The furan approach to azacyclic compounds

Article abstract of DOI:10.1016/j.tetlet.2008.04.010

We describe an efficient new approach to the synthesis of azacyclic compounds that extends our recently developed methodology based on the oxidation of a furan ring with singlet oxygen followed by an intramolecular hetero Michael addition. The new approac

Full text of DOI:10.1016/j.tetlet.2008.04.010

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Tetrahedron Letters 49 (2008) 3609–3612
The furan approach to azacyclic compounds
*
*
Isela Garc ´ı a, Manuel P e´ rez, Zoila G a´ ndara, Generosa G o´ mez , Yagamare Fall
Departamento de Qu ı´ mica Org a´ nica, Facultad de Qu ı´ mica, Universidad de Vigo, 36200 Vigo, Spain
Received 3 March 2008; revised 27 March 2008; accepted 1 April 2008
Available online 4 April 2008
Abstract
We describe an efficient new approach to the synthesis of azacyclic compounds that extends our recently developed methodology
based on the oxidation of a furan ring with singlet oxygen followed by an intramolecular hetero Michael addition. The new approach
gives access to the readily opened bicyclic lactones and novel tricyclic heterocycles containing the piperidine ring.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Azacyclic compounds; Piperidine; Singlet oxygen; Alkaloids; Triazolines
5
a,b
6
The ring system of piperidine is a structural sub-unit
found in many natural compounds with interesting physi-
cal and biological properties, including such pharmaco-
quine,
but side effects such as diarrhoea, liver toxicity
7
and vomiting prevent its medical use. Given the urgent
need for new antimalarial drugs, derivatives and ana-
1
8
logically relevant alkaloids as compounds 1–5 (Fig. 1).
Pharmacological interest in febrifugine (4) and isofebrifu-
logues that are just as effective as 4 but lack its adverse
effects are accordingly being sought.
2
9
gine (5), which were first isolated from Dichroa febrifuga
Numerous syntheses of piperidines have been devised.
3
and Hydrangea umbellata, and whose absolute structures
In the work described here, with a view to the eventual syn-
thesis of febrifugine analogues, we approached these com-
pounds by adapting the methods we have developed for
the synthesis of oxacyclic compounds from methoxyallene
4
were determined in 1999, derives from their potentially
5
powerful antimalarial activity. The in vivo activity of feb-
rifugine is similar to that of the widely used drug chloro-
N
H
N
N
H
CO H
2
H
1
lupetidine
2 coniine
3 pipecolic acid
OH
O
N
O
OH
N
O
N
N
O
N
H
N
H
4
(+) - febrifugine
5 (+) - isofebrifugine
Fig. 1. Structures of natural products containing a piperidine ring.
*
Corresponding authors. Tel.: +34 986 812320; fax: +34 986 81 22 62 (Y.F.).
E-mail addresses: ggomez@uvigo.es (G. G o´ mez), yagamare@uvigo.es (Y. Fall).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.010

3610
I. Garc ı´ a et al. / Tetrahedron Letters 49 (2008) 3609–3612
1
0
or furan. This methodology has given access to chiral
1
1a
11b
butenolides,
panes
natural oxacyclic products,
polyoxe-
1
1c
11d
and polytetrahydropyrans,
and has also been
1.84%
1
2
N
N
extended to the synthesis of carbocyclic systems. We have
now embraced the synthesis of azacyclic compounds.
The bicyclic lactone 11 is a possible precursor of the
piperidine moiety of 4 and 5, previous work having shown
that this kind of lactone is easily opened using lithium alu-
H
N
H
O
2
.7%
O
MeO
12
1
0d
minium hydride. We envisaged that compound 11 could
be prepared from the commercially available furan deriva-
tive 6 via compound 9 as shown in Scheme 1. As expected,
compound 6 (from Avocado Research Chemicals Ltd)
reacted with LAH in ether to give alcohol 7 (89% yield),
Fig. 2. NOE correlations of 12.
1
6
tions into the corresponding free amine, which without
isolation was reacted with Boc O, giving the Boc-protected
amine 13 in excellent yield (96% from azide 9). The oxi-
2
1
3
13
and alcohol 7 was then easily converted into tosylate 8
(
97% yield), which upon reaction with sodium azide in
dation of furan 13 with singlet oxygen, followed by treat-
1
3
DMF (90%) gave azide 9.
ment with acetic anhydride in pyridine, then afforded
1
3
As anticipated, the oxidation of furan 9 with singlet oxy-
gen, followed by treatment with acetic anhydride in pyr-
idine, gave butenolide 10 (99% from 9, crude yield).
Unfortunately, azide 10 proved to be rather unstable,
and upon standing underwent quantitative [3+2] cyclo-
addition to the tricyclic triazoline 12, thus hampering
its conversion to bicyclic lactone 11 under Staudinger con-
ditions. The relative stereochemistry of 12 was confirmed
by NOE experiments (Fig. 2). Although we could not
observe NOE between the methoxy group and the cis
hydrogens of the fused five-membered rings, we know from
butenolide 14 (99%, two steps, crude yield); and the treat-
ment of 14 with sodium hydride in DMF gave the targeted
1
7
bicyclic lactone 15 through an intramolecular Michael
reaction (Scheme 2). The yield of 15 is currently being
optimized.
1
4
1
5
Finally, noting that triazoline 12 might itself be a useful
synthon for the preparation of compounds with piperidine
rings, and as chiral furan 16 was available in our labora-
1
6
1
1b
tory,
we decided to attempt the preparation of chiral
triazolines 20a and 21a as shown in Scheme 3.
The deprotection of 16 with TBAF afforded a 68% yield
1
1e
13
13
the previous work that the fusion between the five- and
six-membered rings is cis.
of alcohol 17, which was transformed into azide 18 by
mesylation followed by azidation (74% from 17). The oxi-
dation of 18 with singlet oxygen, followed by treatment
with acetic anhydride in pyridine, led to butenolide 19,
which upon standing afforded a mixture of two inseparable
In view of the above result, we decided to convert azide
into a protected amine before proceeding further.
9
Accordingly, 9 was transformed under Staudinger condi-
OTs
i
OH
ii
O
O
CO Et
O
2
8
7
6
O
N3
iv
iii
O
N3
OMe
O
10
9
vi
v
N N
H
H
N
N
H
H
O
O
O
MeO
O
12
OMe
11
1
Scheme 1. Reagents and conditions: (i) LiAlH O (89%); (ii) pTsCl, pyr (97 %); (iii) NaN
4
, Et
2
3
, DMF (90%); (iv) (a) O
2
, MeOH, rose bengal, hm; (b)
Ac O, py, DMAP (99%, two steps); (v) PPh , THF, H O; (vi) 10 is converted on standing into 12 (quantitative).
2
3 2

I. Garc ı´ a et al. / Tetrahedron Letters 49 (2008) 3609–3612
3611
i
N3
NHBoc
ii
O
O
9
1
3
Boc
N
H
iii
O
NHBoc
O
OMe
O
O
1
4
OMe
1
5
1
Scheme 2. Reagents and conditions: (i) (a) PPh
3
, THF, H
2
O; (b) Boc
2
O, NaHCO
3
(96%, two steps); (ii) (a) O
2
, MeOH, rose bengal, hm; (b) Ac
2
O, py,
DMAP (99%, two steps); (iii) NaH, DMF (30%).
OH
OTBDPS
O
N3
i
ii
O
O
16
17
18
N3
iv
iii
O
O
MeO
19
N2
N N
H
N
H
H
N
H
O
O
O
MeO
O
2
0b
MeO
2
0a
+
+
N2
N N
H
N
H
H
N
H
O
O
O
MeO
O
MeO
21b
21a
1
Scheme 3. Reagents and conditions: (i) TBAF, THF (68%); (ii) (a) MsCl, Pyr, 0 °C; (b) NaN
3 2
, DMF (74%, two steps); (iii) (a) O , MeOH, rose bengal,
hm; (b) Ac O, pyr, DMAP (77%, two steps, crude yield); (iv) 19 is converted on standing into 20a and 21a.
2
1
3
13
14a
chiral triazolines, 20a and 21a. Herdeis and Schiffer
the synthesis of natural products containing the piperidine
moiety.
reported that triazolines underwent quantitative isomeriza-
tion to the corresponding diazoamines, but in our case no
trace of the formation of diazoamines 20b and 21b was
observed (Scheme 3).
Acknowledgements
In conclusion, we have shown that the furan approach
to oxacycles we developed some years ago can be extended
to the synthesis of azacyclic systems. Work is now in pro-
gress on the use of building blocks 12, 15, 20a and 21a in
This work was supported by grants from the Xunta de
Galicia (PGIDIT04BTF301031PR) and the Spanish Minis-
try of Education and Science (CTQ2007-61788). The work
of the NMR and MS divisions of the research support

3612
I. Garc ı´ a et al. / Tetrahedron Letters 49 (2008) 3609–3612
services of the University of Vigo (CACTI) is gratefully
acknowledged.
C.; Thuy, V. M. Tetrahedron 1997, 53, 8447–8456; (c) Lorthiois, E.;
Marek, I.; Normant, J. F. J. Org. Chem. 1998, 63, 566–574; (d)
Poerwono, H.; Higashiyama, K.; Takahashi, H. J. Org. Chem. 1998,
6
3, 2711–2714; (e) Bailey, P. D.; Millwood, P. A.; Smith, P. D. J.
Supplementary data
Chem. Soc., Chem. Commun. 1998, 633–640; (f) Katritzky, A. R.; Luo,
Z.; Cui, X.-L. J. Org. Chem. 1999, 64, 3328–3331; (g) Back, T. G.;
Nakajima, K. Org. Lett. 1999, 1, 261–263; (h) Haddad, M.;
Larchev eˆ que, M. Tetrahedron: Asymmetry 1999, 10, 4231–4237; (i)
Haddad, M.; Larchev eˆ que, M. Tetrahedron Lett. 2001, 42, 5223–5225;
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
0
4.010.
(
j) Reddy, M. S.; Narender, M.; Rao, K. R. Tetrahedron 2007, 63,
31–336.
10. (a) Fall, Y.; G o´ mez, G.; Fern a´ ndez, C. Tetrahedron Lett. 1999, 40,
307–8308; (b) Fall, Y.; Vidal, B.; Alonso, D.; G o´ mez, G. Tetra-
rez, M.; Canoa, P.; G o´ mez,
3
References and notes
8
´
1
. (a) Sugasawa, T.; Adachi, M.; Sasakura, K.; Matsushita, A.; Eigyo,
M.; Shiomi, T.; Shintaku, H.; Takahara, Y.; Murata, S. J. Med.
Chem. 1985, 28, 699–707; (b) Groopman, J. E. Rev. Infect. Dis. 1990,
hedron Lett. 2003, 44, 4467–4469; (c) Pe
G.; Teijeira, M.; Fall, Y. Synthesis 2005, 411–414; (d) Alonso, D.;
rez, M.; G o´ mez, G.; Covelo, B.; Fall, Y. Tetrahedron 2005, 61,
Pe
2021–2026.
11. (a) Teijeira, M.; Sua
Tetrahedron Lett. 2005, 46, 5889–5892; (b) Garc ´ı a, I.; G o´ mez, G.;
Teijeira, M.; Tera
´
12, 931–937; (c) Karlsson, G. B.; Butters, T. D.; Dwek, R. A.; Platt, F.
´
rez, P. L.; G o´ mez, G.; Ter a´ n, C.; Fall, Y.
M. J. Biol. Chem. 1993, 268, 570–576; (d) Goss, P. E.; Baker, M. A.;
Carver, J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935–944; (e)
Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605–611; (f) Treadway,
J. L.; Mendys, P.; Hoover, D. J. Exp. Opin. Invest. Drugs 2001, 10,
´
n, C.; Fall, Y. Tetrahedron Lett. 2006, 47, 1333–
1335; (c) Canoa, P.; Pe
Tetrahedron Lett. 2007, 48, 3441–3443; (d) Canoa, P.; Vega, N.; Pe
M.; Generosa, G.; Fall, Y. Tetrahedron Lett. 2008, 49, 1149–1151; (e)
a, I.; P e´ rez, M.; Besada, P.; G o´ mez, G.; Fall, Y. Tetrahedron
´
rez, M.; Covelo, B.; G o´ mez, G.; Fall, Y.
rez,
´
439–454; (g) Chand, P.; Kotian, P. L.; Dehghani, A.; El-Kattan, Y.;
Lin, T.-H.; Hutchison, T. L.; Sudhakar Babu, Y.; Bantia, S.; Elliot,
A. J.; Montgomery, J. A. J. Med. Chem. 2001, 44, 4379–4392.
. (a) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem. Soc.
Garcı
´
2
3
Lett. 2008, 49, 1344–1347.
1947, 69, 1837; (b) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J.
12. G o´ mez, G.; Rivera, H.; Garc ´ı a, I.; Est e´ vez, L.; Fall, Y. Tetrahedron
Lett. 2005, 46, 5819–5822.
13. All new compounds exhibited satisfactory H and C NMR,
analytical, and/or high resolution mass spectral data.
14. The formation of triazolines from azides is not unprecedented. See:
(a) Herdeis, C.; Schiffer, T. Tetrahedron 1996, 52, 14745–14756; (b)
Haddad, M.; Larchev eˆ que, M.; Tong, H. M. Tetrahedron Lett. 2005,
46, 6015–6017; (c) Rejzek, M.; Stockman, R. A.; van Maarseveen, J.
Am. Chem. Soc. 1949, 71, 1048–1054.
1
13
. (a) Ablondi, F.; Gordon, S.; Morton, J., II; Williams, J. H. J. Org.
Chem. 1952, 17, 14–18; (b) Kato, M.; Inaba, M.; Itahana, H.; Ohara,
E.; Nakamura, K.; Uesato, S.; Inouye, H.; Fujita, T. Shoyakugaku
Zasshi 1990, 44, 288–292.
4
. (a) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron
Lett. 1999, 40, 2175–2178; (b) Kobayashi, S.; Ueno, M.; Suzuki, R.;
Ishitani, H.; Kim, H.-S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833–
H.; Hughes, D. L. J. Chem. Soc., Chem. Commun. 2005, 4661–4662.
1
6
841.
. (a) Murata, K.; Takano, F.; Fushiya, S.; Oshima, Y. J. Nat. Prod.
998, 61, 729–733; (b) Takaya, Y.; Tasaka, H.; Chiba, T.; Uwai, K.;
15. Selected data for compound 12: H NMR (CDCl
3
, 300 MHz), d: 5.49
-7), 3.96 (1H, d,
J = 9.90 Hz, CH-2), 3.39 (3H, s, OMe), 3.29 (1H, m, CH -7), 2.53
-6), 1.74 (1H, m, CH -6);
), d: 168.99 (CO), 106.16 (C-4), 82.19 (CH-3), 57.96
-7), 28.55 (CH -5), 21.08 (CH -6).
16. (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635–646; (b)
Knousi, N.; Vaultier, M.; Carrie
5
(1H, d, J = 9.90 Hz, CH-3), 4.41 (1H, m, CH
2
1
2
Tanitsu, M.; Kim, H.-S.; Wataya, Y.; Miura, M.; Takeshita, M.;
Oshima, Y. J. Med. Chem. 1999, 42, 3163–3166; (c) Taniguchi, T.;
Ogasawara, K. Org. Lett. 2000, 2, 3193–3195; (d) Ooi, H.; Urushi-
bara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2001, 3,
(1H, m, CH
2
-5), 1.79 (2H, m, CH
2
-5, CH
2
2
1
3
C NMR (CDCl
3
(CH-2), 50.18 (OMe), 45.12 (CH
2
2
2
´
, R. Bull. Soc. Chim. Fr. 1985, 5, 815–
953–955; (e) Zhu, S.; Meng, L.; Zhang, Q.; Wei, L. Bioorg. Med.
Chem. 2006, 16, 1854–1858; (f) Kikuchi, H.; Yamamoto, K.;
Horoiwa, S.; Hirai, S.; Kasahara, R.; Hariguchi, N.; Matsumoto,
M.; Oshima, Y. J. Med. Chem. 2006, 49, 4698–4706.
819; (c) Aragones, S.; Bravo, F.; Diaz, Y.; Matheu, M. I.; Castillon, S.
Tetrahedron: Asymmetry 2003, 14, 1847–1856.
1
17. Selected data for compound 15: H NMR (CDCl
3
, 300 MHz), d: 4.57
),
6
. De Smet, P. A. G. M. Drugs 1997, 54, 801–840.
(1H, t, J = 7.92 Hz, CH-6), 3.70 (1H, m, CH-4), 3.35 (3H, s, OCH
3
7
. (a) Fishman, M.; Cruickshank, P. A. J. Med. Chem. 1970, 13, 155–
2.99 (1H, m, CH-4), 2.87 (1H, dd, J = 8.36 and 17.92 Hz, CH-7), 2.58
(1H, dd, J = 7.62 and 17.94 Hz, CH-7), 1.99 (2H, m, CH-2), 1.68 (1H,
156; (b) Chien, P.-L.; Cheng, C. C. J. Med. Chem. 1970, 13, 867–870.
t
13
8. Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew. Chem.,
Int. Ed. 2003, 42, 5274–5293.
m, CH-3), 1.60 (1H, m, CH-3), 1.4 (9H, s, Bu); C NMR(CDCl
172.64 (CO, C-8), 154.97 (CO, Boc), 107,41 (C), 80.77 (C), 54.54
(CH), 50.46 (OCH ), 48.20 (CH ), 33.96 (CH ), 29.56, 28.44, 28.29,
28.21, 28.00 (CH , tBu), 27.91 (CH ), 19.48 (CH ).
3
), d:
9
. (a) Tamaru, Y.; Kawamura, S.-i.; Bando, T.; Tanaka, K.; Hojo, M.;
Yoshida, Z.-i. J. Org. Chem. 1988, 53, 5491–5501; (b) Freville, S.;
Bonin, M.; Celerier, J.-P.; Husson, H.-P.; Lhommet, G.; Quirion, J.-
3
2
2
3
2
2