A new highly efficient synthetic route to enantiopure 10-bromocamphor

Article abstract of DOI:10.1016/S0957-4166(00)00279-2

A new enantiospecific synthetic route to the interesting chiral synthetic intermediate 10-bromocamphor starting from readily available camphor is described. The procedure takes place straightforwardly in only three synthetic steps with high overall yield. Mechanistically, two interesting enantiospecific Wagner-Meerwein rearrangements involving 2-norbornyl carbocations take place during the process. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00279-2

Tetrahedron: Asymmetry 11 (2000) 3059±3062
A new highly ecient synthetic route to enantiopure
1
0-bromocamphor
a
a,
nez,a,*
Beatriz Lora Maroto, Santiago de la Moya Cerero, * Antonio Garcõ
Â
a Martõ
Â
b
b
Amelia Garcõa Fraile and Enrique Teso Vilar
Â
aDepartamento de QuõÂmica Org a nica I, Facultad de Ciencias QuõÂmicas, Universidad Complutense de Madrid,
Ciudad Universitaria, 28040 Madrid, Spain
Departamento de QuõÂmica Org a nica y BiologõÂa, Facultad de Ciencias, Universidad Nacional de EducacioÂn a Distancia
b
(
UNED), Senda del Rey 9, 28040 Madrid, Spain
Received 11 July 2000; accepted 14 July 2000
Abstract
A new enantiospeci®c synthetic route to the interesting chiral synthetic intermediate 10-bromocamphor
starting from readily available camphor is described. The procedure takes place straightforwardly in only
three synthetic steps with high overall yield. Mechanistically, two interesting enantiospeci®c Wagner±
Meerwein rearrangements involving 2-norbornyl carbocations take place during the process. # 2000
Elsevier Science Ltd. All rights reserved.
Enantiopure C10-substituted camphor derivatives have been widely used as chiral starting
1
materials in asymmetric synthesis, as well as interesting chiral synthetic intermediates in the
2
preparation of natural products. Unfortunately, most of these derivatives have, as a common
1
chemical characteristic, the presence of a sulfur atom attached to the C10 position (C10±S). This
common presence of sulfur at C10 is due to the fact that most of the synthetic routes for the
preparation of C10-substituted camphors start from 10-camphorsulfonic acid (the ®rst C10-sub-
3
stituted camphor derivative obtained), or the now commercially available 10-camphorsulfonyl
�3
chloride.1
Nevertheless, nowadays, several enantiopure camphor derivatives having a C10-substitution
di€erent than the common C10±S, such as C10±O (e.g. 1), C10±N (e.g. 2), C10±halogen (e.g. 3),
C10±P (e.g. 4) or C10±Se (e.g. 5) (Fig. 1), have also been described as very interesting sources of
4
chirality. In this sense, 10-bromocamphor 3 is a very convenient and a key synthetic precursor to
C10-substituted camphor derivatives, since the bromine atom can be replaced via a nucleophilic
4
a
4i
4j
substitution reaction (e.g. C10±Br!C10±O,
C10±Br!C10±Se, or C10±Br!C10±P ).
Unfortunately, up to now 10-bromocamphor 3 has only been prepared enantiospeci®cally from
1
0-camphorsulfonic acid in a very low overall yield (20%), following a procedure described by
*
Corresponding authors. E-mail: santmoya@eucmax.sim.ucm.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00279-2

3
060
B. Lora Maroto et al. / Tetrahedron: Asymmetry 11 (2000) 3059±3062
Figure 1. Some selected C10-substituted camphors with a C10-substitution di€erent than C10±S
4a
Dallacker et al. in 1961. This renders synthetic routes using 10-bromocamphor as starting
material unattractive.4
a,i,j
In this communication, we describe a new highly ecient synthetic route to (1R)-10-bromo-
camphor 3 starting from natural (1R)-camphor 6. Only three simple synthetic steps, which take
place under mild reaction conditions and with excellent yields, are required (Scheme 1).
The ®rst step is the preparation of (1R)-3,3-dimethyl-2-methylenenorborn-1-yl tri¯ate 7 from
5
commercial (1R)-camphor 6 by reaction with tri¯ic anhydride. Tri¯ate 7 is subsequently reduced
6
with lithium aluminum hydride to give the corresponding 2-methylenenorbornan-1-ol 8. Finally,
the treatment of alcohol 8 with N-bromosuccimimide (NBS) yields the desired (1R)-10-bromo-
7
camphor 3. Obtaining synthetic intermediate 8 is necessary since the 2-methylenenorborn-1-yl
tri¯ate 7 does not react with NBS under the same conditions as alcohol 8.
Scheme 1. New highly ecient enantiospeci®c preparation of 10-bromocamphor 3
The key steps of the above-described synthetic procedure are: (1) the enantiospeci®c prepara-
tion of tri¯ate 7 by Wagner±Meerwein rearrangement of 6 by reaction with tri¯ic anhydride; and
(
2) a second enantiospeci®c Wagner±Meerwein rearrangement of the 2-methylenenorbornan-1-ol
+
8 by carbon±carbon double bond addition of electrophilic bromine (Br ), under a straightforward
NBS treatment (Scheme 2).

B. Lora Maroto et al. / Tetrahedron: Asymmetry 11 (2000) 3059±3062
3061
Scheme 2. Wagner±Meerwein rearrangements involved in the described preparation of 10-bromocamphor 3
In conclusion, a new enantiospeci®c route to the interesting chiral source 10-bromocamphor 3
has been described. 10-Bromocamphor 3 is now obtained in only three steps starting from
commercially available (1R)-camphor 6, the complete process having an overall yield of 87%.
This straightforward preparation of 3 opens the way to the ecient preparation of other important
enantiopure C10-substituted camphor derivatives.
Acknowledgements
We would like to thank both the Ministerio de Educacio
CYT, research project PB97-0264) for ®nancial support of this work and the Servicio de
Resonancia Magnetica Nuclear de la Universidad Complutense de Madrid for measurements of
Â
n y Ciencia (MEC) of Spain (DGI-
Â
the NMR spectra. B.L.M. wishes to thank MEC for a postgraduate grant.
References
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3
4
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2
3. (b) Ikota, N.; Sakai, H.; Shibata, H.; Koga, K. Chem. Pharm. Bull. 1986, 34, 1050. (c) Jingen, D.; Yaozong, J.;
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5
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Kornilov, M. Tetrahedron: Asymmetry 1997, 8, 435.

3
062
B. Lora Maroto et al. / Tetrahedron: Asymmetry 11 (2000) 3059±3062
5
. For the enantiospeci®c synthesis of tri¯ate 7, we have used a variant of the standard procedure previously
described by us (Garcõa Martõnez, A.; Teso Vilar, E.; Osõo Barcina, J.; Rodrõguez Herrero, M. E.; de la Moya
Â
Â
Â
Â
Cerero, S.; Hanack, M.; Subramanian, L. R. Tetrahedron: Asymmetry 1993, 4, 2333), in which triisobutylamine
was substituted as the non-nucleophilic base instead of the now commercially unavailable N,N-diisobutyl-2,4-
dimethylpentylamine.
6
7
. (a) Garcõa Martõnez, A.; Teso Vilar, E.; Garcõa Fraile, A.; Ruano Franco, C.; Soto Salvador, J.; Subramanian, L. R.;
  Â
Hanack, M. Synthesis 1987, 321: (b) Enantiopure alcohol 8 has been previously described Libman, J.; Sprecher, M.;
Mazur, Y. Tetrahedron 1969, 25, 1679.
. A solution of alcohol 8 and N-bromosuccinimide in dry CH Cl is stirred at room temperature for 24 h. After the
2
2
ꢀ
20
D
usual work-up, 3 is obtained as a white solid (95% yield). Pf. 69±70 C. ‰ꢀŠ +14.6 (0.20, CH
2 2
Cl ). The structure
1
13
was con®rmed by H NMR, C NMR, IR, MS and HRMS.