‘Non‐covalent synthesis’ of a chiral host of calix[6]arene and enantiomeric discrimination

Abstract

‘Non-covalent synthesis’ of novel chiral hosts (calix[6]arene–chiral amine complexes) and its application to enantiomeric discrimination was investigated by 1H NMR spectroscopy. The topology of a ternary complex was proposed for the calix[6]arene–amine–sulfoxide to rationalize the chiral recognition. Copyright © 2005 John Wiley & Sons, Ltd.

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TETRAHEDRON:
ASYMMETRY
Tetrahedron: Asymmetry 13 (2003) 2515–2519
Pergamon
A novel asymmetric reduction of dihydro-?-carboline derivatives
using calix[6]arene/chiral amine as a host complex
Leonardo Silva Santos, Sergio Antonio Fernandes, Ronaldo Aloise Pilli* and
Anita Jocelyne Marsaioli*
Instituto de Quı ´mica, Departamento de Quı ´mica Orga ˆnica, UNICAMP, PO Box 6154, 13084-971, Campinas, SP, Brazil
Received 3 December 2002; accepted 16 April 2003
Abstract—A novel approach to the asymmetric reduction of dihydro-?-carboline derivatives to the corresponding tetrahydro-?-
carboline is described based on the supramolecular complex formed from calix[6]arene/chiral amine as an enzyme mimetic and
NaBH4as the reducing agent.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
During the course of our recent total synthesis of the
arborescidine alkaloids,1the opportunity arose to inves-
tigate a new approach to the asymmetric reduction of
imines througha host–guest
Although numerous methods for the synthesis of opti-
cally active amines are known, few are based on asym-
metric synthesis and chiral catalysis; among the most
popular are the asymmetric hydrogenation of ketimines
or enamides using chiral biphosphine-rhodium(I) com-
plexes,2iridium(I)3or ruthenium(II) complexes,4chiral
titanium complexes,5chiral amino alcohol–borane,6
and ?-hydroxysulfoximine–borane complexes.7A par-
ticularly efficient method for the reduction of dihydro-
?-carbolines is the asymmetric transfer hydrogenation
but chemists are certainly in need of more general
catalytic systems.8Therefore the search for new enan-
tioselective imine reduction methods were inspired by
the cyclodextrin (CD)/NaBH4asymmetric reduction of
carbonyl compounds.9?-, ?- and ?-CD are cyclic
molecules (host) composed of 6, 7, and 8 glucose
residues, respectively, linked with O-?-D-glucopyran-
osyl-(1,4)-bonds, possessing chiral hydrophobic cavities
thatencapsulates appropriate
molecules.10The intrinsic chirality of the cyclodextrins
is responsible for the enantioselectivity of these reac-
tions, which relies on the affinity of the carbonyl
derivatives to the hydrophobic site of the cyclodextrins
mediatedprocess.
hydrophobicguest
(CDs). These reactions have often been classified as
enzyme mimetic in comparison to the carbonyl reduc-
tion in nature with oxyredutase/NADH or NADPH.11
Herein we report novel results on the enantioselective
reduction of dihydro-?-carboline derivatives with two
enzyme mimetic systems, one composed of ?- or ?- or
?-CD and NaBH4and a second one based on the chiral
complex calix[6]arene/(R)-phenylethylamine, which has
never been reported in the literature in connection with
enantioselective reductions.
We first set out to investigate the reduction of imine 1a
in aqueous solution in the presence of ?-, ?- or ?-CD
and NaBH4(Table 1) at 0°C. In all cases, the reaction
proceeded efficiently and easily with overall yields of
2a12
ranging from 70–90%, after quenching with
aqueous HCl followed by silica gel filtration. However
the level of enantioselection was consistently low (10–
30% ee for 2a). Aiming for a better enantiomeric excess,
several conditions were tested (Table 1). The use of a
sodium bicarbonate buffer improved the solubility of
the host–guest complex while triethylamine (TEA)
proved to be beneficial to the face selectivity in the
chiral induction, but despite these attempts the best
enantiomeric excess during this set of experiments was
observed in the reduction of 1a encapsulated in ?-CD
in the presence of triethylamine (Table 1, entry 3). The
influence of TEA in CD-NaBH4reduction has already
been observed by Deratani et al. during the enantiose-
lective reduction of acetophenone by the NaBH4–CD–
* Corresponding authors. E-mail: pilli@iqm.unicamp.br; anita@
iqm.unicamp.br
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00489-0

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L. S. Santos et al. / Tetrahedron: Asymmetry 14 (2003) 2515–2519 2516
TEA system.13The authors assigned this fact to the
formation of a three-component complex (acetophe-
none, triethylamine and CD).
The reaction conditions depicted in entry 3 (Table 1)
were applied to imines 1b–d and afforded the corre-
sponding carbamates 2b,c and lactam 2d in high yields
but in poor enantiomeric excess (Scheme 1).14The poor
selectivity observed can be based on the: (1) low CD/
imine 1a/TEA binding constant; (2) lower reactivity of
the CD/imine 1a/TEA complex regarding that of free
1a; and/or (3) the topology of the complex does not
favor facial selectivity.15
1H NMR analysis of a sample of 1a/?-CD before the
addition of the reducing agent (ROESY 1D, rOe exper-
iments with shaped pulse and field gradient in z) con-
firmed the formation of the complex by depicting dipo-
lar interactions between H-4, H-5 and H-7 of the imine
1a and H-3 and H-5 of the ?-CD. We have therefore
suggested that the aromatic moiety of imine 1a was
inside the CD cavity thus possessing the complex topol-
ogy as shown in Fig. 1. In such a case the facial
selectivity is not expected to be high and indeed the
imine reduction produced 2a in 30% ee, (Table 1, entry
3).
At this stage we concluded that we needed to change
the structure of the host either by modifying the natural
CDs or by selecting a different class of encapsulating
molecule.
Inspired by our recent results with calix[6]arene(calix)
and (R)-phenylethylamine (R)-PEA, we proposed the
reduction of imine 1a with NaBH4in chloroform and in
the presence of the calix/(R)-PEA complex. This system
was never used before for enantioselective reductions
but our own observation of the power of this complex
in discriminating racemic sulfoxides gave us an idea
that we were dealing with an interesting complex.16
A controlled experiment where racemic phenylethyl-
amine, calix[6]arene and NaBH4
employed affording lactam 2a in 82% yield and estimu-
lated us to evaluate its enantiomerically pure form. Our
initial experiments were conducted with imine 1a,
calix[6]arene/(R)-phenylethylamine as the encapsulating
agent and NaBH4. The use of (R)-phenylethylamine
provided lactam 2a in good yield and 50% enantiomeric
excess when excess NaBH4(7 equiv.) was employed.
Not unexpectedly, a decrease in the amount of the
reducing agent resulted in a significant increase in the
enantiomeric excess of 2a (77% ee, entry 2). In the
absence of calix[6]arene, racemic 2a was formed which
established the need for the three-component complex.
in CHCl3
were
The topology of the complex calix[6]arene/(R)-PEA/
imine 1a was investigated by1H NMR using ROESY
1D experiments (Fig. 2). The main dipolar interactions
are between CH and CH3of the (R)-PEA and H-m and
H-p of the calix[6]arene; H-9, H-12 and H-13 of the
imine 1a and H-m and H-p of the calix[6]arene. No
Table 1. CD-mediated asymmetric reduction of 1a
EntryCond.HostMaj. Yield (%)a
ee%b
A
B
C
D
E
F
?-CD
?-CD
?-CD
?-CD
?-CD
?-CD
1
2
3
4
5
6
R
R
R
R
R
R
88
90
85
70
86
70
10
14
30
22
14
20
aDetermined for isolated product.
bDetermined by HPLC (ChiralCell OD or Welk-01 Column- hex-
ane:iso-propanol, 85:15). Condition A: ?-CD/H2O:1a:NaBH4, 1:1:7;
B: ?-CD/Na2CO3(0.2 mol/L):1a:NaBH4, 1:1:7; C: ?-CD/Na2CO3
(0.2 mol/L):Et3N:1a:NaBH4,1:1:1:7
DMSO:Et3N:1a:NaBH4,1:1:1:7;
M):Et3N:1a:NaBH4, 1:1:1:7 or 2:2:1:7; F: ?-CD/Na2CO3 (0.2
M):Et3N:1a:NaBH4, 1:1:1:7.
or 2:2:1:7;
?-CD/Na2CO3
D:
?-CD/
(0.2
E:
Scheme 1. Reagents and conditions: (i) ?-CD, Et3N, NaBH4,
0°C, 1 h, then HCl (10%); (ii) ClCO2Me, Et3N, CH2Cl2.
Figure 1. Proposed topology of the two-component complex
(imine 1a:?-cyclodextrin) based on NMR experiments.

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L. S. Santos et al. / Tetrahedron: Asymmetry 14 (2003) 2515–2519 2517
Figure 2. Proposed topology of the three-component complex
imine
1a/calix[6]arene/(R)-(−)-phenylethylamine
NMR experiments.
based on
Low temperature1H NMR experiments (varying from
213 to 298 K) revealed that the methylene hydrogens of
the calix[6]arene/PEA/imine which absorbed at 3.89
ppm as a broad singlet at room temperature split into
four sharp doublets at 3.50; 3.66; 4.02 and 4.35 ppm in
a 1:2:1:2 ratio at 213 K. The two doublets of higher
amplitude belong to the same spin system observed by
2D NMR (H,H COSY). The same is true for the
doublet in 3.66 and 4.35 ppm, suggesting a slow equi-
librium (for the NMR timescale) between the two cone
conformations (Fig. 2). To determine the predominance
of one supramolecule in relation to the others is beyond
the scope of the present investigations.
In order to probe the importance of the intermolecular
forces and how they affect the superstructure and the
final product stereochemistry we have changed the (R)-
PEA to (R)-naphthylethylamine 4 affording 2a in a
somewhat lower yield (75%) and selectivity (61% ee).
Interestingly, inversion of the configuration of 2a was
achieved with (R)-2-amine-1-butanol 5. Unfortunately,
the enantiomeric excess of (R)-2a was very low (6% ee)
as depicted in Table 2 (entry 6). Thus we concluded
that the ?–? interactions or hydrogen bonding play a
significant role in the complex formation.
Next we extended the method to imines 1b–d, synthe-
sized as described previously (Scheme 2).1Structurally
similar dihydro-?-carboline 1c afforded the correspond-
ing carbamate 2c, after nitrogen protection with methyl
chloroformate, in 88% yield and 65% ee. However, the
bromine substituent in the aromatic ring proved to be
essential for good facial discrimination as the debromi-
nated ?-carboline 1d afforded the corresponding lactam
2d,17in good yield but in disappointingly low enan-
tiomeric excess (ee 20%). The same behaviour was
dipolar interactions between PEA and the imine 1a
were observed. In order to fit all these dipolar interac-
tions we suggested the formation of a three-component
complex. Searching for more evidence we measured the
diffusion coefficient of the pure species 1a, calix and
(R)-PEA and that of the complex by1H NMR (pulsed
field gradient spin echo, DgcsteSL) which is the perfect
technique to probe encapsulation.16As expected the
diffusion coefficients in deuterochloroform of free 1a
and (R)-PEA (about D1a=11.3×10−10m2s−1and D(R)-PEA
=18.9×10−10m2s−1) were higher than that of the
calix[6]arene (7.9×10−10m2s−1) and higher than the
diffusion coefficients of these three species in solution
(D1a=10.2×10−10m2s−1; D(R)-PEA=16.4×10−10m2s−1
and Dcalix[6]=7.8×10−10m2s−1) clearly indicating an
association between 1a/PEA/calix. Thus the diffusion
coefficients and the dipolar interactions support the
interaction between the three molecules. These can exist
in a fast equilibrium regime (coherent with only one set
of signals for all species Fig. 2) of two or more
supramolecules or in assemblies of supramolecules.
Table 2. Calix[6]arene/chiral-inductor mediated asymmetric reduction of 1a
Cond.Entry Host InductorMaj.Yield (%)a
ee%b
Calix[6]arene
Calix[6]arene
Calix[6]arene
–
Calix[6]arene
Calix[6]arene
50
77
–
–
61
6
90
85
95
82
75
75
A
B
B
C
B
B
S
S
–
–
S
R
1
2
3
4
5
6
(R)-3
(R)-3
(±)-3
(R)-3
(R)-4
(R)-5
aDetermined after isolation.
bDetermined by HPLC (ChiralCell OD or Welk-01 Column- hexane: iso-propanol, 85:15). Conditions: A: calixarene:amine:1a:NaBH4, 1:1:1:7; B:
calixarene:amine:1a:NaBH4, 1:1:1:1; C: amine:1a:NaBH4, 1:1:1.

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L. S. Santos et al. / Tetrahedron: Asymmetry 14 (2003) 2515–25192518
observed for dihydro-?-carboline 1b (90% yield, 22%
ee).18The decrease in selectivity found in the debromo
compounds 1b and 1d can be rationalized as a weaker
?–? interaction between the calix and 1b and 1d as
compared to that of 1a (Scheme 2).
In conclusion, the potential use of the supramolecular
complexcalix[6]arene/(R)-phenylethylamine
enantioselective NaBH4
derivatives has been established. We continue to
explore this conceptually novel approach to the enan-
tioselective reduction of cyclic imines as well as the
origin of the asymmetric induction observed.
in the
reduction of
?-carboline
2. Experimental
2.1. General information
NMR spectra were recorded on either a Varian-Gemini
2000 (300 MHz) or a Bruker instruments (400 MHz).
HRMS were run on MicroMass-VG Autospec equip-
ment. HPLC analyses were performed in a Hewlett
Packard HP1050 equipment. The ?maxwere measured
in an Agilent 8453 equipment.
2.2. General method to CD-mediated reduction
An equimolar amount of imine (0.5 mmol) and Et3N
(0.5 mmol) was added to a suspension of dried CD (0.5
mmol) in 2.5 mL of aqueous sodium bicarbonate solu-
tion (0.2 mol/L). The mixture was stirred at room
temperature overnight and the resulting slurry used
without further processing. NaBH4(0.5–3.5 mmol) was
then added to the mixture obtained previously and
stirred at 0°C for 1 h. After acidification with aqueous
solution of HCl (10%) the mixture was stirred for an
additional period of 1 h at room temperature. Extrac-
tion with CH2Cl2(3×10 mL), and the combined organic
layer washed with water (2×10 mL) and dried with
MgSO4. After evaporation of solvent, the resulting title
compound was filtered through silica using CHCl3/
MeOH. Analysis by NMR showed these compounds to
be free of impurities. Enantiomeric excess (ee%) was
determined by HPLC on a chiral column (Welk-01)
using hexane:iso-propanol (10–15%) with a flow rate of
1.0 mL/min. The ?max was measured in a Hewlett
Packard equipment for each compound.
2.3. General method to calix[6]arene/chiral inductor
mediated reduction
Chloroform was added to an equimolar amount of
calix[6]arene (0.12 mmol) and chiral inductor (0.12
mmol) and stirred at room temperature overnight. The
resulting mixture was then added to an equimolar
amount of imine (0.12 mmol) and stirred for 1 h.
NaBH4(0.12 mmol) was then added to the mixture and
stirred at 0°C for 1 h. After acidification with an
aqueous solution of HCl (10%), the mixture was stirred
for an additional period of 1 h at room temperature.
Extraction with CH2Cl2(3×10 mL), and the combined
organic layer washed with water (2×10 mL) and dried
with MgSO4. After evaporation of solvent, the resulting
title compound was filtered through silica using CHCl3/
MeOH. Analysis by NMR showed these compounds to
be free of impurities. Enantiomeric excess (ee%) was
determined by HPLC on a chiral column (Welk-01)
using hexane:iso-propanol (10–15%) with a flow rate of
1.0 mL/min. The ?max was measured in a Hewlett
Packard equipment for each compound.
2.4. Preparation of compounds 2a–d
Lactam (S)-2a: According to general procedures, the
crude was purified by flash chromatography (CHCl3/
MeOH, 10%, Rf=0.7) to afford the lactam 2a as a
cream solid. [?]D=−0.7 (c 0.9, CHCl3) to 77% ee. Mp
242–243°C.1H NMR (CDCl3, 300 MHz) ?: 1.71–1.94
(3H, m), 2.34–2.66 (2H, m), 2.73 (1H, m), 2.84 (2H, d,
J 9.5), 2.94 (1H, d, J 11.5), 4.74 (1H, br dd, J 9.1 and
3.3), 5.16 (1H, d, J 8.8), 7.19 (1H, dd, J 8.4 and 0.7),
7.33 (1H, d, J 8.4), 7.46 (1H, s), 8.62 (1H, s).13C NMR
(CDCl3, 75 MHz) ?: 19.4, 21.0, 29.0, 32.5, 40.1, 54.4,
109.4, 113.9, 115.2, 119.5, 122.9, 125.7, 134.0, 137.0,
169.1. IR (KBr film) cm−1: 3265, 3101, 2924, 2854,
1616, 1462, 1442, 1311, 1269, 1232, 1038, 754. HRMS
(70 eV): C15H15N2OBr calcd 318.0368, found 318.0366.
Carbamate (R)-2b: According to general procedures,
the crude was purified by flash chromatography
(CHCl3/MeOH, 3.3%, Rf=0.75) to afford the carba-
mate 2b as a brown oil. [?]D=−0.2 (c 0.5, CHCl3) to
22% ee.
1.68–1.72 (1H, m), 1.72 (1H, dt, J 9.0 and 1.6), 1.81
(1H, dt, J 10.6 and 2.9), 1.96 (1H, quint, J 7.1),
2.12–2.13 (2H, m), 2.34–2.39 (1H, m), 2.65 (1H, d, J
3.8), 2.68 (1H, dq, J 11.5 and 5.1), 3.14 (1H, dtd, J 11.1
and 4.7), 3.66 (3H, s), 4.23 (1H, br s), 4.99 (2H, dd, J
1H NMR (d6-DMSO, 333 K, 400 MHz) ?:
Scheme 2.

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L. S. Santos et al. / Tetrahedron: Asymmetry 14 (2003) 2515–25192519
17.1 and 9.9), 5.09 (1H, dd, J 17.1 and 7.4), 5.32 (1H,
br s), 5.77 (1H, ddt, J 17.1, 9.4 and 7.4), 5.88 (1H, ddt,
J 17.1, 9.4 and 7.4), 6.97 (1H, dt, J 7.9 and 0.7), 7.04
(1H, dt, J 7.9 and 0.9), 7.31 (1H, d, J 7.9), 7.36 (1H, d,
J 7.9), 10.69 (1H, s).13C NMR (d6-DMSO, 333 K, 100
MHz) ?: 20.5, 33.6, 36.6, 37.3, 49.2, 52.1, 78.8, 106.1,
110.7, 116.0, 117.2, 118.2, 120.5, 126.2, 134.9, 135.7,
136.5, 155.6. IR (KBr film) cm−1: 3306, 3074, 3001,
2922, 2852, 1680, 1469, 1442, 1410, 802, 760. HRMS
(70 eV): C21H26N2O2calcd. 338.1994, found 338.1997.
Carbamate (S)-2c: According to general procedures, the
crude was purified by flash chromatography (CHCl3/
MeOH, 2.5%, Rf=0.51) to afford the carbamate 2c as a
brown solid. [?]D=+23.5 (c 0.6, CHCl3) to 65% ee. Mp
62–63°C.
1.45–1.55 (2H, m), 1.73–1.82 (1H, m), 1.89–1.91 (1H,
m), 2.09 (2H, quint, J 5.9), 2.64 (1H, dd, J 5.9 and 2.2),
2.63–2.67 (1H, m), 3.16 (1H, ddd, J 12.8, 10.2 and 6.6),
3.66 (3H, s), 4.25 (1H, dd, J 15.2 and 3.2), 4.96 (1H, dd,
J 10.3 and 1.5), 5.02 (1H, dd, J 17.1 and 1.5), 5.16 (1H,
dd, J 9.2 and 4.1), 5.82 (1H, ddt, J 17.1, 10.3 and 6.7),
7.07 (1H, dd, J 8.4 and 1.5), 7.31 (1H, d, J 8.4), 7.48
(1H, d, J 1.5), 10.83 (1H, s).13C NMR (d6-DMSO, 343
K, 100 MHz) ?: 20.3, 24.6, 32.5, 33.4, 37.5, 50.7, 51.9,
106.6, 113.1, 113.3, 114.3, 118.8, 121.0, 125.2, 135.6,
136.6, 138.1, 155.4. IR (KBr film) cm−1: 3306, 3074,
3001, 2922, 2852, 1680, 1469, 1442, 1410, 802, 760.
HRMS (70 eV): C18H21N2O2Br calcd 376.0786, found
376.0789.
1H NMR (d6-DMSO, 343 K, 400 MHz) ?:
Lactam 2d: According to general procedures, the crude
was purified by flash chromatography (CHCl3/MeOH,
10%, Rf=0.85) to give lactam 2d as a brown oil.
[?]D=−0.3 (c 0.5, CHCl3) to 20% ee.1H NMR (CDCl3,
333 K, 300 MHz) ?: 1.74–2.02 (3H, m), 2.38–2.50 (2H,
m), 2.63 (1H, m), 2.76–2.81 (2H, m, 2.87–2.92 (1H, m),
4.81 (1H, br dd, J 9.1 and 3.3), 5.15–5.22 (1H, m), 7.14
(1H, td, J 7.5 and 0.9), 7.20 (1H, td, J 7.5 and 0.9), 7.36
(1H, d, J 7.5), 7.52 (1H, d, J 7.5), 7.88 (1H, s).
NMR (CDCl3, 75 MHz) ?: 19.4, 21.0, 29.1, 32.4, 40.2,
54.4, 109.7, 110.9, 118.4, 119.9, 122.2, 126.9, 133.3,
136.3, 169.3. IR (KBr film) cm−1: 3223, 2926, 2856,
1609, 1470, 1440, 1409, 1325, 1268, 1234, 1038, 741.
HRMS (70 eV): C15H16N2O calcd. 240.1263, found
240.1259.
13C
Acknowledgements
Fapesp and CAPES for financial support.
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52, 3769.
12. Compound 2a was previously used in the synthesis of
(+)-arborescidine A, Ref. 1.
13. Deratani, A.; Renard, E.; Djedaı ¨ni-Pilard, F.; Perly, B. J.
Chem. Soc., Perkin Trans. 2 1997, 1517.
14. We tried to reduce the amount of NaBH4employed, but
unfortunately the hydrogenation of the corresponding
imines 1a–d only proceeded with 7 or more equivalents of
the reducing agent.
15. Takahashi, K.; Hattori, K. J. Incl. Phenom. 1994, 17, 1.
16. (a) Fernandes, S. A.; Porto, A. L. M.; Nachtigall, F. F.;
Lazzarotto, M.; Marsaioli, A. J., manuscript in prepara-
tion; (b) Borges, R. B.; Laverde, A., Jr.; Porto, A. L. M.;
Marsaioli, A. J. Spectrosc-Int J. 2000, 14, 203; (c)
Laverde, A., Jr.; Conceic ¸a ˜o, G. J. A.; Queiroz, S. C. N.;
Fujiwara, F. Y.; Marsaioli, A. J. Magn. Reson. Chem.
2002, 40, 433.
17. Compound 2b was previously prepared in the total syn-
thesis of (R)-akagerine, Santos, L. S.; Pilli, R. A.; Rawal,
V. H., manuscript in preparation.
18. Compound 2c was previously used in the total synthesis
of (−)-arborescidine C and D, Ref. 1.