.7 The effective-
ness of these multicomponent reactions was demonstrated
in the synthesis of natural products.8 Also, a number of
functionalized cyclic ether derivatives have shown intriguing
activity against HIV-1 protease.9 As outlined in Figure 1,
the reaction proceeded by addition of vinyl ether (1) to a
TiCl4 activated electrophile followed by addition of an
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Chem., Int. Ed. 2012, 51, 2–27.
(2) Han, L.; Huang, X.; Sattler, I.; Moellmann, U.; Lin, W.; Grabley,
S. Planta Med. 2005, 17, 160–164.
(3) Lefort, A.; Baptista, M.; Fantin, B.; Depardieu, F.; Arthur, M.;
Carbon, C.; Courvalin, P. Antimicrob. Agents Chemother. 1999, 43,
476–482.
(4) (a) Sammes, P. G.; Whitby, R. J. J. Chem. Soc., Chem. Commun.
1984, 702–703. (b) Marson, C. M.; Campbell, J.; Hursthouse, M. B.;
Abdul Malic, K. M. Angew. Chem., Int. Ed. 1998, 37, 1122–1124. (c)
Oda, K.; Nakagami, R.; Nishizono, N.; Machida, M. Chem. Lett. 2000,
29, 1386–1387. (d) Wu, Y.; Li, Y.; Wu, Y.-L. Helv. Chim. Acta 2001, 84,
163–171.
(5) (a) Solorio, D. M.; Jennings, M. P. J. Org. Chem. 2007, 72, 6621–
6623. (b) Ramana, C. V.; Salian, S. R.; Gonnade, R. G. Eur. J. Org.
Chem. 2007, 5483–5486. (c) Fananas, F. J.; Fernandez, A.; Cevic, D.;
Rodriguez, F. J. Org. Chem. 2009, 74, 932–934. (d) Sarkar, D.;
Venkateswaran, R. V. Tetrahedron Lett. 2011, 52, 3232–3233.
(e) Hu, B.; Xing, X.; Ren, J.; Wang, Z. Tetrahedron 2010, 66, 5671–5674.
(6) (a) Ghosh, A. K; Kawahama, R. Tetrahedron Lett. 1999, 40,
1083–1086. (b) Ghosh, A. K; Kawahama, R. Tetrahedron Lett. 1999, 40,
4751–4754.
(7) (a) Ghosh, A. K; Kawahama, R; Wink, D. Tetrahedron Lett.
2000, 41, 8425–8429. (b) Ghosh, A. K; Xu, C.-X; Kulkarni, S. S; Wink,
D. Org. Lett. 2005, 7, 7–10. (c) Ghosh, A. K; Kulkarni, S; Xu, C-X;
Fanwick, P. E. Org. Lett. 2006, 8, 4509–4511. (d) Ghosh, A. K; Kass, J.
Chem. Commun. 2010, 46, 1218–1220.
(8) (a) Ghosh, A. K.; Kawahama, R. J. Org. Chem. 2000, 65, 5433–
5435. (b) Ghosh, A. K.; Kass, J. Org. Lett. 2012, 14, 510–512.
(9) Ghosh, A. K. PCT Int. appl. 2009, WO 2009091941 A1 20090723.
r
10.1021/ol300494q
Published on Web 04/04/2012
2012 American Chemical Society