(S)-1-aminoindane: Synthesis by chirality transfer using (R)-phenylglycine amide as chiral auxiliary

Article abstract of DOI:10.1016/j.tetasy.2003.08.040

A practical asymmetric synthesis of nearly enantiomerically pure (S)-1-aminoindane has been developed. The key step involves the diastereoselective heterogeneous metal-catalyzed reduction of the ketimine of 1-indanone with the chiral auxiliary (R)-phenylglycine amide. The selectivity of the asymmetric hydrogenation step was optimized with regard to metal catalyst, solvent and catalyst loading. The chiral auxiliary was removed by means of a novel non-reductive procedure. Thus, (S)-1-aminoindane with an ee of 96% was prepared in 58% overall yield from (R)-phenylglycine amide in an effective three-step procedure.

Full text of DOI:10.1016/j.tetasy.2003.08.040

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3479–3485
(S)-1-Aminoindane: synthesis by chirality transfer using
(R)-phenylglycine amide as chiral auxiliary
Patrick G. H. Uiterweerd,a Marcel van der Sluis,a Bernard Kaptein,b Ben de Lange,b
Richard M. Kellogga and Quirinus B. Broxtermanb,*
aSyncom B.V., Kadijk 3, 9747 AT Groningen, The Netherlands
bDSM Pharma Chemicals—Advanced Synthesis and Catalysis, PO Box 18, 6160 MD Geleen, The Netherlands
Received 21 July 2003; accepted 25 August 2003
Abstract—A practical asymmetric synthesis of nearly enantiomerically pure (S)-1-aminoindane has been developed. The key step
involves the diastereoselective heterogeneous metal-catalyzed reduction of the ketimine of 1-indanone with the chiral auxiliary
(R)-phenylglycine amide. The selectivity of the asymmetric hydrogenation step was optimized with regard to metal catalyst,
solvent and catalyst loading. The chiral auxiliary was removed by means of a novel non-reductive procedure. Thus, (S)-1-aminoin-
dane with an ee of 96% was prepared in 58% overall yield from (R)-phenylglycine amide in an effective three-step procedure.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
with the potential for treatment of Alzheimer’s disease,7
pyrazole urea-based p38 MAP kinase inhibitors as can-
didates for treatment of inflammatory diseases,8 orally
bioavailable aggrecanase inhibitors,9 or irindalone,
which displays potent antihypertensive activity.10
Enantiomerically pure (R)-phenylglycine amide [(R)-
PGA] is readily available at DSM as a result of its
application on an industrial scale as key intermediate in
the enzymatic synthesis of b-lactam antibiotics.1
Recently, the versatility of (R)-PGA as a chiral auxil-
iary has been demonstrated. High diastereoselectivities
were found in addition reactions to imines of (R)-PGA.
For example, addition of HCN via a diastereoselective
Strecker reaction in combination with a crystallization-
induced asymmetric transformation, gave nearly
diastereomerically pure aminonitriles.2 As an example,
the aminonitrile obtained from pivaldehyde was con-
verted into (S)-tert-leucine in 73% yield and with >98%
ee. In another application, homoallylamines with high
enantiomeric excesses were obtained from diastereose-
lective additions of allylzinc reagents to aldimines
derived from (R)-PGA. Diastereoselective ratio’s of
>99:1 were typically observed.3
Herein, we present the application of (R)-PGA as a
chiral auxiliary in the preparation of (S)-1-aminoin-
dane.4 This chiral amine is of pharmaceutical impor-
tance as a key structural element in therapeutic agents
under clinical investigations. Examples are Rasagiline
mesylate for the treatment of Parkinson’s disease,5 and
derivatives thereof either with antimalarial activity6 or
Methodologies employed for the synthesis of enan-
tiomerically pure (R)- or (S)-1-aminoindane include
classical or enzymatic resolutions. For example, resolu-
tions of racemic N-benzyl-1-aminoindane with (S)-
mandelic acid11 or (R,R)-tartaric acid12 furnished, after
hydrogenation, (R)-1-aminoindane with >99% ee (over-
all yields were 21–39 and 15–19%, respectively). Enzy-
matic resolution of racemic 1-aminoindane through
* Corresponding author. Tel.: +31 (0)464767596; fax: +31
(0)464767604; e-mail: rinus.broxterman@dsm.com
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.040

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P. G. H. Uiterweerd et al. / Tetrahedron: Asymmetry 14 (2003) 3479–3485
acylation with 2,2,2-trifluoroethyl butyrate using the
rather expensive enzyme subtilisin afforded (R)-1-
aminoindane in 40% yield with an ee of 98%.13 An
evident limitation of these resolution methods is that
the yield never exceeds 50%.14
metric transamination reaction for the synthesis of (S)-
1-aminoindane, which involves three steps: imine
formation, diastereoselective reduction and removal of
the chiral auxiliary.
Recently, much effort has been directed towards devel-
oping procedures for asymmetric synthesis of enantio-
pure 1-aminoindane. For example, routes using chiral
rhodium15 and ruthenium catalysts16 have been
described for the enantioselective hydrosilylation of
1-indanoxime with Ph2SiH2 to yield, after hydrolysis,
(R)-1-aminoindane. However, ee values and yields were
low, 8–35 and 10–41%, respectively. Using indene as
starting material, (S)-1-aminoindane was synthesized in
three steps in 61% isolated yield and 77% ee via
hydroboration involving a chiral rhodium catalyst.17
2. Results and discussion
2.1. Synthesis of the amine (R,S)-2
On treatment of (R)-PGA with 1-indanone in the pres-
ence of a catalytic amount of p-TsOH·H2O in boiling
i-PrOAc, (R)-1 was isolated in 90% yield and 99% ee
1
(Scheme 1, conversion >98%). H NMR spectroscopic
analysis of (R)-1 gave no evidence for the formation of
a cis/trans mixture. Therefore, on the basis of steric
hindrance, it is assumed that solely trans-(R)-1 was
formed. Removal of water during the reaction via a
Dean–Stark trap proved essential in order to obtain
high yields. As soon as the calculated amount of water
was collected, the reaction was terminated, usually after
ca. 6 h. Prolonged reflux of the mixture resulted in
slight racemization of the product.
For the preparation of enantiopure amines, diastereose-
lective synthesis using a chiral auxiliary can be a viable
alternative. In this concept, an imine is formed in the
first step by reaction of a prochiral ketone with a chiral
auxiliary. The second step consists of a diastereoselec-
tive reaction (chirality transfer) followed by cleavage of
the chiral auxiliary. Previously, this approach has been
employed in the synthesis of enantiomerically pure
1-aminoindane. For example, (R)-phenylethylamine has
been used for the synthesis of (R)-1-aminoindane from
1-indanone in three steps, with an overall yield of 5%
and >99% ee.18 This route was hampered by the non-
selective removal of the chiral auxiliary after its use. In
The second and key step in the preparation of (R,S)-2,
and eventually (S)-5, is the diastereoselective metal-cat-
alyzed hydrogenation20 of (R)-1 to afford the desired
amine (Scheme 1). Hydrogenation of (R)-1 at 3.5 bar
H2 and 40°C in i-PrOAc using Raney-nickel as catalyst
afforded the diastereomers (R,S)-2 and (R,R)-2 in a
94:6 ratio. The diastereomeric ratio of (R,S)-2 and
a
similar approach, (R)-phenylglycinol has been
employed as a chiral auxiliary in the synthesis of (S)-1-
aminoindane from 1-indanone. The three-step proce-
dure afforded the product in 39% overall yield; the
specific rotation of the (S)-1-aminoindane indicated
that nearly enantiomerically pure material was
obtained.19 The limited availability and cost of this
chiral auxiliary are the main drawbacks of this com-
pound, especially when use on industrial scale is envis-
aged. Furthermore, chromatography is used to obtain
diastereomerically pure intermediates, followed by
removal of the chiral auxiliary by procedures unsuitable
for large-scale preparations, e.g. oxidation with
Pb(OAc)4.
1
(R,R)-2 was determined by H NMR analysis on the
basis of the relative integration of the aminoindanyl-
CH triplets of (R,S)-2 at 4.39 ppm and (R,R)-2 at 4.19
ppm. The diastereomeric ratio was confirmed by HPLC
analysis. Purification via one efficient crystallization of
the HCl-salt provided a single diastereomer identified as
(R,S)-2 in 84% overall yield, based on the imine (R)-1,
and 98% ee. The assignment of the absolute configura-
tion was made by conversion of (R,S)-2 to (S)-1-
aminoindane (vide infra).
Disadvantages of this approach were the necessity to
use large amounts of Raney-nickel (>100 w/w%) to
ensure complete conversion of (R)-1 into (R,S)-2 and
the low solubility of (R)-1 in i-PrOAc. Therefore, we
We now report the application of (R)-phenylglycine
amide as a highly efficient chiral auxiliary in an asym-
Scheme 1. Synthesis of amine (R,S)-2. Reagents and conditions: (i) p-TsOH·H2O, i-PrOAc, reflux, ca. 6 h; (ii) Ra-Ni, 3.5 bar H2,
40°C, 45 h.

P. G. H. Uiterweerd et al. / Tetrahedron: Asymmetry 14 (2003) 3479–3485
3481
sought to optimize this reduction step in terms of
catalyst loading, solvent and type of catalyst by using
Argonaut’s parallel pressure reactor, the Endeavor.21
The effect of solvent and catalyst loading22 on the
hydrogenation of (R)-1 with Raney-nickel was exam-
ined (Table 1).
The best result was found by using the 5% Pd/C
catalyst in i-PrOAc; (R,S)-2 was formed with a de of
82% at complete conversion after 5 h (entry 2). Most
importantly, hydrogenations with the Pd- or Pt-cata-
lysts required a significantly lower amount of catalyst
than reactions with Raney-nickel (10 versus 100 w/w%,
respectively). Additionally, the Pd- and Pt-catalyzed
reductions can be performed at room temperature,
whereas hydrogenations with Raney-nickel required ele-
vated temperatures.
The influence of the catalyst loading on the reaction
time is significant: decrease of the amount of catalyst
results in an increase in reaction time, entries 1–3. The
conversion using 25 w/w% Raney-nickel was still not
complete after 20 h (entry 1). However, the influence on
the de is only marginal.23
This promising result prompted us to investigate fur-
ther the possibilities and a series of experiments with
the 5% Pd/C catalyst was conducted with variation of
the solvent. The results are summarised in Table 3.
In a protic solvent (entry 4), the reaction time
decreased, but unfortunately the de decreased as well.
The rather low solubility of (R)-1 in i-PrOAc and
i-PrOH could possibly have an effect on the speed of
reaction. For this reason, alternative solvents were
sought. It was found that (R)-1 was readily soluble in
THF and NMP. Hydrogenation in the former is fast
(entry 5), with a de of the product that is comparable to
that obtained from reactions in i-PrOAc. However, in
NMP, the reaction is slow and the diastereoselectivity is
low, entry 6.
Toluene is the most suitable solvent (entry 2): (R,S)-2
was obtained with a de of 89% at complete conversion
in 3 h. The de is comparable to the result with Raney-
nickel in i-PrOAc (Table 1). A high yield crystallization
procedure to obtain diastereomerically pure (R,S)-2 via
the HCl salt had already been developed for the Raney-
nickel hydrogenations (vide supra).
Interestingly, a clear correlation between solvent polar-
ity (as measured by the dielectric constant m) and the de
is found (Fig. 1).
As the amount of Raney-nickel that is needed to hydro-
genate (R)-1 effectively is high and handling of this
large amount on production scale would be difficult, we
focused our attention on palladium and platinum cata-
lysts for the formation of (R,S)-2.
Entries 7–11 clearly show that an increase in polarity of
the alcohol decreases the de, from 63% for n-octanol to
42% for ethanol. Generally, the de in polar solvents is
low. Also, the diastereoselectivity in MTBE is high
(entry 3), but the conversion is not complete. In 2-
methyltetrahydrofuran (CH3-THF; entry 5), the reduc-
tion is fast with complete conversion, and the de is
comparable to the reduction in i-PrOAc, entry 4. Hep-
The results of the first screening are shown in Table 2.
In general, nearly complete conversions with the Pd, Pt
and Pd/Pt mixed catalysts (10 w/w%) in i-PrOAc were
reached in 2–10 h, but the de values of the product were
lower than those with Raney-nickel.
Table 1. The effect of solvent and catalyst loading on the hydrogenation of (R)-1 with Raney-nickela at 50°C, 3.5 bar H2
Entry
Loading (w/w%)
Solvent
Time (h)
Conversion (%)
De (%)
1
2
3
4
5
6
25
50
100
100
100
100
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOH
THF
>20
10
98
>99
>99
>99
>99
86
93
92
89
82
88
38
8
4.5
3.5
>20
NMP
a Doduco ACTIMET ‘S’, charge 768-18071.
Table 2. The effect of type of catalyst on the hydrogenation of (R)-1 in i-PrOAc
Entry
Catalyst
Loading (w/w%)
Conditions
Time (h)
Conversion (%)
De (%)
1
2
3
4
5
Ra-Nia
100
10
10
10
50°C, 3.5 bar H2
25°C, 3.5 bar H2
25°C, 3.5 bar H2
25°C, 3.5 bar H2
25°C, 3.5 bar H2
8
5
2
>99
>99
98
98
>99
89
82
64
68
76
5% Pd/Cb
5% Pt/Cc
1% Pt/Cd
>10
5
8% Pd/2% Pt/Ce
10
a Doduco ACTIMET ‘S’, charge 768-18071.
b Engelhard ESCAT 142, moist-reduced, 52% moisture.
c Aldrich, dry.
d Engelhard ESCAT 261, moist-reduced, 51% moisture.
e Johnson-Matthey, 1130/8, batch 10, type 464, 51% moisture.

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P. G. H. Uiterweerd et al. / Tetrahedron: Asymmetry 14 (2003) 3479–3485
Table 3. The effect of the solvent on the hydrogenation of (R)-1 with 5% Pd/Ca (8 w/w%) at 25°C, 3.5 bar H2
Entry
Solvent
m
Time (h)
Conversion (%)
De (%)
1
2
3
4
5
6
7
8
Heptane
Toluene
MTBE
i-PrOAc
CH3-THFc
THF
n-Octanol
n-Pentanol
s-BuOH
i-PrOH
EtOH
1.92
2.38
4.5
>10
3
>10
6
37
>99
74
98
>99
97
99
98
>99
>99
97
50
89
85
80
79
68
63
57
53
47
42
5b
5.26
7.58
10.34
13.9
16.56
19.92
24.55
2
2
8
6
6
7
2
9
10
11
a Engelhard ESCAT 142, moist-reduced, 52% moisture.
b Not found in the literature. The value given here is estimated from the values of 4.63 for i-pentyl acetate and 6.68 for MeOAc.
c 2-Methyltetrahydrofuran.
Table 4. The effect of catalyst loading on the hydrogena-
tion of (R)-1 with 5% Pd/Ca in toluene at 25°C, 3.5 bar
H2
Entry
Loading
(w/w%)
Time (h)
Conversion
(%)
De (%)
1
2
3
4
5
6
7
2
4
6
15
7
4
>99
>99
>99
>99
>99
>99
>99
91
91
89
89
88
88
88
8
3
10
12
14
2.7
2.4
2.3
Figure 1. Correlation of the solvent polarity (m) with the de of
the hydrogenation of (R)-1 with 5% Pd/Ca (8 w/w%) at 25°C,
3.5 bar H2. From left to right: toluene (m=2.38), MTBE
(m=4.5), CH3-THF (m=5.26), THF (m=7.58), n-octanol (m=
10.34), n-pentanol (m=13.9), s-BuOH (m=16.56), i-PrOH (m=
19.92) and EtOH (m=24.55). aEngelhard ESCAT 142,
moist-reduced, 52% moisture.
a Engelhard ESCAT 142, moist-reduced; 52% moisture.
In order to prove the reaction conditions on larger scale
[Endeavor runs were carried out using 2 mmol of
(R)-1], the reduction of (R)-1 was performed on a 100
mmol scale, employing the conditions represented by
entry 3 in Table 4. Thus, 26.4 g of the imine was
suspended in 250 mL of toluene and 1.7 g of 5% Pd/C
was added. The mixture was hydrogenated for 3 h at 3
bar H2 and 25°C. Filtration and evaporation of the
solvent, afforded (R,S)-2 as a yellow oil in quantitative
yield with a de of 90%. Purification to diastereomeri-
cally pure (R,S)-2 in 85% overall yield has been done
via the HCl-salt as described in the experimental section
for a Raney-nickel reduction.
tane is a clear exception, which is probably due to the
fact that (R)-1 is completely insoluble in this solvent
(hence, the low conversion).
Next, we decided to study improvement of the reduc-
tion of (R,S)-2 in toluene by variation of the amount of
catalyst (Table 4).
Upon increase of the amount of catalyst, the reaction
time to obtain >99% conversion decreases, but the de
value is not significantly affected. The best conditions
were found at 4–6 w/w% of 5% Pd/C, which ensured
short reaction times, complete conversion and high de
values. Furthermore, in preliminary experiments, it was
demonstrated that concentrations of the imine (R)-1 in
toluene could be increased to 0.25 g mL−1 without any
effect on hydrogenation rate and diastereoselectivity.24
These high substrate concentrations, low catalyst load-
ings (Pd/C might be recycled, a point that has not yet
been tested) in combination with high diastereoselectiv-
ity and easy enrichment via crystallization leads to an
industrially viable procedure for this step.
2.2. Non-reductive chiral auxiliary removal
Catalytic hydrogenolysis of (R,S)-2 to remove the chi-
ral auxiliary afforded (S)-1-aminoindane (S)-5 in 40%
yield (5% Pd/C, 5 bar H2, 40°C, EtOH, AcOH). In this
specific case, the regioselectivity of the N-debenzylation
step was in favor of cleavage of the other N–C bond,
thus affording (R)-PGA and indane. Therefore, we
sought for alternative routes for the conversion of
(R,S)-2 to (S)-5. For this purpose, we developed the
retro-Strecker method. Initially, the (R)-PGA chiral
auxiliary was removed in three separate steps from
(R,S)-2, affording (S)-5 (Scheme 2).

P. G. H. Uiterweerd et al. / Tetrahedron: Asymmetry 14 (2003) 3479–3485
3483
Scheme 2. Non-reductive chiral auxiliary removal furnishing (S)-5. Reagents and conditions: (i) POCl3, Et3N, CH2Cl2, 0°C“rt, 1
h; (ii) K2CO3, EtOH, reflux, 1 h; (iii) NH2OH·HCl, THF/H2O 1:1, 20 h; (iv) POCl3, Et3N, THF, 0°C“reflux, 5 h; NH2OH·HCl,
H2O, 16 h.
Dehydration of (R,S)-2 with POCl3 in CH2Cl2 in the
presence of Et3N afforded the nitrile (R,S)-3. Crude
(R,S)-3 generally contained residual Et3N and invari-
ably, minor quantities of (S)-4 were detected, probably
since excess base is used in the procedure, thus effecting
the subsequent retro-Strecker reaction. Previously, in
the syntheses of chiral homoallylamines, we performed
the dehydration step according to the Vilsmeier proce-
dure (oxalyl chloride and DMF in CH2Cl2).3 In the case
of (R,S)-2, dehydration with POCl3 is less time-con-
suming, cleaner, and the yield is improved.
More examples of this chirality transfer approach to
enantiomerically pure amines using (R)- or (S)-phenyl-
glycine amide are currently under investigation.
4. Experimental
4.1. Materials and methods
All reactions were performed using commercially avail-
able solvents and reagents, purchased from Acros
Organics, which were used without further purification.
(R)-Phenylglycine amide is provided by DSM Geleen,
the Netherlands. 1H and 13C NMR spectra were
recorded on a Varian Gemini spectrometer at 200
MHz. Chemical shifts are denoted in ppm and were
referenced to residual solvent resonances. HPLC analy-
ses were performed on a HP1100 apparatus.
Treatment of crude (R,S)-3 with K2CO3 in boiling
ethanol, the retro-Strecker procedure, furnished the
imine (S)-4 in 94% yield from (R,S)-2, which was
subjected to NH2OH·HCl to afford (S)-5 in 82% yield,
96% ee. The configuration of (S)-5 was established by
comparison of the HPLC analysis with that of an
authentic sample.
4.2. Synthetic procedures
This three-step sequence was greatly improved by per-
forming the procedure in one pot without isolation of
the intermediates (R,S)-3 and (S)-4. Thus, treatment of
(R,S)-2 with POCl3 in THF at 0°C in the presence of a
large excess of Et3N resulted in dehydration. Subse-
quently, the mixture was heated at reflux to effect the
retro-Strecker reaction. Finally, addition of an aqueous
solution of NH2OH·HCl afforded (S)-5 as a partly
crystalline, brown oil in 70% isolated yield from (R,S)-2
and 96% ee. The deprotection of (S)-4 can also be
accomplished by acidic hydrolysis using an excess of
30% HCl at reflux temperature for 24 h, furnishing
(S)-5 in 73% isolated yield from (R,S)-2, 96% ee.
4.2.1. Synthesis of the Schiff base (R)-1. A one-neck
flask of 2 L, fitted with a Dean–Stark trap, was charged
with (R)-PGA (101.9 g, 0.68 mol), 1-indanone (97.9 g,
1.1 equiv.) and p-TsOH·H2O (6.50 g, 5 mol%). The
mixture was suspended in i-PrOAc (500 mL) and boiled
under reflux until the expected amount of water had
collected in the Dean–Stark trap (ca. 6 h; 50 mL of
solvent and water was removed via the trap in total).
The mixture was allowed to cool to room temperature
and stirred for 3 h, then the residue was filtered off. The
cream-colored solid was stirred in H2O (500 mL) for 5
min to remove unreacted (R)-PGA. The product was
filtered off, washed with i-PrOAc (2×150 mL) and dried
under reduced pressure, affording (R)-1 as a white solid
1
3. Conclusions
(160.7 g, 90%); H NMR (CDCl3, 200 MHz): l 2.42–
2.59 (m, 1H, indane-CH2), 2.82–3.00 (m, 1H, indane-
CH2), 3.08–3.21 (m, 2H, indane-CH2), 5.11 (s, 1H,
PGA-CH), 5.96 (br s, 1H, CONH2), 7.35–7.60 (m, 8H,
aryl-CH), 7.67 (br s, 1H, CONH2), 7.99 (d, 1H, aryl-
CH); 13C NMR (CDCl3, 75 MHz): l 28.6, 29.2, 70.3,
122.9, 125.7, 126.1, 127.4, 127.9, 128.1, 128.3, 129.0,
129.3, 132.3, 139.7, 150.7, 175.7, 176.6; HPLC (Crown-
pak) 99% ee; [h]2D3=−45.0 (c 1.0, CHCl3).
The method presented here allows the asymmetric syn-
thesis of (S)-1-aminoindane (S)-5 from 1-indanone,
employing (R)-phenylglycine amide as the chiral auxil-
iary. Thus, (S)-5 was prepared in 58% overall yield
from (R)-PGA and 1-indanone in an effective three-
step procedure. As (R)-phenylglycine amide is readily
available within DSM, scale-up of this procedure is
envisaged. Obviously, (S)-phenylglycine amide is also
accessible and can be used for the preparation of
(R)-1-aminoindane.
4.2.2. Synthesis of the amine (R,S)-2. In a 500 mL
high-pressure hydrogenation flask, (R)-1 (11.97 g, 45.3

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P. G. H. Uiterweerd et al. / Tetrahedron: Asymmetry 14 (2003) 3479–3485
mmol) was suspended in i-PrOAc (200 mL). Raney-
nickel (ca. 15 g, 125 w/w%) was washed with MeOH
(2×50 mL) and i-PrOAc (2×50 mL) and added to the
reaction mixture. The flask was charged with 3.5 bar
H2, heated to 40°C and shaken for 45 h. At room
temperature, the mixture was filtered over a P3 glass
frit covered with Celite® and the residue was extracted
with i-PrOAc (300 mL). The volatiles were removed
under reduced pressure and the residual yellow oil was
dissolved in acetone (500 mL). Under vigorous mechan-
ical stirring, 15 mL of 6N HCl was added dropwise,
during which a white precipitate formed. The thick
slurry was stirred for 15 min, then filtered over a P3
glass frit and washed with acetone (50 mL). The result-
ing white solid was dissolved in demineralised water
(500 mL) and EtOAc (300 mL). To this, anhydrous
Na2CO3 was added in portions to pH 10, after which
the layers were separated. The aqueous layer was
extracted with EtOAc (300 mL); the combined organic
fractions were dried on Na2SO4, filtered, and the
volatiles were removed under reduced pressure, furnish-
1H, indane-CH2), 3.16–3.32 (m, 1H, indane-CH2), 5.02
(t, 1H, indane-CH), 7.19–7.40 (m, 4H, aryl-CH), 7.45–
7.58 (m, 3H, aryl-CH), 7.84–7.95 (m, 2H, aryl-CH),
8.57 (s, 1H, N=CH).
4.2.4. Synthesis of (S)-1-aminoindane (S)-5. Imine (S)-4
(10.00 g, 45.2 mmol) was dissolved in THF/H2O 1:1
(250 mL) and NH2OH·HCl (9.42 g, 3 equiv.) was
added. The mixture was stirred for 20 h and subse-
quently, THF was removed in vacuo. The residual
emulsion was acidified with 1N HCl to pH 1 and
washed with EtOAc (200 mL). 10% NaOH was added
to pH 8 and the aqueous layer was extracted with
CH2Cl2 (250 mL). The organic layer was dried on
Na2SO4 and the volatiles were removed in vacuo, yield-
ing (S)-5 as a brown oil (4.96 g, 82%); 1H NMR
(CDCl3) l 1.73 (br s, 2H, NH2), 1.74–1.84 (m, 1H,
indane-CH2), 2.51–2.66 (m, 1H, indane-CH2), 2.80–2.95
(m, 1H, indane-CH2), 2.97–3.15 (m, 1H, indane-CH2),
4.43 (t, 1H, indane-CH), 7.27–7.35 (m, 3H, aryl-CH),
7.38–7.45 (m, 1H, aryl-CH); 13C NMR (CDCl3, 75
MHz): l. 30.1, 37.0, 57.0, 123.5, 124.4, 126.5, 127.2,
142.9, 147.3; HPLC (Crownpak) 96% ee; [h]2D3=+20.0
(c 1.0, CHCl3).
1
ing (R,S)-2 as a slightly yellow oil (10.13 g, 84%); H
NMR (CDCl3) l 1.78–1.88 (m, 1H, indane-CH2), 1.97
(br s, 1H, NH), 2.56–2.71 (m, 1H, indane-CH2), 2.80–
3.14 (m, 2H, indane-CH2), 4.39 (t, 1H, indane-CH),
4.52 (s, 1H, PGA-CH), 6.43 (br s, 1H, CONH2), 7.28–
7.57 (m, 10H, aryl-CH/CONH2); (R,R)-2 l 4.19 (t,
indane-CH); 13C NMR (CDCl3, 75 MHz): l 30.5, 34.5,
62.8, 65.9, 124.5, 125.3, 126.8, 127.6, 127.9, 128.1,
128.2, 128.6, 129.3, 139.9, 143.8, 144.7, 175.8; HPLC-
MS (Discovery C18) 99% pure, 99% de. HPLC (Chiral-
cel OD) 98% ee; [h]2D3=−6.00 (c 1.0, CHCl3).
4.2.5. One-pot chiral auxiliary removal to afford (S)-5.
In a 250 mL one-neck flask, (R,S)-2 (5.54 g, 20.8 mmol)
was dissolved in THF (75 mL) and Et3N (35 mL, 12
equiv.). The mixture was cooled to 0°C and POCl3 (4.3
mL, 2.2 equiv.) was added dropwise, during which the
solution slowly adopted an orange-brown color. After
the addition was completed, the mixture was stirred at
0°C for 15 min, then allowed to warm to room temper-
ature at which it was stirred for 1 h. Subsequently, the
reaction mixture was boiled under reflux for 5 h, then
allowed to cool to room temperature. A solution of
NH2OH·HCl (4.34 g, 3 equiv.) in H2O (75 mL) was
added and the mixture was stirred at room temperature
for 16 h. Subsequently, THF was removed in vacuo and
a 30% HCl solution was added dropwise to pH 1. The
aqueous layer was washed with MTBE (2×75 mL) and
subsequently, CH2Cl2 (100 mL) and a 33% NaOH
solution were added successively (the latter dropwise) to
pH 9. The layers were separated and the organic layer
was dried on Na2SO4. Removal of the volatiles in
vacuo afforded (S)-5 as a brown oil (1.93 g, 70%),
which partly crystallized on standing; analytical data as
above (Section 4.2.4).
4.2.3. Synthesis of the nitrile (R,S)-3 and the imine (S)-4.
A 250 mL one-neck flask was charged with (R,S)-2
(6.16 g, 23.1 mmol), CH2Cl2 (100 mL) and Et3N (16
mL, 5 equiv.). The mixture was cooled to 0°C and
POCl3 (4.8 mL, 2.2 equiv.) was added dropwise. The
solution adopted an orange-brown color and was
stirred at 0°C for 10 min. Subsequently, the mixture
was allowed to warm to room temperature and stirred
for 1 h. Water (100 mL) was added carefully, followed
by Na2CO3 to pH 8. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (50 mL). The
combined organic layers were dried on Na2SO4 and the
volatiles were removed in vacuo, affording (R,S)-3 as a
brown oil; 1H NMR (CDCl3) l 1.98–2.17 (m, 1H,
indane-CH2), 2.12 (br s, 1H, NH), 2.52–2.67 (m, 1H,
indane-CH2), 2.89–3.03 (m, 1H, indane-CH2), 3.09–3.23
(m, 1H, indane-CH2), 4.64 (t, 1H, indane-CH), 4.99 (s,
1H, PGA-CH), 7.22–7.57 (m, 7H, aryl-CH), 7.61–7.69
(m, 2H, aryl-CH). Crude (R,S)-3 was dissolved in
EtOH (250 mL) and K2CO3 (6.81 g, 2 equiv.) was
added. The mixture was boiled under reflux for 1 h and
subsequently, EtOH was removed in vacuo. The residue
was partitioned between CH2Cl2 and H2O (2×200 mL),
the layers were separated and the aqueous layer was
extracted with CH2Cl2 (200 mL). The combined organic
layers were washed with brine (200 mL), dried on
Na2SO4 and the volatiles were removed in vacuo, fur-
nishing (S)-4 as a brown, partly crystalline solid (4.79
g, 94%); 1H NMR (CDCl3) l 2.33–2.45 (m, 1H, indane-
CH2), 2.51–2.65 (m, 1H, indane-CH2), 2.97–3.15 (m,
Acknowledgements
We sincerely thank Erik van Echten, Josien Lamain,
Hanneke van der Deen and Henk Elsenberg for the
HPLC analyses. Fre`de`ric Friscourt is acknowledged for
performing part of the Endeavor runs.
References
1. Bruggink, A.; Roos, E.; de Vroom, E. Org. Process Res.
Dev. 1998, 2, 128–133.
2. (a) Boesten, W. H. J.; Seerden, J.-P. G.; de Lange, B.;
Dielemans, H. J. A.; Elsenberg, H. L. M.; Kaptein, B.;

P. G. H. Uiterweerd et al. / Tetrahedron: Asymmetry 14 (2003) 3479–3485
3485
Moody, H. M.; Kellogg, R. M.; Broxterman, Q. B. Org.
Lett. 2001, 3, 1121–1124; (b) Boesten, W. H. J.; Seerden,
J.-P. G.; de Lange, B.; van der Sluis, M.; Kaptein, B.;
Moody, H. M.; Kellogg, R. M.; Broxterman, Q. B. PCT
Int. Appl, WO 01 42,173, 2001.
Brenner, D.; Boltanski, A. Annals New York Acad. Sci.
1996, 799, 620–632.
14. For other enzymatic approaches, see: (a) Stirling, D. I.;
Matcham, G. W.; Zeitlin, A. L. US Patent 5,300,437,
1994; (b) Shin, J.-S.; Kim, B.-G.; Shin, D.-H. Enzyme
Microbial Technol. 2001, 29, 232–239; (c) Laumen, K.;
Brunella, A.; Graf, M.; Kittelmann, M.; Walser, P.;
Ghisalba, O. Pharmacochem. Lib. 1998, 29, 17–28.
15. Brunner, H.; Becker, R.; Gauder, S. Organometallics
1986, 5, 739–746.
16. Takei, I.; Nishibayashi, Y.; Ishii, Y.; Mizobe, Y.;
Uemura, S.; Hidai, M. Chem. Commun. 2001, 2360–2361.
17. (a) Fernandez, E.; Hooper, M. W.; Knight, F. I.; Brown,
J. M. Chem. Commun. 1997, 173–174; (b) Fernandez, E.;
Maeda, K.; Hooper, M. W.; Brown, J. M. Chem. Eur. J.
2000, 6, 1840–1846.
18. (a) Gutman, A. L.; Etinger, M.; Nisnevich, G.; Polyak, F.
Tetrahedron: Asymmetry 1998, 9, 4369–4379; (b) For a
review on the application of (R)- and (S)-phenylethyl-
amine as chiral auxiliary, see: Juaristi, E.; Le´on-Romo, J.
L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry
1999, 24, 2441–2495.
19. Stalker, R. A.; Munsch, T. E.; Tran, J. D.; Nie, X.;
Warmuth, R.; Beatty, A.; Aakero¨y, C. B. Tetrahedron
2002, 58, 4837–4849.
3. Van der Sluis, M.; Dalmolen, J.; de Lange, B.; Kaptein,
B.; Kellogg, R. M.; Broxterman, Q. B. Org. Lett. 2001, 3,
3943–3946.
4. Using (S)-PGA as the chiral auxiliary would yield (R)-1-
aminoindane.
5. Graul, A.; Castaner, J. Drugs of the Future 1998, 23,
903–905.
6. Singh, T.; Stein, R. G.; Hoops, J. F.; Biel, J. H.; Hoya,
W. K.; Cruz, D. R. J. Med. Chem. 1971, 14, 283–286.
7. Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.;
Lerner, D.; Goldenberg, W.; Miskolczi, I.; Molnar, S.;
Rantal, F.; Tamas, T.; Toth, G.; Zagyva, A.; Zekany, A.;
Lavian, G.; Gross, A.; Friedman, R.; Razin, M.; Huang,
W.; Krais, B.; Chorev, M.; Youdim, M. B.; Weinstock,
M. J. Med. Chem. 2002, 45, 5260–5279.
8. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Gra-
ham, A. G.; Hickey, E.; Klaus, B.; Madwed, J.; Moriak,
M.; Moss, N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer,
A.; Tong, L.; Torcellini, C. J. Med. Chem. 2002, 45,
2994–3008.
9. Yao, W.; Wasserman, Z. R.; Chao, M.; Reddy, G.; Shi,
E.; Liu, R.-Q.; Covington, M. B.; Arner, E. C.; Pratta,
M. A.; Tortorella, M.; Magolda, R. L.; Newton, R.;
Qian, M.; Ribadeneira, M. D.; Christ, D.; Wexler, R. R.;
Decicco, C. P. J. Med. Chem. 2001, 44, 3347–3350.
10. Bøgesø, K. P.; Arnt, J.; Boeck, V.; Christensen, A. V.;
Hyttel, J.; Gundertofte Jensen, K. J. Med. Chem. 1988,
31, 2247–2256.
20. Reduction of (R)-1 with an excess of NaBH4 in EtOH
afforded (R,S)-2 in 79% isolated yield but in only 16%
de.
21. For a review on the power of High Throughput Experi-
mentation (HTE) in Homogeneous Catalysis Research
for Fine Chemicals, see: de Vries, J. G.; de Vries, A. H.
M. Eur. J. Org. Chem. 2003, 799–811.
22. The catalyst loading is defined as the weight percentage
of catalyst in relation to the amount of substrate.
23. The de values of several samples presented in this paper
have been determined by 1H NMR spectral analysis in
addition to their HPLC analyses. A good correlation was
observed.
11. (a) Lidor, R.; Bahar, E. W. O. Patent 96/21640, 1996; (b)
Lidor, R.; Bahar, E.; Zairi, O.; Atili, G.; Amster, D. Org.
Prep. Proced. Int. 1997, 29, 701–706.
12. Gutman, A. L.; Zaltzman, I.; Ponomarev, V.; Sotrihin,
M.; Nisnevich, G. W. O. Patent 02/068376 A1, 2002.
13. (a) Gutman, A. L.; Meyer, E.; Kalerin, E.; Polyak, F.;
Sterling, J. Biotechnol. Bioeng. 1992, 40, 760–767; (b)
Gutman, A. L.; Shkolnik, E.; Meyer, E.; Polyak, F.;
24. All Endeavor experiments were conducted with a concen-
tration of (R)-1 of 0.1 g mL−1
.