Enzymatic resolution of (±)-cis- and (±)-trans-1-aminoindan-2-ol and (±)-cis- and (±)-trans-2-aminoindan-1-ol

Article abstract of DOI:10.1016/S0957-4166(99)00200-1

Pseudomonas cepacia lipase (PSL) efficiently catalyses the kinetic resolution of (±)-cis- and (±)-trans-1-aminoindan-2-ol through the O- acylation reaction of the corresponding N-benzyloxycarbonyl derivative using vinyl acetate as the acyl donor. In a similar way, cis-N-Cbz-2-aminoindan-1- ol is resolved when isopropenyl acetate is used as the acylating agent. The enantioselectivity of the reaction was lower for (±)-trans-N-Cbz-2- aminoindan-1-ol due to the different steric requirements for the two conformers of this substrate.

Full text of DOI:10.1016/S0957-4166(99)00200-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1969–1977
Enzymatic resolution of (ꢀ)-cis- and (ꢀ)-trans-1-aminoindan-
2-ol and (ꢀ)-cis- and (ꢀ)-trans-2-aminoindan-1-ol
Amparo Luna,a Alicia Maestro,b Covadonga Astorga a and Vicente Gotor a,∗
aDepartamento de Química Orgánica e Inorgánica, Facultad de Química, Universidad de Oviedo, 33071 Oviedo, Spain
bDepartamento de Química Orgánica, E.T.S. Ingenieros Industriales, Universidad de Valladolid, 47011 Valladolid, Spain
Received 21 April 1999; accepted 17 May 1999
Abstract
Pseudomonas cepacia lipase (PSL) efficiently catalyses the kinetic resolution of (ꢀ)-cis- and (ꢀ)-trans-1-
aminoindan-2-ol through the O-acylation reaction of the corresponding N-benzyloxycarbonyl derivative using
vinyl acetate as the acyl donor. In a similar way, cis-N-Cbz-2-aminoindan-1-olis resolved when isopropenyl acetate
is used as the acylating agent. The enantioselectivity of the reaction was lower for (ꢀ)-trans-N-Cbz-2-aminoindan-
1-ol due to the different steric requirements for the two conformers of this substrate. © 1999 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Chiral 1,2-aminoalcohols have proved to be a functionally diverse class of compounds with a wide
range of applicability in coordination chemistry, organic synthesis and medicinal chemistry.1 In particu-
lar, enantiomerically pure cis- and trans-1,2-cycloaminoalcohols are compounds of great interest due to
its presence in many products with physiological activity.2 Moreover, the cyclic cis isomers have special
relevance as chiral auxiliaries in asymmetric synthesis.3
Recently, we have developed a simple strategy for the resolution of (ꢀ)-cis- and (ꢀ)-trans-1,2-
aminocyclopentanol and 1,2-aminocyclohexanol.4,5 In these studies, the best results were achieved
through a lipase-catalysed O-acylation of the N-Cbz protected aminoalcohols.
Taking these results into account, it seemed very interesting to apply this methodology to the
resolution of (ꢀ)-cis- and (ꢀ)-trans-1-aminoindan-2-ol and 2-aminoindan-1-ol. It is of note that the
∗
Corresponding author. E-mail: vgs@sauron.quimica.uniovi.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00200-1

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A. Luna et al. / Tetrahedron: Asymmetry 10 (1999) 1969–1977
preparation of enantiomerically pure cis-1-aminoindan-2-ol has become a subject of special relevance
in the last few years due to its importance in asymmetric synthesis.6 Moreover, this compound is a key
component of indinavir, which is a potent inhibitor of the protease of human inmunodeficiency virus7
(HIV). Several enzymatic and non-enzymatic procedures have been described for the preparation of
racemic8 and optically active9 cis-1-aminoindan-2-ol. The esterification reaction of the corresponding
azidoindanols10 and bromoindanols11 has been the most common strategy when enzymes are used. Less
attention has been paid to the trans isomers. However, enzymatic transesterification has been used to
obtain enantiomerically pure trans-2-aminoindan-1-ol.12 Finally, the synthesis of the four isomers of 1,2-
diaminoindane with high enantiomeric excesses has been performed with the lipase-catalysed selective
transesterification of (ꢀ)-cis-2-azidoindan-1-ol and (ꢀ)-trans-1-azidoindan-2-ol as the key step.13
2. Results and discussion
We have prepared the corresponding N-benzyloxycarbonyl derivatives of the cis and trans isomers of
1-aminoindan-2-ol, and 2-aminoindan-1-ol following the procedure described in earlier papers.4,5 The
protecting group (benzyloxycarbonyl) was chosen because it can be selectively introduced in good yield
to give a substrate that is stable under the projected reaction conditions and which can be removed
easily.14 Initially, we tried the kinetic resolution of these N-protected aminoindanols by means of an
enzymatic transesterification reaction.
2.1. Resolution of cis-1-aminoindan-2-ol
Racemic cis-1-aminoindan-2-ol was prepared following the procedure described by Igarashi et al.11
The aminoalcohol was conveniently protected and its Cbz derivative 1 was used as starting material. The
resolution of 1 was carried out in 1,4-dioxane at 30°C using Pseudomonas cepacia lipase (PSL) as the
biocatalyst and vinyl acetate as the acyl donor (Scheme 1 and Table 1).
Scheme 1.
Under these reaction conditions, PSL exhibited high enantioselectivity towards the substrate. The
enzyme preferred the R isomer of the carbamate, yielding the O-acetylderivative (1S,2R)-2 with an
enantiomeric excess of >99% ([α]D23=−69.6 (c 0.775, EtOH)) and 2-hydroxycarbamate (1R,2S)-1 was
recovered in 78% ee ([α]D23=−4.8 (c 0.25, CHCl3)). These data correspond to a conversion value (c)
of 44% and an enantiomeric ratio higher than 200 (Table 1, entry 2). The absolute configuration of the
Table 1

A. Luna et al. / Tetrahedron: Asymmetry 10 (1999) 1969–1977
1971
remaining substrate (1R,2S) was assigned by comparison between the sign of the specific rotation for the
corresponding unprotected cis-aminoalcohol with the value found in the literature.10b
2.2. Resolution of trans-1-aminoindan-2-ol
Racemic trans-1-aminoindan-2-ol was prepared by ammonolysis of racemic epoxyindane. This reac-
tion was carried out in a similar way to that described for the preparation of the corresponding (ꢀ)-trans-
1,2-aminocyclohexanol and (ꢀ)-trans-1,2-aminocyclopentanol.4 The aminoindanol was converted into
its N-benzyloxycarbonyl derivative 3. We performed the resolution of compound 3 following the same
methodology developed for 1 (Scheme 2 and Table 2). The very high enantiomeric ratio of this reaction
made it possible to achieve both the product and the remaining substrate in enantiomerically pure form
by controlling the percent conversion.
Scheme 2.
Table 2
The enzyme showed preference for the R isomer of the carbamate, yielding the (1R,2R) O-acetyl-
carbamate 4 with 98% ee [α]D23=−57.6 (c 0.25, CHCl3). The substrate (1S,2S) 2-hydroxycarbamate 3
was recovered with 99% ee [α]D23=−29.6 (c 0.25, CHCl3). The absolute configuration of (1S,2S) was
assigned after its transformation to the corresponding trans-aminoalcohol and comparison of its specific
rotation with the data given in the literature.9b
2.3. Resolution of cis-2-aminoindan-1-ol
Synthesis of racemic cis-2-aminoindan-1-ol was carried out following the procedure developed by
Corey et al.16 As in the above cases, the corresponding carbamate derivative 7 was prepared. We
accomplished its resolution under the same conditions used for their isomers (ꢀ)-cis- and (ꢀ)-trans-1-
aminoindan-2-ol. Even though the enantiomeric ratio was very high, the process took place very slowly,
achieving only 2% conversion even after 5 days of reaction (Table 3, entry 1). We tried changing the
reaction conditions such as lipase type, acyl donor, solvent and increasing the temperature to 60°C in
order to improve the reaction rate. In all cases the E value was higher than 200, but it seems to be clear
that the main role in increasing the conversion in this reaction was played by the solvent. When tert-
butyl methyl ether (TBME) was used instead of 1,4-dioxane, it was possible to reach a conversion value
of about 50% and product 6 and substrate 5 could be obtained enantiomerically pure (Table 3, entry 3;
Scheme 3).

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A. Luna et al. / Tetrahedron: Asymmetry 10 (1999) 1969–1977
Scheme 3.
Table 3
The different behaviour shown by cis-2-aminoindan-1-ol with respect to its 1-amino isomer in terms
of rate of reaction, could be due to the fact that the hydroxyl group in this form is more hindered than
in the cis-1-aminoindan-2-ol. Nevertheless, the enzyme showed preference towards the (R)-configuration
of the carbon that bears the hydroxyl group. The absolute configuration of the remaining substrate was
assigned after the deprotection reaction and recovery of the cis-2-aminoindan-1-ol and comparison of its
specific rotation with the data given in the literature.12
2.4. Resolution of trans-2-aminoindan-1-ol
Synthesis of trans-2-amino-1-indanol was possible through a Mitsunobu9a reaction of the cis-2-
azidoindan-1-ol (Scheme 4). After this, the carbamate 7 was prepared as starting material for the
enzymatic resolution. Reaction conditions were the same as those used for cis-2-amino-1-indanol
(Table 3, entry 3). In this case the acylated product (1R,2R)-8 was obtained with a high enantiomeric
excess (96%), along with the substrate (1S,2S)-7 with 20% ee after 10 days of reaction (Table 4, entry 1).
In order to improve these results, we tried other reaction conditions. We used vinyl acetate as acyl donor,
and with the aim of increasing the temperature to accelerate the acetylation reaction rate, 1,4-dioxane was
used at 60°C. However, the results obtained were disappointing (Table 4, entry 2). The best result (E=59)
was obtained when (ꢀ)-trans-2-amino-1-indanol was exposed to PSL as a biocatalyst and isopropenyl
acetate as the acylating agent in tert-butyl methyl ether at 40°C. The absolute configuration of (1S,2S)-7
was assigned after its conversion to the corresponding trans-2-aminoindan-1-ol and comparison of its
specific rotation with the value given in the literature.12
Scheme 4.

A. Luna et al. / Tetrahedron: Asymmetry 10 (1999) 1969–1977
1973
Table 4
Figure 1.
Based on the observed reactivity of the four diastereoisomers towards the enzymatic O-acylation
process, it must be pointed out that the reactivity of the (R)-enantiomer was faster in all the cases. These
results are in accordance with Kazlauskas’ rule17 for resolution of secondary alcohols.
In the cases of (ꢀ)-cis- and (ꢀ)-trans-1-aminoindan-2-ol the large substituent is N-benzyloxycarbonyl,
and the methylene group is the medium substituent. The great difference in size for both groups could
confirm the very high enantioselectivity observed. For the resolution of (ꢀ)-cis-2-aminoindan-1-ol, the
difference of size between the medium substituent and the large substituent is smaller, but this difference
might be enough to explain the high E value measured in this compound.
On the other hand, the poorer resolution of (ꢀ)-trans-2-aminoindan-1-ol could be explained using
1
the same empirical rule. H NMR spectrum showed a broad signal for CH-OH suggesting a fast
conformational equilibrium between two conformers in the NMR time-scale. MM† studies revealed the
existence of two conformers with similar energy (Fig. 1). As is shown in Fig. 1, both conformers would
present different steric requirements and would lead to a reverse order in the size of the substituents. This
could give an explanation for the moderate enantioselectivity value of this isomer.
In conclusion, we have developed an efficient method for the resolution of (ꢀ)-cis- and (ꢀ)-trans-
†
MM:MMX force field calculations18 predict an energy difference of about 0.2 kcal/mol between both conformations and the
energy barrier (for the transformations of one to the other) lower than 2 kcal/mol.

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A. Luna et al. / Tetrahedron: Asymmetry 10 (1999) 1969–1977
1-aminoindan-2-ol and (ꢀ)-cis- and (ꢀ)-trans-2-aminoindan-1-ol through their N-benzyloxycarbonyl
derivatives, in order to obtain enantiomerically pure products and substrates. The relative position of the
hydroxyl and amino group has a special relevance in the enzymatic O-acylation of these compounds.
3. Experimental
3.1. General
Pseudomonas cepacia lipase (PSL) was purchased from Amano Pharmaceutical Co. All reagents were
of commercial quality and were purchased from Aldrich Chemie. Solvents were distilled over an adequate
desiccant and stored under nitrogen. Precoated TLC plates of silica gel 60 F254 from Merck were used,
while for column chromatography, Merck silica gel 60/230–400 mesh was applied. Mps were measured
with a Gallenkamp apparatus and are uncorrected. Optical rotations were measured with a Perkin–Elmer
241 polarimeter. IR spectra were recorded on a Perkin–Elmer Mattson 3000 Fourier transform infrared
1
spectrophotometer. H and 13C NMR spectra were obtained with a Bruker AC-300 (1H 300 MHz and
13C 75 MHz) spectrometer. Mass spectra were recorded on a Hewlett–Packard 5897 A spectrometer and
HPLC analyses were carried out on a Shimadzu LC liquid chromatograph.
3.2. Preparation of racemic benzyl N-(1 and 2-hydroxyindane)carbamates
To a solution of amino alcohol (2 mmol) and sodium carbonate (0.254 g, 2.4 mmol) in water (3.4 mL),
benzyl chloroformate (2.4 mmol) was added dropwise over a 0.5 h period at 0–5°C. The reaction mixture
was stirred for an additional 6 h at room temperature and extracted with dichloromethane. The organic
layer was dried and evaporated to dryness, to give the desired product in 85–100% yield.
3.2.1. (ꢀ)-cis-Benzyl N-(1-hydroxyindan-2-yl)carbamate 1
The racemic 1-hydroxycarbamate 1 was purified by flash chromatography, using ethyl acetate:hexane
1
(1:2) as eluent; it was a white solid, mp 140–142°C. H NMR (300 MHz, CDCl3) δ 2.21 (br. s, 1H,
OH), AB portion of ABX multiplet (δA 2.89, δB 3.10, JAB 16.78), 4.56 (br. s, 1H, CH-OH), 5.16 (m,
3H, O-CH2-Ph and CH-NH), 5.53 (m, 1H, NH), 7.24–7.40 (m, 9Harm); 13C NMR (75 MHz, CDCl3) δ
39.4 (CH2), 59.2 (CH), 67.0 (CH2), 73.5 (CH), 124.4 (CHarm), 125.3 (CHarm), 127.1 (CHarm), 128.1
(CHarm), 128.2 (CHarm), 128.3 (CHarm), 128.5 (CHarm), 136.2 (Carm), 139.7 (Carm), 140.4 (Carm),
156.8 (CO carbamate); IR (KBr) 3476, 3339, 1668, 1549, 1254 cm−1. MS (FAB+, nitrobenzyl alcohol)
m/z: 284 [(M+1)+, 100], [(M+Na)+, 70].
3.2.2. (ꢀ)-trans-Benzyl N-(1-hydroxyindan-2-yl)carbamate 3
The racemic 1-hydroxycarbamate 3 was purified by flash chromatography, using ethyl acetate:hexane
(1:2) as eluent; it was a brown solid, mp 135–137°C. 1H NMR (300 MHz, CDCl3) AB portion of ABX
multiplet (δA 2.92, δB 3.28, JAB 16.13), 4.44 (m, 1H, CH-OH), 4.99 (m, 1H, CH-NH), 5.16 (m, 3H, OH
and O-CH2-Ph), 5.33 (d, 1H, NH), 7.18–7.38 (m, 9Harm); 13C NMR (75 MHz, CDCl3) δ 38.2 (CH2),
64.2 (CH), 67.3 (CH2), 81.6 (CH), 123.0 (CHarm), 125.1 (CHarm), 126.9 (CHarm), 127.2 (CHarm),
127.5 (CHarm), 128.1 (CHarm), 128.3 (CHarm), 128.4 (CHarm), 128.5 (CHarm), 135.9 (Carm), 138.9
(Carm), 140.0 (Carm), 157.6 (CO carbamate); IR (KBr) 3405, 3281, 1691, 1563, 1265 cm−1. MS (FAB+,
nitrobenzyl alcohol) m/z: 284 [(M+1)+, 52], [(M+Na)+, 26].

A. Luna et al. / Tetrahedron: Asymmetry 10 (1999) 1969–1977
1975
3.2.3. (ꢀ)-cis-Benzyl N-(2-hydroxyindan-1-yl)carbamate 5
The racemic 2-hydroxycarbamate 5 was purified by flash chromatography, using ethyl acetate:hexane
(1:2) as eluent; it was a white solid, mp 84–86°C. 1H NMR (300 MHz, CDCl3) δ 2.93 (br. s, 1H, OH),
AB portion of ABX multiplet (δA 2.87, δB 3.19, JAB 16.08), 4.36 (m, 1H, CH-NH), 4.96 (br. s, 1H, CH-
OH), 5.08 (m, 2H, O-CH2-Ph), 5.67 (d, 1H, NH), 7.20–7.38 (m, 9Harm); 13C NMR (75 MHz, CDCl3) δ
36.5 (CH2), 54.7 (CH), 66.7 (CH2), 74.2 (CH), 125.0 (CHarm), 127.0 (CHarm), 128.0 (CHarm), 128.4
(CHarm), 129.0 (CHarm), 136.2 (Carm), 140.7 (Carm), 141.9 (Carm), 156.4 (CO carbamate); IR (KBr)
3246, 1691, 1549, 1291 cm−1. MS (FAB+, nitrobenzyl alcohol) m/z: 284 [(M+1)+, 53], [(M+Na)+, 52].
3.2.4. (ꢀ)-trans-Benzyl N-(2-hydroxyindan-1-yl)carbamate 7
The racemic 2-hydroxycarbamate 7 was purified by flash chromatography, using ethyl acetate:hexane
1
(1:2) as eluent; it was a light yellow solid, mp 162–164°C. H NMR (300 MHz, CDCl3) δ 1.68 (br. s,
1H, OH), AB portion of ABX multiplet (δA 2.72, δB 3.33, JAB 15.26), 4.17 (m, 1H, CH-NH), 5.13 (m,
3H, NH and O-CH2-Ph), 5.24 (m, 1H, CH-OH), 7.18–7.44 (m, 9Harm); 13C NMR (75 MHz, CDCl3)
δ 35.9 (CH2), 61.9 (CH), 67.1 (CH2), 81.5 (CH), 124.3 (CHarm), 124.4 (CHarm), 127.4 (CHarm),
128.2 (CHarm), 128.3 (CHarm), 128.5 (CHarm), 136.0 (Carm), 138.0 (Carm), 142.1 (Carm), 156.4 (CO
carbamate); IR (KBr) 3371, 3292, 1688, 1563, 1274 cm−1. MS (FAB+, nitrobenzyl alcohol) m/z: 284
[(M+1)+, 85], [(M+Na)+, 76].
3.3. General procedure for the syntheses of benzyl carbamates 2 and 4
Vinyl acetate (10 mmol) and carbamate (ꢀ)-cis-1 or (ꢀ)-trans-3 (1 mmol) were added to a suspension
of PSL (320 mg) in 1,4-dioxane (9 mL) under nitrogen. The mixture was shaken at 30°C and 250 rpm
during 9 and 3 days, respectively. The enzyme was then filtered off and washed with dichloromethane
(2×10 mL) and the organic solvents were evaporated off. The crude residue was subjected to column
chromatography, with ethyl acetate:hexane (1:2) as eluent.
Isopropenyl acetate (5 mmol) or vinyl acetate (10 mmol) and carbamate (ꢀ)-cis-5 or (ꢀ)-trans-7 (1
mmol) were added to a suspension of PSL (320 mg) in tert-butyl methyl ether (2 mL) under nitrogen.
The mixture was shaken at 40°C and 250 rpm during 6 and 10 days. The enzyme was then filtered off
and washed with dichloromethane (2×10 mL) and the organic solvents were evaporated off. The crude
residue was subjected to column chromatography, with ethyl acetate:hexane (1:2) as eluent.
3.3.1. Benzyl (1R,2S)-N-(1-hydroxyindan-2-yl)carbamate 1
The previously described procedure gave 55% of (1R,2S)-1 as a white solid, mp 127–129°C.
[α]D23=−4.8 (c 0.25 in CHCl3). Determination of ee for (1R,2S)-1, 78% by chiral HPLC (Chiralcel
OD), hexane:ethanol (97%, 3 v/v) in isocratic conditions (flux 0.8 mL/min) and the λ was 210 nm. The
retention times of the stereoisomers were 33.63 min for the SR and 36.79 min for the RS; Rs, 1.8.
3.3.2. Benzyl (1S,2S)-N-(1-hydroxyindan-2-yl)carbamate 3
The previously described procedure gave 75% of (1S,2S)-3 as a white solid, mp 165–167°C.
[α]D23=−29.6 (c 0.25 in CHCl3). Determination of ee for (1S,2S)-3, 99% ee was determined from its
methyl ester derivative by chiral HPLC (Chiralcel OD), hexane:propan-2-ol (90%, 10 v/v) in isocratic
conditions (flux 0.8 mL/min) and the λ was 210 nm. The retention times of the stereoisomers were 20.24
min for the SS and 23.04 min for the RR; Rs, 2.02.

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A. Luna et al. / Tetrahedron: Asymmetry 10 (1999) 1969–1977
3.3.3. Benzyl (1S,2R)-N-(2-hydroxyindan-1-yl)carbamate 5
The previously described procedure gave 78% of (1S,2R)-5 as a white solid, mp 75–77°C.
[α]D23=−26.0 (c 0.25 in CHCl3). Determination of ee for (1S,2R)-5, 96% by chiral HPLC (Chiralcel
OD), hexane:propan-2-ol (80%, 20 v/v) in isocratic conditions (flux 0.8 mL/min) and the λ was 210 nm.
The retention times of the stereoisomers were 15.23 min for the RS and 23.07 min for the SR; Rs, 4.94.
3.3.4. Benzyl (1S,2S)-N-(2-hydroxyindan-1-yl)carbamate 7
The previously described procedure gave 79% of (1S,2S)-7 as a white solid, mp 161–163°C.
[α]D23=−4.0 (c 0.25 in CHCl3). Determination of ee for (1S,2S)-7, 20% by chiral HPLC (Chiralcel OD),
hexane:propan-2-ol (80%, 20 v/v) in isocratic conditions (flux 0.8 mL/min) and the λ was 210 nm. The
retention times of the stereoisomers were 13.89 min for the SS and 16.72 min for the RR; Rs, 2.4.
3.3.5. Benzyl (1S,2R)-N-(1-acetoxyindan-2-yl)carbamate 2
The previously described procedure gave 86% of (1S,2R)-2 as a white solid, mp 147–149°C. 1H NMR
(300 MHz, CDCl3) δ 2.0 (s, 3H, CH3), AB portion of ABX multiplet (δA 3.02, δB 3.20, JAB 17.0),
5.2 (br. s, 2H, CH2-Ph), 5.33 (d, 1H, NH), 5.43 (m, 1H, CH-NH), 5.58 (m, 1H, CH-OAc), 7.20–7.47
(m, 9Harm); 13C NMR (75 MHz, CDCl3) δ 20.9 (CH3), 37.2 (CH2), 57.3 (CH), 67.0 (CH2), 75.6
(CH), 123.8 (CHarm), 125.0 (CHarm), 127.2 (CHarm), 128.2 (CHarm), 128.3 (CHarm), 128.5 (CHarm),
136.2 (Carm), 139.1 (Carm), 140.3 (Carm), 156.2 (CO carbamate), 170.2 (CO ester); IR (KBr) 3315,
1730, 1701, 1535, 1261 cm−1. MS (FAB+, nitrobenzyl alcohol) m/z: 326 [(M+1)+, 78], [(M+Na)+, 100].
[α]D23=−69.6 (c 0.775 in EtOH). Determination of ee for (1S,2R)-2, 99% by chiral HPLC (Chiralcel
OD-H), T=0°C, hexane:ethanol (97%, 3 v/v) in isocratic conditions (flux 0.5 mL/min) and the λ was 210
nm. The retention times of the stereoisomers were 44.74 min for the SR and 50.22 min for the RS; Rs,
1.73.
3.3.6. Benzyl (1R,2R)-N-(1-acetoxyindan-2-yl)carbamate 4
1
The previously described procedure gave 82% of (1R,2R)-4 as a white solid, mp 115–117°C. H
NMR (300 MHz, CDCl3) δ 2.08 (s, 3H, CH3), AB portion of ABX multiplet (δA 2.86, δB 3.37, JAB
16.13), 5.18 (m, 4H, O-CH2-Ph, CH-NH, CH-OAc), 5.38 (d, 1H, NH), 7.13–7.43 (m, 9Harm); 13C
NMR (75 MHz, CDCl3) δ 20.8 (CH3), 35.95 (CH2), 60.6 (CH), 66.7 (CH2), 80.0 (CH), 124.0 (CHarm),
124.6 (CHarm), 127.2 (CHarm), 127.8 (CHarm), 128.3 (CHarm), 128.4 (CHarm), 136.13 (Carm), 138.6
(Carm), 139.4 (Carm), 156.1 (CO carbamate), 170.8 (CO ester); IR (KBr) 3319, 1739, 1696, 1539, 1240
cm−1. MS (FAB+, nitrobenzyl alcohol) m/z: 326 [(M+1)+, 100], [(M+Na)+, 67]. [α]D23=−57.6 (c 0.25
in CHCl3). Determination of ee for (1R,2R)-4, 98% by chiral HPLC (Chiralcel OD), hexane:propan-2-ol
(90%, 10 v/v) in isocratic conditions (flux 0.8 mL/min) and the λ was 210 nm. The retention times of the
stereoisomers were 20.24 min for the SS and 23.04 min for the RR; Rs, 2.02.
3.3.7. Benzyl (1R,2S)-N-(2-acetoxyindan-1-yl)carbamate 6
The previously described procedure gave 82% of (1R,2S)-6 as a white solid, mp 153–155°C. 1H NMR
(300 MHz, CDCl3) δ 2.03 (s, 3H, CH3), AB portion of ABX multiplet (δA 2.95, δB 3.27, JAB 15.48),
4.67 (m, 1H, CH-NH), 5.16 (m, 2H, O-CH2-Ph), 5.32 (m, 1H, CH-OAc), 6.06 (d, 1H, NH), 7.24–7.51
(m, 9Harm); 13C NMR (75 MHz, CDCl3) δ 21.0 (CH3), 36.9 (CH2), 53.1 (CH), 66.9 (CH2), 76.0
(CH), 124.7 (CHarm), 126.7 (CHarm), 127.0 (CHarm), 128.2 (CHarm), 128.5 (CHarm), 129.5 (CHarm),
136.1 (Carm), 138.8 (Carm), 141.4 (Carm), 155.7 (CO carbamate), 170.1 (CO ester); IR (KBr) 3290,
1736, 1693, 1555, 1276 cm−1. MS (FAB+, nitrobenzyl alcohol) m/z: 326 [(M+1)+, 6], [(M+Na)+, 100].
[α]D23=−115.42 (c 0.24 in CHCl3). Determination of ee for (1R,2S)-6, 99% by chiral HPLC (Chiralcel
OD), hexane:propan-2-ol (80%, 20 v/v) in isocratic conditions (flux 0.8 mL/min) and the λ was 210 nm.
The retention times of the stereoisomers were 10.5 min for the SR and 11.71 min for the RS; Rs, 1.53.

A. Luna et al. / Tetrahedron: Asymmetry 10 (1999) 1969–1977
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1
3.3.8. Benzyl (1R,2R)-N-(2-acetoxyindan-1-yl)carbamate 8
The previously described procedure gave 75% of (1R,2R)-8 as a white solid, mp 103–105°C. H
NMR (300 MHz, CDCl3) δ 2.14 (s, 3H, CH3), AB portion of ABX multiplet (δA 2.78, δB 3.53, JAB
15.48), 4.41 (m, 1H, CH-NH), 5.14 (m, 2H, O-CH2-Ph), 5.36 (m, 1H CH-OAc), 6.13 (d, 1H, NH),
7.23–7.37 (m, 9Harm); 13C NMR (75 MHz, CDCl3) δ 21.0 (CH3), 37.2 (CH2), 58.6 (CH), 66.8 (CH2),
81.1 (CH), 124.9 (CHarm), 125.0 (CHarm), 127.2 (CHarm), 128.1 (CHarm), 128.5 (CHarm), 129.2
(CHarm), 136.2 (Carm), 138.4 (Carm), 140.3 (Carm), 156.0 (CO carbamate), 171.4 (CO ester); IR (KBr)
3330, 1732, 1692, 1541, 1273 cm−1. MS (FAB+, nitrobenzyl alcohol) m/z: 326 [(M+1)+, 32], [(M+Na)+,
48]. [α]D23=−77.7 (c 0.26 in CHCl3). Determination of ee for (1R,2R)-8, 96% by chiral HPLC (Chiralcel
OD-H), T=40°C, hexane:ethanol (99%, 1 v/v) in isocratic conditions (flux 0.4 mL/min) and the λ was
210 nm. The retention times of the stereoisomers were 96.43 min for the RR and 104.29 min for the SS;
Rs, 1.38.
Acknowledgements
Financial support of this work by CICYT (Project BIO-98-0770) is gratefully acknowledged. A.L.
thanks CONACYT in Mexico for a predoctoral scholarship.
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