The furan approach to oxacycles: Synthesis of medium-size 2,3-disubstituted oxacycles

Article abstract of DOI:10.1016/j.tetlet.2004.05.035

We describe an efficient new approach for the synthesis of medium-size oxacycles that is based on the oxidation of a furan ring with singlet oxygen followed by an intramolecular Michael addition. This present study enlarges the scope of the furan approach strategy for the synthesis of oxepanes.

Full text of DOI:10.1016/j.tetlet.2004.05.035

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5207–5209
The furan approach to oxacycles: synthesis of medium-size
2,3-disubstituted oxacycles
*
ꢀ
Manuel Perez, Pilar Canoa, Generosa Gomez, Carmen Teran and Yagamare Fall
ꢀ
ꢀ
Departamento de Quꢀımica Orgꢀanica, Facultad de Ciencias, Universidad de Vigo, 36200 Vigo, Spain
Received 22 April 2004; accepted 10 May 2004
Abstract—We describe an efficient new approach for the synthesis of medium-size oxacycles that is based on the oxidation of a furan
ring with singlet oxygen followed by an intramolecular Michael addition. This present study enlarges the scope of the furan ap-
proach strategy for the synthesis of oxepanes.
Ó 2004 Elsevier Ltd. All rights reserved.
Marine polycyclic ethers of the brevetoxin (Fig. 1) and
ciguatoxin family are interesting synthetic targets due to
their unusual molecular architecture and potent bio-
logical activity.1 They are challenging synthetic targets
in terms of medium-size ring construction and have
provided a stimulus for the development of a plethora of
new reactions and strategies for the construction of
polycyclic systems, culminating with the total syntheses
of brevetoxins A and B by Nicolaou et al.2 and of
ciguatoxin by Hirama et al.3
mining the scope and limitations of the furan approach.
A series of 2-alkylfurans 6 were prepared from com-
mercially available diols 4 and oxidized with singlet
oxygen to give after removal of the silyl protecting
group, bicyclic lactones 9a–e, which on reaction with
LAH afforded 2,3-disubstituted oxacycles 3a–e (Scheme
1).
Monosilylation6 of commercially available diol 4 afford-
ed alcohol 5,7 which was easily converted into iodide
2.7;8 Lithiation of furan 1 and reaction with 2 afforded
the alkylated furan 6.7 Oxidation of 6 with singlet oxy-
gen followed by treatment with acetic anhydride in
pyridine, afforded butenolide 7.7;9 Reaction of 7 with
TBAF then not only removed its silyl group, but also led
We recently described two new strategies for the syn-
thesis of seven-membered oxacycles using methoxy-
allene4 or furan5 as the key starting material. We now
report the results of our investigation aimed at deter-
Figure 1. Brevetoxin A.
Keywords: 2,3-Disubstituted oxacycles; Oxepanes; Tetrahydrofurans; Tetrahydropyranes; Furan; Polyoxacycles; Toxins.
* Corresponding author. Tel.: +34-986-81-23-20; fax: +34-986-81-22-62; e-mail: yagamare@uvigo.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.035

5208
M. Pꢀerez et al. / Tetrahedron Letters 45 (2004) 5207–5209
i
ii
OTBDPS
n
OTBDPS
n
OH
n
HO
I
HO
5
2
4
4a, n = 1; 4b, n = 2; 4c, n =3
4d, n = 4; 4e, n = 5
iv
OTBDPS
O
iii
n
O
OTBDPS
O
OMe
n
7
6
O
1
O
O
HO
O
O
vi
v
O
n
HO
n
MeO
9
3
+
OH
n
O
OMe
8
Scheme 1. Reagents and conditions: (i) NaH, TBDPSCl, THF, rt; (ii) PPh3, I2, Imid, THF, 0 °C; (iii) 1, bipy, nBuLi, THF, 0 °C to rt; (iv) (a) 1O2,
MeOH, rose bengal, hm (b) Ac2O, py, DMAP; (v) TBAF, THF, rt; (vi) LAH, BF3 Á OEt2, Et2O, rt.
Table 1.
Entry
4
5
Yield
(%)
2
Yield
(%)
6
Yield
(%)
OH
OTBDPS
OTBDPS
HO
HO
I
1
65
90
70
OTBDPS
OTBDPS
O
4a
5a
2a
6a
OTBDPS
I
OTBDPS
HO
OH
HO
2
3
4
5
73
71
30
21
66
97
94
93
85
94
74
71
O
2b
2c
4b
4c
5b
5c
6b
6c
HO
HO
I
OH
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
OTBDPS
O
HO
OH
HO
I
4d
2d
O
5d
6d
HO
HO
I
OTBDPS
OTBDPS
OTBDPS
OTBDPS
O
4e
5e
2e
6e
to the bicyclic lactone 97 through an intramolecular
Michael addition. Opening of lactone 9 using LAH in
the presence of BF3ÆOEt2 afforded 2,3-disubstituted oxa-
cycle 3.7 Furans 6 could be synthesized in large scale
from cheap commercial diols 4 and the results of their
synthesis and subsequent transformation into 3 are
summarized in Tables 1 and 2, respectively.
tuted tetrahydrofuran 3a, tetrahydropyran 3b and oxe-
pane 3c, entries 1, 2 and 3). Formation of eight- and
nine-membered oxacycles 9d and 9e was notobserved,
the key message being that with unsubstituted side
chains, eight- and nine-membered rings cannot be made
using this method. We are currently looking for an
alternative for the synthesis of 9d and 9e. Diols 3a, 3b
and 3c were obtained as a mixture of cis- and trans-
isomers, which could be separated by column chroma-
tography only in the case of 3b. Work is now in progress
for the assignment of the stereochemistry of isomers 3b
From the results of Table 2 it can be concluded that the
present methodology is convenient for the synthesis of
five-, six- and seven-membered oxacycles (2,3-disubsti-

M. Pꢀerez et al. / Tetrahedron Letters 45 (2004) 5207–5209
5209
Table 2.
Entry
6
7
Yield
(%)
9
Yield
(%)
3
Yield
(%)
O
O
O
HO
O
1
86
73
54
O
OTBDPS
OTBDPS
O
O
OMe
OMe
OMe
O
HO
MeO
6a
7a
3a
9a
O
OTBDPS
OTBDPS
HO
HO
O
O
O
O
O
O
O
2
3
89
90
81
89
74
HO
MeO
6a
7b
3b
9b
O
O
OTBDPS
OTBDPS
O
O
O
78
16
HO
MeO
6a
7c
9c
8c
3c
O
O
OTBDPS
O
O
OTBDPS
O
O
O
OMe
OMe
O
4
5
91
86
0
––
O
MeO
6a
9d
7d
8d
71
OTBDPS
OTBDPS
O
O
0
––
O
MeO
6a
7e
9e
8e
57
12631–12670; (g) Murata, M.; Yasuoto, T. Nat. Prod. Rep.
2000, 293–314; (h) Tetrahedron Symposium-in-Print 90.
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as well as the stereoselective obtention of the cis- and
trans-isomers from 3a–c, which are interesting building
blocks for an iterative approach to polycyclic ethers.10
2. (a) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35,
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This work was supported by grants from the Xunta de
Galicia (PGIDT01PXI30105PR) and the Vicerectorate
for Research of the University of Vigo. We also thank
the NMR service of the CACTI, University of Vigo, for
NMR studies.
ꢀ
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References and notes
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