New 1,3-amino alcohols derived from enantiopure bridgehead β-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acids

Article abstract of DOI:10.1007/s00726-011-1097-6

Constrained enantiopure bicyclic β-amino acids derived from the asymmetric Diels-Alder reaction of the (R)-benzyl-4-(3-acryloyloxy-4,4-dimethyl- 2-oxopyrrolidin-1-yl)-benzoate and the 1-(benzyloxycarbonylamino)cyclohexadiene provide original templates for

Full text of DOI:10.1007/s00726-011-1097-6

Amino Acids (2012) 43:415–421
DOI 10.1007/s00726-011-1097-6
ORIGINAL ARTICLE
New 1,3-amino alcohols derived from enantiopure bridgehead
b-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acids
•
Christophe Andre Monique Calmes
•
´
`
•
Franc¸oise Escale Muriel Amblard
•
•
Jean Martinez Olivier Songis
Received: 24 June 2011 / Accepted: 19 September 2011 / Published online: 4 October 2011
Ó Springer-Verlag 2011
Abstract Constrained enantiopure bicyclic b-amino acids
derived from the asymmetric Diels–Alder reaction of
the (R)-benzyl-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrro-
lidin-1-yl)-benzoate and the 1-(benzyloxycarbonyl-
amino)cyclohexadiene provide original templates for the
construction of new rigid enantiopure 1,3-amino alcohols.
derivatives for the synthesis of various chemical com-
pounds. They constitute convenient starting materials for
the synthesis of various 1,3-heterocycles for example (Ager
¨
¨
et al. 1996; Fu¨lop et al. 1997; Gyonfalvi et al. 2003; Kivela
et al. 2003, 2005). Although 1,2-amino alcohols have
received much attention because they are generally readily
accessible in enantiomerically pure form from natural pre-
cursors (Gyonfalvi et al. 2003; Reetz et al. 1987; Delair
et al. 1994; Masui and Shiori 1998; Laczkowski et al. 2009;
Keywords Bicyclic b-amino acid derivatives ꢀ Cyclic
amino alcohols ꢀ Constrained chiral b-amino acids ꢀ
Reduction
¨
Kiss and Fu¨lop 2009), the synthesis and the use of chiral
1,3-amino alcohols are still undergoing development and
remain a challenge (Lait et al. 2007; Didier et al. 1991;
Barluenga et al. 1993; Bartoli et al. 1994; Kossenjans and
Martens 1999; Kochi et al. 2003; Raghavan et al. 2004;
Murai et al. 2005; Balazs et al. 2007).
Introduction
Synthesis of enantiopure amino alcohols is of great
importance in synthetic organic chemistry since they are a
well established source of ligands for asymmetric synthesis
(Blaser 1992; Ager et al. 1996; Lait et al. 2007) including
enantioselective borane reduction of prochiral ketones
(Corey et al. 1987; Corey and Helal 1998; Deloux and
This prompted us to synthesize new constrained 1,3-
amino alcohols from some enantiopure bicyclic b-amino
acids recently developed in our group (Songis et al. 2007,
2008a, b). These bicyclic b-amino acids were obtained by
using the asymmetric Diels–Alder cycloaddition between
´
Screbnik 1993; Li et al. 1999; Krzeminski and Wojtczak
´
2005; Krzeminski and Zaidlewicz 2003; Hobuss et al. 2008)
`
the chiral acrylate (R)-1 (Akkari et al. 2004; Calmes et al.
2005) and the 1-(benzyloxycarbonylamino)cyclohexadiene
2 (Fig. 1).
or enantioselective addition of dialkylzinc (Kitamura et al.
1986; Kossenjans and Martens 1998; Garcia Martinez et al.
2002; Oliveira and Costa 2004; Szakonyi et al. 2006; Binder
et al. 2009; Scarpi et al. 2009; Wu et al. 2009). Apart from
this property, enantiopure amino alcohols are also important
The resulting Diels–Alder cycloadducts were obtained
in high yield and moderate selectivity using optimized
conditions mainly contained the two diastereoisomers 3
(60%) and 4 (30%). These two major Diels–Alder adducts
(30R,1S,2R,4R)-3 and (30R,1R,2R,4S)-4 (Fig. 2), resulting
from an endo and an exo selectivity on the same Ca Si face
of the chiral dienophile (R)-1 respectively, were isolated in
pure form after column chromatography on silica gel.
Stereochemistry of the endo adduct 3, that crystallized
from diethyl ether/petroleum ether, has been confirmed
unambigously by X-ray diffraction analysis (Songis et al.
2007).
´
`
C. Andre ꢀ M. Calmes (&) ꢀ F. Escale ꢀ M. Amblard ꢀ
J. Martinez ꢀ O. Songis
´
Institut des Biomolecules Max Mousseron (IBMM) UMR 5247
CNRS-Universite Montpellier 1 et 2, Batiment Chimie (17),
´
ˆ
´
Universite Montpellier 2, place E. Bataillon,
34095 Montpellier Cedex 5, France
e-mail: monique.calmes@univ-montp2.fr
123

´
C. Andre et al.
416
O
N
O
2
CO2H
(R)– 1
CO2H
CO2H
(
O
BnO
NHZ
O
ZHN
H2N
(R)-7
ZHN
H
H
H
Fig. 1 Chiral acrylate (R)-1 and protected aminodiene 2
5
(1S,2R,4R )-
(1R,2R,4S -6
Fig. 3 Bicyclic b-amino acids 5, 6 and 7
Removal of the chiral auxiliary of (30R,1S,2R,4R)-3 and
(30R,1R,2R,4S)-4 afforded the two bicyclic b-amino acids
(1S,2R,4R)-5 and (1R,2R,4S)-6. Then, the palladium-cata-
lyzed hydrogenation/hydrogenolysis of both carboxylic
acids 5 and 6 yielded the corresponding saturated bicyclic-
b-amino acid (R)-7 (Fig. 3).
were recorded in positive mode using NBA (3-nitroben-
zylalcohol or GT (Glycerol/thioglycerol) as matrix. HPLC
analyses were performed with a Waters model 510
instrument or a Beckman System Gold 126 instrument with
variable detector using: column A SymmetryShieldTM RP-
18, 3.5 l (50 mm 9 4.6 mm), flow 1 ml/min, H2O (0.1%
TFA)/CH3CN (0.1% TFA), gradient 0 ? 100% (15 min)
and 100% (4 min); column B ChromolithÒ SpeedROD RP-
18e, 2 l, (50 9 4.6 mm), flow 3 ml/min, H2O (0.1%
TFA)/CH3CN (0.1% TFA), gradient 0 ? 100% (4 min)
and 100% (1 min).
These three bicyclic compounds bearing an amino group
at the bridgehead and possessing the particular structural
¨
properties of constrained cyclic amino acids (Fu¨lop 2001;
Park and Kurth 2002; Kiss et al. 2009) represent useful
templates for the construction of new rigid enantiopure
amino alcohols. Here, we proposed the synthesis of original
rigid bicyclic amino alcohols from compounds 5, 6 and 7.
General procedure for the reduction of compounds 5, 6, 14
and 16
Experimental
Materials
To a stirred solution of the N-protected amino acid
(1 equiv) in THF was added at room temperature
benzotriazol-1-yloxytris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP reagent) (1 equiv) and N,N-
diisopropylethylamine (DIEA) (1.5 equiv). The resulting
solution was stirred for 10 min, then NaBH4 (3 equiv) was
added by portionwise at 0°C. After stirring at room tem-
perature until completion of the reaction (monitored by
HPLC, column A or B), the solvent was evaporated and the
residue was dissolved in ethyl acetate (20 ml). This organic
layer was washed with 0.1 N HCl (2 9 5 ml), dried over
Na2SO4 and concentrated in vacuo.
All reagents were used as purchased from commercial
suppliers without further purification. Solvents were dried
and purified by conventional methods prior to use. The
enantiopure compounds (1S,2R,4R)-5, (1R,2R,4S)-6 and
(2R)-7 were prepared as previously described (Songis et al.
2007, 2008a, b).
Techniques
Melting points were determined with a Kofler Heizbank
apparatus and are uncorrected. Optical rotations were
measured with a Perkin Elmer 341 polarimeter. H or 13C
1
(1S,2R,4R)-(1-Benzyloxycarbonylaminobicyclo[2.2.2]oct-
5-ene-2-yl)methanol (8)
NMR spectra (DEPT, 1H/13C 2D-correlations) were
recorded with a Bruker A DRX 400 spectrometer using the
solvent as internal reference. Data are reported as follows:
chemical shifts (d) in parts per million, coupling constants
(J) in hertz (Hz). The ESI mass spectra were recorded with
a platform II quadrupole mass spectrometer (Micromass,
Manchester, UK) fitted with an electrospray source. HRMS
Synthesized according to the general procedure from the
N-Z amino acid (1S,2R,4R)-5 (170 mg, 0.56 mmol, 1
equiv) in THF (4 ml), BOP reagent (255 mg, 0.56 mmol, 1
equiv), DIEA (0.15 ml, 0.85 mmol, 1.5 equiv) and NaBH4
(64 mg, 1.68 mmol, 3 equiv). After stirring for 40 min at
Fig. 2 Major Diels–Alder
adducts 3 and 4
O
O
O
O
O
O
O
O
OBn
ZHN
OBn
H
N
N
ZHN
H
(3'R,1S,2R,4R )-3
(3'R,1R,2R,4S-4
123

1,3-amino alcohols b-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acids
417
(R)-(1-Benzyloxycarbonylaminobicyclo[2.2.2]octane-2-
yl)methanol (15)
room temperature, concentration of the solvent and wash-
ings, the residue was purified by column chromatography
on silica gel, using dichloromethane/ethyl acetate (9/1) as
eluent to yield the expected compound (1S,2R,4R)-8 as a
Synthesized according to the general procedure from N-Z-
amino acid (R)-14 (100 mg, 0.33 mmol, 1 equiv) in THF
(4 ml), BOP reagent (145 mg, 0.33 mmol, 1 equiv), DIEA
(86 ll, 0.49 mmol, 1.5 equiv) and NaBH4 (37 mg,
0.99 mmol, 3 equiv). After stirring for 40 min at room
temperature, the residue obtained after treatment was
purified by column chromatography on silica gel, using
dichloromethane/ethyl acetate (9/1) as eluent to yield the
pure expected compound (R)-15 as a colourless oil (64 mg,
0.22 mmol, 65% yield); [a]2D0 = -37 (c = 1.5 in CH2Cl2);
tR (HPLC, column B) 2.0 min; MS (ESI) m/z 246.2 [(M-
colourless oil (99 mg, 0.35 mmol, 62% yield); [a]D20
=
-16 (c = 1.1 in CH2Cl2), tR (HPLC, column B) 2.19 min,
MS (ESI) m/z 244.3 [(M-CO2 ? H)?], 288.2 [(M ? H)?],
575.3 [(2 M ? H)?], 1H NMR (400 MHz, CDCl3, 25°C) d
0.63–0.79 (m, 1H, HCH), 1.25–1.36 (m, 1H, HCH),
1.39–1.54 (m, 2H 2HCH), 1.66–1.75 (m, 1H, HCH),
1.86–1.97 (m, 2H, HCH and CH-CH2-OH), 2.38–2.44 (m,
1H, 4-H), 2.62–2.46 (br s, 1H, OH), 3.20–3.42 (m, 2H,
CH2-OH), 4.97 (d, J = 12.5 Hz, 1H, OHCHC6H5), 5.02 (d,
J = 12.5 Hz, 1H, OHCHC6H5), 6.11–6.21 (m, 2H, 6-H
and 5-H), 6.26–6.42 (br s, 1H, NH), 7.18–7.26 (m, 5H, CH-
arom); 13C NMR (100 MHz, CDCl3, 25°C) d 24.2 (CH2),
28.5 (C-4), 29.9 (CH2), 30.9 (CH2), 42.5 (2-C), 56.3 (1-C),
64.8 (CH2OH), 65.2 (OCH2C6H5), 126.9, 127.1, 127.4
(CH-arom), 132.1 and 132.6 (CH=), 135.7 (C-arom), 154.8
(CO); HRMS (ESI) Calcd for C17H22NO3 (MH?)
288.1600, found 288.1599.
CO2 ? H)?], 290.3 [(M ? H)?], 312.1 [(M ? Na)?]; H
1
NMR (400 MHz, CDCl3, 25°C) d 1.16–1.21 (m, 1H,
HCH), 1.55–1.95 (2 m, 9H, 3CH2, 2HCH and 4-H),
2.10–2.18 (m, 2H, HCH and 2-H), 3.59 (dd, J = 5.1 and
11.1 Hz, 1H, HCH-OH), 3.78 (dd, J = 7.8 and 11.1 Hz,
1H, HCH-OH), 5.08 (s, 2H, OCH2C6H5), 7.28–7.36 (m,
5H, CH-arom); 13C NMR (100 MHz, CDCl3, 25°C) d 24.5
(4-C), 25.9 (CH2), 26.0 (CH2), 26.4 (CH2), 30.7 (CH2),
32.0 (CH2), 41.1 (2-C), 52.9 (1-C), 64.9 (CH2), 66.0 (CH2),
128.1, 128.2, 128.6 (CH-arom), 135.9 (C-arom), 155.4
(CO); HRMS (ESI) calculated for C17H24NO3 (MH?)
290.1756, found 290.1755.
(1R,2R,4S)-(1-Benzyloxycarbonylaminobicyclo[2.2.2]oct-
5-ene-2-yl)methanol (9)
Synthesized according to the general procedure from the
N-Z amino acid (1S,2R,4R)-6 (170 mg, 0.56 mmol, 1
equiv) in THF (4 ml) containing BOP reagent (255 mg,
0.56 mmol, 1 equiv), DIEA (0.15 ml, 0.85 mmol, 1.5
equiv) and NaBH4 (64 mg, 1.68 mmol, 3 equiv). After
stirring for 40 min at room temperature, the residue
obtained after treatment was purified by column chroma-
tography on silica gel, using dichloromethane/ethyl acetate
(9/1) as eluent to yield the expected compound (1S,2R,4R)-
9 as a colourless oil (108 mg, 0.38 mmol, 67% yield);
[a]2D0 = -46 (c = 1 in CH2Cl2), tR (HPLC, column A)
8.5 min, MS (ESI) m/z 288.4 [(M ? H)?], 1H NMR
(400 MHz, CDCl3, 25°C) d 0.72–0.86 (m, 1H, HCH),
1.28–1.45 (2 m, 2H, CH2), 1.48–1.58 (m, 1H, HCH),
1.60–1.78 (m, 2H, CH2), 1.80–1.95 (m, 1H, CH-CH2-OH),
2.02–2.30 (br s, 1H, OH), 2.34–2.42 (m, 1H, 4-H),
3.56–3.72 (m, 2H, CH2-OH), 4.97 (d, J = 12.5 Hz, 1H,
OHCHC6H5), 5.02 (d, J = 12.5 Hz, 1H, OHCHC6H5),
6.10 (dd, J = 6.7 and 8.3 Hz, 1H, 5-H), 6.42 (br d, 2H,
NH and 6-H), 7.18–7.32 (m, 5H, CH-arom); 13C NMR
(100 MHz, CDCl3, 25°C) d 24.7 (CH2), 26.4 (CH2), 29.3
(C-4), 30.4 (CH2), 41.4 (2-C), 56.5 (1-C), 64.8 (CH2OH),
66.2 (CH2C6H5), 127.9, 128.1, 128.4 (CH-arom), 131.4
(CH=), 136.9 (C-arom), 138.6 (CH=), 155.4 (CO); HRMS
(ESI) calculated for C17H22NO3 (MH?) 288.1600, found
288.1594.
(R)-(1-Butyloxycarbonylaminobicyclo[2.2.2]octane-2-
yl)methanol (17)
Synthesized according to the general procedure from N-Boc-
amino acid (R)-16 (100 mg, 0.37 mmol, 1 equiv) in THF
(4 ml), BOP reagent (145 mg, 0.33 mmol, 1 equiv), DIEA
(86 ll, 0.49 mmol, 1.5 equiv) and NaBH4 (37 mg,
0.99 mmol, 3 equiv). After stirring for 40 min at room tem-
perature, the residue obtained after treatment was purified by
column chromatography on silica gel, using cyclohexane/
ethyl acetate (7/3) as eluent to yield the pure expected
compound (R)-17 as a colourless oil (66 mg, 0.23 mmol,
62% yield); [a]2D0
=
-106 (c = 0.7 in CH2Cl2); MS
(ESI) m/z 156.2[(M-BOC ? H)?], 200.2 [(M-(CH2 =
C(CH3)2) ? H)?], 256.2 [(M ? H)?], 278.2 [(M ? Na)?];
1H NMR (400 MHz, CDCl3, 25°C) d 1.18–1.26 (m, 1H,
HCH), 1.41 (s, 9H, C(CH3)3), 1.51–1.82 (2 m, 8H, 2CH2,
3HCH and 4-H), 1.88–1.98 (m, 2H, 2HCH), 2.12–2.18 (m,
1H, 2-H), 3.58 (dd, J = 4.8 and 11.2 Hz, 1H, HCH-OH), 3.73
(dd, J = 7.2 and 11.2 Hz, 1H, HCH-OH); 13C NMR
(100 MHz, CDCl3, 25°C) d 23.9 (4-C), 25.3 (CH2), 25.8
(CH2), 26.0 (CH2), 26.5 (C(CH3)3), 27.9 (CH2), 30.2 (CH2),
40.9 (2-C), 51.9 (1-C), 64.6 (CH2), 78.5 (C(CH3)3), 128.1,
128.2, 128.6 (CH-arom), 154.9 (CO); HRMS (ESI) calculated
for C14H26NO3 (MH?) 256.1913, found 290.1919.
123

´
C. Andre et al.
418
(1R,3S,6R,7R)-7-(Benzyloxycarbonylamino)-4-oxa-8-
tricyclo[4.3.1.03,7]decan-5-one (11)
128.4 (CH-arom), 137.4 (C-arom), 155.1 (NHCOO), 177.1
(COOH); HRMS (ESI) calculated for C17H22NO5 (MH?)
320.1498, found 320.1492.
Tributyltin hydride (0.32 ml, 1.17 mmol, 2 equiv) and az-
obis(isobutyronitrile) (20 mg, 0.12 mmol, 0.2 equiv) were
added to a solution of the iodolactone (1R,2R,3R,6R,7R)-
1012 (250 mg, 0.58 mmol) in dry toluene (4 ml) under argon.
After heating by microwave irradiation at 80°C for 1 h, the
solvent was concentrated in vacuo and the c-lactone
(1R,3S,6R,7R)-11 was obtained as a white solid by precipi-
tation from hexane (160 mg, 0.53 mmol, 90% yield); m.p.
143°C; [a]2D0 = ?37 (c = 0.55, AcOEt); tR (HPLC, column
(1R,2R,4R,6S)-1-(Benzyloxycarbonylamino)-6-
(hydroxymethyl)bicyclo[2.2.2]octane-2-ol (13)
To
a stirred solution of the N-protected lactone
(1R,3S,6R,7R)-11 (80 mg, 0.23 mmol, 1 equiv) in a mix-
ture of 2-propanol (4 ml) and H2O (1.2 ml) was added
NaBH4 (43 mg, 5 equiv) by portion wise at room tem-
perature. After stirring at the same temperature until
completion of the reaction (48 h) (monitored by HPLC,
column B), the solvents were concentrated in vacuo. The
residue was dissolved in ethyl acetate (10 ml) and washed
successively with HCl 0.1 N and brine. The organic layer
was dried over Na2SO4 and concentrated in vacuo to yield
the expected dihydroxylated compound (1R,2R,4R,6S)-13
as a colourless oil (43 mg, 0.14 mmol, 62% yield);
[a]2D0 = -9 (c = 1.1 in CH3OH); tR (HPLC, column B)
1.7 min; MS (ESI) m/z 306.3 [(M ? H)?]; 1H NMR
(400 MHz, CD3OD, 25°C) d 1.11–1.31 (m, 2H, CH2),
1.32–1.75 (m, 5H, 2CH2 and HCH), 1.88–2.20 (m, 2H,
3-H), 2.24–2.36 (br m, 1H, 6-H), 3.46 (dd, J = 4.6 and
11.2 Hz, 1H, HCH-OH), 3.54 (dd, J = 4.1 and 11.2 Hz,
1H, HCH-OH), 3.80 (br d, J = 7.2 Hz, 1H, 2-H), 4.89 (d,
J = 12.5 Hz, 1H, HCHC6H5), 4.96 (d, J = 12.5 Hz, 1H,
HCHC6H5), 7.17–7.25 (m, 5H, H-arom); 13C NMR
(100 MHz, CD3OD, 25°C) d 26.3 (4-C), 26.3 (CH2), 30.5
(CH2), 31.2 (CH2), 39.0 (CH2), 39.8 (6-C), 57.3 (1-C), 63.0
(CH2OH), 67.0 (CH2C6H5), 71.4 (2-C), 128.9, 128.9, 129.5
(CH-arom), 138.4 (C-arom), 157.1 (NHCOO); HRMS
(ESI) calculated for C17H24NO4 (MH?) 306.1705, found
306.1705.
1
A) 8.7 min; MS (ESI) m/z 302.2 [(M ? H)?]; H NMR
(400 MHz, CDCl3, 25°C) d 1.65 (t, J = 8.3 Hz, 2H, 8-H),
1.85–2.01 (m, 5H, 1-H, 2-H and 10-H), 2.05–2.22 (m, 2H,
9-H), 2.77 (d, J = 9.2 Hz, 1H, 6-H), 4.91 (s br, 1H, 3-H),
5.03 (s, 2H, CH2O), 5.35 (s, 1H, NH), 7.28–7.38 (m, 5H, H-
arom); 13C NMR (100 MHz, CDCl3, 25°C) d 21.1 (9-C),
23.7 (1-C), 27.5 (8-C), 28.6 (10-C), 33.6 (2-C), 42.8 (6-C),
58.8 (7-C), 66.7 (CH2O), 80.6 (3-C), 128.1, 128.2, 128.3,
128.4, 128.6 (CH-arom), 136.1 (C-arom), 154.9 (NHCOO),
179.9 (COO); HRMS (ESI) calculated for C17H20NO4
(MH?) 302.1392, found 302.1406.
(1R,2R,4R,6S)-1-(Benzyloxycarbonylamino)-6-
hydroxybicyclo[2.2.2]octane-2-carboxylic acid (12)
A solution of LiOHꢀ H2O (27 mg, 0.64 mmol, 1.6 equiv) in
water (0.5 ml) was added dropwise to a solution of the c-
lactone (1R,3S,6R,7R)-11 (120 mg, 0.40 mmol, 1 equiv) in
THF/H2O (2/1) (2 ml) and the mixture was stirred at room
temperature till completion of the hydrolysis (*14 h)
(monitored by HPLC, column A). The solvent was
removed in vacuo and the residue was dissolved in ethyl
acetate/saturated aqueous NaHCO3 (4 ml/20 ml). The
aqueous phase was acidified (pH 2) and extracted with
dichloromethane (4 9 10 ml). The combined organic lay-
ers were dried over anhydrous Na2SO4, concentrated in
vacuo to yield the expected pure hydroxyl b-amino acid
(1R,2R,4R,6S)-12 as a white solid (102 mg, 0.32 mmol,
88% yield), melting point 98°C; [a]2D0 = -48 (c = 3 in
CH3CN); tR (HPLC, column A) 8.1 min; tR (HPLC, col-
umn B) 1.9 min; MS (ESI) m/z 276.1 [(M-CO2 ? H)?],
320.1 [(M ? H)?], 342.0[(M ? Na)?]; 1H NMR
(400 MHz, CD3CN, 25°C) d 1.52–1.62 (m, 4H, 3-H, 5-H,
8-H), 1.75 (q, J = 3.0 Hz, 1H, 4-H,), 1.92–2.06 (m, 2H,
7-H,), 2.12–2.28 (m, 2H, 3-H, and 5-H,), 3.29 (dd, J = 9.9
and 7.4 Hz, 1H, 6-H,), 3.96 (dd, J = 9.9 and 3.0 Hz, 1H,
2-H,), 5.02 (d, J = 12.7 Hz, 1H, HCHO), 5.09 (d,
J = 12.7 Hz, 1H, HCHO), 6.80 (s, 1H, NH), 7.31–7.42 (m,
5H, H-arom); 13C NMR (100 MHz, CD3CN, 25°C) d 23.9
(4-C), 24.5 (8-C), 29.0 (5-C), 29.7 (7-C), 37.2 (3-C), 42.2
(6-C), 55.2 (1-C), 65.5 (CH2O), 70.1 (2-C), 127.6, 127.8,
(R)-1-(Benzyloxycarbonylamino)bicyclo[2.2.2]octane-2-
carboxylic acid (14)
Toa stirred solutionof the (R)-1-Aminobicyclo[2.2.2]octane-
2-carboxylic acid (R)-7 (110 mg, 0.65 mmol, 1 equiv) in a
mixture of aqueous NaHCO3 (164 mg, 1.95 mmol, 3 equiv)
(2 ml) and THF (3 ml), was slowly added benzyl chlorofor-
mate (138 ll, 0.97 mmol, 1.5 equiv) at 0°C. After stirring for
12 h at room temperature, THF was eliminated at reduced
pressure, the mixture was diluted with aqueous NaHCO3
(10 ml) and washed with ethyl acetate (10 ml). The aqueous
phase was acidified to pH 2 and extracted with (3 9 10 ml).
The organic layer was dried over Na2SO4 and concentrated in
vacuo. Theexpected pure compound(R)-14 was obtainedasa
colourless oil after column chromatography on silica gel
using dichloromethane/ethyl acetate 5/5 as eluent (173 mg,
0.57 mmol, 88% yield); [a]2D0 = -78 (c = 2.4 in CH2Cl2);
tR (HPLC, column A) 9.3 min; MS (ESI) m/z 304.0
123

1,3-amino alcohols b-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acids
419
[(M ? H)?]; 1H NMR (400 MHz, CD3CN, 25°C) d 1.50–80
(m, 7H, 4-H, 7-H, 2CH2, HCH), 1.82–2.00 (m, 3H, CH2,
HCH), 2.28–2.38 (m, 1H, 7-H), 3.36 (ddd, J = 10.5 Hz,
6.2 Hz and 2.0 Hz, 1H, 2-H), 4.99 (d, J = 12.8 Hz, 1H,
OHCHC6H5), 5.07 (d, J = 12.8 Hz, 1H, OHCHC6H5), 5.50
(s, 1H, NH) 7.30–7.42 (m, 5H, H-arom); 13C NMR
(100 MHz, CD3CN, 25°C) d 23.8 (4-C), 25.4, 25.5, 27.1,
29.7, 30.3 (3-C, 5-C, 6-C, 7-C, 8-C), 42.8 (2-C), 51.5 (1-C),
65.3 (OCH2), 127.5, 127.7, 128.4 (CH-arom), 137.6 (C-
arom), 154.9, 175.5 (CO); HRMS (ESI) calculated for
C17H22NO4 (MH?) 304.1549, found 304.1550.
a
CO2H
CH2OH
62%
ZHN
ZHN
5
(1S,2R,4R)-
(1S,2R,4R)-8
a
CO2H
CH2OH
67%
ZHN
ZHN
6
(1R,2R,4S)-
9
(1R,2R,4S)-
(R)-1-(tert-Butyloxycarbonylamino)bicyclo[2.2.2]octane-
2-carboxylic acid (16)
Scheme 1 Reagents and conditions: a BOP/DIEA/NaBH4/THF
Starting from the compound (1R,2R,4S)-6 a similar
treatment yielded the N-Z bicyclic 1,3-amino alcohol
(1R,2R,4S)-9. Structures of compounds 8 and 9 were
(R)-1-Aminobicyclo[2.2.2]octane-2-carboxylic acid (R)-7
(100 mg, 0.60 mmol, 1 equiv) was added to acetonitrile
(50 ml) followed by trimethylammonium hydroxide
(TMAH) (162 mg, 1.2 mmol, 1.5 equiv). After stirring for
2–3 h at room temperature (until a homogeneous mixture
was obtained) the di-tert-butyldicarbonate (520 mg,
2.4 mmol, 4 equiv) was added. Stirring was continued for
an additional 12 h at room temperature and acetonitrile was
eliminated at reduce pressure. The residue was diluted with
water (10 ml) and the aqueous layer was washed with ethyl
acetate (10 ml), acidified to pH 3 and extracted with
dichloromethane (3 9 10 ml). The organic layer was dried
over Na2SO4 and concentrated in vacuo.
1
characterized by H and 13C NMR and LC/MS analysis.
In a second set of experiments, we synthesized com-
pounds 12 and 13 from the intermediate lactone 11
(Scheme 2). Stereoselective iodolactonisation was the first
step of the synthesis of (1R,2R,4R,6S)-1-N-Z-amino-6-
hydroxybicyclo[2.2.2]octane-2-carboxylic acid 12 and of
the (1R,2R,4R,6S)-dihydroxylated compound 13. The reac-
tion of (1S,2R,4R)-N-Z-aminobicyclo[2.2.2]oct-5-ene-2-
carboxylic acid 5 with I2/KI in slightly alkaline conditions
yielded the iodolactone (1R,2R,3R,6R,7R)-10 with excellent
regio- and stereoselectivity (Songis et al. 2008b). This iod-
olactone was isolated in pure form in 80% yield after column
chromatography on silica gel. Compound 10 was then treated
with tributyltin hydride and a catalytic amount of azobisi-
sobutyronitrile at 80°C for 1 h under microwave activation.
The corresponding lactone (1R,3S,6R,7R)-11 was obtained
in 85% yield. The hydroxyl b-amino acid (1R,2R,4R,6S)-12
was obtained from compound 11 in good yield, using aque-
ous LiOH in THF at room temperature.
The expected pure compound (R)-16 obtained as a white
solid (131 mg, 0.49 mmol, 81% yield), was used without
further purification; m. p. 124°C; [a]2D0 = -42 (c = 1.1 in
CH2Cl2); MS (ESI) m/z 270.2 [(M ? H)?]; 1H NMR
(400 MHz, CDCl3, 25°C) d 1.42–1.55 (m, 10H, C(CH3)3
and HCH), 1.60–1.70 (m, 5H, 2CH2 and HCH), 1.72–1.82
(m, 2H, CH2), 1.88–2.12 (m, 2H, CH2), 2.34–2.50 (m, 1H,
7-H), 3.28–3.44 (m, 1H, 2-H), 6.27 (br s, 1H, NH) 9.37 (br
s, 1H, OH); 13C NMR (100 MHz, CDCl3, 25°C) d 23.6 (4-
C), 25.7, 25.8 and 27.8 (3CH2), 28.3(C(CH3)3), 29.6 (CH2),
30.4 (7-C), 43.2 (2-C), 51.9 (1-C), 80.9 (C(CH3)3), 178.9
(CO); HRMS (ESI) calculated for C14H24N4O (MH?)
270.1705, found 270.1702.
Furthermore, direct reduction of the lactone 11 using
sodium borohydride yielded the dihydroxylated compound
(1R,2R,4R,6S)-13. Compounds 10–13 were characterized
1
by H, 13C NMR and LC/MS analyses.
In the last investigated pathway (Scheme 3), the amino
group of the saturated (R)-1-aminobicyclo[2.2.2]octane-2-
carboxylicacid(R)-7 was first converted into its N-Z orN-Boc
derivative (R)-14 and (R)-16, respectively. The benzyloxycar-
bonyl group was introduced in good yield using conventional
methods. On the other hand, for the N-tert-butoxycarbonyl
protection of (R)-7, the efficient method developed for sterically
hindered amino acid by Khalil et al. (1996) had to be used, to
increase the low yield obtained when using standard conditions.
Then, reduction of the carboxylic acid function with BOP/
NaBH4 yielded the enantiopure N-protected 1,3-amino alcohol
(R)-15 and (R)-17 (Scheme 3).
Results and discussion
The synthesis of the bicyclo amino alcohols 8 and 9 is
reported in Scheme 1. Compound (1S,2R,4R)-5 was con-
verted into the corresponding N-Z bicyclic 1,3-amino
alcohol (1S,2R,4R)-8 using the method developed by
McGeary (1998). Compound 5 was treated with BOP/
DIEA to activate the carboxylic acid function and then
rapidly reduced using NaBH4 to provide the N-Z amino
alcohol derivative (1S,2R,4R)-8 in good yield.
123

´
C. Andre et al.
420
OH
CO2H
I
c
O
O
ZHN
a
b
88%
d
O
CO2H
O
(1R,2R,4R,6S)-12
90%
80%
ZHN
ZHN
ZHN
(1R,3S,6R,7R)-11
OH
5
(1S,2R,4R)-
(1R,2R,3R,6R,7R )-10
62%
CH2OH
ZHN
-13
(1R,2R,4R,6S)
Scheme 2 Reagents and conditions: a I2, KI, NaHCO3, DCM, H2O, b Bu3SnH/AIBN/toluene, c LiOH, THF, H2O, rt, (d) NaBH4/iPrOH/H2O
Barluenga J, Viado AL, Aguilar E, Fustero S, Olano B (1993) 1,
3-Amino alcohols from 4-amino-1-azadienes. Diastereo- and
a
c
enantioselective approach to the four diastereoisomers of the
N-terminal amino acid component of nikkomycins B and BX.
J Org Chem 58:5972–5975
CO2H
CH2OH
65%
88%
ZHN
ZHN
14
(R)-
15
(R)-
Bartoli G, Cimarelli C, Marcantoni E, Palmieri G, Petrini M (1994)
Chemo- and diastereoselective reduction of beta-enamino esters:
a convenient synthesis of both cis- and trans-c-amino alcohols
and b-amino esters. J Org Chem 59:5328–5335
CO2H
H2N
7
(R)-
c
b
´
Binder CM, Bautista A, Zaidlewicz M, Krzeminski MP, Oliver A,
CO2H
CH2OH
62%
81%
Singaram B (2009) Stereoselectivity in the dialkylzinc reaction
using (-)-b-pinene derived amino alcohol chiral auxiliaries.
J Org Chem 74:2337–2343
BocHN
BocHN
17
(R)-
(R)-16
Blaser HU (1992) The chiral pool as a source of enantioselective
catalysts and auxiliaries. Chem Rev 92:935–952
Scheme 3 Reagents and conditions: a Benzylchloroformate/NaHCO3/
THF/H2O, b Boc2O/Me3NHOH/THF/H2O, c BOP/DIEA/NaBH4/THF
`
Calmes M, Didierjean C, Martinez J, Songis O (2005) (R)-(4-
(Benzyloxycarbonylphenyl)-3-hydroxy-4, 4-dimethyl-2-pyrro-
lidinone) acrylate derivative as a chiral dienophile for the
synthesis of enantiopure 2-aminocyclohexane carboxylic acids.
Tetrahedron Asymmetr 16:2173–2178
Conclusions
Corey EJ, Helal CJ (1998) Reduction of carbonyl compounds with
chiral oxazaborolidine catalysts: A new paradigm for enantio-
selective catalysis and a powerful new synthetic sethod. Angew
Chem Int Ed Engl 37:1986–2012
Corey EJ, Bakshi RK, Shibata S (1987) Highly enantioselective
borane reduction of ketones catalyzed by chiral oxazaboroli-
dines. Mechanism and synthetic implications. J Am Chem Soc
109:5551–5553
In this study, we have established original syntheses of five
enantiopure bicyclic 1,3-amino alcohols bearing an amino
group at the bridgehead. Opposite enantiomers could be
obtained by the same synthetic routes by using the chiral
acrylate (S)-1. These syntheses constitute the first prepa-
ration of such compounds and further studies concerning
their application are currently in progress.
Delair P, Einhorn C, Einhorn J, Luche JL (1994) Synthesis of beta-
J
amino alcohols derived from L-valine.
59:4680–4682
Org Chem
Acknowledgments The authors gratefully acknowledge the CNRS
and the MESR for their financial support.
Deloux L, Screbnik M (1993) Asymmetric boron-catalyzed reactions.
Chem Rev 93:763–784
Didier E, Loubinoux B, Ramos Tombo GM, Rihs G (1991) Chemo-
enzymatic synthesis of 1, 2- and 1, 3-aminoalcohols and their use
in the enantioselective reduction of acetophenone and anti-
acetophenone oxime methyl ether with borane. Tetrahedron
47:4941–4958
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