An efficient route to all stereoisomeric enantiopure 6-amino-3-alkyl-3- azabicyclo[3.2.1]octane-6-carboxylic acids

Article abstract of DOI:10.1021/jo7019702

(Chemical Equation Presented) A single-step synthesis on a gram scale of four pure stereoisomers of the 6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic acid was carried out using (R)-1-phenylethylamine to confer chirality. The phenylethyl group, and the p-

Full text of DOI:10.1021/jo7019702

acid (GABA),3 the major inhibitory neurotransmitter in the
vertebrate central nervous system implicated in many physi-
ological and pathological events.4 The GABAA receptor gates
a Cl--selective channel in response to the binding of the
transmitter as well as of benzodiazepines, barbiturates, and
steroids.5 Selective targeting and modulation of GABA trans-
porter subtypes is of biological interest and additionally of
importance for the elucidation of their specialized physiological
function and individual structure. Different constrained amino
acids have been prepared and tested on GABA receptors such
as nipecotic acid and guvacine,6,7 tiagabine,8 compound SK&F
89976-A,9 and the pyrrolidine-2-alkanoic acids.10
An Efficient Route to All Stereoisomeric
Enantiopure 6-Amino-3-alkyl-3-
azabicyclo[3.2.1]octane-6-carboxylic Acids
Maria Luisa Gelmi,*,† Cristian Cattaneo,† Sara Pellegrino,†
Francesca Clerici,† Marina Montali,‡ and Claudia Martini‡
Istituto di Chimica Organica “A. Marchesini”, Facolta` di
Farmacia, UniVersita` di Milano, Via Venezian 21,
I-20133 Milano, Italy, and Dipartimento di Psichiatria,
Neurobiologia, Farmacologia e Biotecnologie, UniVersita` di
Pisa, Via Bonanno 6, 56126 Pisa, Italy
Considering the general biological interest in new derivatives
possessing affinity for GABA receptors, we planned the
biological evaluation of amino acids 6 and 7 (Schemes 2 and
3) containing the azabicycloctane skeleton. The fact that the
stereochemistry plays a fundamental role in the interaction
between a bioactive molecule and the receptor prompted us to
revisit the previous synthetic procedure, aiming to make
available all the possible stereoisomers of 4 and 5 which
themselves were prepared in a single step. Furthermore, a series
of N-alkyl derivatives were directly prepared from the N-benzyl
derivatives 4a,b and 5a,b taking advantage of a “one-pot”
reaction consisting in the deprotection and reductive alkylation
of N-3.
marialuisa.gelmi@unimi.it
ReceiVed July 18, 2007
The synthetic strategy previously adopted2 to obtain com-
pounds 4a and 5a took advantage of the use of exo and endo
norbornene amino esters 1, which were transformed into
cyclopentyl amino esters 2 and 3 functionalized on C2 and C4
with two formyl groups with the required cis stereochemistry
(Scheme 1). Their reactions with p-methoxybenzylamine, as the
nitrogen donor, and NaBH(OAc)3, as the reducing agent,
allowed the preparation of compounds 4a and 5a. The corre-
sponding enantiopure compounds were also prepared starting
from norbornene derivatives related to 1, containing the (-)-
8-phenylmenthyl group as the chiral auxiliary, which were
obtained in very high de and exo selectivity (exo/endo, 83:17)
through a Diels-Alder reaction. This result obviously disfavored
the preparation of the endo series of compounds 5 when starting
from the (-)-8-phenylmenthyl ester of endo-1. For this reason
and also with the objective of synthesizing all stereoisomers of
compounds 4 and 5, we chose to start from the racemic methyl
A single-step synthesis on a gram scale of four pure
stereoisomers of the 6-amino-3-azabicyclo[3.2.1]octane-6-
carboxylic acid was carried out using (R)-1-phenylethylamine
to confer chirality. The phenylethyl group, and the p-methoxy
group linked to the N-atom, are easily removed by hydro-
genolysis to afford the corresponding NH-3 derivatives. A
series of N-3-alkyl compounds were prepared by way of a
“one-pot” deprotection-alkylation procedure starting from
the above key compounds. Their biological activity has been
evaluated on the GABA receptor.
Compounds containing the 3-azabicyclo[3.2.1]octane scaffold
are of biological interest as evidenced by recent literature1 and
a large number of patents. Recently,2 we reported on the
synthesis of diastereoisomeric 6-amino-3-azabicyclo[3.2.1]-
octane-6-carboxylic acid derivatives exo-4a and endo-5a (Scheme
1), as well as of the corresponding NH-3 derivatives. Com-
pounds 4 and 5 are constrained analogues of γ-aminobutyric
(3) Mehta, A. K.; Ticku, M. K. Brain Res. ReV. 1999, 29, 196-217.
(4) Olsen, R. W.; DeLorey, T. M. GABA and glycine. In Basic
Neurochemistry; Siegel, G. J., Agranoff, B. W., Albers, R. W., Fisher, S.
K., Uhler, M. D., Eds.; Lippincott-Raven: New York, 1999; pp 335-346.
(5) MacDonald, R. L.; Olsen, R. W. Ann. Neurosci. 1994, 17, 569-
602.
† Universita` di Milano.
‡ Universita` di Pisa.
(1) (a) Kumar, N.; Kaur, K.; Gupta, S.; Chugh, A.; Salman, M.;
Shirumalla, R. K.; Malhotra, S. PCT Int. Appl. 2007, PIXXD2 WO
2007039884 A1 20070412; Chem. Abstr. 2007, 146, 401841. (b) Hamamoto,
I.; Takahashi, J.; Yano, M.; Kawaguchi, M.; Hanai, D.; Iwasa, T. PCT Int.
Appl. 2007, PIXXD2 O 2007040280 A1 20070412; Chem. Abstr. 2007,
146, 401834. (c) Sarma, P. K. S.; Shelke, S. Y.; Ashani, K.; Gupta, P.; Pal,
A.; Kondaskar, A.; Dharmarajan, S.; Sharma, S.; Chugh, A.; Tiwari, A.
PCT Int. Appl. 2007, PIXXD2 WO 2007029078 A2 20070315 Chem. Abstr.
2007, 146, 316947. (d) Zierler-Brown, S. L.; Kyle, J. A. Ann. Pharmacother.
2007, 41, 95. (e) Buschmann, H. H. PCT Int. Appl. 2007, PIXXD2 WO
2007009691 A2 20070125; Chem. Abstr. 2007, 146, 163111. (f) Keating,
G. M.; Siddiqui, M. A. A. CNS Drugs 2006, 20, 945. (g) Meinke, L.;
Chitkara, R.; Krishna, G. Exp. Opinion Pharmacother. 2007, 8, 23.
(2) Caputo, F.; Cattaneo. C.; Clerici, F.; Gelmi, M. L.; Pellegrino, S. J.
Org. Chem. 2006, 71, 8467-8472 and references cited therein.
(6) Johnston, G.; Krogsgaard-Larsen, P.; Stephanson, A. Nature 1975,
258, 627-628.
(7) Croucher, M. J.; Meldrum, B. S.; Krogsgaard-Larsen, P. Eur. J.
Pharmacol. 1983, 89, 217-228.
(8) Andersen, K. E.; Braestrup, C.; Grønwald, F. C.; Jørgensen, A. S.;
Nielsen, E. B.; Sonnewald, U.; Sørensen, P. O.; Suzdak, P. D.; Knutsen, L.
J. S. J. Med. Chem. 1993, 36, 1716-1725.
(9) Ali, F. E.; Bondinell, W. E.; Dandridge, P. A.; Frazee, J. S.; Garvey,
W.; Girard, G. R.; Kaiser, C.; Ku, T. W.; Lafferty, J. J.; Moonsammy, G.
I.; Oh, H.-J.; Rush, J. A.; Setler, P. E.; Stringer, O. D.; Venslavsky, J. W.;
Volpe, B. W.; Yunger, L. M.; Zirkle, G. C. L. J. Med. Chem. 1985, 28,
653-660.
(10) Fu¨lep, G. H.; Hoesl, C. E.; Ho¨fner, G.; Wanner, K. T. Eur. J. Med.
Chem. 2006, 41, 809-824.
10.1021/jo7019702 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/08/2007
J. Org. Chem. 2007, 72, 9811-9814
9811

SCHEME 1. Synthesis of 3-N-Alkyl-6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic Acids by Reductive Amination Procedurea
a Reagents and conditions: (i) RNH2, NaBH(OAc)3, AcOH (cat.), ClCH2CH2Cl, 25 °C.
SCHEME 2. Synthesis of 3-N-Alkyl-6-amino-3-azabicyclo[3.2.1]octane-6-carboxylic Acids by a “One-Pot”
Deprotection-Alkylation Procedurea
a Reagents and conditions: (i) 4d,5d,6d′,7d: H2, Pd/C, MeOH; (ii) H2, Pd/C (4c,5c: MeOH/HCHO; 4e,5e: EtOH/MeCHO; 4f: MeCOMe); (iii)
(Ph)2CdCH(CH2)2Br, K2CO3, NaI, DMF; (iv) 6 N HCl, ∆; (v) anhydrous HCl, EtOH.
esters of exo-1 and endo-1 which have been prepared in a 70:
30 ratio and on a multigram scale.11 Following the same
synthetic protocol adopted for the preparation of compounds
4a and 5a,2 all enantiopure stereoisomers exo-4b/4b′ and endo-
5b/5b′ were prepared starting from a mixture of racemic bis-
aldehydes 2 and 3 and performing the reductive amination in
the presence of (+)-(R)-1-phenylethylamine and NaBH(OAc)3
in dichloroethane (25 °C, 12 h) while using AcOH as catalyst.
Using an efficient chromatographic separation, the diastereoi-
someric azabicycloderivatives exo-4b (25%), exo-4b′ (28%),
endo-5b (12%), and endo-5b′ (10%) were isolated (Scheme 1).
The preparation of the above amino acids was performed on
the gram scale (7 g), thus ensuring the availability of enantiopure
materials, using a cheaper chiral reagent such as (R)-1-
phenylethylamine in place of (-)-8-phenylmenthol. The above
method was applied to the preparation of the 3-N-methyl
compounds (()-exo-4c (24%) and (()-endo-5c (11%), which
were obtained in poor yields from the mixture of aldehydes 2
and 3 and methylamine. The p-methoxybenzyl derivatives 4a
and 5a were then selected as key reagents aiming to find a
general procedure to minimize the number of the synthetic steps.
This allowed the NH-compounds as well as a series of N-alkyl
compounds to be synthesized efficiently. The deprotection of
N-3 was performed by hydrogenolysis which made possible an
easy purification of the reaction product (Scheme 2). The
hydrogenolysis of (()-exo-4a and (()-endo-5a (Pd/C, MeOH,
25 °C, 1 atm, 2 days) gave the NH derivative (()-exo-4d (97%)
and (()-endo-5d (93%), respectively.
(11) Bueno, M. P.; Cativiela, C.; Finol, C.; Mayoral, J. A. Can. J. Chem.
1987, 65, 2182-2186.
9812 J. Org. Chem., Vol. 72, No. 25, 2007

SCHEME 3. Enantiopure 6-Amino-3-azabicyclo[3.2.1]octane-6-carboxylic Acids and Their 3-N-Methyl Derivativesa
a Reagents and conditions: (i) R ) Me: H2, Pd/C, MeOH, HCHO; (ii) R ) H: H2, Pd/C, MeOH; (iii) 6 N HCl, ∆.
The same protocol was used efficiently (36 h) to deprotect
(-)-exo-4b′ and (+)-endo-5b, and the pure NH enantiomers (-)-
exo-4d′ (85%) and (+)-endo-5d (73%) were isolated (Scheme
3). In principle, compounds of the d series could also be
precursors for the preparation of N-alkyl compounds using well-
known methods. Here, we report on the use of an alternative
strategy to achieve this synthetic target consisting in a “one pot”
deprotecton and alkylation reaction of the nitrogen atom on N-3,
taking advantage of the use of catalytic hydrogenation in
presence of a carbonyl compound, starting from reagents 4a
and 5a or enantiopure compounds 4b/4b′ and 5b/5b′. When
the hydrogenolysis was performed in presence of a methanolic
solution of formaldehyde (37%), the N-methyl derivatives (()-
exo-4c (74%) and (()-endo-5c (70%) were isolated, respec-
tively, from (()-exo-4a and (()-endo-5a (Scheme 2). It has to
be emphasized that this synthetic approach is a valuable
alternative to the reductive amination of bis-aldehydes 2 and 3
in the presence of MeNH2 which gave the same N-methyl
derivatives 4c and 5c but in very low yield (Scheme 1). The
reductive alkylation of (()-exo-4a was also performed in EtOH/
acetaldehyde and in acetone and the expected N-ethyl and
N-isopropyl derivatives (()-exo-4e (93%) and (()-exo-4f (86%)
were isolated, respectively (Scheme 2). Compound (()-endo-
5e (85%) was obtained from (()-endo-5a.
The “one-pot” deprotection-methylation reaction of the N-3
atom of the four stereoisomers (+)-exo-4b, (-)-exo-4b′, (+)-
endo-5b, and (-)-endo-5b′ using formaldehyde gave the pure
enantiomers (+)-exo-4c (80%), (-)-exo-4c′ (70%), (+)-endo-
5c (83%), and (-)-endo-5c′ (85%), respectively (Scheme 3).
Finally, considering that the 4,4-diphenylbut-3-en-1-yl group
is a typical residue that increases selectivity (see compound
SK&F 89976-A9) on GABA receptors and taking into account
that the appropriate aldehyde is not available, compound (()-
exo-4g (30%) was prepared starting from (()-exo-4d and 4,4-
diphenylbut-3-en-1-yl bromide operating in DMF and in the
presence of K2CO3 and NaI (Scheme 2).
7d ([R]D ) +4.0) derived from the catalytic hydrogenolysis
(Scheme 2) of the known amino acids (-)-exo-6a′2 and (-)-
endo-7a2 followed by their treatment with anhydrous HCl in
EtOH.
The hydrolysis of (+)-exo-4c, (-)-exo-4c′, (+)-endo-5c, and
(-)-endo-5c′ as well as of (()-exo-4e,g performed as described
before gave the corresponding amino acids (+)-exo-6c, (-)-
exo-6c′, (+)-endo-7c, (-)-endo-7c′, and (()-exo-6e,g in quan-
titative yields.
Amino acids exo-6 and endo-7, as well as some of the
corresponding N-acetyl derivatives (see Table TS1 in the
Supporting Information) were tested for their binding ability to
GABAA receptors in rat cerebral cortical membranes using
labeling tests with [3H]muscimol (for GABAA sites) and [3H]-
flunitrazepam (for the benzodiazepine site). In general, these
compounds did not display an appreciable affinity for the
GABAA receptor. Only the N-Me compounds displayed low
affinity for GABAA receptors but the biological activity resides
solely in the (+) enantiomers (i.e., (+)-(1R,5R,6R)-exo-6c and
(+)-(1R,5R,6S)-endo-7c), thus confirming that the stereochem-
istry of the skeleton is an important feature in the binding to
GABA receptors.
In conclusion, a very efficient method to prepare the four
stereoisomers of 6-amino-3-azabicyclo[3.2.1]octane-6-carboxy-
lates on the gram scale in a single step is described using (R)-
1-phenylethylamine as the chiral-inducing moiety. The phenyl-
ethyl and the p-methoxy groups are easily removed by
hydrogenolysis to give the corresponding NH-3 derivatives. By
way of a “one-pot” deprotection-alkylation reaction, a series
of N-3-alkyl compounds were synthesized. It can be concluded
that compounds of the b series are valuable synthons for the
preparation of enantiopure N-3-alkyl substituted derivatives.
Experimental Section
Compounds 2, 3, (()-exo-4a, (()-endo-5a, (-)-exo-6a′, and (-)-
endo-7a are known compounds.2
Aiming to ensure the correct stereochemistry of each stere-
oisomer of the b series, isomers (-)-exo-4d′ and (+)-endo-5d
were hydrolyzed in 6 N HCl (100 °C, 24 h) to give (-)-exo-
6d′ and (+)-endo-7d, respectively, in quantitative yield as the
bishydrochlorides (Scheme 3). Compounds (-)-exo-6d′ ([R]D
) -9.3) and (+)-endo-7d ([R]D ) +4.9) were correlated to
the same compounds (-)-exo-6d′ ([R]D ) -9.0) and (+)-endo-
General Procedure for the Reductive Amination from Alde-
hydes 2 and 3: Synthesis of 3-Azabicyclo[3.2.1]octane exo-
4b,b′,c and endo-5b,b′,c. A mixture of aldehydes 2 and 3 (241
mg, 1 mmol) was dissolved in anhydrous dichloroethane (4 mL)
under N2 with stirring at 25 °C. (R)-1-Phenylethylamine (50 µL,
1.1 mmol) or MeNH2 (32.6 mg, 1.05 mmol), NaBH(OAc)3 (530
mg, 2.5 mmol), and AcOH (catalytic amount) were added. After
J. Org. Chem, Vol. 72, No. 25, 2007 9813

36 h, the solvent was removed, and the mixture was taken up with
CH2Cl2 (5 mL), washed with H2O (5 mL), and dried over MgSO4.
In the case of phenylethylamine (1.45 mL, 31.9 mmol), the reaction
has been scaled up starting from aldehydes 2,3 (7 g, 29 mmol) to
give a mixture of diastereoisomers (7.6 g, 80%), which were
chromatographed on silica gel (CH2Cl2/MeOH, 20:1). This afforded
a mixture of exo-4b/4b′ (5.3 g, 56%) and endo-5b/5b′ (2.3 g, 24%).
Using a Biotage chromatographic system (column: FLASH 65i,
KP-SIL, 65 × 200 mm; exo-4b/4b′: cyclohexane/AcOEt, 3:2; endo-
5b/5b′: CH2Cl2/MeOH, 10:1) pure (+)-exo-4b (2.3 g, 25%) was
separated from (-)-exo-4b′ (2.65 g, 28%) and (+)-endo-5b
(1.15 g, 12%) from (-)-endo-5b′ (0.95 g, 10%). Pure (()-exo-4c
(57 mg, 24%) and (()-endo-5c (21.6 mg, 11%) were isolated after
column chromatography (CH2Cl2/MeOH, 50:1) and crystallization.
General Procedure for the Deprotection of N-3. Compound
(()-exo-4a or (()-endo-5a (346 mg, 1 mmol), (-)-exo-4b′ or (+)-
endo-5b (330 mg, 1 mmol), or (-)-exo-6a′ or (-)-endo-7a (290
mg, 1 mmol) was dissolved in MeOH (10 mL). Pd/C (10%, 100
mg, 0.1 mmol) was added, and the mixture was hydrogenated
(25 °C, 1 atm; exo-4a and endo-5a: 48 h; exo-4b′ and endo-5b:
36 h; exo-6a′ and endo-7a: 24 h). The mixture was filtered through
a Celite pad, the solvent was removed, and the residue was purified
by column chromatography on silica gel (CH2Cl2/MeOH, 1 : 1).
The pure compounds [from (()-exo-4a: (()-exo-4d (165 mg,
73%); from (()-endo-5a: (()-endo-5d (158 mg, 70%); from (-)-
exo-4b′: (-)-exo-4d′ (192 mg, 85%); from (+)-endo-5b: (+)-endo-
5d (165 mg, 73%), from (-)-exo-6a′: (-)-exo-6d′ (142 mg, 84%);
from (-)-endo-7a: (+)-endo-7d (160 mg, 95%)] were obtained
after crystallization. Spectroscopic data of known compounds are
in agreement with literature.2
0.044 mmol) at 25 °C and 1 atm for 24 h. The catalyst was removed
by filtration through celite and the solvent was eliminated affording
the expected compounds of the c series [from (()-exo-4a: (()-
exo-4c (90 mg, 88%); from (()-endo-5a: (()-endo-5c (88 mg,
85%); from (+)-exo-4b: (+)-exo-4c (50 mg, 70%); from (-)-exo-
4b′: (-)-exo-4c′ (58 mg, 80%); from (+)-endo-5b: (+)-endo-5c
(60 mg, 83%); from (-)-endo-5b′: (-)-endo-5c′ (62 mg, 85%)]
or (()-exo-4e (from (()-exo-4a: 100 mg, 90%) or (()-endo-5e
(from (()-endo-5a: 75 mg, 68%) or (()-exo-4f (from (()-exo-
4a: 81 mg, 70%) after crystallization.
Synthesis of Methyl (()-(1S*,5S*,6S*)-6-Acetamido-3-(4,4-
diphenylbut-3-enyl)-3-azabicyclo[3.2.1]octane-6-carboxylate exo-
4g. To a solution of (()-exo-4d (297 mg, 1.3 mmol) in DMF (20
mL) were added 4-bromo-1,1-diphenylbut-1-ene (565 mg, 1.96
mmol), K2CO3 (370 mg, 2.68 mmol), and NaI (78 mg, 0.52 mmol).
The reaction was stirred at reflux for 48 h (TLC: CH2Cl2/n-hexane,
4:1) and then poured into water (10 mL) and extracted with Et2O
(3 × 10 mL). The organic layer was washed with a saturated
solution of NaCl (3 × 10 mL) and dried over Na2SO4. After flash
column chromatography on silica gel (CH2Cl2/MeOH, 40:1) pure
compound (()-exo-4g was obtained (170 mg, 30%).
General Hydrolysis Procedure to obtain Amino Acid Dihy-
drochlorides. Operating in a sealed tube, compound (+)-exo-4c
or (-)-exo-4c′, (+)-endo-5c or (-)-endo-5c′, (+)-exo-4d or (-)-
exo-4d′, (+)-endo-5d or (-)-endo-5d′, or (()-exo-4e or (()-exo-
4g (1 mmol) was suspended in 6 N HCl (1 mL), and the mixture
was heated at 120 °C for 14 h. The solvent was removed, and the
corresponding acids exo-6, exo-6′, endo-7, and endo-7′ were isolated
in quantitative yield. The spectroscopic data of the known com-
pounds are in agreement with the literature.2
6-Amino-3-azabicyclo[3.2.1]octane-6-carboxylic Acids exo-6d′
and endo-7d‚2HCl. The hydrochloride salts were obtained after
treating compounds (-)-exo-6d′ and (+)-endo-7d individually with
a solution of anhydrous HCl in EtOH.
(-)-(1S,5S,6S)-6-Amino-3-azabicyclo[3.2.1]octane-6-carboxy-
lic Acid exo-6d′‚2HCl: [R]25 -9.3 (c 0.5, MeOH).
D
(+)-(1R,5R,6S)-6-Amino-3-azabicyclo[3.2.1]octane-6-carboxy-
lic Acid endo-7d‚2HCl: [R]25 +4.9 (c 0.5, MeOH).
D
(-)-(1S,5S,6S)-exo-6d′‚2HCl: [R]25 -9.0 (c 0.5, MeOH).
D
Acknowledgment. We thank MIUR (PRIN 2006) for
financial support.
(+)-(1R,5R,6S)-endo-7d‚2HCl: [R]25 +4.0 (c 0.5, MeOH).
D
General Procedure for the “One-Pot” Deprotection-Alky-
lation Reaction of N-3. Compound (()-exo-4a or (()-endo-5a (150
mg, 0.432 mmol), (+)-exo-4b or (-)-exo-4b′, or (+)-endo-5b or
(-)-endo-5b′ (100 mg, 0.303 mmol) was dissolved in the appropri-
ate solvent (see below: 10 mL). A catalytic amount of AcOH and
a carbonyl compound were added [for c: MeOH and formaldehyde
(37% MeOH solution, 200 µL, 1.2 mmol); for e: EtOH and
acetaldehyde (25 µL, 0.476 mmol); for f: acetone and water 1:3].
The mixture was hydrogenated over a Pd/C catalyst (10%, 47 mg,
Supporting Information Available: General technique. Ana-
lytical, spectroscopic data, 1H and 13C NMR spectra of compounds
exo-4b-g, exo-4b′-d′, endo-5b-e, endo-5b′-c′, exo-6c,e,g, exo-
6c′, endo-7c, and endo-7c′. Biological activity of compounds exo-
6a,c,c′,d,g, endo-7a,c,c′,d, exo-8, and endo-9. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7019702
9814 J. Org. Chem., Vol. 72, No. 25, 2007