2-Chlorobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2-chlorobicyclo[2.2.1] heptane-2-carboxamide as precursors of bicyclo[2.2.1]hept-5-en-2-one and bicyclo[2.2.1]heptan-2-one: Resolution, absolute configuration and hydrogen-bonding properties

Article abstract of DOI:10.1016/j.tetasy.2005.07.016

The absolute configuration of bicyclo[2.2.1]heptan-2-one has not been correlated with a crystal structure of a chemical precursor. The only chemical correlation available had an ambiguity, which could have reversed the assignment. Herein, we report the resolution of 2-chlorobicyclo[2.2.1]hept-5-en- 2-exo-carboxamide on a cellulose triacetate column and the crystal structures of the enantiomerically pure and racemic α-chloroamide. We found the absolute configuration (1R,2R,4R) for the (+)-enantiomer of the α-chloroamide. This compound was converted to (+)-bicyclo[2.2.1]hept-5- ene-2-one by base hydrolysis, and the 5,6-unsaturated compounds converted to the saturated congeners. This is the first unambiguous experimental determination of the absolute configuration of bicyclo[2.2.1]heptan-2-one and of bicyclo[2.2.1]hept-5-ene-2-one. The three crystal structures of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide reported herein reveal H-bonded dimers, with two distinct orientations of the bicyclic portion relative to the carboxamide dimer. In the racemic crystal, each dimer is composed of two enantiomers, and the bicyclic portions have their bridge carbon atom (C-7) on opposite sides of the H-bonded carboxamide dimer moiety. In the enantiomerically pure crystals, the major dimer had both C-7 atoms on the same side of the carboxamide dimer moiety while the minor dimer had the C-7 atoms on opposite sides. The dimers are present in solution, and can be easily monitored.

Full text of DOI:10.1016/j.tetasy.2005.07.016

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2754–2763
2-Chlorobicyclo[2.2.1]hept-5-ene-2-carboxamide and
2-chlorobicyclo[2.2.1]heptane-2-carboxamide as precursors of
bicyclo[2.2.1]hept-5-en-2-one and bicyclo[2.2.1]heptan-2-one:
resolution, absolute configuration and hydrogen-bonding properties
Erika Plettner,a,* Ashley Mohle,a, Martin T. Mwangi,a, ,à Johanna Griscti,b
Brian O. Patrick,c Ranjeet Nair,a Raymond J. Batchelora and Fredrick Einsteina
aDepartment of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
bBiofine International, 1650 Pandora Street, Vancouver, BC, Canada V5L 1L6
cDepartment of Chemistry, The University of British Columbia, Vancouver, BC, Canada V6T 1Z1
Received 16 June 2005; accepted 11 July 2005
Available online 15 August 2005
Abstract—The absolute configuration of bicyclo[2.2.1]heptan-2-one has not been correlated with a crystal structure of a chemical
precursor. The only chemical correlation available had an ambiguity, which could have reversed the assignment. Herein, we report
the resolution of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide on a cellulose triacetate column and the crystal structures of the
enantiomerically pure and racemic a-chloroamide. We found the absolute configuration (1R,2R,4R) for the (+)-enantiomer of the
a-chloroamide. This compound was converted to (+)-bicyclo[2.2.1]hept-5-ene-2-one by base hydrolysis, and the 5,6-unsaturated
compounds converted to the saturated congeners. This is the first unambiguous experimental determination of the absolute confi-
guration of bicyclo[2.2.1]heptan-2-one and of bicyclo[2.2.1]hept-5-ene-2-one. The three crystal structures of 2-chlorobicy-
clo[2.2.1]hept-5-en-2-exo-carboxamide reported herein reveal H-bonded dimers, with two distinct orientations of the bicyclic
portion relative to the carboxamide dimer. In the racemic crystal, each dimer is composed of two enantiomers, and the bicyclic
portions have their bridge carbon atom (C-7) on opposite sides of the H-bonded carboxamide dimer moiety. In the enantiomerically
pure crystals, the major dimer had both C-7 atoms on the same side of the carboxamide dimer moiety while the minor dimer had the
C-7 atoms on opposite sides. The dimers are present in solution, and can be easily monitored.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
substituted analogues have been used as starting points
or key intermediates for the synthesis of many chiral
compounds with highly substituted cyclopentyl moie-
ties, such as prostaglandins,5–9 some terpenes,10–12 some
iridoids,13,14 methyl epi-jasmonate,15 11-fluorojasmo-
nate,16 carbocyclic sugars,17,18 and cyclopentane-con-
taining polymers.19 We intend to use the framework of
bicyclo[2.2.1]hept-5-en-2-one 2 as a starting point for
the synthesis of conformationally constrained phero-
mone analogues. For all these studies, knowing the
absolute configuration of the enantiomers of bicyclic
compounds 1 and 2 is essential.
Bicyclo[2.2.1]heptane systems are a structural motif in
many naturally and artificially produced compounds.
For example, the motif occurs in complex natural
products such as dolabellane,1 echinosporin2 and the
sesquiterpene pheromone from a stink bug,3 as well as
in synthetic materials, such as norbornyl-containing
peptides where the norbornane group templates the
folding of the peptide in a well-defined manner.4 Bicy-
clo[2.2.1]heptan-2-one (norcamphor) 1, bicyclo[2.2.1]-
hept-5-en-2-one (5,6-dehydronorcamphor) 2 and their
There has been one attempt to correlate the absolute
configuration of (+)-bicyclo[2.2.1]heptan-2-one (+)-1
to (ꢀ)-fenchone (ꢀ)-G, by a six-step chemical conver-
sion (Scheme 1A).20 The problems associated with that
attempt were (1) a moderate ee of the starting (+)-1
*
Corresponding author. Tel.: +1 604 291 3586; fax: +1 604 291
3765; e-mail: plettner@sfu.ca
Equal contribution.
à Present address: Department of Chemistry, University of Iowa, 305
Chemistry Building, Iowa City, IA 52242-1294, USA.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.016

E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
2755
(A) Chemical correlations of configuration at C-4 of (+)-bicyclo[2.2.1]heptan 2-one (+)-1,
Berson et.al. 1961
O
AcO
a
HO
HOAc
O
H2SO4
OH
(-)-G
(-)-E
C
(+)-F
(+)-1
(+)-B
ee unknown
at the time
[α]30D= +17
AcOH
a
b
[α]30D+ 11
HOAc
+
+
=
H
b
b
D
O
OAc
OH
(+)-G
(+)-E
(-)-F
[α]30D = 0
[α]30D = -19.7
[α]30D = -14.7
observed specific rotation
(B) Correlation of (+)-fenchone, (+)-G, with (+)-(2S)-isopropyl butanedioic acid, (+)-J
Wallach
O
Wallach
1911
Fredga
1947
O
1910
HO
OH
NH2
OH
HO
(5 steps)
(3 steps)
O
O
O
(+)-G
(+)-H
(-)-I
(+)-J
(C) Correlation of 2-alkyl, thio and hydroxy butanedioic acids by quasi-racemates
CO2H
OH
CO2H
CO2H
CH3
CO2H
H SH
H
H
H
CH2
CH2
CH2
CH2
I
II
III
CO2H
CO2H
CO2H
CO2H
(+)-J
(+)-K
(+)-L
(+)-M
Scheme 1. (A) Summary of routes used for the correlation of the absolute configuration of (+)-1 to (ꢀ)-fenchone, (ꢀ)-G,20 (B) of (+)-G to (+)-(2S)
isopropyl butanedioic acid, (+)-J21–24 and (C) of (+)-J to (+)-(2R) hydroxybutanedioic acid, (+)-M.24,25 Pairs of compounds, for which the
configuration at C-2 was correlated by the quasi-racemate method are labelled I–III.24,25
(ꢁ41%) and (2) an ambiguity in a rearrangement step (C
to D, Scheme 1A). The rearranged cation D could be
trapped by an acetate via routes a or b, which gave enan-
tiomeric products, (+)-E and (ꢀ)-E. Given that the rel-
ative ratio of the two trapping modes was unknown, this
step could have easily reversed the final result. The (+)-1
enantiomer for that study was prepared from (+)-endo-
bicyclo[2.2.1]heptan-2-ol, which in turn was prepared by
resolution of the corresponding phthalate ester.20 How-
ever, a correlation with the terpene series and, from
there, with the hydroxy diacid/carbohydrate series was
required, in order to correlate the absolute configuration
of (+)-1 to that of D-glyceraldehyde (Scheme 1B and C).
Compound (+)-1 was correlated with (ꢀ)-G, which
connects to earlier work, in which the configuration at
C-4 of (+)-G had been established to be the same as that
of (+)-limonene.21 Compound (+)-G was converted to
(ꢀ)-2-isopropyl pentanedioic acid, (ꢀ)-I (Scheme
1B).22,23 Furthermore, in an effort to compare the
configuration of the terpenes to the configuration of
the sugar series, Fredga devised a scheme to selectively
chain-shorten (ꢀ)-2-isopropyl pentanedioic acid (ꢀ)-I
to (+)-2-isopropyl butanedioic acid (+)-J (Scheme
1B).24 The configuration of this compound was related,
by the quasi-racemate method,25 with (+)-2-methyl
butanedioic acid (+)-K, which had been related with
(+)-2-hydroxy butanedioic acid (+)-M (Scheme 1C).25
These compounds were represented as having an (S)-
configuration. Working back, (+)-G was denoted as
(1S,4R). This, in turn would imply that (+)-bicyclo-
[2.2.1]heptan-2-one (+)-1 is the (1S,4R)-enantiomer.
The absolute configuration of (+)-bicyclo[2.2.1]heptan-
2-one (+)-1 has not been assigned by correlation to a
crystal structure of a chemically related compound.
Herein, we report the chromatographic resolution (on
a
column of microcrystalline cellulose triacetate,
MCTA) of the enantiomers of 2-chloro bicyclo[2.2.1]-
hept-5-ene-2-exo-carboxamide 4 and the absolute con-
figuration of both, the (+)- and the (ꢀ)-enantiomers.
The crystal structures, we present, are the first report
and in addition to enabling us to determine the absolute

2756
E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
(A)
O
O
CN
c
a
b
NH2
NH2
Cl
Cl
CN
Cl
Cl
3
5
4
2
d
d
c
O
O
1
O
7
O
1
O
O
NH2
(B)
6
NH2
2
Cl
4
3 Cl
5
(+)-(1S,2R,4R)-5
[α]D20 = + 25
(+)-(1S,4R)-1
[α]D20 = +27
(+)-(1R,4R)-2
(+)-(1R,2R,4R)-4
[α]D20 = +60
[α]D20 = +1050
chromatography
CTA
4a
O
O
EtOH: H2O 9:1
NH2
Cl
NH2
Cl
O
O
(-)-(1S,2S,4S)-4
[α]D20 = -60
(-)-(1S,4S)-2
(-)-(1R,2S,4S)-5
[α]D20 = - 25
(-)-(1R,4S)-1
[α]D20 = -27
[α]D20 = -1067
Scheme 2. Preparation of the a-chloro amides and ketones and specific rotation data (in CHCl3; see experimental section for concentrations).
Conditions: (a) catalytic ZnI2 or CuSO4/hydroquinone, rt; (b) DMSO, 0.5 M aq NaOH, 50 ꢁC; (c) H2, Pd/C; (d) DMSO, 2.5 M NaOH, 70 ꢁC.
configuration of 4, the structures reveal H-bonded
dimers. For the pure enantiomers, the H-bonded dimers
appeared in two orientations in the crystal, and for the
racemic material, the H-bonded dimers were racemic,
present in one orientation. The two forms of the enantio-
merically pure dimers differed by the orientation of the
bridge carbon (C-7) relative to the H-bonded carbox-
amide unit. To correlate the configuration of (+)- and
(ꢀ)-2-chloro bicyclo[2.2.1]hept-5-ene-2-exo-carboxam-
ide, (+)-4 and (ꢀ)-4, to the configuration of (+)- and
(ꢀ)-bicyclo[2.2.1]hept-5-ene-2-one, (+)-2 and (ꢀ)-2, we
converted (+)-4 and (ꢀ)-4 to (+)-2 and (ꢀ)-2, respec-
tively, in one step. These four compounds were con-
verted to their saturated congeners (Scheme 2), to
correlate the configuration of (+)- and (ꢀ)-2-chloro
bicyclo[2.2.1]heptane-2-exo-carboxamide (+)-5 and
(ꢀ)-5 and to (+)- and (ꢀ)-bicyclo[2.2.1]heptan-2-one
(+)-1 and (ꢀ) 1.
reacted more quickly to afford the corresponding endo
a-chloro amide than did the exo-CN isomer. The
a-chloro amides reacted further to afford ketone 2,30
while the endo-amide reacted faster than the exo-isomer.
Ketone 2 is volatile whereas the exo- and endo a-chloro
amides are not. If the reaction is carried out at 50–60 ꢁC,
until the exo- and endo-chloronitriles have reacted, then
the major product is the exo-amide 4, while the minor
product (ꢁ10%) is the endo-amide isomer of 4. Both
the a-chloro exo- and endo-amides 4 can be converted
to ketone 2 by re-subjecting themto basic conditions.
2.2. Resolution of chloroamide enantiomers 4,
crystallization and absolute configuration
Amide 4 was separated fromtraces of the endo-carbox-
amide by column chromatography. The enantiomers of
pure 4 were resolved on a medium pressure column
packed with microcrystalline cellulose triacetate
(MCTA). Nearly baseline separation was obtained at
roomtemperature, using ethanol–H 2O 9:1 as the mobile
phase (Fig. 1). Crystals of both pure enantiomers were
obtained. Initially, the late-eluting (+)-enantiomer of 4
was used successfully to obtain a crystal diffraction
pattern. In a later experiment, the early-eluting (ꢀ)-
enantiomer was used to obtain crystals and a diffraction
pattern. Because of the anomalous dispersion of the
chlorine atom, it was possible to assign the
(1R,2R,4R)-configuration to the late-eluting (+)-enan-
tiomer. (Fig. 2, Table 1). The early-eluting (ꢀ)- enantio-
mer was (1S,2S,4S). We then subjected (+)-4 to base
hydrolysis and obtained (+)-2. Similarly, (ꢀ)-4 afforded
(ꢀ)-2 upon base hydrolysis (Scheme 2). The correspond-
ing saturated congeners 5 and 1 were obtained by
2. Results and discussion
2.1. Preparation of the a-chloroamide 4
The Diels–Alder adduct 3 was obtained by the reaction
of freshly distilled cyclopentadiene with 2-chloroacrylo-
nitrile, in 92% yield and a 4:1 exo/endo chloronitrile
selectivity. This compared well with the literature val-
ues.26–28 The use of ZnI2 or in situ generated Cu(I)
29
as catalysts gave similar yields and the same exo/endo
selectivity, consistent with previous studies.30,6
When the chloronitrile 3 exo/endo mixture was subjected
to aqueous basic conditions, the endo-CN isomer of 3

E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
2757
compounds and their methyl esters.32 The configuration
of (ꢀ)-exo-bicyclo[2.2.1]heptane-2-carboxylic acid was
correlated with (ꢀ)-exo-2-acetyl bicyclo[2.2.1]heptane.33
Similarly, (+)-2 has been prepared from(+)- exo-
bicyclo[2.2.1]hept-5-en-2-ol while the configuration of
both compounds was correlated with the configuration
of the corresponding hydrogenated products.34
Attempts were also made to predict the chirooptical
behavior of exo-bicyclo[2.2.1]hept-5-ene-2-carboxylic
acid20 and (+)-2.34,35 Finally, (+)-2 (ꢁ83% ee) was
prepared from exo-2-bromobicyclo[2.2.1]hept-5-ene-2-
carboxaldehyde,36 which in turn was generated by an
asymmetric Diels–Alder reaction of cyclopentadiene
and 2-bromoacrolein.36,37 The relative orientation of
the two reactants during the catalyzed Diels–Alder reac-
tion was predicted and correlated to the configuration of
the product. All these correlations of configuration form
a consistent set, but despite an extensive literature
search, we found no direct correlation of the configura-
tion of (+)-1 or (+)-2 with a close synthetic precursor or
derivative, for which the absolute configuration has been
determined by X-ray crystallography.
2500
2000
1500
1000
500
(-) 4
(+) 4
0
0
50
100
volume mL
150
200
Figure 1. Separation of (ꢀ)- and (+)-2-chlorobicyclo[2.2.1]hept-5-ene-
exo-2-carboxamide on column of microcrystalline cellulose
triacetate (MCTA), with ethanol–water 9:1 (see methods). This
chromatogram shows results from a run, in which racemic 4 loaded
on the column.
4
a
hydrogenation (Scheme 2). The specific rotations for
(+)-4 and (ꢀ)-4, and for (+)-5 and (ꢀ)-5 (Scheme 2B)
have not been reported previously; the specific rotations
for (+)-1 and (ꢀ)-1, and for (+)-2 and (ꢀ)-2 are in
agreement with those reported previously (Table 3).
Since amide 4 converts to the corresponding ketone, and
the conversion proceeds without rearrangement of the
bicyclo[2.2.1]heptane framework,30 the crystal structures
determined herein establish the absolute configuration
of (+)-2. The specific rotations observed for the enantio-
mers of 2 and of 1 are in the range of the previously
reported values (Table 2). As (+)-1 was readily obtained
by hydrogenation, this work also establishes the config-
uration of (+)-1. This confirms that the previous work
led to the correct assignment of (+)-1, despite the ambig-
uous step.20
(+)-Bicyclo[2.2.1]heptan-2-one (+)-1 was obtained from
(+)-2, thus allowing the configuration of these two
compounds to be correlated. In a previous work, com-
pound (+)-2 had been prepared from endo-(+)-
bicyclo[2.2.1]hept-5-ene-2-carboxylic acid via a four-step
procedure.18,31 The maximal rotations for endo- and
exo-bicyclo[2.2.1]hept-5-ene-2-carboxylic acids and their
saturated congeners have been determined, and the
configuration has been correlated among these four
Figure 2. Structures obtained by X-ray crystallography for 2-chlorobicyclo[2.2.1]hept-5-ene-exo-2-carboxamide 4: (A) racemic, (B) the early-eluting
(ꢀ)-(1S,2S,4S) enantiomer, and (C) the late-eluting (+)- (1R,2R,4R) enantiomer. Graphics were generated with ORTEP-3, (A)–(C) 50% probability
elipsoids for all non-hydrogen atoms.

2758
E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
Table 1. Summary of crystals of a-chloroamide 4 and their properties
Peak on MCTA
Specific rotation
Late-eluting
Early-eluting
Racemic
N/A
20
D
20
D
½aŠ ¼ þ60 (c 0.4, CHCl3)
½aŠ ¼ ꢀ60 (c 0.6, CHCl3)
O
O
NH2
NH2
Enantiomer
N/A
Cl
Cl
(1S,2S,4S)-4
(1R,2R,4R)-4
Flack parametera
Parameters and notes
x = ꢀ0.01 (16)
x = ꢀ0.02 (8)
N/A
Temperature = 25 ꢁC
Two forms of a H-bonded dimer:
Form1: 58%
Temperature = ꢀ100 ꢁC
Two forms of a H-bonded dimer:
Form1: 57%
Temperature = ꢀ100 ꢁC
One form of H-bonded racemic dimer
Form2: 42%
Form2: 43%
Crystal system: monoclinic
Space group: P21 (#4)
a = 10.1628 (13), b = 6.8521 (11),
Crystal system: monoclinic
Space group: P21 (#4)
a = 10.066 (1), b = 6.8038 (8),
Crystal system: monoclinic
Space group: P21/c (#14)
a = 12.987 (3), b = 5.917 (1),
˚
˚
˚
c = 11.9639 (14) A
c = 11.921 (1) A
c = 10.524 (3) A
a = 90ꢁ, b = 98.923 (10)ꢁ, c = 90ꢁ
V = 823 A
a = 90ꢁ, b = 98.930 (4)ꢁ, c = 90ꢁ
V = 806.5 (1) A
a = 90.0ꢁ, b = 104.006 (9)ꢁ, c = 90.0ꢁ
V = 784.7 (3) A
3
˚
3
3
˚
˚
Z = 4
Z = 4
Z = 4
Dcalc 1.385 g cmꢀ3
l = (MoKa) 4.01 cmꢀ1
F(000) 360
Dcalc 1.413 g cmꢀ3
l = (MoKa) 4.11 cmꢀ1
F(000) 360
Dcalc 1.453 g cmꢀ3
l = (MoKa) 4.22 cmꢀ1
F(000) 360
RF = 0.0411b
RwF = 0.0423c
R1 = 0.041d
wR2 = 0.098e,f
R1 = 0.032d
wR2 = 0.079e,g
No. obs. 1444 (Io P 2.5r(Io))
No. obs. 2327 (Io > 2.0r(Io))
No. obs. 1134 (Io > 2.0r(Io))
2
2
a x is the refined Flack enantiopole parameter, as in the expression: F 2o ¼ ð1 ꢀ xÞF ðhÞ þ xF ðꢀhÞ .
b RF = Rj(jFoj ꢀ jFcj)j/RjFo.
2
2
ꢀ1
.
c RwF ¼ ½RðwðjF oj ꢀ jF cjÞ Þ=RðwF o2ފ1=2, where w ¼ ½rðF oÞ þ 0:0001F 2oŠ
d R1 = RF.
2
2 1=2
e R2 ¼ ½RðwðF o2 ꢀ F c2Þ Þ=RðwF 2oÞ Š
.
2 ꢀ1
2
f w ¼ ½r2ðF 2oÞ þ ð0:0661ðF o2 þ 2F c2Þ=3Þ Š
.
ꢀ1
.
g w ¼ ½r2ðF o2Þ þ ð0:0396ðF o2 þ 2F c2Þ=3Þ þ 0:5393ðF o2 þ 2F 2cÞ=3Š
Table 2. Amide dimer conformers observed by X-ray crystallography
2.3. H-bonding of compounds 4 and 5
Crystal
FormDihedral
Unit 1 (ꢁ) Unit 2 (ꢁ)
The crystal structures reveal that in all cases, the amide
crystallized as H-bonded dimers, regardless of the crys-
tallization conditions (see experimental section). In the
racemic crystal, each dimer was a racemate, and the
hydrogen-bonded dimers were present in a single orien-
tation, with bridge C-7 carbons on opposite sides of the
carboxamide H-bonded moiety (Fig. 2A). In the first
crystal grown from enantiomerically purified material,
two orientations were detected. These dimers differed
in the orientation of C-7 atoms relative to the H-bonded
moiety (Fig. 2B). More quantitatively, the N–C–C2–C1
and the N–C–C2–C1 dihedral angles of the second
amide unit in the dimer differed significantly between
the two forms (Table 2). The second enantiomerically
pure crystal gave the same distribution of the two H-
bonded dimers, even though that the crystal was grown
under very different conditions (water as opposed to
ethyl acetate–hexane) and collected at ꢀ100 ꢁC (as
opposed to roomtemperature). This suggests that the
H-bonding is robust and that the two forms in the
enantiomerically pure crystals are a result of the mole-
cular asymmetry and not of the experimental conditions
used for crystal growth and diffraction.
angle
(+)-4
Major (58%) N–C–C2–C1
97.0
53.0
ꢀ70.4
ꢀ97.5
141.5
N–C–C2–C1 ꢀ24.6
Minor (42%) N–C–C2–C1
97.0
N–C–C2–C1 ꢀ24.6
(ꢀ)-4
Major (57%) N–C–C2–C1 ꢀ98.3
67.8
ꢀ54.0
101.7
ꢀ139.8
N–C–C2–C1
22.9
Minor (43%) N–C–C2–C1 ꢀ98.3
N–C–C2–C1 22.9
Racemic 4 One formN–C–C2–C1 32.8
ꢀ32.8
N–C–C2–C1 ꢀ88.7
88.7
H-bonding interaction. Such an interaction is expected
to cause deshielding of the Hb signal relative to Ha.
Experiments with racemic chloroamide 5 reveal that
the chemical shift of Hb does not change significantly
as the concentration of amide increases or as the temper-
ature decreases. The signal assigned to Ha, on the other
hand becomes increasingly deshielded relative to that of
Hb (Fig. 3) as the temperature decreases or the concen-
tration increases (Table 4). The data are consistent with
Ha being involved in the amide dimer, since H-bonding
is known to cause deshielding of hydrogen atoms
involved as H-bond donors.38 The spectra represent
the time average for the monomeric and dimeric forms,
The crystal structures and the NMR data also suggest
that one of the amide Hs (Hb, Fig. 3A) is influenced
by the a-chloro substituent, perhaps through a weak

E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
Table 3. Specific rotation reported previously for enantiomers of compounds 1 and 2
2759
Compound
Synthetic precursor or approach
Specific rotation of the enantiomer
Reference
of 2 or 1 prepared
23
D
(+)-2
(+)-2
½aŠ ¼ þ1186 (c 0.7, CHCl3)
18
31
CO2H
CO2H
23
D
½aŠ ¼ þ1033 (c 10.1 CHCl3)
23
D
(+)-2
(+)-2
½aŠ ¼ þ1088 (c 1.7, CHCl3)
55, 31
56
CO2H
Enantioselective cycloaddition of a ketene
equivalent to cyclopentadiene
Enantioselective cycloaddition
Not given
25
D
(+)-2
(+)-2
½aŠ ¼ þ1032 (c 0.025, acetone)
57
36
23
D
O
½aŠ ¼ þ980 (c 0.3, CHCl3)
Br
25
D
(ꢀ)-2
(ꢀ)-2
(+)-1
(+)-1
(ꢀ)-1
(ꢀ)-1
Enantioselective cycloaddition
½aŠ ¼ ꢀ1051 (c 0.030, acetone)
57
25
D
Kinetic enzymatic resolution of the racemic endo alcohol
Jones oxidation of endo bicyclo[2.2.1]heptan-2-ol
Frombicyclo[2.2.1]heptan-2-ol by resolution of phthalate
Frombicyclo[2.2.1]heptan-2-ol by resolution of phthalate
Fromnortricyclanone using L-proline perchlorate
½aŠ ¼ ꢀ930 (c 1.1, CHCl3) ee by GC: 82%
58, 59
20
30
D
½aŠ ¼ þ17 (c 4.4, CHCl3)
25
D
½aŠ ¼ þ29.1 (c 1.5, CHCl3)
60
25
D
½aŠ ¼ ꢀ28.7 (c 2.2, CHCl3)
60
25
D
½aŠ ¼ ꢀ4.7 (c not given, CHCl3)
61
very slightly with increasing concentration or decreasing
temperature (H-3exo and H-7A). Both of these signals
became more shielded with lower temperature and/or
higher concentration (Table 4). The slight shielding of
H-7A and H-3exo is more difficult to explain. In the crys-
tal structures, we have obtained H-7A and H-3exo both
placed in the shielding cone of the carboxamide group.
As the concentration of a-chloroamide increases and/
or the temperature decreases, a higher proportion of
dimers was expected to form. In the dimer, the rotation
around the C-2-carboxamide bond should be more
restricted than in the monomer, and H-7A and H-3exo
are more likely to be in the shielding cone of the amide.
The behavior of the amide hydrogens in the NMR and
the observation that dimers were obtained in crystals
grown under different conditions suggests that the
dimers can readily form in solution, and in organic
and aqueous solvent.
6.4
6.2
6
N-Hb
7
O
H
5
H
A
B
8
1
6
H
a
N
2
Cl
5.8
5.6
5.4
5.2
3
H
b
4
H
endo
N-Ha
50
0
10
20
30
40
60
(A)
Termperature ºC
1.00
y = -5638x + 18
R2 = 0.9039
0.00
0.003
0.0032
0.0034
0.0036
0.0038
-1.00
Data fromthe temperature and concentration study of
racemic a-chloroamide 5 (Table 4, Fig. 3) were used to
estimate enthalpy and entropy parameters, DH and
DS, for the dimerization. Two assumptions were made.
First, the spectrumobtained for a 0.1 M solution at
4 ꢁC was assumed to represent 100% dimeric species.
This is reasonable, since these conditions are at the sol-
ubility limit and the crystals contain 100% dimers. Sec-
ond, the spectrumfor a 0.01 M solution at 55 ꢁC was
assumed to represent 100% monomeric species. This is
reasonable, because the chemical shift difference
between Ha and Hb of 5, for the spectra obtained with
0.01 M solutions leveled off at 35 ꢁC (Table 4). The val-
ues obtained (Fig. 3B) suggest a DH for dimerization of
amide 5 of ꢀ11 kcal/mol and a DS of ꢀ36 cal/mol. This
gives a DG at 22 ꢁC of ꢀ0.6 kcal/mol. Such easily mon-
itored H-bonding properties could be very useful in the
assembly of new materials from solutions of H-bonded
-2.00
-3.00
1/T (K-1)
(B)
Figure 3. (A) Chemical shift of the NH protons of amide 5 at different
temperatures in CDCl3. (B) Using the chemical shift difference (see
Table 4) to estimate the percentage of the dimer in solution, the
dimerization reaction has DH = ꢀ11 kcal/mol, DS = ꢀ36 cal/mol.
The percentage of the dimer was estimated, on the assumption that
the chemical shift difference for the 0.1 M amide solution at 4 ꢁC
corresponds to 100% dimer and that chemical shift difference of the
0.01 M solution at 55 ꢁC corresponds to 100% monomer.
consistent with the rapid exchange between monomers
and dimers in the solution. Two other signals change

2760
E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
Table 4. Temperature and concentration dependence of hydrogen chemical shifts in a-chloroamide 5, in CDCl3
Compound (conc. M)
Temperature (ꢁC)
dNHb
dNHa
Dd
dH-3endo
dH-7A
5 (0.01)
0
4
16
22
6.28
6.27
6.26
6.25
6.25
6.22
6.22
6.21
6.19
6.17
5.53
5.53
5.42
5.41
5.39
5.33
5.34
5.31
5.30
5.29
0.74
0.75
0.84
0.84
0.85
0.89
0.87
0.90
0.89
0.90
2.82
2.83
2.83
2.83
2.83
2.83
2.83
2.84
2.83
2.84
1.76
1.76
1.78
1.78
1.78
1.80
1.80
1.80
1.80
1.81
35
40
45
50
55
5 (0.1)
4
22
50
6.29
6.28
6.27
6.20
5.97
5.97
0.10
0.30
0.30
2.79
2.80
2.80
1.72
1.75
1.75
D2–5 (0.01)
22
6.24
5.33
0.92
2.83
1.78
a-chloroamide units. The dimerization may also explain
the low volatility of the a-chloroamides 4 and 5. This
property makes compound 4 a more practical precursor
for synthesis than volatile ketone 2.
Inc., Exton, PA) and programmed isocratically at
0.06 mL/min with hexane–2-propanol 3:1. The eluent
was monitored at 245 nm. Here, the baseline resolution
was obtained (13.5 and 16.4 min). Large-scale low-pres-
sure chromatography (up to 300 mg/run) was performed
on a Varian 5000 LC, equipped with a 3 cminner dia-
meter · 110 cm packed jacketed column. The column
temperature was controlled by a Haake recirculating
water pump. Separations with the column at 50 ꢁC
and a flow rate of 0.2 mL/min gave nearly baseline sep-
aration (Fig. 1). Mass spectra were recorded on a Varian
Saturn 2000 MS coupled to a CP 300 GC, equipped with
a SPB-5 GC column (same type as above). Both EI
(70 eV) and CI (isobutane) modes of ionization were
used. IR was recorded on a Nexus 670 FT-IR. NMR
spectra were recorded using a Varian 500 MHz instru-
ment. Optical rotations were obtained using the sodium
line at 20 ꢁC in a Perkin–Elmer polarimeter 340.
Solvents were distilled under nitrogen before use.
3. Conclusions
We have determined the absolute configuration of the
enantiomers of 2-chloro bicyclo[2.2.1]hept-5-ene-2-
exo-carboxamide 4 by X-ray crystallography. Through
1-step chemical conversions, we have correlated
(+) 2-chloro bicyclo[2.2.1]hept-5-ene-2-exo-carboxamide
(+)-4 with (+)-bicyclo[2.2.1]hept-5-en-2-one (+)-2 and
(+)-bicyclo[2.2.1]heptan-2-one (+)-1. Amides 4 and
2-chloro bicyclo[2.2.1]heptane-2-exo-carboxamide
5
formhydrogen-bonded dimers in the crystals. The
racemic dimers adopted one orientation in the crystal,
while the dimers comprised of a single enantiomer
adopting two orientations in the crystal.
4.2. Preparation of 4 and derivatives
4. Experimental
4.1. General
4.2.1. 2-Chlorobicyclo[2.2.1]hept-5-ene-2-carbonitrile, 3.
Freshly distilled cyclopentadiene (2.41 g, 36.5 mmol)
was added to a solution of 2-chloroacrylonitrile (3.21 g,
36.7 mmol), CuSO4 (7 mg, 0.04 mmol) and hydroqui-
none (5 mg, 0.04 mmol) with gently stirring. The mix-
ture was maintained at room temperature for about
7 h, then quenched with water and extracted with
EtOAc (3 · 10 mL). The organic extract was washed
with water (2 · 5 mL) then with 10 mL brine, dried over
Na2SO4, and concentrated in vacuo to give 2-chloro-2-
cyano bicyclo[2.2.1]hept-5-ene 3 (5.17 g, 92% yield), as
a colorless solid (1:4 endo/exo selectivity). Alternatively,
the reaction was performed with a catalytic amount of
zinc iodide and found to give comparable yields and
selectivity. Mp 38–39 ꢁC (lit. 39 ꢁC26 and 42–43 ꢁC30).
GC Rt (SPB 5) 17.8 and 18.1 (4:1 intensity ratio) (RI
Melting points were determined using a Fisher–Johns
melting point apparatus and are uncorrected. GC were
run on a Hewlett Packard 5890 using a SPB-5 column
(Supelco, 30 m, 0.25 mm i.d., 0.25 lmfilm), pro-
grammed 50 ꢁC (5 min), 5ꢁ/min, 100ꢁ (4 min), 50ꢁ/min,
250ꢁ (20 min). To enable cross-referencing of retention
times between our GC and GC–MS instruments, reten-
tion indices (RI) were calculated for the SPB-5 column
data, with reference to hydrocarbon standards (Sig-
ma).39 Enantiomer compositions were analyzed on a
Varian 3400 gas chromatograph, equipped with a Cyclo-
Sil B column (J & W, 30 m, 0.25 mm i.d., 0.25 lmfilm),
programmed isothermally at 140 ꢁC and 25 psi head
pressure. Since GC retention times of the a-chloro
amide enantiomers did not differ much (16.3 and
16.8 min), analysis was repeated on a Waters 625 HPLC
with a 486 absorbance detector, fitted with a Chiracel
OJ-RH analytical column (2.1 mm i.d., Chiral Tech.
1
1146 and 1153, respectively). H NMR (CDCl3, major
diastereomer) d 6.42 (dd, J = 3.1, 5.7 Hz, 1H, H-6),
6.12 (dd, J = 3.05, 5.7 Hz, 1H, H-5), 3.51 (br, 1H, H-
1), 3.09 (br, 1H, H-4), 2.72 (dd, J = 3.7, 13.2 Hz, 1H,
H-3exo), 1.75–1.83 (m, 2H, H-7), 1.71 (dd, J = 3.7,
13.2 Hz, 1H, H-3endo); (minor diastereomer) d 6.46 (dd,

E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
2761
J = 3.0, 5.7 Hz, 1H, H-6), 6.22 (dd, J = 3.0, 5.8 Hz, 1H,
H-5), 3.35 (br, 1H, H-1), 3.09 (br, 1H, H-4, H-4 of major
diastereomer), 2.36 (dd, J = 3.4, 13.2 Hz, 1H, H-3exo),
2.24 (dd, J = 2.7, 13.2 Hz, 1H, H-3endo), 1.92–1.96 (br
d J = 9.7, 2H, H-7); 13C NMR (CDCl3) d (major diaste-
reomer) 140 (C-6), 132 (C-5), 122 (CN), 55.6 (C-1), 48.8
(C-4), 45.9 (C-7), 43.1 (C-3), 22.8 (C-2) (minor diastereo-
mer) 142 (C-6), 133 (C-5), 121 (CN), 56.3 (C-1), 47.2 (C-
4), 47.1 (C-7), 42.8 (C-3), 24.8 (C-2). The 1H NMR
matches the literature spectrum;26 IR (KBr) 3071,
2990, 2946, 2869, 2235, 1712, 1336, 1269, 766,
725 cmꢀ1; MS (EI): m/z (rel. intensity) 154 (M+Å 11%),
117 (M+Å-HCl, 4%), 91 (M+Å-HClCN, 15%), 66 (retro
Diels–Alder, 100%).
4.2.4. 2-Chlorobicyclo[2.2.1]heptane-exo-2-carboxamide
5. Hydrogenation of 2-chlorobicyclo[2.2.1]hept-5-ene-
exo-2-carboxamide 4 98% yield. H NMR d 6.24 (br s,
1
1H, NH), 5.40 (br s, 1H, NH), 2.82 (ddd, J = 2.8, 4.5,
13.6 Hz, 1H, H-3endo), 2.60 (br d, J = 4.0 Hz 1H, H-1),
2.31 (br t, J = 4.4 Hz, 1H, H-4), 2.13 (m, J = 3.0, 9.2,
12.4 Hz, 1H, H-6endo), 1.78 (br d, J = 10.2 Hz, 1H, H-
7A), 1.62 (m, Jꢁ4 and 8-8.7, 12.3 Hz, 1H, H-6exo), 1.53
(br d, J = 13.5 Hz, 1H, H-5exo), 1.49 (m, 1H, H-3exo),
1.38 (m, J = 3.4, 10.2, 1H, H-7B), 1.34 (m, J = 2.3, 8.9,
11.3, 1H, H-5endo). 13C NMR d 174.9 (C-amide), 75.7
(C-2), 49.0 (C-1), 44.8 (C-4), 38.2, 36.8, 28.3, 25.2. IR
(KBr) 3406, 3295, 3181, 2957, 2873, 1662, 1608, 1386,
769, 589 cmꢀ1; MS 174 (M+Å, 31%), 138 (M+ÅꢀCl,
30%), 129 (18%), 106 (100%), 93 (38%), 67 (30%).
20
4.2.2. 2-Chlorobicyclo[2.2.1]hept-5-ene-exo-2-carboxam-
ide, 4. A solution of 3 (240 mg, 1.56 mmol) in DMSO
(10 mL) and 3 equiv of 0.5 M aqueous NaOH was stir-
red at 50 ꢁC for 4 h. The reaction mixture was diluted
with water (10 mL) and neutralized with concentrated
HCl. The product was extracted into EtOAc
(3 · 10 mL) and dried over Na2SO4. Concentration in
vacuo gave a light yellow solid. Purification by column
chromatography on silica gel with hexane–EtOAc (gra-
dient, starting at 6:1 and ending at 2:1) gave 4 (192 mg,
71% yield, white crystalline, 1:9 endo/exo carboxamide).
The exo-amide diastereomer was purified further by col-
umn chromatography. Found; Mp 112–114 ꢁC (lit. 114–
115 ꢁC),26 GC Rt (SPB 5) 22.2 min (RI 1354); UV–vis
(kmax = 204 nm, emax = 6000 Mꢀ1 cmꢀ1, EtOH 95%);
1H NMR d 6.46 (br, 1H, NH), 6.40 (dd, J = 3.0,
5.6 Hz; 1H, H-6), 6.22 (dd, J = 3.0, 5.6 Hz; 1H, H-5),
5.54 (br, 1H, NH), 3.24 (m, 1H, H-1), 2.98 (m, 1H, H-
4), 2.86 (dd, J 3.7, 12.9 Hz; 1H, H-3endo), 1.89 (br d,
J = 9.1 Hz, 1H, H-7A), 1.57 (br d, J = 8.9 Hz, 1H, H-
7B), 1.50 (dd, J = 3.6, 12.9 Hz; 1H, H-3exo); 13C NMR
d 175.3 (C-amide), 139.4 (C-5), 134.9 (C-6), 74.7 (C-2),
54.3 (C-1), 48.4 (C-4), 42.7 (C-3), 42.3 (C-7); IR (KBr)
3413, 3282, 3188, 2977, 1662, 1604, 1383; MS (EI) 172
(M+Å+1, 40%), 136 (M+Å-Cl, 9%), 106 (79%), 91 (53%),
66 (100%). Anal. Calcd for C8H10OCl: C, 55.8; H,
5.81; N, 8.14. Found: C, 56.1; H, 5.90; N, 8.01.
For the chiral amide ½aŠ ¼ ꢀ25 (c 1.0, CHCl3); Rt
D
20
(Cyclosil B) 19.3 min, and ½aŠ ¼ þ25 (c 0.9, CHCl3);
D
Rt (CycloSil B) 18.9 min.
To facilitate the assignment of the 1H NMR spectrumof
5, racemic 4 (28.7 mg, 0.17 mmol) was deuterated as de-
scribed above to give 5,6-D2-5 27.2 mg (93%); 1H NMR
d 6.21 (br, 1H, NH), 5.30 (br, 1H, NH), 2.83 (ddd, J <2,
J = 4.5, 13.6 Hz), 2.60 (br, 1H, H-1), 2.31 (br, 1H, H-4),
2.15 (dm, 1H, H-6endo), 1.77 (br d, J = 10.2 Hz, 1H, H-
7A), 1.50 (ddd, J = 2.1, 3.3, 13.6 Hz, 1H, H-3exo), 1.36
(br d, J = 10.2, 1H, H-7B), 1.33 (br d, J = 8.9, 1H, H-
5endo); IR (KBr) 3423, 3181, 2967, 2926, 2161 (C-D
str.), 1648, 1373, 779, 588 cmꢀ1. MS 176 (M+Å, 100%),
140 (M+Å-Cl, 28%), 131 (12%), 108 (16%), 106 (50%),
95 (17%), 93 (16%), 67 (13%). Additions of electrophiles
and nucleophiles, halogens or hydrogen to the bicy-
clo[2.2.1]hept-5-ene systemare known to proceed exclu-
sively fromthe exo face.40,41 In this case, the signals
corresponding to H-5exo and H-6exo in compound 5 dis-
appeared in the spectrumof compound 5,6 D2–5, which
facilitated assignment of the spectrum of 5.
4.2.5. ( )-Bicyclo[2.2.1]hept-5-ene-2-one 2. a-Chloro-
nitrile 3 (0.93 g, 6.0 mmol) was placed in a round-bottom
flask, fitted with a condenser, dissolved in a minimum
volume of ether, DMSO (15 mL) and 2.5 M NaOH
(10 mL). The mixture was maintained at 70 ꢁC ca. 4 h.
The product was extracted into freshly distilled ether
(2 · 15 mL), washed with brine (15 mL), and dried over
Na2SO4. The solvent was removed by fractional distilla-
tion to give bicyclo[2.2.1]hept-5-ene-2-one 2 (0.286 g,
44% yield). Similarly, 2-chlorobicyclo[2.2.1]hept-5-ene-
exo-2-carboxamide 4 was converted to ( )-2 in 83%
Pure 2-chlorobicyclo[2.2.1]hept-5-ene-exo-2-carboxam-
ide 4 was then subjected to chromatographic resolution
on a medium-pressure liquid chromatograph equipped
with an MCTA column. This gave the (ꢀ) (1S,2S,4S)-
20
enantiomer first; ½aŠ ¼ ꢀ60 (c 0.6, CHCl3) Rt (Cyclosil
D
B) 16.3 min, (Chiracel) 13.5 min, followed by the (+)
20
1
(1R,2R,4R)-enantiomer; ½aŠ ¼ þ60 (c 0.4, CHCl3) Rt
yield. H NMR d 6.52 (dd, J = 2.8, 5.6 Hz, 1H, H-6),
D
(Cyclosyl B) 16.8 min, (Chiracel) 16.4 min. A typical
separation profile for a large-scale MCTA separation
is shown in Figure 1.
6.06 (m, 1H, H-5), 3.14 (br s, 1H, H-1), 2.95 (m, 1H,
H-4), 2.15 (m, J = 9.2 Hz, 1H, H-7), 1.96–1.88 (m,
J = 9.2, 16.5 Hz, 2H, H-7 and H-3), 1.79 (dd, J = 4.5,
16.5 Hz, 1H, H-3). 13C NMR d 216 (C-2), 143 (C-6),
131 (C-5), 56 (C-1), 51 (C-4), 40, 37; IR 3477 (ꢁtwice
C@O stretch), 3067, 2970, 2936, 1749, 1326, 1125,
709 cmꢀ1; GC Rt (SPB 5) 10.2 min (RI 931); MS m/z
108 (M+Å 48%), 91 (M+Å-OH, 3.8%), 77 (5%), 66 (100%).
4.2.3. Typical hydrogenation of the bicyclo[2.2.1]hept-5-
ene compounds 4 or 2. A solution of the compound in
hexane and a catalytic amount of palladium on charcoal
were placed in a 6 mL vial, fitted with a stirbar, a screw-
cap and a rubber septum. The vial was sealed, pressur-
ized with hydrogen, and the reaction mixture stirred
for ca. for 4 h. The crude product was passed through
a short silica gel column and concentrated in vacuo to
give a reduced compound.
4.2.6. (+)-Bicyclo[2.2.1]hept-5-en-2-one (+)-2 from
(+)-2-chlorobicyclo[2.2.1]hept-5-ene-exo-2-carboxamide
(+)-4. Compound (+)-4 (10 mg, 0.059 mmol) was
placed in a flask with a condenser. DMSO (1 mL) and

2762
E. Plettner et al. / Tetrahedron: Asymmetry 16 (2005) 2754–2763
NaOH (2.5 M, 14 mL) were added, and the mixture
radiation. The data were collected at ꢀ100.0 ꢁC to a
maximum of 2h value of 50.2ꢁ in a series of / and x
scans in 0.50ꢁ oscillations with 30.0 s exposures. The
crystal-to-detector distance was 38.00 mm. The data col-
lection process was controlled with the Brucker SAINT
software.46 Data reduction was performed with Brucker
SADABS software.47 The structures were refined using
the SHELXL software package of Brucker-AXS.48–53
The absolute configuration was determined on the basis
of the Flack enantiopole parameter.54 Crystallographic
data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion numbers CCDC: 274933, 274934 and 274935.
heated at 50 ꢁC for 4 h. The product was isolated as
above to give (+)-2 (4 mg, 65% yield) as a light yellow
20
D
liquid. GC–MS was identical to racemic 2. ½aŠ
¼
þ1050 (c 0.2, CHCl3) lit. Table 2; Rt (Cyclosyl B)
7.0 min. Similarly, (ꢀ)-2 was prepared in 48% yield from
20
D
(ꢀ)-4. ½aŠ ¼ ꢀ1067 (c 0.9, CHCl3); Rt (CycloSil B)
6.7 min.
4.2.7. ( )-Bicyclo[2.2.1]heptan-2-one 1. A solution of 5
(5.7 mg, 0.033 mmol) in 10 mL DMSO was placed in a
flask with a condenser and mixed with NaOH (2.5 M,
6 mL). The mixture was heated to 70 ꢁC and allowed
to stir for 15 min. The product was isolated, as described
above for bicyclo[2.2.1]hept-5-en-2-one 2, to give bicy-
clo[2.2.1]heptan-2-one 1 (3.6 mg, quantitative, colorless
1
Acknowledgements
oil); H NMR d 2.66 (br m, 1H, H-1), 2.59 (br d, J
3.5 Hz, 1H, H-4), 2.02–2.09 (br dd, J = 4.8, 17.8 Hz,
1H, H-3exo), 1.86 (d, J = 4.3 Hz, 1H, H-3endo), 1.77–
1.83 (m, 2H, H-7), 1.73 (dquin, J = 3.6, 10.3 Hz, 1H,
H-6exo), 1.50–1.53 (m, 2H, H-5), 1.40–1.46 (m, 1H, H-
6endo). 13C NMR d 218.5 (C-2), 50.2 (C-1), 45.6 (C-4),
37.8, 35.4, 27.5, 24.0. GC Rt (SPB 5) 12.25 min. (RI
983); IR (KBr) 2957, 2869, 1739, 1460, 1410 cmꢀ1. MS
m/z 110 (M+Å 66%), 95 (7%), 91 (9%), 81 (20%), 79
(12%), 67 (92%), 66 (100%).
We thank Mr. J. Belli, Dr. C. I. Keeling for technical
assistance, Dr. M. Yang for elemental analysis, Ms.
M. Tracey for NMR, Dr. P. Wilson for detailed com-
ments. Supported by the Natural Sciences and Engineer-
ing Research Council of Canada grant 22923-02
(operating) and STPGP 307515 (strategic) to E.P. and
by Research Corporation (Research Innovation Award
to E.P.)
4.2.8. (+)-Bicyclo[2.2.1]heptan-2-one (+)-1 from (+)-
2. Compound (+)-2 was hydrogenated as described
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22
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4.2.9. (ꢀ)-Bicyclo[2.2.1]heptan-2-one (ꢀ)-1 from (ꢀ)-
2-chlorobicyclo[2.2.1]heptane-exo-2-carboxamide (ꢀ)-5.
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described above (98% yield). The reduced enantiomer,
20
(ꢀ)-5, ½aŠ ¼ ꢀ25 (c 1.0 CHCl3), (26 mg, 1.50 mmol)
D
was placed in a reaction vial followed by NaOH
(2.5 M, 5 mL). The mixture was heated to 70 ꢁC and
allowed to stir for 15 min. Product isolation was done
as described above. This gave pure (ꢀ)-1 (7 mg, 39%
20
yield). ½aŠ ¼ ꢀ27 (c 1.1 CHCl3); Rt (CycloSil B)
D
7.4 min.
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43
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