Highly efficient biocatalytic resolution of cis- and trans-3-aminoindan-1- ol: Syntheses of enantiopure orthogonally protected cis- and trans-indane-1,3-diamine

Article abstract of DOI:10.1002/chem.200306070

The efficient chemoenzymatic synthesis of enantiopure 1,3-difunctionalized indane derivatives has been achieved. The corresponding cis and trans N-protected amino alcohols were successfully resolved by acetylation using lipase B, which is a biocatalyst is

Full text of DOI:10.1002/chem.200306070

FULL PAPER
Highly Efficient Biocatalytic Resolution of cis- and trans-3-Aminoindan-1-ol:
Syntheses of Enantiopure Orthogonally Protected cis- and trans-Indane-1,3-
diamine
[a]
MÛnica LÛpez-GarcÌa,Ignacio Alfonso,and Vicente Gotor*
Abstract: The efficient chemoenzymat-
ic synthesis of enantiopure 1,3-difunc-
tionalized indane derivatives has been
achieved. The corresponding cis and
trans N-protected amino alcohols were
successfully resolved by acetylation
using lipase B, which is a biocatalyst
isolated from Candida antarctica. All
the possible isomers were obtained in
very good chemical yields and ee
values (>99%). The utility of these
compounds was subsequently shown by
the preparation of orthogonally pro-
tected cis- and trans-indane-1,3-dia-
mine using a Mitsunobu reaction. Both
enantiomers of the trans isomer and a
desymmetrized cis diastereomer were
prepared in enantiopure form. Com-
plete inversion of configuration during
the Mitsunobu reaction was demon-
strated by a combination of NMR tech-
niques and molecular modeling. The
utility and versatility of the strategy
was also demonstrated by the selective
deprotection of each nitrogen atom
under mild reaction conditions.
Keywords: biotransformations
chemoenzymatic synthesis
enzymes ¥ Mitsunobu reaction
¥
¥
Introduction
structures from this family is the 1,3-disubstituted indane
core, as this moiety is present in some HIV protease inhibi-
tors,[10] in drugs used for cocaine abuse treatment,[11] as well
as in polyamine derivatives used against neurodegenerative
diseases.[12] In addition, both optically active amino alcohols
Biocatalytic processes have been demonstrated to be a pow-
erful tool for the preparation of chiral synthons in organic
synthesis.[1] Simple enzymatic resolution of racemic mix-
tures,[2] sequential kinetic resolution,[3] parallel kinetic reso-
lution,[4] dynamic kinetic resolution,[5] asymmetric redox
processes,[6] and desymmetrization of prochiral substrates[7]
have been used for the efficient and practical preparation of
enantiopure drugs and chemicals. Moreover, enzymes often
display high chemo- and stereoselectivities under mild reac-
tion conditions; this enhances the value of these catalysts
for modern organic chemistry.
In efforts devoted to explore new biotransformations that
have subsequent synthetic applications, we became interest-
ed in 1,3-disubstituted substrates. The efficient enzymatic
resolution of 1,2-amino alcohols[8] and 1,2-diamines[3c,e] has
previously been accomplished in our group. In spite of the
potential applications of 1,3-optically active compounds,
they have received much less attention, especially in the
field of biocatalytic processes.[9] One of the most interesting
[a] M. LÛpez-GarcÌa, Dr. I. Alfonso, Prof. V. Gotor
Departamento de QuÌmica Orgµnica e Inorgµnica
Facultad de QuÌmica, Universidad de Oviedo
Oviedo (Spain)
and diamines have possible interesting applications in asym-
metric synthesis and in the design of new ligands for asym-
metric catalysts.[13] Amino alcohol derivatives have been
used to resolve acids because of the ability of their corre-
sponding crystalline diastereomeric salts to form b-sheet-
E-mail: vgs@sauron.quimica.uniovi.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
3006
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200306070
Chem. Eur. J. 2004, 10, 3006 3014

3006 3014
like structures.[14] Similarly, diamines constitute synthetic
precursors for optically active polyamines and azamacrocy-
cles.[15] As a result, we have been interested in the develop-
ment of chemoenzymatic syntheses of new enantiopure dia-
mines that then could have potential applications in all
these fields. Moreover, it has emerged that the isomers of
indane-1,3-diamine are interesting but as yet unexploited
building blocks. Unfortunately, access to both enantiomers
of these types of molecules still remains a difficult task.
Indeed, only one paper describes the resolution of 3-amino-
indan-1-ol isomers.[14] Several diastereomeric salt recrystalli-
zations using a chiral acid were needed to resolve the trans
isomer, and this was only achieved in poor yields, while tedi-
ous chiral HPLC separation yielded only enantioenriched
rather than the enantiopure cis diastereomer, also in poor
final yields.
the amino group and transformation of the carboxylic acid
group into the acyl chloride followed by in situ intramolecu-
lar Friedel Craft acylation of the aromatic ring afforded (N-
acetyl)-3-aminoindan-1-one (1) in 76% overall yield
(Scheme 1).[14] Standard deprotection of the acetamide
On the basis of these facts, we embarked on the prepara-
tion of a number of different enantiopure 1,3-disubstituted
indane synthons in which all possible relative stereochemis-
tries were accounted for. To achieve this goal, we used a
combination of both biocatalytic and nonenzymatic process-
es. In this way, all the enantiomers of cis- and trans-3-amino-
indan-1-ol and cis- and trans-indane-1,3-diamine were ob-
tained in enantiopure form. Our synthetic strategy afforded
orthogonally protected diamines, which then allowed each
nitrogen atom to be selectively deprotected. In addition, we
will describe the unsymmetrical preparation of an enantio-
pure derivative of cis-indane-1,3-diamine that would be a
meso compound if it were symmetrically substituted.
Scheme 1. Reagents and conditions: i) Ref. [14]; ii) HCl; iii) NaBH4,
MeOH; iv) CbzCl, Na2CO3.
yielded aminoketone 2, which was isolated as its hydrochlo-
ride salt. Borohydride reduction of 2 gave the corresponding
amino alcohols, which were subsequently transformed in
situ into their benzyl carbamate derivatives for easier isola-
tion and manipulation (92% combined overall yield). The
diastereomeric mixture of carbamates was readily separated
by semipreparative HPLC to give (Æ)-trans-3 and (Æ)-cis-3.
The moderate diastereoselectivity (3:1 trans/cis) observed
1
Results
was determined both by H NMR spectroscopy of the crude
product and from signal integration of the HPLC traces.
The result can be explained by analysis of the initial reac-
tion between borohydride and the free amino group to form
the corresponding boramide. In good agreement with previ-
ously published results, this reaction would favor an intra-
molecular reduction that would lead to a trans configura-
tion.[14] The relative configurations of the compounds were
unambiguously established by NOESY experiments. Results
from these experiments are shown in Figure 1. Each proton
Enzymatic resolution of (Æ)-trans- and (Æ)-cis-3-(N-benzyl-
oxycarbonyl)aminoindan-1-ol: We built the 1,3-disubstituted
indane moiety from commercially available racemic 3-
amino-3-phenylpropanoic acid. Conventional acetylation of
Abstract in Spanish: Se ha conseguido la eficiente sÌntesis
quimioenzimµtica de indanos 1,3-difuncionalizados enantio-
puros. Los correspondientes cis y trans aminoalcoholes N-
protegidos se resuelven mediante acetilaciÛn usando la lipa-
sa B de Candida antarctica como biocatalizador. AsÌ se ob-
tienen todos los posibles isÛmeros de forma enantiopura y
con muy buenos rendimientos. La utilidad de estos compues-
tos se muestra mediante la preparaciÛn de la cis y trans
indano-1,3-diamina ortogonalmente protegidas, a travÿs de
una reacciÛn de Mitsunobu. Para el isÛmero trans, ambos
enantiÛmeros pueden ser preparados de forma enantiopura.
En el caso del diastereoisÛmero cis, tambiÿn se obtiene el co-
rrespondiente compuesto desimetrizado enantiomÿricamente
puro. La inversiÛn total de la configuraciÛn durante la reac-
ciÛn de Mitsunobu se demuestra mediante la combinaciÛn de
tÿcnicas de RMN y modelizaciÛn molecular. La utilidad y
versatilidad de la estrategia finalmente se pone de manifiesto
con la desprotecciÛn selectiva de cada µtomo de nitrÛgeno en
condiciones suaves de reacciÛn.
Figure 1. Cross-peaks observed in the NOESY spectra of cis-3 and trans-
3.
of the diastereotopic C2methylene group in the ( Æ)-trans-3
isomer displays strong cross-peaks with a proton at either
C1 or C3 (H1 correlates with H2a and H3 with H2b, respec-
tively); this suggests that H1 and H3 are on opposite faces
of the cylcopentane ring. On the other hand, in the cis
isomer, both H1 and H3 show strong NOE effects with only
Chem. Eur. J. 2004, 10, 3006 3014
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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V. Gotor et al.
FULL PAPER
one proton of the C2methylene group (H1 and H3 corre-
late with H2b). This observation indicates that H1, H3, and
H2b are all on the same side of the cyclopentane ring. It is
also noteworthy that the chemical shift difference for the di-
astereotopic protons of the methylene group at C2is more
pronounced for the cis (Dd=1.20 ppm) than for the trans
(Dd=0.19 ppm) isomer. This effect, which is in accord with
reported data on similar structures, arises because the chem-
ical environment of each C2proton is different to a greater
extent for the cis isomer.[16] We subsequently used these Z-
amino-protected compounds to study enzymatic resolution
by transesterification.
We started the enzymatic resolution screening with (Æ)-
trans-3. Different enzymes, solvents, and acyl donors were
tested (Table 1), and it was found that reactivity and enan-
tioselectivity[17] depended largely on the enzyme used. For
instance, the optimized reaction conditions for similar sub-
strates previously obtained in our laboratory[8] (Table 1,
entry 1) yielded low E values. When the solvent (entry 2),
acyl donor (entry 3), or temperature (entry 4) was changed
the results did not improve. We concluded from these obser-
vations that lipase isolated from Pseudomonas cepacia
(PSL) displays low enantioselectivity towards this substrate.
Moreover, the polymer-supported preparation of this
enzyme (PSL-C) did not fare any better, and the substrate
was almost completely converted into a virtually racemic
product in six hours at 208C (Table 1, entry 5). However, li-
pase B (CAL-B) isolated from Candida antarctica displayed
excellent enantioselectivities upon accurate control of both
the reaction conditions (Table 1, entries 6 10) and the per-
centage of conversion (Table 1, entries 9 and 10), and al-
lowed both the substrate and product to be obtained in
enantiomerically pure form. Under optimized reaction con-
ditions at 308C, vinyl acetate was used as the acyl donor and
tert-butyl methyl ether was used as the solvent. The reaction,
which is very fast, reached 49% conversion in less than
one hour and yielded the enantiopure acylated product
(1R,3R)-4 in 48% yield (50% is the limiting yield for a ki-
netic resolution). On the other hand, 55% conversion was
achieved after 3.5 h, and gave rise to a 43% yield of the re-
maining alcohol in an enantiomeric excess of >99% after
chromatographic purification. The absolute configuration of
the product was inferred by deprotecting the Z group of the
unreacted substrate (Pd0, HCOOH, MeOH) and comparing
the sign of specific rotation with published data.[13] As a
result, the fastest reacting enantiomer was determined to
have a (1R,3R) configuration, which is in good agreement
with the Kazlauskas× rule.
We used the optimized reaction conditions determined for
(Æ)-trans-3 in the enzymatic resolution of (Æ)-cis-3. Al-
though the reaction is slower for the cis isomer, the enantio-
selectivity is better. Moreover, both the substrate and prod-
uct are able to be isolated in enantiopure form from the
same enzymatic reaction (Table 2, entry 3). The process is
also very efficient, as enantiopure ester (1R,3S)-4 and alco-
hol (1S,3R)-3 were isolated in 48 and 49% yield, respective-
ly. The lower reactivity of cis isomers has previously been
observed in our research group with respect to indane-1,2-
amino alcohol derivatives,[8b] and could arise because of the
À
presence of a bulkier (NH Z) substituent on the same face
as the reacting hydroxy group. The absolute configuration
was determined by performing the sequence depicted in
Scheme 2. The unreacted substrate from the enzymatic proc-
Scheme 2. Reagents and conditions: i) PCC, CH2Cl2; ii) NaBH4, MeOH.
ess was first oxidized with pyridinium chlorochromate
(PCC), and was then reduced with borohydride to give a
mixture of cis/trans diastereomers. The reaction is generally
Table 1. Enzymatic resolution screening for (Æ)-trans-3.
[a]
Entry
1
2PSL
3
4
5
6
7
8
Enzyme
PSL
Solvent
R
T
[8C]
t
ees[a]
[%]
eep
c[b]
[%]
E[b]
[h]
[%]
1,4-dioxane
tBuOMe
tBuOMe
tBuOMe
tBuOMe
1,4-dioxane
tBuOMe
tBuOMe
tBuOMe
tBuOMe
vinyl
vinyl
isopropenyl
vinyl
30
30
30
20
20
30
15
15
30
30
48
36
36
27
6
1
288
0.5
0.5
3.5
66
828250 5
16
34
46
81
45
19
2
PSL
PSL
87
88
5
98
47
>99
>99
81
16
28
90
32157
16
21
1.5
PSL-C
CAL-B
CAL-B
CAL-B
CAL-B
CAL-B
vinyl
vinyl
vinyl
vinyl
vinyl
vinyl
47
98
>200
>200
>200
>200
81
94
>99
45
49
55
9
10
[a] Determined by HPLC: ees =ee[(1S,3S)-3] and eep =ee[(1R,3R)-4]. [b] Determined from ees and eep as in ref. [17].
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Chem. Eur. J. 2004, 10, 3006 3014

Highly Efficient Biocatalytic Resolution of cis- and trans-3-Aminoindan-1-ol
3006 3014
Table 2. Enzymatic resolution of (Æ)-cis-3 by using the optimized reaction conditions determined for (Æ)-trans-3.
[a]
Entry
1
2CAL-B
3
Enzyme
Solvent
R
T
[8C]
t
ees[a]
[%]
eep
c[b]
[%]
E[b]
[h]
[%]
CAL-B
CAL-B
tBuOMe
tBuOMe
tBuOMe
vinyl
vinyl
vinyl
30
30
30
14
36
60
36
54
>99
>99
>99
>99
27
35
50
>200
>200
>200
[a] Determined by HPLC: ees =ee[(1S,3R)-3] and eep =ee[(1R,3S)-4)]. [b] Determined from ees and eep as in ref. [17].
diastereoselective, although only a 3:2 cis/trans mole ratio
was obtained in this case. In particular, the carbonyl ketone
is preferentially reduced from the face opposite the Z group
to give the cis isomer. HPLC separation of the diastereo-
meric mixture afforded (+)-trans-3, in which the configura-
tion was determined to be (1R,3R). Since the asymmetric
carbon at the 3-position is not involved in any of the reac-
tions depicted in Scheme 2, the absolute configuration of
the unreacted substrate was unambiguously assigned as
(1S,3R). This configuration is also in good agreement with
the Kazlauskas× rule for enzymatic resolution of secondary
alcohols.
size an enantiopure, asymmetrically substituted meso com-
pound that is chiral.
We used (1S,3S)-3, which was obtained as the unreacted
substrate in the (CAL-B)-catalyzed acetylation described in
the previous section (Table 1, entry 10), as the starting mate-
rial for the synthesis of the cis diastereomer. Compound
(1R,3S)-5 was obtained in 76% yield after chromatographic
purification when enantiopure (1S,3S)-3 was subjected to
Mitsunobu reaction conditions in the presence of PPh3, di-
ethylazodicarboxylate (DEAD), and phthalimide as the nu-
cleophile (Scheme 3). As demonstrated from a combination
Finally, the NMR spectra for the acetylated derivatives
cis-4 and trans-4 were observed to be similar to the spectra
for cis-3 and trans-3. In particular, the difference in the
chemical shifts of the diastereotopic methylene protons at
C2was found to be greater for the cis (Dd=1.15 ppm) than
for the trans (Dd=0.32ppm) isomer, and reflects that the
cyclopentane faces in cis-4 have considerably different
chemical environments. In addition, the assigned stereo-
chemistry was confirmed from the strongest cross-peaks
found in the NOESY spectra of compounds (1R,3R)-4 and
(1R,3S)-4 (Figure 2).
Figure 2. Cross-peaks observed in the NOESY spectra of (1R,3R)-4 and
(1R,3S)-4.
Scheme 3. Reagents and conditions: i) phthalimide, DEAD, PPh3; ii) hy-
drazine, MeOH; iii) Pd, HCOOH, MeOH.
Synthesis of orthogonally protected enantiopure cis- and
trans-indane-1,3-diamine: First of all, some structural char-
acteristics must be considered. The trans isomer exists as a
pair of enantiomers that possess C2 symmetry, while the cis
diastereomeric counterpart is a meso compound. Conse-
quently, the cis isomer is only chiral when the substituents
on the amino groups are different. Here we present a simple
strategy, using the Mitsunobu reaction as the key step, for
the synthesis of orthogonally protected cis- and trans-dia-
mines. We will describe the preparation of both enantiomers
of the trans diastereomer in enantiopure form, while orthog-
onal protection of the cis isomer has allowed us to synthe-
of NMR data and molecular modeling, the reaction took
place with complete inversion of configuration at the 1-posi-
tion. Figure 3 shows the observed cross-peaks in the
NOESY spectrum and the optimized structure (HF/3-21G
level of theory) for (1R,3S)-5. One of the diastereotopic C2
protons (labeled as H2a) displays an NOE effect with the
NH of the carbamate, and strong cross-peaks arise between
H1, H3, and H2b in good agreement with the measured dis-
tances in the optimized geometry (Figure 3). These data al-
lowed the chemical shifts for H2a and H2b to be unambigu-
ously assigned. Again, the anisochrony of the 1H NMR
chemical shifts for the diastereotopic methylene protons at
Chem. Eur. J. 2004, 10, 3006 3014
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V. Gotor et al.
FULL PAPER
ed (1R,3R)-5 in 68% yield (Scheme 4). The selective depro-
tection of each nitrogen atom in (1R,1S)-5 was also success-
fully carried out. Hydrazine deprotection led to monoami-
nocarbamate (1R,3R)-6, while Pd(0) catalyzed hydrogenoly-
Figure 3. Cross-peaks observed in the NOESY spectrum (top) and the
optimized structure (HF/3-21G level of theory) for (1R,3S)-5 (bottom).
C2were considerably greater ( Dd=1.00 ppm). Furthermore,
both H1 and H3 showed large vicinal (3JH,H) coupling con-
stants with one of the protons at C2(H2b) and smaller cou-
pling constants with the other proton (H2a). The minimized
structure depicted in Figure 3 displays an almost planar ge-
ometry for the fused five-membered ring. Analysis of the
energy minimum indicates that a stabilizing eight-mem-
bered-ring hydrogen bond exists between the carbamate NH
at C3 and the phthalimide carbonyl group at C1, and ex-
plains the downfield shift observed for the NH proton signal
in the 1H NMR spectrum. The hydrogen bond renders a
very rigid geometry within the molecule, as the conforma-
Scheme 4. Reagents and conditions: i) phthalimide, DEAD, PPh3; ii) hy-
drazine, MeOH; iii) Pd, HCOOH, MeOH.
sis afforded (1R,3R)-7 in quantitative yield. Subsequent hy-
drogenolysis of (1R,3R)-6 afforded diamine (1R,3R)-8, also
1
tion around C1 C2 C3 is nearly eclipsed. Therefore, large
coupling constants are observed for the protons in a cis dis-
position (3JH1,H2b =3JH3,H2b =9.4 Hz), while the trans disposed
in quantitative yield. The H and 13C NMR spectra of 8 indi-
À
À
cated that the compound contains a C2 symmetry, and there-
by, the C2protons are chemically equivalent (triplet at d=
2.19 ppm).
protons display smaller coupling constants (3JH1,H2a
=
3JH3,H2a =4.4 Hz). All these observations strongly support
that H1 and H3 have a cis configuration, and implies that
the configuration at C1 has undergone inversion.
The (S,S)-enantiomer was synthesized from the product
isolated from the enzymatic resolution of (Æ)-cis-3
(Table 2). Conventional saponification of enantiopure
(1R,3S)-4 led to the N-Z-protected amino alcohol (1R,3S)-3.
This was subsequently transformed into (1S,3S)-5 using the
same Mitsunobu reaction as described above (Scheme 5).
The trans configuration in (1R,3R)-5 was also demonstrat-
ed by NMR experiments. Figure 4 displays the observed
cross-peaks in the NOESY spectrum of (1R,3R)-5, and
Compound (1R,3S)-5 is also interesting because it is chiral
and can be considered as a desymmetrized meso compound.
Therefore, selective cleavage of each protecting group
would access the free amino attached either to the R or S
stereogenic center (Scheme 3). We thereby attempted to fa-
cilitate this transformation. Incubation of (1R,3S)-5 in a
methanolic solution of hydrazine led to deprotection of the
nitrogen atom attached to the R chiral center in 98% yield.
In contrast, conventional hydrogenolysis of (1R,3S)-5 afford-
ed the free amine at the S center in quantitative yield. Thus,
two differently desymmetrized cis diamine derivatives have
been successfully prepared in enantiomerically pure form
from the same synthon.
For the preparation of both enantiomers of the trans
isomer, we used the substrate and product from the resolved
cis amino alcohol derivatives (Table 2). Mitsunobu reaction
of enantiopure (1S,3R)-3 under the same reaction conditions
as previously described (PPh3, DEAD, phthalimide) afford-
Scheme 5. Reagents and conditions: i) NaOH, MeOH; ii) phthalimide,
DEAD, PPh3.
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Chem. Eur. J. 2004, 10, 3006 3014

Highly Efficient Biocatalytic Resolution of cis- and trans-3-Aminoindan-1-ol
3006 3014
was determined to be 1.6 kcalmolÀ1. This explains the rapid
interconversion between both conformers at room tempera-
ture, and again is in good agreement with experimental
data. Once again, all these data strongly support that during
the Mitsunobu reaction the configuration at C1 is complete-
ly inverted.
Conclusion
All the possible isomers of 3-aminoindan-1-ol and indane-
1,3-diamine were prepared in this work using a chemoenzy-
matic strategy. Both the cis and trans diastereomers of the
N-protected amino alcohol were efficiently resolved by
(CAL-B)-catalyzed transesterification reactions in processes
that were highly efficient in terms of both chemical yields
and enantiomeric excesses of the final products. These enan-
tiopure compounds were then used to synthesize the corre-
sponding 1,3-diamines using an easy one-step procedure
based on the Mitsunobu reaction. The orthogonally protect-
ed diamines were obtained with complete inversion of con-
figuration at C1. Both enantiomers of the trans diastereomer
were synthesized with enantiomeric excesses >99%, while
for the cis counterpart, the completely desymmetrized dia-
mine was obtained in enantiomerically pure form. The ver-
satility of these interesting synthons was also demonstrated
by selective deprotection of each nitrogen atom under mild
reaction conditions.
Figure 4. Cross-peaks observed in the NOESY spectrum of (1R,3R)-5
(top), and results of molecular modeling (bottom; see text for details).
shows that the carbamate NH proton correlates with one C2
proton, which has been assigned H2a. This proton also
shows a strong NOE effect with H1, while H2b correlates
with H3. This suggests that H1 and H3 are trans disposed.
Moreover, chemical shift differences for H2a/H2b were
again found to be smaller (Dd=0.50 ppm) for the trans iso-
mers than for the cis diastereomer. Finally, the vicinal cou-
À
À
pling constants for the protons at C1 C2 C3 also inferred a
trans arrangement: H1 shows a large coupling constant
(9.1 Hz) with H2a and a small one (4.6 Hz) with H2b, while
H3 shows a large vicinal coupling constant with H2b
(8.1 Hz) and a small one with H2a (5.1 Hz). On the basis of
the coupling constants measured in cyclopentene,[18] we
would expect JH,Hcis > JH,Htrans, and this was in fact observed
in the experimental values obtained. However, for compari-
son purposes we also performed some molecular modeling
(HF/3-21G level of theory). We found two energy minima
with very similar stability (DE=0.62kcalmol À1), both of
which displayed an envelope conformation for the cyclopen-
Experimental Section
Preparation of racemic (Æ)-cis- and (Æ)-trans-3-(N-benzyloxycarbonyla-
mino)indan-1-ol (Æ)-cis-3 and (Æ)-trans-3: (Æ)-(N-acetyl)-3-aminoin-
dan-1-one (2mmol) was added to a 3 n HCl aqueous solution (4 mL) and
the reaction mixture was stirred overnight at 808C. The reaction mixture
was then washed with CH2Cl2 and the resultant aqueous layer was evapo-
rated under reduced pressure. The residue was washed with heptane to
remove acetic acid, and the product thus obtained was dissolved in
MeOH (6 mL) and then cooled to 08C. Sodium borohydride was then
gradually added and the reaction mixture was stirred at room tempera-
ture for 3 h. The solvent was evaporated to dryness, the crude residue
was dissolved in water (4 mL), and Na2CO3 (2.3 mmol) was added. The
mixture was immediately cooled to 0 58C with vigorous stirring, and
benzyl chloroformate (2.3 mmol) was added dropwise. The reaction mix-
ture, which was allowed to warm to room temperature, was stirred over-
night and the aqueous solution was then extracted with CH2Cl2. The
combined organic layers were dried over Na2SO4, filtered, and evaporat-
ed under vacuum. The residue was purified by column chromatography
on silica using hexane/ethyl acetate (1:1) as eluent to give the title com-
pound as a white solid (92%). The desired compound was obtained as a
mixture of diastereoisomers [(Æ)-cis-3/(Æ)-trans-3 (1:3)]. The isomers
were separated by HPLC (Sample~200 mg, Kromasil 60-silica 7 mm-
250î20, 6 mLminÀ1, CH2Cl2/EtOAc 80:20).
3
3
À
tene rings (Figure 4). One conformer places the NH Z
group in an axial position and the phthalimide in an equato-
rial orientation (trans I), while the other has the inverse con-
formation (trans II). The observed coupling constants are
better described by a combination of the calculated coupling
1
constants obtained for each conformer. The H NMR spec-
trum in deuterated chloroform indicated that interconver-
sion between the different conformations was fast, and that
the solution consisted of 32% trans I and 68% trans II. In-
terestingly, the HF/3-21G energy difference between the
two conformers indicates that the distribution at room tem-
perature should be 26:74 trans I/trans II; this is in good
agreement with the experimental data if the number of ap-
proximations is taken into account. In addition, we also de-
termined the transition state (TS) structure for the equilibri-
um between trans I and trans II. This showed that the five-
membered ring was planar. The calculated energy barrier
Enzymatic acylation of (Æ)-trans-3-(N-benzyloxycarbonylamino)indan-1-
ol (Æ)-trans-3: Vinyl acetate (5.3 mmol) was added to a suspension of
(Æ)-trans-3 (0.53 mmol) and CAL-B (169 mg) in tBuOMe (4.5 mL) that
had previously been dried to avoid enzymatic hydrolysis, under an atmos-
phere of nitrogen. The mixture was then shaken at 308C and 250 rpm for
the time shown in Table 1. The enzyme was filtered off, washed with
CH2Cl2, and the combined organic layers were evaporated under reduced
pressure. The unreacted substrate and product were separated by column
chromatography on silica using ethyl acetate as eluent.
Chem. Eur. J. 2004, 10, 3006 3014
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3011

V. Gotor et al.
FULL PAPER
(1S,3S)-(À)-3-(N-benzyloxycarbonylamino)indan-1-ol (1S,3S)-3: The pre-
viously described procedure gave the title compound as a white solid
(98%) after 3.5 h: m.p. 147 1498C; conversion: 55%, ee>99%; HPLC
À
C19H19NO4 (325.4): C 70.14, H 5.89, N 4.30; found: C 70.32, H 5.73, N
4.52.
HPLC analysis: (À)-(1R,3S)-4 (0.07 mmol) was dissolved in MeOH
(0.25 mL) and was subsequently treated with 1n NaOH (0.07 mL). After
the mixture had been stirred for 20 min at room temperature, the solvent
was removed under reduced pressure. The residue was acidified with 1n
HCl and was then extracted with CH2Cl2. The combined organic fractions
were dried over Na2SO4 and filtered. Removal of the solvent under
vacuum gave (À)-(1R,3S)-3 in quantitative yield. Previously optimized
conditions were used for the HPLC analysis: (Æ)-cis-3, two peaks, tR =
12.6 and 16.7 min; (À)-(1R,3S)-3, one peak, tR =12.6 min.
General procedure for the Mitsunobu reaction: Phthalimide (0.12mmol),
PPh3 (0.12mmol), and DEAD (0.12mmol) were added to a solution of
either (1S,3S)-3, (1S,3R)-3, or (1R,3S)-3 (0.11 mmol) in dry THF (1.5 mL)
under an atmosphere of nitrogen. The reaction mixture was stirred at
room temperature for 24 h and was then evaporated under reduced pres-
sure. The desired compound, (1R,3S)-5, (1R,3R)-5, or (1S,3S)-5, was puri-
fied by column chromatography on silica using CH2Cl2/Et2O (95:5) as
eluent.
analysis (Chiralcel OD H, hexane/EtOH 93:7, 0.6 mLminÀ1
215 nm): (Æ)-trans-3, two peaks, tR =26.3 and 29.4 min; (À)-(1S,3S)-3,
, 308C,
one peak, tR =29.4 min; [a]2D0 =À52.0 (c=1.0 in MeOH); 1H NMR
(400 MHz, CD3OD): d=2.18 (AB portion of an ABXY system, JH2a,H2b
=
13.7, JH2a,H3 =5.2, and JH2a,H1 =5.1 Hz, 1H; H2a), 2.37 (AB portion of an
ABXY system, JH2b,H3 =6.3 and JH2b,H1 =2.2 Hz, 1H; H2b), 5.12 (s, 2H;
OCH2Ph), 5.24 (dd, JH1,H2a =5.1 and JH1,H2b =2.2 Hz, 1H; H1), 5.36 (dd,
J
H3,H2b =6.3 and JH3,H2a =5.2Hz, 1H; H3), 7.29 7.36 ppm (m, 9H; 2îPh);
13C NMR (75 MHz, CDCl3): d=44.2(CH 2), 54.4 (CH), 66.8 (CH2), 73.8
(CH), 124.5 (CH), 124.7 (CH), 128.1 (CH), 128.5 (CH),128.7 (CH), 129.2
(CH), 136.2(C), 143.0 (C), 144.2(C), 156.1 ppm (NCOO); IR (KBr): n˜ =
3511, 3339, 1671 cmÀ1; MS (60 eV, ESI): m/z (%): 284 (4) [M+H]+, 306
(100) [M+Na]+ ; elemental analysis calcd (%) for C17H17NO3 (283.3): C
72.07, H 6.05, N 4.94; found: C 71.92, H 6.25, N 4.89.
(1R,3R)-(+)-1-acetoxy-3-(N-benzyloxycarbonylamino)indan (1R,3R)-4:
The previously described procedure gave the title compound as a white
solid (97%) after 0.5 h: m.p. 117 1198C; conversion: 49%, ee>99%;
À
(+)-cis-1-(N-benzene-1,2-dicarbonyl)amino-3-(N-benzyloxycarbonyl)ami-
noindan,(1 R,3S)-5: The previously described procedure gave the title
HPLC analysis (Chiralcel OD H, hexane/iPrOH 93:7, 0.6 mLminÀ1
,
compound as a white solid (76%): m.p. 201 2038C; ee>99%; [a]D20
=
308C, 215 nm): (Æ)-trans-4, two peaks, tR =26.9 and 29.4 min; (+)-
(1R,3R)-4, one peak, tR =29.4 min; [a]2D0 =+127.3 (c=1.0 in MeOH);
1H NMR (400 MHz, CD3OD): d=2.03 (s, 3H; CH3), 2.23 (AB portion of
an ABXY system, JH2a,H2b =14.2, JH2a,H3 =7.4, and JH2a,H1 =6.3 Hz, 1H;
+106.7 (c=1.5 in CHCl3); 1H NMR (400 MHz, CDCl3): d=2.26 (AB
portion of an ABXY system, JH2a,H2b =14.6, JH2a,H1 =4.4, and JH2a,H3
4.4 Hz, 1H; H2a), 3.21 (AB portion of an ABXY system, JH2b,H1 =9.4 and
=
H2a), 2.55 (AB portion of an ABXY system, JH2b,H3 =7.2and JH2b,H1
1.7 Hz, 1H; H2b), 5.15 (s, 2H; OCH2Ph), 5.39 (dd, JH3,H2a =7.4 and
H3,H2b =7.2Hz, 1H; H3), 6.21 (dd, H1,H2a =6.3 and JH1,H2b =1.7 Hz, 1H;
=
J
J
J
H2b,H3 =9.4 Hz, 1H; H2b), 5.20 (s, 2H; OCH2Ph), 5.50 (ddd, JH3,NH =9.7,
H3,H2b =9.4, and JH3,H2a =4.4 Hz, 1H; H3), 5.80 (dd, JH1,H2b =9.4 and
H1,H2a =4.4 Hz, 1H; H1), 6.30 (d, JNH,H3 =9.7 Hz, 1H; NHCbz), 7.13 7.49
J
J
H1), 7.28 7.49 ppm (m, 9H; 2îPh); 13C NMR (300 MHz, CDCl3): d=
21.1 (CH3), 41.2(CH 2), 54.4 (CH), 66.8 (CH2), 75.6 (CH), 124.0 (CH),
126.1 (CH), 128.0 (CH), 128.1 (CH),128.4 (CH), 128.5 (CH), 129.7 (CH),
136.2(C), 140.1 (C), 144.4 (C), 156.2(NCOO), 170.9 ppm (OCO); IR
(KBr): n˜ =3311, 1735, 1684 cmÀ1; MS (90 eV, ESI): m/z (%): 348 (100)
[M+Na]+ ; elemental analysis calcd (%) for C19H19NO4 (325.4): C 70.14,
H 5.89, N 4.30; found: C 70.02, H 6.01, N 4.10.
(m, 9H; 2îPh), 7.74 7.85 ppm (m, 4H; Ph); 13C NMR (75 MHz, CDCl3):
d=37.5 (CH2), 51.5 (CH), 53.8 (CH), 66.4 (CH2), 123.2 (CH), 123.4
(CH), 124.8 (CH), 127.8 (CH), 128.2 (CH), 128.5 (CH), 128.8 (CH),
131.5 (CH), 134.0 (CH), 136.5 (C), 139.6 (C), 143.4 (C), 156.1 (NCOO),
167.7 ppm (N(CO)2); IR (KBr): n˜ =3335, 1712, 1682 cmÀ1; MS (60 eV,
ESI): m/z (%): 413 (100) [M+H]+, 435 (64) [M+Na]+ ; elemental analy-
sis calcd (%) for C25H20N2O4 (412.4): C 72.80, H 4.89, N 6.79; found: C
72.67, H 5.18, N 6.57.
Enzymatic acylation of (Æ)-cis-3-(N-benzyloxycarbonylamino)indan-1-ol
(Æ)-cis-3: The reaction was carried out as described above for the (Æ)-
trans-3 isomer. In this case, both the substrate and product were obtained
in enantiopure form after 60 h (Table 2, entry 3).
(+)-trans-1-(N-benzene-1,2-dicarbonyl)amino-3-(N-benzyloxycarbonyl)a-
minoindan (1R,3R)-5: The previously described procedure gave the title
compound as a white solid (68%): m.p. 202 2048C; ee>99%; [a]D20
=
+177.0 (c=0.9 in CHCl3); 1H NMR (400 MHz, CDCl3): d=2.41 (AB
portion of an ABXY system, JH2a,H2b =14.3, JH2a,H1 =9.1, and JH2a,H3
5.1 Hz, 1H; H2a), 2.93 (AB portion of an ABXY system, JH2b,H3 =8.1 and
H2b,H1 =4.6 Hz, 1H; H2b), 5.14 (d, JNH,H3 =8.3 Hz, 1H; NHCbz), 5.18 (s,
(1S,3R)-(+)-3-(N-benzyloxycarbonylamino)indan-1-ol (1S,3R)-3: The
previously described procedure gave the title compound as a white solid
(97%): m.p. 162 1648C; conversion: 50%, ee>99%; HPLC analysis
=
(Chiralcel OD H, hexane/EtOH 90:10, 0.6 mLminÀ1, 308C, 215 nm):
À
J
2H; OCH2Ph), 5.80 (ddd, JH3,NH =8.3, JH3,H2b =8.1, and JH3,H2a =5.1 Hz,
1H; H3), 6.00 (dd, JH1,H2a =9.1 and JH1,H2b =4.6 Hz, 1H; H1), 7.17 7.46
(m, 9H; 2îPh), 7.72 7.84 ppm (m, 4H; Ph); 13C NMR (75 MHz, CDCl3):
d=38.4 (CH2), 52.4 (CH), 55.7 (CH), 66.7 (CH2), 123.2 (CH), 123.9
(CH), 124.6 (CH), 128.0 (CH), 128.4 (CH), 128.7 (CH), 128.9 (CH),
131.8 (CH), 133.9 (CH), 136.4 (C), 140.1 (C), 143.6 (C), 156.0 (NCOO),
167.6 ppm (N(CO)2); IR (KBr): n˜ =3335, 1708, 1675 cmÀ1; MS (90 eV,
ESI): m/z (%): 413 (33) [M+H]+, 435 (100) [M+Na]+ ; elemental analy-
sis calcd (%) for C25H20N2O4 (412.4): C 72.80, H 4.89, N 6.79; found: C
72.97, H 4.96, N 6.60.
(Æ)-cis-3, two peaks, tR =12.6 and 16.7 min; (+)-(1S,3R)-3, one peak,
tR =16.7 min; [a]2D0 =+58.5 (c=1.0 in MeOH); 1H NMR (400 MHz,
CD3OD): d=1.73 (AB portion of an ABXY system,
H2a,H1 =7.1, and JH2a,H3 =6.2 Hz, 1H; H2a), 2.93 (AB portion of an
ABXY system, JH2b,H1 =7.0 and JH2b,H3 =6.6 Hz, 1H; H2b), 5.03 (dd,
JH2a,H2b =13.4,
J
J
J
H1,H2a =7.1 and
JH1,H2b =7.0 Hz, 1H; H1), 5.11 (dd, JH3,H2b =6.6 and
H3,H2a =6.2Hz, 1H; H3), 5.17 (s, 2H; OCH 2Ph), 7.27 7.43 ppm (m, 9H;
2îPh); 13C NMR (75 MHz, CD3OD): d=44.9 (CH2), 53.8 (CH), 67.6
(CH2), 73.2 (CH), 124.7 (CH), 125.0 (CH), 128.8 (CH), 129.0 (CH), 129.1
(CH), 129.3 (CH), 129.5 (CH), 138.4 (C), 143.8 (C), 145.9 (C), 158.8 ppm
(NCOO); IR (KBr): n˜ =3443, 3293, 1683 cmÀ1; MS (90 eV, ESI): m/z
(%): 306 (100) [M+Na]+ ; elemental analysis calcd (%) for C17H17NO3
(283.3): C 72.07, H 6.05, N 4.94; found: C 71.98, H 6.31, N 4.78.
(À)-trans-1-(N-benzene-1,2-dicarbonyl)amino-3-(N-benzyloxycarbonyl)-
aminoindan (1S,3S)-5. (1R,3S)-4 (0.26 mmol) was dissolved in MeOH
(1 mL) and was subsequently treated with 1n NaOH (0.27 mL). After
the mixture had been stirred for 20 min at room temperature, the solvent
was removed under reduced pressure. The residue was acidified with 1n
HCl and was then extracted with CH2Cl2. The combined organic fractions
were dried over Na2SO4 and filtered. The solvent was removed under
vacuum to give compound (1R,3S)-3 in quantitative yield. Mitsunobu re-
action of (1R,3S)-3 was carried out as previously described to give the
title compound as a white solid (64%): m.p. 201 2038C; ee>99%;
[a]2D0 =À170.8 (c=0.9 in CHCl3); elemental analysis calcd (%) for
C25H20N2O4 (412.4): C 72.80, H 4.89, N 6.79; found: C 72.68, H 5.04, N
6.95.
(1R,3S)-(À)-1-acetoxy-3-(N-benzyloxycarbonylamino)indan
(1R,3S)-4:
The previously described procedure gave the title compound as a white
solid (96%): m.p. 153 1558C; conversion: 50%, ee>99%; [a]2D0 =À9.3
(c=1.0 in MeOH); 1HNMR (400 MHz, CD3OD): d=1.88 (AB portion
of an ABXY system, JH2a,H2b =13.3, JH2a,H3 =8.3, and JH2a,H1 =7.2Hz, 1H;
H2a), 3.03 (AB portion of an ABXY system, JH2b,H3 =7.9 and JH2b,H1
7.8 Hz, 1H; H2b), 2.11 (s, 3H; CH3), 5.10 (dd, JH3,H2a =8.3 and JH3,H2b
=
=
7.9 Hz, 1H; H3), 5.16 (s, 2H; OCH2Ph), 6.08 (dd,
J
JH1,H2b =7.8 and
H1,H2a =7.2Hz, 1H; H1), 7.31 7.43 ppm (m, 9H; 2îPh); 13C NMR
(75 MHz, CDCl3): d=21.0 (CH3), 40.6 (CH2), 53.2(CH), 66.7 (CH ), 75.0
2
(CH), 124.4 (CH), 125.1 (CH), 128.0 (CH), 128.4 (CH), 128.6 (CH),
129.4 (CH), 136.2 (C), 140.3 (C), 143.0 (C), 155.8 (NCOO), 170.6 ppm
(OCO); IR (KBr): n˜ =3296, 1734, 1685 cmÀ1; MS (90 eV, ESI): m/z (%):
348 (100) [M+Na]+, 348 (4) [M+K]+ ; elemental analysis calcd (%) for
General procedure for hydrazinolysis of the phthalimide group: Diamine
(1R,3S)-5 or (1R,3R)-5 (0.1 mmol) was dissolved in 2m methanolic hydra-
zine (2.2 mL), and was then stirred at room temperature for 2 h. The sol-
vent was evaporated to dryness and the residue was washed with CHCl3
3012
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3006 3014

Highly Efficient Biocatalytic Resolution of cis- and trans-3-Aminoindan-1-ol
3006 3014
and filtered. The filtrate was concentrated under reduced pressure to
give either (1S,3R)-6 or (1R,3R)-6, respectively.
Acknowledgements
We especially thank Dr. Javier Gonzµlez for helpful discussions and assis-
tance with respect to the molecular modelling. We also express our ap-
preciation to Novo Nordisk Co. for the generous gift of the CA lipase. Fi-
nancial support for this work from the Spanish Ministerio de Ciencia y
TecnologÌa (Project PPQ-2001-2683) and from Principado de Asturias
(Project GE-EXP01-03) is gratefully acknowledged. M.L.-G. thanks the
Ministerio de EducaciÛn, Cultura y Deporte for a predoctoral fellowship.
(1S,3R)-(À)-cis-3-amino-1-(N-benzyloxycarbonyl)aminoindan (1S,3R)-6:
The previously described procedure gave the title compound as a white
solid (98%): m.p. 121 1238C; ee>99%; [a]2D0 =À45.9 (c=1.4 in CHCl3);
1H NMR (300 MHz, CDCl3): d=1.49 (m, 1H; H2a), 2.06 (brs, 2H; NH2),
2.97 (m, 1H; H2b), 4.28 (t, J=7.4 Hz, 1H; H1), 5.16 (m, 1H; H3), 5.18
(s, 2H; OCH2Ph), 5.41 (d, J=8.3 Hz, 1H; NHCbz), 7.29 7.41 ppm (m,
9H; 2îPh); 13C NMR (75 MHz, CDCl3): d=45.9 (CH2), 53.4 (CH), 54.0
(CH), 66.7 (CH2), 123.3 (CH), 123.7 (CH), 127.8 (CH), 128.0 (CH), 128.2
(CH), 128.4 (CH), 136.4 (C), 142.5 (C), 146.1 (C), 156.1 ppm (NCOO);
IR (KBr): n˜ =3301, 1684 cmÀ1; MS (90 eV, ESI): m/z (%): 283 (100)
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[M+H]+, 305 (51) [M+Na]+
; elemental analysis calcd (%) for
C17H18N2O2 (282.3): C 72.32, H 6.43, N 9.92; found: C 72.08, H 6.58, N
9.71.
(1R,3R)-(+)-trans-1-amino-3-(N-benzyloxycarbonyl)aminoindan
(1R,3R)-6: The previously described procedure gave the title compound
as an oil (74%): ee>99%; [a]2D0 =+14.1 (c=0.4 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.85 (brs, 2H; NH2), 2.18 2.38 (brm, 2H; CH2),
4.53 (t, J=6.2Hz, 1H; H1), 4.94 (brd, 1H; NHCbz), 5.16 (s, 2H;
OCH2Ph), 5.37 (brm, 1H; H3), 7.28 7.38 ppm (m, 9H; 2îPh); 13C NMR
(75 MHz, CDCl3): d=45.0 (CH2), 54.4 (CH), 54.8 (CH), 66.7 (CH2),
123.9 (CH), 124.7 (CH), 128.1 (CH), 128.5 (CH), 128.7 (CH), 136.4 (C),
142.1 (C), 146.9 (C), 156.0 ppm (NCOO); IR (KBr): n˜ =3310, 1701 cmÀ1
;
MS (90 eV, ESI): m/z (%): 283 (100) [M+H]+, 305 (63) [M+Na]+ ; ele-
mental analysis calcd (%) for C17H18N2O2 (282.3): C 72.32, H 6.43, N
9.92; found: C 72.48, H 6.38, N 9.87.
General procedure for the cleavage of N-benzyloxycarbonylamides: To
compound (1R,3S)-5 or (1R,3R)-5 (0.1 mmol) was added a 10% HCO2H
solution (2.2 mL in MeOH, purged with nitrogen prior to use) followed
by Pd-black (14 mg). The mixture was vigorously stirred for 2h and was
then filtered through Celite and washed with MeOH. The solvent was re-
moved to give the desired product (1R,3S)-7 or (1R,3R)-7, respectively.
(1R,3S)-(+)-cis-3-amino-1-phthalimidoindan as its formic acid salt
(1R,3S)-7: The previously described procedure gave the title compound
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=
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43.
+145.4 (c=1.0 in MeOH); 1H NMR (300 MHz, D2O): d=2.36 (m, 1H;
H2a), 3.04 (m, 1H; H2b), 4.83 (m, 1H; H3), 5.72 (m, 1H; H1), 7.12 7.70
(m, 8H; 2îPh), 8.32ppm (brs, 1H; HCOO À); 13C NMR (75 MHz,
CD3OD): d=35.7 (CH2), 52.8 (CH), 54.5 (CH), 124.5 (CH), 125.3 (CH),
125.9 (CH), 130.4 (CH), 131.4 (CH), 133.0 (CH), 135.8 (CH), 139.7 (C),
142.4 (C), 169.5 ppm (N(CO)2); IR (KBr): n˜ =3446, 2966, 1716 cmÀ1; MS
(60 eV, ESI): m/z (%): 262.1 (100) [(MÀHCOOH)ÀNH2]+, 279.1 (40)
[(MÀHCOOH)+H]+, 301.1 (11) [(MÀHCOOH)+Na]+ ; elemental anal-
ysis calcd (%) for C18H16N2O4 (324.3): C 66.66, H 4.97, N 8.64; found: C
66.45, H 5.07, N 8.74.
(1R,3R)-(+)-trans-3-amino-1-phthalimidoindan as its formic acid salt
(1R,3R)-7: The previously described procedure gave the title compound
in quantitative yield as a white solid: m.p. 177 1798C; ee>99%; [a]D20
=
+167.7 (c=1.1 in MeOH); 1H NMR (300 MHz, CD3OD): d=2.61 (brm,
1H; H2a), 2.99 (brm, 1H; H2b), 5.26 (brm, 1H; H3), 6.11 (m, 1H; H1),
7.26 7.87 (m, 8H; 2îPh), 8.56 ppm (brs, 1H; HCOOÀ); 13C NMR
(75 MHz, CD3OD): d=36.3 (CH2), 53.6 (CH), 56.1 (CH), 124.2 (CH),
125.5 (CH), 125.8 (CH), 130.4 (CH), 131.3 (CH), 133.1 (CH), 135.6
(CH), 140.9 (C), 142.8 (C), 169.1 ppm (N(CO)2); IR (KBr): n˜ =3446,
2968, 1716 cmÀ1
;
MS (60 eV, ESI): m/z (%): 262.1 (100)
[(MÀHCOOH)ÀNH2]+, 279.1 (55) [(MÀHCOOH)+H]+, 301.1 (8)
[(MÀHCOOH)+Na]+
; elemental analysis calcd (%) for C18H16N2O4
(324.3): C 66.66, H 4.97, N 8.64; found: C 66.78, H 5.13, N 8.59.
(1R,3R)-(+)-trans-1,3-indandiamine as its formic acid salt (1R,3R)-8:
The previously described procedure was applied to (1R,3R)-6 to give the
title compound (89%): ee>99%; [a]2D0 =+20.1 (c=0.37 in MeOH);
1H NMR (300 MHz, CD3OD): d=2.19 (t, J=6.0 Hz, 2H; H2a and H2b),
4.56 (t, J=6.0 Hz, 2H; H1 and H3), 7.18 7.47 ppm (m, 4H; Ph);
13C NMR (75 MHz, CD3OD): d=46.6 (CH2), 56.5 (CH), 126.3 (CH),
130.3 (CH), 147.6 ppm (C); MS (30 eV, ESI): m/z (%): 132.1 (60)
[(MÀ2HCOOH)ÀNH2]+, 149.1 (100) [(MÀ2HCOOH)+H]+ ; elemental
analysis calcd (%) for C11H16N2O4 (240.3): C 54.99, H 6.71, N 11.66;
found: C 54.78, H 6.93, N 11.48.
[13] For some recent revisions see: a) P. J. Walsh, Acc. Chem. Res. 2003,
36, 739 749; b) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763
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1070.
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[17] Both percent conversion and enantioselectivity were determined
from ee values of the substrate and product as in: C.-S. Chen, Y. Fu-
Received: December 29, 2003
Published online: April 28, 2004
3014
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 3006 3014