α,γ-diamino acids: Asymmetric synthesis of new constrained 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acids

Article abstract of DOI:10.1021/jo061391o

The synthesis of two new diastereomeric 6-amino-3-azabicyclo[3.2.1]octane- 6-carboxylic acids exo- and endo-8,9 is reported using exo- and endo-norbornene amino acids as chiral building blocks. This method provides a fast access to optically pure amino ac

Full text of DOI:10.1021/jo061391o

r,γ-Diamino Acids: Asymmetric Synthesis of New Constrained
6-Amino-3-azabicyclo[3.2.1]octane-6-carboxylic Acids
Francesco Caputo, Cristian Cattaneo, Francesca Clerici, Maria Luisa Gelmi,* and
Sara Pellegrino
Istituto di Chimica Organica “A. Marchesini”, Facolta` di Farmacia, UniVersita` di Milano,
Via Venezian 21, I-20133 Milano, Italy
marialuisa.gelmi@unimi.it
ReceiVed July 5, 2006
The synthesis of two new diastereomeric 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acids exo- and
endo-8,9 is reported using exo- and endo-norbornene amino acids as chiral building blocks. This method
provides a fast access to optically pure amino acids 8 and 9 which can be considered both R,γ- and
R,δ-diamino acids containing sterical constraints and characterized by R,R-disubstitution.
Introduction
the presence of two amino groups and one carboxy group, make
them very interesting substrates to be used in peptidomimetic
syntheses. Constrained amino acids are able to modulate the
conformation and, as a consequence, the properties of peptides
and their biological activity.4c,5 In particular, few examples of
δ-amino acids are reported even if they seem to be very
promising in view of the synthesis of peptidomimetics.5a,b
To ensure the preparation of both diastereomers of the title
compounds 8 and 9, in enantiopure form too, our retrosynthetic
The syntheses and the biological activities of molecules
containing the 3-azabicyclo[3.2.1]octane scaffold are docu-
mented by more than 250 patents which indicates that this ring
could be the pharmacophore of a bioactive molecule or a
substituent of a different bioactive scaffold. Depending on the
substitution pattern of the 3-azabicyclo[3.2.1]octane ring, dif-
ferent activities were reported, and many of these compounds
were used for treating central nervous system disorders. Among
these molecules, the amino-substituted compounds are of
relevance,1 as well as the carboxylic acid derivatives.2
The diastereo- and enantioselective preparation of new
constrained amino acids has been one of our synthetic targets
since the 1999s.3 Conformationally restricted amino acids are
of great interest and have assumed a prominent role in drug
design and development.4 Going on our research program and
considering the general biological importance of 3-azabicyclo-
[3.2.1]octane derivatives and in view of their use in peptido-
mimetic synthesis, we planned the preparation of compounds
exo- and endo-8,9 (Scheme 1) functionalized both with amino
and carboxy groups on C-6 which, to our knowledge, are
unknown compounds. 6-Amino-3-azabicyclo[3.2.1]octane-6-
carboxylic acids can be considered both R,γ- and R,δ-diamino
acids containing sterical constraints and characterized by R,R-
disubstitution. Their features, such as the R,R-disubstitution,
which gives metabolic stability, the conformational rigidity, and
(1) (a) Heng, R.; Revesz, L.; Schlapbach, A.; Waelchli, R. PCT Int. Appl.
2005, PIXXD2 WO 2005103054 A2 20051103; Chem. Abstr. 2005, 143,
440438. (b) Hamamoto, I.; Takahashi, J.; Yano, M.; Hanai, D.; Iwasa, T.
PCT Int. Appl. 2005, PIXXD2 WO 2005095380 A1 20051013; Chem. Abstr.
2005, 143, 386926. (c) Evertsson, E.; Inghardt, T.; Lindberg, J.; Linusson,
A.; Giordanetto, F. PCT Int. Appl. 2005, PIXXD2 WO 2005066132 A1
20050721; Chem. Abstr. 2005, 143, 172772. (d) Breining, S. R.; Bhatti, B.
S.; Hawkins, G. D.; Miao, L.; Anatoly, P.; Teresa, Y.; Miller, C. H. PCT
Int. Appl. 2005, PIXXD2 WO 2005037832 A2 20050428; Chem. Abstr.
2005, 142, 430157. (e) Dong, J.; Han, H.; Geng, B.; Li, X.; Gong, Z.; Liu,
K. J. Peptide Res. 2005, 65, 440-444. (f) Coe, J. W.; Iredale, P. A.;
McHardy, S. F.; McLean, S. U.S. Patent Appl. Publ. 2005, USXXCO US
2005043345 A1; Chem. Abstr. 2005, 142, 233377. (g) Bridger, G.;
McEachern, E. J.; Skerlj, R.; Schols, D. U.S. Patent Appl. Publ. 2004,
USXXCO US 2004209921 A1 20041021; Chem. Abstr. 2004, 141, 379809.
(h) Lew, W.; Wu, H.; Chen, X.; Graves, B. J.; Escarpe, P. A.; MacArthur,
H. L.; Mendel, D. B.; Kim, C. U. Bioorg. Med. Chem. Lett. 2000, 10, 1257-
1260. (i) Yamashita, A.; Takahashi, N.; Mochizuki, D.; Tsujita, R.; Yamada,
S.; Kawakubo, H.; Suzuki, Y.; Watanabe, H. Bioorg. Med. Chem. Lett.
1997, 7, 2303-2306. (j) Takahashi, N.; Mochizuki, D. U.S. Patent Appl.
USXXAM US 5658923A 19970819, 1997; Chem. Abstr. 1997, 127, 248269.
(k) Rico, B.; Galvez, E.; Izquierdo, M. L.; Arias, M. S.; Orjales, A.; Berisa,
A.; Labeaga, L. J. Heterocycl. Chem. 1994, 31, 313-318. (l) Keasling, H.
H.; Moffett, R. B. J. Med. Chem. 1971, 14, 1106-1112.
* To whom correspondence should be addressed. Phone: +390250314481.
Fax: +390250314476.
10.1021/jo061391o CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/30/2006
J. Org. Chem. 2006, 71, 8467-8472
8467

Caputo et al.
SCHEME 1. Retrosynthetic Analysis
SCHEME 2. Synthesis of Bisaldehydes 3 and 4a
a Reagents and conditions: (i) OsO4, NMO, acetone/H2O, 25 °C; (ii)
NaIO4, dioxane/H2O, 25 °C.
plan features the norbornene amino acids 1 as suitable starting
Alder reaction starting from 2-aminoacrylate derivatives and
cyclopentadiene. The disconnection of ring B of norbornenes 1
by an oxidative reaction (C5-C6 cleavage) yields the cyclopentyl
derivatives 3/4 (ring A in both compounds 1 and 3/4) substituted
with the amino acid function and with two formyl groups with
the proper regiochemistry and cis configuration. From these key
intermediates, the formation of ring C of the 3-azabicyclo[3.2.1]-
octane skeleton was assured by a reductive amination reaction.
By using a very efficient protocol, starting from a mixture of
protected norbornene amino acids exo-1 and endo-1, the new
diastereomeric 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic
acids exo-8,9 and endo-8,9 were prepared in good yields. Amino
acids 8 and 9 are orthogonally protected, allowing the selective
deprotection of both the acid and the two different amino groups.
materials (Scheme 1).
Compounds 1 are readily prepared as endo/exo diastereomers,
both in racemic6 and in enantiopure form,3b by using the Diels-
(2) (a) Butora, G.; Goble, S. D.; Pasternak, A.; Yang, L.; Zhou, C.;
Moyes, C. R. PCT Int. Appl. 2004, PIXXD2 WO 2004094371 A2
20041104; Chem. Abstr. 2004, 141, 410822. (b) Chandrakumar, N. S.; Chen,
B. B.; Clare, M.; Desai, B. N.; Djuric, S. W.; Docter, S. H.; Gasiecki, A.
F.; Haack, R. A.; Liang, C.-D. PCT Int. Appl. 1996, PIXXD2 WO 9611192
A1 19960418; Chem. Abstr. 1996, 125, 142545. (c) Buckley, B. R.; Page,
P. C. B.; Heaney, H.; Sampler, E. P.; Carley, S.; Brocke, C.; Brimble, M.
A. Tetrahedron 2005, 61, 5876-5888. (d) Brocke, C.; Brimble, M. A.;
Lin, D. S.-H.; McLeod, M. D. Synlett 2004, 13, 2359-2363. (e) House, H.
O.; Mueller, H. C. J. Org. Chem. 1962, 27, 4436-4439. (f) Lowe, J. A.,
III; Drozda, S. E.; McLean, S.; Bryce, D. K.; Crawford, R. T.; Snider, R.
M.; Longo, K. P.; Nagahisa, A.; Tsuchiya, M. J. Med. Chem. 1994, 37,
2831-2840. (g) King, F. D. PCT Int. Appl. 1992, PIXXD2 WO 9212149
A1 19920723; Chem. Abstr. 1992, 117, 212337.
Results
(3) (a) Caputo, F.; Clerici, F.; Gelmi, M. L.; Nava, D.; Pellegrino, S.
Tetrahedron 2006, 62, 1288-1294 and references therein. (b) Caputo, F.;
Clerici, F.; Gelmi, M. L.; Pellegrino, S.; Pocar, D. Tetrahedron: Asymmetry
2006, 17, 1430-1436.
The key starting reagents for the preparation of the amino
acids containing the 3-azabicyclo[3.2.1]octane skeleton were the
norbornene derivatives exo-1a and endo-1a as well as the
corresponding enantiopure compounds exo-1b and endo-1b. The
C4-C5 double bond of the norbornene ring was cleaved by a
two-step oxidative process. First, racemic compounds exo-1a
and endo-1a were transformed into the corresponding dihydroxy
derivatives 2 by allowing 1 to react with N-methylmorpholine-
N-oxide (NMO) in acetone/H2O, in the presence of a catalytic
amount of osmium tetroxide (Scheme 2). The diol derivatives
exo-2a (86%) and endo-2a (84%) were obtained in pure form
as single diastereomers characterized by the cis relationship
between both the hydroxy groups and the bridge, as demon-
strated by a NOESY experiment on exo-2a. In fact, spatial
proximity between endo H-3 (δ 1.34) and H-5 (δ 3.73) and
between H-6 (δ 3.97) and the methyl group of the acetyl group
(δ 1.94) was observed.
(4) (a) Gelmi, M. L.; Pocar, D. Org. Prep. Proc. Int. 2003, 35, 141-
205. (b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2000, 11, 645-732. (c) AdVances in Amino Acids Mimetics and Peptido-
mimetics; Abell, A., Ed.; JAI Press Inc.: London, UK, 1998.
(5) (a) Trabocchi, A.; Guarna, F.; Guarna, A. Curr. Org. Chem. 2005,
9, 1127-1153. (b) Baldauf, C.; Gunther, R.; Hofmann, H.-G. J. Org. Chem.
2004, 69, 6214-6220. (c) Kimmerlin, T.; Seebach, D. J. Peptide Res. 2005,
65, 229-260. (d) Ispida, H.; Kyakuno, M.; Oishi, S. Biopolymers 2004,
76, 69-82. (e) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206-243.
(f) Souers, A. J.; Ellman, J. A. Tetrahedron 2001, 57, 7431-7448. (g)
Peptidomimetic Protocols (methods in Molecular Medicine); Kazmierski,
W. M., Ed.; Humana Press Inc.: Totowa, NJ, 1999. (h) Hanessian, S.;
McNaughton-Smith, G.; Lombart, H.; Lubell, W. D. Tetrahedron 1997,
53, 12789-12854. (i) Hruby, W.; Li G., Haskell-Luevano, C.; Shenderovic,
M. Biopolymers 1997, 43, 219-248. (j) Humphrey, J. M.; Chamberlin, A.
R. Chem. ReV. 1997, 97, 2243-2266.
(6) Bueno, M. P.; Cativiela, C.; Finol, C.; Mayoral, J. A. Can. J. Chem.
1987, 65, 2182-2186.
(7) Iriepa, I.; Madrid, A. I.; Morreale, A.; Ga´lvez, E.; Bellanato, J. J.
Mol. Struct. 2003, 651-653, 585-591 and references therein.
(8) Kim, D.-I.; Schweri, M. M.; Deutsch, H. M. J. Med. Chem. 2003,
46, 1456-1464.
The cyclopentyl derivatives functionalized with two formyl
groups with the proper stereochemistry were obtained by
8468 J. Org. Chem., Vol. 71, No. 22, 2006

R,γ-Diamino Acids
SCHEME 3. Synthesis of 3-Azabicyclo[3.2.1]octane Ringa
and (ii) the necessity to perform the reaction twice, both starting
from the exo and the endo norbornenes. A more efficient
synthetic protocol was developed consisting of the preparation
of the exo/endo mixture of compounds 5a by using the same
synthetic procedure described for pure diastereomers and in their
easy separation by column chromatography in the final step.
The mixture of exo- and endo-1a (7:3) was transformed into a
mixture of exo/endo-3-azabicyclo[3.2.1]octane amino acid
derivatives exo-5a (41%) and endo-5a (15%), through the diol
derivatives 2a and bisaldehydes 3a/4a.
The enantiopure amino acids (-)-exo-5b (57%) and
(-)-endo-5b (58%) (Scheme 3) were prepared following the
same synthetic scheme starting from enantiopure compounds
(-)-exo-1b and (+)-endo-1b, transformed into the diol deriva-
tives (-)-exo-2b and (+)-endo-2b, oxidized to bisaldehyde 3b
and 4b, respectively (Scheme 2).
Compounds 5 are orthogonally protected diamino acids which
are selectively deprotected to each functional group. Compound
exo-5a was selected to study the orthogonal deprotection. The
3-aza group was first deprotected, aiming to prepare the NH
azabicyclo[3.2.1]octane derivatives which are valuable and
alternative starting materials for the preparation of other 3-N-
substituted amino acids. To remove the N-p-methoxybenzyl
group (PMB), an oxidative process was performed using cerium
ammonium nitrate (CAN) in acetone/H2O (9:1) at room tem-
perature. This method is reported in the literature, but its
straightforward application in the present case caused difficulties
because of the solubility of the amino acid derivative in water.
The problem was overcome by treating the reaction mixture
with solid NaHCO3 followed by its chromatography on silica
gel. Compound exo-6a was isolated in 90% yield. The same
synthetic protocol allowed us to transform endo-5a into amino
acid endo-6a (62%). The methyl ester group of exo-5a and endo-
5a was selectively hydrolyzed using basic conditions (EtOH/
KOH). The corresponding acids exo-7 (95%) and endo-7 (99%)
were isolated, respectively. Both the amino and the carboxy
functions were deprotected in acid conditions (6 N HCl at 100
°C, 24 h). Amino acids exo-8,9 and endo-8,9 were obtained in
quantitative yield, as bishydrochlorides, from exo-5a,6a and
endo-5a,6a, respectively.
a Reagents and conditions: (i) p-methoxybenzylamine, NaBH(OAc)3,
AcOH (cat.), ClCH2CH2Cl, 25 °C.
cleaving the C4-C5 bond of compounds 2 with sodium periodate
as the oxidant in dioxane/H2O (8:1) at room temperature (4 h).
Bisaldehydes 3a and 4a were quantitatively obtained from exo-
2a and endo-2a, respectively (Scheme 2).
1
Their structure was confirmed by H NMR, which showed
the presence of two singlets in the δ 9.7-9.8 region.
The bisaldehydes are not very stable, and it was chosen to
transform the crude reaction mixtures directly into the corre-
sponding 3-azabicyclo[3.2.1]octane derivatives. A reductive
amination was performed using p-methoxybenzylamine, as the
nitrogen donor, and sodium triacetoxyborohydride, as reducing
agent (1.3 equiv). The reaction was performed at room tem-
perature (4 h) in 1,2-dichloroethane and in the presence of a
catalytic amount of acetic acid. Methyl 6-acetamido-3-azabicyclo-
[3.2.1]octane-6-carboxylate derivative exo-5a (61%) was ob-
tained from 3a. Compound endo-5a was isolated in 53% yield
starting from 4a (Scheme 3).
This synthetic protocol suffers from some limitations related
to (i) the efficiency of the exo/endo norbornenes 1 separation,
SCHEME 4. Orthogonal Deprotectiona
a Reagents and conditions: (i) CAN, acetone/H2O, 25 °C; (ii) KOH, EtOH (95%), 120 °C; (iii) 6 N HCl, 100 °C; (iv) MeOH, Na, 0 °C, then 5b, 100 °C;
(v) SOCl2, MeOH, reflux.
J. Org. Chem, Vol. 71, No. 22, 2006 8469

Caputo et al.
5.5 Hz, 1 H), 2.61 (br s, 1 H), 2.26 (dd, J ) 13.9, 5.1 Hz, 1 H),
2.05-1.77 (m, 3 H), 1.90 (s, 3 H), 1.55-0.72 (m, 9 H), 1.35 (s, 3
H), 1.24 (s, 3 H), 0.86 (d, J ) 6.6 Hz, 3 H); 13C NMR (CD3OD)
δ 172.9, 171.6, 153.3, 128.5, 125.9, 124.9, 77.4, 73.8, 69.3, 62.6,
50.8, 50.2, 43.7, 40.9, 39.7, 38.1, 35.0, 31.5, 29.9, 29.6, 26.8, 24.1,
23.5, 21.9; m/z 466.4 [+Na]. Anal. Calcd for C26H37NO5: C, 70.40;
H, 8.41; N, 3.16. Found: C, 70.33; H, 8.45; N, 3.10.
The hydrolysis of ester and amido functions of enantiopure
compounds exo-5b and endo-5b was successfully achieved with
MeONa in methanol at reflux for 50 h. Acids (-)-exo-8 (45%)
and (-)-endo-8 (60%) were obtained, respectively. Finally, the
reaction of amino acid exo-8 with SOCl2 and MeOH gave the
corresponding methyl ester exo-10 in 89% yield. All compounds
were characterized by spectroscopic data, and as examples, the
NMR discussion on the conformation of compounds 5 is
reported in the Supporting Information (Figure S1).
(-)-8-Phenylmenthyl (1S,2S,4R,5R,6S)-2-Acetylamino-5,6-
dihydroxybicyclo[2.2.1]heptane-2-carboxylate endo-2b: Mp 249
°C; [R]25D ) +13° (c 0.5, MeOH); IR νmax 3375, 1704, 1649 cm-1
;
1
In conclusion, a very efficient protocol for the preparation
of two new diastereomeric constrained diamino acids containing
the 3-azabicyclo[3.2.1]octane skeleton was developed. They
were prepared in good yields and in enantiopure form starting
from readily available enantiopure norbornene amino acids.
Amino acid derivatives 5 are orthogonally protected, and this
allowed the selective deprotection of the N-3 atom or of the
amino group on C-6. In particular, the NH compounds 6 are
expected to be valuable starting materials for the selective
functionalization of amino acid groups on the N-3 atom.
Furthermore, these compounds are very promising amino acids
to be used for peptidomimetic synthesis.
H NMR (CDCl3) δ 7.40-7.16 (m, 5 H), 5.00 (s, 1 H, exch.),
4.69-4.59 (m, 1 H), 3.90 (d, J ) 5.9 Hz, 1 H), 3.82 (d, J ) 6.3
Hz, 1 H), 2.22-2.00 (m, 3 H), 2.00-1.80 (m, 4 H), 1.81 (s, 3 H),
1.79-1.42 (m, 4 H), 1.34 (s, 3 H), 1.30-0.80 (m, 2 H), 1.17 (s, 3
H), 0.87 (d, J ) 6.7 Hz, 3 H); 13C NMR (CDCl3) δ 171.8, 169.9,
152.9, 128.4, 125.9, 125.1, 77.7, 73.2, 69.4, 63.7, 52.3, 49.8, 44.4,
41.0, 39.8, 39.2, 35.0, 32.5, 31.6, 28.9, 27.0, 25.1, 23.3, 22.0; m/z
466.4 [+Na]. Anal. Calcd for C26H37NO5: C, 70.40; H, 8.41; N,
3.16. Found: C, 70.47; H, 8.39; N, 3.13.
General Procedure for the Preparation of Bisaldehydes 3 and
4. Compound 2 (2a, 243 mg, 1 mmol; 2b, 443 mg, 1 mmol) was
dissolved in a mixture of dioxane/H2O (5 mL, 8:1). NaIO4 was
added (1.7 g, 7.92 mmol), and the mixture was stirred at room
temperature for 2 h. The solvent was evaporated, and the reaction
mixture was taken up with CHCl3 (10 mL), and the salts were
filtered and washed with CHCl3. The organic solution was collected,
and after solvent elimination, the crude aldehydes 3 or 4 [exo/endo-
2a, 3a,4a (240 mg); exo-2a, 3a (232 mg); endo-2a, 4a (234 mg);
exo-2b, 3b (395 mg); endo-2b, 4b (398 mg)] were isolated and
used without further purification.
Experimental Section
Compounds exo-1a,6 endo-1a,6 exo-1b,3b and endo-1b3b were
prepared according to a known procedure.
General Procedure for the Synthesis of Diols 2. Compound 1
[exo-1a or endo-1a or a mixture of exo-1a/endo-1a (7:3) (209 mg,
1 mmol); exo-1b or endo-1b (409.6 mg, 1 mmol)] was suspended
in a mixture of acetone/H2O (6 mL, 10:1). After addition of
N-methylmorpholine-N-oxide (176 mg, 1.5 mmol) and OsO4 (1.35
mg, 0.005 mmol), the solution turned brown. The reaction mixture
was stirred at room temperature for 8 h after which the solvent
was evaporated. The crude reaction mixture was filtered on silica
gel (CH2Cl2/MeOH ) 5:1). Pure compound 2 (exo-2a, 209 mg,
86%; endo-2a, 204 mg, 84%; exo-2a/endo-2a, 202 mg, 83%) was
obtained after crystallization. The crude reaction mixture containing
2b was taken up with a saturated solution of Na2S2O4 (5 mL) and
extracted with CH2Cl2 (3 × 5 mL). After drying of the organic
layer with Na2SO4 and column chromatography on silica gel (CH2-
Cl2/MeOH ) 20:1), pure compound 2b (exo-2b, 404 mg, 90%;
endo-2b, 430 mg, 97%) was isolated.
Methyl (1R*,2S*,4S*,5S*,6R*)-2-Acetylamino-5,6-dihydroxy-
bicyclo[2.2.1]heptane-2-carboxylate exo-2a: Mp 161 °C (MeOH/
iPr2O); IR νmax 3500-3100, 1735, 1651 cm-1; 1H NMR (CD3OD)
δ 3.97 (d, J ) 6.2 Hz, 1 H), 3.73 (d, J ) 5.0 Hz, 1 H), 3.67 (s, 3
H), 2.71 (br s, 1 H), 2.22 (dd, J ) 13.8, 5.0 Hz, 1 H), 2.09 (br s,
1 H), 1.94 (s, 3 H), 1.94-1.91 (m, 1 H), 1.64 (d, J ) 10.9 Hz, 1
H), 1.34 (dd, J ) 13.8, 2.9 Hz, 1 H); 13C NMR (CD3OD) δ 174.6,
172.9, 73.9, 69.3, 62.6, 51.8, 50.4, 43.3, 38.3, 31.3, 21.0; m/z 244.2
[M+]. Anal. Calcd for C11H17NO5: C, 54.31; H, 7.04; N, 5.76.
Found: C, 54.28; H, 7.10; N, 5.68.
Methyl (1S*,2R*,4S*)-1-Acetylamino-2,4-diformylcyclopen-
tanecarboxylate 3a: crude compound; IR νmax 3346, 1731, 1694
1
cm-1
;
H NMR (CDCl3) δ 9.76 (s, 1 H), 9.71 (s, 1 H), 6.50 (s, 1
H, exch.), 3.77 (s, 3 H), 3.25-3.05 (m, 1 H), 2.50 (dd, J ) 13.9,
3.7 Hz, 1 H), 2.40-1.90 (m, 4 H), 1.91 (s, 3 H); 13C NMR δ 202.7,
172.0, 170.8, 66.6, 57.2, 53.3, 47.4, 37.0, 24.7, 22.9; m/z 242.1
[M+].
Methyl (1S*,2S*,4R*)-1-Acetylamino-2,4-diformylcyclopen-
tanecarboxylate 4a: crude compound; IR νmax 3391, 1728, 1658
cm-1; 1H NMR (CDCl3) δ 9.68 (s, 1 H), 9.67 (s, 1 H), 6.70 (s, H,
exch.), 3.69 (s, 3 H), 3.20-2.90 (m, 1 H), 2.60-1.90 (m, 4 H),
2.01 (s, 3 H); 13C NMR δ 201.7, 200.0, 173.0, 170.5, 65.7, 58.4,
53.2, 48.9, 36.8, 27.2, 23.9; m/z 242.1 [M+].
(-)-8-Phenylmenthyl (1S,2R,4S)-1-Acetylamino-2,4-diformyl-
cyclopentanecarboxylate 3b: crude compound; IR νmax 3428, 1759,
1
1633 cm-1; H NMR (CDCl3) δ 9.73 (s, 1 H), 9.48 (d, J ) 0.81
Hz, H), 7.39-7.11 (m, 5 H), 6.35 (s, 1 H, exch.), 4.93-4.88 (m,
1 H), 3.02-2.92 (m, 1 H), 2.40-2.31 (m, 1 H), 2.25 (dd, J ) 14.0,
2.3 Hz, 1 H), 2.20-2.13 (m, 1 H), 2.12-1.75 (m, 5 H), 1.84 (s, 3
H), 1.68 (dd, J ) 14.0, 10.1 Hz, 1 H), 1.60-1.50 (m, 1 H), 1.32
(s, 3 H), 1.28-1.18 (m, 1 H), 1.14 (s, 3 H), 1.10-0.97 (m, 2 H),
0.93 (d, J ) 6.6 Hz, 3 H); 13C NMR (CDCl3) δ 202.2, 197.3, 169.6,
168.8, 152.1, 127.4, 124.9, 124.3, 76.6, 65.5, 55.9, 48.5, 45.3, 40.1,
38.7, 35.0, 34.0, 30.7, 30.3, 25.8, 23.3, 21.7, 21.1, 20.8; m/z 442.5
[M+].
Methyl (1S*,2S*,4R*,5R*,6S*)-2-Acetylamino-5,6-dihydroxy-
bicyclo[2.2.1]heptane-2-carboxylate endo-2a: Mp 186 °C (MeOH/
iPr2O); IR νmax 3346, 1731, 1694 cm-1; 1H NMR (CD3OD) δ 3.74
(dd, J ) 6.2, 1.4 Hz, 1 H), 3.66 (s, 3 H), 3.57 (dd, J ) 5.8, 1.4 Hz,
1 H), 2.38 (dd, J ) 13.9, 2.5 Hz, 1 H), 2.23 (br s, 1 H), 2.16-2.14
(m, 1 H), 1.97 (dt, J ) 10.6, 1.1 Hz, 1 H), 1.88 (s, 3 H), 1.65 (dt,
(-)-8-Phenylmenthyl
(1S,2S,4R)-1-Acetylamino-2,4-di-
formylcyclopentanecarboxylate 4b: crude compound; IR νmax
3390, 1727, 1651 cm-1; 1H NMR (CDCl3) δ 9.69 (d, J ) 1.5 Hz,
1 H), 9.61 (d, J ) 1.3 Hz, 1 H), 7.32-7.15 (m, 5 H), 6.05 (s, 1 H,
exch.), 5.04-4.95 (m, 1 H), 3.27-3.12 (m, 1 H), 2.43 (dd, J )
14.0, 10.0 Hz, 1 H), 2.33 (dd, J ) 9.3, 9.2 Hz, 1 H), 2.12-1.95
(m, 2 H), 1.97 (s, 3 H), 1.90-1.80 (m, 2 H), 1.72-1.55 (m, 3 H),
1.50-1.40 (m, 1 H), 1.36 (s, 3 H), 1.22 (s, 3 H), 1.18-0.80 (m, 3
H), 0.90 (d, J ) 6.5 Hz, 3 H); 13C NMR (CDCl3) δ 202.0, 200.1,
171.5, 170.3, 151.7, 128.7, 125.9, 78.8, 67.1, 57.9, 50.3, 48.9, 41.8,
40.3, 35.6, 34.6, 31.8, 27.7, 27.3, 27.0, 26.5, 24.5, 22.1; m/z 442.5
[M+].
J ) 10.6, 1.5 Hz, 1 H), 1.54 (ddd, J ) 14.0, 5.1, 0.7 Hz, 1 H); 13
C
NMR (CD3OD) δ 173.1, 171.5, 72.8, 68.9, 63.8, 52.3, 51.6, 43.9,
38.8, 31.8, 20.8; m/z 244.2 [M+]. Anal. Calcd for C11H17NO5: C,
54.31; H, 7.04; N, 5.76. Found: C, 54.25; H, 7.12; N, 5.67.
(-)-8-Phenylmenthyl (1R,2S,4S,5S,6R)-2-Acetylamino-5,6-
dihydroxybicyclo[2.2.1]heptane-2-carboxylate exo-2b: Mp 235
°C (CH2Cl2/i-Pr2O); [R]25D ) -9.1° (c 0.5, MeOH); IR νmax 3360-
1
3300, 1715, 1647 cm-1; H NMR (CD3OD) δ 7.34-7.11 (m, 5
General Procedure for the Reductive Amination: Synthesis
of 3-Azabicyclo[3.2.1]octane Derivatives 5a,b. Aldehyde [3a/4a
H), 4.83-4.71 (m, 1 H), 3.97 (d, J ) 6.2 Hz, 1 H), 3.66 (d, J )
8470 J. Org. Chem., Vol. 71, No. 22, 2006

R,γ-Diamino Acids
(242 mg, 1 mmol); 3b/4b (442 mg, 1 mmol)] was dissolved in
anhydrous dichloroethane (4 mL) under nitrogen. Operating under
stirring at room temperature, p-methoxybenzylamine (137.2 mg, 1
mmol), NaBH(OAc)3 (487.0 mg, 2.3 mmol), and a catalytic amount
of AcOH were added. After 4 h, the solvent was evaporated, and
the crude reaction mixture was taken up with CH2Cl2 (5 mL). The
organic layer was washed with H2O (5 mL) and dried over MgSO4.
The crude reaction was chromatographed on silica gel (5a, CH2Cl2/
MeOH ) 20:1; 5b, CH2Cl2/MeOH ) 50:1) giving pure 3-azabicyclo-
[3.2.1]octane derivatives 5 after crystallization [3a, exo-5a (211
mg, 61%); 4a, endo-5a (183 mg, 53%); 3a/4a, exo-5a (141 mg,
41%); endo-5a (52 mg, 15%); 3b; exo-5b (311 mg, 57%); 4b, endo-
5b (317 mg, 58%)].
10). A solid was formed. Acetone was evaporated, and the aqueous
layer was filtered through a Celite pad. After elution with warm
EtOH, the organic solution was concentrated under reduced
pressure. The crude material was purified by column chromatog-
raphy on silica gel (CH2Cl2/MeOH/NH4OH ) 5:1:0.025). Com-
pound 6 (exo-6a, 204 mg, 90%; endo-6a, 141 mg, 62%) was
isolated after recrystallization.
Methyl (1S*,5S*,6S*)-6-(Acetylamino)-3-azabicyclo[3.2.1]-
octane-6-carboxylate exo-6a: Mp 110 °C dec (EtOH); IR νmax
1
3400, 1727, 1632 cm-1; H NMR (D2O) δ 3.58 (s, 3 H), 3.10 (br
s, 4 H), 2.86 (br s, 1 H), 2.55 (dd, J ) 15.4, 7.3 Hz, 1 H), 2.39 (br
s, 1 H), 2.11-1.98 (m, 1 H), 1.92 (s, 3 H), 1.83 (dd, J ) 15.4, 3.0
Hz, 1 H), 1.71 (dd, J ) 12.5, 2.6 Hz, 1 H); 13C NMR (D2O) δ
176.5, 175.5, 65.0, 53.5, 49.2, 45.9, 39.2, 38.8, 34.2, 32.0, 21.9;
m/z 227.2 [M+]. Anal. Calcd for C11H18N2O3: C, 58.39; H, 8.02;
N, 12.38. Found: C, 58.21; H, 8.18; N, 12.22.
Methyl (1S*,5S*,6S*)-6-(Acetylamino)-3-(4-methoxybenzyl)-
3-azabicyclo[3.2.1]octane-6-carboxylate exo-5a: Mp 143-145 °C
1
(benzene); IR νmax 3344, 1737, 1637 cm-1; H NMR (CDCl3) δ
7.16, 6.84 (AA′XX′ system, J ) 8.4 Hz, 4 H), 6.44 (s, 1 H, exch.),
3.78 (s, 3 H), 3.67 (s, 3 H), 3.55, 3.17 (AB system, J ) 12.5 Hz,
2 H), 2.83-2.75 (m, 1 H), 2.72 (br s, 1 H), 2.56-2.50 (m, 1 H),
2.40-2.30 (m, 2 H), 2.20 (br s, 1 H), 2.03-1.98 (m, 2 H), 1.72
(dd, J ) 13.5, 2.5 Hz, 1 H), 1.57 (s, 3 H), 1.50 (dd, J ) 11.1, 2.5
Hz, 1 H); 13C NMR (CDCl3) δ 174.4, 171.0, 159.2, 130.6, 130.6,
114.2, 65.9, 62.2, 61.0, 55.6, 54.9, 52.5, 43.0, 40.0, 37.1, 34.7, 22.5;
m/z 347.3 [M+]. Anal. Calcd for C19H26N2O4: C, 65.87; H, 7.56;
N, 8.09. Found: C, 65.85; H, 7.55; N, 8.06.
Methyl (1R*,5R*,6S*)-6-(Acetylamino)-3-azabicyclo[3.2.1]-
octane-6-carboxylate endo-6a: Mp 99 °C dec (EtOH); IR νmax
1
3420, 1720, 1645 cm-1; H NMR (D2O) δ 3.66 (s, 3 H), 3.21 (d,
J ) 12.5 Hz, 1H), 3.18-3.00 (m, 3 H), 2.56 (d, J ) 15.7 Hz, 1 H),
2.47 (br s, 2 H), 2.21-2.00 (m, 2 H), 1.93 (s, 3 H), 1.75 (d, J )
12.5 Hz, 1 H); 13C NMR (D2O) δ 175.1, 173.9, 66.9, 53.9, 49.6,
45.8, 42.3, 39.8, 34.4, 32.5, 21.7; m/z 227.1 [M+]. Anal. Calcd for
C11H18N2O3: C, 58.39; H, 8.02; N, 12.38. Found: C, 58.30; H,
8.20; N, 12.14.
Methyl (1R*,5R*,6S*)-6-(Acetylamino)-3-(4-methoxybenzyl)-
3-azabicyclo[3.2.1]octane-6-carboxylate endo-5a: Mp 155-157
6-Acetylamino-3-(4-methoxybenzyl)-3-azabicyclo[3.2.1]octane-
6-carboxylic Acid (()-7: Operating in a sealed tube, compound
5a (346 mg, 1 mmol) was dissolved in EtOH (95%, 5 mL), and
KOH (112.2 mg, 2 mmol) was added. The solution was heated at
120 °C under stirring for 2 h. The reaction mixture was treated
with HCl (6 N, pH 7), and the solvent was removed. The crude
material was filtered through a pad of silica gel with CH2Cl2/CH3-
OH (5:2). Crystallization from absolute EtOH afforded the pure
carboxylic acid derivative 7 [(()-exo-7 (315 mg, 95%); (()-endo-7
(330 mg, 99%)].
(1S*,5S*,6S*)-(()-exo-7: Mp 200 °C (EtOH); IR νmax 3412,
1740, 1661 cm-1; 1H NMR (CD3OD) δ 7.61, 7.00 (AA′XX′ system,
J ) 8.4 Hz, 4 H), 4.42, 4.01 (AB system, J ) 11.0 Hz, 2 H), 3.83
(s, 3H), 3.56, 3.17 (AB system, J ) 11.0 Hz, 2 H), 3.10-1.90 (br
s, 2 H), 2.81 (d, J ) 12.2 Hz, 1 H), 2.63 (d, J ) 14.2 Hz, 1 H),
2.50 (br s, 1 H), 2.41 (dd, J ) 14.7, 7.0 Hz, 1 H), 2.38-2.29 (m,
1 H), 1.92 (s, 3 H), 1.78 (d, J ) 11.2 Hz, 1 H); 13C NMR (CD3-
OD) δ 176.9, 172.7, 160.2, 131.5, 120.9, 113.4, 65.0, 59.7, 57.6,
53.8, 53.0, 40.0, 36.4, 33.9, 32.8, 20.9; m/z 333.2 [M+]. Anal. Calcd
for C18H24N2O4: C, 65.04; H, 7.28; N, 8.43. Found: C, 65.12; H,
7.38; N, 8.50.
(1R*,5R*,6S*)-(()-endo-7: Mp 202 °C dec (EtOH); IR νmax
3435, 1613, 1516 cm-1; 1H NMR (CD3OD) δ 7.42, 6.98 (AA′XX′
system, J ) 8.4 Hz, 4 H), 4.16, (br s, 2 H), 3.80 (s, 3 H), 3.40-
3.20 (m, 3 H), 3.11 (d, J ) 12.1 Hz, 1 H), 2.66 (d, J ) 15.0 Hz,
1 H), 2.53 (br s, 2 H), 2.30-2.02 (m, 2 H), 1.92 (s, 3 H), 1.88 (d,
J ) 11.5 Hz, 1 H); 13C NMR (CD3OD) δ 177.2, 170.9, 160.2,
131.1, 120.7, 113.6, 67.6, 58.7, 56.2, 54.4, 53.8, 42.3, 41.2, 33.8,
33.6, 20.8; m/z 333.3 [M+]. Anal. Calcd for C18H24N2O4: C, 65.04;
H, 7.28; N, 8.43. Found: C, 65.00; H, 7.30; N, 8.39.
1
°C (benzene); IR νmax 3265, 1747, 1640 cm-1; H NMR (CDCl3)
δ 7.23, 6.84 (AA′XX′ system, J ) 8.5 Hz, 4 H), 5.72 (s, 1 H,
exch.), 3.80 (s, 3 H), 3.69 (s, 3 H), 3.42, 3.33 (AB system, J )
13.0 Hz, 2 H), 3.01 (dd, J ) 13.9, 1.8 Hz, 1 H), 2.84 (d, J ) 10.2
Hz, 1 H), 2.71 (d, J ) 8.4 Hz, 1 H), 2.30 (br s, 1 H), 2.30-1.85
(m, 5 H), 1.96 (s, 3 H), 1.51 (dd, J ) 11.3, 2.2 Hz, 1 H); 13C NMR
(CDCl3) δ 172.5, 169.7, 159.0, 131.1, 130.4, 113.9, 68.5, 62.0, 59.0,
55.9, 55.6, 52.5, 46.8, 39.9, 37.1, 35.1, 23.7; m/z 347.3 [M+]. Anal.
Calcd for C19H26N2O4: C, 65.87; H, 7.56; N, 8.09. Found: C, 65.91;
H, 7.54; N, 8.08.
(-)-Phenylmenthyl (1S,5S,6S)-6-(Acetylamino)-3-(4-methoxy-
benzyl)-3-azabicyclo[3.2.1]octane-6-carboxylate exo-5b: Mp 186
°C (i-Pr2O); [R]25D ) -46.5° (c 5.24, CHCl3); IR νmax 3400, 1730,
1
1657 cm-1
;
H NMR (CDCl3) δ 7.28-7.08 (m, 6 H), 7.08-6.98
(m, 1 H), 6.86 (d, J ) 8.4 Hz, 2 H), 5.94 (s, 1 H, exch.), 4.81-
4.65 (m, 1 H), 3.80 (s, 3 H), 3.54, 3.16 (AB system, J ) 12.5 Hz,
2 H), 2.90-2.70 (m, 1 H), 2.65-2.00 (m, 4 H), 2.00-1.80 (m, 2
H), 1.60-0.70 (m, 11 H), 1.58 (s, 3 H), 1.30 (s, 3 H), 1.19 (s, 3
H), 0.83 (d, J ) 6.2 Hz, 3 H); 13C NMR (CDCl3) δ 173.3, 170.6,
159.2, 151.7, 131.0, 130.5, 128.1, 125.9, 125.2, 114.1, 76.7, 66.2,
62.2, 60.9, 55.6, 54.8, 50.4, 42.1, 41.1, 40.3, 36.7, 34.9, 34.7, 31.5,
28.4, 27.6, 25.0, 23.1, 22.7, 22.0; m/z 547.3 [M+]. Anal. Calcd for
C34H46N2O4: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.53; H, 8.50;
N, 5.09.
(-)-Phenylmenthyl (1R,5R,6S)-6-(Acetylamino)-3-(4-meth-
oxybenzyl)-3-azabicyclo[3.2.1]octane-6-carboxylate endo-5b: Mp
86 °C (CH2Cl2/iPr2O); [R]25D ) -3.5° (c 6.4, CHCl3); IR νmax 3400,
1730, 1657 cm-1 1 H NMR (CDCl3) δ 7.42-7.05 (m, 6 H), 7.05-
;
6.95 (m, 1 H), 6.88 (d, J ) 8.8 Hz, 2 H), 5.42 (s, 1 H, exch.),
4.78-4.66 (m, 1 H), 3.82 (s, 3 H), 3.55, 3.22 (AB system, J )
13.0 Hz, 2 H), 2.90-2.80 (m, 1 H), 2.58-162 (m, 10 H), 1.57 (s,
3H), 1.58-0.70 (m, 7 H), 1.29 (s, 3 H), 1.15 (s, 3 H), 0.84 (d, J )
6.2 Hz, 3 H); 13C NMR (CDCl3) δ 171.0, 169.4, 158.8, 152.3, 131.0,
130.2, 128.1, 125.8, 125.2, 113.7, 77.3, 68.5 61.5, 58.1, 55.7, 55.4,
50.2, 41.1, 40.3, 39.1, 37.1, 35.0, 34.6, 31.6, 28.3, 27.6, 25.4, 23.5,
23.1, 22.1; m/z 547.3 [M+]. Anal. Calcd for C34H46N2O4: C, 74.69;
H, 8.48; N, 5.12. Found: C, 74.50; H, 8.51; N, 5.07.
General Procedure for the Oxidative Deprotection of 5a. To
a solution of compound 5a (346 mg, 1 mmol) in acetone/H2O (23
mL, 9:1) at 0 °C was added (NH4)2Ce(NO3)6 (2.19 g, 4 mmol) in
several portions in 1 h. The mixture was stirred at room temperature
for 3 h and quenched with a saturated solution of NaHCO3 (pH
General Procedure for the Hydrolysis of Amino Acid Func-
tion. (i) Operating in a sealed tube, compounds (()-exo-5a,6a or
(()-endo-5a,6a (1 mmol) were suspended in HCl (1 mL, 6 M),
and the mixture was heated at 120 °C for 24 h. The solvent was
removed, and the crude amino acids (()-exo-8 (mixture of
conformers 7:1), exo-9, and (()-endo-8,9 were isolated as bischlo-
rohydrate in quantitative yield. (ii) Operating in a sealed tube,
MeOH (5 mL) was cooled at 0 °C, and Na (161 mg, 7 mmol) was
added. Compound 5b (546.7 mg, 1 mmol) was added, and the
mixture was heated at 100 °C under stirring for 50 h (TLC, CH2-
Cl2/MeOH, 50:1). The solvent was removed, and the crude reaction
mixture was taken up with distilled H2O (5 mL) and extracted with
AcOEt (3 × 10 mL). The aqueous solution was treated with HCl
(6 N, pH 1) and was purified by a Dowex 50W × 4-50
J. Org. Chem, Vol. 71, No. 22, 2006 8471

Caputo et al.
ion-exchange resin which was first activated with NH4OH (2 N)
then with AcOH (2 N, pH 4) followed by washing with H2O (pH
7). The reaction mixture was deposited on the resin which was
rinsed with water. The amino acid was eluted with aqueous NH4OH
(2 N). Ninhydrin positive fractions (TLC, CH2Cl2/MeOH/NH4OH-
(15%) ) 5:3:0.9) were pooled and evaporated to give (-)-exo-8
(130 mg, 45%) from (-)-exo-5b and (-)-endo-8 (172 mg, 60%)
from (-)-endo-5b.
3.45 (dt, J ) 14.6, 2.2 Hz, 1 H), 3.37-3.24 (m, 2 H), 2.89 (dd, J
) 15.9, 8.0 Hz, 1 H), 2.78 (br s, 1 H), 2.62 (br s, 1 H), 2.45-2.28
(m, 1 H), 1.85 (dd, J ) 15.9, 1.9 Hz, 1 H), 1.79 (dd, J ) 13.0, 2.1
Hz, 1 H); 13C NMR δ 172.6, 63.1, 48.9, 42.9, 39.6, 33.6, 32.2,
31.0; m/z 172.2 [M]+. Anal. Calcd for C8H16Cl2N2O2: C, 39.52;
H, 6.63; N, 11.52. Found: C, 39.05; H, 6.96; N, 11.30.
(1R*,5R*,6S*)-6-Amino-3-azabicyclo[3.2.1]octane-6-carbox-
ylic Acid 2 HCl (()-endo-9: IR νmax 3600-2950, 1697, 1627 cm-1
;
6-Amino-3-(4-methoxybenzyl)-3-azabicyclo[3.2.1]octane-6-
carboxylic Acids: (1S*,5S*,6S*) (()-exo-8‚2 HCl: mixture of
isomers (8:1); mp 176 °C (acetone/H2O); IR νmax 3470-3370, 1742,
1614 cm-1; 1H NMR (D2O) δ (major isomer) 7.32, 6.92 (AA′BB′
system, J ) 8.8 Hz, 4 H), 4.29, 4.13 (AB system, J ) 12.8 Hz, 2
H), 3.70 (s, 3 H), 3.52, 3.37 (AB system, J ) 14.3 Hz, 2 H), 3.15
(br s, 2 H), 2.70-2.55 (m, 2 H), 2.52-2.48 (m, 1 H), 2.30-2.10
(m, 1 H), 1.62 (d, J ) 4.0 Hz, 1 H), 1.56 (d, J ) 8.4 Hz, 1 H);
(minor isomer (significative signals)) 7.18, 6.80 (AA′BB′ system,
J ) 8.8 Hz, 4 H); 13C NMR (D2O) δ 173.1, 160.5, 133.3 (133.5),
120.3, 114.5 (115.9), 64.6, 61.9, 57.5, 55.5, 52.5, 41.5, 33.8, 33.0,
32.5; m/z 291.8 [M+]. Anal. Calcd for C16H24Cl2N2O3: C, 52.90;
H, 6.66; N, 7.71. Found: C, 52.50; H, 7.00; N, 7.28.
1H NMR (D2O) δ 3.35 (dt, J ) 12.7, 2.4 Hz, 1 H), 3.27 (br s, 2
H), 3.23 (d, J ) 12.7 Hz, 1 H), 2.71 (br s, 1 H), 2.68 (br s, 1 H),
2.57 (dd, J ) 15.9, 2.1 Hz, 1 H), 2.24 (dd, J ) 15.9, 7.4 Hz, 1 H),
2.20-2.12 (m, 1 H), 1.98 (dd, J ) 13.2, 2.1 Hz, 1 H); 13C NMR
(D2O) δ 173.2, 66.3, 48.4, 45.7, 41.4, 37.7, 33.2, 32.6; m/z 172.2
[M]+. Anal. Calcd for C8H16Cl2N2O2: C, 39.52; H, 6.63; N, 11.52.
Found: C, 39.01; H, 6.98; N, 11.28.
(1S*,5S*,6S*) Methyl 6-Amino-3-azabicyclo[3.2.1]octane-6-
carboxylate (()-exo-10: Amino acid exo-9 (53 mg, 0.31 mmol)
was dissolved in MeOH (3 mL), and SOCl2 was added (100 µL,
0.62 mmol), and the mixture was refluxed for 5 h. After cooling,
the reaction mixture was treated with a saturated solution of
NaHCO3 (pH 10). The solid was filtered, and the solution, after
solvent evaporation of the solvent, was chromatographed on silica
(1S,5S,6S) (-)-exo-8: [R]25 ) -36.3° (c 3.7, MeOH).
D
(1R*,5R*,6S*) (()-endo-8‚2 HCl: mixture of isomers (3:1); mp
gel (CH2Cl2/MeOH/NH4OH(15%) ) 25:5:0.1). Compound
1
220-221 °C (EtOH); IR νmax 3405-2950, 1725, 1614 cm-1; H
(()-exo-10 was isolated and crystallized (51 mg, 89%): Mp 250
°C dec (EtOH); IR νmax 3466, 1731, 1637 cm-1; 1H NMR (D2O) δ
3.77 (s, 3 H), 3.30-3.05 (m, 4 H), 2.57 (br s, 1 H), 2.40-1.95 (m,
4 H), 1.75 (dd, J ) 12.4, 1.8 Hz, 1 H); 13C NMR δ 175.8, 81.3,
53.0, 49.0, 44.8, 44.3, 40.9, 33.4, 31.8. Anal. Calcd for
C9H16N2O2: C, 58.67; H, 8.75; N, 15.21. Found: C, 56.60; H, 8.78;
N, 15.18.
NMR (D2O) δ (major isomer) 7.35, 7.01 (AA′BB′ system, J ) 8.8
Hz, 4 H), 4.18, 4.12 (AB system, J ) 13.1 Hz, 2 H), 3.79 (s, 3 H),
3.44, 3.16 (AB system, J ) 11.2 Hz, 2 H), 3.28-3.13 (m, 2 H),
2.71 (br s, 1 H), 2.66 (br s, 1 H), 2.46 (dd, J ) 15.7, 2.1 Hz, 1 H),
2.17 (dd system, J ) 15.7, 7.2 Hz, 1 H), 2.09-2.07 (m, 1 H), 1.94
(d, J ) 13.5 Hz, 1 H); (minor isomer (significative signals)) 7.28,
6.90 (AA′BB′ system, J ) 8.8 Hz, 4 H); 13C NMR (D2O) δ 174.6,
160.3, 132.4 (132.2), 121.3 (120.6), 114.9 (116.2), 67.1, 59.96
(60.03), 56.99 (56.93), 55.5, 54.5, 42.8, 38.9, 34.2, 33.9; m/z 291.8
[M+]. Anal. Calcd for C16H24Cl2N2O3: C, 52.90; H, 6.66; N, 7.71.
Found: C, 52.53; H, 7.69; N, 7.29.
Acknowledgment. We thank MIUR (PRIN 2004) for
financial support.
Supporting Information Available: General technique, NMR
1
discussion for compounds 5a, and H and 13C NMR spectra of
(1R,5R,6S) (-)-endo-8: [R]25 ) -14.0° (c 4.25, MeOH).
D
2-10. This material is available free of charge via the Internet at
http://pubs.acs.org.
(1S*,5S*,6S*)-6-Amino-3-azabicyclo[3.2.1]octane-6-carboxy-
lic Acid 2 HCl (()-exo-9: IR νmax 3600-2950, 1695, 1626 cm-1
;
1H NMR (2‚HCl salt D2O) δ 3.51 (dd, J ) 14.6, 3.1 Hz, 1 H),
JO061391O
8472 J. Org. Chem., Vol. 71, No. 22, 2006