Synthesis of optically active heterocyclic compounds by preparation of 1,3-dinitro derivatives and enzymatic enantioselective desymmetrization of prochiral diamines

Article abstract of DOI:10.1002/ejoc.200900875

A general approach for the highly efficient chemical preparation of novel optically active 2-substituted propane-1,3-diamines is described. Diamines have been obtained from the corresponding commercially available aldehydes in a straightforward, two-step synthesis via the corresponding 1,3-dinitro compounds, which were hydrogenated under mild reaction conditions by using platinum dioxide as the catalyst. Subsequent enzymatic enantioselective desymmetrization mediated by Pseudomonas cepacia lipase allowed the recovery of a family of monocarbamates in good to high, enantiomeric excesses (70-90% ee).

Full text of DOI:10.1002/ejoc.200900875

FULL PAPER
DOI: 10.1002/ejoc.200900875
Synthesis of Optically Active Heterocyclic Compounds by Preparation of
1,3-Dinitro Derivatives and Enzymatic Enantioselective Desymmetrization of
Prochiral Diamines
Nicolás Ríos-Lombardía,[a] Eduardo Busto,[a] Vicente Gotor-Fernández,*[a] and
Vicente Gotor*[a]
Keywords: Asymmetric catalysis / Hydrogenation / Desymmetrization / Amines / Heterocycles
A general approach for the highly efficient chemical prepara-
tion of novel optically active 2-substituted propane-1,3-di-
amines is described. Diamines have been obtained from the
action conditions by using platinum dioxide as the catalyst.
Subsequent enzymatic enantioselective desymmetrization
mediated by Pseudomonas cepacia lipase allowed the recov-
ery of a family of monocarbamates in good to high enantio-
meric excesses (70–90% ee).
corresponding commercially available aldehydes in
a
straightforward two-step synthesis via the corresponding 1,3-
dinitro compounds, which were hydrogenated under mild re-
pose.[13] Recently, we described a novel chemoenzymatic
strategy for the production of optically active amines that
involves the synthesis of 2-substituted propane-1,3-di-
amines for use in subsequent enantioselective enzymatic de-
symmetrization reactions, the corresponding amino carb-
amates being obtained with good to excellent enantiomeric
excesses depending on the C-2 substituent present in the
1,3-diamine core.[14] This methodology allows the prepara-
tion of a wide range of optically active compounds through
a multi-step pathway by using carboxylic acids, acyl chlo-
rides, malonates or diols as commercially available starting
materials. On the other hand, carbamates are a family of
organic compounds with multiple applications in the textile
industry, agriculture and especially in the design of new en-
zyme inhibitors and drugs, making attractive the develop-
ment of novel compounds with this structural motif,[15]
which is usually accessible only by the employment of
harmful reagents such as phosgene or its derivatives.[16]
Introduction
The search for chiral materials has attracted considerable
attention in recent years driven by the need of the industrial
sector, in particular, to synthesize single enantiomeric com-
pounds.[1] For instance, optically active amines are ubiqui-
tous in a wide range of biologically active compounds, and
they can also be used in a number of applications for the
preparation of agrochemicals and pharmaceuticals.[2] These
compounds have been extensively studied as organocata-
lysts and ligands in asymmetric synthesis and have shown
strong potential in this field.[3] However, their main limita-
tions reside in their difficult preparation because of their
poor solubility in organic solvents, notorious instability
towards moisture and cumbersome isolation protocols.
Thus, the most popular asymmetric chemical syntheses are
based on the reductive amination of ketones,[4] the catalytic
hydrogenation of imines[5] or enamines,[6] the hydro-
silylation of imines or oximes[7] and the alkylation of im-
ines[8] or amino hydroxylation.[9]
In this synthetic context, biotransformations have pre-
sented themselves as practical tools for the production of
chiral amines, with lipases,[10] amino oxidases[11] or trans-
aminases[12] being the most efficient enzymes for this pur-
Results and Discussion
In the course of our ongoing research we attempted the
synthesis of 2-(4-chlorophenyl)propane-1,3-diamine (7a)
from the acyl chloride precursor 1 (Scheme 1). Thus, 1 was
subjected to an esterification reaction with ethanol at room
temperature leading to the corresponding ester 2 in 91%
isolated yield. This ester was transformed into 3 by using
lithium bis(trimethylsilyl)amide [(Me3Si)2NLi] and ethyl cy-
anoformate (EtOCOCN) prior to the reduction of the mal-
onate with lithium aluminium hydride (LiAlH4) to give
diol 4, which at this stage was protected with methanesul-
fonyl chloride (MsCl) and pyridine in nearly quantitative
[a] Departamento de Química Orgánica e Inorgánica, Instituto
Universitario de Biotecnología de Asturias, Universidad de
Oviedo,
33006 Oviedo, Spain
Fax: +34-985-103448
E-mail: vgs@fq.uniovi.es
vicgotfer@fq.uniovi.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900875.
484
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Optically Active Heterocyclic Compounds
Scheme 1. Initial attempts at the synthesis of diamine 7a with dechlorination occurring in the hydrogenolysis step.
yield. Nucleophilic substitution of the resulting mesylated subjected to a hydrogenation reaction at room temperature
diol 5 with sodium azide at 55 °C in dry DMF allowed the catalysed by platinum dioxide in MeOH. As occurred with
recovery of diazide 6, which was immediately hydrogenated basic alumina, the use of a heterogeneous catalyst facili-
in the presence of Pd/C in MeOH: unfortunately, we ob- tated the recovery of the diamines, avoiding extraction or
tained a prochiral dehalogenated diamine as the unique fi- chromatographic procedures that are incompatible with the
nal product instead of the desired chlorinated diamine 7a. physical properties of the diamine structures. Other advan-
For this reason we decided to search for a more general tages are that unsophisticated systems can be used and that
synthetic route towards prochiral diamines, and we present the transformations are performed under safe and mild re-
in this paper the latest results of our research into the prep- action conditions at room temperature.
aration of novel propane-1,3-diamine derivatives with high
optical purity by chemoenzymatic processes.
The versatility of the “nitro route” has been compared
with the synthetic approach that involves the use of com-
We thus turned our attention to the potential of 1,3-dini- mercially available acyl chlorides, carboxylic acids or
tro compounds, building blocks of significant interest as malonates as starting materials.[14] This “old route” requires
they are ideal precursors for the production of 1,3-difunc- six steps depending on the starting material. For this
tionalized molecules.[17] During recent years the efficient reason, 2-(4-methoxyphenyl)propane-1,3-diamine, 2-(1-
preparation of 1,3-dinitro compounds has been reported by naphthyl)propane-1,3-diamine, 2-(2-naphthyl)propane-1,3-
using inexpensive aldehydes as the starting materials in the diamine and 2-(4-biphenyl-4-yl)propane-1,3-diamine were
presence of nitromethane (MeNO2) and basic alumina synthesized by using both methodologies, and their isolated
(Al2O3).[18] This simple methodology presents the ad- yields are compared in Table 1 to illustrate the efficacy of
ditional advantage that non-aqueous workup is possible, the new synthetic strategy. As can be seen, fewer reaction
because the heterogeneous catalyst can be easily removed steps are necessary for the preparation of the desired di-
by filtration. Another interesting issue from a synthetic amines when the 1,3-dinitro compounds serve as intermedi-
point of view is that many different functionalities can be ates, and higher yields were obtained (21–37% compared
preserved under these mild reaction conditions.
with 49–57%).
Thus, we explored this approach in the synthesis of novel
The enzymatic enantioselective desymmetrization
dinitro derivatives, which can be used as precursors of the (EED)[19] reactions of these novel diamines 7a–i were inves-
interesting and previously unreported heterocyclic and non- tigated under an inert gas by using diallyl carbonate as an
heterocyclic 1,3-diamines 7a–i bearing a phenyl, pyridine, alkoxycarbonylating agent and Pseudomonas cepacia lipase
indole, thiophene, furan or pyrrole nucleus (Scheme 2). (also called Burkholderia cepacia lipase, PCL) as the biocat-
Thus, aldehydes 8a–i were heated at 100 °C in the presence alyst (Scheme 2), a resolving agent and enzyme that have
of basic alumina and nitromethane as solvent, recovering previously shown the best results in this type of stereoselec-
the dinitro compounds 9a–i with an excellent level of purity tive process with other 2-substituted propane-1,3-di-
and in moderate to good yields (53–72%). Then 9a–i were amines.[14]
Scheme 2. Synthesis of diamines 7a–i from aldehydes 8a–i and their enantioselective enzymatic desymmetrization. R = 4-ClC6H4 (a),
pyridin-3-yl (b), 1H-indol-2-yl (c), 1H-indol-3-yl (d), thien-2-yl (e), thien-3-yl (f), furan-2-yl (g), furan-3-yl (h), 1H-pyrrol-2-yl (i).
Eur. J. Org. Chem. 2010, 484–493
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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485

N. Ríos-Lombardía, E. Busto, V. Gotor-Fernández, V. Gotor
FULL PAPER
Table 1. Synthesis of propane-1,3-diamines by the “nitro” and ford the corresponding racemic amido carbamates 11a–i in
“old” routes.
very high yields (91–95%). At this point appropriate chiral
R
Starting material[a] Old route [%][b] Nitro route [%][c]
HPLC methods were developed and optimized, finding reli-
able conditions for the measurement of the enantiomeric
excesses of the chiral monocarbamates obtained in the en-
zymatic desymmetrization processes (see the chromato-
grams in the Supporting Information). Thus, chemical acyl-
ation of the chiral amino carbamates 10a–i obtained after
lipase-catalysed desymmetrization was carried out by using
acetyl or benzoyl chloride in the presence of Et3N, which
allowed the recovery of the amido carbamates 11a–i after
flash chromatography (91–96%).
4-MeOC6H4
2-Naphthyl
1-Naphthyl
4-PhC6H4
acyl chloride
carboxylic acid
carboxylic acid
carboxylic acid
37
26
32
21
56
57
49
52
[a] Starting material used in the “old route”. [b] Isolated yield of
the diamine after six steps starting from the corresponding acyl
chloride or carboxylic acid.[14] [c] Isolated yield of the diamine after
two steps starting from the corresponding aldehyde.
Although enantioselective desymmetrizations can theo-
retically reach yields of 100%, optically active amino carb-
amates were obtained in moderate isolated yields in all
cases after the hydrogenation of the dinitro compounds and
the enzymatic desymmetrization of the diamines (45–58%).
To account for this we reasoned that the biotransformations
did not proceed to complete conversion, and also in some
cases a small amount of the diamine could be lost in the
purification process.
A detailed study of the experimental data revealed lower
conversions when using benzo-fused rings (Table 2, En-
tries 3 and 4) or for compounds with a heteroatom located
at the C-2 position of the ring (Entries 5 and 7). At the
same time good to very high enantiomeric excesses were
attained (70–91%), with lower values obtained for furan de-
rivatives (Entries 7 and 8) and higher values for 4-chloro-
phenyl, pyridine and indole substitutions (Entries 1–4).
Scheme 3. Preparation of the optically active and racemic amido
carbamates 12a–i for enantiomeric excess measurements. R = 4-
ClC6H4 (a), pyridin-3-yl (b), 1H-indol-2-yl (c), 1H-indol-3-yl (d),
thien-2-yl (e), thien-3-yl (f), furan-2-yl (g), furan-3-yl (h), 1H-pyr-
rol-2-yl (i).
Table 2. Lipase-mediated desymmetrization of diamines 7a–i by
using PCL and diallyl carbonate at 30 °C and 250 rpm.
Entry
Product
R
Yield [%][a]
ee [%][b]
To assign the absolute configurations of the amido carb-
amates obtained by PCL-mediated enantioselective de-
symmetrization, different attempts were made to obtain
suitable crystals for X-ray diffraction analysis, but all of
them were unsuccessful. Afterwards, 1H NMR analysis was
performed by treating a selection of monocarbamates
10b,d,h in racemic and optically active form with (+)-
(S)-α-methoxy-α-(trifluoromethyl)-α-phenylacetyl chloride
(Scheme 4).[20]
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
10f
10g
10h
10i
4-ClC6H4
pyridin-3-yl
1H-indol-2-yl
1H-indol-3-yl
thien-2-yl
thien-3-yl
furan-2-yl
52
58
47
45
47
55
48
54
53
90
89
88
87
78
79
71
70
76
furan-3-yl
1H-pyrrol-2-yl
[a] Isolated yield of the monocarbamate after purification by flash
chromatography. Two-step process: hydrogenation of the 1,3-dini-
tro compound and enzymatic desymmetrization of the diamine. [b]
Determined by HPLC after suitable derivatization.
Racemic compounds 11a–i were required for the mea-
surement of the enantiomeric excesses by chiral HPLC
analysis. They were prepared by
a
non-enzymatic
monoacylation with acetic or benzoic anhydride followed
by an alkoxycarbonylation with allyl chloroformate in the
presence of pyridine (Scheme 3). In the monoacylation pro-
cess, small portions of the corresponding anhydride were
added at 10 min intervals to keep a low concentration of
the acylating agent to minimize the amount of diacylated
product. Nevertheless, both mono- and diamides were ob-
served and separated by flash chromatography, obtaining
Scheme 4. Preparation of racemic and optically active (R,R)-
Mosher derivatives.
As previously occurred with other 2-arylpropane-1,3-di-
racemic monoamides 12a–i in low yields but with enough amines, for example, the 4-methylphenyl or 4-meth-
to carry out the chemical alkoxycarbonylation to finally af- oxyphenyl derivatives (see the Supporting Information),[14a]
486
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Eur. J. Org. Chem. 2010, 484–493

Optically Active Heterocyclic Compounds
at reflux for 5–24 h. Then the reaction mixture was cooled to room
temperature and filtered and the solid washed with EtOAc
(5ϫ10 mL). The solvent of the combined organic phases was evap-
orated under reduced pressure, and the resulting reaction crude was
purified by flash chromatography on silica gel (mixtures of EtOAc/
hexane), yielding the corresponding dinitro compounds 9a–i (53–
73%).
the signals of the heterocyclic hydrogen atoms of the (R,R)
isomer appear at lower fields than those of the (R,S) isomer.
Thus, the (R) configuration was assigned to amino carb-
amates obtained through the lipase-catalysed desymmetri-
zation processes.
1-Chloro-4-[2-nitro-1-(nitromethyl)ethyl]benzene (9a): Yield: 57%
(1.30 g). Rf (30% EtOAc/hexane) = 0.35. M.p. 79–81 °C. IR (KBr):
Conclusions
ν = 3059, 2919, 1564, 1551, 1494, 1426, 1379, 1352, 1267, 1230,
˜
We have reported a practical and straightforward synthe-
sis of novel 2-substituted propane-1,3-diamines bearing
phenyl, furan, indole, pyrrole, pyridine or thiophene moie-
ties by the preparation and subsequent hydrogenation of
1,3-dinitro compounds using two heterogeneous catalysts,
namely basic alumina and platinum dioxide, which have al-
1112, 1096 cm–1. 1H NMR (CDCl3, 300.13 MHz): δ = 4.30 (m, 1 H,
1-H), 4.68–4.81 (m, 4 H, 2-H), 7.16 (AЈBЈ system, 3JAЈBЈ = 8.3 Hz, 2
H, 4-H), 7.35 (AЈBЈ system, JAЈBЈ = 8.3 Hz, 2 H, 5-H) ppm. 13C
NMR (CDCl3, 75.5 MHz): δ = 41.0 (C-1), 76.4 (2 C-2), 128.7 (2
C-4), 129.7 (2 C-5), 132.5 (C-6), 135.1 (C-3) ppm. MS (APCI–):
m/z (%) = 243 (100) [M – H]–, 198 (25) [M – NO2]–. HRMS (ESI–):
lowed the recovery of prochiral diamines through very sim- calcd. for C9H9ClN2O4 [M – H]– 243.0173; found 243.0152.
ple and clean processes under mild reaction conditions. A
significant advantage of this approach is the recovery of
3-[2-Nitro-1-(nitromethyl)ethyl]pyridine (9b): Yield: 60% (1.18 g). Rf
(70% EtOAc/hexane) = 0.33. M.p. 97–99 °C. IR (KBr): ν = 3018,
˜
some known propane-1,3-diamines in better isolated yields 2917, 1559, 1482, 1425, 1379, 1305, 1209, 1103 cm–1. 1H NMR
(MeOD, 300.13 MHz): δ = 4.49–4.71 (m, 1 H, 2-H), 5.04–5.25 (m,
and after fewer reaction steps compared with previously re-
ported methods. We have also described the enantioselective
enzymatic desymmetrizations of this novel class of 2-substi-
tuted propane-1,3-diamines mediated by Pseudomonas ce-
pacia lipase, obtaining the monoamino carbamates in mod-
erate yields and with good to high enantiomeric excesses
through an environmentally friendly approach.
3
3
4 H, 1-H), 7.63 (dd, JHH = 7.9, JHH = 4.8 Hz, 1 H, 5-H), 8.07
3
(d, JHH = 7.9 Hz, 1 H, 4-H), 8.69–8.76 (m, 2 H, 6-H + 7-H) ppm.
13C NMR (MeOD, 75.5 MHz): δ = 41.1 (C-2), 77.4 (2 C-1), 125.9
(C-5), 134.2 (C-3), 137.8 (C-4), 150.5 (C-6 + C-7) ppm. MS
(APCI+): m/z (%) = 212 (100) [M + H]+, 213 (10) [M + 2 H]+.
HRMS (ESI–): calcd. for C8H9N3O4 [M – H]– 210.0515; found
210.0532.
2-[2-Nitro-1-(nitromethyl)ethyl]-1H-indole (9c): Yield: 72% (1.68 g).
R (40% EtOAc/hexane) = 0.33. IR (NaCl): ν = 3405, 3059, 2923,
˜
f
1556, 1455, 1428, 1377, 1342, 1313, 1290, 1266, 797, 737 cm–1. H
1
Experimental Section
NMR (CDCl3, 300.13 MHz): δ = 4.26 (m, 1 H, 9-H), 4.63–4.51 (m,
General Methods: Pseudomonas cepacia lipase (PCL) immobilized
on ceramics (PSL-C I, 1638 U/g), available from Sigma-Aldrich,
was used for the desymmetrization procedure. Aluminium oxide
(Al2O3; activated, basic, 50–200 micron, Brockmann activity I) was
purchased from Acros Organics. All other reagents were purchased
from different commercial sources and used without further purifi-
cation. Solvents were distilled from an appropriate desiccant under
nitrogen. Flash chromatography was performed on silica gel 60
(230–240 mesh). The full characterization of the new compounds
is available in the Supporting Information. Melting points were
measured on samples in open capillary tubes and are uncorrected.
4 H, 10-H), 6.28 (s, 1 H, 2-H), 7.12 (td, 3JHH = 7.7, 4JHH = 1.0 Hz,
4
1 H, 6-H), 7.19 (td, 3JHH = 8.0, JHH = 1.3 Hz, 1 H, 5-H), 7.29 (d,
3
3JHH = 8.0 Hz, 1 H, 4-H), 7.54 (d, JHH = 7.7 Hz, 1 H, 7-H), 8.40
(br. s, 1 H, NH) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 35.2 (C-
9), 75.4 (2 C-10), 100.7 (C-2), 111.1 (C-7), 120.3 (C-4), 120.5 (C-
6), 122.7 (C-5), 127.5 (C-3), 131.5 (C-1), 135.9 (C-8) ppm. MS
(APCI–): m/z (%) = 248 (100) [M – H]–. HRMS (ESI–): calcd. for
C11H11N3O4 [M – H]– 248.0672; found 248.0659.
3-[2-Nitro-1-(nitromethyl)ethyl]-1H-indole (9d): Yield: 55% (1.28 g).
R (20% EtOAc/hexane) = 0.11. M.p. 95–97 °C. IR (NaCl): ν =
˜
f
1
3427, 3132, 3045, 2915, 1551, 1456, 1420, 1378, 1337, 1230,
1104 cm–1. 1H NMR ([D6]DMSO, 300.13 MHz): δ = 4.70 (m, 1 H,
9-H), 5.09–5.26 (m, 4 H, 10-H), 7.15–7.26 (m, 2 H, 5-H + 6-H),
IR spectra were recorded by using NaCl plates or KBr pellets. H,
13C NMR and DEPT spectra were obtained by using a variety of
spectrometers (1H: 300.13 or 400.13 MHz; 13C: 75.5 or
100.6 MHz). The chemical shifts are given in δ values and the cou-
pling constants (J) in Hertz (Hz). The atomic numbering used for
NMR assignment is presented in the Supporting Information.
ESI+, APCI+ or APCI– experiments were carried out to record
mass spectra (MS) by using a liquid chromatograph mass detector.
High-resolution mass spectra (HRMS) were recorded in ESI+ or
ESI– mode. Optical rotations were measured with a Perkin–Elmer
241 polarimeter. High-performance liquid chromatography
(HPLC) analyses were carried out with a liquid chromatograph UV
detector at 210 nm by using a CHIRALCEL OD, CHIRALPAK AS,
CHIRALPAK IA or a CHIRALPAK IC column (25 cmϫ4.6 mm
i.d.); conditions and retention times are given in the Supporting
Information.
3
7.50–7.51 (m, 2 H, 1-H + 4-H), 7.80 (d, JHH = 7.4 Hz, 1 H, 7-H),
11.26 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 75.5 MHz): δ =
37.9 (C-9), 81.2 (2 C-10), 112.6 (C-2), 115.9 (C-7), 122.4 (C-4),
123.2 (C-6), 125.7 (C-5), 127.9 (C-1), 129.8 (C-3), 140.2 (C-8) ppm.
MS (APCI–): m/z (%) = 248 (100) [M – H]–. HRMS (ESI–): calcd.
for C11H11N3O4 [M – H]+ 248.0672; found 248.0690.
2-[2-Nitro-1-(nitromethyl)ethyl]thiophene (9e): Yield: 56% (1.13 g).
R (20% EtOAc/hexane) = 0.18. M.p. 39–41 °C. IR (NaCl): ν =
˜
f
3113, 3023, 2922, 1560, 1429, 1378, 1347, 1252, 1203, 1139 cm–1.
1H NMR (CDCl3, 300.13 MHz): δ = 4.60 (m, 1 H, 5-H), 4.70–4.84
(m, 4 H, 6-H), 6.96 (s, 1 H, 2-H), 6.97 (s, 1 H, 3-H), 7.27 (t, JHH
3
= 3.3 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 36.9
(C-5), 76.8 (2 C-6), 125.9 (C-4), 126.5 (C-2), 127.3 (C-3), 135.9 (C-
1) ppm. MS (APCI–): m/z (%) = 215 (100) [M – H]–. HRMS (ESI–):
calcd. for C7H8N2O4S [M – H]– 215.0127; found 215.0112.
General Procedure for the Synthesis of the 1,3-Dinitro Compounds
9a–i: Basic Al2O3 (4.66 g, 45.7 mmol) was added to a solution of
the corresponding aldehyde 8a–i (9.34 mmol) in nitromethane
(9.31 mL, 172.8 mmol) under nitrogen, and the mixture was heated
3-[2-Nitro-1-(nitromethyl)ethyl]thiophene (9f): Yield: 55% (1.11 g).
R (30% EtOAc/hexane) = 0.35. M.p. 81–83 °C. IR (NaCl): ν =
˜
f
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N. Ríos-Lombardía, E. Busto, V. Gotor-Fernández, V. Gotor
3056, 1561, 1421, 1376, 1337, 1266, 1190, 1088 cm–1. 1H NMR + 4 10-H), 6.39 (s, 1 H, 2-H), 7.10–7.22 (m, 2 H, 5-H + 6-H), 7.47
FULL PAPER
3
3
(CDCl3, 300.13 MHz): δ = 4.45 (m, 1 H, 5-H), 4.69–4.82 (m, 4 H,
(d, JHH = 8.0 Hz, 1 H, 4-H), 7.62 (d, JHH = 7.7 Hz, 1 H, 7-H)
6-H), 6.97 (dd, JHH = 5.1, JHH = 1.4 Hz, 1 H, 3-H), 7.19–7.20 ppm. 13C NMR (MeOD, 75.5 MHz): δ = 44.9 (2 C-10), 47.0 (C-9),
3
4
3
4
(m, 1 H, 1-H), 7.38 (dd, JHH = 5.1, JHH = 2.6 Hz, 1 H, 4-H)
ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 37.2 (C-5), 76.5 (2 C-6),
123.5 (C-1), 125.6 (C-4), 127.7 (C-3), 134.3 (C-2) ppm. MS
(APCI–): m/z (%) = 215 (100) [M – H]–. HRMS (ESI–): calcd. for
C7H8N2O4S [M – H]– 215.0127; found 215.0134.
101.2 (C-2), 112.1 (C-7), 120.5 (C-4), 120.9 (C-6), 122.3 (C-5), 130.1
(C-3), 138.4 (C-1), 140.8 (C-8) ppm.
2-(1H-Indol-3-yl)propane-1,3-diamine (7d): Rf (3% NH3/MeOH) =
0.06. H NMR (MeOD, 400.13 MHz): δ = 3.03 (d, JHH = 6.6 Hz,
4 H, 10-H), 3.10–3.17 (m, 1 H, 9-H), 7.15 (t, JHH = 8.2 Hz, 1 H,
1
3
3
3
2-[2-Nitro-1-(nitromethyl)ethyl]furan (9g): Yield: 53% (988 mg). Rf
6-H), 7.22–7.26 (m, 2 H, 1-H + 5-H), 7.53 (d, JHH = 8.2 Hz, 1 H,
4-H), 7.71 (d, JHH = 8.1 Hz, 1 H, 7-H) ppm. 13C NMR (MeOD,
3
(30% EtOAc/hexane) = 0.30. IR (NaCl): ν = 3056, 1562, 1508,
˜
1422, 1375, 1266, 1149, 1018 cm–1. 1H NMR (CDCl3,
100.6 MHz): δ = 43.2 (C-9), 43.9 (2 C-10), 111.4 (C-7), 113.5 (C-
2), 118.4 (C-4), 118.6 (C-6), 121.4 (C-5), 122.6 (C-1), 126.8 (C-3),
137.3 (C-8) ppm.
3
300.13 MHz): δ = 4.42 (m, 1 H, 5-H), 4.75 (d, JHH = 6.6 Hz, 4 H,
6-H), 6.27 (d, 3JHH = 3.4 Hz, 1 H, 2-H), 6.33 (dd, 3JHH = 3.1, 3JHH
3
4
= 1.7 Hz, 1 H, 3-H), 7.38 (dd, JHH = 2.0, JHH = 1.1 Hz, 1 H, 4-
H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 35.6 (C-5), 74.4 (2 C-
6), 108.6 (C-2), 110.6 (C-3), 143.2 (C-4), 147.2 (C-1) ppm. MS
(APCI–): m/z (%) = 199 (100) [M – H]–. HRMS (ESI–): calcd. for
C7H8N2O5 [M – H]– 199.0355; found 199.0362.
2-(Thien-2-yl)propane-1,3-diamine (7e): Rf (3% NH3/MeOH) =
0.18. 1H NMR (MeOD, 400.13 MHz): δ = 2.93–2.98 (m, 2 H, 6-
H), 3.08–3.13 (m, 2 H, 6-H), 3.20–3.30 (m, 1 H, 5-H), 7.11 (d, 3JHH
3
= 2.0 Hz, 1 H, 2-H), 7.16 (d, JHH = 3.6 Hz, 1 H, 3-H), 7.46 (d,
3JHH = 3.6 Hz, 1 H, 4-H) ppm. 13C NMR (MeOD, 100.6 MHz): δ
= 47.0 (2 C-6), 48.5 (C-5), 125.5 (C-4), 126.8 (C-2), 128.4 (C-3),
145.8 (C-1) ppm.
3-[2-Nitro-1-(nitromethyl)ethyl]furan (9h): Yield: 55% (1.02 g). Rf
(30% EtOAc/hexane) = 0.30. M.p. 63–65 °C. IR (NaCl): ν = 3137,
˜
3036, 1549, 1506, 1430, 1383, 1338, 1268, 1201, 1160, 1092,
1
1032 cm–1. H NMR (CDCl3, 400.13 MHz): δ = 4.25 (m, 1 H, 5-
2-(Thien-3-yl)propane-1,3-diamine (7f): Rf (3% NH3/MeOH) =
0.12. H NMR (MeOD, 400.13 MHz): δ = 2.91–3.07 (m, 5 H, 5-H
1
H), 4.65–4.77 (m, 4 H, 6-H), 6.30 (s, 1 H, 3-H), 7.38 (s, 1 H, 1-H),
7.41 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 33.1
(C-5), 76.2 (2 C-6), 108.3 (C-3), 118.7 (C-2), 140.3 (C-1), 144.3 (C-
4) ppm. MS (APCI–): m/z (%) = 199 (100) [M – H]–. HRMS (ESI–):
calcd. for C7H8N2O5 [M – H]– 199.0355; found 199.0327.
3
+ 4 6-H), 7.18 (d, JHH = 3.0 Hz, 1 H, 3-H), 7.34 (s, 1 H, 1-H),
7.58 (s, 1 H, 4-H) ppm. 13C NMR (MeOD, 100.6 MHz): δ = 45.9
(2 C-6), 48.5 (C-5), 123.2 (C-1), 127.8 (C-4), 127.9 (C-3), 143.6 (C-
2) ppm.
2-[2-Nitro-1-(nitromethyl)ethyl]-1H-pyrrole (9i): Yield: 60%
(1.12 g). Rf (30% EtOAc/hexane) = 0.25. M.p. 128–130 °C. IR
2-(2-Furyl)propane-1,3-diamine (7g): Rf (3% NH3/MeOH) = 0.22.
1H NMR (MeOD, 300.13 MHz): δ = 3.03 (br. s, 5 H, 5-H + 4 6-
3
(NaCl): ν = 3414, 3025, 1553, 1542, 1423, 1379, 1364, 1197, 1122,
˜
H), 6.38 (d, JHH = 3.2 Hz, 1 H, 2-H), 6.52–6.54 (m, 1 H, 3-H),
1
1031 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 4.32 (m, 1 H, 5-
3
7.61 (d, JHH = 2.0 Hz, 1 H, 4-H) ppm. 13C NMR (MeOD,
H), 4.67 (d, 3JHH = 6.8 Hz, 4 H, 6-H), 6.05 (s, 1 H, 2-H), 6.13 (dd,
75.5 MHz): δ = 44.0 (2 C-6), 46.8 (C-5), 108.3 (C-2), 111.5 (C-3),
143.5 (C-4), 156.5 (C-1) ppm.
3
3
4
3JHH = 6.0, JHH = 3.9 Hz, 1 H, 3-H), 6.69 (dd, JHH = 4.0, JHH
= 2.6 Hz, 1 H, 4-H), 8.52 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3,
75.5 MHz): δ = 34.9 (C-5), 76.0 (2 C-6), 106.3 (C-2), 108.8 (C-3),
118.8 (C-4), 124.2 (C-1) ppm. MS (APCI–): m/z (%) = 198 (100)
[M – H]–. HRMS (ESI–): calcd. for C7H9N3O4 [M – H]– 198.0515;
found 198.0532.
2-(3-Furyl)propane-1,3-diamine (7h): Rf (3% NH3/MeOH) = 0.12.
1H NMR (MeOD, 400.13 MHz): δ = 2.84–3.03 (m, 5 H, 5-H + 4
6-H), 6.55 (s, 1 H, 3-H), 7.60 (s, 1 H, 1-H), 7.67 (s, 1 H, 4-H) ppm.
13C NMR (MeOD, 100.6 MHz): δ = 43.8 (C-5), 45.4 (2 C-6), 110.3
(C-3), 126.2 (C-2), 142.0 (C-1), 145.3 (C-4) ppm.
General Procedure for the Synthesis of Diamines 7a–i: Deoxy-
genated MeOH (3.7 mL) was carefully added to a suspension con-
taining the dinitro compound 9a–i (1.00 mmol) and PtO2 (45.4 mg,
0.20 mmol) in a 100 mL round-bottom flask to which a H2 balloon
was connected. The resulting suspension was stirred at room tem-
perature for 6 h, and after this time the reaction was stopped and
the mixture filtered through Celite® and washed with MeOH
(5ϫ10 mL). The solvent was evaporated under reduced pressure to
afford the corresponding diamine 7a–i, which was used in enzy-
matic desymmetrization without further purification.
2-(1H-Pyrrol-2-yl)propane-1,3-diamine (7i): Rf (3% NH3/MeOH) =
0.08. H NMR (MeOD, 400.13 MHz): δ = 2.80–3.06 (m, 5 H, 5-H
+ 4 6-H), 6.10 (s, 1 H, 2-H), 6.23 (s, 1 H, 3-H), 6.86 (s, 1 H, 4-H)
ppm. 13C NMR (MeOD, 100.6 MHz): δ = 45.3 (2 C-6), 46.5 (C-5),
106.8 (C-2), 108.9 (C-3), 118.7 (C-4), 132.3 (C-1) ppm.
1
General Procedure for the Enzymatic Desymmetrization of Diamines
7a–i by Using Diallyl Carbonate: Diallyl carbonate (144 µL,
1.00 mmol) was added to a suspension of the corresponding di-
amine 7a–i (1.00 mmol) and PCL (300 mg) in dry 1,4-dioxane
(10.2 mL) under nitrogen and the mixture shaken at 30 °C and
250 rpm. The progress of the reaction was monitored by TLC
analysis. The reaction was stopped after 72 h, the enzyme was fil-
tered off and then washed with MeOH (3ϫ5 mL). The solvent was
evaporated under reduced pressure, and the resulting crude was
purified by flash chromatography on silica gel (mixtures MeOH/
EtOAc) to afford the corresponding amino carbamate (R)-10a–i
(see Table 2).
2-(4-Chlorophenyl)propane-1,3-diamine (7a): Rf (3% NH3/MeOH)
= 0.08. 1H NMR (MeOD, 400.13 MHz): δ = 2.90–2.98 (m, 3 H, 1-
H + 2 2-H), 3.02–3.09 (m, 2 H, 2-H), 7.40 (AЈBЈ system, JAЈBЈ
=
8.1 Hz, 2 H, 4-H), 7.49 (AЈBЈ system, JAЈBЈ = 8.1 Hz, 2 H, 5-H)
ppm. 13C NMR (MeOD, 100.6 MHz): δ = 46.2 (2 C-2), 52.6 (C-1),
130.2 (2 C-4), 131.1 (2 C-5), 133.9 (C-6), 141.7 (C-3) ppm.
2-(Pyridin-3-yl)propane-1,3-diamine (7b): Rf (3% NH3/MeOH) =
1
0.12. H NMR (MeOD, 300.13 MHz): δ = 3.04–3.08 (m, 5 H, 1-H
3
3
+ 4 2-H), 7.73 (dd, JHH = 7.9, JHH = 4.8 Hz, 1 H, 5-H), 8.06 (d,
3JHH = 7.9 Hz, 1 H, 4-H), 8.73–8.76 (m, 2 H, 6-H + 7-H) ppm.
13C NMR (MeOD, 75.5 MHz): δ = 46.1 (2 C-1), 51.0 (C-2), 125.8
(C-5), 137.8 (C-4), 139.7 (C-3), 149.0 (C-6), 150.9 (C-7) ppm.
Allyl (R)-[3-Amino-2-(4-chlorophenyl)propyl]carbamate (10a): Yield:
52% (139 mg). R (60% MeOH/EtOAc) = 0.12. IR (NaCl): ν =
˜
f
3319, 2931, 1712, 1651, 1538, 1493, 1412, 1258, 1145, 1092, 1014,
1
993, 929, 825, 777 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.53
2-(1H-Indol-2-yl)propane-1,3-diamine (7c): Rf (3% NH3/MeOH) =
0.18. H NMR (MeOD, 300.13 MHz): δ = 2.92–3.11 (m, 5 H, 9-H 1 H, 2-H), 3.49–3.57 (m, 1 H, 1-H), 4.52 (d, JHH = 5.5 Hz, 2 H,
(br. s, 2 H, NH2), 2.78–3.01 (m, 3 H, 2-H + 2 3-H), 3.29–3.38 (m,
1
3
488
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 484–493

Optically Active Heterocyclic Compounds
3
3
9-H), 5.02 (br. s, 1 H, NH), 5.18 (d, Jcis = 10.4 Hz, 1 H, 11-H),
(m, 1 H, 7-H), 3.46–3.54 (m, 1 H, 5-H), 4.50 (d, JHH = 5.4 Hz, 2
3
3
3
5.23 (d, Jtrans = 17.2 Hz, 1 H, 11-H), 5.80–5.93 (m, 1 H, 10-H), H, 9-H), 5.15 (d, Jcis = 10.2 Hz, 1 H, 11-H), 5.23 (d, Jtrans
=
7.11 (AЈBЈ system, JAЈBЈ = 8.4 Hz, 2 H, 5-H), 7.30 (AЈBЈ system,
JAЈBЈ = 8.4 Hz, 2 H, 6-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ
= 43.9 (C-3), 44.9 (C-2), 48.4 (C-1), 65.3 (C-9), 117.4 (C-11), 128.7
17.1 Hz, 1 H, 11-H), 5.43 (br. s, 1 H, NH), 5.79–5.91 (m, 1 H, 10-
H), 6.84 (d, JHH = 3.6 Hz, 1 H, 2-H), 6.93 (dd, JHH = 5.1, JHH
3
3
3
3
4
= 3.4 Hz, 1 H, 3-H), 7.16 (dd, JHH = 5.1, JHH = 1.1 Hz, 1 H, 4-
(2 C-5), 129.0 (2 C-6), 132.6 (C-7 + C-10), 139.0 (C-4), 156.0 (C- H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 44.3 (C-5 + C-6), 45.3
8) ppm. MS (ESI+): m/z (%) = 269 (100) [M + H]+. HRMS (ESI+):
calcd. for C13H17ClN2O2 [M + H]+ 269.1057; found 269.1044.
[α]2D0 = –5.6 (c = 0.5, EtOH) for 90% ee.
(C-7), 65.3 (C-9), 117.4 (C-11), 123.9 (C-4), 124.8 (C-2), 126.8 (C-
3), 132.7 (C-10), 143.7 (C-1), 156.3 (C-8) ppm. MS (APCI+): m/z
= 241 (100) [M + H]+, 242 (15) [M + 2 H]+. HRMS (ESI+): calcd.
for C11H16N2O2S [M + H]+ 241.1010; found 241.1034. [α]2D0 = –5.5
(c = 0.5, EtOH) for 78% ee.
Allyl (R)-[3-Amino-2-(pyridin-3-yl)propyl]carbamate (10b): Yield:
58% (163 mg). R (50% MeOH/EtOAc) = 0.11. IR (NaCl): ν =
˜
f
3288, 3045, 2933, 2863, 1706, 1646, 1550, 1477, 1429, 1325, 1259,
Allyl (R)-[3-Amino-2-(3-thienyl)propyl]carbamate (10f): Yield: 55%
1147, 1026, 991, 930, 813, 773 cm–1. 1H NMR (CDCl3, (136 mg). R (40% MeOH/EtOAc) = 0.14. IR (NaCl): ν = 3308,
˜
f
300.13 MHz): δ = 1.40 (br. s, 2 H, NH2), 2.77–2.96 (m, 3 H, 2 1-
3095, 1704, 1648, 1538, 1411, 1320, 1259, 1145, 993, 930, 858 cm–1.
H + 3-H), 3.27–3.36 (m, 1 H, 3-H), 3.43–3.56 (m, 1 H, 2-H), 4.43 1H NMR (CDCl3, 300.13 MHz): δ = 1.91 (br. s, 2 H, NH2), 2.80–
(d, 3JHH = 5.4 Hz, 2 H, 10-H), 4.92–5.28 (m, 2 H, 12-H), 5.53–5.91 3.01 (m, 3 H, 2 6-H + 7-H), 3.29–3.50 (m, 2 H, 5-H + 7-H), 4.48
3
3
3
(m, 2 H, 11-H + NH), 7.18 (dd, JHH = 7.7, JHH = 4.8 Hz, 1 H,
(d, JHH = 5.4 Hz, 2 H, 9-H), 5.12–5.38 (m, 3 H, 2 11-H + NH),
3
3
4
6-H), 7.45 (d, JHH = 7.9 Hz, 1 H, 5-H), 8.21–8.48 (m, 2 H, 7-H + 5.78–5.91 (m, 1 H, 10-H), 6.92 (dd, JHH = 4.8, JHH = 1.1 Hz, 1
8-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 43.6 (C-1), 44.6 (C- H, 3-H), 7.00 (dd, 4JHH = 2.8, JHH = 1.4 Hz, 1 H, 1-H), 7.27 (dd,
4
4
3), 46.6 (C-2), 65.2 (C10), 117.3 (C-12), 123.4 (C-6), 132.6 (C-5),
3JHH = 5.1, JHH = 3.0 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3,
135.0 (C-11), 136.3 (C-4), 148.1 (C-7), 149.5 (C-8), 156.2 (C-9) 75.5 MHz): δ = 43.5 (C-6), 44.2 (C-5), 44.5 (C-7), 65.2 (C-9), 117.4
ppm. MS (ESI+): m/z (%) = 236 (100) [M + H]+, 258 (20) [M +
Na]+. HRMS (ESI+): calcd. for C12H17N3O2 [M + H]+ 236.1399;
found 236.1378. [α]2D0 = –5.0 (c = 0.5, EtOH) for 89% ee.
(C-11), 121.3 (C-1), 126.1 (C-4), 126.4 (C-3), 132.7 (C-10), 141.3
(C-2), 156.2 (C-8) ppm. MS (ESI+): m/z (%) = 241 (100) [M +
H]+, 263 (20) [M + Na]+. HRMS (ESI+): calcd. for C11H16N2O2S
[M + H]+ 241.1010; found 241.1000. [α]2D0 = +5.1 (c = 0.5, EtOH)
for 79 % ee.
Allyl (R)-[3-Amino-2-(1H-indol-2-yl)propyl]carbamate (10c): Yield:
47% (128 mg). R (60% MeOH/EtOAc) = 0.24. IR (NaCl): ν =
˜
f
3320, 3059, 2932, 1704, 1651, 1548, 1532, 1488, 1456, 1291, 1265,
Allyl (R)-[3-Amino-2-(2-furyl)propyl]carbamate (10g): Yield: 48%
1152, 1075, 993, 929, 788, 737 cm–1. 1H NMR (CDCl3, (107 mg). R (20% MeOH/EtOAc) = 0.09. IR (NaCl): ν = 3321,
˜
f
300.13 MHz): δ = 2.50 (br. s, 2 H, NH2), 3.01 (s, 3 H, 2 10-H +
3117, 3082, 1704, 1538, 1441, 1417, 1328, 1259, 1149, 1012, 994,
3
11-H), 3.38–3.64 (m, 2 H, 9-H + 11-H), 4.54 (d, JHH = 5.7 Hz, 2
926 cm–1. 1H NMR (CDCl3, 300.13 MHz): δ = 1.78 (br. s, 2 H,
3
3
H, 13-H), 5.19 (d, Jcis = 10.5 Hz, 1 H, 15-H), 5.27 (d, Jtrans
=
NH2), 2.87–3.00 (m, 3 H, 2 6-H + 7-H), 3.38–3.53 (m, 2 H, 5-H +
3
17.1 Hz, 1 H, 15-H), 5.39 (br. s, 1 H, NH), 5.81–5.94 (m, 1 H, 14- 7-H), 4.50 (d, JHH = 5.4 Hz, 2 H, 9-H), 5.14–5.35 (m, 3 H, 2 11-
3
H), 6.25 (s, 1 H, 2-H), 7.07–7.17 (m, 2 H, 5-H + 6-H), 7.32 (d,
H + NH), 5.80–5.93 (m, 1 H, 10-H), 6.09 (d, JHH = 3.1 Hz, 1 H,
2-H), 6.27 (dd, 3JHH = 3.1, 3JHH = 1.7 Hz, 1 H, 3-H), 7.31 (d, 3JHH
= 1.7 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 41.5
3
3JHH = 7.6 Hz, 1 H, 4-H), 7.54 (d, JHH = 7.4 Hz, 1 H, 7-H), 9.69
(br. s, 1 H, NH) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 41.9 (C-
9), 42.8 (C-10), 43.5 (C-11), 65.5 (C-13), 99.3 (C-2), 110.8 (C-7), (C-6), 42.4 (C-5), 42.6 (C-7), 65.3 (C-9), 106.2 (C-2), 110.0 (C-3),
117.6 (C-15), 119.4 (C-4), 119.8 (C-6), 121.2 (C-5), 128.1 (C-3),
132.6 (C-14), 135.9 (C-1), 138.7 (C-8), 156.6 (C-12) ppm. MS
(APCI+): m/z = 274 (100) [M + H]+. HRMS (ESI+): calcd. for
C15H19N3O2 [M + H]+ 274.1555; found 274.1532. [α]2D0 = –1.8 (c =
0.5, EtOH) for 88% ee.
117.4 (C-11), 132.7 (C-10), 141.6 (C-4), 154.3 (C-8), 156.3 (C-1)
ppm. MS (APCI+): m/z = 225 (100) [M + H]+, 226 (10) [M +
2 H]+. HRMS (ESI+): calcd. for C11H16N2O3 [M + H]+ 225.1239;
found 225.1245. [α]2D0 = +3.7 (c = 0.5, EtOH) for 71% ee.
Allyl (R)-[3-Amino-2-(3-furyl)propyl]carbamate (10h): Yield: 54%.
Allyl (R)-[3-Amino-2-(1H-indol-3-yl)propyl]carbamate (10d): Yield:
R (60% MeOH/EtOAc) = 0.14. IR (NaCl): ν = 3324, 3142, 3081,
˜
f
1
45% (123 mg). R (60% MeOH/EtOAc) = 0.09. IR (NaCl): ν =
1703, 1648, 1540, 1438, 1327, 1259, 1160, 1026, 993, 931 cm–1. H
˜
f
3311, 3056, 2929, 2874, 1698, 1649, 1520, 1456, 1340, 1266, 1148,
NMR (CDCl3, 300.13 MHz): δ = 1.56 (br. s, 2 H, NH2), 2.71–2.87
(m, 3 H, 2 6-H + 7-H), 3.26–3.45 (m, 2 H, 5-H + 7-H), 4.49 (d,
1
1104, 1046, 1011, 993, 930 cm–1. H NMR (CDCl3, 300.13 MHz):
δ = 1.89 (br. s, 2 H, NH2), 2.99–3.01 (m, 2 H, 10-H), 3.13–3.17 (m, 3JHH = 5.1 Hz, 2 H, 9-H), 5.13–5.33 (m, 3 H, 2 11-H + NH), 5.79–
3
1 H, 11-H), 3.45–3.63 (m, 2 H, 9-H + 11-H), 4.54 (d, JHH
=
5.91 (m, 1 H, 10-H), 6.25 (s, 1 H, 3-H), 7.26 (s, 1 H, 1-H), 7.36 (s,
5.1 Hz, 2 H, 13-H), 5.16–5.34 (m, 3 H, 2 15-H + NH), 5.82–5.95
1 H, 4-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 39.5 (C-5), 43.1
3
(m, 1 H, 14-H), 6.93 (s, 1 H, 1-H), 7.09 (t, JHH = 7.7 Hz, 1 H, 6- (C-6), 44.1 (C-7), 65.3 (C-9), 108.9 (C-3), 117.4 (C-11), 124.0 (C-
3
H), 7.19 (t, 3JHH = 7.9 Hz, 1 H, 5-H), 7.34 (d, JHH = 7.9 Hz, 1 H,
2), 132.7 (C-10), 139.6 (C-1), 143.3 (C-4), 156.2 (C-8) ppm. MS
4-H), 7.58 (d, 3JHH = 7.7 Hz, 1 H, 7-H), 9.09 (br. s, 1 H, NH) ppm.
(APCI+): m/z = 225 (100) [M + H]+. HRMS (ESI+): calcd. for
13C NMR (CDCl3, 75.5 MHz): δ = 40.4 (C-9), 43.3 (C-10), 43.9 C11H16N2O3 [M + H]+ 225.1239; found 225.1229. [α]2D0 = +5.3 (c
(C-11), 65.3 (C-13), 111.4 (C-7), 114.0 (C-2), 117.5 (C-15), 118.7
(C-4), 119.2 (C-6), 121.9 (C-5 + C-1), 126.5 (C-3), 132.8 (C-14),
136.5 (C-8), 156.5 (C-12) ppm. MS (APCI+): m/z = 274 (100) [M
+ H]+. HRMS (ESI+): calcd. for C15H19N3O2 [M + H]+ 274.1555;
found 274.1570. [α]2D0 = +6.8 (c = 0.5, EtOH) for 87% ee.
= 0.5, EtOH) for 70% ee.
Allyl (R)-[3-Amino-2-(1H-pyrrol-2-yl)propyl]carbamate (10i): Yield:
53% (121 mg). R (20% MeOH/EtOAc) = 0.08. IR (NaCl): ν =
˜
f
3345, 3097, 2937, 2871, 1702, 1650, 1538, 1261, 1146, 1097, 1029,
1
993, 932 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 2.51 (br. s, 2
Allyl (R)-[3-Amino-2-(2-thienyl)propyl]carbamate (10e): Yield: 47%
H, NH2), 2.81–2.92 (m, 3 H, 2 6-H + 7-H), 3.29–3.45 (m, 2 H, 5-
H + 7-H), 4.51 (d, JHH = 7.2 Hz, 2 H, 9-H), 5.16–5.28 (m, 2 H,
3
(113 mg). R (20% MeOH/EtOAc) = 0.08. IR (NaCl): ν = 3318,
˜
f
3078, 2934, 2867, 1714, 1651, 1538, 1440, 1259, 1148, 1038, 993,
11-H), 5.57 (br. s, 1 H, NH), 5.80–5.92 (m, 2 H, 2-H + 10-H), 6.11
930 cm–1. 1H NMR (CDCl3, 300.13 MHz): δ = 2.19 (br. s, 2 H, (s, 1 H, 3-H), 6.66 (s, 1 H, 4-H), 9.78 (br. s, 1 H, NH) ppm. 13C
NH2), 2.83–2.98 (m, 2 H, 6-H), 3.10–3.19 (m, 1 H, 7-H), 3.30–3.39 NMR (CDCl3, 75.5 MHz): δ = 41.1 (C-5), 43.0 (C-6), 43.6 (C-7),
Eur. J. Org. Chem. 2010, 484–493
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
489

N. Ríos-Lombardía, E. Busto, V. Gotor-Fernández, V. Gotor
65.4 (C-9), 104.7 (C-2), 107.8 (C-3), 117.0 (C-4), 117.4 (C-11), 130.9 calcd. for C22H23N3O3 [M + Na]+ 400.1637; found 400.1649. [α]2D0
FULL PAPER
(C-1), 132.6 (C-10), 156.6 (C-8) ppm. MS (APCI+): m/z = 224 (100)
[M + H]+. HRMS (ESI+): calcd. for C11H17N3O2 [M + H]+
224.1399; found 224.1379. [α]2D0 = +5.5 (c = 0.5, EtOH) for 76%
ee.
= –1.1 (c = 0.5, EtOH) for 88% ee.
Allyl [3-(Benzoylamino)-2-(1H-indol-3-yl)propyl]carbamate (11d):
Yield: 94% (32 mg). R (60% EtOAc/hexane) = 0.29. IR (NaCl): ν
˜
f
= 3320, 3058, 2932, 1704, 1651, 1538, 1488, 1457, 1435, 1264, 1149,
1105, 993, 929 cm–1. 1H NMR (CDCl3, 300.13 MHz): δ = 3.36–
3.60 (m, 3 H, 10-H + 2 16-H), 3.68–3.77 (m, 1 H, 10-H), 3.98–4.06
General Procedure for the Synthesis of Chiral Amido Carbamates
11a–i: Et3N (13 µL, 0.10 mmol) and acetyl or benzoyl chloride
(0.10 mmol) were successively added to a solution of the corre-
sponding compound (R)-10a–i (0.09 mmol) in dry CH2Cl2 (0.9 mL)
under nitrogen. The mixture was stirred at room temperature for
4 h, and after this time the solvent was evaporated under reduced
pressure to give a reaction crude that was purified by flash
chromatography on silica gel (100% EtOAc) to afford the amido
carbamate (R)-11a–i (91–96%).
3
(m, 1 H, 9-H), 4.58 (d, JHH = 5.4 Hz, 2 H, 18-H), 5.19–5.33 (m,
3 H, 2 20-H + NH), 5.85–5.98 (m, 1 H, 19-H), 6.97 (s, 1 H, 1-H),
7.06–7.12 (m, 2 H, 5-H + NH), 7.19 (t, JHH = 7.7 Hz, 1 H, 6-H),
3
3
7.35–7.43 (m, 3 H, 2 14-H + 1 15-H), 7.46 (d, JHH = 7.1 Hz, 1 H,
3
3
4-H), 7.60 (d, JHH = 7.7 Hz, 1 H, 7-H), 7.60 (d, JHH = 7.1 Hz, 2
H, 13-H), 8.61 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3,
75.5 MHz): δ = 37.1 (C-9), 40.7 (C-10), 42.2 (C-16), 65.6 (C-18),
111.4 (C-7), 114.3 (C-2), 117.6 (C-20), 118.8 (C-4), 119.6 (C-6),
121.4 (C-5), 122.3 (C-1), 126.4 (C-3), 126.9 (2 C-13), 128.5 (2 C-
14), 131.4 (C-15), 132.7 (C-19), 134.2 (C-12), 136.4 (C-8), 157.1 (C-
17), 167.8 (C-11) ppm. MS (APCI+): m/z = 378 (100) [M + H]+.
HRMS (ESI+): calcd. for C22H23N3O3 [M + Na]+ 400.1637; found
400.1632. [α]2D0 = –2.2 (c = 0.5, EtOH) for 87% ee.
Allyl [3-(Acetylamino)-2-(4-chlorophenyl)propyl]carbamate (11a):
Yield: 93% (26 mg). R (70% EtOAc/hexane) = 0.10. IR (NaCl): ν
˜
f
= 3313, 3084, 2934, 1710, 1651, 1538, 1494, 1440, 1371, 1261, 1148,
1093, 1014, 993, 932, 825, 777, 737 cm–1. 1H NMR (CDCl3,
300.13 MHz): δ = 1.93 (s, 3 H, 9-H), 2.94–3.02 (m, 1 H, 2-H), 3.28–
3
3.57 (m, 4 H, 1-H + 2-H + 2 3-H), 4.51 (d, JHH = 5.4 Hz, 2 H,
Allyl [3-(Acetylamino)-2-(2-thienyl)propyl]carbamate (11e): Yield:
11-H), 5.17–5.28 (m, 3 H, 2 13-H + NH), 5.80–5.93 (m, 1 H, 12-
H), 6.10 (br. s, 1 H, NH), 7.08 (AЈBЈ system, JAЈBЈ = 8.5 Hz, 2 H,
5-H), 7.27 (AЈBЈ system, JAЈBЈ = 8.5 Hz, 2 H, 6-H) ppm. 13C NMR
(CDCl3, 75.5 MHz): δ = 23.1 (C-9), 41.1 (C-3), 42.9 (C-2), 44.6 (C-
1), 65.6 (C-11), 117.6 (C-13), 128.8 (2 C-5), 128.9 (2 C-6), 132.6
(C-7), 132.9 (C-12), 138.6 (C-4), 156.7 (C-10), 170.5 (C-8) ppm.
MS (ESI+): m/z (%) = 311 (100) [M + H]+, 333 (10) [M + Na]+.
HRMS (ESI+): calcd. for C15H19ClN2O3 [M + Na]+ 333.0982;
found 333.0956. [α]2D0 = –5.1 (c = 0.5, EtOH) for 90% ee.
92% (23 mg). R (70% EtOAc/hexane) = 0.26. IR (NaCl): ν = 3313,
˜
f
3083, 2933, 1705, 1652, 1538, 1439, 1372, 1258, 1150, 1091, 1039,
1
993, 930, 849 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.98 (s, 3
H, 8-H), 3.24–3.37 (m, 3 H, 6-H + 2 9-H), 3.55–3.64 (m, 1 H, 6-
3
2
H), 3.68–3.74 (m, 1 H, 5-H), 5.20 (dd, Jcis = 10.2, Jgem = 1.4 Hz,
3
2
1 H, 13-H), 5.28 (dd, Jtrans = 17.4, Jgem = 1.4 Hz, 1 H, 13-H),
5.45 (br. s, 1 H, NH), 5.83–5.96 (m, 1 H, 12-H), 6.24 (br. s, 1 H,
NH), 6.85 (d, 3JHH = 3.4 Hz, 1 H, 2-H), 6.97 (dd, 3JHH = 5.1, 3JHH
3
= 3.4 Hz, 1 H, 3-H), 7.19 (d, JHH = 5.1 Hz, 1 H, 4-H) ppm. 13C
NMR (CDCl3, 75.5 MHz): δ = 23.2 (C-8), 40.9 (C-5), 41.4 (C-6),
43.1 (C-9), 65.6 (C-11), 117.6 (C-13), 123.9 (C-4), 124.6 (C-2), 126.9
(C-3), 132.6 (C-12), 142.8 (C-1), 156.8 (C-10), 170.6 (C-7) ppm.
MS (APCI+): m/z = 283 (100) [M + H]+. HRMS (ESI+): calcd. for
C13H18N2O3S [M + Na]+ 305.0940; found 305.0946. [α]2D0 = –5.1 (c
= 0.5, EtOH) for 78% ee.
Allyl [3-(Acetylamino)-2-pyridin-3-ylpropyl]carbamate (11b): Yield:
91% (22.5 mg). R (100% EtOAc) = 0.09. IR (NaCl): ν = 3314,
˜
f
3088, 2932, 1707, 1650, 1594, 1550, 1476, 1438, 1373, 1295, 1264,
1
1151, 991 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.94 (s, 3 H,
10-H), 3.01–3.05 (m, 1 H, 2-H), 3.31–3.63 (m, 4 H, 2 1-H + 2 3-
H), 4.51 (d, 3JHH = 5.5 Hz, 1 H, 12-H), 5.18 (dd, 3Jcis = 10.4, 2Jgem
3
= 1.3 Hz, 1 H, 14-H), 5.25 (d, Jtrans = 16.9 Hz, 1 H, 14-H), 5.62
Allyl [3-(Acetylamino)-2-(3-thienyl)propyl]carbamate (11f): Yield:
(br. s, 1 H, NH), 5.80–5.93 (m, 1 H, 13-H), 6.51 (br. s, 1 H, NH),
93% (24 mg). R (70% EtOAc/hexane) = 0.29. IR (NaCl): ν = 3311,
˜
f
3
3
3
7.23 (dd, JHH = 7.9, JHH = 5.0 Hz 1 H, 6-H), 7.50 (d, JHH
=
3092, 1704, 1651, 1539, 1437, 1371, 1259, 1147, 1091, 993, 930,
7.9 Hz, 1 H, 5-H), 8.37–8.40 (m, 2 H, 7-H + 8-H) ppm. 13C NMR
(CDCl3, 75.5 MHz): δ = 23.0 (C-10), 40.8 (C-1), 42.6 (C-3), 43.1
(C-2), 65.6 (C-12), 117.6 (C-14), 123.6 (C-6), 132.6 (C-5), 135.2 (C-
13), 135.9 (C-4), 148.4 (C-8), 149.2 (C-7), 156.8 (C-11), 170.8 (C-
9) ppm. MS (ESI+): m/z (%) = 278 (80) [M + H]+, 300 (100) [M +
Na]+. HRMS (ESI+): calcd. for C14H19N3O3 [M + Na]+ 300.1324;
found 300.1307. [α]2D0 = –6.1 (c = 0.5, EtOH) for 89% ee.
1
857 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.97 (s, 3 H, 8-H),
3.11–3.17 (m, 1 H, 9-H), 3.25–3.36 (m, 2 H, 6-H + 9-H), 3.50–3.70
3
(m, 2 H, 5-H + 6-H), 4.54 (d, JHH = 5.7 Hz, 2 H, 11-H), 5.18–
5.31 (m, 3 H, 2 13-H + NH), 5.83–5.96 (m, 1 H, 12-H), 6.14 (br.
3
4
s, 1 H, NH), 6.95 (dd, JHH = 4.9, JHH = 1.1 Hz, 1 H, 3-H), 7.02
(d, 4JHH = 2.3 Hz, 1 H, 1-H), 7.31 (dd, 3JHH = 5.1, JHH = 3.1 Hz,
4
1 H, 4-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 23.2 (C-8), 40.7
(C-6), 40.8 (C-5), 42.5 (C-9), 65.6 (C-11), 117.6 (C-13), 121.1 (C-
1), 126.3 (C-4), 126.7 (C-3), 132.7 (C-12), 140.7 (C-2), 156.8 (C-
10), 170.6 (C-7) ppm. MS (ESI+): m/z (%) = 283 (30) [M + H]+,
305 (100) [M + Na]+. HRMS (ESI+): calcd. for C13H18N2O3S [M
+ Na]+ 305.0940; found 305.0919. [α]2D0 = –7.3 (c = 0.5, EtOH) for
79% ee.
Allyl [3-(Benzoylamino)-2-(1H-indol-2-yl)propyl]carbamate (11c):
Yield: 95% (32 mg). R (60% EtOAc/hexane) = 0.37. IR (NaCl): ν
˜
f
= 3305, 3057, 2933, 1704, 1524, 1457, 1425, 1343, 1265, 1149, 991,
1
788, 736 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 3.30–3.38 (m,
1 H, 16-H), 3.43–3.52 (m, 1 H, 10-H), 3.66–3.74 (m, 2 H, 10-H +
3
16-H), 3.89–3.97 (m, 1 H, 9-H), 4.57 (d, JHH = 5.5 Hz, 2 H, 18-
3
3
H), 5.20 (d, Jcis = 10.4 Hz, 1 H, 20-H), 5.28 (d, Jtrans = 17.2 Hz, Allyl [3-(Acetylamino)-2-(2-furyl)propyl]carbamate (11g): Yield:
1 H, 20-H), 5.48 (br. s, 1 H, NH), 5.83–5.96 (m, 1 H, 19-H), 6.29
96% (25 mg). R (100% EtOAc) = 0.25. IR (NaCl): ν = 3317, 3085,
˜
f
(s, 1 H, 2-H), 7.06–7.16 (m, 2 H, 5-H + 6-H), 7.30–7.55 (m, 6 H,
2944, 1714, 1660, 1651, 1538, 1436, 1732, 1258, 1149, 1012, 995,
3
1
4-H + 7-H + 2 14-H + 15-H + NH), 7.79 (d, JHH = 7.4 Hz, 2 H, 931 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.99 (s, 3 H, 8-H),
13-H), 9.32 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3, 75.5 MHz): 3.08–3.16 (m, 1 H, 9-H), 3.22–3.34 (m, 2 H, 6-H + 9-H), 3.60–3.69
δ = 39.7 (C-9), 40.1 (C-10), 41.9 (C-16), 65.8 (C-18), 95.5 (C-2), (m, 1 H, 6-H), 3.75–3.84 (m, 1 H, 5-H), 4.52 (d, JHH = 5.5 Hz, 2
3
111.0 (C-7), 117.8 (C-20), 119.7 (C-4), 119.8 (C-6), 121.6 (C-5),
126.9 (2 C-13), 128.3 (C-3), 128.6 (2 C-14), 131.6 (C-15), 132.5 (C- 12-H), 6.11 (d, JHH = 3.1 Hz, 1 H, 2-H), 6.18 (br. s, 1 H, NH),
H, 11-H), 5.19–5.37 (m, 3 H, 2 13-H + NH), 5.84–5.97 (m, 1 H,
3
3
3
3
19), 133.8 (C-12), 135.9 (C-1), 137.3 (C-8), 157.3 (C-17), 168.2 (C-
6.32 (dd, JHH = 3.2, JHH = 1.9 Hz, 1 H, 3-H), 7.34 (d, JHH
=
11) ppm. MS (APCI+): m/z = 378 (100) [M + H]+. HRMS (ESI+):
1.7 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 23.2
490
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 484–493

Optically Active Heterocyclic Compounds
(C-8), 38.8 (C-6), 39.2 (C-5), 40.5 (C-9), 65.6 (C-11), 106.4 (C-2), 1 H, 6-H), 7.51–7.55 (m, 1 H, 5-H), 8.38–8.51 (m, 2 H, 7-H + 8-
110.3 (C-3), 117.6 (C-13), 132.7 (C-12), 141.7 (C-4), 153.9 (C-10),
H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 23.0 (C-10), 42.5 (C-
3), 45.1 (C-1), 46.0 (C-2), 123.7 (C-6), 135.1 (C-5), 136.5 (C-4),
156.9 (C-1), 170.6 (C-7) ppm. MS (APCI+): m/z = 267 (100) [M +
H]+, 268 (10) [M + 2 H]+. HRMS (ESI+): calcd. for C13H18N2O4 148.4 (C-7), 149.6 (C-8), 170.3 (C-9) ppm. MS (ESI+): m/z (%) =
[M + Na]+ 289.1165; found 289.1130. [α]2D0 = –2.8 (c = 0.5, EtOH)
for 71 % ee.
194 (100) [M + H]+, 216 (85) [M + Na]+. HRMS (ESI+): calcd. for
C10H15N3O [M + H]+ 194.1293; found 194.1271.
Allyl [3-(Acetylamino)-2-(3-furyl)propyl]carbamate (11h): Yield:
N-[3-Amino-2-(1H-indol-2-yl)propyl]benzamide (12c): Yield: 5%
93% (21.5 mg). R (60% EtOAc/hexane) = 0.16. IR (NaCl): ν =
(14.5 mg). R (100% MeOH) = 0.20. IR (NaCl): ν = 3291, 3062,
˜
˜
f
f
3316, 3085, 1704, 1651, 1539, 1440, 1371, 1259, 1161, 1028, 993,
2929, 1643, 1577, 1535, 1488, 1457, 1290, 909, 790, 732 cm–1. 1H
1
930, 874 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.97 (s, 3 H, NMR (CDCl3, 300.13 MHz): δ = 1.94 (br. s, 2 H, NH2), 3.08–3.27
8-H), 2.88–2.97 (m, 1 H, 9-H), 3.16–3.26 (m, 2 H, 6-H + 9-H), (m, 3 H, 2 10-H + 11-H), 3.67–3.75 (m, 1 H, 11-H), 3.88–3.97 (m,
3
3.46–3.55 (m, 1 H, 6-H), 3.58–3.67 (m, 1 H, 5-H), 4.54 (d, JHH
=
1 H, 9-H), 6.31 (s, 1 H, 2-H), 7.03–7.16 (m, 2 H, 5-H + 6-H), 7.32–
7.57 (m, 6 H, 4-H + 7-H + 2 15-H + 16-H + NH), 9.76 (br. s, 1
H, NH) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 41.2 (C-9), 42.2
5.4 Hz, 2 H, 11-H), 5.18–5.33 (m, 3 H, 2 13-H + NH), 5.83–5.95
(m, 1 H, 12-H), 6.17 (br. s, 1 H, NH), 6.28 (s, 1 H, 3-H), 7.27 (s, 1
H, 1-H), 7.39 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ (C-10), 44.2 (C-11), 99.3 (C-2), 110.9 (C-7), 119.5 (C-4), 119.9 (C-
= 23.2 (C-8), 36.5 (C-5), 40.2 (C-6), 41.9 (C-9), 65.6 (C-11), 109.4
(C-3), 117.6 (C-13), 123.7 (C-2), 132.7 (C-12), 139.2 (C-1), 143.4
(C-4), 156.8 (C-10), 170.6 (C-7) ppm. MS (APCI+): m/z = 267 (100)
[M + H]+, 268 (15) [M + 2 H]+. HRMS (ESI+): calcd. for
C13H18N2O4 [M + Na]+ 289.1165; found 289.1150. [α]2D0 = –4.8 (c
= 0.5, EtOH) for 70% ee.
6), 121.4 (C-5), 126.8 (2 C-14), 128.2 (C-3), 128.5 (2 C-15), 131.5
(C-16), 134.1 (C-13), 136.0 (C-1), 139.0 (C-8), 167.9 (C-12) ppm.
MS (APCI+): m/z (%) = 294 (100) [M + H]+. HRMS (ESI+): calcd.
for C18H19N3O [M + H]+ 294.1606; found 294.1623.
N-[3-Amino-2-(1H-indol-3-yl)propyl]benzamide (12d): Yield: 8%
(23 mg). R (3% NH /MeOH) = 0.34. IR (NaCl): ν = 3288, 3062,
˜
f
3
Allyl [3-(Acetylamino)-2-(1H-pyrrol-2-yl)propyl]carbamate (11i):
2926, 1844, 1833, 1538, 1488, 1456, 1312, 1224, 1105, 1012, 929,
1
Yield: 94% (22 mg). R (100% EtOAc) = 0.22. IR (NaCl): ν = 3321,
803 cm–1. H NMR (MeOD, 300.13 MHz): δ = 3.23–3.25 (m, 2 H,
˜
f
3096, 2934, 1704, 1651, 1538, 1434, 1370, 1260, 1148, 1100, 1031,
10-H), 3.58–3.66 (m, 1 H, 11-H), 3.83–4.01 (m, 2 H, 9-H + 11-H),
1
3
4
3
992, 930 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.98 (s, 3 H, 7.20 (td, JHH = 8.1, JHH = 1.1 Hz, 1 H, 6-H), 7.30 (td, JHH
=
=
4
3
8-H), 3.05–3.10 (m, 1 H, 9-H), 3.33–3.59 (m, 4 H, 5-H + 2 6-H +
7.1, JHH = 1.1 Hz, 1 H, 5-H), 7.36 (s, 1 H, 1-H), 7.58 (t, JHH
3
3
9-H), 4.55 (d, JHH = 5.4 Hz, 2 H, 11-H), 5.19–5.32 (m, 2 H, 13-
7.7 Hz, 3 H, 2 15-H + 16-H), 7.66 (d, JHH = 7.3 Hz, 1 H, 4-H),
H), 5.47 (br. s, 1 H, NH), 5.84–5.94 (m, 2 H, 2-H + 12-H), 6.15 (s, 7.84 (d, 3JHH = 8.1 Hz, 1 H, 7-H), 7.90 (d, 3JHH = 7.7 Hz, 2 H, 14-
1 H, 3-H), 6.49 (br. s, 1 H, NH), 6.70 (s, 1 H, 4-H), 9.32 (br. s, 1
H) ppm. 13C NMR (MeOD, 75.5 MHz): δ = 41.2 (C-9), 44.0 (C-
H, NH) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 23.2 (C-8), 39.2 10), 44.8 (C-11), 112.8 (C-7), 115.1 (C-2), 119.9 (C-4), 120.2 (C-6),
(C-5), 40.0 (C-6), 42.1 (C-9), 65.7 (C-11), 105.1 (C-2), 108.3 (C-3),
117.3 (C-4), 117.7 (C-13), 129.8 (C-1), 132.6 (C-12), 157.2 (C-10),
171.2 (C-7) ppm. MS (APCI+): m/z = 266 (100) [M + H]+, 267 (10)
[M + 2 H]+. HRMS (ESI+): calcd. for C13H19N3O3 [M + Na]+
288.1324; found 288.1346. [α]2D0 = –4.5 (c = 0.5, EtOH) for 76% ee.
122.9 (C-1), 123.6 (C-5), 128.5 (2 C-14 + C-3), 129.8 (2 C-15), 132.9
(C-16), 136.0 (C-13), 138.7 (C-8), 170.8 (C-12) ppm. MS (APCI+):
m/z (%) = 294 (100) [M + H]+, 295 (20) [M + 2 H]+. HRMS (ESI+):
calcd. for C18H19N3O [M + H]+ 294.1606; found 294.1614.
N-[3-Amino-2-(2-thienyl)propyl]acetamide (12e): Yield: 8% (16 mg).
General Procedure for the Synthesis of Racemic Amido Amines 12a–
i: Acetic or benzoic anhydride (1 mmol) was added in small por-
tions at 10 min intervals to a solution of compound 7a–i (1 mmol)
in dry CH2Cl2 (2.0 mL) under nitrogen. The mixture was stirred
at room temperature for 4 h, and after this time the solvent was
evaporated under reduced pressure to give a reaction crude that
was purified by flash chromatography on silica gel (100% MeOH
to 1% NH3/MeOH) to afford the corresponding racemic amino
amide 12a–i (5–23%).
R (2% NH /MeOH) = 0.31. IR (NaCl): ν = 3292, 3073, 2931,
˜
f 3
1
2873, 1654, 1561, 1438, 1373, 1268, 1107, 1039, 897, 837 cm–1. H
NMR (CDCl3, 300.13 MHz): δ = 1.53 (br. s, 1 H, NH2), 1.91 (s, 3
H, 9-H), 2.86–2.99 (m, 2 H, 6-H), 3.09–3.18 (m, 1 H, 7-H), 3.36–
3.44 (m, 1 H, 7-H), 3.59–3.68 (m, 1 H, 5-H), 6.13 (br. s, 1 H, NH),
3
3
3
6.86 (d, JHH = 3.3 Hz, 1 H, 2-H), 6.96 (dd, JHH = 5.0, JHH
=
3.3 Hz, 1 H, 3-H) 7.18 (d, JHH = 5.0 Hz, 1 H, 4-H) ppm. 13C
NMR (CDCl3, 75.5 MHz): δ = 23.1 (C-9), 43.1 (C-7), 44.2 (C-5),
45.9 (C-6), 123.9 (C-4), 124.7 (C-2), 126.9 (C-3), 144.1 (C-1), 170.2
(C-8) ppm. MS (APCI+): m/z (%) = 199 (100) [M + H]+. HRMS
(ESI+): calcd. for C9H14N2OS [M + H]+ 199.0905; found 199.0927.
3
N-[3-Amino-2-(4-chlorophenyl)propyl]acetamide (12a): Yield: 21%
(47 mg). R (100% MeOH) = 0.12. IR (NaCl): ν = 3406, 2934,
˜
f
1643, 1564, 1493, 1377, 1306, 1093, 1014, 825 cm–1. 1H NMR N-[3-Amino-2-(3-thienyl)propyl]acetamide (12f): Yield: 17%
(CDCl3, 400.13 MHz): δ = 1.69–2.02 (s, 5 H, 3 9-H + NH2), 2.77– (33 mg). R (3% NH /MeOH) = 0.40. IR (NaCl): ν = 3294, 3072,
2.95 (m, 3 H, 2-H + 2 3-H), 3.30–3.36 (m, 1 H, 2-H), 3.54–3.60 2933, 2870, 1655, 1562, 1440, 1365, 1269, 1107, 1036 cm–1. 1H
(m, 1 H, 1-H), 6.25 (br. s, 1 H, NH), 7.10 (AЈBЈ system, JAЈBЈ NMR (CDCl3, 400.13 MHz): δ = 1.90 (s, 3 H, 9-H), 2.86–3.00 (m,
˜
f
3
=
8.3 Hz, 2 H, 5-H), 7.27 (AЈBЈ system, JAЈBЈ = 8.3 Hz, 2 H, 6-H) 3 H, 2 6-H + 7-H), 3.38–3.45 (m, 1 H, 7-H), 3.57–3.63 (m, 1 H, 5-
3
ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 23.0 (C-9), 42.6 (C-2), H), 6.08 (br. s, 1 H, NH), 6.95 (d, JHH = 3.2 Hz, 1 H, 3-H), 7.03
45.3 (C-3), 47.8 (C-1), 128.8 (2 C-5), 129.1 (2 C-6), 132.7 (C-7),
(s, 1 H, 1-H), 7.30–7.32 (m, 1 H, 4-H) ppm. 13C NMR (CDCl3,
100.6 MHz): δ = 23.1 (C-9), 42.4 (C-7), 43.9 (C-5), 45.2 (C-6), 121.3
139.3 (C-4), 170.1 (C-8) ppm. MS (APCI+): m/z (%) = 227 (100)
[M + H]+. HRMS (ESI+): calcd. for C11H15ClN2O [M + H]+ (C-1), 126.3 (C-4), 126.5 (C-3), 141.6 (C-2), 170.1 (C-8) ppm. MS
227.0951; found 227.0949.
(APCI+): m/z (%) = 199 (100) [M + H]+. HRMS (ESI+): calcd. for
C9H14N2OS [M + H]+ 199.0905; found 199.0918.
N-(3-Amino-2-pyridin-3-ylpropyl)acetamide (12b): Yield: 23%
(44.5 mg). R (3% NH /MeOH) = 0.36. IR (NaCl): ν = 3349, 2932,
N-[3-Amino-2-(2-furyl)propyl]acetamide (12g): Yield: 9% (16 mg).
˜
f
3
2911, 2863, 1637, 1572, 1481, 1429, 1381, 1329, 1138, 1107 cm–1.
R (3% NH /MeOH) = 0.34. IR (NaCl): ν = 3291, 3112, 2936,
˜
f
3
1H NMR (CDCl3, 300.13 MHz): δ = 1.89 (s, 3 H, 10-H), 2.00 (br.
2876, 1650, 1563, 1506, 1440, 1376, 1301, 1149, 1108, 1074, 1012,
s, 2 H, NH2), 2.81–3.04 (m, 3 H, 2 1-H + 2-H), 3.41–3.50 (m, 1 H, 915, 808 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.63 (br. s, 2
1
3-H), 3.57–3.66 (m, 1 H, 3-H), 6.41 (br. s, 1 H, NH), 7.20–7.27 (m,
H, NH2), 1.91 (s, 3 H, 9-H), 2.89–2.99 (m, 3 H, 2 6-H + 7-H),
491
Eur. J. Org. Chem. 2010, 484–493
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

N. Ríos-Lombardía, E. Busto, V. Gotor-Fernández, V. Gotor
FULL PAPER
3.45–3.60 (m, 2 H, 5-H + 7-H), 6.09 (d, JHH = 3.1 Hz, 1 H, 2-H),
3
[2]
a) M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Kesseler,
R. Stuermer, T. Zelinski, Angew. Chem. Int. Ed. 2004, 43, 788–
824; b) N. J. Turner, R. Carr in Biocatalysis in the Pharmaceuti-
cal and Biotechnology Industries (Ed.: R. N. Patel), CRC Press,
Boca Raton, 2007, pp. 743–755.
3
4
6.24–6.36 (m, 2 H, 3-H + NH), 7.32 (dd, JHH = 1.7, JHH
=
0.8 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 23.1
(C-9), 40.2 (C-7), 42.1 (C-5), 43.0 (C-6), 106.4 (C-2), 110.1 (C-3),
141.6 (C-4), 154.6 (C-1), 170.3 (C-8) ppm. MS (APCI+): m/z (%) =
183 (100) [M + H]+. HRMS (ESI+): calcd. for C9H14N2O2 [M +
H]+ 183.1133; found 183.1142.
[3]
[4]
L.-W. Xu, J. Luo, Y. Lu, Chem. Commun. 2009, 1807–1821.
See, for example: a) V. I. Tararov, A. Börner, Synlett 2005, 203–
211; b) T. C. Nugent, A. K. Ghosh, V. N. Wakchaure, R. R.
Mohanty, R. Rashmi, Adv. Synth. Catal. 2006, 348, 1289–1299;
c) T. C. Nugent, M. El-Shazly, V. N. Wakchaure, J. Org. Chem.
2008, 73, 1297–1305; d) L. Rubio-Perez, F. J. Perez-Flores, P.
Sharma, L. Velasco, A. Cabrera, Org. Lett. 2009, 11, 265–268;
e) C. Li, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2009, 131,
6967–6969.
For recent publications, see: a) N. Mrsic, A. J. Minnaard, B. L.
Feringa, J. G. de Vries, J. Am. Chem. Soc. 2009, 131, 8358–
8359; b) H. Matsunaga, K. Nakanishi, K. Makoto, Heterocy-
cles 2009, 78, 617–622; c) S.-Y. Shirai, H. Nara, Y. Kayaki, T.
Ikariya, Organometallics 2009, 28, 802–809; d) N. Haraguchi,
K. Tsuru, Y. Arakawa, S. Itsuno, Org. Biomol. Chem. 2009, 7,
69–75; e) C. Li, J. Xiao, J. Am. Chem. Soc. 2009, 131, 13208–
13209.
a) P. Cheruku, T. L. Church, A. Trifonova, T. Wartmann, P. G.
Andersson, Tetrahedron Lett. 2008, 49, 7290–7293; b) G.-H.
Hou, J.-H. Xie, P.-C. Yan, Q.-L. Zhou, J. Am. Chem. Soc. 2009,
131, 1366–1367; c) X.-B. Wang, D.-W. Wang, S.-M. Lu, C.-B.
Yu, Y.-G. Zhou, Tetrahedron: Asymmetry 2009, 20, 1040–1045;
d) A. Baeza, A. Pfaltz, Chem. Eur. J. 2009, 15, 2266–2269; e)
G.-H. Hou, J.-H. Xie, P.-C. Yan, J. Am. Chem. Soc. 2009, 131,
1366–1367.
a) B. H. Lipshutz, H. Shimizu, Angew. Chem. Int. Ed. 2004, 43,
2228–2230; b) B.-M. Park, S. Mun, J. Yun, Adv. Synth. Catal.
2006, 348, 1029–1032; c) P. Wu, Z. Wang, M. Cheng, L. Zhou,
J. Sun, Tetrahedron 2008, 64, 11304–11312; d) M. Hatano, Y.
Hattori, Y. Furuya, K. Ishihara, Org. Lett. 2009, 11, 2321–
2324; e) S. Guizzeti, M. Benaglia, F. Cozzi, E. Annunziata,
Tetrahedron 2009, 65, 6354–6363.
a) S. E. Denmark, O. J. C. Nicaise in Comprehensive Asymmet-
ric Catalysis, vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yama-
moto), Springer, Berlin, 1999, pp. 923–961; b) D. Ferraris, Tet-
rahedron 2007, 63, 9581–9597; c) K.-i. Yamada, K. Tomioka,
Chem. Rev. 2008, 108, 2874–2886.
a) C. Bolm, J. P. Hildebrand, K. Muniz in Catalytic Asymmet-
ric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH, New York,
2000, pp. 399–428; b) G. Kim, N. Kim, Tetrahedron Lett. 2007,
48, 4481–4483; c) J. A. Bodkin, G. B. Bacskay, M. D. Mac-
Leod, Org. Biomol. Chem. 2008, 6, 2544–2553; d) M. Harding,
J. A. Bodkin, F. Issa, C. A. Hutton, A. C. Willis, M. D.
McLeod, Tetrahedron 2009, 65, 831–843.
See, for example: a) V. Gotor-Fernández, V. Gotor, Curr. Org.
Chem. 2006, 10, 1125–1143; b) V. Gotor-Fernández, E. Busto,
V. Gotor, Adv. Synth. Catal. 2006, 348, 797–812; c) H. Ismail,
R. M. Lau, F. van Rantwijk, R. A. Sheldon, Adv. Synth. Catal.
2008, 350, 1511–1516; d) K. Han, J. Park, M.-J. Kim, J. Org.
Chem. 2008, 73, 4302–4304; e) K. Ditrich, Synthesis 2008,
2283–2287; f) C. E. Hoben, L. Kanupp, J.-E. Bäckvall, Tetrahe-
dron Lett. 2008, 49, 977–979; g) L. K. Thalén, D. Zhao, J.-B.
Sortais, J. Paetzold, C. Hoben, J.-E. Bäckvall, Chem. Eur. J.
2009, 15, 3403–3410.
N-[3-Amino-2-(3-furyl)propyl]acetamide
(12h):
Yield:
10%
(17.5 mg). R (3% NH /MeOH) = 0.33. IR (NaCl): ν = 3291, 3082,
˜
f
3
2932, 2878, 1732, 1652, 1558, 1441, 1371, 1293, 1162, 1126, 1027,
1
913, 874 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.58 (br. s, 2
H, NH2), 1.92 (s, 3 H, 9-H), 2.72–2.80 (m, 1 H, 6-H), 2.82–2.90
(m, 2 H, 6-H + 7-H), 3.33–3.42 (m, 1 H, 7-H), 3.49–3.57 (m, 1 H,
5-H), 6.11 (br. s, 1 H, NH), 6.28 (s, 1 H, 3-H), 7.29 (s, 1 H, 1-H)
7.40 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 23.1
(C-9), 39.1 (C-5), 42.0 (C-7), 44.7 (C-6), 109.1 (C-3), 124.3 (C-2),
139.5 (C-1), 143.5 (C-4), 170.1 (C-8) ppm. MS (APCI+): m/z (%) =
183 (100) [M + H]+. HRMS (ESI+): calcd. for C9H14N2O2 [M +
H]+ 183.1133; found 183.1122.
[5]
[6]
[7]
N-[3-Amino-2-(1H-pyrrol-2-yl)propyl]acetamide (12i): Yield: 17%
(31 mg). R (3% NH /MeOH) = 0.30. IR (NaCl): ν = 3288, 3097,
˜
f
3
2933, 2871, 1651, 1563, 1439, 1374, 1269, 1098, 1031, 954, 909,
1
801 cm–1. H NMR (CDCl3, 300.13 MHz): δ = 1.87–2.10 (m, 5 H,
3 9-H + NH2), 2.86–3.10 (m, 3 H, 2 6-H + 7-H), 3.35–3.44 (m, 1
H, 7-H), 3.56–3.65 (m, 1 H, 5-H), 5.95 (s, 1 H, 2-H), 6.12–6.30 (m,
2 H, 3-H + NH), 6.70 (s, 1 H, 4-H), 9.74 (br. s, 1 H, NH) ppm.
13C NMR (CDCl3, 75.5 MHz): δ = 23.2 (C-9), 40.8 (C-5), 41.7 (C-
7), 44.3 (C-6), 104.9 (C-2), 107.9 (C-3), 117.1 (C-4), 131.5 (C-1),
170.6 (C-8) ppm. MS (APCI+): m/z (%) = 182 (100) [M + H]+.
HRMS (ESI+): calcd. for C9H15N3O [M + H]+ 182.1293; found
182.1276.
General Procedure for the Synthesis of Racemic Amido Carbamates
11a–i: Pyridine (8 µL, 0.09 mmol) and allyl chloroformate (10 µL,
0.09 mmol) were successively added to a solution of the racemic
amino amide 12a–i (0.08 mmol) in dry CH2Cl2 (0.8 mL) under ni-
trogen. The mixture was stirred at room temperature for 4 h, and
after this time the solvent was evaporated under reduced pressure
to give a reaction crude that was purified by flash chromatography
on silica gel (EtOAc/hexane mixtures) to afford the corresponding
racemic amido carbamate 11a–i (18.5–30.5 mg, 91–95%). Isolated
yields for the racemic compounds 11a–i: 11a: 92%; 11b: 92%; 11c:
94%; 11d: 91%; 11e: 95%; 11f: 91%; 11g: 92%; 11h: 91%; 11i:
93%.
[8]
[9]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for com-
pounds 2–6, examples of the atomic numbering used for NMR
assignment, conditions for analytical separation by chiral HPLC of
compounds 10a–i, experimental protocols and characterization
data for the Mosher derivatives and NMR spectra for the new com-
pounds.
[10]
Acknowledgments
[11]
This work was supported by the Spanish Ministerio de Ciencia
e Innovación (MICINN) (Project MEC-CTQ2007-61126). V. G.-F.
thanks the MICINN for a personal grant (Ramón y Cajal Pro-
gram). N. R.-L. thanks the Fundación para el Fomento en Asturias
de la Investigación Científica Aplicada y la Tecnología (FICYT)
for a predoctoral fellowship.
a) M. Alexeeva, A. Enright, M. J. Dawson, M. Mahmoudian,
N. J. Turner, Angew. Chem. Int. Ed. 2002, 41, 3177–3180; b) R.
Carr, M. Alexeeva, A. Enright, T. S. C. Eve, M. J. Dawson,
N. J. Turner, Angew. Chem. Int. Ed. 2003, 42, 4807–4810; c) R.
Carr, M. Alexeeva, M. J. Dawson, V. Gotor-Fernández, C. E.
Humphrey, N. J. Turner, ChemBioChem 2005, 6, 637–639; d)
C. J. Dunsmore, R. Carr, T. Fleming, N. J. Turner, J. Am.
Chem. Soc. 2006, 128, 2224–2225; e) K. R. Bailey, A. J. Ellis,
R. Reiss, T. J. Snape, N. J. Turner, Chem. Commun. 2007, 3640–
3642; f) K. E. Atkin, R. Reiss, V. Koehler, K. R. Bailey, S. Hart,
[1] J. S. Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Bio-
mol. Chem. 2006, 4, 2237–2247.
492
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 484–493

Optically Active Heterocyclic Compounds
J. P. Turkenburg, N. J. Turner, A. M. Brzozowski, G. Grogan,
J. Mol. Biol. 2008, 384, 1218–1231.
[14]
a) E. Busto, V. Gotor-Fernández, J. Montejo-Bernardo, S.
García-Granda, V. Gotor, Org. Lett. 2007, 9, 4203–4206; b)
N. Ríos-Lombardía, E. Busto, E. García-Urdiales, V. Gotor-
Fernández, V. Gotor, J. Org. Chem. 2009, 74, 2571–2574; c) E.
Busto, V. Gotor-Fernández, V. Gotor, Tetrahedron 2009, 65,
8393–8401.
S. Ray, S. R. Pathak, D. Chaturvedi, Drugs Fut. 2005, 30, 161–
180.
a) D. Chaturvedi, N. Mishra, V. Mishra, Curr. Org. Synth.
2007, 4, 308–320; b) T. Sakakura, Chem. Commun. 2009, 1312–
1330; c) M. Carfa, E. Quaranta, Mini-Rev. Org. Chem. 2009,
6, 168–183.
[12] a) R. L. Hanson, B. L. Davis, Y. Chen, S. L. Goldberg, W. L.
Parker, T. P. Tully, M. A. Montana, R. N. Patel, Adv. Synth.
Catal. 2008, 350, 1367–1375; b) D. Koszelewski, I. Lavandera,
D. Clay, G. M. Guebitz, D. Rozzell, W. Kroutil, Angew. Chem.
Int. Ed. 2008, 47, 9337–9340; c) D. Koszelewski, I. Lavandera,
D. Clay, D. Rozzell, W. Kroutil, Adv. Synth. Catal. 2008, 350,
2761–2766; d) M. D. Truppo, J. D. Rozzell, J. C. Moore, N. J.
Turner, Org. Biomol. Chem. 2009, 7, 395–398; e) D. Koszelew-
ski, D. Clay, D. Rozell, W. Kroutil, Eur. J. Org. Chem. 2009,
2289–2292; f) M. D. Truppo, N. J. Turner, J. D. Rozzell, Chem.
Commun. 2009, 2127–2129; g) K. Smithies, M. E. B. Smith, U.
Kaulmann, J. L. Galman, J. M. Ward, H. C. Hailes, Tetrahe-
dron: Asymmetry 2009, 20, 570–574.
[13] a) R. N. Patel, Coord. Chem. Rev. 2008, 252, 659–701; b) V.
Gotor, I. Alfonso, E. García-Urdiales (Eds.), Asymmetric Or-
ganic Synthesis with Enzymes, Wiley-VCH, Weinheim, 2008; c)
J. Tao, J.-H. Xu, Curr. Opin. Chem. Biol. 2009, 13, 43–50; d)
M. Höhne, U. T. Bornscheuer, ChemCatChem 2009, 1, 42–51;
e) V. Gotor-Fernández, V. Gotor, Curr. Opin. Drug. Discov. De-
vel. 2009, 12, 784–797.
[15]
[16]
[17]
R. Ballini, A. Palmieri, P. Righi, Tetrahedron 2007, 63, 12099–
12121.
[18] R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, Synthesis 2004,
1938–1940.
[19] E. García-Urdiales, I. Alfonso, V. Gotor, Chem. Rev. 2005, 105,
313–345.
[20] D. R. Kelly, Tetrahedron: Asymmetry 1999, 10, 2927–2934.
Received: July 31, 2009
Published Online: December 1, 2009
Eur. J. Org. Chem. 2010, 484–493
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
493