Synthesis of enantiopure 7-azanorbornane proline-α-amino acid chimeras by highly efficient HPLC resolution of a phenylalanine analogue

Article abstract of DOI:10.1016/j.tetasy.2003.12.008

The enantiomerically pure conformationally constrained prolines, (1S,2S,4R)- and (1R,2R,4S)-2-phenyl-7-azabicyclo [2.2.1]heptane-1-carboxylic acid hydrochlorides, which are proline-phenylalanine chimeras, have been separately obtained by resolution of a key intermediate using chiral high performance liquid chromatography. The efficiency of the chromatographic resolution provides a general methodology for the preparation of both enantiomers of a broad variety of proline-α-amino acid chimeras with a 7-azanorbornane skeleton in enantiomerically pure form.

Full text of DOI:10.1016/j.tetasy.2003.12.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 811–819
Synthesis of enantiopure 7-azanorbornane proline–a-amino acid
chimeras by highly efficient HPLC resolution of a
phenylalanine analogue
a
Ana M. Gil, Elena Bunuel, Pilar Lopez and Carlos Cativiela
b,
a
a,
*
*
~
ꢀ
a
ꢀ
ꢀ
Departamento de Quımica Organica, ICMA, Universidad de Zaragoza––CSIC, 50009 Zaragoza, Spain
b
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Universidad Autonoma de Madrid, 28049 Madrid, Spain
Received 24 November 2003; accepted 3 December 2003
Abstract—The enantiomerically pure conformationally constrained prolines, (1S,2S,4R)- and (1R,2R,4S)-2-phenyl-7-azabicyclo
[2.2.1]heptane-1-carboxylic acid hydrochlorides, which are proline–phenylalanine chimeras, have been separately obtained by res-
olution of a key intermediate using chiral high performance liquid chromatography. The efficiency of the chromatographic reso-
lution provides a general methodology for the preparation of both enantiomers of a broad variety of proline–a-amino acid chimeras
with a 7-azanorbornane skeleton in enantiomerically pure form.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
combined with the conformational restrictions charac-
teristic of the cyclic amino acid residue.8 Replacement of
the natural amino acids in peptides with such proline–a-
amino acid chimeras has led to a better understanding of
the bioactive conformations of cholecystokinin,9–11
angiotensin II,12;13 bradykinin,14 and opioide pep-
tides.15–17 Also, b-alkylproline analogues have served for
the development of enzyme inhibitors,17–19 as well as
peptidomimetics exhibiting improved bioactivity and
greater metabolic stability.12–17
The introduction of conformational constraints consti-
tutes one of the most promising approaches to the
construction of peptide analogues of pharmaceutical
interest.1–4 Furthermore, it has become a useful tool for
the elucidation of biologically active conformations1;5 by
providing information about the spatial requirements
for optimal interaction with the receptor.5–7
Several b-substituted prolines (Fig. 1) have been syn-
thesised to serve as amino acid chimeras in which the
functional groups of the amino acid side-chain are
The proline analogues containing
a
7-azabicy-
clo[2.2.1]heptane structure (Fig. 1) constitute a distinct
class of aminoacids due to their extra conformational
restriction. Hence, the benefits of the parent compound
(R ¼ H), as a replacement for proline in a boroarginine
thrombin inhibitor20 and as starting material in the
synthesis of a new class of HIV-1 protease inhibitor,21
have already been established.
H
H
N
N
R
COOH
COOH
R
N
H
N
Ph
H
HOOC
HOOC
At present, there are a few examples on the asymmetric
synthesis of prolines with a 7-azanorbornane skele-
ton.22–27 On the other hand, the literature reports only
one resolution procedure to obtain separately both
enantiomers of an azabicyclic b-hydroxyproline.28 This
strategy consists of the formation of diastereomers and
subsequent separation by crystallisation, which involves
the introduction of additional synthetic steps to the
pathway towards the final products.
Pro
Pro-α-Aminoacid chimeras
Pro-Phe chimera
R = amino acid side chain
Figure 1. Structure of some proline analogues.
* Corresponding authors. Tel./fax: +34-976-761210; e-mail addresses:
elena.bunnuel@uam.es; cativiela@unizar.es
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.008

812
A. M. Gil et al. / Tetrahedron: Asymmetry 15 (2004) 811–819
Our main objective herein is the development of a highly
efficient and facile resolution method for an azanor-
bornane proline–phenylalanine chimera analogue in
order to facilitate the synthesis of a wide variety of
a-amino acid chimeras with 7-azabicyclo[2.2.1]heptane
skeleton in enantiomerically pure form. To this end we
have used chiral high performance liquid chromatogra-
phy (HPLC), since we have already shown the efficacy of
this methodology for resolving racemic mixtures of
other constrained phenylalanine analogues.29–32 The
incorporation of some of these analogues,33–37 such as
1-amino-2-phenylcyclopropanecarboxylic acid (c3Phe),
1-amino-2-phenylcyclohexanecarboxylic acid (c6Phe)
and 1-amino-2,3-diphenylcyclopropanecarboxylic acid
(c3diPhe), into model peptides has allowed the explora-
tion of structural properties.
placement of the methanesulfonate group on rac-4a was
achieved by treatment of the mixture of rac-4a and rac-
4b with NaH in DMF, instead of potassium tert-
butoxide in THF as previously reported.38;39 Finally, the
separation of the product rac-5 from the non-cyclisable
methanesulfonate rac-4b was easily achieved by column
chromatography.
In this way, the synthesis was accomplished on a mul-
tigram scale and ca. 5 g of a racemic mixture of rac-5
could be obtained from oxazolone 1 in seven steps in
27% overall yield.
2.1. HPLC resolution of rac-5
Once the synthesis of the racemic compound rac-5 had
been achieved, we undertook the preparation of this
product in enantiomerically pure form by HPLC reso-
lution using a chiral stationary phase. Specifically, a
non-commercial polysaccharide-derived support con-
sisting of mixed 10-undecenoate/3,5-dimethylphenyl-
carbamate of cellulose covalently attached to allylsilica
gel was used.40;41 The excellent chiral discrimination
exhibited by this stationary phase towards a variety of
compounds40 together with its high chemical stability,
make it especially suitable for resolutions on a pre-
parative scale. The efficiency of this system has actually
been demonstrated in the preparative enantiosepara-
tions of various phenylalanine surrogates.29–32
2. Results and discussion
Initially the multigram scale synthesis of the racemic
proline–phenylalanine chimera derivative, rac-5, was
performed according to a modified literature procedure
(Scheme 1).38;39 Thus, the Diels–Alder reaction of
DanishefskyÕs diene and a C-4 unsaturated oxazolone
derived from benzaldehyde, (Z)-2-phenyl-4-benzylidene-
5(4H)-oxazolone 1, followed by hydrolysis of the adduct
mixture and subsequent elimination of the methoxy
group with oxazolone ring opening led to rac-2 in 81%
overall yield. Heterogeneous hydrogenation of the
double bond of enone rac-2, by using 20% Pd(OH)2/C
instead of the originally reported catalyst Pd/C, afforded
ketone rac-3 in 95% yield. Reduction of rac-3 with
L-selectrideꢁ (lithium tri-sec-butylborohydride) pro-
vided preferentially the axial alcohol (stereoselectivity
ratio: 63:37). Then, the mixture of alcohols was trans-
formed into the corresponding methanesulfonate deriv-
atives, rac-4a and rac-4b in 71% combined yield from
rac-3, by treatment with methanesulfonyl chloride in
triethylamine. In order to prepare the bicyclic product
rac-5, the base-promoted internal nucleophilic dis-
The resolution of rac-5 was initially investigated on an
analytical scale (eluent: 95:5 n-hexane/2-propanol,
k10 ¼ 1:77, a ¼ 1:70, Rs ¼ 3:04). From these satisfactory
results, the optimal separation conditions were deter-
mined by adding a certain amount of chloroform to the
eluent to enhance the solubility of the compound. The
extension of the analytical conditions to the preparative
scale proved extremely efficient, resulting in a baseline
separation of both enantiomers (see Fig. 2). Working on
repetitive injection mode, 1.2 g of racemate were injected
onto a 150 · 20 mm ID column with a total time of 4–5 h
O
COOMe
H
COOMe
i
ii
O
NHCOPh
Ph
NHCOPh
Ph
Ph
N
O
O
Ph
rac-3
1
rac-2
iii
O
Ph
N
COOMe
NHCOPh
COOMe
iv
NHCOPh
Ph
+
Ph
MsO
Ph
MsO
MeOOC
rac-5
rac-4a
rac-4b
Scheme 1. Synthesis of 7-azabicyclo[2.2.1]heptane analogue of phenyl-
alanine rac-5. Reagents and conditions: (i) (a) DanishefskyÕs diene,
toluene, reflux, (b) 0.005 N HCl/THF (1:4), (c) DBU, MeOH, 0 ꢂC
(81% from 1); (ii) H2, 20% Pd(OH)2/C, CH2Cl2, rt (95%); (iii) (a) L-
selectrideꢁ, THF, )78 ꢂC, (b) MsCl, Et3N, CH2Cl2, rt (71% from rac-
3); (iv) NaH, DMF, )78 ꢂC, then column chromatography (49% from
rac-4a+rac-4b).
Figure 2. HPLC preparative resolution of rac-5. Column: 150 · 20 mm
ID, eluent: n-hexane/chloroform/2-propanol (93:2:5), flow rate:
18 mL minꢀ1. UV detection at 270 nm. Injection of 50 mg of rac-5 in
0.2 mL of dichloromethane. See Section 4.2 for definition of the
chromatographic parameters.

A. M. Gil et al. / Tetrahedron: Asymmetry 15 (2004) 811–819
813
to complete the process. Valley–valley collection of the
eluting peaks afforded the enantiomerically pure first
eluted enantiomer. The second collected enantiomer was
obtained in a 99:1 enantiomeric ratio. After recrystalli-
sation of the last enantiomer from ethyl acetate a
>99.9:0.1 enantiopurity was achieved. Thus, the reso-
lution of 1.2 g of rac-5 finally resulted in 1.037 g of
enantiomerically pure material (ca. 517 and 520 mg of
the first and second eluted enantiomer, respectively).
The enantiomeric excess of the resolved enantiomers
was assessed at analytical level, and the assignment of
their absolute configurations was carried out by means
of the incorporation of the separated enantiomers into
dipeptide derivatives, as described below.
of rac-5 using potassium hydroxide in methanol led to
the corresponding acid rac-6 in 97% yield. The sub-
sequent coupling of this racemic mixture with enantio-
merically pure
L-phenylalanine isopropylamide using
the reagent designed by Castro et al.,44 (1H-benzotriazol-
1-yloxy)tris(dimethylamino)phosphonium hexaflurophos-
phate (BOP), provided a mixture of two diastereomeric
dipeptide derivatives 7 and 8 in 98% combined yield.
After complete separation of the dipeptides by column
chromatography, both compounds were individually
characterised. A crystal suitable for X-ray crystallogra-
phy was finally obtained for 8, the second chromato-
graphic component.
Hence, the absolute configuration of the proline ana-
logue contained in the dipeptide 8 could be unques-
tionably determined by X-ray diffraction analysis of a
crystal, easily obtained by slow evaporation from a
solution in dichloromethane/n-hexane. The known (S)
configuration for the phenylalanine residue allowed the
determination of the absolute configuration of the aza-
bicyclic residue as (1S,2S,4R).45
2.2. Assignment of absolute configurations
The assignment of absolute configuration was per-
formed by X-ray diffraction analysis of a single crystal
obtained from a solution of one of the diastereomeric
dipeptides resulting from the coupling of the racemic
mixture with an
L-phenylalanine derivative. Obrecht
et al. had described phenylalanine cyclohexylamide as a
very convenient auxiliary for the efficient assignment of
the absolute configurations of a,a-disubstituted amino
acids.42;43 According to this approach, we coupled the
racemic mixture of the 7-azanorbornane proline rac-5
Independently, the firstly eluting enantiomer of 5 was
also coupled with
L-phenylalanine isopropylamide
under the conditions previously developed for the
racemic material (Scheme 2). Comparison of the spec-
troscopic data of this dipeptide analogue with those
obtained for compound 8, which had provided the
suitable single crystal for the X-ray diffraction analysis,
allowed the identification of this enantiomer as the one
bearing the same (1S,2S,4R) absolute configuration of
the azabicyclic residue contained in peptide 8.
with this enantiomerically pure
L-phenylalanine ana-
logue. However, all the attempts to obtain a suitable
crystal to perform single crystal X-ray analysis, from
either of the two resulting diastereomeric dipeptides,
failed.
With this result in mind, a different phenylalanine
derivative was selected for coupling to the racemic 7-
azanorbornane proline (Scheme 2). The saponification
Great interest has been focused on dipeptide 8 since
the X-ray diffraction analysis45 has revealed that, in the
solid state, this constrained peptide containing the
O
Ph
N
Ph
ii
MeOOC
i
rac-5
O
O
O
Ph
N
Ph
Ph
N
N
Ph
Ph
Ph
HOOC
MeOOC
COOMe
(1R,2R,4S)-5
rac-6
iii
(1S,2S,4R)-5
ii
O
O
Ph
Ph
O
N
N
N
Ph
O
Ph
O
iii
Ph
HN
Ph
NH
CONHiPr
Ph
Ph
HOOC
iPrHNOC
(1S,2S,4R)-6
(1S,2S,4R)-(S)-8
(1R,2R,4S)-(S)-7
Scheme 2. Resolution of rac-5 and assignment of the absolute configurations. Reagents and conditions: (i) HPLC resolution; (ii) KOH, MeOH,
reflux (97%); (iii) (a) Et3N, BOP, -phenylalanine isopropylamide hydrochloride, CH3CN, then column chromatography (98%).
L

814
A. M. Gil et al. / Tetrahedron: Asymmetry 15 (2004) 811–819
azanorbornane proline adopts a type Ib-turn whereas
the analogous dipeptide sequence incorporating -pro-
separately treated with aqueous 6 N HCl under reflux to
provide the enantiomerically pure proline–phenylala-
nine chimeras (1S,2S,4R)-9 and (1R,2R,4S)-9 both in
quantitative yield (Scheme 3). The resulting amino acids,
which may be also considered to be (2S,3S) and
(2R,3R)-3-phenylproline analogues, were fully charac-
terised.
L
line has been shown to accommodate a bII-turn dispo-
sition. As we recently have described, attractive
interactions involving the central NH group and either
the aromatic rings or the pyramidalised bicyclic nitrogen
seem to play a role in the stabilisation of the observed
bI-turn conformation.
The synthesis of the proline–aspartic acid chimeras was
also embarked upon (Scheme 3). Oxidative cleavage of
the phenyl substituent on the azabicyclic ring of
(1S,2S,4R)-5 and (1R,2R,4S)-5 proceeded in 45% yield
and led to the intermediates (1S,2R,4R)-10 and
(1R,2S,4S)-10. Treatment of each enantiomer with
aqueous 6 M HCl under reflux supplied the enantio-
merically pure (2S,3R) and (2R,3S)-3-carboxyproline ana-
2.3. Synthesis of proline–a-amino acid chimeras in
enantiomerically pure form
After HPLC resolution of rac-5, the isolated enantio-
mers were subjected to hydrolysis. A small quantity of
each enantiomer, (1S,2S,4R) and (1R,2R,4S)-5, was
rac-5
i
O
O
H2Cl
N
H2Cl
N
Ph
Ph
N
N
ii
ii
Ph
Ph
Ph
Ph
HOOC
MeOOC
COOMe
COOH
(1S,2S,4R)-9
(1S,2S,4R)-5
(1R,2R,4S)-5
(1R,2R,4S
)
-9
iii
iii
O
N
O
H2Cl
N
H2Cl
N
Ph
Ph
N
ii
ii
COOH
COOH
MeOOC
(1S,2R,4R)-10
HOOC
HOOC
HOOC
COOMe
COOH
(1S,2R,4R)-11
(1R,2S,4S)-10
(1R,2S,4S)-11
iv
O
iv
O
Ph
N
Ph
N
CH2OH
HOH2C
MeOOC
COOMe
(1S,2R,4R)-12
(1R,2S,4S)-12
v
v
O
O
H2Cl
N
H2Cl
N
Ph
N
Ph
N
R
CHO
OHC
R
Ref. 27
HOOC
MeOOC
COOMe
COOH
L
-Proline-α-amino acid
(1S,2R,4R)-13
(1R,2S,4S)-13
D
-Proline-α-amino acid
chimeras
chimeras
R= α-amino acid side chain
Scheme 3. Synthetic route to enantiomerically pure 7-azanorbornane proline–a-amino acid chimeras. Reagents and conditions: (i) HPLC resolution;
(ii) 6 N HCl, reflux (P95%); (iii) NaIO4, RuCl3, CCl4/CH3CN/H2O, rt (45%); (iv) (a) Et3N, IBCF, THF, )15 ꢂC, (b) NaBH4, H2O, )15 ꢂC then rt
(88%); (v) Dess–Martin periodinane reagent, CH2Cl2, rt (80%).

A. M. Gil et al. / Tetrahedron: Asymmetry 15 (2004) 811–819
815
logues, (1S,2R,4R)-11 and (1R,2S,4S)-11, in quantita-
tive yield. The determinations of the specific rotations
for the enantiomers (1S,2R,4R)-10 and (1S,2R,4R)-11
supplied further confirmation of the absolute stereo-
chemistry, since these values agree with the corre-
sponding data for the same compounds previously
obtained by asymmetric synthesis.46;47
methodology to the preparation of other proline–a-
amino acid chimeras in enantiomerically pure form via
the b-formyl derivative, as we have recently described,
or by means of the corresponding b-carboxylic or
b-hydroxymethyl derivatives, which are presently under
investigation.
Therefore, the methodology described herein constitutes
an efficient strategy that supplies both enantiomers of a
very special kind of amino acid where the rigidity pro-
vided by the azabicyclic skeleton and a b-substituent,
which mimics the a-amino acid side chain, are com-
bined. These proline–a-amino acid chimeras are new
surrogates to be incorporated into peptides whose
structural and biological study shed light upon the
nature of the effects induced by this type of conforma-
tional restriction and the influence of the absolute con-
figurations of the stereogenic centres.
Carboxylic acids (1S,2R,4R)-10 and (1R,2S,4S)-10
constitute key intermediates for the preparation of a
wide variety of other enantiomerically pure proline–a-
amino acid chimeras, either directly, thanks to the ver-
satility of the acidic group, or by transformation into
other synthetically flexible functions, such as a hydroxyl
or formyl groups.
Thus, the reduction of the acid to the alcohol was per-
formed for both enantiomers, (1S,2R,4R)-10 and
(1R,2S,4S)-10. The procedure involving the acyl chlo-
ride intermediate was unsuccessful, but the mixed
anhydride method led to excellent results (Scheme 3).
Separate treatment of (1S,2R,4R)-10 and (1R,2S,4S)-10
with N-methylmorpholine (NMM) and isobutylchloro-
formate and subsequent addition of NaBH4 over the
resulting anhydrides supplied the enantiomerically pure
alcohols (1S,2R,4R)-12 and (1R,2S,4S)-12 in 88% yield.
The utility of this b hydroxymethyl function to achieve
the synthesis of new azabicyclic prolines is under current
investigation.
4. Experimental
4.1. General
€
Melting points were determined using a Buchi SMP-20
apparatus. IR spectra were registered on a Mattson
Genesis FTIR spectrophotometer; mmax is given for the
1
main absorption bands. H and 13C NMR spectra were
recorded on a Varian Unity-300 or a Bruker ARX-300
apparatus at room temperature, using the residual sol-
vent signal as the internal standard; chemical shifts (d)
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 ꢂC using a JASCO
P-1020 polarimeter. Elemental analyses were carried out
on a Perkin–Elmer 200 C, H, N, S analyser. TLC was
performed on Polygramꢁ sil G/UV254 precoated silica
gel polyester plates and products were visualised under
UV light (254 nm), ninhydrin, anisaldehyde or phos-
phomolybdic acid developers. Column chromatography
was performed using silica gel (Kieselgel 60). (Z)-2-
Phenyl-4-benzylidene-5(4H)-oxazolone 1 was prepared
by condensation of hippuric acid (benzoylglycine) and
benzaldehyde in the presence of anhydrous sodium
acetate and acetic anhydride.38;39
Finally, the oxidation of the hydroxyl group was easily
carried out after selecting the best oxidation conditions
by testing the racemic mixture of alcohols. Treatment of
racemic 12 with chromium trioxide resulted in low yields
(69%). On the other hand, a 70:30 mixture of the
b-formyl derivative 13 and its C-2 epimer was obtained
in a 97% combined yield when the alcohol 12 was
treated under Swern conditions with oxalyl choride
(1.5 equiv), Et3N (5 equiv) and DMSO (4.5 equiv) in dry
dichloromethane. The best results on this oxidation
reaction were obtained by using the Dess–Martin
reagent.48;49 In this case, the process took place in high
yield and without any epimerisation detectable in the
crude reaction mixture. So, the separate oxidation of
the alcohols (1S,2R,4R)-12 and (1R,2S,4S)-12 using the
Dess–Martin periodinane in dry dichloromethane gave
rise to the enantiopure aldehydes (1S,2R,4R)-13 and
(1R,2S,4S)-13, respectively, in 80% yield. It is note-
worthy that the formyl derivative (1S,2R,4R)-13 has
recently proved to be a versatile synthetic intermediate
in the preparation of a wide variety of azabicyclic pro-
lines b-substituted through olefination processes.27
4.2. High performance liquid chromatography
HPLC was carried out on a system equipped with a
Waters 600-E pump and a Waters 991 photodiode array
detector. The preparation of the chiral stationary phase,
consisting of mixed 10-undecenoate/3,5-dimethylphe-
nylcarbamate of cellulose covalently attached to allyl-
silica gel, has been already described.40;41 The solvents
used as mobile phases were of spectral grade. The HPLC
analytical assays were carried out on a 150 · 4.6 mm ID
column with an eluent flow rate of 1.0 mL minꢀ1 and
UV monitoring at 220 nm. The capacity (k0) k10 1.77,
selectivity (a) 1.70 and resolution (Rs) 3.04 factors
are defined as follows: k0 ¼ ðtr ꢀ t0Þ=t0, a ¼ k20 =k10 ,
3. Conclusion
The high efficacy of the HPLC resolution has provided
the enantiomerically pure enantiomers of a constrained
proline–phenylalanine chimera and a proline–aspartic
acid chimera with a 7-azabicyclo[2.2.1]heptane skeleton.
We have also shown the possibility of extending this

816
A. M. Gil et al. / Tetrahedron: Asymmetry 15 (2004) 811–819
Rs ¼ ðt2 ꢀ t1Þ=½ðw1=2Þ þ ðw1=2Þ ꢁ, where subscripts 1 and
enantiomeric pure form. The second fraction collected
(55 mg) contained a 37:63 mixture of the first and the
second eluted enantiomers, (1S,2S,4R)-5/(1R,2R,4S)-5.
2
1
2 refer to the first and second eluted enantiomer,
respectively, tr (r ¼ 1; 2) are their retention times, and
ðw1=2Þ and ðw1=2Þ denote their half high peak widths; t0
1
2
is the dead time. The preparative resolution of rac-5 was
carried out on a 150 · 20 mm ID column. A mixture of
n-hexane/chloroform/2-propanol (93:2:5) was used as
the eluent, at a flow rate of 18 mL minꢀ1. UV detection
was performed at 270 nm.
Spectroscopic data for both (1S,2S,4R)-5 and
(1R,2R,4S)-5 were the same as those described in the
literature for rac-5.38
(1S,2S,4R)-5: Mp 185–186 ꢂC. ½aꢁ ¼ +52.9 (c 1.0,
D
CHCl3)
4.3. Preparation of methyl (1S,2S,4R)- and (1R,2R,4S)-
N-benzoyl-2-phenyl-7-azabicyclo[2.2.1]heptane-1-carbox-
ylate, (1S,2S,4R)-5 and (1R,2R,4S)-5
(1R,2R,4S)-5: Mp 186–187 ꢂC. ½aꢁ ¼ )52.5 (c 1.0,
D
CHCl3)
4.3.1. Synthesis of methyl N-benzoyl-2-phenyl-7-azabicy-
clo[2.2.1]heptane-1-carboxylate, rac-5. . The synthesis of
the racemic mixture was basically carried out according
to the procedure previously reported in the litera-
ture.38;39 The main modification was introduced into the
last step concerning the transformation of rac-4a into
azabicylclic rac-5. For this purpose, a solution of the
mixture of both methanesulfonates, rac-4a and rac-4b,
(13.5 g, 31.3 mmol) in dry DMF (200 mL) was added to
a suspension of NaH (1.54 g, 64.2 mmol) in dry DMF
(150 mL) at )78 ꢂC under an argon atmosphere. After
stirring at this temperature for 30 min, the mixture was
allowed to warm up to room temperature and stirring
was maintained at this temperature for an additional
2 h. Saturated aqueous NH4Cl was added and, after
stirring for a further 15 min, the solution was extracted
with ethyl acetate (3 · 200 mL). The combined organic
layers were washed with water (150 mL) and saturated
brine (2 · 100 mL). The organic phase was dried over
anhydrous MgSO4, filtered and the solvent was evapo-
rated in vacuo. Column chromatography of the result-
ing residue, using dichloromethane/ethyl acetate (7:3) as
eluent, provided compound rac-5 (5.11 g, 15.2 mmol) in
49% yield.
4.4. Synthesis of N-benzoyl-2-phenyl-7-azabicy-
clo[2.2.1]heptane-1-carboxylic acid, 6
4.4.1. rac-N-Benzoyl-2-phenyl-7-azabicyclo[2.2.1]heptane-
1-carboxylic acid, rac-6.. A 2 N solution of KOH in
methanol (12 mL) was added to rac-5 (300 mg,
0.9 mmol) and the reaction mixture was stirred at 40 ꢂC
for 7 h. After evaporation of the solvent, the remaining
residue was redissolved in water and followed by addi-
tion of 2 N HCl until pH 2. Then, compound rac-6
precipitated as a white solid that was separated by fil-
tration (277 mg, 0.86 mmol, 97% yield). IR (KBr) m
(cmꢀ1): 3100–2800, 2275, 1892, 1712, 1534, 1447; 1H
NMR (CDCl3) d (ppm): 16.00 (br s, 1H); 7.62–7.48 (m, 5
H); 7.37–7.21 (m, 5H); 4.50–4.47 (m, 1H); 3.57 (dd, 1H,
J ¼ 7:3 Hz, J ¼ 6:9 Hz); 2.51–2.35 (m, 2H); 2.17–2.10
(m, 2H); 2.04–1.88 (m, 1H); 1.74–1.65 (m, 1H). 13C
NMR (CDCl3) (ppm): 170.1, 168.9, 134.5, 131.5, 128.9,
128.8, 127.6, 127.6, 126.9, 78.4, 62.2, 52.9, 37.9, 36.3,
28.2. Anal. Calcd for C20H19NO3: C: 74.75, H: 5.96, N:
4.36; found C: 74.70, H: 6.01, N: 4.34.
4.4.2. (1S,2S,4R)- and (1R,2R,4S)-N-Benzoyl-2-phenyl-7-
azabicyclo[2.2.1]heptane-1-carboxylic acid, (1S,2S,4R)-6
and (1R,2R,4S)-6.. An identical procedure to that
described above was used for the conversion of
(1S,2S,4R)-5 or (1R,2R,4S)-5 (100 mg, 0.29 mmol) into
(1S,2S,4R)-6 or (1R,2R,4S)-6, respectively (86.2 mg,
0.27 mmol, 91% yield). Spectroscopic data were identical
to those reported for rac-6.
The whole procedure for the synthesis of rac-5 was
performed in a multigram scale. Therefore, starting
from 14.0 g (56.5 mmol) of the oxazolone 1, 5.11 g
(15.2 mmol) of a racemic mixture of compound rac-5
could be obtained through seven steps in 27% overall
yield.
(1S,2S,4R)-6: Mp 168 ꢂC. ½aꢁ ¼ +82.6 (c 0.5, CHCl3)
D
4.3.2. Resolution of rac-5.. HPLC resolution of rac-5
(1.2 g) dissolved in dichloromethane (4.8 mL) was car-
ried out by successive injections of 0.2 mL on a
150 · 20 mm ID column filled with 10-undecenoate/3,5-
dimethylphenylcarbamate of cellulose bonded on
allylsilica gel and using a 93:2:5 mixture of n-hexane/
chloroform/2-propanol as the eluent (flow rate
18 mL minꢀ1). A total of 24 injections were required with
one injection being performed every 10 min. Three sep-
arate fractions were collected. Evaporation of the first
fraction provided 517 mg of the enantiopure first eluted
enantiomer (1S,2S,4R)-5. The third fraction was further
submitted to recrystallisation from ethyl acetate in order
to reach a higher purity. This procedure supplied 520 mg
of the last eluted enantiomer (1R,2R,4S)-5, also in
(1R,2R,4S)-6: Mp 168 ꢂC. ½aꢁ ¼ )80.5 (c 0.5, CHCl3)
D
4.5. Synthesis of N-benzoyl-2-phenyl-7-azabicyclo-
[2.2.1]heptane-1-carbonyl-(S)-N0-isopropylphenylalanin-
amide, (1R,2R,4S)-(S)-7 and (1S,2S,4R)-(S)-8
L
-Phenylalanine isopropylamide hydrochloride (77.4
mg, 0.32 mmol), triethylamine (48.6 mg, 0.48 mmol) and
the coupling reagent BOP, (1H-benzotriazol-1-yl-
oxy)tris(dimethylamino)phosphonium hexaflurophos-
phate, (71 mg, 0.16 mmol) were added to a solution of
N-benzoyl-2-phenyl-7-azabicyclo[2.2.1]hepta-ne-1-car-
boxylic acid rac-6 (50 mg, 0.16 mmol) in acetonitrile

A. M. Gil et al. / Tetrahedron: Asymmetry 15 (2004) 811–819
817
(4 mL). The mixture was stirred for 30 h at room tem-
perature. After the completion of the reaction, the sol-
vent was removed under vacuum and the resulting
mixture was partitioned between water (10 mL) and
dichloromethane (20 mL). The organic layer was washed
with two more portions of water (2 · 10 mL) and, then,
dried over anhydrous MgSO4, filtered and evaporated
under vacuum to give a residue containing the diaste-
reomeric dipeptide analogues. They were fully separated
by silica gel column chromatography, eluting with ethyl
acetate/n-hexane (8:2), which provided 40.6 and 38.8 mg
of (1R,2R,4S)-(S)-7 and (1S,2S,4R)-(S)-8, respectively,
in 98% combined yield (79.4 mg, 0.16 mmol).
residue dissolved in water (30 mL). The solution was
extracted with dichloromethane (3 · 20 mL) and the
separated aqueous phase was evaporated to dryness.
Total removal of water was achieved by final lyophili-
sation. This procedure gave the amino acid hydrochlo-
rides (1S,2S,4R)-9 or (1R,2R,4S)-9, respectively, in 95%
yield (72 mg, 0.28 mmol). IR (nujol) (cmꢀ1): 3500–2500,
1
1737, 1603. H NMR (D2O) d (ppm): 7.48–7.26 (m, 5
H); 4.43 (dd, 1H, J ¼ 4:2 Hz, J ¼ 4:2 Hz); 3.69 (dd, 1H,
J ¼ 9:2 Hz, J ¼ 6:6 Hz); 2.52 (dd, 1H, J ¼ 13:9 Hz,
J ¼ 9:2 Hz); 2.40–2.15 (m, 4H); 2.12–1.97 (m, 1H). 13C
NMR (D2O) d (ppm): 173.3, 141.1, 131.4, 130.6, 130.4,
79.6, 60.6, 51.1, 39.3, 34.1, 28.7.
(1R,2R,4S)-(S)-7: White solid. Mp 162–163 ꢂC.
(1S,2S,4R)-9: White solid. Mp dec. ½aꢁ ¼ )23.8 (c 0.5,
D
½aꢁ ¼ )44.7 (c 0.36, CHCl3). IR (nujol) m (cmꢀ1): 3346–
H2O)
D
1
3208, 1661, 1643. H NMR (CDCl3) d (ppm): 7.75–7.72
(m, 2H); 7.60–7.48 (m, 3H); 7.24–7.12 (m, 8H); 7.09–
7.02 (m, 3H); 5.17 (d, 1H, J ¼ 7:7 Hz); 4.36 (dd, 1H,
J ¼ 4:8 Hz, J ¼ 4:8 Hz); 4.21 (dd, 1H, J ¼ 13:9 Hz,
J ¼ 7:3 Hz), 3.79 (m, 1H); 3.30 (dd, 1H, J ¼ 9:2 Hz,
J ¼ 5:5 Hz); 3.01 (dd, 1H, J ¼ 13:6 Hz, J ¼ 6:2 Hz); 2.91
(dd, 1H, J ¼ 13:6 Hz, J ¼ 7:3 Hz); 2.29–2.17 (m, 2H);
2.10–1.99 (m, 2H); 1.76–1.53 (m, 2H); 0.95 (d, 3H,
J ¼ 6:6 Hz); 0.85 (d, 3H, J ¼ 6:6 Hz). 13C NMR
(CDCl3) d (ppm): 173.2, 169.2, 168.8, 142.8, 137.5,
135.5, 131.6, 129.5, 128.6, 128.6, 128.3, 128.2, 128.1,
127.1, 126.5, 75.4, 63.0, 54.9, 53.1, 41.2, 38.8, 37.7, 32.7,
30.1, 22.3, 22.1. Anal. Calcd for C32H35N3O3: C: 75.41,
H: 6.92, N: 8.25; found C: 75.30, H: 6.90, N: 8.35.
(1R,2R,4S)-9: White solid. Mp dec. ½aꢁ ¼ +23.6 (c 0.5,
D
H2O)
4.7. Preparation of (1S,2R,4R)- and (1R,2S,4S)-7-azabi-
cyclo[2.2.1]heptane-1,2-dicarboxylic acid hydrochloride,
(1S,2R,4R)-11 and (1R,2S,4S)-11
4.7.1. Synthesis of (1S,2R,4R)- and (1R,2S,4S)-N-benzo-
yl-1-carbomethoxy-7-azabicyclo[2.2.1]heptane-2-carb-
oxylic acid, (1S,2R,4R)-10 and (1R,2S,4S)-10. . NaIO4
(3.8 g, 17.8 mmol) was added to a stirred solution of
(1S,2S,4R)-5 or (1R,2R,4S)-5 (300 mg, 0.89 mmol) in
31.5 mL of a 1:1:1.5 mixture of acetonitrile/carbon
tetrachloride/water. The resulting two-phase solution
was treated with RuCl3 (4 mg, 0.02 mmol) and stirred at
this temperature for 1 d. Water was added (10 mL), the
organic phase was separated and the aqueous phase was
extracted with dichloromethane (5 · 20 mL). The
organic extracts were combined, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. Purification
of the residue by flash column chromatography using
n-hexane/ethyl acetate (1:1) and 2% of acetic acid on
silica gel supplied the corresponding carboxylic acid
(1S,2R,4R)-10 or (1R,2S,4S)-10 in 45% yield (121 mg,
0.4 mmol). The spectroscopic data for each enantiomer
were the same as described in the literature for
(1S,2R,4R)-10.26
(1S,2S,4R)-(S)-8: White solid. Mp 157 ꢂC. ½aꢁ ¼ +92.6
D
(c 0.5, CHCl3). IR (nujol) m (cmꢀ1): 3429, 3325, 1676,
1
1660, 1639. H NMR (CDCl3) d (ppm): 7.70–7.67 (m,
2H); 7.54–7.50 (m, 1H); 7.49–7.28 (m, 7H); 6.94–6.88
(m, 2H); 6.83–6.74 (m, 2H); 5.42 (d, 1H, J ¼ 6:8 Hz);
4.39 (m, 1H); 3.94–3.82 (m, 2H); 3.37 (dd, 1H,
J ¼ 9:5 Hz, J ¼ 5:1 Hz), 2.84 (dd, 1H, J ¼ 13:6 Hz,
J ¼ 3:4 Hz); 2.57–2.49 (m, 1H); 2.44–2.34 (m, 1H); 2.16–
1.99 (m, 2H); 1.76–1.69 (dd, 1H, J ¼ 13:6 Hz,
J ¼ 6:1 Hz); 1.66–1.57 (m, 2H); 1.02 (d, 3H, J ¼ 6:6 Hz);
0.85 (d, 3H, J ¼ 6:6 Hz). 13C NMR (CDCl3) d (ppm):
175.3, 169.3, 168.2, 142.0, 135.8, 134.5, 132.2, 129.0,
128.7, 128.5, 128.4, 128.1, 127.6, 126.6, 75.1, 64.2, 53.5,
53.2, 41.2, 36.2, 35.9, 31.1, 29.8, 22.2, 21.9. Anal. Calcd
for C32H35N3O3: C 75.41, H 6.92, N 8.25; found C 75.48,
H 6.85, N 8.30.
(1S,2R,4R)-10: Mp 169 ꢂC. ½aꢁ ¼ )18.8 (c 0.5, CHCl3);
D
½aꢁ ¼ )24.1 (c 0.2, MeOH)46
D
An identical procedure to that described above was
applied to transform (1S,2S,4R)-6 (50 mg, 0.15 mmol)
into (1S,2S,4R)-(S)-8, which was obtained in 98% yield
(78 mg, 0.15 mmol). The spectroscopic data were the
same as described above.
(1R,2S,4S)-10: Mp 170 ꢂC. ½aꢁ ¼ +19.9 (c 0.5, CHCl3);
D
½aꢁ ¼ +22.3 (c 0.2, MeOH)
D
4.7.2. Synthesis of (1S,2R,4R)- and (1R,2S,4S)-7-azabi-
cyclo[2.2.1]heptane-1,2-dicarboxylic acid hydrochloride,
(1S,2R,4R)-11 and (1R,2S,4S)-11.. Aqueous 6 N HCl
(15 mL) was added to the amido esters (1S,2R,4R)-10 or
(1R,2S,4S)-10 (60 mg, 0.2 mmol) and the mixture was
heated under reflux for 32 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 dichloromethane (3 · 20 mL) and the
separated aqueous phase was evaporated to dryness.
4.6. Synthesis of (1S,2S,4R)- and (1R,2R,4S)-2-phenyl-7-
azabicyclo[2.2.1]heptane-1-carboxylic acid hydrochloride,
(1S,2S,4R)-9 and (1R,2R,4S)-9
Aqueous 6 N HCl (15 mL) was added to the amido
esters (1S,2S,4R)-5 or (1R,2R,4S)-5 (100 mg, 0.3 mmol)
and the mixture was heated under reflux for 48 h. The
solvent was, then, evaporated under vacuum and the

818
A. M. Gil et al. / Tetrahedron: Asymmetry 15 (2004) 811–819
Total removal of water was achieved by final lyophili-
sation. This procedure provided the corresponding
amino acid hydrochlorides (1S,2R,4R)-11 or (1R,
2S,4S)-11 in quantitative yield (44 mg, 0.2 mmol). The
spectroscopic data for each enantiomer were the same as
described in the literature for (1S,2R,4R)-11.26
the solvent under vacuum followed by column chro-
matography, using as eluent ethyl acetate/n-hexane
(6:4), gave pure aldehyde (1S,2R,4R)-13 or (1R,2S,4S)-
13, respectively, in 80% yield (238 mg, 0.83 mmol). The
spectroscopic data for each enantiomer were identical to
those described in the literature for (1S,2R,4R)-13.26
(1S,2R,4R)-11: Mp dec. ½aꢁ ¼ )28.0 (c 0.20, H2O)47
(1S,2R,4R)-13: Mp 108 ꢂC. ½aꢁ ¼ )7.1 (c 1.0, CHCl3)
D
[lit.27 mp 110 ꢂC. ½aꢁ ¼ )7.6 (cD1, CHCl3)]
D
(1R,2S,4S)-11: Mp dec. ½aꢁ ¼ +27.3 (c 0.20, H2O)
D
(1R,2S,4S)-13: Mp 108 ꢂC. ½aꢁ ¼ +7.1 (c 1.0, CHCl3)
D
4.8. Preparation of methyl (1S,2R,4R)- and (1R,2S,4S)-
N-benzoyl-2-hydroxymethyl-7-azabicyclo[2.2.1]heptane-
1-carboxylate, (1S,2R,4R)-12 and (1R,2S,4S)-12
Acknowledgements
To
a
cold ()17 ꢂC) solution of carboxylic acid
This work was carried out with the financial support of
ꢀ
(1S,2R,4R)-10 or (1R,2S,4S)-10 (100 mg, 0.33 mmol) in
THF (2 mL), were successively added dropwise a solu-
tion of n-methylmorpholine (36.7 mg, 0.36 mmol) in
THF (0.5 mL) and a solution of isobutylchloroformate
(IBCF) (45 mg, 0.33 mmol) in THF (0.5 mL). After
10 min, a solution of NaBH4 (38 mg, 0.99 mmol) in
water (1 mL) was added at once and the reaction mix-
ture is allowed to reach room temperature along 15 min.
Then, water was added (10 mL) and the reaction mixture
was extracted with dichloromethane (3 · 20 mL). The
combined organic phases were dried over MgSO4, fil-
tered and the solvent was evaporated in vacuo. The
resulting crude was purified by column chromatogra-
phy, using as eluent ethyl acetate/dichloromethane
(85:15), and the alcohols (1S,2R,4R)-12 or (1R,2S,4S)-
12 were respectively obtained in 88% yield (84 mg,
Ministerio de Ciencia y Tecnologıa and FEDER (pro-
ject PPQ2001-1834). A. M. Gil would like to thank
CSIC for an I3P grant.
References and notes
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D
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oxylate, (1S,2R,4R)-13 and (1R,2S,4S)-13
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1,2-benziodoxol-3(1H)-one, (399 mg, 0.94 mmol) in dry
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~
ꢀ
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~
ꢀ
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46. NOTE: New polarimetry measurements on two different
samples of (1S,2R,4R)-10, prepared following the proce-
dure described in Ref. 26, led to the following values:
½aꢁ ¼ )18.8 (c 0.5, CHCl3); ½aꢁ ¼ )24.2 (c 0.2, MeOH).
~
ꢀ
27. Gil, A. M.; Bunuel, E.; Dıaz-de-Villegas, M. D.; Cativiela,
C. Tetrahedron: Asymmetry 2003, 14, 1479–1488.
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632.
D
D
Polarimetry data on these new samples are completely
different from the one that we previously described in 26
and perfectly agree with the values obtained for samples of
(1S,2R,4R)-10 prepared according to the resolution pro-
ꢀ
29. Cativiela, C.; Dıaz-de-Villegas, M. D.; Jimenez, A. I.;
Lopez, P.; Marraud, M.; Oliveros, L. Chirality 1999, 11,
ꢀ
ꢀ
cedure described in this report [½aꢁ ¼ )18.8 (c 0.5,
D
583–590.
ꢀ
CHCl3); ½aꢁ ¼ )24.1 (c 0.2, MeOH)].
D
ꢀ
ꢀ
30. Alıas, M.; Cativiela, C.; Jimenez, A. I.; Lopez, P.;
Oliveros, L.; Marraud, M. Chirality 2001, 13, 48–55.
47. NOTE: New polarimetry measurements on two different
samples of (1S,2R,4R)-11, prepared according to the
asymmetric procedure described in Ref. 26, led to the
ꢀ
ꢀ
31. Jimenez, A. I.; Lopez, P.; Oliveros, L.; Cativiela, C.
Tetrahedron 2001, 57, 6019–6026.
following value: ½aꢁ ¼ )27.4 (c 0.2, H2O). Polarimetry
D
ꢀ
ꢀ
32. Royo, S.; Lopez, P.; Jimenez, A. I.; Oliveros, L.; Cativiela,
C. Chirality 2002, 14, 39–46.
data for these new samples are different from the one that
we previously described in 26 and agree with the value
obtained for the samples of (1S,2R,4R)-11 prepared
according to the resolution procedure described in this
ꢀ
33. Jimenez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M.
J. Am. Chem. Soc. 1998, 120, 9452–9459.
ꢀ
34. Jimenez, A. I.; Vanderesse, R.; Marraud, M.; Aubry, A.;
Cativiela, C. Tetrahedron Lett. 1997, 38, 7559–7562.
report [½aꢁ ¼ )28.0 (c 0.2, H2O)].
D
48. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156–
ꢀ
ꢀ
35. Jimenez, A. I.; Cativiela, C.; Parıs, M.; Peregrina, J. M.;
Avenoza, A.; Aubry, A.; Marraud, M. Tetrahedron Lett.
1998, 39, 7841–7844.
4158.
49. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.