Enantioselective synthesis of [(1R,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept- 5-en-3-yl]methanol via Aza-Diels-Alder reaction

Article abstract of DOI:10.1055/s-2004-836068

The asymmetric aza-Diels-Alder reaction of the 8-phenylneomenthyl (or 8-phenylisomenthyl) glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding [(1R,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-

Full text of DOI:10.1055/s-2004-836068

LETTER
319
Enantioselective Synthesis of [(1R,3-exo)-2-Benzyl-2-azabicyclo[2.2.1]hept-5-
en-3-yl]methanol via Aza-Diels–Alder Reaction
S
ynthesisof [(
r
1
R
,
3-
e
xo
a
)
-2-Benzyl
n
-2-azabicyclo
c
[2.2.1]hep
o
t-5-en-3-yl]methan
F
ol ernández,a Xerardo García-Mera,*a Maria Luísa C. Vale,b José Enrique Rodríguez-Borges*b
a
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Fax +34(981)594912; E-mail: qoxgmera@usc.es
CIQ, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal
Fax +351(22)6082959; E-mail: jrborges@fc.up.pt
b
Received 11 October 2004
NH2
CO2H
Ph
Ph
CO2R*
Abstract: The asymmetric aza-Diels–Alder reaction of the 8-phe-
nylneomenthyl (or 8-phenylisomenthyl) glyoxylate-derived N-ben-
zylimine with cyclopentadiene resulted in the enantioselective
synthesis of the corresponding [(1R,3-exo)-2-benzyl-2-azabicy-
clo[2.2.1]hept-5-en-3-yl]carboxylate. In both cases, the (1R,3-exo)-
adduct was the main diastereomer and was isolated in 70% and 65%
yield, respectively. Reduction of the (1R,3-exo)-adducts with
LiAlH4 afforded [(1R,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-
en-3-yl]methanol, with recovery of the chiral auxiliaries with reten-
tion of configuration.
NH
O
N
N
OH
H
H
4
3
2
1
1a: R* = 8-phenylneomenthyl
1b: R* = 8-phenylisomenthyl
Figure 1
Key words: asymmetric synthesis, chiral auxiliaries, Diels–Alder
reactions, induction
In the course of our work aimed at the enantioselective
synthesis of 3-substitued 2-azabyciclo[2.2.1]hept-5-enes
and similar species, using asymmetric aza-Diels–Alder
reactions, we recently prepared all the diastereomers of
the auxiliary 8-phenylmenthol.8a
2-Azabicyclo[2.2.1]heptane and its derivatives are useful
as synthetic intermediates in the preparation of a great va-
riety of compounds of chemical, pharmaceutical and/or
biological interest. For example, 2-azabicyclo[2.2.1]hept-
5-enyl-3-carboxylates 1 are used in the preparation of
the corresponding bicyclic derivatives of 2-azabicy-
clo[2.2.1]hept-5-enyl-3-methanol 2, which have been
successfully employed as chiral ligands in asymmetric
synthesis/catalysis (carbon-carbon bond formation,1
asymmetric transfer hydrogenation of ketones2). Carbox-
ylates 1 have also been used in the enantioselective syn-
thesis of lactam 3 and its saturated analogue,3 key
intermediates in the synthesis of several compounds with
biological interest; among them are the four stereoisomers
of 4-aminocyclopent-2-ene carboxylic acid (4) and the
corresponding saturated analogues,4 which show specific
inhibitory activity towards some processes of the action
and metabolism of GABA;5 furthermore, isomer (1R,3S)-
3-aminocyclopentane carboxylic acid is the core structure
of the antibiotic amidomycin.6 These bicyclic compounds
containing the 2-azabicyclo[2.2.1]hept-5-ene system
represent an important group of synthons useful in the
preparation of amino alcohols derived from cyclopentene
(or cyclopentane), necessary for the synthesis of carbo-
cyclic analogues of nucleosides which are potential anti-
viral and antineoplastic drugs.7
In this communication we report the high asymmetric
(1R,3-exo) induction observed in the aza-Diels–Alder re-
action between cyclopentadiene and the iminium ions of
the N-benzylimines of the glyoxylates of two of the re-
ferred chiral auxiliaries, (+)-8-phenylneomenthyl and (+)-
8-phenylisomenthyl, leading to the diastereoselective
synthesis of two optically pure (2-azabicyclo[2.2.1]hept-
5-en-3-yl)carboxylates (1a,b). Reduction of adducts 1a
and 1b afforded the aminoalcohol 2, the chiral alcohols
5a,b being recovered with retention of configuration
(Figure 1).
OH
OH
Ph
Ph
5a
5b
Figure 2
The starting pure chiral alcohols, (+)-8-phenylneomen-
thol [5a, prepared by Herbert Brown reduction of (2S,5R)-
5-methyl-2-(1-methyl-1-phenylethyl)cyclohexanone with
L-Selectride®, Figure 2]8b and (+)-8-phenylisomenthol
[5b, prepared by reduction of (1R,2S,3R,6R)-1,2-epoxy-
3-methyl-6-(1-methyl-1-phenylethyl)cyclohexane with
Super-Hydride®],8c were converted into the correspond-
ing glyoxylates 7a,b (Scheme 1) by reaction with acryloyl
SYNLETT 2005, No. 2, pp 0319–0321
0
1.
0
2.
2
0
0
5
Advanced online publication: 10.12.2004
DOI: 10.1055/s-2004-836068; Art ID: G40504ST
© Georg Thieme Verlag Stuttgart · New York

320
F. Fernández et al.
LETTER
O
chloride in the presence of triethylamine and DMAP, fol-
lowed by treatment of the resulting acrylates 6a,b either
with ozone (with dimethyl sulfide quenching) or with
osmium tetroxide. The glyoxylates were characterized by
determination of their spectroscopic and physical proper-
ties and those of their 2,4-dinitrophenylhydrazone deriva-
tives 8a,b. Although the glyoxylates were isolated
initially as a mixture of the glyoxylate and its hydrate, this
presented no problem since both compounds react with
primary amines to give the desired imines. Treatment of
the glyoxylates with equimolar amounts of benzylamine,
trifluoroacetic acid and boron trifluoride etherate in
dichloromethane generated the corresponding iminium
salt (protonated imine), which was reacted in situ with ex-
cess cyclopentadiene at –78 °C. Chromatographic purifi-
cation of the mixture of adducts obtained allowed
isolation of the most abundant (1R,3-exo)-diastereoiso-
mers [1a (70% yield) and 1b (65% yield)].9,10
OR*
OH
H
H
N
N
R* = 8-phenylmenthyl
10
9
Figure 3
Diels–Alder reaction between cyclopentadiene and the
imine ion formed in the reaction of benzyl amine with the
corresponding glyoxylates of these alcohols.
Acknowledgment
The authors thank the Xunta de Galicia for financial support of
this work under projects PGIDT01PXI20302PR and
PGIDT02BTF2030SPR.
Treatment of the cycloadducts 1a,b with LiAlH4 then
afforded aminoalcohol 2,11 while allowing recovery of the
chiral auxiliaries 5a,b with retention of configuration in
both cases.
Comparison of the spectroscopic data (1H NMR and 13C
NMR) and specific rotation of aminoalcohol 2 with those
of aminoalcohol 9, the absolute configuration of which
has been established by crystallography X-ray of its pre-
cursor ester 10,12 allowed determination of the absolute
configurations of adducts 1a,b (1R,3-exo in both cases,
Figure 3).
References
(1) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem.
1998, 63, 2350.
(2) Alonso, D.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson,
P. G. J. Org. Chem. 1998, 63, 2749.
(3) (a) Stella, L.; Abraham, H.; Feneau-Dupont, J.; Tinant, B.;
De Clerq, J. P. Tetrahedron Lett. 1990, 31, 2603.
(b) Bailey, P. D.; Brown, G. R.; Korber, F.; Reed, A.;
Wilson, R. D. Tetrahedron: Asymmetry 1991, 2, 1263.
(c) Taylor, S. J. C.; Sutherland, A. G.; Lee, C.; Wisdom, R.;
Thomas, S.; Roberts, S. M.; Evans, C. J. J. Chem. Soc.,
Chem. Commun. 1990, 16, 1120.
(4) (a) Choi, S.; Storici, P.; Schirmer, T.; Silverman, R. B. J.
Am. Chem. Soc. 2002, 124, 1620. (b) Smith, M. E. B.;
Lloyd, M. C.; Derrien, N.; Lloyd, R. C.; Taylor, S. J. C.;
Chaplin, D. A.; Casy, G.; McCague, R. Tetrahedron:
Asymmetry 2001, 12, 703.
The results obtained illustrate the utility of 8-phenylneo-
menthol and 8-phenylisomenthol as two easily recover-
able stereocontrolling auxiliaries, affording optically pure
3-functionalized 2-azabyciclo[2.2.1]hept-5-enes with
(1R,3-exo) induction (majority) by asymmetric aza-
O
O3
SMe2
O
O
Cl
H
R*OH
R*O
R*O
DMAP / Et3N
5a,5b
O
NH-NH2
NO2
OsO4
7a,7b
NaIO4
6a,6b
NH2
Ph
NO2
O
H
R*O
N
LiAlH4
O
N
N
NH
NO2
OR*
OH
R*OH
5a,5b
H
H
2
1a,1b
8a,8b
NO2
Scheme 1
Synlett 2005, No. 2, 319–321 © Thieme Stuttgart · New York

LETTER
Synthesis of [(1R,3-exo)-2-Benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol
321
(5) (a) Ashby, C. R. Jr.; Paul, M.; Gardner, E. L.; Gerasimov, M.
R.; Dewey, S. L.; Lennon, I. C.; Taylor, S. J. C. Synapse
(New York, U.S.A.) 2002, 44, 61. (b) Allan, R. D.; Johnston,
G. A. R. Med. Res. Rev. 1983, 3, 91; and references therein.
(6) Nakamura, S. Chem. Pharm. Bull. 1961, 9, 641.
(7) (a) Zhu, X.-F. Nucleosides, Nucleotides Nucleic Acids 2000,
19, 651. (b) Rodríguez, J. B.; Comin, M. J. Mini-Rev. Med.
Chem. 2003, 3, 95.
(8) (a) Fernández, F.; Garcia-Mera, X.; Lopez, C.; Rodríguez,
G.; Rodríguez-Borges, J. E. Tetrahedron: Asymmetry 2000,
41, 4123. (b) Caamaño, O.; Fernández, F.; Garcia-Mera, X.;
Rodríguez-Borges, J. E. Tetrahedron Lett. 2000, 11, 4805.
(c) Fernández, F.; Garcia-Mera, X.; Rodríguez-Borges, J. E.;
Blanco, J. M. Tetrahedron Lett. 2001, 42, 5239.
Compound 1a: [a]D25 +52.5 (c 1, CHCl3). IR (NaCl):
n = 3059, 2948, 1734 (CO), 1601, 1560, 1496, 1455, 1368,
1322, 1170, 1146, 1096, 1031, 978, 919, 846, 761, 733, 699,
661 cm–1. 1H NMR (CDCl3): d = 0.84 (d, J = 6.5 Hz, 3 H, 5¢-
CH3), 0.88–1.05 (m, 2 H), 1.18 and 1.20 [2 s, 6 H, 8¢-(CH3)2],
1.30–1.49 (m, 2 H), 1.50–1.79 (m, 4 H), 1.82–1.88 (m, 1 H),
1.94 (virtual d, J = 8.3 Hz, 1 H, 7sin-H), 2.29 (br s, 1 H, 3endo
-
H), 3.06 (br s, 1 H, 4-H), 3.55 (s, 2 H, CH2Ph), 3.88 (br s, 1
H, 1-H), 5.03 (br s, 1 H, 1¢eq-H), 6.25 (dd, J = 5.5 Hz, J = 1.8
Hz, 1 H, 5-H), 6.49 (dd, J = 5.5 Hz, J = 3.4 Hz, 1 H, 6-H),
7.10–7.45 (m, 10 H, C6H5). 13C NMR (CDCl3): d = 22.57
(5¢-CH3), 22.75 (C-3¢), 26.11 (C-5¢), 27.06 and 27.38 [8¢-
(CH3)2], 35.79 (C-4¢), 40.14 (C-8¢), 40.33 (C-6¢), 47.00 (C-
7), 48.95 (C-4), 51.63 (C-2¢), 59.50 (NCH2-Ph), 64.52 (C-1),
65.96 (C-3), 71.64 (C-1¢), 125.95 [aromatic C-4 (Ph)],
126.43 [aromatic C-2 + C-6 (Ph)], 127.47 [aromatic C-4
(Bn)], 128.35 [aromatic C-3 + C-5 (Ph)], 128.68 [aromatic
C-2 + C-6 (Bn)], 129.39 [aromatic C-3 + C-5 (Bn)], 134.12
(C-5), 136.76 (C-6), 139.53 [aromatic C-1 (Bn)], 150.34
[aromatic C-1 (Ph)], 173.09 [C(O)O]. HRMS: m/z calcd for
C30H37NO2: 443.2824. Found: 443.2817.
(9) General Procedure for the Synthesis of 1a.
A solution of acryloyl chloride (2.10 mL, 25.8 mmol) in dry
CH2Cl2 (40 mL) was added dropwise under argon to a
solution of (+)-8-phenylneomenthol [(5a, 3.00 g, 12.9
mmol)], Et3N (3.6 mL, 26 mmol) and 4-
(dimethylamino)pyridine (227 mg, 1.81 mmol) in dry
CH2Cl2 (60 mL) at 0 °C. The mixture was stirred for 2 h at
r.t. and was then treated with sat. NaHCO3 solution (125 mL)
and extracted with Cl2CH2 (3 × 100 mL). The pooled
organic layers were washed with sat. NaHCO3 solution
(2 × 100 mL) and brine (100 mL), and were then dried with
Na2SO4. The solvent was removed in a rotary evaporator,
and purification of the resulting residue on a short column of
silica gel using Et2O–EtOAc 9:1 as eluent afforded 6a as a
yellow oil. Yield 3.29g (89%).
A mixture of 6a (2.35 g, 8.21 mmol), OsO4 (20.8 mg, 10
equiv), H2O (9 mL) and dioxane (30 mL) was stirred at r.t.
for 5 min, during which time the mixture became dark
brown. Then NaIO4 (3.51 g, 2 equiv) was added in portions
over 30 min, and the mixture (now pale brown) was stirred
at r.t. for another 2 h and then extracted thoroughly with
Et2O. The combined organic extracts were dried (Na2SO4)
and concentrated, affording a yellow oil that upon filtration
through a short column of silica gel using hexane–EtOAc 3:1
as eluent afforded 7b as a mixture of the glyoxylate and its
hydrate which was used without further purification. Yield
2.31 g (98%).
A solution of benzylamine (0.57 mL, 5.2 mmol) in dry
Cl2CH2 (10 mL) was added under argon to a stirred
suspension of 7b (1.5 g, 5.2 mmol) and 3 Å molecular sieves
(4 g) in dry Cl2CH2 (30 mL) at 0 °C. When the addition was
complete the reaction mixture was cooled to –78 °C and
treated successively with TFA (0.4 mL, 1 equiv), BF3·OEt2
(0.65 mL, 1 equiv) and freshly distilled cyclopentadiene (1
mL, ca. 2 equiv). After 6 h a mixture of sat. aq NaHCO3
solution (13 mL) and then solid NaHCO3 (1.3 g) were added.
The reaction mixture was allowed to reach r.t. and filtered.
The organic layer was separated from the filtrate and washed
with H2O and CH2Cl2 on a celite pad; the organic layer of the
resulting mixture was separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 80 mL). The pooled organic
layers were washed with sat. NaHCO3 solution (80 mL) and
brine (90 mL), and were dried over Na2SO4.
(10) Compound 1b: yield 65%; [a]D25 +53.5 (c 1, CHCl3). IR
(NaCl): n = 3021, 3062, 2966, 1732 (CO), 1598, 1560, 1494,
1464, 1452, 1386, 1366, 1358, 1324, 1241, 1217, 1202,
1187, 1172, 1078, 1043, 1018, 919, 859, 768, 741, 734, 704
cm–1. 1H NMR (CDCl3): d = 0.93 (d, J = 7.1 Hz, 3 H, 5¢-
CH3), 1.172 and 1.177 [2 s, 6 H, 8¢-(Me2)], 1.20–1.35 (m, 4
H), 1.36–1.50 (m, 2 H), 1.52–1.65 (m, 2 H), 1.82 (virtual d,
J = 8.3 Hz, 1 H, 7sin-H), 1.85–1.90 (m, 1 H), 1.95 (s, 1 H,
3endo-H), 2.84 (br s, 1 H, 4-H), 3.42 and 3.52 (AB system, 2
H, J = 13.0 Hz), 3.82 (br s, 1 H, 1-H), 5.02 (td, 1 H, Jt = 10.8
Hz, Jd = 4.18 Hz, 1¢ax-H), 6.20 (dd, 1 H, J = 5.6 Hz, J = 1.8
Hz, 1 H, 5-H), 6.38 (dd, 1 H, J = 5.6 Hz, J = 3.3 Hz, 1 H, 6-
H), 7.10–7.40 (m, 10 H, C6H5). 13C NMR (CDCl3): d = 19.52
(5¢-CH3), 21.79 (C-3¢), 26.45 (C-5¢), 27.51 and 27.89 [8¢-
(CH3)2], 31.52 (C-4¢), 40.40 (C-8¢), 38.30 (C-6¢), 46.75 (C-
7), 49.02 (C-4), 50.74 (C-2¢), 59.31 (NCH2-Ph), 64.45 (C-1),
65.50 (C-3), 71.93 (C-1¢), 125.53 [aromatic C-4 (Ph)],
126.03 and 126.12 [aromatic C-2 + C-6 (Ph)], 127.36
[aromatic C-4 (Bn)], 128.30 [aromatic C-3 + C-5 (Ph)],
128.54 and 128.60 [aromatic C-2 + C-6 (Bn)], 129.39
[aromatic C-3 + C-5 (Bn)], 134.05 (C-5), 136.80 (C-6),
139.63 [aromatic C-1 (Bn)], 151.32 [aromatic C-1 (Ph)],
173.08 [C(O)O]. HRMS: m/z calcd for C30H37NO2:
443.2824. Found: 443.2814.
(11) Compound 2: yield 92%; colorless oil; [a]D25 +71.5 (c 1,
CHCl3). IR (NaCl): n = 3364, 3060, 2985, 2870, 1495, 1452,
1367, 1324, 1208, 1134, 1028, 910, 717 cm–1. 1H NMR
(CDCl3): d = 1.25–1.28 (d, 1 H, J = 8.40 Hz, 7anti-H), 1.68–
1.71 (d, 1 H, J = 8.40 Hz, 7sin-H), 1.82–1.86 (t, 1 H, J = 5.55
Hz, 3-H), 2.32 (br s, 1 H, OH), 2.69 (s, 1 H, 4-H), 3.32–3.44
(m, 4 H, CH2OH + CH2Ph), 3.69 (s, 1 H, 1-H), 6.10–6.13
(dd, 1 H, J = 5.65, 1.80 Hz, 5-H), 6.41–6.45 (dd, 1 H,
J = 5.65, 3.24 Hz, 6-H), 7.16–7.28 (m, 5 H, C6H5). 13C NMR
(CDCl3): d = 46.13 (C-7), 47.16 (C-4), 59.34 (NCH2Ph),
64.43 (C-1), 64.98 (C-3), 65.66 (CH2OH), 127.55 (C-4¢),
128.80 (C-2¢ + C-6¢), 129.43 (C-3¢ + C-5¢), 132.71 (C-5),
138.27 (C-6), 140.11 (C-1¢). HRMS: m/z calcd for
Removal of the solvent on a rotary evaporator yielded an
orange oil (2.3 g) which was purified by column
C14H17NO: 215.1310. Found: 215.1319.
chromatography (silica gel) using hexane–EtOAc 3:1 as
eluent. Fractions 7–10 afforded a colorless oil (1.61 g)
identified as the pure major adduct (1R,3-exo) 1a. Yield
70%.
(12) Blanco, J. M.; Caamaño, O.; Fernández, F.; Garcia-Mera,
X.; López, C.; Rodríguez, G.; Rodríguez-Borges, J. E.;
Rodríguez-Hergueta, A. Tetrahedron Lett. 1998, 39, 5663.
Synlett 2005, No. 2, 319–321 © Thieme Stuttgart · New York