New enantiopure 7-azanorbornane β-substituted prolines by S N2 displacements at the Cγ of the side chain

Article abstract of DOI:10.1016/j.tetasy.2005.08.003

Continuing our work on building new β-substituted prolines in enantiomerically pure form as new surrogates to be incorporated into model peptides, we describe functional group conversions and carbon-carbon bond forming reactions by S_N2 displace

Full text of DOI:10.1016/j.tetasy.2005.08.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3115–3123
New enantiopure 7-azanorbornane b-substituted prolines
by SN2 displacements at the Cc of the side chain
a
a
b
´
´
Ana M. Gil, Ester Oru´s, Veronica Lopez-Carrillo,
Elena Bunuelb,* and Carlos Cativielaa,*
˜
aDepartamento de Quı´mica Orga´nica, ICMA, Universidad de Zaragoza—CSIC, 50009 Zaragoza, Spain
bDepartamento de Quı´mica Orga´nica, Universidad Auto´noma de Madrid, 28049 Madrid, Spain
Received 27 July 2005; accepted 1 August 2005
Abstract—Continuing our work on building new b-substituted prolines in enantiomerically pure form as new surrogates to be incor-
porated into model peptides, we describe functional group conversions and carbon–carbon bond forming reactions by SN2 displace-
ments at the c-position of the a-amino acid side chain of an azanorbornane derivative. This work extends efforts on the elaboration
of the side arm at carbon C2 of the 7-azabicyclo[2.2.1]heptane core.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
this sequence by an analogue of azanorbornane struc-
ture (Fig. 1).16
Several b-substituted prolines have been synthesised to
serve as amino acid chimeras, in which the functional
groups of the amino acid side chain are combined
with the conformational restrictions characteristic of
the cyclic amino acid residue.1 Replacement of the nat-
ural amino acids in peptides for such proline–a-amino
acid chimeras has led to a better understanding of the
bioactive conformations.2–10 Additionally, b-alkylpro-
line analogues have served for the development of
enzyme inhibitors,11,12 as well as peptidomimetics exhib-
iting improved bioactivity and greater metabolic
stability.5,12
O
Ph
N
O
H
Ph
N
N
H
O
Ph
Figure 1. Structure of (1S,2S,4R)-N-benzoyl-2-phenyl-7-azabi-
cyclo[2.2.1]heptane-1-carbonyl-(S)-N0-isopropylphenylalaninamide.
In this proline surrogate, the flexibility of the pyrrolidine
ring was frozen by linking the a- and d-carbons through
an ethylene bridge, and an additional phenyl substituent,
which can interact with the backbone both sterically and
electronically, incorporated at the b-position. This result
provides evidence that the bicyclic proline system
exhibits a higher propensity for bI-folding than proline
itself. Several factors contribute to the stabilisation
of the type I b-turn observed in the crystalline structure
of (1S,2S,4R)-N-benzoyl-2-phenyl-7-azabicyclo[2.2.1]-
heptane-1-carbonyl-(S)-N0-isopropylphenylalaninamide
(Fig. 1).16
We are currently involved in a research project devoted
to determining the conformational preferences of con-
strained analogues of proteinogenic amino acids when
incorporated into a peptide chain. In this context, we
have evaluated the relative stability of the bI- and bII-
turn conformations in model peptides RCO-L-Pro-L-
Phe-NHR0, in which phenylalanine has been replaced
by different constrained derivatives.13–15 Recently, we
reported the first results on the structural consequences
arising from the replacement of the proline residue in
Promising results in this area have focussed our interest
on the synthesis of new 7-azanorbornane proline–a-ami-
no acid chimeras as a source of surrogates for the study
of structural peculiarities induced by their introduction
in model peptides.
*
Corresponding authors. Tel./fax: +34 976 761210; e-mail addresses:
elena.bunnuel@uam.es; cativiela@unizar.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.003

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A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
2. Results and discussion
85% yield. A higher efficiency was obtained by treatment
of the alcohol with CBr4 and triphenylphosphine
(Scheme 1), which gave compound 6 in very good yield
(92%).
After optimisation of the procedure for the synthesis of
the key intermediate methyl (1S,2R,4R)-N-benzoyl-2-
[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]-
heptane-1-carboxylate 2,17–19 we were able to scale up
the process and proceed to undertake the preparation
of this enantiomerically pure product on a 40 gram
scale. This process involved seven stereocontrolled steps
and gave an overall yield of 30% from a 95:5 mixture of
the two geometric isomers (Z/E) of the chiral oxazolone
1. From intermediate 2, the transformation of the 1,3-
dioxolane ring into a formyl group was easily achieved
with aldehyde 3 being obtained in 88% yield by using
periodic acid according to the procedure described in
the literature (Scheme 1).18 Subsequent reduction of
aldehyde (1S,2R,4R)-3 was simply carried out by treat-
ment with NaBH4 in a methanol/water mixture and pro-
vided the primary alcohol (1S,2R,4R)-4 (Scheme 1) in
almost quantitative yield (97%).
Tosylate 7 was synthesised by treatment of the alcohol
with tosyl chloride and triethylamine in dichlorometh-
ane and, in this way, derivative 7 (Scheme 1) was iso-
lated in low yield (44%). A similar procedure, using
mesyl chloride instead of tosyl chloride, readily led to
isolated mesylate 8 (Scheme 1) in excellent yield (98%).
2.2. Functionalisation and carbon–carbon bond formation
reactions at the Cc of the a-amino acid side chain: study
of SN2 displacements
Given the ready availability of mesylate 8 and its gener-
ally good behaviour as a leaving group, we initially
focussed our attention on a detailed study into SN2
displacements of this compound (Scheme 2).
In order to explore the versatility of the SN2 reaction at
the c-position, the transformation of the hydroxyl group
into a good leaving group was initially tested and then
the displacement by different nucleophiles attempted
on the most suitable derivatives.
O
O
Ph
N
Ph
N
MNu
MLg
+
Nu
Lg
MeOOC
MeOOC
6-8
9-13
2.1. Introduction of leaving groups at the Cc of the
a-amino acid side chain
6: Lg = Br
7: Lg = OTs
8: Lg = OMs
9: Nu = H
12: Nu =CN
13: Nu = N3
10: Nu = SMe
11: Nu = SBn
Treatment of alcohol (1S,2R,4R)-4 with PCl5/chloro-
form or SOCl2/pyridine was tried, but chloride 5 could
not be obtained under any of these reaction conditions.
However, the use of triphenylphosphine and dry carbon
tetrachloride as the halide source gave 5 in 96% yield
(Scheme 1).
Scheme 2. SN2 study.
The exchange of the leaving group for hydride was
achieved from mesylate 8 by treatment with sodium
borohydride in HMPA. This provided compound 9 in
good yield (79%), although it should be noted that an
additional portion of the hydride had to be added to
achieve complete consumption of the starting material
The introduction of bromide as a leaving group was
achieved by treatment of (1S,2R,4R)-4 with N-bromo-
succinimide, which provided bromo derivative 6 in
O
O
O
H
Ph
N
Ph
N
ref 17-19
ref 18
O
O
N
CHO
O
Ph
1 95:5 Z/E
O
MeOOC
MeOOC
(1S,2R,4R)-2
O
ca 40 g
30% from 1
(1S,2R,4R)-3
a
O
O
Ph
N
Ph
N
b
Lg
OH
MeOOC
MeOOC
(1S,2R,4R)-4
5-8
5: Lg = Cl 7: Lg = OTs
6: Lg = Br
8: Lg = OMs
Scheme 1. Synthesis of the derivatives containing a Cc leaving group, 5–8. Reagents and conditions: (a) NaBH4, MeOH/H2O, 0 ꢁC, 50 min (97%).
(b) (i) PPh3, CCl4, reflux, 48 h (5, 96%); (ii) PPh3, CBr4, 35 ꢁC, 24 h (6, 92%); (iii) TsCl, Et3N, CH2Cl2, from 0 ꢁC to reflux, 24 h (7, 44%); (iv) MsCl,
Et3N, CH2Cl2, from 0 ꢁC to rt, 4 h (8, 98%).

A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
3117
(Table 1, entry 1). Nucleophilic substitution on mesylate
8 by the thiomethoxide ion was also achieved, but this
reaction was not reproducible and the isolated yield of
compound 10 (Table 1, entry 2) never surpassed 60%.
The replacement of the mesylate by the benzylthiolate
group was also successful and benzylthioether 11 (Table
1, entry 3) was isolated in 70% yield. This route provided
a conveniently protected 7-azanorbornane cysteine
analogue.
Table 1. Nucleophilic displacements on 6 and 8
Entry Lg
MNu (equiv)
Temp Time Compound Yielda
(ꢁC)
Figure 2. Structure of 14.
1
2
3
4
5
6
7
8
OMs NaBH4 [12+8] 70
2 d
9
79
<60
70
<28
83
75
87
88
77
OMs NaSCH3 [3]
OMs NaSBn [2]
OMs KCN [5]b
OMs NaN3 [2]
OMs LiBr [4+4]
60
60
90
100
2 d 10
5 d 11
1 d 12
1 d 13
The substitution with mesylate 8 did not produce com-
pletely satisfactory results due to low yields, long reac-
tion times and, in some cases, lack of reproducibility.
For these reasons, the study was repeated on bromo
derivative 6. This compound, which contained a bro-
mide that is considered a good leaving group, could also
be obtained in very high yield from alcohol (1S,2R,4R)-
4.
Reflux 6 d
6
9
Br
Br
Br
Br
Br
NaBH4 [12]
NaSCH3 [3]
NaSBn [2]
KCN [5]c
70
60
60
90
90
12 h
28 h 10
3 h 11
1 d 12
5 h 13
9
10
11
76
92
NaN3 [2]
The solvent used was dry DMF except for entries 1 and 7 where
HMPA was the solvent of choice.
a Yield of isolated product.
Fortunately, displacements on bromide 6 were much
better in all cases than the corresponding reactions with
8. Substitution by hydride (Table 1, entry 7) was more
easily achieved on the bromide, with a shorter reaction
time and lower reagent/starting material ratio required,
while the reaction gave derivative 9 in higher yield
(87%). Substitutions on bromide derivative 6 also
allowed the isolation of derivatives 10 and 11 in better
yields (88% and 77%, respectively) and much shorter
reaction times (Table 1, entries 8 and 9) than the same
substitutions on mesylate 8. Displacement of the bro-
mide group on 6 by the cyanide ion also proceeded
much more efficiently and, in the absence of the two
aforementioned additives, gave cyano derivate 12 in
61% yield. Addition of a catalytic amount of 18-
crown-6 ether led to the best result and this modification
provided, from bromide 6, cyano derivative 12 in good
yield (76%) (Table 1, entry 10). Once again, a better re-
sult was obtained in the substitution of azide on bro-
mide 6 and this allowed the isolation of azide 13 in
excellent yield (92%) with a marked decrease in the reac-
tion time (Table 1, entry 11).
b CsF (4 equiv) and 18-crown-6 ether (cat) were also used as additives.
c 18-Crown-6 ether (cat) was added.
On the other hand, reaction of mesylate 8 with the cya-
nide ion proved disappointing. The reaction with
sodium cyanide led to complex mixtures that could
not be characterised, even when using a phase transfer
catalyst [Bn(Et)3NH4Cl] or in the presence of sodium io-
dide. In an attempt to promote carbon–carbon bond
formation with cyanide ion, we systematically varied
the solvent and additives such as crown ether and cae-
sium fluoride.20 The use of DMF as solvent, CsF and
18-crown-6 ether made the process slightly more favour-
able and the substitution product 12 (Scheme 2) was iso-
lated for the first time—albeit in very poor yield (<28%)
(Table 1, entry 4). The substitution product could not be
detected when the solvent was changed from DMF to
toluene, which has been described as the solvent of
choice for other azabicyclic substrates.20 Under these
reaction conditions, the major product 14, proceeding
from the nucleophilic attack of the cyanide ion on the
methyl ester and subsequent cyclisation by substitution
of the mesylate, could be isolated and its structure unde-
niably determined by X-ray analysis (Fig. 2).
2.3. Transformations of substitution products
The introduction of different functional groups contain-
ing nitrogen at the Cc was also investigated. We decided
to take advantage of the availability of azide 13, ob-
tained as an SN2 substitution product, and explore its
potential reactivity.
Substitution by cyanide on tosylate 7 was also tested and
gave rise to very low yields (<28%). However, introduc-
tion of the azide ion into mesylate 8 was acceptably
achieved by treatment with sodium azide in DMF to
give azide 13 in good yield (83%) (Table 1, entry 5).
Simple hydrogenation of 13 using Pd/C at 30 ꢁC and
atmospheric pressure, cleanly yielded an unstable amine
derivative 15 (Scheme 3).
In addition, the mesylate leaving group was exchanged
for bromide in moderate yield by treatment of 8 with
lithium bromide and, in this way, bromide 6 was
obtained in 75% yield (Table 1, entry 6).
Given the lack of stability of amine 15, and with the aim
of facilitating the preparation and isolation of a stable

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A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
O
O
O
Ph
N
Ph
N
Ph
N
a
d
N3
c
NO2
NH2
MeOOC
MeOOC
MeOOC
15
13
18
O
O
b
Ph
N
Ph
N
MeOOC
O
COOMe
OtBu
N
N
N
MeOOC
MeOOC
H
N
16
17
Scheme 3. Transformations on the azide 13. Reaction conditions: (a) 10% Pd/C, H2, MeOH, 30 ꢁC, 3 h. (b) 10% Pd/C, H2, Boc2O, EtOAc, rt, 36 h
(88%). (c) dimethylacetylenedicarboxylate, EtOH, reflux, 24 h (92%). (d) (i) 10% Pd/C, H2, MeOH, 30 ꢁC, 3 h; (ii) MCPBA, 1,2-dichloroethane,
75 ꢁC, immediate (31%).
amine derivative for later manipulation, direct protec-
tion of the amine function with a suitable group, such
as Boc, was tried from azide 13. Both the reduction
and protection steps could be performed with hydro-
gen-presaturated Pd/C21 in the presence of di-tert-butyl-
dicarbonate (Boc2O). Under these conditions,
derivative 16 (Scheme 3) was isolated in good yield
(88%).
aqueous 6 M HCl under reflux to provide enantiomeri-
cally pure proline–a-amino acid chimeras in quantitative
or nearly quantitative yields (Scheme 4). The resulting
amino acids 19–21, which can also be considered as
(2S,3R)-3-methylproline, (2S,3R)-3-methylthiomethyl-
proline and (2S,3S)-3-carboxymethylproline analogues,
respectively, were fully characterised. These amino acids
can also be considered as a combination of proline with
L-valine, L-methionine and L-glutamic acid with a 7-aza-
norbornane skeleton.
In addition, other one-pot conversions of azides into
Boc-protected amines were assessed. For example, treat-
ment of azide 13 with Et3SiH (2.0 equiv), Pd(OH)2/C
(10 mg/mmol) and Boc2O (1.5 equiv) in EtOH22 also
led to the corresponding Boc-protected amine, albeit
in low yield. On the other hand, the formation of a Stau-
dinger intermediate (phosphazenes from azides and ter-
tiary phosphines) shows it to be a convenient method for
generating a nucleophilic amine from an azide.23,24 In
our case, according to the procedure described by Vilar-
rasa et al.,25 the use of triphenylphosphine (1.1 equiv)
and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonit-
rile (Boc-ON, 1.1 equiv) enabled us to directly obtain
the desired Boc-amine 16 in moderate yield from azide
13 (68%).
O
H2Cl
N
Ph
N
R'
R
HOOC
MeOOC
9,10,12
19-21
9: R = H
10: R = SMe
12: R = CN
19: R' = H
20: R' = SMe
21: R' = COOH
Scheme 4. Synthetic route to enantiomerically pure 7-azanorbornane
proline–a-amino acid chimeras, 19–21. Reaction conditions: 6 M HCl,
reflux, 24 h (19), 30 h (20), or 48 h (21).
In order to demonstrate the synthetic versatility of the
azide group in this 7-azanorbornane skeleton, we pro-
ceeded to carry out transformations into other interest-
ing functional groups. For example, derivative 13 was
treated with dimethylacetylenedicarboxylate.26 The
azide underwent 1,3-dipolar cycloaddition very readily
to give triazol derivative 17 (Scheme 3) in excellent yield
(92%).
3. Conclusion
Manipulation of the dioxolane moiety in the key
intermediate methyl (1S,2R,4R)-N-benzoyl-2-[(S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]heptane-
1-carboxylate has made it possible to introduce a
b-hydroxymethyl group. This functionalisation gener-
ates a huge range of possibilities for the preparation
of a very special type of amino acid where the rigidity
provided by the azabicyclic skeleton is combined
with the presence of a b-substituent, which mimics
the a-amino acid side chain. Further studies on the
structural consequences arising from the replacement
of the proline residue by analogues of bicyclic struc-
ture into model peptides are currently underway
The transformation of the azide function into a nitro
group was also achieved by means of a simple two-step
procedure.27 Reduction of the azide to the amine by sim-
ple hydrogenation with Pd/C at 30 ꢁC was followed by
the addition of MCPBA to the amine solution. This sim-
ple procedure supplied the nitro derivative 18 in 31%
yield (Scheme 3).
Finally, other compounds proceeding from the SN2 dis-
placements, such as 9, 10 and 12, were treated with

A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
3119
and the results of this study will be published in due
course.
UK [fax: +44(0)-1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
4.3. Methyl (1S,2R,4R)-N-benzoyl-2-hydroxymethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 4
4. Experimental section
4.1. General methods
Over a solution of methyl (1S,2R,4R)-N-benzyl-2-form-
yl-7-azabicyclo[2.2.1]heptane-1-carboxylate 3 (3 g, 10.4
mmol) in methanol (240 mL) at 0 ꢁC, a suspension of
NaBH4 (195 mg, 5 mmol) in water (36 mL) was slowly
added. When the reaction was finished, after 50 min
under stirring at the same temperature, the resulting
mixture was neutralised by an aqueous solution
of 0.5 M hydrochloric acid and the methanol was evap-
orated under vacuum. Then, water was added (100 mL)
and the crude extracted with dichloromethane
(3 · 100 mL). The organic layers were combined, dried
over anhydrous magnesium sulfate, filtered and evapo-
rated under vacuum. The resulting mixture was
purified by column chromatography, using 9:1 ether/
ethanol mixture as an eluent. In this way, compound
4 was obtained as a white solid in 97% yield
(2.91 g, 10 mmol). Mp 91–93 ꢁC. [a]D = ꢀ40.7 (c 1.0,
CHCl3) {lit.30 Mp 91–93 ꢁC. [a]D = ꢀ40.7 (c 1.0,
CHCl3)}.
Melting points were determined using a Buchi SMP-20
¨
apparatus. IRspectra were registered on a Mattson
Genesis FTIRspectrophotometer; mmax is given for
1
the main absorption bands. H and 13C NMRspectra
were recorded on a Varian Unity-300 or a Bruker
ARX-300 apparatus at room temperature, using the
residual solvent signal as the internal standard; chemi-
cal shifts (d) are quoted in ppm, and coupling con-
stants (J) measured in Hertz. Optical rotations were
measured in a cell with a 10 cm path length at 25 ꢁC
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 Polygramꢂ sil G/
UV254 precoated silica gel polyester plates and the
products were visualised under UV light (254 nm),
ninhydrin, anisaldehyde or phosphomolybdic acid
developers. Column chromatography was performed
using silica gel (Kieselgel 60). (1S,2R,4R)-N-Benzoyl-
2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]-
heptane-1-carboxylate 2 was obtained according to the
literature procedure.17,19
4.4. Methyl (1S,2R,4R)-N-benzoyl-2-chloromethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 5
To a solution of (1S,2R,4R)-N-benzoyl-2-hydroxy-
methyl-7-azabicyclo[2.2.1]heptane-1-carboxylate (100
mg, 0.35 mmol) in dry carbon tetrachloride 4 (10 mL)
was added triphenylphosphine (183 mg, 0.7 mmol).
The reaction mixture was refluxed for two days under
argon atmosphere. The solvent was then evaporated
under vacuum and the resulting mixture was chromato-
graphed. The column chromatography (hexane/ethyl
acetate, 1:1) provided the product in 96% yield
(103 mg, 0.33 mmol). Colourless oil. [a]D = ꢀ84.2 (c
4.2. X-ray diffraction
The X-ray diffraction data were collected at room
temperature on a Bruker Smartapex CCD Area diffrac-
tometer, using graphite-monochromated Mo-Ka radia-
˚
tion (k = 0.71073 A). The structure was solved by
direct methods using SHELXS 9728 and refinement
was performed using SHELXL 9729 by the full-matrix
least-squares technique with anisotropic thermal factors
for heavy atoms.
1.0, CHCl3). IR(neat) m (cmꢀ1): 3650–3461, 1741,
1
1657, 1644; H NMR(CDCl ) d (ppm): 7.71–7.68 (m,
3
2H), 7.53–7.48 (m, 1H), 7.43–7.39 (m, 2H), 4.24 (dd,
1H, J = 4.8 Hz, J = 4.8 Hz), 3.95 (dd, 1H,
J = 10.9 Hz, J = 5.5 Hz), 3.80 (s, 3H), 3.44 (dd, 1H,
J = 10.6 Hz, J = 10.4 Hz), 2.48–2.39 (m, 2H), 1.93–
Colourless single crystals of 14 were obtained by slow
evaporation from an ether solution. Reflections were
measured in the x/2h-scan mode in the 2h range 2.02–
25.03ꢁ. Hydrogen atoms were located by calculation
and affected by an isotropic thermal factor fixed to 1.2
times the Ueq of the carrier atom (1.5 for the methyl pro-
tons). Crystallographic data: orthorhombic, P212121;
a = 7.0710(2) A; b = 12.3060(3) A, c = 17.6070(4) A;
Z = 4; d (calcd) = 1.293 g cmꢀ3; reflections collected/
independent: 8880/2689 [R(int) = 0.0414]; data/parame-
ters: 2698/201; final R indices [I > 2r(I)]: R1 = 0.0370,
wR2 = 0.0801; final R indices (all data): R1 = 0.0470,
wR2 = 0.0848.
1.72 (m, 4H), 1.58–1.51 (m, 1H); 13C NMR(CDCl ) d
3
(ppm): 173.6, 169.9, 134.3, 131.9, 128.8, 128.4, 69.7,
61.7, 52.3, 48.7, 47.5, 37.3, 31.7, 30.3.
˚
˚
˚
4.5. Methyl (1S,2R,4R)-N-benzoyl-2-bromomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 6
Triphenylphosphine (1.1 g, 4.14 mmol) was slowly
added, under argon atmosphere, over a 0 ꢁC chilled
solution of (1S,2R,4R)-N-benzoyl-2-hydroxymethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate 4 (400 mg, 1.38
mmol) and carbon tetrabromide (1.4 g, 4.14 mmol) in
dry dichloromethane (20 mL). After the addition, the
reaction mixture was allowed to warm up to room
temperature followed by heating at 35 ꢁC for one day.
Then, the mixture was chilled at room temperature
and the solid filtered and washed with dichloromethane.
Crystallographic data (excluding structure factors) for
the structure of compound 14 have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 279067. Copies of
the data can be obtained, free of charge, via
www.ccdc.cam.uk/conts/retrieving.html or on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ,

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A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
The filtrate was concentrated under vacuum and the
residue purified by column chromatography, using 7:3
mixture of hexane/ethyl acetate as an eluent, which
allowed the isolation of compound 6 in 92% yield
(447 mg, 1.27 mmol). Colourless oil. [a]D = ꢀ92.3 (c
were dried with anhydrous magnesium sulfate and fil-
tered. The oil resulting from the complete evaporation
of the solvent under vacuum was purified by column
chromatography, using 8:2 ether/dichloromethane
mixture as an eluent. This procedure provided product
8 in 98% yield (1.66 g, 4.52 mmol). Colourless oil.
1
1.0, CHCl3). IR(neat) m (cmꢀ1): 1744, 1658, 1642; H
NMR(CDCl ) d (ppm): 7.69–7.66 (m, 2H), 7.50–7.46
[a]D = ꢀ32.4 (c 0.5, CHCl3). IR(neat)
m (cmꢀ1):
3
1
(m, 1H), 7.42–7.37 (m, 2H), 4.21 (dd, 1H, J = 4.8 Hz,
J = 4.5 Hz), 3.84 (dd, 1H, J = 9.8 Hz, J = 4.8 Hz),
3.77 (s, 3H), 3.30 (dd, 1H, J = 10.6 Hz, J = 9.8 Hz),
2.55–2.47 (m, 1H), 2.44–2.35 (m, 1H), 1.90 (dd, 1H,
J = 12.1 Hz, J = 8.3 Hz), 1.83–1.73 (m, 3H), 1.55–1.48
(m, 1H); 13C NMR(CDCl 3) d (ppm): 173.5, 169.7,
134.3, 131.8, 128.7, 128.4, 70.3, 61.7, 52.2, 48.7, 38.8,
37.1, 32.0, 30.2.
1737, 1651; H NMR(CDCl ) d (ppm): 7.72–7.67 (m,
3
2H), 7.55–7.48 (m, 1H), 7.46–7.38 (m, 2H), 4.53 (dd,
1H, J = 10.1 Hz, J = 7.6 Hz), 4.24 (dd, 1H, J =
4.8 Hz, J = 4.5 Hz), 4.16 (dd, 1H, J = 9.8 Hz,
J = 7.1 Hz), 3.81 (s, 3H), 3.03 (s, 3H), 2.59–2.38 (m,
2H), 1.92–1.68 (m, 4H), 1.64–1.51 (m, 1H); 13C
NMR(CDCl 3) d (ppm): 173.6, 169.8, 134.1, 131.9,
128.7, 128.4, 70.6, 68.5, 61.4, 52.4, 45.4, 37.3, 34.6,
31.3, 30.4.
4.6. Methyl (1S,2R,4R)-N-benzoyl-2-(4-methylphen-
yl)sulfonyloxymethyl-7-azabicyclo[2.2.1]heptane-
1-carboxylate, 7
4.8. Methyl (1S,2R,4R)-N-benzoyl-2-methyl-7-aza-
bicyclo[2.2.1]heptane-1-carboxylate, 9
Over a solution of methyl (1S,2R,4R)-N-benzoyl-
2-hydroxymethyl-7-azabicyclo[2.2.1]heptane-1-carboxy-
late 4 (50 mg, 0.17 mmol) in dry dichloromethane
(5 mL) at 0 ꢁC and under argon atmosphere was added
triethylamine (35.5 mg, 0.35 mmol) followed by p-tolu-
enesulfonyl chloride (66.5 mg, 0.35 mmol). The reac-
tion mixture was allowed to warm up to room
temperature and stirred for an additional 24 h under
reflux. The solvent was evaporated under vacuum
and the resulting residue was redissolved in dichloro-
methane (10 mL) and washed with water (3 · 5 mL).
The organic layer was dried with anhydrous magne-
sium sulfate, filtered and evaporated under vacuum.
The resulting oil was purified by column chromatogra-
phy, using 1:1 ethyl acetate/hexane mixture as an elu-
ent. This procedure provided product 7 in 44% yield
(33.14 mg, 0.07 mmol). White solid. Mp 49 ꢁC.
[a]D = ꢀ6.7 (c 0.4, CHCl3). IR(nujol) m (cmꢀ1): 1737,
1651; 1H NMR(CDCl 3) d (ppm): 7.78 (d, 2H,
J = 8.1 Hz), 7.61 (d, 2H, J = 7.0 Hz), 7.52–7.43 (m,
1H), 7.42–7.29 (m, 4H), 4.39 (dd, 1H, J = 9.6 Hz,
J = 7.3 Hz), 4.17 (dd, 1H, J = 4.4 Hz, J = 4.4 Hz),
3.95 (dd, 1H, J = 9.6 Hz, J = 8.8 Hz), 3.72 (s, 3H),
2.51–2.28 (m, 5H), 1.86–1.43 (m, 5H); 13C NMR
(CDCl3) d (ppm): 173.4, 169.6, 144.8, 134.2, 132.9,
131.9, 129.9, 128.7, 128.4, 127.9, 71.2, 68.6, 61.5,
52.3, 45.1, 35.0, 31.7, 30.2, 21.7.
A solution of methyl (1S,2R,4R)-N-benzoyl-2-bromo-
methyl-7-azabicyclo[2.2.1]heptane-1-carboxylate 6 (100
mg, 0.28 mmol) and NaBH4 (31.8 mg, 0.84 mmol) in
HMPA (4 mL) was heated at 70 ꢁC for 12 h. Then, the
solution was allowed to cool down to room temperature
and the resulting mixture diluted with water (20 mL).
The mixture was extracted with dichloromethane
(3 · 10 mL). The combined organic layers were washed
with water (10 mL), dried over anhydrous magnesium
sulfate, filtered and the solvent was removed under vac-
uum. Finally, the residue was chromatographed, using
9:1 dichloromethane/ethyl acetate as an eluent. Com-
pound 9 was isolated in 87% yield (66.5 mg, 0.24 mmol).
White solid. Mp 86 ꢁC. [a]D = ꢀ94.1 (c 1.0, CHCl3). IR
(nujol) m (cmꢀ1): 1746, 1647; 1H NMR(CDCl 3) d (ppm):
7.74–7.70 (m, 2H), 7.52–7.46 (m, 1H), 7.43–7.37 (m,
2H), 4.17 (dd, 1H, J = 4.8 Hz, J = 4.8 Hz), 3.78 (s,
3H), 2.40 (ddd, 1H, J = 12.1 Hz, J = 12.1 Hz,
J = 4.4 Hz), 2.22–2.10 (m, 1H), 1.89–1.75 (m, 2H),
1.70–1.44 (m, 3H), 1.09 (d, 3H, J = 6.9 Hz); 13C NMR
(CDCl3) d (ppm): 174.1, 170.9, 134.9, 131.6, 128.8,
128.2, 70.3, 62.2, 51.7, 41.6, 39.5, 30.7, 30.6, 19.9. Anal.
Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.48; H, 6.92; N, 4.98.
4.9. Methyl (1S,2R,4R)-N-benzoyl-2-methylthiomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 10
4.7. Methyl (1S,2R,4R)-N-benzoyl-2-methylsulfonyl-
oxymethyl-7-azabicyclo[2.2.1]heptane-1-carboxylate, 8
Over a solution of methyl (1S,2R,4R)-N-benzoyl-2-bro-
momethyl-7-azabicyclo[2.2.1]heptane-1-carboxylate
6
(100 mg, 0.27 mmol) in dry DMF (8 mL), NaSCH3
(57.0 mg, 0.81 mmol) was added under an argon atmo-
sphere. The resulting solution was heated at 60 ꢁC for
18 h. Then, the reaction mixture was allowed to cool
down to room temperature and the solvent was evapo-
rated under vacuum. The resulting crude mixture was
dissolved in a water/dichloromethane mixture. The
aqueous layer was washed with dichloromethane
(3 · 10 mL), the combined organic layers were dried
over anhydrous magnesium sulfate, filtered and the sol-
vent was removed under vacuum. A column chromato-
graphy, using a 6:4 mixture of hexane/ethyl acetate,
provided the thioether derivative 10 in 88% yield
Over a solution of methyl (1S,2R,4R)-N-benzoyl-2-
hydroxymethyl-7-azabicyclo[2.2.1]heptane-1-carboxyl-
ate 4 (1.34 g, 4.65 mmol) in dry dichloromethane
(50 mL) under argon at 0 ꢁC was added triethylamine
(941.3 mL, 9.32 mmol) followed by methanesulfonyl
chloride (1.06 g, 9.32 mmol). The reaction mixture
was allowed to warm up to room temperature and
stirred for an additional 4 h until the total consump-
tion of the starting material. Then, the solvent was
evaporated under vacuum and the resulting residue
redissolved in dichloromethane (100 mL) and extracted
with water (3 · 50 mL). The combined organic layers

A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
3121
(76.6 mg, 0.24 mmol). Colourless oil. [a]D = ꢀ90.0 (c
hexane/ethyl acetate as an eluent, supplied the cyano-
methyl derivative 12 in 76% yield (63.0 mg, 0.22 mmol).
Colourless oil. [a]D = ꢀ60.2 (c 0.3, CHCl3). IR(nujol)
m (cmꢀ1): 3060–2854, 2246, 1745, 1648; 1H NMR
(CDCl3) d (ppm): 7.70–7.68 (m, 2H), 7.54–7.49 (m,
1H), 7.44–7.40 (m, 2H), 4.28 (dd, 1H, J = 4.8 Hz,
J = 4.8 Hz), 3.81 (s, 3H), 2.96 (dd, 1H, J = 16.2 Hz,
J = 4.8 Hz), 2.54–2.40 (m, 3H), 2.01 (dd, 1H,
J = 12.7 Hz, J = 8.2 Hz), 1.88–1.72 (m, 3H), 1.59–1.52
(m, 2H); 13C NMR(CDCl 3) d (ppm): 173.3, 169.6,
134.0, 132.0, 128.7, 128.5, 118.7, 69.1, 61.6, 52.4, 42.1,
38.0, 32.1, 30.1, 22.1.
1
0.4, CHCl3). IR(neat) m (cmꢀ1): 1738, 1651; H NMR
(CDCl3) d (ppm): 7.71–7.65 (m, 2H), 7.45–7.44 (m,
1H), 7.42–7.34 (m, 2H), 4.18 (dd, 1H, J = 4.4 Hz,
J = 4.4 Hz), 3.76 (s, 3H), 2.87 (dd, 1H, J = 12.9 Hz,
J = 5.2 Hz), 2.51–2.34 (m, 2H), 2.29–2.18 (m, 1H),
2.06 (s, 3H), 1.89–1.70 (m, 4H), 1.54–1.43 (m, 1H); 13C
NMR(CDCl 3) d (ppm): 173.9, 170.3, 134.5, 131.7,
128.8, 128.3, 70.2, 62.0, 52.1, 45.7, 38.5, 37.8, 31.3,
30.4, 15.4.
4.10. Methyl (1S,2R,4R)-N-benzoyl-2-benzylthiomethyl-
7-azabicyclo[2.2.1]heptane-1-carboxylate, 11
4.12. Methyl (1S,2S,4R)-N-benzoyl-2-azidomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 13
Over a suspension of NaH (13.0 mg, 0.54 mmol) in dry
DMF (5 mL) under argon atmosphere was slowly added
benzylmercaptane (67.0 mg, 0.54 mmol) and the mixture
stirred at room temperature for one hour. Then, a solu-
tion of methyl (1S,2R,4R)-N-benzoyl-2-bromomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate 6 (100 mg, 0.27
mmol) in dry DMF (2 mL) was added and the resulting
solution heated at 60 ꢁC for 3 h under an argon atmo-
sphere. Then, the reaction mixture was allowed to cool
down to room temperature and the solvent evaporated
under vacuum. The resulting crude mixture was
dissolved in a water/dichloromethane mixture. The
aqueous layer was washed with dichloromethane
(3 · 10 mL), the combined organic layers were dried
over anhydrous magnesium sulfate, filtered and the
solvent was removed under vacuum. A column chroma-
tography, using a 7:3 mixture of hexane/ethyl acetate,
provided the thioether derivative 11 in 77% yield
(85.2 mg, 0.22 mmol). Colourless oil. [a]D = ꢀ75.1 (c
Sodium azide (36.4 mg, 0.56 mmol) was added over a
solution of methyl (1S,2R,4R)-N-benzoyl-2-bromo-
methyl-7-azabicyclo[2.2.1]heptane-1-carboxylate 6 (100
mg, 0.28 mmol) in dry DMF (5 mL) under an argon
atmosphere and the mixture heated at 90 ꢁC for 5 h.
Then, the solvent was evaporated under vacuum, the
residue redissolved in dichloromethane (100 mL), and
washed with water (3 · 50 mL). The organic layer was
dried over anhydrous magnesium sulfate, filtered and
the solvent eliminated under vacuum. The residue was
purified by column chromatography (eluent: 6:4 hex-
ane/ethyl acetate). The product was obtained in this
way as a white solid in 92% yield (81.0 mg, 0.26 mmol).
White solid. Mp 115 ꢁC. [a]D = ꢀ62.3 (c 0.5, CHCl3). IR
1
(nujol) m (cmꢀ1): 2093, 1737, 1646; H NMR(CDCl ) d
3
(ppm): 7.74–7.66 (m, 2H), 7.55–7.36 (m, 3H), 4.22 (dd,
1H, J = 4.8 Hz, J = 4.4 Hz), 3.83 (s, 3H), 3.78–3.70
(m, 1H), 3.27 (dd, 1H, J = 12.5 Hz, J = 8.1 Hz), 2.50–
2.36 (m, 1H), 2.33–2.19 (m, 1H), 1.90–1.66 (m, 4H),
0.5, CHCl3). IR(neat) m (cmꢀ1): 3059–2874, 1737,
1
1656; H NMR(CDCl ) d (ppm): 7.60–7.57 (m, 2H),
1.59–1.47 (m, 1H). 13C NMR(CDCl ) d (ppm): 173.7,
3
3
7.43–7.39 (m, 1H), 7.33–7.30 (m, 2H), 7.27–7.20 (m,
4H), 7.19–7.15 (m, 1H), 4.07 (dd, 1H, J = 4.8 Hz,
J = 4.5 Hz), 3.66 (s, 3H), 3.62 (s, 2H), 2.77 (dd, 1H,
J = 12.8 Hz, J = 5.2 Hz), 2.36–2.28 (m, 2H), 2.02–2.01
(m, 1H), 1.74–1.53 (m, 4H), 1.42–1.35 (m, 1H); 13C
NMR(CDCl 3) d (ppm): 173.8, 170.1, 138.3, 134.4,
131.6, 128.8, 128.7, 128.4, 128.2, 126.9, 70.1, 62.0,
51.9, 45.9, 37.7, 36.3, 35.7, 31.0, 30.3.
169.9, 134.2, 131.8, 128.7, 128.3, 77.2, 68.9, 61.7, 54.0,
52.3, 45.8, 35.8, 31.1, 30.3. Anal. Calcd for
C16H18N4O3: C, 61.13; H, 5.77; N, 17.82. Found: C,
61.20; H, 5.68; N, 17.67.
4.13. Methyl (1S,2S,4R)-N-benzoyl-2-aminomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 15
To a solution of methyl (1S,2S,4R)-N-benzoyl-2-azi-
domethyl-7-azabicyclo[2.2.1]heptane-1-carboxylate 13
(100 mg, 0.32 mmol) in dry methanol (10 mL), 10%
Pd/C (20 mg) was added and the resulting suspension
heated at 30 ꢁC under hydrogen atmosphere for 3 h.
The catalyst was then filtered off through a Celite pad,
which was washed with dichloromethane. The solvent
was evaporated under vacuum until dryness. This proce-
dure supplied the unstable amino derivative in pure
4.11. Methyl (1S,2S,4R)-N-benzoyl-2-cyanomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 12
To a suspension of potassium cyanide (91.2 mg,
1.4 mmol) and a catalytic quantity of 18-crown-6 ether
in dry DMF (2 mL) under argon atmosphere, a solution
of methyl (1S,2R,4R)-N-benzoyl-2-bromomethyl-7-aza-
bicyclo[2.2.1]heptane-1-carboxylate
6 (100 mg, 0.28
mmol) in dry DMF (2 mL) was added. The mixture
was heated at 80 ꢁC for one day and, then, it was al-
lowed to cool down to room temperature and the sol-
vent was evaporated under vacuum. The resulting
crude mixture was dissolved in a water/dichloromethane
mixture. The aqueous layer was washed with dichloro-
methane (3 · 10 mL), the combined organic layers dried
over anhydrous magnesium sulfate, filtered and the sol-
vent was removed under vacuum. The column chroma-
tography of the resulting oil, using a 1:1 mixture of
NMRspectroscopic form. 1H NMR(CDCl ) d (ppm):
3
7.77–7.67 (m, 2H), 7.50–7.44 (m, 1H), 7.41–7.35
(m, 2H), 4.17 (dd, 1H, J = 4.8 Hz, J = 4.4 Hz), 3.78
(s, 3H), 2.94 (dd, 1H, J = 12.9 Hz, J = 6.2 Hz), 2.65
(dd, 1H, J = 12.9 Hz, J = 6.6 Hz), 2.40 (ddd, 1H,
J = 12.5 Hz, J = 12.1 Hz, J = 4.6 Hz), 2.14–2.03
(m, 1H), 1.86–1.59 (m, 4H), 1.54–1.45 (m, 3H). 13C
NMR(CDCl 3) d (ppm): 173.7, 170.8, 134.7, 131.6,
128.8, 128.3, 69.5, 62.0, 51.9, 50.1, 44.8, 35.1, 31.1,
30.6.

3122
A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
4.14. Methyl (1S,2S,4R)-N-benzoyl-2-tert-butoxy
carbonylaminomethyl-7-azabicyclo[2.2.1]heptane-1-
carboxylate, 16
0.32 mmol) in dry methanol (6 mL) was added 10%
Pd/C (20 mg) and the resulting suspension heated at
30 ꢁC under a hydrogen atmosphere for 3 h. The reac-
tion mixture was filtered through Celite and the solvent
evaporated to dryness. Then, over a solution of the
resulting residue in 1,2-dichloroethane (6 mL), heated
at 75 ꢁC, was added a solution of MCPBA (358 mg,
2.08 mmol) in 1,2-dichloroethane (4 mL). The reaction
went to completion immediately and the solvent evapo-
rated under vacuum. A column chromatography, using
a 1:1 mixture of hexane/ethyl acetate, provided the com-
pound as a white solid in 31% yield (32 mg, 0.1 mmol).
Mp 134–135 ꢁC. [a]D = ꢀ34.0 (c 0.6, CHCl3). IR(neat)
m (cmꢀ1): 1737, 1709, 1737; 1H NMR(CDCl 3) d
(ppm): 7.69–7.67 (m, 2H), 7.54–7.51 (m, 1H), 7.45–
7.41 (m, 2H), 5.07 (dd, 1H, J = 14.2 Hz, J = 6.3 Hz),
4.34 (dd, 1H, J = 14.3 Hz, J = 9.0 Hz), 4.31–4.28 (m,
1H), 3.77 (s, 3H), 3.02–2.95 (m, 1H), 2.51–2.44 (m,
1H), 1.97–1.86 (m, 3H), 1.69–1.57 (m, 2H). 13C NMR
(CDCl3) d (ppm): 173.2, 169.6, 133.9, 132.1, 128.7,
128.5, 77.7, 68.5, 61.3, 52.5, 42.9, 36.3, 32.5, 30.1. Anal.
Calcd for C16H18N2O5: C, 60.37; H, 5.70; N, 8.80.
Found: C, 60.56; H, 6.02; N, 8.55.
Over a suspension of 10% Pd/C (10 mg) in ethyl acetate
(5 mL) under hydrogen atmosphere were added methyl
(1S,2S,4R)-N-benzoyl-2-azidomethyl-7-azabicyclo[2.2.1]-
heptane-1-carboxylate 13 (100 mg, 0.32 mmol) and di-
tert-butyldicarbonate (104.8 mg, 0.48 mmol). The mix-
ture was vigorously stirred at room temperature until
complete consumption of the starting material (36 h).
The catalyst was then filtered off by means of a Celite
pad and the solvent eliminated under vacuum. The res-
idue was purified by column chromatography (eluent:
1:1 hexane/ethyl acetate) and the compound obtained
in 88% yield (109 mg, 0.28 mmol). White solid. Mp
59–60 ꢁC. [a]D = ꢀ68.1 (c 1.0, CHCl3). IR(nujol)
m
1
(cmꢀ1): 1737, 1709, 1654; H NMR(CDCl ) d (ppm):
3
7.70–7.68 (m, 2H), 7.50–7.47 (m, 1H), 7.41–7.37 (m,
2H), 5.34–5.28 (m, 1H), 4.15 (dd, 1H, J = 4.5 Hz,
J = 4.5 Hz), 3.82 (s, 3H), 3.42–3.35 (m, 1H), 3.14 (ddd,
1H, J = 14.2 Hz, J = 3.7 Hz, J = 3.7 Hz), 2.41 (ddd,
1H, J = 12.4 Hz, J = 12.4 Hz, J = 4.2 Hz), 2.32–2.22
(m, 1H), 1.86–1.60 (m, 4H), 1.55–1.48 (m, 1H), 1.44 (s,
9H). 13C NMR(CDCl ) d (ppm): 173.5, 171.0, 134.5,
4.17. General procedure for the hydrolysis of compounds
9, 10 and 12
3
131.8, 128.8, 128.3, 79.0, 77.3, 69.3, 61.8, 52.4, 46.8,
42.5, 34.1, 30.8, 28.5. Anal. Calcd for C21H28N2O5: C,
64.93; H, 7.27; N, 7.21. Found: C, 64.82; H, 7.39; N,
7.10.
Aqueous 6 M HCl (15 mL) was added to the amido
esters 9, 10 or 12 (100 mg) and the mixture heated under
reflux for 24, 30 or 48 h, respectively. 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 sep-
arated aqueous phase evaporated to dryness. Total
removal of water was achieved by final lyophilisation.
In this way the amino acid hydrochlorides 19–21 were
obtained.
4.15. Methyl (1S,2S,4R)-N-benzoyl-2-(4,5-dimethoxy-
carbonyl-1,2,3-triazol-1-yl)methyl-7-azabicyclo[2.2.1]
heptane-1-carboxylate, 17
Dimethylacetylenedicarboxylate (59.7 mg, 0.42 mmol)
was added to a solution of (1S,2S,4R)-N-benzoyl-2-azi-
domethyl-7-azabicyclo[2.2.1]heptane-1-carboxylate 13
(100 mg, 0.32 mmol) in ethanol (10 mL) and the mixture
refluxed for one day. Then, the mixture was allowed to
cool down to room temperature and the solvent
removed under vacuum. The resulting residue was puri-
fied by column chromatography (eluent: 6:4 hexane/
ethyl acetate) and the compound was obtained in 92%
yield (134 mg, 0.29 mmol). White solid. Mp 60–62 ꢁC.
(1S,2R,4R)-2-Methyl-7-azabicyclo[2.2.1]heptane-1-carb-
oxylic acid hydrochloride, 19. Quantitative yield. White
solid. Mp dec. [a]D = ꢀ34.1 (c 0.4, H2O). IR(nujol) m
(cmꢀ1): 3200–2522, 1726; 1H NMR(D 2O) d (ppm):
4.11 (dd, 1H, J = 4.7 Hz, J = 4.1 Hz), 2.40–2.28 (m,
1H), 2.16–1.97 (m, 4H), 1.81–1.70 (m, 1H), 1.58–
1.49 (m, 1H), 0.93 (d, 3H, J = 7.3 Hz); 13C NMR
(D2O) d (ppm): 171.7, 75.9, 58.4, 37.5, 36.7, 30.5, 26.6,
17.0.
[a]D = ꢀ72.4 (c 1.0, CHCl3). IR(nujol) m (cmꢀ1):
1
3059–2850, 1743, 1648, 1600, 1578; H NMR(CDCl )
3
d (ppm): 7.71–7.69 (m, 2H), 7.49–7.45 (m, 1H), 7.41–
7.37 (m, 2H), 5.08 (dd, 1H, J = 13.9 Hz, J = 5.0 Hz),
4.57 (dd, 1H, J = 13.6 Hz, J = 10.9 Hz), 4.23 (dd, 1H,
J = 4.8 Hz, J = 4.5 Hz), 3.98 (s, 3H), 3.90 (s, 3H), 3.75
(s, 3H), 2.95–2.87 (m, 1H), 2.44–2.37 (m, 1H), 1.92–
1.82 (m, 2H), 1.75–1.69 (m, 1H), 1.51–1.46 (m, 2H).
(1S,2R,4R)-2-Methylthiomethyl-7-azabicyclo[2.2.1]hep-
tane-1-carboxylic acid hydrochloride, 20. White solid
containing a small amount of impurity. IR(nujol)
m
(cmꢀ1): 3500–3300, 1640; 1H NMR(D 2O) d (ppm):
4.16 (dd, 1H, J = 4.0 Hz, J = 4.0 Hz), 2.88 (d, 1H,
J = 6.3 Hz), 2.68 (dd, 1H, J = 12.9 Hz, J = 4.8 Hz),
2.60–2.42 (m, 1H), 2.37–2.27 (m, 1H), 2.19–1.94 (m,
7H), 1.85–1.71 (m, 3H); 13C NMR(D 2O) d (ppm):
173.6, 77.9, 60.8, 44.2, 37.7, 37.4, 33.4, 29.0, 28.9, 16.6.
13C NMR(CDCl ) d (ppm): 173.1, 169.8, 160.5, 159.0,
3
139.6, 134.2, 131.9, 130.8, 128.8, 128.4, 68.9, 61.5,
53.5, 52.8, 52.6, 52.3, 45.0, 35.6, 33.1, 30.1. Anal. Calcd
for C22H24N4O7: C, 57.89; H, 5.30; N, 12.27. Found: C,
57.55; H, 5.21; N, 12.03.
4.16. Methyl (1S,2S,4R)-N-benzoyl-2-nitromethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate, 18
(1S,2S,4R)-2-Carboxymethyl-7-azabicyclo[2.2.1]heptane-
1-carboxylic acid hydrochloride, 21. Quantitative yield.
Mp dec. [a]D = ꢀ25.5 (c 0.4, H2O). IR(nujol)
m
To a solution of (1S,2S,4R)-N-benzoyl-2-azidomethyl-7-
azabicyclo[2.2.1]heptane-1-carboxylate 13 (100 mg,
(cmꢀ1): 3600–2800, 1723; 1H NMR(D 2O) d (ppm):
4.16 (dd, 1H, J = 4.4 Hz, J = 4.4 Hz), 2.71–2.53 (m,

A. M. Gil et al. / Tetrahedron: Asymmetry 16 (2005) 3115–3123
3123
Mental Health Administration, National Institute on
Drug Abuse, Rockville (MD), U.S.A.; For sale by the
Supt. of Docs., U.S. Government Printing Office, Wash-
ington (DC), U.S.A., 1986; p. 204.
2H), 2.51 (d, 1H, J = 5.2 Hz), 2.41 (dd, 1H, J = 16.6 Hz,
J = 8.5 Hz), 2.18 (dd, 1H, J = 13.6 Hz, J = 8.8 Hz),
2.13–1.96 (m, 3H), 1.84–1.64 (m, 2H); 13C NMR
(D2O) d (ppm): 177.8, 173.4, 77.1, 60.8, 41.2, 38.6,
37.4, 33.6, 29.0.
11. Ghose, A. K.; Logan, M. E.; Treasurywala, A. M.; Wang,
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Acknowledgements
This work was carried out with the financial support of
´
Ministerio de Ciencia y Tecnologıa and FEDER(pro-
´
13. Jimenez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M.
ject PPQ2001-1834). A. M. Gil would like to thank
CSIC for an I3P grant.
J. Am. Chem. Soc. 1998, 120, 9452–9459.
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14. Jimenez, A. I.; Cativiela, C.; Gomez-Catalan, J.; Perez, J.
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J.; Aubry, A.; Parıs, M.; Marraud, M. J. Am. Chem. Soc.
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