C(10)-substituted camphors and fenchones by electrophilic treatment of 2-methylenenorbornan-1-ols: Enantiospecificity, scope, and limitations

Article abstract of DOI:10.1021/jo026566i

Valuable chiral sources of C(10)-substituted camphors and C(10)-substituted fenchones can be straightforwardly obtained by treatment of an appropriate, easily obtainable, camphor- or fenchonederived 2-methylenenorbornan-1-ol with an electrophilic reagent. The process takes place via a tandem regioselective carbon-carbon double-bond addition/stereocontrolled Wagner-Meerwein rearrangement. A complete study of the enantiospecificity, scope, and limitations of this process, as well as about the role played by the hydroxyl group attached at the C(1) bridgehead position of the starting 2-methylenenorbornan-1-ols, has been realized. The feasibility of the described methodology has been exemplified by the highly efficient enantiospecific preparation of several interesting C(10)-halogen-, C(10)-O-, C(10)-S-, C(10)-Se-, or C(10)-C-substituted camphors and fenchones.

Full text of DOI:10.1021/jo026566i

C(10)-Su bstitu ted Ca m p h or s a n d F en ch on es by Electr op h ilic
Tr ea tm en t of 2-Meth ylen en or bor n a n -1-ols: En a n tiosp ecificity,
Scop e, a n d Lim ita tion s
Santiago de la Moya Cerero,*,† Antonio Garc´ıa Mart´ınez,† Enrique Teso Vilar,‡
Amelia Garc´ıa Fraile,‡ and Beatriz Lora Maroto‡
Departamento de Quı´mica Orga´nica I, Facultad de Ciencias Qu´ımicas, Universidad Complutense de
Madrid, Ciudad Universitaria, 28040-Madrid, Spain
santmoya@quim.ucm.es
Received October 15, 2002
Valuable chiral sources of C(10)-substituted camphors and C(10)-substituted fenchones can be
straightforwardly obtained by treatment of an appropriate, easily obtainable, camphor- or fenchone-
derived 2-methylenenorbornan-1-ol with an electrophilic reagent. The process takes place via a
tandem regioselective carbon-carbon double-bond addition/stereocontrolled Wagner-Meerwein
rearrangement. A complete study of the enantiospecificity, scope, and limitations of this process,
as well as about the role played by the hydroxyl group attached at the C(1) bridgehead position of
the starting 2-methylenenorbornan-1-ols, has been realized. The feasibility of the described
methodology has been exemplified by the highly efficient enantiospecific preparation of several
interesting C(10)-halogen-, C(10)-O-, C(10)-S-, C(10)-Se-, or C(10)-C-substituted camphors and
fenchones.
In tr od u ction
(+)-(1S)-fenchone (en t-2) are available, which enhances
the utility of the camphor- and fenchone-based synthetic
routes.
The naturally occurring ketones (+)-(1R)-camphor (1)
and (-)-(1R)-fenchone (2) (Scheme 1) have been widely
used as key intermediates for the synthesis of interesting
optically enriched organic molecules, as well as for the
construction of chiral auxiliaries, chiral catalysts, and
chiral reagents for asymmetric synthesis.1 This is due to
(a) the abundance, and therefore low price, of these
bicyclic terpenic ketones, (b) the facility to realize several
functionalizations on the norbornane skeleton in a high
stereocontrolled form,1a,b and (c) the fact that the rigid
norbornane framework can easily undergo fragmentation,
generally by the C(1)-C(2) or the C(2)-C(3) bond, to
generate interesting chiral cyclopentanoids.2 On the other
hand, also the enantiomers (-)-(1S)-camphor (en t-1) and
Among the great variety of camphor-derived chiral
sources (generally C(2)-substituted camphors, see type
II in Scheme 1),3 the group of C(10)-substituted camphors
(types IV and V) must be outlined. This is due to the fact
that these kinds of camphor derivatives have been
demonstrated to act as valuable chiral auxiliaries [e.g.
Oppolzer’s sultam (3)],4 chiral catalysts [e.g. amino
alcohol 4],5 and chiral reagents [e.g. Davis’ oxaziridine
(5)]6 for asymmetric synthesis, chiral resolving agents for
the resolution of racemic mixtures (e.g. sulfonic acid 6),7
as well as key chiral intermediates for the total synthesis
of natural products [e.g. 10-methylenecamphor (7) in
(3) For example see: (a) Palomo, C.; Oiarbide, M.; Sharma, A. K.;
Gonza´lez-Rego, M. C.; Linden, A.; Garc´ıa, J . M.; Gonza´lez, A. J . Org.
Chem. 2000, 65, 9007. (b) Palomo, C.; Oiarbide, M.; Gonza´lez-Rego,
M. C.; Sharma, A. K.; Garc´ıa, J . M.; Gonza´lez, A.; Landa, C.; Linden
A. Angew. Chem., Int. Ed. 2000, 39, 1063. (c) Xu, Q.; Wang, G.; Pan,
X.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 381. (d) Dimitrov,
V.; Dobrikov, G.; Genov, N. Tetrahedron: Asymmetry 2001, 12, 1323.
(e) Malaise`, G.; Barloy, L.; Osaborn, J . A. Tetrahedron Lett. 2001, 42,
7417. (f) Hung, S.-C.; Wen, Y.-F.; Chang, J .-W.; Liao, C.-C.; Vang, B.-
J . J . Org. Chem. 2002, 67, 1308.
(4) Among the great number of examples concerning to the use of
Oppolzer’s sultame, some modern ones are: (a) Sasaki, H.; Carreira,
E. M. Synthesis 2000, 135. (b) Miyabe, H.; Ushiro, C.; Ueda, M.;
Yamakawa, K.; Naito, T. J . Org. Chem. 2000, 65, 176. (c) Xu, M.-H.;
Wang, W.; Xia, L.-J .; Lin, G.-Q. J . Org. Chem. 2001, 66, 3953. (d)
Szymansky, S.; Chapuis, C.; J urczak, J . Tetrahedron: Asymmetry 2001,
12, 1939. (e) J ullian, V.; Monjardet Bas, V.; Fosse, C.; Lavielle, S.;
Chassaing, G. Eur. J . Org. Chem. 2002, 1677. (f) Schmidt, B.;
Wildermann, H. J . Chem. Soc., Perkin Trans. 1 2002, 1050. (g)
Karlsonn, S.; Ho¨gberg, H.-E. J . Chem. Soc., Perkin Trans. 1 2002, 1076.
(5) (a) Hanyu, N.; Aoki, T.; Mino, T.; Sakamoto, M.; Fujita, T.
Tetrahedron: Asymmetry 2000, 11, 4127 and 2971. (b) Hanyu, N.;
Mino, T.; Sakamoto, M.; Fujita, T. Tetrahedron Lett. 2000, 41, 4587.
† Telephone: +91 394 42 36. Fax: +91 394 41 03.
‡ Current address: Departamento de Qu´ımica Orga´nica y Biolog´ıa,
Facultad de Ciencias, Universidad Nacional de Educacio´n a Distancia,
28040-Madrid, Spain.
(1) Some interesting general reviews are: (a) Oppolzer, W. Tetra-
hedron 1987, 43, 1969. (b) Money, T. Nat. Prod. Rep. 1985, 2, 253. (c)
Ho, T.-L. In Enantioselective Synthesis: Natural Products from Chiral
Terpenes; J ohn Wiley and Sons: New York. 1992. (d) Money, T. In
Studies in Natural Products Chemistry; Atta-ur-Rahmann, Ed.; Else-
vier: Amsterdam, The Netherlands, 1989. (e) Eliel, E. L.; Wilen, S. H.
In Stereochemistry of Organic Compounds; J ohn Wiley and Sons: New
York. 1994. (f) Seyden-Penne J . In Chiral Auxiliaries and Ligands in
Asymmetric Synthesis; J ohn Wiley and Sons: New York. 1995.
(2) Some recent examples are the following: concerning the C1/C2
fragmentation: (a) Mermet-Mouttet, M. P.; Gabriel, K.; Heissler, D.
Tetrahedron Lett. 1999, 40, 843. (b) Mehta, G.; Mohal, N. Tetrahedron
Lett. 1999, 40, 5791 and 5795. (c) Mehta, G.; Venkateswaran, R. V.
Tetrahedron 2000, 56, 1399. (d) Mehta, G.; Mohal, N. Tetrahedron Lett.
2001, 42, 4227. Concerning the C2/C3 fragmentation see: (e) Na-
gakawa, H.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42,
4523. (f) Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J . 2001, 7, 945.
Also see refs 1b and 8.
10.1021/jo026566i CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/24/2003
J . Org. Chem. 2003, 68, 1451-1458
1451

de la Moya Cerero et al.
F IGURE 1. Some relevant C(10)-substituted camphor-based chiral sources.
SCHEME 1. Ma in Typ es of Non r a cem ic Ca m p h or a n d F en ch on e Der iva tives by Ster eocon tr olled
F u n ction a liza tion of (+)-Ca m p h or (1) a n d (-)-F en ch on e (2)
Paquette’s approach to the anticancer natural product
taxol]8 (Figure 1). Most of the C(10)-substituted camphors
are C(10)-S-substituted, mainly C(10)-S(VI)-substituted
(e.g. 3, 5, and 6 in Figure 1). This is due to the fact that
almost all of the synthetic routes described for the
preparation of these kinds of camphor derivatives use
commercial enantiopure 10-camphorsulfonic acid (6) (the
first C(10)-substituted camphor derivative obtained),9 or
enantiopure 10-camphorsulfonyl chloride, as starting
material. Nevertheless, several modern enantiopure cam-
phor ligands with a C(10)-substitution different from the
common C(10)-S, such as C(10)-O-, C(10)-N-, C(10)-
halogen-, C(10)-P-, C(10)-Se-, C(10)-Te-, or C(10)-C-, also
have been described as interesting chiral sources (e.g. 4
and 7 in Figure 1).10 In these last cases, the necessity of
using 6, or other derivatives obtained from it, as the
starting material makes most of those synthetic routes
result in low overall yields.10
On the other hand, despite the complementarities
existing between camphor- and fenchone-derived chiral-
ity transfers,11 C(10)-substituted fenchones have not been
obtained, nor probed. This is due to the fact that
enantiopure 10-fenchonesulfonic acid (the fenchone ana-
logue of 6 and, therefore, the potential key starting
(6) Some modern examples are: (a) Tagami, K.; Nakazawa, N.; Sano,
S.; Nagao, Y. Heterocycles 2000, 53, 771. (b) Wang, C.-C.; Li, J . J .;
Huang, H.-C.; Lee, L. F.; Reitz, D. B. J . Org. Chem. 2000, 65, 2711. (c)
Pabmanabhan, S.; Lavin, R. C.; Durant, G. J . Tetrahedron: Asymmetry
2000, 11, 3455.
(7) As examples, see: (a) Cermak, D. M.; Du, Y.; Wiemer, D. J . Org.
Chem. 1999, 64, 388. (b) Yoshioka, R.; Hiramatsu, H.; Okamura, K.;
Tsujioka, I.; Yamada, S.-I. J . Chem. Soc., Perkin Trans. 2 2000, 2121.
(c) Kaptein, B.; Elsenberg, H.; Gringergen, R. F. P.; Broxterman, Q.
B.; Hulshof, L. A.; Pouwer, K. L.; Vries, T. R. Tetrahedron: Asymmetry
2000, 11, 1343. (d) Ba`lint, J .; Hell, Z.; Markovits, I.; Pa`rka`nyi, L.;
Fogassy, E. Tetrahedron: Asymmetry 2000, 11, 1323. (e) Andersen,
N. G.; Ramsden, P. D.; Che, D.; Parvez, M.; Keay, B. A. J . Org. Chem.
2001, 66, 7478.
(10) For example, see the following: Referred to C(10)-O-substituted
camphors: (a) Chu, Y.-Y.; Yu, C.-S.; Chen, C.-J .; Yang, K.-S.; Lian,
J .-C.; Lin, C.-H.; Chen, K. J . Org. Chem. 1999, 64, 6993. (b) Hiroi, K.;
Watanabe, K. Tetrahedron: Asymmetry 2001, 12, 3067. Referred to
C(10)-N-substituted camphors: (c) Seo, R.; Ishizuka, T.; Abdel-Aziz,
A. A.-M.; Kunieda, T. Tetrahedron Lett. 2001, 42, 6353. (d) Sakamoto,
M.; Fujita, T. Tetrahedron Lett. 2001, 42, 4837. (e) Yang, K.-S.; Chen,
K. J . Org. Chem. 2001, 66, 1676. Referred to C10-halogen-substituted
camphors: (f) Fergurson, C. G.; Money, T.; Portillo, J .; Whitelaw, P.
D. M.; Wong, M. K. C. Tetrahedron 1996, 52, 14461. Referred to C(10)-
P-substituted camphors: (g) Komarov, I. V.; Gorichko, M. V.; Kornilov,
M. Tetrahedron: Asymmetry 1997, 8, 435. (h) Sell, T.; Laschat, S.; Dix,
I.; J ones, P. G. Eur. J . Org. Chem. 2000, 4119. (i) Monsess, A.; Laschat,
S. Synlett 2002, 1011. Referred to C(10)-Se-substituted camphors: (j)
Takahashi, T.; Nakao, N.; Koizumi, T. Tetrahedron: Asymmetry 1997,
8, 3293. (k) Eames, J .; Weerasooriya, N. Tetrahedron: Asymmetry
2001, 12, 1. Referred to C(10)-Te-substituted camphors: (l) Zhang, J .;
Saito, S.; Koizumi, T. J . Org. Chem. 1998, 63, 5423. Referred to C(10)-
C-substituted camphors, see refs 5 and 8.
(8) (a) Paquette, L. A.; Zhao, M.; Montgomery, F.; Zeng, Q.; Wang,
T. Z.; Elmore, S.; Combink, K.; Wang, H.-L.; Bailey, S.; Zhuang, S.
Pure Appl. Chem. 1998, 70, 1449. (b) Paquette, L.; Zhao, M. J . Am.
Chem. Soc. 1998, 120, 5203. (c) Paquette, L.; Zeng, Q.; Wang, H.-L.;
Shih, T.-L. Eur. J . Org. Chem. 2000, 2187.
(9) Reychler, A. Bull. Soc. Chim. Paris 1898, 19, 120.
1452 J . Org. Chem., Vol. 68, No. 4, 2003

Electrophilic Treatment of 2-Methylenenorbornan-1-ols
SCHEME 2. Str a igh tfor w a r d P r ep a r a tion of C(10)-Su bstitu ted Ca m p h or s a n d F en ch on es fr om Ca m p h or
(1) a n d F en ch on e (2)
material for other C(10)-substituted fenchones) is not
commercially available.12
ner-Meerwein rearrangement of the starting optically
active 1-methylnorbornan-2-one (1 or 2) to produce the
corresponding bridgehead 2-methylenenorborn-1-yl tri-
flate 8 and (2) a second electrophile-promoted Wagner-
Meerwein rearrangement of 2-methylenenorbornan-1-ols
9 to yield the corresponding C(10)-substituted camphor
or fenchone 10(E).
In this paper we provide insight into the enantiospeci-
ficity, scope, and limitations of the second Wagner-
Meerwein rearrangement of the above-described route
[i.e. the rearrangement of 9 upon treatment with the
electrpophilic reagent (E+)], for the preparation of enani-
omerically pure, or enantiomerically enriched, C(10)-
substituted camphors and fenchones [10(E)].
From all the above, it is easy to understand that the
establishment of a straightforward synthetic route to
both nonracemic C(10)-substituted camphors and fen-
chones is of a great interest. In this sense, and related
to our interest in the synthetic applications of the
Wagner-Meerwein rearrangement in the preparation of
bridgehead norbornane derivatives, starting from readily
available (+)-camphor 1 and (-)-fenchone 2,13 we have
recently reported in some communications a new and
versatile synthetic route to these kinds of derivatives
(Scheme 2).14 The established route includes two key
stereocontrolled Wagner-Meerwein rearrangements: (1)
a first base-controlled triflic-anhydride-promoted Wag-
Resu lts a n d Discu ssion
(11) For the influence of the topological differences of camphor- and
fenchone-derived chiral sources on the chirality transfer, see: (a)
Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron Asymmetry 1997,
8, 1869. (b) Suzuki, Y.; Ogata, Y.; Hiroi, K. Tetrahedron: Asymmetry
1999, 10, 1219. (c) Page, P. C. B.; Murrell, V. L.; Limousin, C.; Laffan,
D. D. P.; Bethell, D.; Slawin, A. M. Z.; Smith, T. A. D. J . Org. Chem.
2000, 65, 4204. Also see refs 5 and 13g.
(1) En a n tiosp ecificity. In an earlier publication in
1901,15 Forster described that the treatment of an opti-
cally active camphor-derived alcohol of unknown struc-
ture [nowadays we know such alcohol is 3,3-dimethyl-2-
methylenenorbornan-1-ol (9a )] with an excess of ice-
cooled sulfuric acid gave enantiopure camphor (1),16
which constitutes the first example of the reaction
considered herein (see Scheme 2, E+ ) H+, 10a (H) ) 1).
The enantiospecificity of Forster’s result contrasts with
the well-known fact that Wagner-Meerwein rearrange-
ment of 3,3-dimethylnorborn-2-yl carbocations use to be
accompanied by a competitive Nametkin rearrangement,
consecutive 6,2-hydride shift between enantiomeric car-
bocations, and subsequent carbocation rearrangements,
which are conducive to the formation of racemic mixtures,
or, at least, products with a low optical purity (scalemic
mixtures).17 Thus, the addition of a proton to the carbon-
carbon double bond of 3,3-dimethyl-2-methylenenor-
bornan-1-ol (9a ) could take place with a Wagner-
Meerwein rearrangement to give enantiopure (1R)-
camphor (1), or with both Wagner-Meerwein and
competitive Nametkin rearrangements to give 1 together
with a certain amount of its enantiomer (en t-1) (Scheme
3).
(12) For the preparation of 10-fenchonesulfonic acid, see: Verfu¨rth,
V.; Ugi, I. Chem. Ber. 1991, 124, 1627.
(13) (a) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de la
Moya Cerero, S.; D´ıaz Oliva, C.; Subramanian, L. R.; Maichle, C.
Tetrahedron: Asymmetry 1994, 5, 949. (b) Garc´ıa Mart´ınez, A.; Teso
Vilar, E.; Garc´ıa Fraile, A.; de la Moya Cerero, S.; Subramanian, L. R.
Tetrahedron: Asymmetry 1994, 5, 1373. (c) Garc´ıa Mart´ınez, A.;
Subramanian, L. R.; Hanack, M. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol.
7, p 5146. (d) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de
la Moya Cerero, S.; Mart´ınez Ruiz, P.; Subramanian, L. R. Tetrahe-
dron: Asymmetry 1996, 7, 1257. (e) Garc´ıa Mart´ınez, A.; Teso Vilar,
E.; Moreno J ´ımenez, F.; Mart´ınez Bilbao, C. Tetrahedron: Asymmetry
1997, 8, 3031. (f) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile,
A.; Herrera Ferna´ndez, A.; de la Moya Cerero, S.; Moreno J ime´nez, F.
Tetrahedron 1998, 54, 6539. (g) Garc´ıa Mart´ınez, A.; Teso Vilar, E.;
Garc´ıa Fraile, A.; de la Moya Cerero, S.; Mart´ınez Ruiz, P. Tetrahe-
dron: Asymmetry 1998, 9, 1737. (h) Garc´ıa Mart´ınez, A.; Teso Vilar,
E.; Moreno J ´ımenez, F.; Garc´ıa Amo, M. Tetrahedron: Asymmetry
2000, 11, 1709. (i) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile,
A.; Mart´ınez Ruiz, P. Eur. J . Org. Chem. 2001, 2805. (j) Garc´ıa
Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; Mart´ınez Ruiz, P.
Tetrahedron: Asymmetry 2001, 12, 2153. (k) Garc´ıa Mart´ınez, A.; Teso
Vilar, E.; Garc´ıa Fraile, A.; de la Moya Cerero, S.; Mart´ınez Ruiz, P.;
Chicharro Villas, P. Tetrahedron: Asymmetry 2002, 13, 1.
(14) (a) Lora Maroto, B.; de la Moya Cerero, S.; Garc´ıa Mart´ınez,
A.; Garc´ıa Fraile, A.; Teso Vilar, E. Tetrahedron: Asymmetry 2000,
11, 3059. (b) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de
la Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2000,
11, 4437. (c) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de
la Moya Cerero, S.; Lora Maroto, B. Tetrahedron Lett. 2001, 42, 5017.
(d) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de la Moya
Cerero, S.; Lora Maroto, B. Tetrahedron Lett. 2001, 42, 6539. (e) Garc´ıa
Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de la Moya Cerero, S.;
Lora Maroto, B. Tetrahedron: Asymmetry 2001, 12, 3325. (f) Garc´ıa
Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de la Moya Cerero, S.;
Lora Maroto, B. Tetrahedron Lett. 2002, 43, 1183.
In this sense, we have also repeated such a rearrange-
ment, treating now enantiopure 9a with 10% HCl. In
(15) Forster, M. O. J . Chem. Soc. 1901, 79, 644.
(16) The obtained camphor was identified as the corresponding
enantiopure oxime with [R]D -40.2 in absolute ethanol.
(17) Some examples are: (a) Eck, R.; Mills, R. W.; Money, T. J .
Chem. Soc., Perkin Trans. 1 1975, 521. (b) Money, T.; Palme, M. H.
Tetrahedron: Asymmetry 1993, 4, 2363. Also see ref 13f.
J . Org. Chem, Vol. 68, No. 4, 2003 1453

de la Moya Cerero et al.
TABLE 1. Electr op h ilic Tr ea tm en t of
2-Meth ylen en or bor n a n -1-ols 9a a n d 9b: En a n tiosp ecific
P r ep a r a tion of C(10)-Su bstitu ted Ca m p h or s [10a (E)] a n d
C(10)-Su bstitu ted F en ch on es [10b(E)]
SCHEME 3. P ossible Rea ction P a th w a ys for th e
P r oton Ad d ition to 3,3-Dim eth yla ted
2-Meth ylen en or bor n a n -1-ol 9a
starting
alcohol
reaction
product
yield
(%)
reagent
9a
9b
9a
9b
9a
9b
9a
9b
9a
9b
9a
9b
9a
9b
NCS
NCS
NBS
NBS
NISa
NISa
m-CPBA
m-CPBA
p-NO2-C6H4-SCl
p-NO2-C6H4-SCl
C6H5-SeCl
10a (Cl)
10b(Cl)
10a (Br )
10b(Br )
10a (I)
10b(I)
10a (OH)
10b(OH)
10a (p-NO2-C6H4-S)
10b(p-NO2-C6H4-S)
10a (C6H5-Se)
10b(C6H5-Se)
10a (CH2NMe2)
10b(CH2NMe2)
73
87
96
96
67
86
78
82
70
95
82
88
98
97
C6H5-SeCl
[CH2dNMe2]+,I-
[CH2dNMe2]+,I-
a
NIS ) N-iodosuccinimide.
difficulties and low yield in obtaining the enantiopure
starting material 9a .15,22 On the other hand, this proce-
dure presents the unsuitability of using very reactive and
toxic bromine as the electrophilic reagent.
We have found that such problems can be avoided
using (a) our straightforward methodology for the prepa-
ration of enantiopure 9a (see Scheme 2) and (b) N-
bromosuccinimide (NBS) as the electrophilic brominating
reagent instead of bromine. Thus, the reaction of 9a with
NBS takes place enantiospecifically and in mild reaction
conditions (methylene dichloride/room temperature) to
give 10a (Br ) as the only reaction product in high yield
(Scheme 4).14a The use of a base, such as pyridine, is now
not necessary, since during the course of the reaction
succinimide, a weak acid, is formed instead of hydrogen
bromide. Analogously, 10-chlorocamphor [10a (Cl)] and
10-iodocamphor [10a (I)] can be easily obtained from 9a
by using N-chlorosuccinimide (NCS) and N-iodosuccin-
imide (NIS), respectively, instead of NBS (see Table 1).
This exposed synthetic methodology has been extended
to other electrophilic reagents, such as m-chloroperoxy-
benzoic acid (m-CPBA), p-nitrobenzenesulfenyl chloride,
benzeneselenyl chloride, and N,N-dimethylmethanimin-
ium iodide (Eschenmoser’s salt), which has allowed the
straightforward preparation of several interesting enan-
tiopure C(10)-substituted camphors [10a (E)], such as
C(10)-O-, C(10)-S-, C(10)-Se-, and C(10)-C-substituted
camphors (see Table 1). On the other hand, fenchone-
derived 2-methylenenorbornan-1-ol 9b can be used in-
stead of 9a , which allows the preparation of the corre-
sponding optically active C(10)-substituted fenchones
[10b(E)] (see Table 1).
agreement with Forster’s result, enantiopure (1R)-
camphor (1) was obtained in approximately quantitative
yield (Scheme 3). In both cases, the reached enantiospeci-
ficity can be explained by the presence of the electron-
donating hydroxyl group (+K effect) attached to the C(1)
position in the initial carbocation 11 (Scheme 3). Thus,
such a hydroxyl group must stabilize the new carbocation
formed after the Wagner-Meerwein rearrangement of
11 (i.e. the 2-norbornyl cation 12), which makes the
Wagner-Meerwein process much more rapid than the
competitive Nametkin rearrangement to less stable car-
bocation 13 (see Scheme 3).18
(2) Scop e. Forster also essayed the addition of bromine
to his optically active camphor-derived alcohol (i.e. enan-
tiopure 9a ),15 obtaining an optically active bromoketone
that was identified as 6-bromocamphor,19 although it was
really enantiopure 10-bromocamphor [10a (Br )] (see
Scheme 2).20,21a Unfortunately, the addition of bromine
to 9a produces camphor (1) as a secondary product, due
to the formation of hydrogen bromide during the course
of the reaction. This problem can be avoided by using
pyridine as the solvent, which acts as a scavenger of the
formed acid.18a Nevertheless, this methodology has not
been employed as the common procedure to obtain
enantiopure 10a (Br ), a valuable key intermediate to
other C(10)-substituted camphors,21 probably due to the
It is interesting to note that, when 3,3-dimethyl-2-
methylenenorbornan-1-ol (9a ) is reacted with other elec-
trophiles (E+) different from a proton, formation of
scalemic mixtures of the corresponding C(10)-substituted
camphor is not possible (cf. Schemes 3 and 4). This is
due to the fact that the possible competitive Nametkin
rearrangement of the initially formed 2,3,3-trimethyl-
norborn-2-yl carbocations [14(E )] would give a subse-
(18) This bridgehead-substituent effect has been previously dem-
onstrated in: (a) Paukstelis, J . V.; Macharia, B. W. Chem. Commun.
1970, 131. Also see: (b) Thomas, A. A.; Monk, K. A.; Abraham, S.;
Lee, S.; Garner, C. M. Tetrahedron Lett. 2001, 42, 2261. (c) Gosselin,
P.; Lelie`vre, M.; Poissonnier, B. Tetrahedron: Asymmetry 2001, 12,
2091.
(19) Forster, M. O. J . Chem. Soc. 1902, 81, 264.
(20) By the measurement of the specific optical rotation.
(21) The bromine atom of 10a (Br ) can be easily replaced by other
functional groups via
example see: Dallacker, F.; Alroggen, I.; Krings, H.; Laurs, B.; Lipp.
M. Liebigs Ann. Chem. 1961, 647, 23. Also see refs 10g,h,j, l.
a
nucleophilic-substitution reaction. As an
(22) (a) Libman, J .; Sprecher, M.; Mazur, Y. Tetrahedron 1969, 25,
1679. Nonoptically pure 9a can be obtained in better yield through
another synthetic route (see ref 18a and references therein).
1454 J . Org. Chem., Vol. 68, No. 4, 2003

Electrophilic Treatment of 2-Methylenenorbornan-1-ols
different electrophiles, such as I+, Cl+ or Br+, takes place
with formation of mixtures of reaction products,18a,24
whereas the reaction of 1-acetoxy-2-methylenenorbor-
nane [16a (OAc)] with bromine generates 10-bromocam-
phor [10a (Br )].18a To gain an insight into the influence
that the presence of a electron-donating group attached
at the C(1) position of 3,3-dimethyl-2-methylenenorbor-
nanes has on the behavior of these derivatives under
electrophilic treatment, we have comparatively studied
the addition of NBS and m-CPBA to the 3,3-dimethyl-
2-methylenenorbornanes 16a (OMe) and 16a (OTf), C(1)-
methoxy and C(1)-triflyloxy subtituted, respectively
(Scheme 5).
SCHEME 4. P ossible Rea ction P a th w a ys for th e
Electr op h ile-Differ en t-to-P r oton Ad d ition to
3,3-Dim eth yla ted Nor bor n a n -1-ol 9a
When 2-methylenenorbornane 16a (OMe), with an
electron-donating methoxyl group attached to the C(1)
position, is treated with NBS or m-CPBA, in the same
reaction conditions in which bridgehead norbornane-
based alcohol of identical structure 9a was reacted,
corresponding enantiopure 10-bromocamphor [10a (Br )]
and 10-hydroxycamphor [10a (OH)] were obtained, re-
spectively, as the only reaction products (Scheme 5). On
the other hand, electron-withdrawing triflate 16a (OTf)
does not react under the same electrophilic treatments
and reaction conditions.25 Therefore, the presence of the
activating electron-donating group at the C(1) position
is necessary, not only for promoting the Wagner-Meer-
wein rearrangement,18a avoiding a possible competitive
nondesirable Nametkin rearrangement, but also for
activating the initial electrophilic addition to the carbon-
carbon double bond.
SCHEME 5. Beh a vior of 2-Meth ylen en or bor n a n es
16a (OMe) a n d 16a (OTf) u n d er NBS a n d m -CP BA
Tr ea tm en t
In most cases, the presence of trace amounts of a strong
Bro¨nsted acid, together with the electrophilic reagent in
the reaction media makes the major process the proton
addition, giving the formation of camphor (1) or fenchone
(2), respectively, as the only reaction product. This
undesirable collateral reaction usually occurs with easily
hydrolyzable electrophilic reagents, such as some strong
Lewis’ acids (e.g. SO3, AlCl3, BF3, Meerwein’s salt, etc.).
Su m m a r y
We have shown that the electrophilic treatment of the
2-methylenenorbornan-1-ols 9, which are easily and
enantiospecifically obtained from commercial camphor (1)
or fenchone (2), takes place with a stereocontrolled
tandem carbon-carbon double-bond addition/Wagner-
Meerwein rearrangement, to give the corresponding
C(10)-substituted camphors 10a (E) and C(10)-substi-
tuted fenchones 10b(E). The reaction occurs under very
mild conditions and with good-to-excellent yields. The
electron-donating hydroxyl group attached to the C(1)
norbornane position of the starting 2-methylenenorbor-
nanes 9 is necessary to promote both the electrophilic
quent 6,2-hydride shift between different (nonenantio-
meric) carbocations (Scheme 4). But, by the same
reasoning, C(8)-substituted camphors [15a (E)] could be
now obtained (Scheme 4).23
Nevertheless, in all the studied reactions (see Table
1) C(8)-substituted camphors [15a (E)] have not been
detected. Once again, the control of the reaction pathway
is due to the electronic effect exerted by the hydroxyl
group attached at the C(1) position of the initially formed
2-norbornyl carbocation 14(E), which favors the Wag-
ner-Meerwein rearrangement over a possible competi-
tive Nametkin rearrangement (see Scheme 4).
On the other hand, it has been previously reported that
the reaction of some C(1)-substituted 3,3-dimethyl-2-
methylenenorbornanes [16a (X)] (Scheme 5), such as 3,3-
dimethyl-2-methylenenorbornane [16a (H)] or 1-chloro-
3,3-dimethyl-2-methylenenorbornane [16a (Cl)], with
(24) In relation to I+ see: (a) Bochwic, B.; Kuswik, G.; Olejniczak,
B. Tetrahedron 1975, 31, 1607. In relation to Cl+ see: (b) Masson, S.;
Thuillier, A. Bull. Soc. Chim. Fr. 1969, 4368. (c) Melpolder, J . B.; Heck,
R. F. J . Org. Chem. 1976, 41, 265. (d) Chalk, A. J .; Magennis, S. A. J .
Org. Chem. 1976, 41, 273. (e) Chalk, A. J .; Magennis, S. A. J . Org.
Chem. 1976, 41, 1206. See also: (f) de Meijere, A.; Meyer, F. E. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379.
(25) 2-Methylenenorborn-1-yl triflate 16a (OTf) is able to react with
m-CPBA under more energetic conditions (refluxing methylene dichlo-
ride) to yield the corresponding nonrearranged spiranic oxirane as a
mixture of epimers: Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile,
A.; de la Moya Cerero, S.; Lora Maroto, B.; D´ıaz Morillo, C. Tetrahedron
Lett. 2001, 42, 8293.
(23) C(8)-substituted camphor derivatives are spectroscopically quite
different from the corresponding C(10)-substituted camphors. As an
example, see the described spectroscopic data for 8-bromocamphor
[15a (Br )] in ref 17a.
J . Org. Chem, Vol. 68, No. 4, 2003 1455

de la Moya Cerero et al.
extraction, washing, drying, filtration, and solvent evaporation,
the obtained residue was purified by column chromatography
(silica gel, hexane/ether 50:50) to yield pure 9b30 (2.57 g, 96%
addition to the carbon-carbon double bond and the
subsequent Wagner-Meerwein rearrangement, as well
as to avoid the formation of mixtures of isomers.
yield) as a white solid: Mp 55-57 °C. [R]20 -230 (0.51, CH2-
D
The described process has allowed the highly efficient
preparation of interesting C(10)-heteroatom-substituted
camphors, such as 10-bromocamphor [10a (Br )] or 10-
hydroxycamphor [10a (OH)],26 which are valuable inter-
mediates to other enantiopure C(10)-substituted cam-
phors.14a,b On the other hand, the reaction of 9a with
p-nitrobenzenesulfenyl chloride and benzeneselenyl chlo-
ride constitutes a new model procedure for the enan-
tiospecific preparation of valuable C(10)-S- and C(10)-
Se-substituted camphor-derived chiral sources.14c We also
have been able to form a new carbon-carbon bond at the
C(10) position of the camphor skeleton by using an
iminium salt (Eschenmoser’s salt) as the electrophilic
reagent, which allows the preparation of interesting
C(10)-C-substituted camphor-derived chiral sources.14f In
this sense, derivative 10a (CH2NMe2) has been recently
used by us as the chiral key precursor of the taxoid-
intermediate 10-methylenecamphor (7).27
Cl2). FTIR (CCl4) ν 3412 (br), 3074, 2955, 1664, 1148 cm-1
.
O
MS m/z 152 (M+•, 9). HRMS 152.1204 [calcd for C10H16
152.1201]. 1H NMR (CDCl3, 200 MHz) δ 4.98 (dd, J ) 2.4, J )
2.4, 1H), 4.76 (dd, J ) 2.1, J ) 2.1, 1H), 2.44 (dm, J ) 16.5,
1H), 2.01 (ddd, J ) 16.4, J ) 2.1, J ) 2.1, 1H), 1.93-1.81 (m,
2H), 1.77 (s, 1H), 1.68 (dd, J ) 4.3, J ) 4.3, 1H), 1.54-1.43
(m, 1H), 1.34-1.23 (m, 1H), 1.00 (s, 3H), 0.84 (s, 3H) ppm. 13
C
NMR (CDCl3, 50 MHz) δ 155.8, 101.4, 85.9, 46.0, 40.9, 35.5,
32.4, 27.2, 18.5, 18.0 ppm.
Tr ea tm en t of 2-Meth ylen en or bor n a n -1-ol 9a w ith HCl.
A suspension of 9a (152 mg, 1.0 mmol) in 10 mL of 10% HCl
was stirred at room temperature for 6 h (the reaction progress
was monitored by GLC). Finally, the reaction mixture was
diluted with 15 mL of water and extracted with CH2Cl2. The
organic layer was washed with saturated sodium hydrogen-
carbonate solution and with brine, and dried over anhydrous
magnesium sulfate. After filtration and solvent evaporation,
pure 1 (150 mg, approximately quantitative yield) was ob-
tained. Optical purity (>98%) was determined by measure-
ment of the specific optical rotation in comparison with that
obtained from a pure sample of commercial 1.
Finally, the extension of the above-described reactivity
to optically active 2-methylenenorbornan-1-ol 9b, instead
of 9a , has allowed the easy enantiospecific access to the
C(10)-substituted fenchone-derived chiral sources.14d,e
(1S)-10-Ch lor oca m p h or [10a (Cl)]. A solution of 9a (152
mg, 1.0 mmol) and NCS (147 mg, 1.1 mmol) in 10 mL of dry
CH2Cl2 was stirred at room temperature for 48 h (the reaction
time was monitored by GLC). Finally, the reaction mixture
was poured into 15 mL of saturated sodium hydrogencarbonate
solution and extracted with CH2Cl2. The organic layer was
washed with brine, and dried over anhydrous magnesium
sulfate. After filtration and solvent evaporation, the residue
was purified by column chromatography (silica gel, hexane/
CH2Cl2 50:50) to yield pure 10a (Cl) (136 mg, 73% yield) as a
Exp er im en ta l Section
Gen er a l In for m a tion . All starting materials and reagents
were obtained from well-known commercial suppliers and were
used without further purification. Ether and THF were dried
by distillation over sodium/benzophenone, under argon atmo-
sphere, immediately prior to use. CH2Cl2 and CHCl3 were dried
by distillation over P2O5. Flash chromatography was performed
over silica gel (230-400 mesh) or neutral aluminum oxide (150
mesh). 1H and 13C NMR were recorded on a 200-MHz spec-
trometer for 1H and on a 50-MHz spectrometer for 1H or 13C.
white solid. Mp 110-111 °C. [R]20 +38 (0.22, CH2Cl2). FTIR
D
(CCl4) ν 2962, 1742, 1390 cm-1. MS m/z 186 [M+•(35Cl), 3], 188
[M+•(37Cl), 1]. HRMS m/z 186.0806 [calcd for C10H15OCl (35Cl)
1
186.0811]. H NMR (CDCl3, 200 MHz) δ 3.79 (AB, J ) 12.1,
1H), 3.60 (AB, J ) 12.1, 1H), 2.41 (ddd, J ) 18.3, J ) 4.4, J )
2.2, 1H), 2.22-1.95 (m, 3H), 1.74 (d, J ) 18.3, 1H), 1.55-1.33
(m, 2H), 1.12 (s, 3H), 0.97 (s, 3H) ppm. 13C NMR (CDCl3, 50
MHz) δ 215.9, 61.6, 47.8, 43.9, 43.1, 41.4, 26.7, 26.2, 20.5, 20.4
ppm.
1
Chemical shifts (δ) for H and 13C NMR were recorded in ppm
downfield relative to the internal standard tetramethylsilane
(TMS), and coupling constants (J ) are in Hz. IR spectra were
recorded on a FT spectrometer. Mass spectra were recorded
on a 60-eV mass spectrometer. HRMS were recorded by using
the FAB technique. For gas-liquid chromatography (GLC), a
chromatograph equipped with a capillary silicon-gum column
(TRB-1) was used.
(1S)-10-Ch lor ofen ch on e [10b(Cl)]. Following the above-
described procedure for the preparation of 10a (Cl), 152 mg
(1.0 mmol) of 9b was reacted with NCS with a reaction time
of 48 h. After extraction, washing, drying, filtration, and
solvent elimination [vide supra in the preparation of 10a (Cl)],
the obtained residue was purified by column chromatography
(silica gel, hexane/CH2Cl2 50:50) to yield pure 10b(Cl)30 (162
(1R)-3,3-Dim eth yl-2-m eth ylen en or bor n a n -1-ol (9a ). Al-
cohol 9a 22 was prepared by LAH reduction of triflate 8a ,28
according to a general procedure previously described by us.29
(1S)-7,7-Dim eth yl-2-m eth ylen en or bor n a n -1-ol (9b). Fol-
lowing the above-described procedure for the preparation of
9a ,29 5.00 g (17.6 mmol) of triflate 8b28,30 was reacted with
lithium aluminum hydride for 24 h. After standard hydrolysis,
mg, 87% yield) as a colorless liquid: [R]20 -1630 (0.23, CH2-
D
Cl2). FTIR (CCl4) ν 2970, 1744, 1385 cm-1. MS m/z 186
[M+•(35Cl), 5], 188 [M+•(37Cl), 2]. HRMS m/z 186.0817 [calcd
1
for C10H15OCl (35Cl) 186.0811]. H NMR (CDCl3, 200 MHz) δ
3.83 (AB, J ) 11.6, 1H), 3.63 (AB, J ) 11.6, 1H), 2.20 (br s,
1H), 2.02 (ddd, J ) 10.7, J ) 1.9, J ) 1.9, 1H), 1.95-1.69 (m,
(26) Both enantiopure 10-bromocamphor [10a (Br )] and 10-hydroxy-
camphor [10a (OH)] have been previously prepared from 10-camphor-
sulfonic acid in a very low overall yield (20% and 12%, respectively)
according to the procedure described by Dallacker in ref 21. Alcohol
10a (OH) can be also prepared in 72% yield from â-pinene oxide
(Villemin, D.; Hammandi, M. Synth. Commun. 1995, 25, 3141).
(27) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; de la Moya
Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2002, 13, 17.
(28) For the enantiospecific synthesis of triflates 8a and 8b, we have
used a variant of the standard procedure previously described by us
(Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Os´ıo Barcina, J .; Rodr´ıguez
Herrero, M. E.; de la Moya Cerero, S.; Hanack, M.; Subramanian, L.
R. Tetrahedron: Asymmetry 1993, 4, 2333), consisting of the use of
triisobutylamine as the nonnucleophilic base instead of N,N-diisobutyl-
2,4-dimethyl-3-pentanamine, which is no longer commercially avail-
able.
(30) Since the starting commercial (-)-fenchone (2) has an ee of 82%,
all products enantiospecifically obtained from it [i.e. 8b , 9b , and
10b (E )] must possess the same opticaly purity. This fact has been
tested for the case of 10b(OH), by comparison of the obtained specific
optical rotation with the measured one for enantiopure 10-hydroxy-
fenchone (see ref 32b).
(31) Enantiopure 10a (I) has been previously prepared from 10-
camphorsulfonyl chloride (Oae, S.; Togo, H. Bull. Chem. Soc. J pn. 1983,
7, 3553).
(32) 10-Hydroxyfenchone has been previously prepared from fen-
chone following a six-step route with low overall yield: (a) Paquette,
L. A.; Teleha, C. A.; Taylos, R. T.; Maynard, G. D.; Rogers, R. D.;
Gallucci, J . C.; Springer, J . P. J . Am. Chem. Soc. 1990, 112, 265 and
references therein. Enantiopure 10-hydroxyfenchone has been de-
scribed as the major metabolite in the biotransformation of (+)-
camphor in rabbits: (b) Miyazawa, M.; Kameoka, H. Chem. Express
1988, 3, 503.
(29) Garc´ıa Mart´ınez, A.; Teso Vilar, E.; Garc´ıa Fraile, A.; Ruano
Franco, C.; Soto Salvador, J .; Subramanian, L. R.; Hanack, M.
Synthesis 1987, 321.
1456 J . Org. Chem., Vol. 68, No. 4, 2003

Electrophilic Treatment of 2-Methylenenorbornan-1-ols
3H), 1.69 (dd, J ) 10.5, J ) 1.9, 1H), 1.37-1.23 (m, 1H), 1.05
(s, 6H) ppm. 13C NMR (CDCl3, 50 MHz) δ 219.8, 59.6, 48.2,
44.9, 43.6, 38.1, 27.9, 24.8, 23.0, 21.5 ppm.
of dry CH2Cl2, under argon atmosphere, was added p-nitroben-
zenesulfenyl chloride (568 mg, 3.0 mmol). The reaction mixture
was stirred at room temperature for 24 h (the reaction time
was monitored by GLC). Finally, the reaction mixture was
poured into 20 mL of saturated sodium hydrogencarbonate
solution and extracted with CH2Cl2. The organic layer was
washed with brine and dried over anhydrous magnesium
sulfate. After filtration and solvent evaporation, the residue
was purified by column chromatography (silica gel, hexane/
CH2Cl2 80:20) to yield pure [10a (p-NO2-C6H4-S)] (213 mg,
(1S)-10-Br om oca m p h or [10a (Br )]. Following the above-
described procedure for the preparation of 10a (Cl), 152 mg
(1.0 mmol) of 9a was reacted with NBS instead of NCS with
a reaction time of 24 h. After extraction, washing, drying,
filtration, and solvent elimination [vide supra in the prepara-
tion of 10a (Cl)], the obtained residue was purified by column
chromatography (silica gel, hexane/CH2Cl2 50:50) to yield pure
10a (Br )15,21a (222 mg, 96% yield).
70% yield) as a pale-brown solid: Mp >100 °C dec. [R]20 +7
D
(0,22, CH2Cl2). FTIR (CCl4) ν 2962, 1745, 1583, 1520, 1338
cm-1. MS m/z 305 [M+•(32S), 25], 307 [M+•(34S), 1]. HRMS m/z
305.1090 [calcd for C16H19NO3S (32S) 305.1086]. 1H NMR
(CDCl3, 200 MHz) δ 8.13 (AA′XX′, 2H), 7.37 (AA′XX′, 2H), 3.37
(AB, J ) 12.6, 1H), 2.99 (AB, J ) 12.6, 1H), 2.52-2.37 (dm,
J ) 18.5, 1H), 2.17-1.94 (m, 3H), 1.94 (d, J ) 18.5, 1H), 1.62-
1.35 (m, 2H), 1.21 (s, 3H), 0.98 (s, 3H) ppm. 13C NMR (CDCl3,
50 MHz) δ 216.4, 148.6, 145.0, 126.1 (two signals), 123.9 (two
signals), 60.4, 48.0, 43.5, 43.0, 29.2, 26.9, 26.7, 20.3, 20.2 ppm.
(1S)-10-Br om ofen ch on e [10b(Br )]. Following the above-
described procedure for the preparation of 10a (Cl), 152 mg
(1.0 mmol) of 9b was reacted with NBS instead of NCS with
a reaction time of 24 h. After extraction, washing, drying,
filtration, and solvent elimination [vide supra in the prepara-
tion of 10a (Cl)], the obtained residue was purified by column
chromatography (silica gel, hexane/CH2Cl2 50:50) to yield pure
10b(Br )30 (222 mg, 96% yield) as a colorless liquid: [R]20D -330
(0.31, CH2Cl2). FTIR (film) ν 2926, 1740, 1385 cm-1. MS m/z
230 [M+•(79Br), 3], 232 [M+•(81Br), 3]. HRMS m/z 230.0303
[calcd for C10H15OBr (79Br) 230.0306]. 1H NMR (CDCl3, 200
MHz) δ 3.71 (AB, J ) 10.7, 1H), 3.51 (AB, J ) 10.7, 1H), 2.19
(br s, 1H), 2.08-1.98 (dm, J ) 10.5, 1H), 1.94-1.70 (m, 3H),
1.70 (dd, J ) 10.5, J ) 1.9, 1H), 1.55-1.22 (m, 1H), 1.07 (s,
6H) ppm. 13C NMR (CDCl3, 50 MHz) δ 219.4, 59.1, 48.3, 44.8,
39.2, 32.3, 28.9, 25.2, 22.9, 21.5 ppm.
(1S)-10-Iod oca m p h or [10a (I)]. Following the above-
described procedure for the preparation of 10a (Cl), 152 mg
(1.0 mmol) of 9a was reacted with NIS instead of NCS with a
reaction time of 2 h. After extraction, washing, drying,
filtration, and solvent elimination [vide supra in the prepara-
tion of 10a (Cl)], the obtained residue was purified by column
chromatography (silica gel, hexane/CH2Cl2 50:50) to yield pure
10a (I)31 (186 mg, 67% yield).
(1S)-10-[(p-Nitr op h en yl)su lfa n yl]fen ch on e [10b(p-NO2-
C6H4-S)]. Following the above-described procedure for the
preparation of 10a (p-NO2-C6H4-S), 152 mg (1.0 mmol) of 9b
was reacted with p-nitrobenzenesulfenyl chloride with
a
reaction time of 24 h. After extraction, washing, drying,
filtration, and solvent elimination [vide supra in the prepara-
tion of 10a (p-NO2-C6H4-S)], the obtained residue was purified
by column chromatography (silica gel, hexane/CH2Cl2 80:20)
to yield pure 10b(p-NO2-C6H4-S)30 (290 mg, 95% yield) as a
pale-yellow liquid: [R]20 -430 (0,51, CH2Cl2). FTIR (CCl4) ν
D
2970, 1743, 1603, 1581, 1518, 1340 cm-1. MS m/z 151 (M+•
-
SAr, 66). HRMS m/z 305.1089 [calcd for C16H19NO3S (32S)
305.1086]. 1H NMR (CDCl3, 200 MHz) δ 8.11 (AA′XX′, 2H),
7.37 (AA′XX′, 2H), 3.40 (AB, J ) 13.1, 1H), 3.25 (AB, J ) 13.1,
1H), 2.18 (br s, 1H), 1.98-1.71 (m, 4H), 1.65 (dd, J ) 10.5,
J ) 1.9, 1H), 1.49-1.35 (m, 1H), 1.08 (s, 3H), 1.07 (s, 3H) ppm.
13C NMR (CDCl3, 50 MHz) δ 220.5, 148.0, 145.1, 126.4 (two
signals), 124.5 (two signals), 58.0, 47.7, 45.2, 38.9, 32.0, 29.5,
24.7, 23.1, 21.5 ppm.
(1S)-10-Iod ofen ch on e [10b (I)]. Following the above-
described procedure for the preparation of 10a (Cl), 152 mg
(1.0 mmol) of 9b was reacted with NIS instead of NCS with a
reaction time of 2 h. After extraction, washing, drying,
filtration, and solvent elimination [vide supra in the prepara-
tion of 10a (Cl)], the obtained residue was purified by column
chromatography (silica gel, hexane/CH2Cl2 50:50) to yield pure
10b(I)30 (239 mg, 86% yield) as a colorless liquid: [R]20D +1030
(0.22, CH2Cl2). FTIR (film) ν 2968, 1742, 1383 cm-1. MS m/z
151 (M+• - I, 18). HRMS m/z 278.0169 (calcd for C10H15OI
(1S)-10-(P h en ylsela n yl)ca m p h or [10a (C6H5-Se)]). Fol-
lowing the above-described procedure for the preparation of
10a (p-NO2-C6H4-S), 152 mg (1.0 mmol) of 9a was reacted with
benzeneselenyl chloride instead of p-nitrobenzenesulfenyl
chloride with a reaction time of 24 h. After extraction, washing,
drying, filtration, and solvent elimination [vide supra in the
preparation of 10a (p-NO2-C6H4-S)], the obtained residue was
purified by column chromatography (silica gel, hexane/CH2-
Cl2 80:20) to yield pure 10a (C6H5-Se) (252 mg, 82% yield) as
1
278.0168). H NMR (CDCl3, 200 MHz) δ 3.49 (AB, J ) 10.5,
1H), 3.31, (AB, J ) 10.5, 1H), 2.17 (br s, 1H), 2.05-1.75 (m,
4H), 1.68 (dd, J ) 10.5, J ) 1.7, 1H), 1.44-1.32 (m, 1H), 1.06
(s, 6H) ppm. 13C NMR (CDCl3, 50 MHz) δ 218.8, 58.6, 48.5,
44.6, 41.2, 30.1, 25.7, 22.9, 21.6, 5.9 ppm.
a pale-brown solid: Mp 36-38 °C. [R]20 -52 (0.22, CH2Cl2).
D
FTIR (CCl4) ν 3055, 2959, 1742, 1578, 1477, 1389 cm-1. MS
m/z 304 [M+•(76Se), 4], 305 [M+•(77Se), 4], 306 [M+•(78Se), 12],
308 [M+•(80Se), 24], 310 [M+•(82Se), 4]. HRMS 308.0679 [calcd
(1R)-10-H yd r oxyca m p h or [10a (OH )]. A solution of 9a
(152 mg, 1.0 mmol) and 599 mg of m-CPBA (57-86% purity)
in 15 mL of CH2Cl2 was stirred at room temperature for 24 h
(the reaction time was monitored by GLC). Finally, the
reaction mixture was treated with 15 mL of saturated sodium
hydrogensulfite solution and extracted with CH2Cl2. The
organic layer was washed with saturated sodium hydrogen-
carbonate solution and with brine, and dried over anhydrous
magnesium sulfate. After filtration and solvent evaporation,
the residue was purified by column chromatography (silica gel,
CH2Cl2/ether 80:20) to yield pure 10a (OH)26 (131 mg, 78%
yield).
(1R)-10-Hydr oxyfen ch on e [10b(OH)]. Following the above-
described procedure for the preparation of 10a (OH), 152 mg
(1.0 mmol) of 9b was reacted with m-CPBA with a reaction
time of 24 h. After extraction, washing, drying, filtration, and
solvent elimination [vide supra in the preparation of 10a (OH)],
the obtained residue was purified by column chromatography
(silica gel, CH2Cl2/ether 80:20) to yield pure 10b(OH)30,32 (138
mg, 82% yield).
1
for C16H20OSe (80Se) 308.0679]. H NMR (CDCl3, 200 MHz) δ
7.56-7.51 (m, 2H), 7.26-7.22 (m, 3H), 3.26 (AB, J ) 12.2, 1H),
2.78 (AB, J ) 12.2, 1H), 2.40 (dm, J ) 18.4, 1H), 2.12-2.09
(m, 1H), 2.00-1.87 (m, 2H), 1.89 (d, J ) 18.3, 1H), 1.69 (dd,
J ) 9.0, J ) 9.0, 1H), 1.38 (dd, J ) 9.0, J ) 9.0, 1H), 1.02 (s,
3H), 0.91 (s, 3H) ppm. 13C NMR (CDCl3, 50 MHz) δ 217.3,
132.6, 132.4 (two signals), 129.0 (two signals), 126.6, 61.3, 48.1,
43.5, 43.1, 27.8, 26.8, 25.3, 20.1, 20.0 ppm.
(1S)-10-(P h en ylsela n yl)fen ch on e [10b(C6H5-Se)]. Fol-
lowing the above-described procedure for the preparation of
10a (p-NO2-C6H4-S), 152 mg (1.0 mmol) of 9b was reacted with
benzeneselenyl chloride instead of p-nitrobenzenesulfenyl
chloride with a reaction time of 24 h. After extraction, washing,
drying, filtration, and solvent elimination [vide supra in the
preparation of 10a (p-NO2-C6H4-S)], the obtained residue was
purified by column chromatography (silica gel, hexane/CH2-
Cl2 80:20) to yield pure 10b(C6H5-Se)30 (270 mg, 88% yield)
as a yellow liquid. [R]20 +930 (0.22, CH2Cl2). FTIR (film)
D
(1S)-10-[(p-Nitr op h en yl)su lfa n yl]ca m p h or [10a (p-NO2-
C6H4-S)]. Over a solution of 9a (152 mg, 1.0 mmol) in 15 mL
ν 3059, 2968, 1742, 1580, 1477, 1383 cm-1. MS m/z 304
[M+•(76Se), 2], 305 [M+•(77Se), 2], 306 [M+•(78Se), 7], 308
J . Org. Chem, Vol. 68, No. 4, 2003 1457

de la Moya Cerero et al.
[M+•(80Se), 14], 310 [M+•(82Se), 2]. HRMS 308.0674 [calcd for
16H20OSe (80Se) 308.0679]. 1H NMR (CDCl3, 200 MHz) δ
1H), 0.93 (s, 3H), 0.92 (s, 3H) ppm. 13C NMR (CDCl3, 50 MHz)
δ 218.6, 56.6, 55.9, 47.4, 45.1 (two signals), 44.9, 38.4, 30.2,
26.7, 24.1, 22.8, 21.3 ppm.
C
7.54-7.49 (m, 2H), 7.27-7.21 (m, 3H), 3.28 (AB, J ) 12.9, 1H),
3.11 (AB, J ) 12.9, 1H), 2.13 (br s, 1H), 1.93-1.66 (m, 4H),
1.57 (dd, J ) 10.5, J ) 1.7, 1H), 1.41-1.25 (m, 1H), 1.05 (s,
3H), 1.04 (s, 3H) ppm. 13C NMR (CDCl3, 50 MHz) δ 220.0, 132.3
(two signals), 131.6, 129.0 (two signals), 126.7, 59.1, 47.8, 45.0,
39.5, 30.1, 28.2, 24.9, 23.0, 21.5 ppm.
(1R )-3,3-Dim e t h yl-1-m e t h oxy-2-m e t h yle n e n or b or -
n a n e [16a (OMe)]. Over a solution of 9a (152 mg, 1.0 mmol)
in 10 mL of dry THF at -78 °C under argon atmosphere was
added dropwise 0.9 mL of butyllithium 1.6 M in hexane (1.1
mmol) via syringe. After that, the reaction mixture was
allowed to warm to room temperature and stirred for 30 min.
Then, 710 mg (5.0 mmol) of methyl iodide was added dropwise
via syringe at room temperature. When the addition was
complete, the mixture was refluxed for 3 h (the reaction
progress was monitored by GLC). Finally, the reaction was
cooled to 0 °C, carefully hydrolyzed with 10 mL of saturated
ammonium chloride solution, and extracted with ether. The
organic layer was washed with saturated sodium hydrogen-
carbonate solution and with brine, and dried over anhydrous
magnesium sulfate. After filtration and solvent evaporation,
the residue was purified by column chromatography (silica gel,
hexane), to yield pure 16a (OMe) (149 mg, 90% yield) as a
colorless liquid: [R]20D -16 (0.71, CH2Cl2). FTIR (film) ν 3072,
2960, 1662, 1306, 1030 cm-1. MS m/z 166 (M+•, 13). HRMS
(1S)-10-[(Dim eth yla m in o)m eth yl]ca m p h or [10a (CH2-
NMe2)]. A dispersion of 152 mg of 9a (1.0 mmol) and 204 mg
of Eschemoser’s salt (1.1 mmol) in 30 mL of dry CHCl3 was
stirred at refluxing temperature under argon atmosphere for
36 h. After extraction, washing, drying, filtration, and solvent
elimination [vide supra in the preparation of 10a (Br )], the
obtained residue was purified by column chromatography
(neutral aluminum oxide, CH2Cl2/ethyl acetate, 50:50) to yield
pure 10a (CH2NMe2) (205 mg, 98% yield) as a colorless oil.
[R]20 +8 (0.95, CHCl3). FTIR (film) ν 2960, 1736 cm-1. MS
D
m/z 209 (M+•, 3). HRMS 209.1787 (calcd for C13H23NO 209.1780).
1H NMR (CDCl3, 200 MHz) δ 2.80 (td, J ) 11.8, J ) 4.9, 1H),
2.36 (td, J ) 11.8, J ) 4.9, 1H), 2.33 (s, 6H), 2.03 (dd, J ) 3.3,
J ) 3.3, 1H), 2.00-1.86 (m, 1H), 1.78 (d, J ) 18.1, 1H), 1.80-
1.25 (m, 6H), 0.94 (s, 3H), 0.85 (s, 3H) ppm. 13C NMR (CDCl3,
50 MHz) δ 219.0, 59.1, 55.1, 47.6, 45.0 (two signals), 43.4, 43.2,
27.0, 26.7, 23.4, 20.2, 19.6 ppm.
1
166.1354 (calcd for C11H18O 166.1358). H NMR (CDCl3, 200
MHz) δ 4.81 (s, 1H), 4.68 (s, 1H), 3.32 (s, 3H), 1.94-1.54 (m,
5H), 1.44 (dd, J ) 9.2, J ) 1.4, 1H), 1.42-1.26 (m, 1H), 1.07
(s, 3H), 1.03 (s, 3H) ppm. 13C NMR (CDCl3, 50 MHz) δ 161.9,
99.0, 90.2, 53.1, 43.9, 42.0, 37.5, 32.3, 29.1, 26.3, 24.5 ppm.
(1R)-10-[(Dim eth yla m in o)m eth yl]fen ch on e [10b(CH2-
NMe2)]. Following the above-described procedure for the
preparation of 10a (CH2NMe2), 152 mg (1.0 mmol) of 9b was
reacted with a reaction time of 36 h. After extraction, washing,
drying, filtration, solvent elimination, and purification by
column chromatography [vide supra in the preparation of 10a -
(CH2NMe2)], pure 10b(CH2NMe2)30 (205 mg, 98% yield) was
Ack n ow led gm en t. We thank the Ministerio de
Ciencia y Tecnolog´ıa of Spain (research project BQU2001-
1347-C02-02) and UNED (research project 2001V/
PROYT/18) for financial support of this work. B.L.M.
thanks the Ministerio de Educacio´n Cultura y Deportes
of Spain for a postgraduate grant.
obtained as a colorless oil. [R]20 -20.130 (1.1, CHCl3). FTIR
D
(film) ν 2947, 1738 cm-1. MS m/z 181 (M+• - 28, 3). HRMS
209.1779 (calcd for C13H23NO 209.1780). 1H NMR (CDCl3, 200
MHz) δ 2.49-2.19 (m, 2H), 2.24 (s, 6H), 2.08 (m, 1H), 1.93-
1.53 (m, 6H), 1.39 (dd, J ) 10.4, J ) 1.8, 1H), 1.33-1.19 (m,
J O026566I
1458 J . Org. Chem., Vol. 68, No. 4, 2003