Amino acids as a chiral pool: Synthesis of (S)- and (R)-2-N-carbomethoxy-5- aminoindane from (S)- and (R)-phenylalanines

Article abstract of DOI:10.1080/00397910701226905

Enantioselective syntheses of (R)-and (S)-2-N-carbomethoxy-5-aminoindanes from (R)- and (S)-phenylalanines, respectively, are described. A Friedel-Crafts reaction employing N-carbomethoxy phenylalanine leads to chiral 2-N-carbomethoxy-1-indanone, which is

Full text of DOI:10.1080/00397910701226905

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Amino Acids as a Chiral Pool: Synthesis of
(S)‐and (R)‐2‐N‐Carbomethoxy‐5‐aminoindane
from (S)‐ and (R)‐Phenylalanines
a
a
a
Liladhar M. Waykole , Joseph J. McKenna , Andrew Bach , Mahavir
a
a
a
Prashad , Oljan Repič & Thomas J. Blacklock
a
Process Research and Development, Chemical and Analytical
Development , Novartis Pharmaceuticals Corporation , One Health Plaza,
East Hanover, New Jersey, 07936, USA
Published online: 11 May 2007.
To cite this article: Liladhar M. Waykole , Joseph J. McKenna , Andrew Bach , Mahavir Prashad ,
Oljan Repič & Thomas J. Blacklock (2007) Amino Acids as a Chiral Pool: Synthesis of (S)‐and
(
R)‐2‐N‐Carbomethoxy‐5‐aminoindane from (S)‐ and (R)‐Phenylalanines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:9, 1445-1454, DOI:
0.1080/00397910701226905
1
To link to this article: http://dx.doi.org/10.1080/00397910701226905
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Synthetic Communications , 37: 1445–1454, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701226905
Amino Acids as a Chiral Pool: Synthesis
of (S)- and (R)-2-N-Carbomethoxy-
5
-aminoindane from (S)- and
R)-Phenylalanines
(
Liladhar M. Waykole, Joseph J. McKenna, Andrew Bach,
Mahavir Prashad, Oljan Repi cˇ , and Thomas J. Blacklock
Process Research and Development, Chemical and Analytical
Development, Novartis Pharmaceuticals Corporation, New Jersey, USA
Abstract: Enantioselective syntheses of (R)- and (S)-2-N-carbomethoxy-5-aminoin-
danes from (R)- and (S)-phenylalanines, respectively, are described. A Friedel–Crafts
reaction employing N-carbomethoxy phenylalanine leads to chiral 2-N-carbo-
methoxy-1-indanone, which is diastereoselectively reduced to 1-hydroxy-2-N-carbo-
methoxyindane. After protection of the hydroxyl group, a regioselective nitration
gives a 6-nitroindane intermediate, which upon hydrogenation affords (R)- or (S)-2-
N-carbomethoxy-5-aminoindane.
Keywords: Amino acids, aminoindane, chiral pool, phenylalanine
INTRODUCTION
Substituted indanes, especially with a vicinal amino-alcohol, constitute an
important subunit of biologically significant molecules. The most important
feature of these medicinal agents is the chirality at the stereogenic
[
1]
centers. Synthetic procedures that deliver indane derivatives with known
absolute configurations are needed. Our interest in this area was to prepare
Received in the USA October 9, 2006
Address correspondence to Liladhar M. Waykole, Process Research and Develop-
ment, Chemical and Analytical Development, Novartis Pharmaceuticals Corporation,
One Health Plaza, East Hanover, NJ 07936, USA. E-mail: liladhar.waykole@
novartis.com
1
445

1
446
L. M. Waykole et al.
Figure 1. 2-N-carbomethoxy-5-aminoindane.
(
R)-2-N-carbomethoxy-5-aminoindane [(R)-8] and (S)-2-N-carbomethoxy-
-aminoindane [(S)-8] (Fig. 1). These are pivotal intermediates in the
syntheses of several of the compounds in our MTP (microsomal triglycer-
5
[2]
ide-transfer protein) inhibitor program.
[3]
Racemic 2,5-diaminoindane or 2-amino-5-nitroindane can be easily
prepared. However, one must rely on classical resolution to afford enantiopure
compounds and prove the absolute configuration at C-2 by some unambiguous
method. Although chiral cis-1-amino-2-indanol has been studied exten-
[
1,4]
sively,
vatives have been studied to a limited extent.
the isomeric 2-amino-1-indanol and its aromatic-substituted deri-
We envisioned that an
[5,6]
appropriately protected chiral 2-amino-1-indanol derivative, prepared from
a chiral amino acid, might lend itself to regioselective nitration, which upon
further manipulation would provide the target compound. Unfortunately,
literature points to a severe racemization problem of the amino ketone
[
5,6]
intermediate in this synthesis.
Despite this, we decided to pursue this
approach because the absolute configuration at the C-2 center of the target
compound is known, cheaper and easily accessible starting materials are
available, and racemization might be controlled through optimized reaction
conditions. In this article, we describe a synthesis of enantiomerically pure
[
(R)-8] and [(S)-8] from optically pure phenylalanines.
RESULTS AND DISCUSSION
An efficient preparation of intermediates [(R)-8] and [(S)-8] would be via
intramolecular Friedel–Crafts cyclization of appropriately protected (R)-4-
aminophenylalanine or (S)-4-aminophenylalanine, prepared from commer-
cially available (R)-(þ)-4-nitrophenylalanine or (S)-(2)-4-nitrophenylalanine,
to the appropriately substituted indanone followed by deoxygenation
[7]
(
Scheme 1). Buckley and Rapoport have reported such aminoacylation.
Thus, we attempted a regioselective cyclization of appropriately substituted
enantiopure amino acids (I–III) to a desired 5-substituted 2-aminoindanone
derivative (Scheme 1). However, these attempts were futile in spite of the
use of various N-protecting groups (e.g., Boc, acetyl) and combinations in
different solvents under different experimental conditions.
After these disappointing results, we set out to pursue cyclization
of an appropriately N-protected (S)-phenylalanine to a 2-N-protected

Amino Acids as a Chiral Pool
1447
Scheme 1.
amino-1-indanone and then introduce the amino functionality at the 6-position
via nitration (Scheme 2). Unsubstituted phenylalanine undergoes intramolecu-
[5,6]
lar Friedel–Craft aminoacylation to afford 2-amino-1-indanone. Thus,
carbomethoxylation of (S)-phenylalanine under Schotten–Baumann
Scheme 2.

1
448
L. M. Waykole et al.
conditions followed by intramolecular Friedel–Crafts acylation of the
resulting (S)-2-N-carbomethoxyphenylalanine with an excess of phosphorus
pentachloride and aluminum trichloride (3.0 equiv) in dichloromethane
afforded 3. We found that the acid chloride formation was most efficient
using phosphorus pentachloride. Methyl carbamate was the choice of protect-
[3]
ing group because it was also part of the desired active compound and was
stable under these conditions. One of the major hurdles was to avoid the race-
[
5,6]
mization of the 2-carbomethoxyamino-1-indanone (3).
of the reaction mixture at low temperature (25 to 18C) into 3 N HCl over
5 min controlled racemization. The pH of the mixture had to be adjusted
Reverse quenching
4
to 6.9 by adding aqueous sodium bicarbonate. This afforded 2-carbomethox-
yamino-1-indanone (3) without racemization in 75% yield.
Because indanone (3) is extremely sensitive to racemization, we decided
to reduce the ketone to alcohol 4. The stereoselective reduction of 2-carbo-
[6]
methoxyamino-1-indanone (3) has been reported with BH and sodium
3
bis(2-methoxyethoxy)aluminum hydride with no racemization when the
substrate was added to the reagent. We found that such a reduction of 3
with sodium bis(2-methoxyethoxy)aluminum hydride gave 4 in a 95:5 ratio
of trans:cis, and the trans-isomer could be easily purified by recrystallization
from t-butyl methyl ether in 70% yield.
Direct nitration of 4 was unsuccessful, and the alcohol required protection.
Thus, 4 was acylated with acetyl chloride and pyridine in dichloromethane to
afford 5. We realized that anhydrous conditions were essential for a successful
regioselective nitration of 5. We decided to make use of a combination of nitric
acid in trifluoroacetic acid and trifluoroacetic anhydride as the nitrating agent.
To our delight, the nitration of 5 went smoothly to afford a 80:20 mixture of
6-nitro and 5-nitro derivatives. The desired 6-nitro compound 6 was isolated
in 52% yield after recrystallization from ethyl acetate. Because the nitration
step utilized trifluoroacetic anhydride, it is quite possible that protection of
alcohol in 4 and nitration could be accomplished in one pot, had the acetyl
protecting group been changed to trifluoroacetyl.
The next step was the reduction of the nitro group and the reductive
cleavage of the benzylic hydroxyl group. Ideally both of these transformations
could be accomplished in one hydrogenation step. Under catalytic hydrogen-
ation conditions, the nitro group was easily reduced to the amino group.
However, the benzylic acetoxy moiety or the hydroxyl group was not
reduced, and harsher reaction conditions were required. Attempts using
triethylsilane/TFA, sodium borohydride/aluminum trichloride, and TMSCl/
NaI were unsuccessful. A saponification to a free hydroxyl group followed
by reduction gave the same results as when the benzylic acetoxy group was
present. However, reduction of 6 or 7 using Pd/C in acetic acid and HClO4
at room temperature afforded [(S)-8] in 71% and 88% yield, respectively.
The stereochemical outcome was established based on spectroscopic data
[
3]
and chiral HPLC. The synthesis of the antipode [(R)-8] was carried out
following the same protocol starting with enantiopure (R)-phenylalanine.

Amino Acids as a Chiral Pool
1449
In summary, we have developed an efficient enantioselective syntheses
for [(R)-8] and [(S)-8] from commercially available enantiopure phenyl-
alanines as the chiral pool. A regioselective nitration of 2-carbomethoxy-1-
acetoxy-indane was also developed.
EXPERIMENTAL
General Methods
All solvents were used as received from the suppliers. All reagents were used as
1
received from Aldrich Chemical Co. H NMR (300 MHz) and C NMR
13
1
75 MHz) spectra were obtained on a Bruker 300 instrument, and H NMR
(
1
500 MHz) and C NMR (125 MHz) spectra were obtained on a Bruker
3
(
ARX 500-MHz spectrometer. Desorption chemical ionization (DCI) mass-
spectral data were recorded on a Hewlett-Packard 598B mass spectrometer.
Electrospray ionization (ESI) mass spectra were recorded on a Micromass
Platform II mass spectrometer. Optical rotations were determined on a
Rudolph Research Autopol III polarimeter. Melting points were measured on
a B u¨ chi 535 melting-point apparatus and are uncorrected. The enantiopurity
of compounds was determined by chiral high performance liquid chromato-
graphy (HPLC) on a Waters Alliance system with photodiode array UV detector.
(S)-N-(Methoxycarbonyl) phenylalanine [(S)-2]
To a solution of (S)-(2)-phenylalanine 1 (16.5 g, 0.1 mol) in 1 N NaOH
100 mL, 0.1 mol) at 238C, sodium carbonate (5.3 g, 0.05 mol) was added,
(
and the mixture was cooled to 08C. Methyl chloroformate (9.4 g, 0.1 mol)
was added to the mixture over 3 min and stirred for 30 min at 08C. It was
allowed to warm to 238C and stirred for 30 min until a clear solution
resulted. The reaction mixture was acidified to pH 3 with 3 N HCl. The
solution was extracted with dichloromethane (2 ꢀ 100 mL). The dichloro-
methane extract was dried over anhydrous MgSO and filtered. The filtrate
4
was concentrated under vacuum at 208C to afford the carbamate 2 (21 g,
[8]
9
4.1%). The spectroscopic data matched with those described in literature.
(S)-2-[(Methoxycarbonyl)amino]-1-indanone [(S)-3]
The carbamate 2 (34 g, 0.152 mol) was dissolved in dichloromethane
(300 mL) under nitrogen and cooled to –108C. Phosphorus pentachloride
(31.3 g, 0.15 mol) was added in portions over 10 min, maintaining the temp-
erature at –10 to –58C. The mixture was warmed to 08C and held for 30 min
prior to warming to 208C. Aluminum chloride (60 g, 0.45 mol) was added in

1
450
L. M. Waykole et al.
portions over 10 min at 228C to 288C to afford a dark red solution and stirred
at 238C for 30 min (TLC indicated complete reaction). The mixture was added
to 3 N HCl (800 mL) over 45 min with rapid stirring at 25 to 18C. The
resulting mixture was stirred at 08C for 30 min. The dichloromethane layer
was separated, and the aqueous layer was extracted with dichloromethane
(2 ꢀ 300 mL). Ice-cold water (700 mL) was added to the organic extract,
and pH was adjusted to 6.9 by adding aqueous saturated sodium bicarbonate
at 18C. The dichloromethane layer was separated, dried over MgSO and silica
4
gel (3 teaspoons each), and filtered. It was concentrated under vacuum at 158C
to afford 3 (23.3 g, 75%, .99% ee), mp 153–1578C. HPLC (Chiralpak AD
column, hexanes/2-propanol (80:20) isocratic, 1 mL/min, at l ¼ 200–
3
00 nm): t (R-3) 7.8 min, t (S-3) 7.2 min.
R R
The spectroscopy data of the product matched those described in
[
6]
the literature.
trans-(1S,2S)-2-[(Methoxycarbonyl)amino]-1-indanol [trans-(S,S)-4]
Procedure A
Ketone 3 (5.15 g, 0.025 mol) was dissolved in THF (150 mL) under nitrogen
and cooled to 08C. Borane solution in THF (1 N, 50 mL, 0.05 mol) was
added over 10 min at 08C and allowed to warm to 238C. The mixture was
stirred for 1 h, and acetic acid (25 mL) was added dropwise, keeping the
mixture at 208C. Methanol (25 mL) was added dropwise, and the mixture
was stirred for 10 min. The yellow solution was evaporated under vacuum at
308C, followed by high vacuum at 208C. This was repeated twice to afford a
yellow residue, which upon trituration with (50 mL) afforded 4 (2.4 g, 47%);
mp 176–1788C. The spectroscopy data matched those described in the
literature.
[
6]
Procedure B
The Red-Al solution in toluene (528 mL, 1.79 mol, 65þ wt% solution of
sodium bis(2-methoxyethoxy)aluminum hydride) was cooled to 08C under
nitrogen. The anhydrous THF (2.4 L) was added with stirring. Ketone 3
(
246 g, 1.2 mol) was added in portions over 1 h at 210 to 08C. The mixture
was stirred rapidly for 30 min. After checking an aliquot for completion of
the reduction, the reaction mixture was quenched by pouring it into an
aqueous saturated solution of sodium potassium tartarate (2.0 L) over 1 h,
keeping the temperature at 22 to 18C. The layers were separated, and the
aqueous layer was extracted with THF (2 ꢀ 1.5 L). The combined THF
extracts were washed with brine (1.5 L), dried over anhydrous MgSO
4
(
600 g), and filtered and concentrated under vacuum at 208C. The gray solid
residue was stirred in tert-butyl methyl ether (1.5 L) at 238C for 15 min,

Amino Acids as a Chiral Pool
1451
filtered and washed with tert-butyl methyl ether (0.2 L). The solid was dried at
2
98C for 20 h under vacuum to obtain 4 (175 g, 70.6%, .99% ee); mp 176–
788C. Chiral HPLC (4.6 ꢀ 250 mm Chiralpak AS column, hexanes/
1
ethanol/TFA (95:5:0.1) isocratic, 1 mL/min, at l ¼ 200–300 nm): t
R
(1S,2R-4) 19.9 min, t (1S,2S-4) 21.6 min. The spectroscopy data matched
those described in the literature.
R
[
6]
trans-(1S,2S)-2-[(Methoxycarbonyl)amino]-1-acetoxyindane
trans-(S,S)-5]
[
The alcohol 4 (219 g, 1.05 mol) was suspended in dichlromethane (2.8 L) and
cooled to 08C. Pyridine (124.5 g, 1.575 mol) was added to the suspension under
nitrogen. Acetyl chloride (122.9 g, 1.575 mol) was added to the mixture,
keeping the temperature at 25 to 08C. The mixture was stirred for 1 h at
08C. After checking an aliquot for completion of the reaction by TLC (silica,
EtOAc/heptane, 1:1), the mixture was washed at 08C with aqueous saturated
NaHCO (2 ꢀ 2 L), 1 N HCl (2 ꢀ 2 L), and brine (2 L). The organic layer
3
was dried over Na SO , filtered, and concentrated under vacuum to afford 5
4
2
1
as a yellow solid (265 g, 100% with .99% ee); mp 84–888C. H NMR
(
300 MHz, CDCl ) d 7.2–7.4 (m, 4H), 6.15 (d, 1H, J ¼ 7 Hz), 5.4 (H, bs),
3
4
.3 (m, 1H), 3.6 (s, 3 H), 3.5 (dd, 1H, J ¼ 10, 18 Hz), 2.8 (dd, 1H, J ¼ 10,
8 Hz), 2.1 (s, 3H). Chiral HPLC (4.6 ꢀ 250 mm Chiralpak AS column,
1
hexanes/ethanol/TFA (95:5:0.1) isocratic, 1 mL/min, at l ¼ 200–300 nm):
t (1R, 2R-5) 20 min, t (1S,2S-5) 16 min.
R
R
trans-(1S,2S)-6-Nitro-2-[(methoxycarbonyl)amino]-1-
acetoxyindane [trans-(S,S)-6]
A 90% HNO solution (324.5 g, 4.72 mol) was placed in a four-necked
3
reaction flask under nitrogen and cooled to 2308C. Trifluoroacetic acid
(600 mL) was added, and the mixture was cooled to 2358C. Trifluoroacetic
anhydride (590 g, 2.8 mol) was added over 5 min to the reaction mixture.
Carbamate 5 (118 g, 0.47 mol) dissolved in dichloromethane (200 mL) was
added over 45 min with stirring while maintaining the reaction temperature
at 2358C to 2308C. The reaction was checked by TLC (silica, EtOAc/
heptane, 1:1). The reaction was worked up by addition of water (750 mL)
at –308C and warmed to 08C. The upper dichloromethane layer was
separated, and the lower aqueous layer was extracted with dichloromethane
(
1 L). The combined organic extract was washed with water (2 ꢀ 1 L), and
the pH was adjusted to 8.5 using aqueous saturated NaHCO solution
3
(100 mL). It was again washed with cold water (1 L). The organic extract
was dried over anhydrous MgSO and filtered. The filtrate was concentrated
under vacuum to afford crude solid (144 g), which was dissolved in EtOAc
4
(560 mL) at 708C to obtain a yellow-orange solution. The solution was

1
452
L. M. Waykole et al.
slowly cooled to 478C, resulting in a thick slurry. Heptane (1 L) was added to
the slurry over 1 h at 478C to 238C and cooled to 08C prior to filtration. The
filter cake was washed with heptane (500 mL). The solid was dried at 238C for
2
D
5
2
0 h under vacuum to obtain 6 (73 g, 52.6%); mp 165–1678C. [a] þ16.88
þ
21
(
c ¼ 1.0, MeOH). MH 294.9. IR (Nujol) cm 3370, 1735, 1695, 1544,
1
525, 1344, 1278, 1240, 1066, 1037, 900, 740. H NMR (300 MHz, CDCl )
1
3
d 8.1 (dd, 1H, J ¼ 9, 3 Hz), 8.0 (s, 1H), 7.2 (d, 1H, J ¼ 9 Hz), 6.1 (d, 1H,
J ¼ 7 Hz), 5.5 (bs, 1H), 4.4 (m, 1H), 3.6 (s, 3H), 3.5 (dd, 1H, J ¼ 10,
1
3
1
8 Hz), 2.9 (dd, 1H, J ¼ 10, 18 Hz), 2.2 (s, 3H). C NMR (75 MHz,
CDCl ) d 173.0, 156.6, 147.7, 147.5, 140.3, 125.6, 124.5, 120.3, 79.7, 59.1,
3
52.3, 37.0, 20.9. Anal. calcd. for C H O N : C, 53.06; H 4.80; N, 9.52.
13 14 6 2
Found: C, 53.1; H, 4.85; N, 9.42.
trans-(1S,2S)-6-Nitro-2-[(methoxycarbonyl)amino]-1-indanol
trans-(S,S)-7]
[
Acetate 6 (16.5 g, 0.056 mol) was suspended in methanol (275 mL) in a three-
necked reaction flask at 238C under nitrogen. To the suspension, 1 N NaOH
(112 mL) was added dropwise, maintaining the temperature at 238C. The
mixture was stirred for another 15 min and checked by TLC (dissolve
sample in excess MeOH, silica, EtOAc/heptane, 1:1). After completion of
the reaction, the mixture was diluted with water (275 mL). The solid was
filtered, washed with water (275 mL), and dried at 238C under vacuum to
þ
afford 7 (13.1 g, 92.9%, .99% ee); mp 201–2038C. MH 252.98 IR (KBr)
cm
2
1
1
3500, 3350, 1691, 1533, 1355, 1288, 1272, 1234, 1041, 740. H
NMR (500 MHz, DMSO-d ) d 8.1 (dd, 1H, J ¼ 9, 3 Hz), 8.0 (s, 1H), 7.6
6
(
(
(
d, 1 H, J ¼ 7 Hz), 7.45 (d, 1H, J ¼ 9 Hz), 9 Hz, 5.9 (d, 1H, J ¼ 7 Hz), 5.0
d, 1H, J ¼ 7 Hz), 4.0 (m, 1H), 3.5 (s, 3H), 3.2 (dd, 1H, J ¼ 18, 6 Hz), 2.7
1
3
dd, 1H, J ¼ 18, 10 Hz). C NMR (125 MHz, DMSO-d ) d 156.5, 147.2,
6
1
46.9, 146.0, 125.8, 125.1, 118.8, 77.1, 60.9, 51.3, 35.5. Chiral HPLC
(
4.6 ꢀ 250 mm Chiralpak AS column, hexanes/ethanol (80:20) isocratic,
mL/min, at l ¼ 200–300 nm): t (1S,2R-7) 7.8 min, t (1S,2S-7) 9.0 min.
1
R
R
(S)-(1)-5-Amino-2-[(methoxycarbonyl)amino]-1-indane [(S)-8]
from 7
A 2-L Parr hydrogenation reactor was charged with alcohol 7 (25 g, 0.099 mol)
in acetic acid (300 mL) at 238C under nitrogen. Perchloric acid (70%, 25 g) was
added. To the mixture, 10% Pd/C (25 g, 50% water wet) was added, and the
mixture was hydrogenated at 50 psi of hydrogen for 1.5 h and 42 psi of
w
hydrogen overnight (14 h). The mixture was filtered through a Celite pad,
prewashed with acetic acid. The filtrate was evaporated under high vacuum
at 35–408C to an oil. The oily residue was triturated with tert-butyl methyl

Amino Acids as a Chiral Pool
1453
ether (2 ꢀ 400 mL), and tert-butyl methyl ether was decanted off. The gummy
residue was dissolved in water (deionized, 1 L) at 238C and dichloromethane (1
L). The pH of the mixture was adjusted to pH 8.0 by dropwise addition of
aqueous saturated NaHCO3 (300 mL). The dichloromethane layer was
separated, and the aqueous layer was extracted with dichloromethane
(
2 ꢀ 500 mL). The combined organic extracts were washed with cold water
(
500 mL), dried over MgSO , and filtered. The filtrate was concentrated
4
under vacuum at 258C to obtain [(S)-8] (14.7 g, 71.4%, .99% ee); mp 145–
þ
25
1
1
468C. MH 207. [a]D ¼ þ26.40 (c ¼ 1.0, DMSO). H NMR (300 MHz,
CDCl ) d 7.0 (d, J ¼ 9 Hz, 1H), 6.8 (s, 1H), 6.5 (d, J ¼ 9 Hz, 1H), 4.9 (bs,
3
1
3
C
1
NMR (125 MHz, DMSO-d ) d 156.3, 147.3, 141.6, 127.8, 124.4, 112.5,
H), 4.5 (bs, 1H), 3.7 (s, 3H), 3.5 (bs, 2H), 3.2 (m, 2H), 2.7 (m, 2H).
6
1
10.0, 52.0, 51.1, 38.1. Chiral HPLC (4.6 ꢀ 250 mm Chiralpak AD column,
R
hexanes/2-propanol (80:20) isocratic, 1 mL/min, at l ¼ 200–300 nm): t
(2R-8) 13.0 min, t (2S-8) 11.5 min.
R
(S)-(1)-5-Amino-2-[(methoxycarbonyl)amino]-1-indane [(S)-8]
from 6
A 2-L Parr hydrogenation flask was charged with 6 (60 g, 0.2 mol), acetic acid
800 mL), and perchloric acid (70%, 60 g) under nitrogen. A 10% Pd/C (40 g,
0% water wet) was added to the mixture at 258C. The mixture was hydrogenw-
(
5
ated at 50 psi at 258C over 6 h. The catalyst was filtered off using a Celite
pad, prewashed with acetic acid. The filter cake was washed with acetic
acid (200 mL), and the filtrate was concentrated under vacuum at 30–348C.
The residue was dissolved in water (1.5 L) and dichloromethane (1.5 L) and
cooled to 228C. The pH of the mixture was adjusted to pH 6.8–8 by
adding aqueous saturated NaHCO (1L). The dichloromethane layer was
separated, and the aqueous layer was extracted with dichloromethane
3
(
2 ꢀ 500 mL). The combined organic extracts were washed with ice
water (1 L), dried over MgSO4 (200 g), and filtered. The filtrate was
concentrated under vacuum at 208C to afford [(S)-8] (36.5 g, 88.5%) as an
off-white solid.
Purification
The crude product [(S)-8] (131 g) was dissolved in EtOAc (1.3 L) at 708C to
obtain an orange-colored solution. The solution was allowed to cool to 238C.
A thick suspension resulted. Heptane (1.3 L) was added to the slurry over
1
.5 h. The solid was filtered and washed with heptane (2 ꢀ 0.5 L). The
solid was dried under vacuum at 288C over 20 h to afford pure 8 (104 g,
7
[
3]
9% recovery, .99% chiral purity), mp 143–1468C.

1
454
L. M. Waykole et al.
(R)-(–)-5-Amino-2-[(methoxycarbonyl)amino]-1-indane [(R)-8]
(R)-(2)-5-Amino-2-[(methoxycarbonyl)amino]-1-indane [(R)-8] with more
than 99% ee was prepared from (R)-(þ)-phenylalanine following the same
procedures as described previously. All spectroscopy data were the same as
2
5
for the (S)-enatiomer except the optical rotation. [a]D –25.47 (c ¼ 1.04,
DMSO). Anal. calcd. for C H O N : C, 64.04; H 6.84; N, 13.58. Found:
1
1 14 2 2
C, 63.92; H, 6.71; N, 13.56.
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