Olefination of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate, a synthetic approach to new conformationally constrained prolines

Article abstract of DOI:10.1016/S0957-4166(03)00200-3

Wittig olefinations of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate with several phosphoranes and the Horner-Wittig reaction, using methyl diethylphosphonoacetate, have been tested in order to evaluate their utility in the synthesis of β-substituted conformationally constrained prolines. Subsequent elaboration of the resulting alkenes has provided proline-amino acid chimeras [combinations of proline with other α-amino acids, such as L-norvaline, L-norleucine, L-α-(3-phenylpropyl)glycine or L-homoglutamic acid] with the 7-azabicyclo[2.2.1]heptane skeleton in an enantiomerically pure form.

Full text of DOI:10.1016/S0957-4166(03)00200-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1479–1488
Olefination of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, a synthetic approach to
new conformationally constrained prolines
Ana M. Gil,a Elena Bun˜uel,b Mar´ıa D. D´ıaz-de-Villegasa and Carlos Cativielaa,*
aDepartamento de Qu´ımica Orga´nica, ICMA, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
bDepartamento de Qu´ımica Orga´nica, Universidad Auto´noma de Madrid, 28049 Madrid, Spain
Received 31 January 2003; accepted 24 February 2003
Abstract—Wittig olefinations of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate with several
phosphoranes and the Horner–Wittig reaction, using methyl diethylphosphonoacetate, have been tested in order to evaluate their
utility in the synthesis of b-substituted conformationally constrained prolines. Subsequent elaboration of the resulting alkenes has
provided proline–amino acid chimeras [combinations of proline with other a-amino acids, such as
L
-norvaline,
L-norleucine,
L
-a-(3-phenylpropyl)glycine or
L-homoglutamic acid] with the 7-azabicyclo[2.2.1]heptane skeleton in an enantiomerically pure
form. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Since the discovery of epibatidine by Daly et al. in
1992,12 we have witnessed a proliferation of synthetic
methods to create azabicyclic systems.13 However, few
procedures have been described on the asymmetric
synthesis of proline analogues containing the 7-azabicy-
clo[2.2.1]heptane skeleton.14–18
The introduction of conformationally constrained
amino acid analogues in place of natural a-amino acids
in parent peptide can generate structurally defined pep-
tides that serve a dual role as conformational probes
and bioactive peptidomimetics.1–4 The suitability of
cyclic amino acids in this area has translated into the
development of the different stereoselective synthetic
methods that supply them.5,6
We recently proposed a practical route to methyl
(1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]hep-
tane-1-carboxylate 3 (Scheme 1). Our strategy is based
on the preparation of the azabicyclic intermediate 2
from the chiral oxazolone 1Z through seven fully stere-
ocontrolled steps that proceed with an overall yield of
57%.18
Incorporation of proline-related residues, where the
nitrogen forms part of the ring, constitutes one way to
strongly decrease the conformational freedom of pep-
tides. Several detailed studies concerning a-
alkylprolines7–9 initially indicated the potential
importance of introducing an extra conformational
restriction by connecting the a-carbon with another
proline ring carbon. In this context, the first results
regarding the benefits of proline analogues containing
the 7-azabicyclo[2.2.1]heptane skeleton have unques-
tionably contributed to the increased interest shown in
this kind of amino acid.10,11
Substrate 2 is a valuable intermediate since it possesses
an acetal moiety in the b-position, which can be easily
transformed into a wide variety of functional groups
such as the formyl group in 3. b-Substituted prolines
can be considered as amino acid chimeras in which the
functional groups of the amino acid side-chain are
combined with the conformational restrictions specific
to the cyclic amino acid residue. Thus, several chimeras
based on proline bodies have been synthesised and used
to provide a better understanding of the relationship
between the side-chain geometry and the bioactive
conformations.19,20
* Corresponding author. Tel./fax: +34-976-761210; e-mail: cativiela@
unizar.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00200-3

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A. M. Gil et al. / Tetrahedron: Asymmetry 14 (2003) 1479–1488
As described recently, the preparation of compound 3
can be achieved in 60% yield through a two-step pro-
cess that involves hydrolysis of the acetal in intermedi-
ate 2 and oxidation of the resulting diol. The moderate
yield of this procedure was mainly caused by the forma-
tion of an undesired side product identified as a six-
membered lactone, which was formed by cyclisation of
the methyl ester with the corresponding hydroxy
group.18 At this point in our investigation, a re-exami-
nation of this synthetic procedure seemed appropriate
in order to obtain compound 3 in a more efficient
manner.
A highly effective synthesis of 3 was achieved by direct
transformation of the acetal moiety into the formyl
group (Scheme 2). Treatment of 1.0 g of compound 2
21
with H5IO6 gave product 3 in 88% yield through a
one-step procedure, with no evidence for the formation
of any lactonisation product. This synthesis therefore
represents a marked improvement on the methodology
previously reported. The behaviour of 3 in reaction
with several triphenylphosphonium ylides was then
evaluated (Scheme 2).
The reaction of 3 with methylenetriphenylphosphorane
involved treatment of methyltriphenylphosphonium
iodide with n-BuLi in THF and subsequent addition of
the carbonyl compound to the reaction mixture. This
procedure gave the desired methyl (1S,2S,4R)-N-ben-
zoyl-2-vinyl-7-azabicyclo[2.2.1]heptane-1-carboxylate
4a, which was isolated in 75% yield under the optimum
reaction conditions (see Table 1, entry 1).
Scheme 1. Suggested route to 7-azabicyclo[2.2.1]heptane
amino acids.
Wittig olefination is widely recognised as one of the
most useful ways to create CꢀC bonds from aldehydes
and so we studied the behaviour of compound 3 with
several phosphoranes. This study was performed in
order to evaluate the versatility of this approach as a
synthetic route to new enantiopure conformationally
restricted b-substituted prolines via the corresponding
Wittig adducts 4 (Scheme 1).
In order to compare the efficacy of the Wittig proce-
dure to obtain the vinyl product we also explored an
alternative method (Scheme 3). Diol 5, obtained from
hydrolysis of the acetal in key intermediate 2,18 was
converted into the vinyl azabicyclic product 4a through
the two-step Corey–Winter procedure to obtain olefins
from 1,2-diols via a thionocarbonate intermediate.22–24
This method was carried out using N,N%-thiocar-
bonyldiimidazole (TCDI) under reflux in toluene, as in
the original protocol,22 instead of thiophosgene/
DMAP.24 The procedure gave thionocarbonate 6 in
good yield (83%) and treatment of this compound with
trimethylphosphite afforded 4a in 72% yield. When
1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (DMP-
DAP)24 was used instead of trimethylphosphite, the
yield of 4a increased to 86%. In summary, this proce-
2. Results and discussion
The excellent results obtained in an initial study aimed
at exploring the behaviour of methyl (1S,2R,4R)-N-
benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxyl-
ate 3 in the Wittig reaction18 prompted us to extend this
olefination study.
Scheme 2. Wittig and Horner–Wittig olefination of compound 3.

A. M. Gil et al. / Tetrahedron: Asymmetry 14 (2003) 1479–1488
1481
Table 1. The best results in Wittig and Horner–Wittig olefination of compound 3
Entry
R%
Reagent
Basea
Time and temperature
Yieldb (%)
Z/Ec
1
2
3
4
5
6
7
H
Me
Ph
Ph3PMeI
Ph3PEtBr
Ph3PCH2PhCl
n-BuLi
n-BuLi
n-BuLi
n-BuLi
Propylene oxide
Propylene oxide
NaH
10 min at −65°C, then 45 min at rt
Immediate at −65°C
5 h at −40°C
10 min at 0°C, then 20 min at rt
1 day at rt
75
90
85
71/29
6/94
d
CO2Me Ph3PCH2CO2MeCl
CO2Me Ph3PCH2CO2MeCl
CN
–
–
e
Ph3PCH2CNCl
3 days under reflux
45 min at rt
99
95
52/48
12/88
CO2Me (EtO)2POCH2CO2Me
a Reactions using n-BuLi or NaH were carried out in dry THF.
b After isolation of the isomeric mixtures by column chromatography.
c Determined by integration of the 1H NMR spectra of the reaction mixtures.
d Complete disappearance of 3 was observed but no Wittig adducts were detected.
e Mixtures of products were obtained due to partial epimerization at C-2.
Scheme 3. Wittig and Corey–Winter procedures to obtain 4a.
iment on the mixture enriched with the minor isomer,
by irradiation of the olefinic methyl signals of both
isomers, revealed a coupling constant (J=15.0 Hz)
consistent with an E stereochemistry for the double
bond of the minor reaction product.
dure gave 48% overall yield from the key intermediate
2 through a three-step transformation. No improve-
ment was observed in comparison to the Wittig proce-
dure, which also provided 4a in 66% yield from 2
through a two-step process beginning with the direct
transformation of the acetal moiety into a formyl group
(Scheme 3).
The reaction of 3 with the semi-stabilised ylide benzyli-
denetriphenylphosphorane led to a 6/94 mixture of
(Z/E)-methyl (1S,2S,4R)-N-benzoyl-2-(2-phenylvinyl)-
7-azabicyclo[2.2.1]heptane-1-carboxylate 4c (Scheme 2)
in 85% yield under the reaction conditions given in
Table 1 (entry 3). The major product was fully charac-
terised and analysis of the single-crystal X-ray data
unequivocally confirmed the stereochemistry (Fig. 1).
The coupling constants between the olefinic protons
The Wittig reaction of 3 with ethylidenetriphenylphos-
phorane (Scheme 2) under previously reported
conditions18—represented here in Table 1, entry 2—
provided methyl (1S,2S,4R)-N-benzoyl-2-(1-propenyl)-
7-azabicyclo[2.2.1]heptane-1-carboxylate 4b as a 71/29
mixture of the Z and E isomers in excellent yield (90%).
The determination of the Z/E ratio was carried out by
1
1
integration of the appropriate signals in the H NMR
were determined from the H NMR spectra obtained
spectrum of the crude reaction mixture and was possi-
ble thanks to the partial separation of the isomers by
HPLC, which afforded a pure analytical sample of the
major isomer. The double bond stereochemistry of each
from benzene-d6 solutions (J=11.4 Hz and J=15.4 Hz
for the Z and E isomers, respectively).
As far as the stabilised ylides are concerned, reaction of
3 with carbomethoxymethylenetriphenylphosphorane
did not give acceptable yields of the corresponding
Wittig adducts under any of the reaction conditions
tested. Treatment of carbomethoxymethyltriphenyl-
phosphonium chloride with an aqueous solution of
sodium hydroxide and reaction of the carbonyl com-
pound 3 with the isolated ylide gave only a very
1
isomer was elucidated by H NMR experiments. Thus,
1
irradiation of the olefinic methyl signal in the H NMR
spectrum of the pure isolated isomer of 4b gave a
spectrum where the coupling constant between the
olefinic protons could be clearly measured (J=11.0
Hz), allowing the assignment of the Z configuration for
the double bond in the major product. A similar exper-

1482
A. M. Gil et al. / Tetrahedron: Asymmetry 14 (2003) 1479–1488
diethylphosphonoacetate and NaH in dry THF at room
temperature, cleanly provided a 12/88 Z/E mixture of
4e in excellent yield (95%) after only 45 min (Table 1,
entry 7). For characterisation purposes, the isomers
were separated by column chromatography and mea-
surement of the coupling constants for the olefinic
proton signals in the 1H NMR spectra allowed the
double bond stereochemistry to be assigned (J=12.0
Hz and J=15.0 Hz for the Z and E isomers,
respectively).
Bearing in mind the possible epimerization problem
detected at C-2 and in order to verify the exo stereo-
chemistry of the isolated Wittig adducts, oxidative
cleavage of the double bond under Sharpless
conditions25 was carried out on 4a and the isomeric
mixtures (Z/E)-4b–e. This procedure transformed all
the products into the carboxy derivative 7 (Scheme 4).
The stereochemistry at C-2 of these Wittig adducts was
therefore confirmed, since we had already reported the
synthesis of 7 through two consecutive stereocontrolled
processes that involved acetal hydrolysis of the key
intermediate 2 and subsequent oxidative cleavage of the
resulting diol.18
Figure 1. ORTEP drawing of compound (E)-4c. The C-2
hydrogen is represented by a sphere of arbitrary size, the rest
of the hydrogen atoms have been omitted for clarity. Non-
hydrogen atoms are represented by ellipsoids corresponding
to 50% probability.
low conversion into products. The use of strong bases,
such as n-BuLi or MeONa, to generate the ylide under
anhydrous conditions did not improve the results.
Thus, starting material 3 was completely consumed
upon addition to the phosphorane generated with n-
BuLi, but Wittig adducts were not detected (Table 1,
entry 4). On using MeONa the conversion of 3 was
total at room temperature after only 20 min, but a
complex mixture of products was obtained due to par-
tial epimerization at C-2. Formation of the ylide in situ
using propylene oxide also led to a mixture of C-2
epimeric products (Table 1, entry 5).
As an alternative, we explored the reactivity of 3 with
cyanomethylenetriphenylphosphorane, which would
also allow access to a carboxylic acid function by
hydrolysis of the cyano group. The method involving
cyanomethyltriphenylphosphonium chloride and n-
BuLi in THF proved to be unsuitable due to a lack of
reproducibility in these experiments. After numerous
trial reactions, generation of the ylide—from the freshly
prepared phosphonium halide—with an excess of pro-
pylene oxide in the presence of the carbonyl compound
3 cleanly led to a 52/48 Z/E mixture of methyl
(1S,2S,4R)-N-benzoyl-2-(2-cyanovinyl)-7-azabicyclo-
[2.2.1]heptane-1-carboxylate 4d (Table 1, entry 6).
Although this process required 3 days for total conver-
sion, the isomers were isolated by column chromatogra-
phy in excellent yield (99%) and were separated for full
characterisation. The assignment of the double bond
stereochemistry for each isomer was made according to
the coupling constants between the olefinic proton sig-
Scheme 4. Oxidative cleavage of 4a–e.
Moreover, an additional and rigorous proof of the
assignment of the stereochemistry at C-2 was provided
by single-crystal X-ray analysis of 7, the direct precur-
sor of the 7-azabicyclo[2.2.1]heptane
L-aspartic acid
analogue, as shown in Fig. 2. These data unquestion-
ably demonstrate the exo configuration at the b-
position.
1
nals in the H NMR spectra of the isolated products
(J=11.0 Hz and J=16.2 Hz for the Z and E isomers,
respectively).
The results obtained with the stabilised ylides were not
completely satisfactory due to the formation of
epimeric mixtures of isomers and the long reaction
times required to achieve total conversion of 3. There-
fore, in order to improve the efficiency of this method-
ology, the reaction of 3 with a phosphonate was tested
(Scheme 2). The Horner–Wittig reaction, using methyl
Figure 2. ORTEP drawing of compound 7. This picture
shows the molecules comprised in the asymmetric unit cell.
Non-hydrogen atoms are represented by ellipsoids corre-
sponding to 30% probability. The acidic and C-2 hydrogens
are represented by spheres of arbitrary size, the rest of the
hydrogen atoms have been omitted for clarity.

A. M. Gil et al. / Tetrahedron: Asymmetry 14 (2003) 1479–1488
1483
The next stage of our investigation involved the elabo-
4. Experimental
ration of these systems to give azabicyclic amino acids
(Scheme 5). The first step involved hydrogenation of
the double bond and the use of a catalytic amount of
palladium hydroxide at room temperature and atmo-
spheric pressure cleanly afforded the corresponding sat-
urated compounds 8a–e in excellent yields (]91%).
Final hydrolysis of compounds 8a–e with 6N hydro-
chloric acid under reflux gave the desired products in
very good yields (94% for 9a, 97% for 9b,18 85% for 9c
and quantitative yield for 9d from 8d or 8e). Com-
pounds 9a–d are (2S,3R)-3-ethylproline, (2S,3R)-3-
propylproline, (2S,3R)-3-(2-phenylethyl)proline and
(2S,3R)-3-(2-carboxyethyl)proline analogues, respec-
tively. These products can also be considered as pro-
4.1. General
Melting points were determined using a Gallenkamp
apparatus and are uncorrected. IR spectra were regis-
tered on a Mattson Genesis FTIR spectrophotometer;
wmax is given for the main absorption bands. H and 13
C
1
NMR spectra were recorded on a Varian Unity-300 or
a Bruker ARX-300 apparatus at rt, using the residual
solvent signal as the internal standard; chemical shifts
(l) are quoted in ppm, and coupling constants (J) are
measured in hertz. Optical rotations were measured in a
cell with a 10 cm pathlength at 25°C using a JASCO
P-1020 polarimeter. Elemental analyses were carried
out on a Perkin–Elmer 200 C, H, N, S analyser. High
resolution mass spectral data (HRMS) were obtained
on a VG AutoSpec spectrometer. TLC was performed
on Polygram® sil G/UV254 precoated silica gel polyester
plates and products were visualised under UV light (254
nm) or using ninhydrin, anisaldehyde or phospho-
molybdic acid developers. Column chromatography
was performed using silica gel (Kieselgel 60). HPLC
was carried out on a system equipped with a Waters
600-E pump and a Waters 2487 dual absorbance detec-
tor and the solvents used as mobile phases were of
spectral grade. Methyl (1S,2R,4R)-N-benzoyl-2-[(S)-
2,2 - dimethyl - 1,3 - dioxolan - 4 - yl] - 7 - azabicyclo[2.2.1]-
line–
proline–
L
-norvaline
9a,
proline–
L
-norleucine
9b,
L
-a-(3-phenylpropyl)glycine 9c and proline–L-
homoglutamic acid 9d chimeras with a 7-azabicy-
clo[2.2.1]heptane skeleton.
3. Conclusions
Wittig olefination of compound 3 has been shown to be
an efficient way of introducing amino acid side chains
via the corresponding non-stabilised and semi-stabilised
triphenylphosphonium ylides. In this way, (2S,3R)-3-
ethylproline 9a, (2S,3R)-3-propylproline 9b and
(2S,3R)-3-(2-phenylethyl)proline 9c analogues, which
actually consist of combinations of proline with
heptane-1-carboxylate
218
and
cyanomethyltri-
phenylphosphonium chloride26 were obtained according
to the literature procedures.
L
-norvaline,
L
-norleucine
and
L
-a-(3-phenyl-
propyl)glycine containing a 7-azabicyclo[2.2.1]heptane
structure, have been obtained in enantiopure form in
35, 41 and 34% overall yield, respectively, from oxa-
zolone 1Z.
4.2. X-Ray diffraction
The X-ray diffraction data were collected at rt on a
Bruker Smartapex CCD Area diffractometer, using
graphite-monochromated Mo-Ka radiation (u=
The use of the Horner–Wittig variation leads to an
improvement in the results obtained in comparison to
the Wittig procedure with stabilised phosphoranes and
provides excellent conditions for the synthesis of the
,
0.71073 A). The structure was solved by direct methods
using SHELXS-9727 and refinement was performed
using SHELXL-9728 by the full-matrix least-squares
technique with anisotropic thermal factors for heavy
atoms.
enantiomerically
pure
(2S,3R)-3-(2-carboxyethyl)-
proline analogue 9d with a 7-azabicyclo[2.2.1]heptane
skeleton. The product, a combination of proline with
L
-homoglutamic acid, was obtained in 48% overall yield
Colourless single crystals of (E)-4c were obtained by
slow evaporation from an ether solution. Reflections
from 1Z.
Scheme 5. Elaboration to the azabicyclic amino acids.

1484
A. M. Gil et al. / Tetrahedron: Asymmetry 14 (2003) 1479–1488
were measured in the ꢀ/2q-scan mode in the q range
2–28°. Hydrogen atoms were located by calculation and
affected by an isotropic thermal factor fixed to 1.2
times the Ueq value of the carrier atom (1.5 for the
methyl protons). Crystallographic data: orthorhombic,
added a solution of n-BuLi (0.75 mL, 1.6 M in n-hex-
ane, 1.2 mmol) at rt and the mixture was stirred at this
temperature for 30 min. The mixture was cooled (see
Table 1) and a solution of aldehyde 3 (300 mg, 1.0
mmol) in dry THF (6 mL) was added. The mixture was
stirred at the temperature indicated in Table 1. When
the reaction was complete (see Table 1), it was
quenched by addition of saturated aqueous NH4Cl. The
resulting mixture was stirred for 5 min at rt. The
solution was concentrated under vacuum and the
aqueous residue was extracted with dichloromethane
(3×10 mL). The organic layers were combined, dried
over anhydrous MgSO4, filtered and the solvent was
evaporated under reduced pressure. The resulting
residues were analysed by 1H NMR spectroscopy.
Where appropriate, the Z/E ratios were determined by
,
,
P212121; a=9.7030(8) A; b=12.6509(11) A, c=
15.5470(13) A; Z=4; dcalcd=1.258 g cm−3; reflections
,
collected/independent: 12310/4404 [R(int)=0.0388];
data/parameters: 4404/244; final R indices [I>2|(I)]:
R1=0.037, wR2=0.069; final R indices (all data): R1=
0.050, wR2=0.072.
Colourless single crystals of 7 were obtained by slow
evaporation from a dichloromethane/n-hexane solu-
tion. Reflections were measured in the ꢀ/2q-scan mode
in the q range 2–25°. Hydrogen atoms were located by
calculation (with the exception of the acidic proton,
which was found on the E-map) and affected by an
isotropic thermal factor fixed to 1.2 times the Ueq value
of the carrier atom (1.5 for the methyl protons). Crys-
1
integration of the signals in the H NMR spectrum of
the crude product and the Wittig adducts were purified
by column chromatography.
,
tallographic data: triclinic, P31; a=b=11.0492(17) A,
Method b. The corresponding phosphonium halide (2.0
mmol) was added to a solution of aldehyde 3 (100 mg,
0.35 mmol) in propylene oxide (20 mL) at rt and the
mixture was stirred (see Table 1 for temperature and
reaction time). When the reaction was complete the
solvent was evaporated under reduced pressure and the
residue dissolved in dichloromethane. The organic layer
was washed with water, dried over MgSO4 and concen-
trated under vacuum. The reaction residues were
c=21.961(5) A; Z=6; dcalcd=1.301 g cm−3; reflections
,
collected/independent: 12723/5427 [R(int)=0.0558];
data/parameters: 5427/404; final R indices [I>2|(I)]:
R1=0.042, wR2=0.071; final R indices (all data): R1=
0.084, wR2=0.080.
Crystallographic data (excluding structure factors) for
the structures of compounds 4c and 7 have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
200457 and 200458, respectively. Copies of the data can
1
analysed by H NMR spectroscopy. Where appropri-
ate, the Z/E ratios were determined by integration of
the signals in the 1H NMR spectrum of the crude
product and the resulting adducts were purified by
column chromatography.
be
obtained,
free
of
charge,
via
http://
www.ccdc.cam.uk/conts/retrieving.html or on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44(0)-1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
4.4.1. Methyl (1S,2S,4R)-N-benzoyl-2-vinyl-7-azabicy-
clo[2.2.1]heptane-1-carboxylate, 4a. According to
method a, the use of methyltriphenylphosphonium
iodide as the reagent and flash chromatography (eluent:
9/1 dichloromethane/ethyl acetate) as the purification
technique afforded compound 4a as an oil in 75% yield.
[h]D=−53.6 (c 1, CHCl3). IR (neat) w (cm−1): 3070–
4.3. Synthesis of methyl (1S,2R,4R)-N-benzoyl-2-for-
myl-7-azabicyclo[2.2.1]heptane-1-carboxylate, 3
A mixture of methyl (1S,2R,4R)-N-benzoyl-2-[(S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]heptane-
1-carboxylate 2 (1.0 g, 2.8 mmol) and H5IO6 (1.3 g, 5.6
mmol) in a 1/1 ether/THF mixture (100 mL) was stirred
at rt for 8 h. The resulting mixture was filtered and the
1
2873, 1737, 1657. H NMR (CDCl3) l (ppm): 1.48–1.57
(m, 1H), 1.60–1.72 (m, 1H), 1.81–1.95 (m, 3H), 2.42
(ddd, 1H, J=4.6 Hz, J=12.7 Hz, J=12.7 Hz), 2.61–
2.69 (m, 1H), 3.72 (s, 3H), 4.22 (dd, 1H, J=4.6 Hz,
J=4.6 Hz), 4.93 (m, 2H), 5.93 (ddd, 1H, J=9.8 Hz,
J=10.6 Hz, J=16.5 Hz), 7.38–7.44 (m, 2H), 7.71–7.75
(m, 1H), 7.69–7.72 (m, 2H). 13C NMR (CDCl3) l
(ppm): 30.3, 30.6, 37.9, 51.6, 51.8, 62.1, 71.4, 114.1,
128.3, 128.8, 131.7, 134.6, 139.9, 170.1, 173.9.
solvent
was
evaporated
under
vacuum.
Dichloromethane was added and the organic phase was
washed with water and brine. The organic layer was
dried over anhydrous MgSO4, filtered and the solvent
was evaporated under reduced pressure. Compound 3
was isolated from the crude mixture by flash chro-
matography (eluent: 1/1 ethyl acetate/n-hexane) as a
white solid in 88% yield (702 mg, 2.4 mmol). Mp=
110°C. [h]D=−7.6 (c 1, CHCl3). [lit.18 mp=108°C.
[h]D=−6.7 (c 1, CHCl3)].
4.4.2. (Z/E)-Methyl (1S,2S,4R)-N-benzoyl-2-(1-pro-
penyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate, 4b. Fol-
lowing method a, with ethyltriphenylphosphonium
bromide as the reagent and flash chromatography (elu-
ent: 6/4 ethyl acetate/n-hexane) as purification tech-
nique, a 71/29 mixture of (Z/E)-4b was obtained in
93% yield. This compound was used in the next step
without purification. However, the separation of (Z)-
and (E)-4b was carried out for characterisation
purposes.
4.4. General procedures for the Wittig olefination of
methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo-
[2.2.1]heptane-1-carboxylate, 3
Method a. To a suspension of the corresponding phos-
phonium halide (1.2 mmol) in dry THF (9 mL) was

A. M. Gil et al. / Tetrahedron: Asymmetry 14 (2003) 1479–1488
1485
High performance liquid chromatography. HPLC was
performed using a non-commercial polysaccharide-
derived support, consisting of mixed 10-undecenoate/4-
methylbenzoate of cellulose covalently bonded to
allylsilica gel, as the chiral stationary phase.29,30 The
separation of (Z/E)-4b was carried out by successive
injections of 2.5 mL (c 100 mg mL−1 in
dichloromethane) on a 150×4.6 mm ID column using as
eluent a 98/2 mixture of n-hexane/ethanol with a flow
rate of 1 mL min−1 and UV monitoring at 280 nm. A
total of 37 injections were required with an injection
being performed every 8 min. Three separate fractions
were collected. Evaporation of the first fraction pro-
vided an analytically pure sample (2.1 mg) of the major
isomer. The second (2.0 mg) and third (2.5 mg) frac-
tions contained (Z/E)-4b mixtures, the latter consisting
of a mixture enriched with the minor isomer (23/77).
(E)-4c: White solid. Mp=173°C. [h]D=−125.1 (c 0.5,
CHCl3). IR (Nujol) w (cm−1): 1734, 1648. 1H NMR
(benzene-d6) l (ppm): 0.98 (m, 1H), 1.24–1.36 (m, 2H),
1.53–1.62 (m, 1H), 1.76 (ddd, 1H, J=4.8 Hz, J=9.2
Hz, J=12.5 Hz), 2.51 (ddd, 1H, J=4.8 Hz, J=9.2 Hz,
J=9.2 Hz), 2.70 (ddd, 1H, J=4.0 Hz, J=12.5 Hz,
J=12.5 Hz), 3.43 (s, 3H), 3.75 (dd, 1H, J=4.8 Hz,
J=4.8 Hz), 6.22 (d, 1H, J=15.8 Hz), 6.50 (dd, 1H,
J=9.9 Hz, J=15.8 Hz), 7.01–7.15 (m, 6H), 7.33–7.36
(m, 2H), 7.78–7.82 (m, 2H). 13C NMR (CDCl3) l
(ppm): 30.1, 30.3, 38.2, 51.2, 51.7, 62.2, 71.8, 126.3,
127.2, 128.3, 128.5, 128.9, 129.4, 131.7, 131.9, 134.7,
137.2, 170.2, 174.0. Elemental analysis calcd for
C23H23NO3: C, 76.43; H, 6.41; N, 3.88. Found: C,
76.83; H, 6.61; N, 3.87.
4.4.4. (Z/E)-Methyl (1S,2S,4R)-N-benzoyl-2-(2-cyano-
vinyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate, 4d. Fol-
lowing method b, using cyanomethyltriphenylphospho-
nium chloride as the reagent gave a 52/48 mixture of
(Z/E)-4d. Purification of the crude reaction product by
flash chromatography (eluent: 9/1 ether/n-hexane) pro-
vided the Z and E isomers in 99% yield and allowed
their partial separation for characterisation purposes.
Assignment of the double bond stereochemistry. The
double bond stereochemistry of the isomers was
1
assigned by H NMR experiments. Irradiation of the
1
olefinic methyl signal in the H NMR analysis of the
first HPLC fraction, which contained a pure sample of
the major isomer, provided a spectrum in which the
olefinic proton signals at 5.44 ppm (d, 1H, J=11.0 Hz)
and 5.53 ppm (dd, 1H, J=9.6 Hz, J=11.0 Hz) did not
show any coupling with the olefinic methyl group.
Therefore, the coupling constant between olefinic pro-
tons could be clearly measured (J=11.0 Hz), allowing a
Z configuration to be assigned to the major product. A
similar experiment was also performed on the spectrum
of the third HPLC fraction, which was a mixture
enriched with the minor isomer. In this case, irradiation
of the olefinic methyl signals of both isomers revealed
the signals corresponding to the olefinic protons for the
minor reaction product at 5.36 ppm (d, 1H, J=15.0
Hz) and 5.51 ppm (dd, 1H, J=9.3 Hz, J=15.0 Hz).
The observed coupling constant between them (J=15.0
Hz) confirmed an E stereochemistry for this isomer.
Having assigned the stereochemistry of each isomer, the
Z/E ratio of the reaction mixture was determined as
(Z)-4d: White solid. Mp=107°C. [h]D=+32.1 (c 1,
CHCl3). IR (Nujol) w (cm−1): 2214, 1728, 1644. 1H
NMR (CDCl3) l (ppm): 1.58–1.73 (m, 2H), 1.85–2.01
(m, 2H), 2.08 (dd, 1H, J=8.8 Hz, J=12.9 Hz), 2.44
(ddd, 1H, J=5.1 Hz, J=13.2 Hz, J=13.2 Hz), 3.30 (m,
1H), 3.78 (s, 3H), 4.31 (dd, 1H, J=4.8 Hz, J=4.8 Hz),
5.26 (d, 1H, J=11.0 Hz), 6.81 (dd, 1H, J=11.0 Hz,
J=11.0 Hz), 7.39–7.44 (m, 2H), 7.49–7.54 (m, 1H),
7.67–7.72 (m, 2H). 13C NMR (CDCl3) l (ppm): 30.0,
32.2, 38.2, 47.5, 52.3, 61.5, 70.4, 97.5, 115.9, 128.4,
128.7, 131.9, 134.0, 155.7, 169.2, 172.9.
(E)-4d: White solid. Mp=137°C. [h]D=+4.8 (c 0.5,
CHCl3). IR (Nujol) w (cm−1): 2220, 1737, 1656. 1H
NMR (CDCl3) l (ppm): 1.50–1.59 (m, 1H), 1.71–1.96
(m, 4H), 2.36–2.46 (m, 1H), 2.78 (ddd, 1H, J=4.4 Hz,
J=8.8 Hz, J=9.9 Hz), 3.74 (s, 3H), 4.27 (dd, 1H,
J=4.8 Hz, J=4.8 Hz), 5.23 (d, 1H, J=16.2 Hz), 6.84
(dd, 1H, J=10.3 Hz, J=16.2 Hz), 7.38–7.43 (m, 2H),
7.47–7.53 (m, 1H), 7.66–7.69 (m, 2H). 13C NMR
(CDCl3) l (ppm): 30.3, 31.3, 37.6, 50.0, 52.2, 61.7, 70.9,
98.6, 117.1, 128.5, 128.7, 132.1, 134.0, 155.9, 169.3,
173.3. Elemental analysis calcd for C18H18N2O3: C,
69.66; H, 5.85; N, 9.03. Found: C, 69.65; H, 5.90; N,
9.04.
1
71/29 by integration of its H NMR spectrum.
1
(Z)-4b: H NMR (CDCl3) l (ppm): 1.50–1.62 (m, 6H),
1.86–1.96 (m, 2H), 2.43 (ddd, 1H, J=4.8 Hz, J=12.1
Hz, J=12.5 Hz), 3.02 (ddd, 1H, J=4.8 Hz, J=8.8 Hz,
J=9.2 Hz), 3.72 (s, 3H), 4.22 (dd, 1H, J=4.4 Hz,
J=4.8 Hz), 5.41–5.60 (m, 2H), 7.38–7.53 (m, 3H),
7.72–7.75 (m, 3H). Note: the small quantity of single
pure isomer (the major Z isomer) only allowed its IR
1
and H NMR characterisation.
4.5. Procedure for the Horner–Wittig olefination of
(1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]hept-
ane-1-carboxylate, 3
4.4.3. (Z/E)-Methyl (1S,2S,4R)-N-benzoyl-2-(2-phenyl-
vinyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate, 4c. Fol-
lowing method a, with benzyltriphenylphosphonium
chloride as the reagent and flash chromatography (elu-
ent: 6/4 ethyl acetate/n-hexane), as the purification
technique gave a mixture 6/94 of (Z/E)-4c in 93% yield.
This compound was used in the next step without
further purification. The chromatographic purification
also allowed the partial separation of the major E
isomer.
To a suspension of NaH (33.6 mg, 1.4 mmol) in dry
THF (6 mL) was added methyl diethylphosphonoac-
etate (294 mg, 1.4 mmol) and the mixture was stirred
for 1 h. A solution of the carbonyl compound 3 (200
mg, 0.70 mmol) in THF (4 mL) was added at rt and the
stirring was continued for 45 min. When the reaction
was complete it was quenched by the addition of water

1486
A. M. Gil et al. / Tetrahedron: Asymmetry 14 (2003) 1479–1488
(10 mL). The solution was concentrated under vacuum
and the aqueous residue was extracted with
dichloromethane (3×20 mL). The organic layers were
combined, dried over anhydrous MgSO4, filtered and
the solvent was evaporated under vacuum. The 1H
NMR spectrum of the crude product revealed a 12/88
mixture of (Z/E)-methyl (1S,2S,4R)-N-benzoyl-2-(2-
carbomethoxyvinyl)-7-azabicyclo[2.2.1]heptane-1-car-
boxylate 4e. The geometric isomers were purified by
column chromatography (eluent: 1/1 ethyl acetate/n-
hexane), which afforded the two compounds in 95%
yield (228 mg, 0.66 mmol). Moreover, the chromato-
graphic separation supplied a small amount of the Z
isomer (25 mg) and a mixture of the two isomers from
which the E isomer was isolated in pure form by
precipitation with ether.
Mp=97°C. [h]D=−61.9 (c 1, CHCl3). IR (Nujol) w
(cm−1): 1730, 1650, 1335, 1299, 1276. 1H NMR (CDCl3)
l (ppm): 1.56–1.64 (m, 2H), 1.81–2.13 (m, 3H), 2.38–
2.53 (m, 2H), 3.79 (s, 3H), 4.32 (dd, 1H, J=4.8 Hz,
J=4.8 Hz), 4.47 (dd, 1H, J=7.0 Hz, J=9.6 Hz), 4.90
(dd, 1H, J=7.7 Hz, J=9.6 Hz), 5.23 (ddd, 1H, J=7.0
Hz, J=7.7 Hz, J=10.3 Hz), 7.41–7.47 (m, 2H), 7.51–
7.57 (m, 1H), 7.66–7.69 (m, 2H). 13C NMR (CDCl3) l
(ppm): 29.7, 33.4, 35.6, 50.0, 52.8, 61.2, 69.0, 75.1,
83.74, 128.6, 128.7, 132.1, 133.6, 170.3, 172.9, 191.3.
Elemental analysis calcd for C18H19NO5S: C, 59.82; H,
5.30; N, 3.88. Found: C, 60.15; H, 5.09; N, 3.73.
4.6.2. Synthesis of methyl (1S,2S,4R)-N-benzoyl-2-
vinyl-7-azabicyclo[2.2.1]heptane-1-carboxylate, 4a. 1,3-
Dimethyl-2-phenyl-1,3,2-diazaphospholidine
(DMP-
DAP) (91 mL, 0.49 mmol) was added to a solution of
thionocarbonate 6 (59 mg, 0.16 mmol) in dry THF (1
mL). The mixture was heated under reflux under an
argon atmosphere during 15 h. The solvent was evapo-
rated under vacuum and the residue was purified by
flash chromatography (eluent: 8/2 n-hexane/ethyl ace-
tate). This procedure provided 4a in 86% yield (39 mg,
0.14 mmol).
(Z)-4e: Oil. [h]D=−7.9 (c 0.5, CHCl3). IR (neat) w
(cm−1): 3056–2853, 1741, 1638, 1629, 1599, 1577. 1H
NMR (CDCl3) l (ppm): 1.53–1.70 (m, 2H), 1.72–1.85
(m, 1H), 1.89–1.97 (m, 1H), 2.08 (dd, 1H, J=8.8 Hz,
J=12.2 Hz), 2.41 (ddd, 1H, J=4.9 Hz, J=12.2 Hz,
J=12.7 Hz), 3.68 (s, 3H), 3.74 (s, 3H), 4.11 (ddd, 1H,
J=4.9 Hz, J=9.3 Hz, J=9.3 Hz), 4.24 (dd, 1H, J=4.9
Hz, J=4.9 Hz), 5.71 (dd, 1H, J=1.0 Hz, J=11.7 Hz),
6.60 (dd, 1H, J=10.2 Hz, J=11.7 Hz), 7.36–7.42 (m,
2H), 7.45–7.51 (m, 1H), 7.67–7.69 (m, 2H). 13C NMR
(CDCl3) l (ppm): 30.4, 31.6, 38.5, 44.5, 51.1, 52.1, 61.7,
70.5, 117.1, 128.4, 128.7, 131.7, 134.5, 150.9, 166.7,
169.7, 174.1. HRMS m/z (EI) calcd for C19H21NO5:
343.1420. Found: 343.1407.
4.7. General procedure for the oxidative cleavage of 4a
and the Z/E mixtures of 4b–e
NaIO4 (1.44 mmol) was added to a solution of com-
pound 4a or the Z/E mixtures of 4b–e (0.18 mmol) in a
1/1/1.2 carbon tetrachloride/acetonitrile/water mixture
(1.6 mL). The biphasic solution was treated with RuCl3
(2 mg, 0.01 mmol) and the mixture was vigorously
stirred for 12 h at rt. Dichloromethane (5 mL) was
added, the organic phase was separated and the
aqueous phase extracted with dichloromethane (3×5
mL). The organic extracts were dried over MgSO4 and
concentrated under vacuum. The residue was analysed
(E)-4e: White solid. Mp=145°C. [h]D=−42.3 (c 1,
CHCl3). IR (Nujol) w (cm−1): 1728, 1712, 1652. 1H
NMR (CDCl3) l (ppm): 1.49–1.58 (m, 1H), 1.64–1.75
(m, 1H), 1.81–1.91 (m, 3H), 2.44 (ddd, 1H, J=4.4 Hz,
J=12.5 Hz, J=12.5 Hz), 2.74–2.82 (m, 1H), 3.69 (s,
3H), 3.71 (s, 3H), 4.25 (dd, 1H, J=3.7 Hz, J=3.7 Hz),
5.70 (d, 1H, J=15.4 Hz), 7.02 (dd, 1H, J=10.3 Hz,
J=15.8 Hz), 7.37–7.43 (m, 2H), 7.47–7.52 (m, 1H),
7.70–7.73 (m, 2H). 13C NMR (CDCl3) l (ppm): 30.4,
30.5, 37.3, 49.5, 51.5, 51.8, 61.9, 71.1, 120.0, 128.4,
128.8, 131.8, 134.2, 149.1, 166.6, 169.6, 173.6. Elemen-
tal analysis calcd for C19H21NO5: C, 66.46; H, 6.16; N:
4.08. Found: C, 66.11; H, 6.28; N, 4.31.
1
by H NMR spectroscopy and, in all cases, carboxylic
acid 7 was the only compound detected.18
4.8. General procedure for the hydrogenation of 4a and
the alkene mixtures 4b–e
Compound 4a or the corresponding Z/E mixtures of
4b–e (100 mg) were dissolved in methanol (10 mL) and
hydrogenated at atmospheric pressure and rt using
palladium hydroxide (10 mg) as a catalyst. After 1 day
the catalyst was filtered off through a Celite pad and
the solvent was removed under vacuum to provide the
corresponding saturated compound 8a–e.
4.6. Procedure for the Corey–Winter olefination of
methyl (1S,2R,4R)-N-benzoyl-2-[(S)-2,2-dimethyl-1,3-
dioxolan-4-yl]-7-azabicyclo[2.2.1]heptane-1-carboxylate,
2
4.6.1. Synthesis of methyl (1S,2S,4R)-N-benzoyl-2-[(S)-
2-thionocarbonyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]-
heptane-1-carboxylate, 6. To a solution of diol 5 (100
mg, 0.31 mmol) in dry toluene (10 mL) was added
N,N%-thiocarbonyldiimidazole (TCDI) (84 mg, 0.47
mmol). The mixture was kept under an argon atmo-
sphere and heated under reflux for 1 h. The solution
was concentrated under reduced pressure and the
residue was purified by flash chromatography (eluent:
6/4 ethyl acetate/n-hexane). Thionocarbonate 6 was
obtained in 83% yield (93 mg, 0.26 mmol) as a white
solid.
4.8.1. Methyl (1S,2R,4R)-N-benzoyl-2-ethyl-7-azabicy-
clo[2.2.1]heptane-1-carboxylate, 8a. Oil, 98% yield.
[h]D=−111.5 (c 1, CHCl3). IR (neat) w (cm−1): 3059–
1
2874, 1733, 1656. H NMR (CDCl3) l (ppm): 0.83 (t,
3H, J=7.2 Hz), 1.24–1.52 (m, 2H), 1.56–1.69 (m, 3H),
1.75–1.83 (m, 2H), 1.86–1.95 (m, 1H), 2.38 (ddd, 1H,
J=4.6 Hz, J=12.1 Hz, J=12.4 Hz), 3.77 (s, 3H), 4.17
(dd, 1H, J=4.6 Hz, J=4.6 Hz), 7.36–7.42 (m, 2H),
7.45–7.51 (m, 1H), 7.69–7.73 (m, 2H). 13C NMR
(CDCl3) l (ppm): 11.1, 26.4, 30.5, 31.0, 37.1, 49.0, 51.7,
62.3, 70.5, 128.2, 128.8, 131.5, 134.8, 171.0, 174.1.

A. M. Gil et al. / Tetrahedron: Asymmetry 14 (2003) 1479–1488
1487
HRMS (EI) m/z calcd for C17H21NO3: 287.1521.
Found: 287.1527.
yield. Mp=dec. [h]D=−48.3 (c 1, H2O). IR (Nujol) w
1
(cm−1): 3700–2000, 1728. H NMR (D2O) l (ppm): 0.72
(t, 3H, J=7.3 Hz), 0.95–1.10 (m, 1H), 1.38–1.48 (m,
1H), 1.54–1.63 (m, 1H), 1.69–1.80 (m, 1H), 1.91–2.14
(m, 5H), 4.08 (dd, 1H, J=4.4 Hz, J=4.8 Hz).13C NMR
(D2O) l (ppm): 9.9, 24.5, 26.6, 30.9, 34.5, 44.5, 58.4,
76.1, 172.2.
4.8.2. Methyl (1S,2R,4R)-N-benzoyl-2-n-propyl-7-azabi-
cyclo[2.2.1]heptane-1-carboxylate, 8b. Obtained in 91%
yield and completely characterised, as described previ-
ously in the literature.18
4.8.3. Methyl (1S,2R,4R)-N-benzoyl-2-(2-phenylethyl)-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 8c. Oil, 95%
yield. [h]D=+62.4 (c 1, CHCl3). IR (neat) w (cm−1):
3056–2855, 1739, 1726, 1657, 1639, 1600, 1579. 1H
NMR (CDCl3) l (ppm): 1.41–1.51 (m, 1H), 1.58–1.86
(m, 5H), 1.91–2.05 (m, 2H), 2.33–2.49 (m, 2H), 2.58–
2.67 (m, 1H), 3.76 (s, 3H), 4.18 (dd, 1H, J=4.4 Hz,
J=4.8 Hz), 7.14–7.19 (m, 3H), 7.24–7.29 (m, 2H),
7.37–7.42 (m, 3H), 7.45–7.50 (m, 2H). 13C NMR
(CDCl3) l (ppm): 30.4, 31.1, 32.9, 35.1, 37.7, 46.5, 51.8,
62.2, 70.4, 125.8, 128.3, 128.4, 128.4, 128.8, 131.6,
134.9, 141.7, 170.8, 174.1.
4.9.2. (1S,2R,4R)-2-Propyl-7-azabicyclo[2.2.1]heptane-1-
carboxylic acid hydrochloride, 9b. Prepared in 97% yield
according to the procedure reported previously.18
4.9.3. (1S,2R,4R)-2-(2-Phenylethyl)-7-azabicyclo[2.2.1]-
heptane-1-carboxylic acid hydrochloride, 9c. White solid,
86% yield. Mp=dec. [h]D=−48.5 (c 0.5, H2O). IR
1
(Nujol) w (cm−1): 3500–3200, 1725. H NMR (D2O) l
(ppm): 1.32–1.45 (m, 1H), 1.62–1.74 (m, 3H), 1.81–2.12
(m, 5H), 2.29–2.43 (m, 1H), 2.53–2.62 (m, 1H), 4.07
(dd, 1H, J=3.3 Hz, J=4.0 Hz), 7.10–7.13 (m, 3H),
7.18–7.23 (m, 2H). 13C NMR (D2O) l (ppm): 26.5,
30.9, 31.4, 33.1, 34.8, 41.9, 58.4, 76.1, 126.3, 128.6,
128.7, 141.4, 171.9.
4.8.4. Methyl (1S,2R,4R)-N-benzoyl-2-(2-cyanoethyl)-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 8d. White solid,
98% yield. Mp=108°C. [h]D=−66.8 (c 0.5, CHCl3). IR
1
(neat) w (cm−1): 2245, 1743, 1667, 1602, 1578. H NMR
4.9.4.
(1S,2R,4R)-2-(2-Carboxyethyl)-7-azabicyclo-
(CDCl3) l (ppm): 1.47–1.91 (m, 7H), 2.07–2.45 (m,
4H), 3.78 (s, 3H), 4.21 (dd, 1H, J=4.4 Hz, J=4.8 Hz),
7.36–7.42 (m, 2H), 7.46–7.52 (m, 1H), 7.65–7.69 (m,
2H). 13C NMR (CDCl3) l (ppm): 14.7, 29.1, 30.2, 31.7,
37.2, 45.2, 52.2, 61.9, 70.0, 119.3, 128.4, 128.8, 131.9,
134.4, 170.3, 173.7. Elemental analysis calcd for
C18H22N2O3: C, 69.21; H, 6.45; N, 8.97. Found: C,
69.10; H, 6.05; N, 8.39.
[2.2.1]heptane-1-carboxylic acid hydrochloride, 9d. White
solid, quantitative yield. Mp=dec. [h]D=−44.5 (c 0.5,
H2O): (from 8d). [Pale brown solid, quantitative yield.
Mp: dec. [h]D (c 0.5, H2O): −42.3 (from 8c)]. IR (Nujol)
w (cm−1): 3256–2558, 1732, 1600. 1H NMR (D2O) l
(ppm): 1.27–1.40 (m, 1H), 1.54–1.63 (m, 1H), 1.68–1.79
(m, 2H), 1.91–2.06 (m, 4H), 2.13–2.35 (m, 3H), 4.08
(dd, 1H, J=4.4 Hz, J=4.4 Hz). 13C NMR (D2O) l
(ppm): 26.5, 26.8, 30.5, 31.0, 34.6, 41.8, 58.2, 76.3,
172.1, 177.6.
4.8.5.
Methyl
(1S,2R,4R)-N-benzoyl-2-(2-carbo-
methoxyethyl)-7-azabicyclo[2.2.1]heptane-1-carboxylate,
8e. Oil, quantitative yield. [h]D=−76.3 (c 1, CHCl3). IR
(neat) w (cm−1): 3059–2850, 1743, 1648, 1600, 1578. H
1
Acknowledgements
NMR (CDCl3) l (ppm): 1.40–1.51 (m, 1H), 1.59–1.83
(m, 5H), 1.93–2.06 (m, 2H), 2.13–2.44 (m, 3H), 3.66 (s,
3H), 3.78 (s, 3H), 4.17 (dd, 1H, J=4.8 Hz, J=4.8 Hz),
7.36–7.41 (m, 2H), 7.45–7.50 (m, 1H), 7.67–7.71 (m,
2H). 13C NMR (CDCl3) l (ppm): 28.9, 30.4, 31.0, 31.4,
37.2, 46.2, 51.7, 52.0, 62.1, 70.3, 128.3, 128.8, 131.7,
134.6, 170.6, 173.6, 174.1. HRMS (EI) m/z calcd for
C19H23NO5: 345.1576. Found: 345.1577.
This work was carried out with the financial support of
Ministerio de Ciencia y Tecnolog´ıa and FEDER (pro-
ject PPQ2001-1834). A. M. Gil would like to thank
CSIC for a I3P grant. The authors thank Dr. P. Lo´pez
for HPLC assistance and the Centro de Excelencia
Bruker—ICMA for collection and preliminary data
treatment on the X-ray structural studies.
4.9. General procedure for the hydrolysis of compounds
8a–d
Aqueous 6N HCl (15 mL) was added to the amido
esters 8a–e (100 mg) and the mixture was heated under
reflux for 24 h. After the reaction was complete the
solvent was evaporated under vacuum and the residue
dissolved in water (30 mL). The solution was extracted
with chloroform (3×20 mL) and the separated aqueous
phase was evaporated to dryness. Total removal of
water was achieved by final lyophilization. This proce-
dure gave the amino acid hydrochlorides 9a–e.
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