Solid-phase synthesis of functionalized tropane derivatives via 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/S0040-4039(01)00565-2

1,3-Dipolar cycloaddition of 3-oxidopyridinium betaine to activated olefins on solid-phase leads to resin-bound 8-azabicyclo[3.2.1]octenones which undergo further transformations such as 1,4-addition of nucleophiles. Cleavage of benzyl linker is achieved

Full text of DOI:10.1016/S0040-4039(01)00565-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3721–3723
Solid-phase synthesis of functionalized tropane derivatives via
1,3-dipolar cycloaddition
Sandrine Caix-Haumesser,a Issam Hanna,a,* Jean-Yves Lallemanda and Jean-Franc¸ois Peyronelb
aLaboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France
bAventis Pharma, Paris Research Center, 13 quai Jules Guesde BP 14, F-94403 Vitry sur Seine, France
Received 19 March 2001; accepted 5 April 2001
Abstract—1,3-Dipolar cycloaddition of 3-oxidopyridinium betaine to activated olefins on solid-phase leads to resin-bound
8-azabicyclo[3.2.1]octenones which undergo further transformations such as 1,4-addition of nucleophiles. Cleavage of benzyl
linker is achieved using acid chlorides in the presence of potassium iodide to give substituted tropane derivatives. © 2001 Elsevier
Science Ltd. All rights reserved.
The tropane ring system is found in numerous naturally
occurring alkaloids, many of which possess potent bio-
logical activity such as atropine, scopolamine and
cocaine.1 Although many synthetic methods are avail-
able for the preparation of this structural component in
solution phase,2 their extension to solid-phase synthesis
and chemical library production3 has been very limited.
Until now, only two reports on the solid-phase chem-
istry of tropane derivatives are known. In an interesting
revisitation of the classical Robinson tropinone synthe-
sis, a solid-phase version has been developed, which
involved reacting a resin-bound o-amine of lysine with
succinic dialdehyde and 1.3-acetonedicarboxylic acid.4
In the second report, an already prepared tropane
scaffold was attached to dihydropyran linker, followed
by subjection to further transformations.5
Ph
O
Z
N
Solution phase
N
7
O
Z=electron
withdrawing
groups
Z
Ph
6
Pyridinium betaine
O
O
O
OH
OH
PhCH2Br
MeONa
(REM) 1
N
N
PrOH, reflux
Ph
MeOH, PrOH, rt
N
Br
THF, reflux
Ph
2
Ph
N
Ph
N
O
1) TFA - CH2Cl2 , rt
O
O
MeO2C
O
2) CH2N2, Et2O-CH2Cl2, rt
3
4 (45%, overall)
Scheme 1.
* Corresponding author. Fax: +33 1 69 33 30 10; e-mail: hanna@poly.polytechnique.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00565-2

3722
S. Caix-Haumesser et al. / Tetrahedron Letters 42 (2001) 3721–3723
1,3-Dipolar cycloaddition of pyridinium betaine to acti-
vated alkenes, initially developed by Katritzky et al.,
provided one of the most powerful and versatile tools for
the construction of 8-azabicyclo-[3.2.1]octane deriva-
tives.6 We describe herein the first application of this
method to solid-phase synthesis of tropane derivatives.
ately subjected to 1,3-dipolar cycloaddition conditions.
Heating 7 in the presence of excess phenyl vinyl sulfone
(6 equiv.) in THF at refluxing temperature for 16 h led
to resin-bound cycloadduct 8 [IR (KBr): wmax 1691
cm−1].15
While releasing bicyclic enone 4 from the resin was
straightforward, the benzyl linker in 8 has been found to
be very stable towards a variety of cleavage conditions.
First attempts using acidic (TFA, pure or as a solution
in CH2Cl2, for 1 h to 3 days) or oxidative [2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) in benzene or in
CH2Cl2–H2O,16 ceric ammonium nitrate (CAN) in
CH3CN–H2O] conditions were disappointing. Under
these conditions the cleavage was incomplete releasing
the tropane derivative in low yield. After extensive
experimentations, the best results have been found when
8 was treated with acid chlorides in acetonitrile in the
presence of potassium iodide.17 Thus heating 8 with
acetyl chloride (7.5 equiv.) and potassium iodide (5
equiv.) in refluxing acetonitrile for 6 h furnished a
separable mixture of amides 9a (6-exo sulfone) and 10a
(7-exo sulfone) (87:13 ratio) in 51% overall yield on the
basis of the initial loading level of resin.18,19 The use of
KI in this reaction was crucial, otherwise the cleavage
was inefficient. When acetyl chloride was replaced by
benzoyl chloride, only the 6-exo isomer 9b can be isolated
in 54% overall yield. The cleavage using acryloyl chloride
led to a separable mixture of amides 9c and 10c in a
similar ratio as with acetyl chloride in 58% overall yield
(Scheme 2).
To demonstrate the feasibility of this reaction, the
commercially available and easily cleavable REM resin
(hydroxymethyl polystyrene resin-bound acrylate) 17 was
first used. Treatment of this resin with excess (6 equiv.)
3-oxidopyridinium betaine 2, readily prepared from
3-hydroxypyridine, in refluxing THF for 36 h gave the
polymer-bound a,b-unsaturated ketone 3 [IR (KBr): wmax
1731, 1690 cm−1] (Scheme 1).8 In order to determine the
regio- and stereoselectivity of this solid-phase [3+2]
cycloaddition reaction, the polymer bead was subjected
to the cleavage conditions. To this end, stirring ketone
3 in trifluoroacetic acid (TFA)–CH2Cl2 (1:3) for 1 h at
room temperature furnished, after treatment with diazo-
methane, the 8-azabicyclo[3.2.1]octane derivative 4 in
45% overall yield on the basis of the initial loading level
of REM resin. This product was found to be a mixture
of four regio- and stereoisomers in 50:25:20:5 ratio.9,10
These selectivities are comparable to those observed for
the analogous reaction in solution.11
We turned next to the 1,3-dipolar cycloaddition of the
polymer-supported betaine 7 to phenyl vinyl sulfone. In
fact, it was established that in contrast to methyl acrylate,
the reaction with phenyl vinyl sulfone in solution was
highly regio- and stereoselective, and led to the 6-exo-sul-
fone in good overall yield.12,13 This sequence began with
the bromomethyl linker 5 obtained by bromination of
Wang resin (CBr4, PPh3, DMF).14 Reaction of 5 with
3-hydroxypyridine in refluxing propanol for 30 h gave the
polymer-bound 3-hydroxypyridinium bromide 6 [IR
(KBr): wmax 3318 cm−1], which was treated with sodium
methoxide (MeONa) in propanol to afford 7 (Scheme 2).
This resin-bound betaine, readily isolated by washing
with propanol and drying under vacuum, was immedi-
The success of this reaction prompted us to explore
further transformations on the resin-supported 8-azabi-
cyclo[3.2.1]octenone 8 (Scheme 3). 1,4-Addition of thio-
phenol was first attempted. Stirring of 8 with thiophenol
and triethylamine in chloroform at room temperature for
20 h led to 11 as shown from the IR spectrum [IR (KBr):
wmax 1728 cm−1]. Cleavage of the product from the solid
support was readily achieved using benzoyl chloride–
potassium iodide in refluxing acetonitrile. As in solution
O
OH
MeONa, MeOH
3-hydroxypyridine
O
N
N
X
X=OH Wang resin
5 X=Br
PrOH, reflux
Br
PrOH, rt
CBr4
PPh3
DMF
rt
6
7
O
R
O
R
N
N
O
RCOCl, KI
CH3CN, reflux
N
SO2Ph
THF, reflux
PhSO2
O
+
O
O
7
PhSO2
PhSO2
R = CH3, 51%
R = Ph, 54%
R = vinyl, 58%
6
9:10 ratio
9a (R=CH3)
9b (R=Ph)
87:13
100:0
87:13
10a (R=CH3)
10c (R=vinyl)
8
9c (R=vinyl)
Scheme 2.

S. Caix-Haumesser et al. / Tetrahedron Letters 42 (2001) 3721–3723
3723
O
O
N
N
PhSH, Et3N
CH3Cl, rt
Et2AlCN
toluene, 0˚C
O
O
PhSO2
8
PhSO2
SPh
12
11
CN
PhCOCl, KI
CH3CN, reflux
Ph
O
N
O
PhSO2
PhS
Major isomer
Scheme 3.
phase,10 the crude product was found to be a mixture of
4-endo and 4-exo isomers (7:3) as shown from 1H NMR
analysis.20 Next, the resin-bound enone 8 was treated
with diethylaluminum cyanide (Et2AlCN) in toluene at
0°C for 4 h. As above, the IR spectrum of the resin 12
showed the complete disappearance of the enone band
and the presence of absorbances at 1731 cm−1 (CO) and
2244 cm−1 (CN).
Trans. 1 2000, 3815–4195 and references cited therein.
4. Jo¨nsson, D.; Molin, H.; Unde´n, A. Tetrahedron Lett.
1998, 39, 1059–1062.
5. Koh, J. S.; Ellman, J. A. J. Org. Chem. 1996, 61, 4494–
4495.
6. Dennis, N.; Katritzky, A. R. Chem. Rev. 1989, 89, 827–
861.
7. For a review see: Morphy, J. R.; Rankovic, Z.; Rees, D.
C. Tetrahedron Lett. 1996, 37, 3209–3212.
8. 1H NMR analysis of this polymer revealed the presence
of about 10% unreacted starting REM resin, despite the
use of a large excess of betaine.
In conclusion, we have successfully implemented 1,3-
dipolar cycloaddition of 3-oxidopyridinium betaine to
activated olefins on solid-phase. Cleavage of tropane
derivatives using acid chlorides–KI was achieved in
good overall isolated yield. Furthermore, we have
shown that the formed resin-bound 8-azabicy-
clo[3.2.1]octenone may undergo further transformation
such as 1,4-addition of nucleophiles affording substi-
tuted tropane derivatives.
9. This 6,7, exo:endo ratio (6 exo/6 endo/7 exo/7 endo:
1
50/25/20/5) was determined using 400 MHz H NMR of
the mixture, after flash column chromatography.
10. Caix-Haumesser, S. Thesis, University of Paris 6, 2000.
11. (a) Kozikowski, A. P.; Araldi, G. L.; Ball, R. G. J. Org.
Chem. 1997, 62, 503–509; (b) The selectivities observed in
solution with methyl acrylate are 6 exo/6 endo/7 exo/7
endo: 55/25/15/510.
Acknowledgements
12. Takahashi, T.; Hagi, T.; Kitano, K.; Takeuchi, Y.;
Koizumi, T. Chem. Lett. 1989, 593–596.
13. Ducrot, P.-H.; Lallemand, J.-Y. Tetrahedron Lett. 1990,
31, 3879–3882.
We thank Aventis Pharma Company and the CNRS
for a grant (BDI to S.C.-H.).
14. Morales, G. A.; Corbett, J. W.; DeGrado, W. F. J. Org.
Chem. 1998, 63, 1172–1177.
15. 1H NMR analysis of this resin seemed to be in agreement
with structure 8, which was confirmed after cleavage.
16. For the cleavage using DDQ see: Kobayashi, S.; Aoki, Y.
Tetrahedron Lett. 1998, 39, 9211–9214 and references
cited therein.
References
1. (a) For reviews on tropane alkaloids see: Fodor, G. R.
Nat. Prod. Rep. 1994, 11, 603–612 and references cited
therein; (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–
446 and references cited therein.
2. The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1988; Vol. 33
3. For recent and comprehensive reviews on solid-phase
organic synthesis, see: (a) Solid-Phase Organic Synthesis;
Burgess, K., Ed.; John Wiley & Sons: New York, 2000;
(b) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson,
P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott,
J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc. Perkin
17. Coskun, N.; Tirli, F. Synth. Commun. 1997, 27, 1–9.
18. According to 1H and 13C NMR spectra, each of these
isomers was found to be a mixture of atropoisomers.
19. IR analysis of polymer recovered from the cleavage reac-
tion shows complete disappearance of the carbonyl
absorbance of the enone (1691 cm−1).
20. Only the major isomer was isolated and the endo configu-
ration was assigned from its 400 MHz 1H NMR spec-
trum. As for compounds 9 and 10, this product was
found to be a mixture of atropoisomers
.