Asymmetric synthesis of (S)-1-aminoindan-1,5-dicarboxylic acid and related analogues via intramolecular acylation of enantiopure α,α-disubstituted amino acids

Article abstract of DOI:10.1016/S0957-4166(02)00224-0

α,α-disubstituted amino acid derivatives are synthesized either by a self-regeneration of stereocenter strategy or using the asymmetric Strecker reaction/alkylation method. Of the four types of substrates tested for intramolecular acylation, those with a

Full text of DOI:10.1016/S0957-4166(02)00224-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 961–969
Asymmetric synthesis of (S)-1-aminoindan-1,5-dicarboxylic acid
and related analogues via intramolecular acylation of enantiopure
a,a-disubstituted amino acids
Dawei Ma,a,* Ke Ding,b Hongqi Tian,a Baomin Wangc and Dongliang Chengc
aState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
bDepartment of Chemistry, Fudan University, Shanghai 200433, China
cDepartment of Chemistry, Lanzhou University, Lanzhou 730000, China
Received 5 March 2002; accepted 1 May 2002
Abstract—a,a-Disubstituted amino acid derivatives are synthesized either by a self-regeneration of stereocenter strategy or using
the asymmetric Strecker reaction/alkylation method. Of the four types of substrates tested for intramolecular acylation, those with
a 4-alkoxyl group do not react, those with a 4-bromo substituent give lower conversions, while those without a 4-substituent or
with a 4-methyl group work well to give the desired cyclization products. Based on these investigations, a new route for preparing
(S)-1-aminoindan-1,5-dicarboxylic acid (S)-AIDA and its analogues was developed. © 2002 Published by Elsevier Science Ltd.
1. Introduction
stereoselective recognition to mGluRs. Thus, an
efficient protocol to prepare enantiopure AIDA is
highly desirable to investigate the particular role of
each enantiomer. The first asymmetric route to (S)-
AIDA and (S)-APICA was developed in our group.8
However, in the asymmetric Strecker reaction of aryl
ketones, which was the key step in that protocol, both
conversion rates and diastereoselectivities were unsatis-
factory. These drawbacks make it difficult to prepare
(S)-AIDA or (S)-APICA on large scale, which led us to
seek an alternative route as described below.
1-Aminoindan-1,5-dicarboxylic acid (AIDA)1 and 1-
amino-5-phosphenoindan-1-carboxylic acid (APICA)2
(Scheme 1) are two subtype-selective antagonists for
metabotropic glutamate receptors (mGluRs).3 Both
compounds are conformationally constrained analogues
of a-methyl-4-carboxyphenglycine (a-M4CPG) or a-
methyl-4-phosphonophenglycine (MPPG), two antago-
nists for mGluRs with lower subtype selectivity.3
Recently, both racemic AIDA4 and APICA5 have
become useful pharmaceutical tools in seeking the roles
of mGluRs in physiological processes. It was reported
that for enantiopure phenylglycine-type mGluRs antag-
onists that have been tested, only the (S)-isomers are
antagonists for mGluRs while (R)-isomers may be
antagonists for other glutamate receptor subtypes,6,7
which implied that this class of antagonists had marked
2. Results and discussion
Our new strategy to synthesize these compounds is
shown in Scheme 2. The target molecules were expected
to be prepared from ketone A, which could be obtained
H2N CO2H
Me
H2N CO2H
Me
H2N CO2H
H2N CO2H
HO2C
(HO)2(O)P
HO2C
(HO)2(O)P
(S)-APICA
(S)-AIDA
(S)-αM4CPG
(S)-MPPG
Scheme 1.
* Corresponding author.
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00224-0

962
D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 961–969
H
H
PG N CO2R
PG N CO2R
H2N CO2H
Y
O
Y
O
X
HO
(S)-AIDA
A
B
(S)-APICA
PG = protecting group
Scheme 2.
acylation.13 In order to see if this role worked in our
case, we converted the benzyl ether 5a into i-propyl
ether 6. However, using 6 as an intramolecular
acylation substrate we still did not get the desired
product even when 100 mol% AlCl3 was used.
by intramolecular acylation of enantiopure a,a-disubsti-
tuted amino acid derivative B. Obviously, the key prob-
lems for this plan were effecting the intramolecular
acylation of B and how to obtain the desired a,a-disub-
stituted amino acid derivative B in enantiopure form.
When they investigated the intramolecular Friedel–
Crafts reaction of protected amino acids, McClure and
co-workers found that the phenylalanine-derived acid
worked for this reaction while the tyrosine-derived ana-
logue could not be applied in this reaction.14 This
stimulated us to use acid 9 (Scheme 4) without the
4-alkoxyl group for the intramolecular acylation. If this
reaction worked out, we would be able to obtain the
target molecules by introducing a functional group at
the 4-position of the benzene ring at a later stage. With
this idea in mind, we prepared the acid 9 from (R)-
phenylglycine using the reaction sequence shown in
Scheme 3. This time acylation through the acyl chloride
or the N-carboxyanhydride worked very well to afford
the cyclized product 10 in 92% yield.
Initially, we planed to prepare the intermediate B via
the self-regeneration of stereocenter strategy.9 Accord-
ingly, protection of (S)-4-benzoxyphenylglycine 110
with methyl chloroformate afforded the carbamate,
which was reacted with benzaldehyde dimethyl acetal in
methylene chloride in the presence of boron trifluoride
etherate to produce cis-oxazolidinone 2 (Scheme 3).11
Alkylation of 2 with tert-butyl bromoacetate provided
3 in 88% yield with over 97% diastereoselectivity. The
oxazolidinone ring of 3 was opened by treatment with
lithium hydroxide in methanol to give diester 4. Selec-
tive deprotection of 4 with hydrogen chloride in meth-
ylene chloride produced acid 5a. Intramolecular
acylation of 5a was attempted under various conditions
such as PCl3/AlCl3, (COCl)2/AlCl3, PPA and
(CF3CO)2O/H3PO4.12 Unfortunately no desired cycliza-
tion product was obtained after working up. In most
cases the starting material or debenzylation product 5b
was isolated. Buckley and Rapoport reported that
reducing the amount of catalyst or using sterically
bulky alkyl groups was helpful for aryl ether
Direct iodination or bromination of 10 using I2/
Hg(OTf)2,15 I2/PhI(OAc)2 or Br2/AgOCOCF3 was
attempted, but under these conditions only the starting
material was recovered. Thus, we had to move our
attention to iodination of the more reactive compound
16
17
Ph
Ph
NH2
MeO2C
MeO2C
N
N
O
1. ClCOOMe/NaHCO3
LiHMDS then
O
CO2H
BrCH2CO2Bu-t
2. PhCH(OMe)2,
76%
BF3 Et2O
BnO
O
H
O
88%
BnO
CO2Bu-t
3
2
1
MeO2C
MeO2C
MeO2C
NH CO2Me
NH CO2Me
O
1. Pd/C/H2
2. i-PrI/Et3N
LiOH
MeOH
95%
NH CO2Me
O
3. HCl
i-PrO
O
i-PrO
BnO
HO
t-BuO
6
8
4
HCl, 86%
MeO2C
MeO2C
NH CO2Me
NH CO2Me
O
RO
O
BnO
HO
5a: R = Bn
5b: R = H
7
Scheme 3.

D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 961–969
963
MeO2C
MeO2C
MeO2C
X
NH CO2Me
NH2
CO2H
See
Scheme 3
NH CO2Me
NH CO2Me
O
Iodination
or bromination
1. PCl5
2. AlCl3
92%
O
HO
O
11
9
10
X = I or Br
NH CO2H
14
Pd/C/H2
100%
1. Hg(OTf)2/I2
2. Pd(OAc)2/
CO/MeOH
MeO2C
MeO2C
HO2C
MeO2C
NH CO2H
NH CO2Me
HO2C
6 N HCl
reflux
79%
3. 1 N NaOH
51%
13
12
Scheme 4.
Inspired by the above observation, we realized that if
we completed the acylation on 12 and then converted
the ketone moiety to a phenol by Baeyer–Villiger oxida-
tion,18 we would be able to introduce an orientation-
directing group onto the benzene ring and thereby
effect the desired iodination. If this idea worked out, we
could prepare the two conformationally constrained
analogues, 18 and 19 of (S)-3-hydroxy-4-carboxy-
phenylglycine ((S)-3H4CPG), another known mGluR
modulator (Scheme 5). Thus, treatment of 12 with
acetyl chloride catalyzed by AlCl3 followed by oxida-
tion with m-CPBA and subsequent hydrolysis with
K2CO3/MeOH provided phenol 15. Iodination of 15
with I2/Py afforded an iodide, which was directly sub-
jected to palladium-catalyzed carbonylation or phos-
phonation to produce 16 or 17. Deprotection of 16 or
17 with TMSI gave 18 or 19, respectively (Scheme 6).
12. When 12 was treated with I2/Hg(OTf)2 the reaction
occurred to give an inseparable mixture of two iodina-
1
tion products in a ratio of about 3/1 as shown by H
NMR analysis. This mixture was directly subjected to
palladium-catalyzed carbonylation before the two ester
groups were hydrolyzed. The major isomer in the resul-
tant mixture was carefully purified by column chro-
matography to provide the diacid 13. Deprotection of
13 then gave amino acid 14. By comparing the 1H
NMR data with those reported,1 we were disappointed
to find that this product was 1-aminoindan-1,6-dicar-
boxylic acid instead of the desired 1,5-diacid, (S)-
AIDA, which indicated that iodination of 12 took place
mainly at the 6-position. This observation can be
explained as follows: the 1-N moiety might coordinate
with Hg(II) to make the 1-NCO2Me group electron-
deficient, which, together with the 1-methyl ester group
make the 1-quarternary carbon a strongly electron-
withdrawing group, thereby giving the observed orien-
tation of iodination.
The successful acylation of 12 encouraged us to try
using a similar acid with a suitable substituent at the
4-position of the benzene ring to access the target
H2N CO2H
H2N CO2H
H2N CO2H
HO
HO
HO
H
HO2C
HO2C
(HO)2(O)P
(S)-3H4CPG
19
18
Scheme 5.
MeO2C
MeO2C
NH CO2Me
NH CO2Me
1. CH3COCl/AlCl3, 70%
1. I2/Py
TMSI
75%
12
HO
18
HO
2. m-CPBA, 90%
2. Pd(OAc)2/
3. K2CO3/MeOH, 98%
CO/EtOH
55%
EtO2C
15
1. I2/Py
16
2. Pd(PPh3)4/HP(O)(OEt)2
58%
MeO2C
NH CO2Me
TMSI
HO
19
82%
(EtO)2(O)P
17
Scheme 6.

964
D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 961–969
molecules. This time we chose our own method to
assemble the intramolecular acylation precursor. This
method is based on alkylation of the product from
asymmetric Strecker reaction of an aldehyde.19 As out-
lined in Scheme 7, asymmetric Strecker reaction of
4-methylbenzaldehyde followed by esterification and
lactonization provided lactone 20. Alkylation of 20
with tert-butyl bromoacetate followed by opening of
the lactone ring with Et3N/MeOH delivered two
diastereomers 21 and 22 in a ratio of 4/1. Although we
had observed that if the amino group was masked as
NBn the diastereoselectivity could be improved
greatly,19 this strategy could not be used in this case
because benzylation of 20 failed.
acid;21 and (3) esterification of the acid with MeI/
K2CO3 in DMF to afford 26. Finally, reduction of
ketone 26 by Pd/C-catalyzed hydrogenation provided
27, which was heated in refluxing in 6N aqueous HCl to
remove all protecting groups, giving crude (S)-AIDA as
its hydrochloride salt. Treatment of this salt with pro-
pylene oxide furnished free (S)-AIDA.
It is notable that we also prepared acid 28 with a
4-bromo group using a similar procedure for preparing
23. When this compound was subjected to intramolecu-
lar acylation, less than 10% conversion was observed
(Scheme 9). Prolonging the reaction time or increasing
the reaction temperature gave decomposition products.
Taking this result and the above observations together,
we conclude that the acylation of structure B-type
compounds is heavily dependent on the nature of the
4-substitutent of the benzene ring.
With 21 in hand, we finally found a useful route to
(S)-AIDA as shown in Scheme 8. Removal of the chiral
auxiliary of 21 was achieved by oxidation with
Pb(OAc)4 followed by protection of the resulting amine
with methyl chloroformate to produce the acid 23.
Intramolecular acylation worked again to give 24 and
subsequent bromination of 24 with NBS yielded the
dibromide 25 in high yield,20 which was transformed
into diester 26 in three steps: (1) treatment of 25 with
Ag2O to provide the aldehyde; (2) oxidation of the
aldehyde generated with AgNO3/NaOH to give the
MeO2C
MeO2C
NH CO2Me
NH CO2Me
oxalyl chloride
then AlCl3
~10%
Br
HO
28
O
Br
O
29
Scheme 9.
O
O
1. LHMDS then
BrCH2CO2Bu-t
CHO
1. (R)-phenylglycinol/NaCN/NH4Cl
N
H
Ph
2. Et3N/MeOH
65%
2. HCl/MeOH then
TsOH/toluene, reflux
57%
Me
Me
20
OMe OH
OMe
O
O
OH
Ph
+
N
H
Ph
N
H
CO2Bu-t
CO2Bu-t
Me
Me
21
22
Scheme 7.
MeO2C
MeO2C
1. Pb(OAc)4/NaOAc
2. 3 N HCl
3. ClCO2Me/NaHCO3
NH CO2Me
NH CO2Me
NBS/AIBN
87%
oxalic chloride
then AlCl3
93%
21
Me
HO
23
O
Me
75%
O
24
MeO2C
MeO2C
MeO2C
NH CO2Me
NH CO2Me
1. Ag2O/H2O/THF
2. AgNO3/NaOH
NH CO2Me
Pd/C/H2
97%
3. MeI/DMF/K2CO3
64%
Br2HC
MeO2C
O
MeO2C
O
27
26
25
MeO2C
NH CO2H
1. 6 N HCl
2. proplyene oxide
78%
HO2C
(S)-AIDA
Scheme 8.

D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 961–969
965
3. Conclusion
4.3. (S)-2-(Methoxycarbonyl)amino-2-(4-phenyl-
methoxy)phenylsuccinic acid, 1-methyl ester, 4-tert-
In brief, we have developed a new strategy to access
(S)-AIDA and related analogues using intramolecular
acylation of suitable a,a-disubstituted amino acid
derivatives as a key step. The results presented here are
not only useful for synthesizing these mGluR modula-
tors, but also of benefit for related amino acid
chemistry.
butyl ester, 4
To a solution of 3 (4.6 g, 8.9 mmol) in MeOH (160 mL)
was added 4N LiOH (4.5 mL). The resultant mixture
was stirred at room temperature for 24 h and concen-
trated via rotavapor. The residue was partitioned
between ethyl acetate and water. The organic layer was
washed with brine, dried over MgSO4. The solvent was
evaporated and the residual oil was chromatographed
to afford 4 as a colorless oil (3.8 g, 95%). [h]2D0=+19.3
4. Experimental
1
(c 1.0, CHCl3); H NMR (300 MHz, CDCl3) l 7.45 (m,
4.1. (2R,4S)-2-Phenyl-4-((4-phenylmethoxy)phenyl)-5-
7H), 6.90 (d, J=7.8 Hz, 2H), 6.50 (s, 1H), 5.01 (s, 2H),
3.75 (d, J=15.6 Hz, 1H), 3.70 (s, 3H), 3.60 (s, 3H), 3.51
(d, J=15.6 Hz, 1H), 1.43 (s, 9H); MS m/z 443 (M+).
Anal. calcd for C24H29NO7: C, 65.01; H, 6.55; N, 3.16.
Found: C, 64.83; H, 6.61; N, 2.98%.
oxo-3-oxazolidinine-carboxylic acid, methyl ester, 2
A suspension of (S)-4-benzoxyphenylglycine (20 g, 77.8
mmol), NaHCO3 (13.0 g, 155.6 mmol) in water (120
mL) and chloroform (20 mL) was treated with methyl
chloroformate (12.0 mL, 155.6 mmol) in a dropwise
manner. The solution was stirred for 24 h and 1N aq.
HCl was added to adjust the pH to 4. The mixture was
extracted with ethyl acetate and the organic layer was
washed with brine, dried over MgSO4, and concen-
trated to yield a crude solid residue. The residue was
dissolved in dry methylene chloride (400 mL) and
treated with benzaldehyde dimethyl acetal (11.8 mL,
85.6 mmol) and boron trifluoride etherate (40.7 mL,
331.6 mmol) by syringe at 0°C. The mixture was stirred
for 2 h at the same temperature and satd aq. NaHCO3
(100 mL) was added to quench the reaction. The aq.
layer was separated and extracted with methylene chlo-
ride. The combined organic extracts were washed with
brine, dried over Na2SO4, and concentrated. The resid-
ual oil was chromatographed to afford 2 (23.6 g, 76%).
4.4. (S)-2-(Methoxycarbonyl)amino-2-(4-phenyl-
methoxy)phenylsuccinic acid, 1-methyl ester, 5a
To a solution of 4 (2.34 g, 5.28 mmol) in methylene
chloride (100 mL) was introduced gaseous hydrochlo-
ride until no more starting material was detected by
TLC. After the solvent was evaporated, the residual oil
was chromatographed to afford 5 (1.76 g, 86%). [h]2D0=
1
+32.8 (c 1.1, CHCl3); H NMR (300 MHz, CDCl3) l
7.45–7.30 (m, 7H), 6.90 (d, J=8.9 Hz, 2H), 6.50 (s,
1H), 5.05 (s, 2H), 3.95 (d, J=15.9 Hz, 1H), 3.70 (s,
3H), 3.65 (d, J=15.9 Hz, 1H), 3.62 (s, 3H); MS m/z
387 (M+); HRMS found m/z 387.1310 (M+);
C20H21NO7 requires 387.1319.
4.5. (S)-2-(Methoxycarbonyl)amino-2-phenylsuccinic
acid, 1-methyl ester, 9
1
[h]2D0=+68 (c 2.5, CHCl3); H NMR (300 MHz, CDCl3)
l 7.50–7.25 (m, 12H), 7.05 (d, J=8.5 Hz, 2H), 6.75 (s,
1H), 5.40 (s, 1H), 5.10 (s, 2H), 3.50 (s, 3H); MS m/z
403 (M+); HRMS found m/z 403.1412 (M+);
C24H21NO5 requires 403.1421.
Following the procedure for preparing 5a from (S)-4-
benzoxyphenylglycine, acid 9 was prepared from (S)-
1
phenylglycine. [h]D20=+31.3 (c 1.1, CHCl3); H NMR
(300 MHz, CDCl3) l 7.44–7.27 (m, 5H), 6.60 (s, 1H),
4.00 (d, J=17.0 Hz, 1H), 3.71 (s, 3H), 3.69 (d, J=17.0
Hz, 1H), 3.61 (s, 3H); MS m/z 282 (M++H+); HRMS
found m/z 281.0916 (M+); C13H15NO6 requires
281.0899.
4.2. (2R,4S)-[2-Phenyl-3-(methoxycarbonyl)amino-4-(4-
phenylmethoxy)phenyloxazolidin-4-yl]acetic acid, tert-
butyl ester, 3
A solution of 2 (2.0 g, 6.7 mmol) in anhydrous THF
(100 mL) was cooled to −78°C and treated with
KHMDS (1 M in THF, 7.4 mL, 7.4 mmol) at −78°C
under an argon atmosphere. The mixture was stirred
for 30 min and tert-butyl bromoacetate (1.4 g, 7.4
mmol) was added by syringe. The reaction mixture was
stirred for 2 h and allowed to warm to room tempera-
ture. The mixture was partitioned between ethyl acetate
and water and separated, the organic layer was washed
with brine and dried over MgSO4. After the solvent was
evaporated, the residual oil was purified by flash chro-
matography to afford 3 as colorless oil (2.4 g, 88%).
[h]2D0=−9.2 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3) l 7.60–7.40 (m, 12H), 7.05 (d, J=9.0 Hz, 2H),
6.80 (s, 1H), 5.20 (s, 2H), 3.81 (s, 3H), 3.54–3.31 (m,
2H), 1.62 (s, 9H); MS m/z 517 (M+). Anal. calcd for
C30H31NO7: C, 69.63; H, 6.00; N, 2.71. Found: C,
69.34; H, 6.06; N, 2.57%.
4.6. (S)-1-(Methoxycarbonyl)amino-3-oxoindan-1-car-
boxylic acid, methyl ester, 10
To a solution of 9 (9.8 g, 35.6 mmol) in anhydrous
ether (120 mL) was added PCl5 (7.4 g, 35.6 mmol) in
three portions at 0°C. After the addition the solution
was stirred at room temperature for 1 h. The solvent
was removed in vacuo and the residue was dissolved in
dry methylene chloride (100 mL). This solution was
added dropwise to a suspension of AlCl3 (14.2 g, 106.8
mmol) in methylene chloride (120 mL). The resultant
mixture was stirred for 2 h at room temperature before
pouring into 1N aq. HCl (100 mL) at 0°C to quench
the reaction. The organic layer was separated and the
aq. layer was extracted with methylene chloride. The
combined organic extracts were washed with water and
brine, dried over Na2SO4, and concentrated. The resid-

966
D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 961–969
ual solid was recrystallized from hexane/ethyl acetate to
afford 8.3 g (91%) of 10 as a white crystal. Mp 67°C;
[h]2D0=+188.4 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3) l 7.81 (d, J=7.6 Hz, 1H), 7.63 (t, J=7.6 Hz,
1H), 7.53 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H),
6.18 (br s, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 3.44 (d,
J=18.5 Hz, 1H), 3.17 (d, J=18.1 Hz, 1H); MS m/z 263
(M+); HRMS found m/z 263.0802 (M+); C13H13NO5
requires 263.0794.
cooled solution was concentrated to dryness and the
residue was dissolved in ethanol (1 mL). To this solu-
tion was added propylene oxide (0.5 mL). The resultant
precipitate was filtered, washed with ethanol and dried
in vacuo to afford 14 (63 mg, 79%). [h]2D0=+81 (c 0.13,
1
H2O); H NMR (300 MHz, D2O) l 8.02 (d, J=7.8 Hz,
1H), 7.99 (s, 1H), 7.48 (d, J=7.8 Hz, 1H), 3.22 (t,
J=6.0 Hz, 1H), 2.88 (dt, J=14.1, 7.1 Hz, 2H), 2.42 (dt,
J=14.2, 7.1 Hz, 1H); MS (ESI) m/z 221 (M+).
4.7. (S)-1-(Methoxycarbonyl)aminoindan-1-carboxylic
acid, methyl ester, 12
4.10. (S)-6-Hydroxy-1-(methoxycarbonyl)aminoindan-1-
carboxylic acid, methyl ester, 15
A suspension of 10 (5.0 g, 19.0 mmol), 10% Pd/C (0.5
g) in methanol (100 mL) and 25% aq. HCl (13 mL) was
hydrogenated at atmospheric pressure and room tem-
perature for 6 h. The Pd/C was removed by filtration
and the filtrate was diluted with water (50 mL) and
evaporated via rotavapor to remove methanol. Extrac-
tive work-up with ether, followed by chromatography
afforded 12 (4.45 g, 94%). [h]2D0=+118.6 (c 0.95,
To a mixture of 12 (1.42 g, 5.7 mmol) in carbon
disulfide (20 mL) was added AlCl3 (3.0 g, 22.8 mmol)
and acetyl chloride (0.5 mL, 6.8 mmol) at 0°C. The
reaction mixture was stirred at room temperature for 12
h and poured into ice-water (20 mL). Extractive work-
up with ether, followed by chromatography afforded
the acylation product (1.2 g, 70%), which was dissolved
in chloroform (20 mL). To this solution was added
m-CPBA (50%, 2.5 g, 7.3 mmol). The resultant solution
was heated under reflux for 24 h in the dark, and then
partitioned between ethyl acetate and satd aq. Na2SO3.
The organic extract was concentrated and the residue
was dissolved in MeOH (20 mL) and 10% aq. K2CO3
(10 mL) was added at 0°C. The resultant mixture was
stirred for 1 h at 0°C and then acidified with 1N aq.
HCl. Extractive work-up with ether followed by chro-
matography afforded 15 (0.95 g, 63% overall yield for
1
CHCl3); H NMR (300 MHz, CDCl3) l 7.31–7.18 (m,
4H), 5.66 (br s, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 3.14–
2.99 (m, 3H), 2.45 (m, 1H); MS m/z 250 (M++H+);
HRMS found m/z 249.1020 (M+); C13H15NO4 requires
249.1001.
4.8. (S)-1-(Methoxycarbonyl)aminoindan-1,6-dicar-
boxylic acid, 13
To a mixture of 12 (1.0 g, 4.0 mmol) and Hg(OTf)2 (2.0
g, 4.0 mmol) in methylene chloride (5 mL) was added
dropwise a solution of iodine (1.0 g, 4.0 mmol) in
methylene chloride (5 mL). The resultant solution was
stirred for 24 h at room temperature and partitioned
between ethyl acetate and water. The organic layer was
washed with aq. Na2SO3, aq. KI, and brine, respec-
tively. After drying over Na2SO4, the organic phase was
concentrated and chromatographed to afford a mixture
of iodides, which was dissolved in DMF (10 mL) and
EtOH (10 mL). To this solution was added Et3N (4.1
mL, 29.3 mmol), dppp (60 mg, 0.15 mmol) and
Pd(OAc)2 (33 mg, 0.15 mmol). The resulting solution
was bubbled with CO and heated at 60°C for 2 h. The
mixture was cooled and poured into water (50 mL) and
then extracted with ethyl acetate. The organic phase
was dried over Na2SO4 and concentrated. The residue
was dissolved in MeOH (10 mL) and treated with 1N
KOH (5 mL). The resultant mixture was stirred for 2 h
and 1N aq. HCl was added to adjust the mixture to pH
2. Extractive work-up with ether, followed by chro-
matography afforded 13 (569 mg, 51%). [h]2D0=+124.1
1
three steps). [h]2D0=+45.5 (c 0.6, CHCl3); H NMR (300
MHz, CDCl3) l 7.31–7.18 (m, 4H), 5.66 (br s, 1H), 3.71
(s, 3H), 3.64 (s, 3H), 3.14–2.99 (m, 3H), 2.45 (m, 1H),
7.09 (d, J=8.3 Hz, 1H), 6.77–6.74 (m, 2H), 5.72 (br s,
1H), 3.69 (s, 3H), 3.63 (s, 3H), 3.02–2.99 (m, 3H),
2.55–2.38 (m, 1H); MS m/z 265 (M+); HRMS found
m/z 265.0950 (M+); C13H15NO5 requires 265.0922.
4.11. (S)-6-Hydroxy-1-(methoxycarbonyl)aminoindan-
1,5-dicarboxylic acid, dimethyl ester, 16
To a solution of 15 (63 mg, 0.24 mmol) in dioxane (1.2
mL) was added pyridine (0.2 mL) and iodine (73 mg,
0.28 mmol). The resultant mixture was heated under
reflux for 24 h and then the cooled solution was parti-
tioned between ethyl acetate and water. The organic
extract was dried over Na2SO4 and concentrated to
afford crude iodide, which was dissolved in DMF (2
mL) and ethanol (2 mL). To this solution was added
triethylamine (0.5 mL), dppp (10 mg, 0.024 mmol) and
Pd(OAc)2 (6 mg, 0.024 mmol), the mixture was bubbled
with CO and heated at 60°C for 2 h. The mixture was
cooled and partitioned between ethyl acetate and water.
The organic extract was dried over Na2SO4 and concen-
trated and the residue was chromatographed to afford
16 (44 mg, 55%). [h]2D0=+116.3 (c 0.94, CHCl3); 1H
NMR (300 MHz, CDCl3) l 10.85 (s, 1H), 7.75 (s, 1H),
6.86 (s, 1H), 5.89 (br s, 1H), 4.42 (q, J=6.5 Hz, 2H),
3.73 (s, 3H), 3.65 (s, 3H), 3.05 (t, J=6.9 Hz, 2H), 2.90
(dt, J=14.6, 6.8 Hz, 1H), 2.55 (m, 1H), 1.30 (t, J=6.9
Hz, 3H); MS m/z 337 (M+); HRMS found m/z
337.1152 (M+); C16H19NO7 requires 337.1160.
1
(c 0.11, CHCl3); H NMR (300 MHz, CD3SOCD3) l
8.04 (s, 1H), 7.99 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.36
(d, J=7.9 Hz, 1H), 3.51 (s, 3H), 2.97 (m, 2H), 2.77 (m,
1H), 2.24 (m, 1H); MS m/z 280 (M++H+); HRMS
found m/z 279.0756 (M+); C13H13NO6 requires
297.0745.
4.9. (S)-1-Aminoindan-1,6-dicarboxylic acid, 14
A mixture of 13 (100 mg, 0.36 mmol) in 6N aq. HCl (3
mL) in a sealed tube was heated at 100°C for 24 h. The

D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 961–969
967
4.12. (S)-6-Hydroxy-5-diethylphosphono-1-(methoxycar-
was washed with brine and dried over Na2SO4. After
the solvent had been evaporated in vacuo, the residue
was dissolved in satd methanolic hydrochloride (50
mL). The resultant solution was stirred overnight and
then evaporated in vacuo. The residue was dissolved in
water and the solution was neutralized with aq. sodium
bicarbonate until pH 8. Extractive work-up with ether
followed by chromatography gave the corresponding
amino ester, which was dissolved in toluene (2000 mL).
After it was added TsOH (0.86 g, 5 mmol), the solution
was refluxed for 24 h under argon. The solvent was
evaporated and the residue was purified by chromatog-
raphy to give 15.2 g (57%) of 20 as a mixture of two
diastereomers. 1H NMR (300 MHz, CDCl3) l 7.51–
7.20 (m, 9H), 5.02 (s, 1H), 5.53–4.39 (m, 3H), 2.36 (s,
1H); MS m/z 268 (M++H+).
bonyl)aminoindan-1-carboxylic acid, methyl ester, 17
To a solution of 15 (101 mg, 0.38 mmol) in 2 mL of
dioxane were added 0.3 mL of pyridine and iodine (117
mg, 0.45 mmol). The resultant mixture was refluxed for
24 h and then the cooled solution was partitioned
between ethyl acetate and water. The organic extract
was dried over Na2SO4 and concentrated to afford
crude iodide, which was dissolved in 3 mL of triethy-
lamine. To this solution were added diethyl phosphite
(58 mL, 0.44 mmol) and Pd(PPh3)4 (80 mg, 0.07 mmol)
under a nitrogen atmosphere. The resultant mixture
was heated at 100°C in a sealed tube for 24 h before it
was partitioned between ethyl acetate and water. The
organic extract was dried over Na2SO4 and concen-
trated, the residue was chromatographed to afford 88
1
mg (58%) of 17. [h]D20=+103.9 (c 0.2, CHCl3); H NMR
4.16. (S)-2-((R)-2-Hydroxy-1-phenylethylamino)-2-(4-
methylphenyl)succinic acid 4-tert-butyl ester, 1-methyl
ester, 21 and (R)-2-((R)-2-hydroxy-1-phenylethyl-
amino)-2-(4-methylphenyl)succinic acid 4-tert-butyl
ester, 1-methyl ester, 22
(300 MHz, CDCl3) l 10.20 (s, 1H), 7.24 (d, J=14.1 Hz,
1H), 6.88 (d, J=5.9 Hz, 1H); 5.74 (br s, 1H), 4.18–3.98
(m, 4H), 3.72 (s, 3H), 3.65 (s, 3H), 3.05–2.97 (m, 3H),
2.55–2.45 (m, 1H), 1.30 (t, J=6.9 Hz, 6H); MS m/z 401
(M+); HRMS found m/z 401.1239 (M+); C17H24NPO8
requires 401.1240.
A solution of 20 (10.0 g, 37.5 mmol) in 1/1 n-hexane/
THF (250 mL) was cooled to −78°C under argon. To
this solution was added LHMDS (1.0 M in THF, 45
mL, 45.0 mmol) over 30 min. Stirring was continued
for 1 h at the same temperature and a solution of
tert-butyl bromoacetate (8.4 g, 43.1 mmol) in THF (20
mL) was added dropwise. The reaction mixture was
stirred at −78°C for 12 h before satd aq. ammonium
chloride (100 mL) was added to quench the reaction.
The mixture was partitioned between ethyl acetate and
brine. The organic phase was dried over Na2SO4 and
concentrated. The residue was purified by chromatogra-
phy to give the alkylation products (9.85 g, 69%).
4.13. (S)-6-Hydroxy-1-aminoindan-1,5-dicarboxylic
acid, 18
To a solution of 16 (25 mg, 0.074 mmol) in acetonitrile
(3 mL) under argon was added TMSI (53 mL, 0.37
mmol). The reaction mixture was heated at 50°C for 24
h and then concentrated. The residue was dissolved in
distilled water (2 mL) and washed with ethyl acetate.
The aq. layer was concentrated and the residue was
purified with Dowex-50W eluting with water to afford
1
18 (14 mg, 75%). [h]2D0=+87.2 (c 0.1, 6N aq. HCl); H
NMR (300 MHz, D2O) l 7.53 (s, 1H), 6.81 (s, 1H),
2.93 (t, J=6.9 Hz, 2H), 2.76 (dt, J=14.1, 6.9 Hz, 1H),
2.28 (dt, J=14.1, 7.0 Hz, 1H); MS (ESI) m/z 238
(M++H+).
A solution of the above products (9.5 g, 24.9 mmol)
and triethylamine (10 mL) in methanol (200 mL) was
stirred at room temperature overnight. The solvent was
evaporated and the residue was chromatographed to
afford 21 (4.41 g, 76% yield based on 57% conversion),
22 (1.15 g, 20% yield based on 57% conversion),
together with starting material (4.12 g). 21: [h]1D8=−2.6
4.14. (S)-6-Hydroxy-5-phosphono-1-aminoindan-1-car-
boxylic acid, 19
1
Following the same procedure for preparing 18 from
16, 19 was obtained from 17 in 82% yield. [h]2D0=+76.3
(c 1.5, CHCl3); H NMR (300 MHz, CDCl3) l 7.13 (m,
3H), 6.98 (d, J=8.4 Hz, 2H), 6.94–6.87 (m, 4H), 3.62
(s, 3H), 3.51 (m, 1H), 3.46 (d, J=6.6 Hz, 2H), 3.38 (m,
1H), 3.25 (d, J=14.9 Hz, 1H), 3.18 (d, J=15.1 Hz,
1H), 2.26 (s, 3H), 1.48 (s, 9H); MS m/z 414 (M++H+);
HRMS found m/z 413.2212 (M+); C24H31NO5 requires
413.2202. 22: [h]D18=+23.5 (c 2.6, CHCl3); 1H NMR
(300 MHz, CDCl3) l 7.23–7.19 (m, 3H), 7.17 (d, J=8.5
Hz, 2H), 7.11–7.07 (m, 4H), 5.30 (s, 1H), 3.62–3.55 (m,
2H), 3.51–3.42 (m, 4H), 3.18 (d, J=16.2 Hz, 1H), 3.16
(m, 1H), 2.74 (d, J=16.4 Hz, 1H), 2.31 (s, 3H), 1.31 (s,
9H); MS m/z 414 (M++H+); HRMS found m/z
382.2012 (M+−OMe); C23H28NO4 requires 282.2018.
1
(c 0.1, 6N aq. HCl); H NMR (300 MHz, D2O) l 7.50
(d, J=14.3 Hz, 1H), 6.83 (d, J=6.1 Hz, 1H), 2.95 (t,
J=7.1 Hz, 2H), 2.79 (dt, J=14.5, 7.0 Hz, 1H), 2.28 (dt,
J=14.5, 7.0 Hz, 1H); MS (ESI) m/z 274 (M++H+).
4.15. (3R,5R)-3-(4-Methylphenyl)-5-phenyl-2-morphol-
inone and (3S,5R)-3-(4-methylphenyl)-5-phenyl-2-mor-
pholinone, 20
To a solution of 4-methylbenzaldehyde (12.0 g, 100
mmol), (R)-phenylglycinol (15.1 g, 110 mmol), ammo-
nium chloride (7.0 g, 130 mmol) in methanol (75 mL)
and water (75 mL) was added sodium cyanide (4.9 g,
100 mmol) with cooling by ice-water. The solution was
stirred at room temperature for 8 h before MeOH was
evaporated in vacuo. The aq. phase was extracted three
times with ethyl acetate. The combined organic extract
4.17. (S)-2-(Methoxycarbonyl)amino-2-(4-methyl-
phenyl)succinic acid, 1-methyl ester, 23
To a solution of 21 (3.0 g, 7.3 mmol) in 1/1 MeOH/
CH2Cl2 (150 mL) were added NaOAc (1.9 g, 23.1

968
D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 961–969
mmol), Pb(OAc)4 (4.9 g, 11.0 mmol) at 0°C. The mix-
ture was stirred at 0°C for 30 min, filtered through
silica gel. The filtrate was evaporated in vacuo and the
residue was dissolved in THF (30 mL). To this solution
was added 3N aq. HCl (50 mL) and the mixture stirred
for 2 h. After the solvent was evaporated in vacuo, the
residue was dissolved in water (30 mL). The solution
was cooled to 0°C and NaHCO3 (2.5 g, 29.2 mmol) was
added. To this mixture methyl chloroformate (1.4 g,
14.6 mmol) was added dropwise. The mixture was
stirred at room temperature overnight and then aci-
dified with 1N aq. HCl to pH 3. The solution was
extracted three times with chloroform, the combined
organic phase was washed with brine and dried over
Na2SO4. The solvent was evaporated in vacuo, the
residue was purified by chromatography to afford 1.62
4.20. (S)-1-(Methoxycarbonyl)amino-3-oxoindan-1,5-
dicarboxylic acid, dimethyl ester, 26
To a solution of 25 (1.25 g, 2.89 mmol) in THF (30
mL) and H2O (20 mL) was added freshly prepared
Ag2O (1.07 g, 4.62 mmol). The mixture was stirred at
room temperature for 12 h and filtered. The filtrate was
evaporated in vacuo and the residue was dissolved in
MeOH (10 mL) for use in the next synthetic step.
To a solution of silver nitrate (2.46 g, 14.47 mmol) in
H2O (20 mL) was added a solution of NaOH (1.16 g,
29.00 mmol) in H2O (15 mL) dropwise. The mixture
was stirred for 20 min and the above methanolic solu-
tion was added with ice-water cooling. Stirring was
continued until the reaction was complete (monitored
by TLC). The mixture was filtered and the filtrate was
acidified with 1N aq. HCl to give pH 1. The solution
was extracted six times with chloroform and the com-
bined organic extract was washed with brine and dried
over Na2SO4. The solvent was evaporated in vacuo, the
residue was dissolved in DMF (30 mL). To this solu-
tion were sequentially added K2CO3 (0.75 g, 7.09
mmol) and MeI (0.81 g, 5.70 mmol). After the mixture
was stirred at room temperature overnight, the solvent
was evaporated in vacuo and the residue was suspended
in ethyl acetate and then washed with water and brine.
The organic extract was dried over Na2SO4 and concen-
trated. The residue was purified by chromatography to
afford 26 (591 mg, 64%). [h]1D8=+87.4 (c 2.8, CHCl3);
1H NMR (300 MHz, CDCl3) l 8.49 (s, 1H), 8.35 (dd,
J=8.0, 1.6 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 6.32 (br s,
1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.63 (s, 3H), 3.17 (t,
J=7.4 Hz, 2H), 2.95 (dt, J=13.0, 7.4 Hz, 1H), 2.55 (m,
1H); MS m/z 322 (M++H+); HRMS found m/z
290.0627 (M+−OMe); C14H12NO6 requires 290.0665.
1
g (75%) of 23. [h]D18=+12.0 (c 2.3, CHCl3); H NMR
(300 MHz, CDCl3) l 7.36 (d, J=8.1 Hz, 2H), 7.18 (d,
J=8.1 Hz, 2H), 6.59 (s, 1H), 3.97 (d, J=16.7 Hz, 1H),
3.71–3.62 (m, 1H), 3.70 (s, 3H), 3.61 (s, 3H), 2.34 (s,
3H); MS m/z 294 (M+−H+); HRMS found m/z
250.1085 (M+−CO2); C13H17NO4 requires 250.1079.
4.18. (S)-1-(Methoxycarbonyl)amino-5-methyl-3-oxoin-
dan-1-carboxylic acid methyl ester, 24
To a solution of 23 (1.5 g, 5.1 mmol) in ether (10 mL)
was added oxalyl chloride (0.7 g, 6.0 mmol) at 0°C. A
drop of DMF was added and the solution was stirred at
0°C for 0.5 h. The solvent was evaporated in vacuo and
the residue was dissolved in CH2Cl2 (20 mL). To this
solution was added a suspension of anhydrous alu-
minum chloride (3.1 g, 22.9 mmol) in CH2Cl2 (200 mL)
at 0°C. The mixture was stirred for 12 h at room
temperature before it was poured onto a mixture of ice
(about 80 g) and 3N aq. HCl (150 mL). The organic
layer was separated and washed with brine, dried over
Na2SO4. After removal of solvent the residue was
purified by chromatography to afford 24 (1.3 g, 93%).
4.21. (S)-1-(Methoxycarbonyl)amino-3-indan-1,5-dicar-
boxylic acid, dimethyl ester, 27
1
[h]1D8=+78 (c 0.7, CHCl3); H NMR (300 MHz, CDCl3)
l 7.60 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0
Hz, 1H), 6.10 (br s, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 3.45
(d, J=18.0 Hz, 1H), 3.16 (d, J=18.0 Hz, 1H), 2.42 (s,
3H); MS m/z 278 (M++H+); HRMS found m/z
277.0943 (M+); C14H15NO5 requires 277.1013.
A suspension of 26 (500 mg, 1.56 mmol), 50 mg of 10%
Pd/C in 20 mL of MeOH was stirred under H2 (10 atm)
at 30°C for 8 h. The catalyst was removed by filtration
and the filtrate was concentrated, the residue was
purified by chromatography to afford product 27 (463
1
mg, 97%). [h]1D8=+44.8 (c 3.2, CHCl3); H NMR (300
4.19. (S)-1-(Methoxycarbonyl)amino-5-dibromomethyl-
3-oxoindan-1-carboxylic acid methyl ester, 25
MHz, CDCl3) l 7.95 (s, 1H), 7.90 (d, J=8.4 Hz, 1H),
7.33 (d, J=8.2 Hz, 1H), 5.82 (br s, 1H), 3.90 (s, 3H),
3.70 (s, 3H), 3.65 (s, 3H), 3.15 (t, J=7.4 Hz, 2H), 2.95
(dt, J=13.0, 7.4 Hz, 1H), 2.55 (m, 1H); MS m/z 276
(M+−OMe); HRMS found m/z 276.0893 (M+−OMe);
C14H14NO5 requires 276.0872.
To a refluxing solution of 24 (1.0 g, 3.6 mmol) in CCl4
(70 mL) were sequentially added NBS (0.71 g, 4.0
mmol) and AIBN (30 mg). The solution was stirred
under reflux for 0.5 h, and further NBS (0.71 g, 4.0
mmol) was added. Stirring was continued for 3.5 h at
the same temperature and the solvent was evaporated
in vacuo. The residue was purified by chromatography
4.22. (S)-1-Amino-3-indan-1,5-dicarboxylic acid, (S)-
AIDA
1
to afford 25 (1.4 g, 87%). [h]1D8=+51 (c 1.0, CHCl3); H
In a sealed tube were placed 27 (400 mg, 1.3 mmol) and
6N aq. HCl (15 mL). The mixture was heated to 130°C
with stirring for 24 h. The solvent was evaporated in
vacuo and the residue was dissolved in EtOH (50 mL).
To this solution propylene oxide (5 mL) was added
with stirring and the resultant solution was heated to
60°C. The mixture was stirred for 30 min. The white
NMR (300 MHz, CDCl3) l 7.96 (s, 1H), 7.94 (d, J=8.1
Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 6.23 (br
s, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 3.43 (d, J=18.4 Hz,
1H), 3.27 (d, J=18.4 Hz, 1H); MS m/z 434 (M+, 81Br).
Anal. calcd for C14H13Br2NO5: C, 38.65; H, 3.01; N,
3.22. Found: C, 38.22; H, 3.05; N, 3.23%.

D. Ma et al. / Tetrahedron: Asymmetry 13 (2002) 961–969
969
precipitate was collected by suction filtration and
recrystallized from distilled water to afford (S)-AIDA
(225 mg, 78%). [h]2D0=+83.5 (c 0.9, 6N aq. HCl) [lit.8
Camodeca, N.; Prreakwell, N. A.; Rowan, M. J.; Anwyl,
R. Neuropharmacology 1999, 38, 1597; (g) Maiese, K.;
Ahmad, I.; Teubroeke, M.; Gallant, J. J. Neurosci. Res.
1999, 55, 472; (h) Kleinlogel, S.; Oestreichen, E.; Arnold,
T.; Ehrenberger, K.; Felix, D. NeuroReport 1999, 10,
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Garcia, M.; Puri, A.; Zucca, G.; Botta, L.; Valli, P. Hear.
Res. 1998, 125, 154.
1
[h]2D0=+86.3 (c 0.8, 6N aq. HCl)]; H NMR (300 MHz,
D2O) l 7.98 (s, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.48 (d,
J=8.0 Hz, 1H), 3.23 (t, J=7.2 Hz, 2H), 2.89 (dt,
J=14.4, 7.2 Hz, 1H), 2.43 (dt, J=14.4, 7.3 Hz, 1H);
MS (ESI) m/z 221 (M+).
5. (a) Krenz, W. D.; Ngugen, D.; Perez-Acevedo, N. L.;
Selverston, A. I. J. Neurophysiol. 2000, 83, 1188; (b)
Raymond, V.; Hamon, A.; Grau, Y.; Lapied, B. Neu-
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Acknowledgements
6. Hayashi, Y.; Sekiyama, N.; Nakanishi, S.; Jane, D. E.;
Sunter, D. C.; Bire, E. F.; Udvarhelyi, P. M.; Watkins, J.
C. J. Neurosci. 1994, 14, 3370.
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1994, 15, 333.
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (grant 20132030), and Qiu Shi Science & Tech-
nologies Foundation for their financial support.
8. Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120.
9. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
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