Straightforward synthesis of (1S)-10-dimethylaminomethylcamphor: An enantiospecific model procedure to C10-C-substituted camphor-derived chiral sources

Article abstract of DOI:10.1016/S0040-4039(01)02343-7

Enantiopure 3,3-dimethyl-2-methylenenorbornan-1-ol, readily obtained from commercially available camphor, is able to react with Eschenmoser's salt under very soft reaction conditions. This reaction constitutes the first example in which a non-mesomerically activated olefin easily adds the Eschenmoser's salt. The addition takes place regiospecifically and it is followed by an enantiospecific Wagner-Meerwein rearrangement of the norbornane skeleton to afford enantiopure 10-dimethylaminomethylcamphor, an interesting chiral δ-amino ketone, with excellent yield. The obtained amino ketone is a key intermediate to new valuable C10-C-substituted camphor-derived chiral sources.

Full text of DOI:10.1016/S0040-4039(01)02343-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1183–1185
Straightforward synthesis of
(1S)-10-dimethylaminomethylcamphor: an enantiospecific model
procedure to C10ꢀC-substituted camphor-derived chiral sources
Antonio Garc´ıa Mart´ınez,a,* Enrique Teso Vilar,b Amelia Garc´ıa Fraile,b
Santiago de la Moya Cereroa,* and Beatriz Lora Marotob
aDepartamento de Qu´ımica Orga´nica, Fac. de Cc. Qu´ımicas, Universidad Complutense de Madrid, 28040 Madrid, Spain
bDepartamento de Qu´ımica Orga´nica y Biolog´ıa, Fac. de Ciencias, UNED, Senda del Rey 9, 28040 Madrid, Spain
Received 2 November 2001; accepted 10 December 2001
Abstract—Enantiopure 3,3-dimethyl-2-methylenenorbornan-1-ol, readily obtained from commercially available camphor, is able
to react with Eschenmoser’s salt under very soft reaction conditions. This reaction constitutes the first example in which a
non-mesomerically activated olefin easily adds the Eschenmoser’s salt. The addition takes place regiospecifically and it is followed
by an enantiospecific Wagner–Meerwein rearrangement of the norbornane skeleton to afford enantiopure 10-dimethyl-
aminomethylcamphor, an interesting chiral d-amino ketone, with excellent yield. The obtained amino ketone is a key intermediate
to new valuable C10ꢀC-substituted camphor-derived chiral sources. © 2002 Elsevier Science Ltd. All rights reserved.
C10-Substituted camphor derivatives are an important
class of chiral sources which have been widely used as
chiral auxiliaries (e.g. Oppolzer’s sultame 1), chiral
reagents (e.g. Davis’ oxaziridine 2), chiral resolving
agents (e.g. 10-camphorsulfonic acid 3) or chiral cata-
lysts (e.g. Yus’ sulfonamide 4) in many asymmetric
transformations (Fig. 1).1 Most of the described C10-
substituted camhor-derived chiral sources are C10-
heteroatomically subtituted, such as C10-S, C10-Se,
C10-O, C10-N, C10-halogen, C10-P or C10-Te, C10-S
is the most frequent substitution.2 Oppositely, examples
of C10–C-substituted camphor-derived chiral sources
are practically inexistent. This is due to the fact that
most of the described C10-substituted camphors are
prepared from 3, the first obtained C10-substituted
camphor, or by nucleophilic bromine-substitution in
10-bromocamphor (a key intermediate to C10-
heteroaromatic-substituted camphors, also obtained,
up to recent days, from 3).2
Nevertheless, some interesting C10–C-substituted cam-
phors have been prepared and used as valuable chiral
sources (e.g. 10-methylenecamphor 5 as starting inter-
mediate in the Paquette’s approach to anticancer taxol,3
or b-amino alcohol 6 as chiral catalyst for the asymmet-
ric addition of diethylzinc to benzaldehyde).4
Related to the preparation of enantiopure C10-substi-
tuted camphors, we have recently reported that (1R)-
3,3-dimethyl-2-methylenenorbornan-1-ol 7, which is
straightforwardly obtained from commercially available
natural (1R)-camphor,5 is a key intermediate to these
kind of camphor derivatives.6 Thus, the treatment of 7
with electrophiles able to react easily with car-
bonꢀcarbon double bonds, such as N-bromosuccin-
Figure 1. Some selected C10-substituted camphors.
* Corresponding authors.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02343-7

1184
A. Garc´ıa Mart´ınez et al. / Tetrahedron Letters 43 (2002) 1183–1185
Scheme 1. Key tandem electrophilic carbonꢀcarbon double-bond addition—Wagner–Meerwein rearrangement.
Scheme 2. Two different reaction pathways of 7 with carbon electrophiles (Meerwein’s salt versus Eschenmoser’s salt).
imide, m-CPBA, arylsulfenyl halides or arylselenyl
halides (E+=Br+, OH+, ArS+ or ArSe+), takes place
with a tandem of regiospecific carbonꢀcarbon double-
bond addition—Wagner–Meerwein rearrangement to
give straightforwardly the corresponding 10-bromo-
camphor (8, E=Br), 10-hydroxycamphor (8, E=OH),
10-arylsulfanylcamphor (E=ArS) and 10-arylselanyl-
camphor (E=ArSe) (Scheme 1).6
non-mesomerically activated olefin, but with a homo-
conjugated one (note activation of the carbonꢀcarbon
double bond by homoconjugation with the bridgehead
hydroxy group in 7).10
In summary, the reaction of the enantiopure camphor-
derived 2-methylenenorbornan-1-ol 7 with Eschenmos-
er’s salt yields the corresponding 10-aminomethyl-
camphor 9, a C10ꢀC-subtituted camphor. The reaction
takes place enantiospecifically, constituting a straight-
forward model procedure to other C10ꢀC-substituted
camphor-derived chiral sources from readily available
camphor (i.e. the reaction of 7 with other iminium
salts). Moreover, described enantiopure camphor-
derived b-amino ketone 9 is a key intermediate to
enantiopure b-amino alcohols of the type of 6 (e.g. via
nucleophilic addition to the carbonyl group), which
could be used as valuable catalysts for the asymmetric
addition of diethylzinc to aldehydes.4a,b
As a result of this, we attempted to obtain 10-methyl-
camphor (8, E=Me), a simple C10ꢀC-substituted cam-
phor, by reacting 7 with the stabilized carbon–
electrophile Meerwein’s salt (trimethyloxonium tetra-
fluoroborate, Me3O+BF4 ).7 Nevertheless, when 7 is
−
reacted with Meerwein’s salt, only camphor was the
obtained reaction product (Scheme 2).7 This result can
be explained due to the favored reaction of the hydroxy
group of 7 with the hard Lewis acid Meerwein’s salt.8
We have now found that the treatment of 7 with the
softer Lewis acid Eschenmoser’s salt takes place with
carbonꢀcarbon double-bond addition and Wagner–
Meerwein rearrangement to give enantiopure (1S)-10-
dimethylaminomethylcamphor 9 as the only camphor-
derived product with ca. quantitative yield (Scheme 2).
The reaction occurs under mild reaction conditions
(refluxing CHCl3 solution) according to the mechanism
described in Scheme 1.9
Acknowledgements
We would like to thank the Ministerio de Educacio´n y
Ciencia (MEC) of Spain (DGICYT, research project
PB97-0264) for the financial support of this work.
B.L.M. wishes to thank the Ministerio de Educacio´n,
Cultura y Deportes (MECD) for a post-graduate grant.
Mechanistically, the described reaction constituted the
first example in which Eschenmoser’s salt reacts with a

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1185
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[h]2D0 +7.68 (0.95, CHCl3). MS m/z 209 (M , 3), 58 (100).
+
’
IR (film) 1736 cm−1 1H NMR (CDCl3, 200 MHz) 2.80
.
(td, J=11.8 Hz, J=4.9 Hz, 1H), 2.36 (td, J=11.8 Hz,
J=4.9 Hz, 1H), 2.35–2.22 (m, 1H), 2.33 (s, 6H), 2.03 (dd,
J=3.3 Hz, J=3.3 Hz, 1H), 2.00–1.86 (m, 1H), 1.78 (d,
J=18.1 Hz, 1H), 1.80–1.25 (m, 5H), 0.94 (s, 3H), 0.85 (s,
3H) ppm. 13C NMR (CDCl3, 50 MHz) 219.0, 59.1, 55.1,
47.6, 45.0, 43.4, 43.2, 27.0, 26.7, 23.4, 20.2, 19.6 ppm.
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