Synthesis of enantiomerically pure 3-aminochroman derivatives

Article abstract of DOI:10.1016/S0957-4166(01)00202-6

Enantiomerically pure (3R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran was successfully synthesised in nine steps starting from L-serine. The same synthetic pathway was used to prepare the (3S)-aminochroman derivative starting from D-serine. The enantiomeric purity of the final aminochroman derivatives was determined by capillary electrophoresis using β-cyclodextrin as the chiral selector.

Full text of DOI:10.1016/S0957-4166(01)00202-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1689–1694
Synthesis of enantiomerically pure 3-aminochroman derivatives
Ste´phanie Usse,a Gre´goire Pave,a Ge´rald Guillaumeta and Marie-Claude Viaud-Massuardb,*
aInstitut de Chimie Organique et Analytique, UMR CNRS 6005, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans Cedex 2, France
bUFR Sciences Pharmaceutiques, Laboratoire de Chimie Organique, 31 avenue Monge, 37200 Tours, France
Received 9 April 2001; accepted 3 May 2001
Abstract—Enantiomerically pure (3R)-amino-5-methoxy-3,4-dihydro-2H-1-benzopyran was successfully synthesised in nine steps
starting from L-serine. The same synthetic pathway was used to prepare the (3S)-aminochroman derivative starting from D-serine.
The enantiomeric purity of the final aminochroman derivatives was determined by capillary electrophoresis using b-cyclodextrin
as the chiral selector. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
To date, only a racemic synthesis of this 3-aminochro-
man derivative has been described. Each enantiomer
was subsequently resolved using homochiral acetyl-
valine as the resolving agent.9 The (S)-absolute configu-
ration of the dextrogyre enantiomer was determined by
X-ray crystallography. The difficulty of the resolution
encouraged us to devise an asymmetric synthesis of this
Serotonin (5-HT) is a neurotransmitter of the central
nervous system and its receptors have a strong influence
at the physiological and pathophysiological levels.1,2
The dysfunction in serotoninergic systems has been
linked to various behavioural problems involving mem-
ory, thermoregulation, sleep and sexual behaviour and
it is also implicated in numerous neuropsychiatry disor-
ders such as anxiety, depression, schizophrenia and
Alzheimer’s disease.3–5 Due to the role of 5-HT1A recep-
tors in anxiety and depression behavioural disorders,
the synthesis of 5-HT1A agonists appears to be a very
attractive goal. In our laboratory, previous work6–8 has
led to new therapeutic agents that demonstrate a good
affinity and high selectivity for the 5-HT1A receptors.
Among them, the compound (+)-S 20499 (Fig. 1) has
been taken to phase II in clinical trials.
compound using
D-serine as the starting material.
In view of the cost difference between
-serine, we decided to optimise the synthesis of the
(3R)-aminochroman derivative from the cheapest -ser-
ine and then to transpose this synthesis to the prepara-
D-serine and
L
L
tion of the active (S)-enantiomer from
D-serine.
Federsel’s publication,10 which proposed a synthesis of
enantiomerically pure 3-aminochroman derivatives sim-
ilar to our own previously communicated results,11
prompted us to publish them.
2. Results and discussion
The retrosynthetic pathway of this synthesis is illus-
trated in Scheme 1. The first reaction, which is the key
step in our synthetic pathway, involves alkylation at
position 2 of 1-methoxy-3-(methoxymethoxy)benzene12
1 with Garner’s aldehyde 2. Aldehyde 2 was prepared
in three steps from
L
-serine.13,14 Treatment of 1 with
n-butyllithium in refluxing diethyl ether followed by the
addition of aldehyde 2 at room temperature gave a
diastereoisomeric mixture of alcohols 3 (ratio 7/3, as
measured by NMR) in 70% yield (Scheme 2). This ratio
agrees well with other similar additions described in the
literature.15
Figure 1.
* Corresponding author. Tel.: 33 247 36 72 27; fax: 33 247 36 72 29;
e-mail: mcviaud@univ-tours.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00202-6

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S. Usse et al. / Tetrahedron: Asymmetry 12 (2001) 1689–1694
Scheme 1.
Scheme 2.
The next step, which involved removal of the hydroxyl
group of 3, proved to be difficult and several reduction
procedures were examined. First, catalytic hydrogena-
tion according to standard procedures afforded only
returned starting material. The next approach involved
the replacement of the hydroxyl group with iodide
using Garreg’s methodology16 followed by reduction.
stirring 3 with N,N-thiocarbonyldiimidazole in reflux-
ing tetrahydrofuran. The thiocarbamate moiety was
then reduced using tributyltin hydride in the presence of
AIBN in refluxing toluene (Scheme 4) to give the
desired compound 6 in 60% yield.
In order to avoid aziridine formation during the final
ring closure, the MOM ether and isopropylidene pro-
tective groups would need to be cleaved while conserv-
ing the tert-butoxycarbonyl amine protection. Several
standard procedures were examined, as depicted in
Scheme 5. The use of p-toluenesulfonic acid in
methanol20 or in refluxing acetic acid21 led to the alco-
hol 7, with the MOM ether still intact, in 82 and 54%
yields, respectively. The hydrolysis was accomplished in
Treatment of compounds
3
(Scheme 3) with
triphenylphosphine, imidazole and iodide in a mixture
of toluene and acetonitrile led to the unwanted forma-
tion of the oxazolidinones 4. This cyclisation has been
described in the literature.17,18 The reduction of 3 was
finally achieved using the Barton–McCombie reac-
tion.19 The diastereoisomeric mixture of thiocarbamate
derivatives 5 (Scheme 4) was obtained in 66% yield by
Scheme 3.

S. Usse et al. / Tetrahedron: Asymmetry 12 (2001) 1689–1694
1691
Scheme 4.
1
good yield and with the desired selectivity by treatment
of 6 with tert-butyldimethylsilyl bromide in methylene
chloride at −30°C22 to furnish the desired diol 8 in 64%
yield.
were fully characterized (IR, H, 13C NMR, mass and
specific rotation) and physical data are identical to
those described for their enantiomers.
The enantiomeric purities of aminochromans 10 and 11
were determined by capillary electrophoresis using b-
cylcodextrin as the chiral selector.24 In each case, we
obtained the desired enantiomer with an e.e. of >99.5%.
Scheme 6 illustrates the synthesis of derivative 10,
which was obtained in two steps from 8. Ring closure
of 8 under Mitsunobu conditions23 using triphenylphos-
phine and diethyl azodicarboxylate at 80°C in toluene
provided the benzopyran 9 in 74% yield. The tert-
butoxycarbonyl group was removed with trifluoroacetic
acid in methylene chloride to give the desired
aminochroman 10 in 78% yield. The final step, leading
to the (+)-S 20499 analogue, involves N,N-dialkylation
of amine 10, a sequence which has already been
described in the literature.6
3. Conclusion
In conclusion, the synthesis of (3R)-3-amino-5-
methoxy-3,4-dihydro-2H-1-benzopyran was accom-
plished starting with the (S)-Garner’s aldehyde
prepared from naturally occurring L-serine. The synthe-
sis was completed in six steps with an overall yield of
10%. The (S)-enantiomer was synthesised using an
analogous route starting from (R)-Garner’s aldehyde
with a similar overall yield. The key step in our synthe-
(3S)-3-Amino-5-methoxy-3,4-dihydro-2H-1-benzopyran
11 was prepared according to the same synthetic path-
way starting from
D-serine (Scheme 7). All compounds
Scheme 5.
Scheme 6.
Scheme 7.

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S. Usse et al. / Tetrahedron: Asymmetry 12 (2001) 1689–1694
sis was the alkylation at position 2 of 1-methoxy-3-
(methoxymethoxy)benzene 1 with Garner’s aldehyde.
The benzopyran targets 10 and 11 were obtained from
the synthesis in enantiomerically pure form with e.e.s of
>99.5%.
(CH), 65.1 (CH), 66.3 (CH2), 78.6 (C), 93.7 (C), 95.2
(CH2), 106.2 (CH), 108.2 (CH), 119.5 (C), 129.4 (CH),
151.9 (C), 156.1 (C), 157.0 (C). MS (IS): m/z=398
(M+1). Anal. calcd for C20H31NO7: C, 60.44; H, 7.86;
N, 3.52. Found: C, 60.19; H, 7.98; N, 3.50%.
4.2. (7aS)-1-[2-Methoxy-6-(methoxymethoxy)phenyl]-
5,5-dimethyldihydro-1H-[1,3]-oxazolo-[3,4-c][1,3]oxazol-
3-one 4
4. Experimental
All air- and moisture-sensitive reactions were carried
out under an argon atmosphere. Anhydrous solvents
(Et2O and THF) were freshly distilled from sodium/
Under an argon atmosphere, the mixture of
diastereoisomeric alcohols 3 (110 mg, 0.28 mmol) was
dissolved in a mixture of toluene (2 mL) and acetoni-
trile (1 mL). The mixture was cooled to 0°C, and Ph3P
(220 mg, 0.84 mmol), imidazole (114 mg, 1.68 mmol)
and iodine (213 mg, 0.84 mmol) were added. The
mixture was allowed to warm to room temperature and
stirred for 15 h. After evaporation, the residue was
hydrolysed and extracted with CH2Cl2. The organic
layers were combined and dried over MgSO4, concen-
trated, and purified by flash chromatography (eluent:
petroleum ether/EtOAc, 4/1) to give 4 as a colourless
benzophenone under nitrogen prior to use. H and 13C
1
NMR spectra were obtained with a Bruker instrument
Avance DPX250 at 250.131 and 62.9 MHz, respec-
tively. Chemical shifts (l values) are reported in parts
per million and coupling constants (J) in Hz. Carbon
multiplicities were assigned by distortionless enhance-
ment by polarisation transfer (DEPT) experiments.
Infrared spectra were recorded using NaCl film or KBr
pellets techniques on a Perkin–Elmer spectrometer FT
PARAGON 1000PC. Mass spectra (MS) were recorded
on a Perkin–Elmer mass spectrometer SCIEX API 300
by ion spray (IS). Melting points (mp) were determined
in open capillary tubes and are uncorrected. Analytical
thin-layer chromatography was performed on Merck
60F254 silica gel precoated plates. Flash chromatogra-
phy was performed using silica gel Merck 40–70 mm
(230–400 mesh). Garner’s aldehyde was prepared
1
oil (50 mg, 56%). IR (NaCl): w cm−1 1758 (CꢀO). H
NMR (CDCl3): l ppm major isomer 1.48 (s, 3H), 1.79
(s, 3H), 3.47 (s, 3H), 3.74 (t, 1H, J=8.2 Hz), 3.83 (s,
3H), 4.12 (dd, 1H, J=8.2 Hz, J%=6.3 Hz), 4.40–4.52
(m, 1H), 5.20 (s, 2H), 5.89 (d, 1H, J=5.9 Hz), 6.61 (d,
1H, J=8.4 Hz), 6.77 (d, 1H, J=8.4 Hz), 7.28 (t, 1H,
J=8.4 Hz). 13C NMR (CDCl3): l ppm major isomer
23.3 (CH3), 27.5 (CH3), 55.9 (CH3), 56.3 (CH3), 63.7
(CH), 69.1 (CH2), 72.0 (CH), 94.4 (CH2), 94.6 (C),
104.9 (CH), 107.1 (CH), 113.8 (C), 130.9 (CH), 156.6
(C), 157.5 (C), 158.8 (C). MS (IS): m/z=324 (M+1).
Anal. calcd for C16H21NO6: C, 59.43; H, 6.55; N, 4.33.
Found: C, 59.20; H, 6.41; N, 4.69%.
according to
a
methodology described in the
literature.14
4.1. tert-Butyl (4S)-4-[hydroxy(2-methoxy-6-(methoxy-
methoxy)phenyl)methyl]-2,2-di-methyl-1,3-oxazo-
lidine-3-carboxylate 3
Under
an
argon
atmosphere,
1-methoxy-3-
(methoxymethoxy)benzene 1 (1.13 g, 6.72 mmol) was
dissolved in anhydrous Et2O and n-butyllithium (1.6 M
solution in hexane, 5.0 mL, 8.06 mmol) was slowly
added. The mixture was stirred under reflux for 2 h and
a solution of aldehyde 2 (1.70 g, 7.39 mmol) in anhy-
drous Et2O (2 mL) was added. After stirring under
reflux for 15 min the mixture was cooled to room
temperature, hydrolysed and extracted with EtOAc.
The organic layers were dried over MgSO4, concen-
trated, and purified by flash chromatography (eluent:
petroleum ether/EtOAc, 8/2) to give a mixture of the
desired alcohols 3 as a colourless oil (1.87 g, 70%). IR
(NaCl): w cm−1 3543 (OH), 1704 (CꢀO). 1H NMR
(DMSO-d6, 80°C): l ppm major isomer 1.11 (s, 9H),
1.48 (s, 6H), 3.41 (s, 3H), 3.76 (s, 3H), 3.65–3.90 (m,
2H), 4.21–4.42 (m, 2H), 5.14 (d, 1H, J=4.3 Hz), 5.18
(s, 2H), 6.59–6.77 (m, 2H), 7.14 (t, 1H, J=8.2 Hz);
minor isomer 1.11 (s, 9H), 1.48 (s, 6H), 3.42 (s, 3H),
3.80 (s, 3H), 3.65–3.90 (m, 2H), 4.21–4.42 (m, 2H), 5.14
(d, 1H, J=4.3 Hz), 5.18 (s, 2H), 6.59–6.77 (m, 2H),
7.20 (t, 1H, J=8.2 Hz). 13C NMR (DMSO-d6, 80°C): l
ppm major isomer 28.0 (3CH3), 28.6 (2CH3), 55.9
(2CH3), 60.3 (CH), 65.1 (CH), 66.3 (CH2), 78.6 (C),
93.7 (C), 95.3 (CH2), 105.7 (CH), 108.0 (CH), 119.5 (C),
128.7 (CH), 151.9 (C), 156.1 (C), 157.0 (C); minor
isomer 28.0 (3CH3), 28.6 (2CH3), 56.1 (2CH3), 60.3
4.3. tert-Butyl (4S)-4-{[(1H-imidazol-1-ylthiocarbonyl)-
oxy](2-methoxy-6-methoxymethoxy)phenyl)-
methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 5
Under an argon atmosphere, N,N-thiocarbonyldiimid-
azole (540 mg, 3.02 mmol) was added to a solution of
the mixture of alcohols 3 (480 mg, 1.21 mmol) in
anhydrous THF (12 mL). The mixture was heated for
18 h. N,N-Thiocarbonyldiimidazole (540 mg, 3.02
mmol) was added and the mixture was stirred under
reflux for a further 8 h. After concentration, the residue
was hydrolysed and extracted with CH2Cl2. The
organic layers were dried over MgSO4, concentrated
and purified by flash chromatography (eluent:
petroleum ether/EtOAc, 4/1 and 3/2) to give the desired
thiocarbamate compounds 5 as a yellow oil (402 mg,
1
66%). IR (NaCl): w cm−1 1697 (CꢀO), 1055 (CꢀS). H
NMR (DMSO-d6, 80°C): l ppm major isomer 1.17 (s,
9H), 1.39 (s, 6H), 3.47 (s, 3H), 3.83 (s, 3H), 3.90–4.15
(m, 2H), 4.55–4.71 (m, 1H), 5.21 (s, 2H), 5.78 (d, 1H,
J=8.5 Hz), 6.66 (d, 1H, J=8.5 Hz), 6.71 (d, 1H, J=8.5
Hz), 7.07–7.08 (m, 1H), 7.18 (t, 1H, J=8.5 Hz), 7.62–
7.63 (m, 1H), 8.28 (s, 1H). 13C NMR (DMSO-d6, 80°C):
l ppm major isomer 27.2 (2CH3), 28.0 (3CH3), 56.3
(CH3), 59.5 (CH3), 66.1 (CH2), 79.3 (CH), 94.4 (CH2),
95.0 (C), 95.3 (CH), 105.6 (CH), 107.3 (CH), 116.1 (C),

S. Usse et al. / Tetrahedron: Asymmetry 12 (2001) 1689–1694
1693
116.7 (CH), 129.5 (CH), 131.0 (CH), 135.9 (CH), 151.8
(C), 158.7 (2C), 166.8 (C). MS (IS): m/z=508 (M+1).
Anal. calcd for C24H33N3O7S: C, 56.79; H, 6.55; N,
8.28. Found: C, 57.01; H, 6.36; N, 7.95%.
(s, 1H), 6.56 (d, 1H, J=8.3 Hz), 6.75 (d, 1H, J=8.3
Hz), 7.12 (t, 1H, J=8.3 Hz). 13C NMR (CDCl3): l ppm
24.6 (CH2), 28.3 (3CH3), 52.8 (CH), 55.6 (CH3), 56.2
(CH3), 65.6 (CH2), 79.1 (C), 94.6 (CH2), 104.4 (CH),
106.9 (CH), 114.9 (C), 127.8 (CH), 156.1 (C), 156.5 (C),
158.3 (C). MS (IS): m/z=342.5 (M+1), 364.5 (M+Na).
[h]2D0=+13.9 (c 1.0, CHCl3). Anal. calcd for C17H27NO6:
C, 59.81; H, 7.97; N, 4.10. Found: C, 60.07; H, 7.73; N,
3.87%.
4.4. tert-Butyl (4R)-4-[2-methoxy-6-(methoxymethoxy)-
benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 6
Under an argon atmosphere, a solution of compounds
5 (564 mg, 1.11 mmol) in anhydrous toluene (3 mL)
was slowly added to a refluxing mixture of tributyltin
hydride (0.6 mL, 2.22 mmol) in anhydrous toluene (5
mL) in the presence of AIBN. The mixture was heated
for 18 h and hydrolysed. The tributyltin salts were
filtered off and washed with CH2Cl2. After extraction
of the aqueous layer with CH2Cl2, the organic layers
were dried over MgSO4, concentrated and purified by
flash chromatography (eluent: petroleum ether/EtOAc,
95/5) to furnish the desired compound 6 (253 mg, 60%)
4.6. tert-Butyl (1R)-2-hydroxy-1-(2-hydroxy-6-methoxy-
benzyl)ethylcarbamate 8
Under an argon atmosphere, compound 6 (50 mg, 0.13
mmol) was dissolved in anhydrous CH2Cl2 (2 mL). The
mixture was cooled to −30°C and bromotrimethylsilane
(52 mL, 0.39 mmol) was added. The solution was stirred
for 2 h at −30°C and then hydrolysed by a saturated
NaHCO3 solution. The mixture was allowed to warm
to room temperature and the aqueous layer was
extracted with CH2Cl2. The organic layers were dried
over MgSO4, and, after concentration, the residue was
purified by flash chromatography (eluent: petroleum
ether/EtOAc, 7/3 and 6/4) to give the desired com-
pound 8 (25 mg, 64%) as a colourless oil. IR (NaCl): w
cm−1 3700–3046 (NH, OH), 1693 (CꢀO). 1H NMR
(CDCl3): l ppm 1.45 (s, 9H), 2.80–3.08 (m, 2H), 3.45–
3.80 (m, 4H), 3.82 (s, 3H), 5.45 (d, 1H, J=7.3 Hz), 6.45
(d, 1H, J=8.0 Hz), 6.57 (d, 1H, J=8.0 Hz), 7.07 (t, 1H,
J=8.0 Hz), 8.14 (s, 1H). 13C NMR (CDCl3): l ppm
24.4 (CH2), 28.3 (3CH3), 52.5 (CH), 55.6 (CH3), 63.3
(CH2), 79.9 (C), 102.4 (CH), 109.7 (CH), 112.2 (C),
127.9 (CH), 156.4 (C), 156.7 (C), 158.4 (C). MS (IS):
m/z=298 (M+1). [h]D20=+11.2 (c 1.0, CHCl3). Anal.
calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71.
Found: C, 60.91; H, 7.47; N, 4.52%.
1
as a colourless oil. IR (NaCl): w cm−1 1699 (CꢀO). H
NMR (CDCl3): l ppm 1.44 (s, 9H), 1.48 (s, 6H),
2.85–3.05 (m, 1H), 3.13 (dd, 1H, J=12.5 Hz, J%=5.7
Hz), 3.48 (s, 3H), 3.81 (s, 3H), 3.65–3.95 (m, 2H),
4.10–4.35 (m, 1H), 5.19 (s, 2H), 6.56 (d, 1H, J=8.3
Hz), 6.75 (d, 1H, J=8.3 Hz), 7.13 (t, 1H, J=8.3 Hz).
13C NMR (CDCl3): l ppm 17.5 (CH2), 26.8 (CH3), 27.8
(CH3), 28.4 (3CH3), 55.4 (CH3), 56.1 (CH3), 56.4 (CH),
66.8 (CH2), 79.6 (C), 94.1 (C), 94.3 (CH2), 104.2 (CH),
106.7 (CH), 115.1 (C), 127.5 (CH), 152.1 (C), 156.6 (C),
158.9 (C). MS (IS): m/z=382 (M+1). [h]2D0=+19.7 (c
1.0, CHCl3). Anal. calcd for C20H31NO6: C, 62.97; H,
8.19; N, 3.67. Found: C, 63.19; H, 7.94; N, 3.56%.
4.5. tert-Butyl (1R)-2-hydroxy-1-[2-methoxy-6-
(methoxymethoxy)benzyl]ethylcarbamate 7
4.5.1. Method A. Under an argon atmosphere,
APTS·H2O (5 mg, 0.026 mmol) was added to a mixture
of compound 6 (100 mg, 0.26 mmol) in anhydrous
MeOH (2 mL). The mixture was stirred for 24 h at
room temperature and neutralised with a saturated
NaHCO3 solution. After evaporation of MeOH, the
aqueous layer was extracted with EtOAc, and the
organic layers were dried over MgSO4 and concen-
trated. The residue was purified by flash chromatogra-
phy (eluent: petroleum ether/EtOAc, 3/2) to give
compound 7 as a white solid (73 mg, 82%).
4.7. tert-Butyl (3R)-5-methoxy-3,4-dihydro-2H-
chromen-3-yl-carbamate 9
Under an argon atmosphere, Ph3P (39 mg, 0.15 mmol)
and diethyl azodicarboxylate (24 mL, 0.15 mmol) were
added to a solution of diol 8 (36 mg, 0.12 mmol) in
anhydrous toluene (2 mL). The mixture was heated for
1 h and allowed to reach room temperature. After
evaporation, the residue was purified by flash chro-
matography (eluent: petroleum ether/EtOAc, 9/1) to
give the desired compound 9 (25 mg, 74%) as a colour-
4.5.2. Method B. A solution of compound 6 (54 mg,
0.14 mmol) in acetic acid (2 mL) was heated for 3 h and
then cooled to room temperature. After evaporation of
the acetic acid, the residue was dissolved in AcOEt and
the organic layer was washed several times with an
Na2CO3 solution (2 M). The organic layer was dried
over MgSO4, concentrated and purified by flash chro-
matography (eluent: petroleum ether/EtOAc, 6/4) to
give compound 7 (26 mg, 54%) as a white solid. Mp
69–70°C. IR (KBr): w cm−1 3695–3060 (NH, OH), 1681
less oil. IR (NaCl): w cm−1 3354 (NH), 1698 (CꢀO). H
1
NMR (CDCl3): l ppm 1.44 (s, 9H), 2.55–2.75 (m, 1H),
2.88 (dd, 1H, J=17.5 Hz, J%=5.4 Hz), 3.80 (s, 3H),
4.07 (bs, 2H), 4.10–4.25 (m, 1H), 4.83 (s, 1H), 6.45 (d,
1H, J=8.2 Hz), 6.50 (d, 1H, J=8.2 Hz), 7.08 (t, 1H,
J=8.2 Hz). 13C NMR (CDCl3): l ppm 26.1 (CH2), 28.3
(3CH3), 42.8 (CH), 55.4 (CH3), 68.0 (CH2), 79.5 (C),
102.4 (CH), 109.3 (CH), 108.6 (C), 127.3 (CH), 154.7
(C), 155.2 (C), 158.4 (C). MS (IS): m/z=280 (M+1).
[h]2D0=+25.8 (c 1.0, CHCl3). Anal. calcd for C15H21NO4:
C, 64.50; H, 7.58; N, 5.01. Found: C, 64.86; H, 7.44; N,
5.32%.
1
(CꢀO). H NMR (CDCl3): l ppm 1.36 (s, 9H), 2.73–
3.00 (m, 2H), 3.21 (s, 1H), 3.35–3.65 (m, 2H), 3.46 (s,
3H), 3.66–3.95 (m, 1H), 3.80 (s, 3H), 5.18 (s, 2H), 5.37

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S. Usse et al. / Tetrahedron: Asymmetry 12 (2001) 1689–1694
4.8. (3R)-3-Amino-5-methoxy-3,4-dihydro-2H-1-benzo-
pyran 10
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Synth. Commun. 1993, 23, 153.
15. Gruza, H.; Kiciak, K.; Krasinski, A.; Jurczak, J. Tetra-
hedron: Asymmetry 1997, 8, 2627.
16. Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem.
Commun. 1979, 979.
Under an argon atmosphere, a solution of trifluoro-
acetic acid (194 mL, 2.5 mmol) in CH2Cl2 (1 mL) was
transferred to a cold solution of protected amine 9 (60
mg, 0.21 mmol) in CH2Cl2 (2 mL). The mixture was
allowed to warm to room temperature, stirred for 9 h
and hydrolysed by a saturated NaHCO3 solution. After
extraction of the aqueous layer with CH2Cl2, the
organic layers were dried over MgSO4, concentrated
and then purified by flash chromatography (eluent:
CH2Cl2/MeOH, 9/1) to give the desired amine 10 as a
colourless oil (30 mg, 78%). IR (NaCl): w cm−1 3690–
1
3050 (NH2). H NMR (CDCl3): l ppm 2.16 (s, 2H),
2.44 (dd, 1H, J=16.9 Hz, J%=6.6 Hz), 2.97 (dd, 1H,
J=16.9 Hz, J%=5.2 Hz), 3.30–3.45 (m, 1H), 3.75–3.95
(m, 1H), 3.81 (s, 3H), 4.05–4.18 (m, 1H), 6.44 (d, 1H,
J=8.2 Hz), 6.50 (d, 1H, J=8.2 Hz), 7.07 (t, 1H, J=8.2
Hz). 13C NMR (CDCl3): l ppm 29.3 (CH2), 43.8 (CH),
55.4 (CH3), 71.0 (CH2), 102.1 (CH), 109.2 (CH), 109.4
(C), 127.1 (CH), 154.7 (C), 158.3 (C). MS (IS): m/z=
180 (M+1). [h]2D0=−13.7 (c 1.0, CHCl3). Anal. calcd for
C10H13NO2: C, 67.02; H, 7.31; N, 7.81. Found: C,
67.13; H, 7.12; N, 8.03%.
17. Agami, C.; Couty, F.; Hamon, L.; Venier, O. Tetrahedron
Lett. 1993, 34, 4509.
Acknowledgements
18. Curran, T. P.; Pollastri, M. P.; Abelleira, S. M.; Messier,
R. J.; McCollum, T. A.; Rowe, C. G. Tetrahedron Lett.
1994, 35, 5409.
19. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc.,
Perkin Trans. 1 1975, 1574.
20. Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi,
E.; Riva, R.; Rocca, V. Tetrahedron 1995, 51, 8121.
21. Katritzky, A. R.; Lang, H.; Lan, X. Synth. Commun.
1993, 23, 1175.
We are very grateful to Professor M. Dreux, Dr P.
Morin, D. Depernet, S. Grard and N. Mesplet, ICOA,
University of Orleans, for performing capillary elec-
trophoresis analyses.
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