Synthesis of atropisomeric 1-phenylpyrrole-derived amino alcohols: New chiral ligands

Article abstract of DOI:10.1002/chir.22049

An efficient synthetic method has been developed for the preparation of a new family of atropisomeric amino alcohols with 1-phenylpyrrole backbone. The synthesis is based on the different reactivities of the two carboxylic groups in optically active 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2- carboxylic acid (1). The chemical structures of the key intermediates were confirmed by spectroscopic methods and single crystal X-ray diffraction measurements. The very first application of a new optically active amino alcohol as catalyst for the enantioselective addition of diethylzinc to benzaldehyde demonstrated the practical usefulness of atropisomeric compounds in which there are six-atom chains between the two functional groups.

Full text of DOI:10.1002/chir.22049

CHIRALITY (2012)
Synthesis of Atropisomeric 1-Phenylpyrrole-Derived Amino Alcohols:
New Chiral Ligands
2
3
4
4
4
FERENC FAIGL,1,2 BÉLA MÁTRAVÖLGYI, ÁRON SZÖLLOSY, MÁTYÁS CZUGLER, GÁBOR TÁRKÁNYI, KÁROLY VÉKEY AND
´´
*
MIKLÓS KUBINYI5
1Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary
2Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, Budapest, Hungary
3Department of General and Analytical Chemistry, Budapest University of Technology and Economics, Budapest, Hungary
4Institute of Organic Chemistry, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
5Institute of Molecular Pharmacology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
ABSTRACT
An efficient synthetic method has been developed for the preparation of a new
family of atropisomeric amino alcohols with 1-phenylpyrrole backbone. The synthesis is based
on the different reactivities of the two carboxylic groups in optically active 1-[2-carboxy-6-
(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid (1). The chemical structures of the key
intermediates were confirmed by spectroscopic methods and single crystal X-ray diffraction
measurements. The very first application of a new optically active amino alcohol as catalyst
for the enantioselective addition of diethylzinc to benzaldehyde demonstrated the practical
usefulness of atropisomeric compounds in which there are six-atom chains between the two
functional groups. Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: site selective reaction; metalation; enantioselective reaction; chiral amino alcohol;
organocatalyst
INTRODUCTION
the rotationally restricted 1-phenylpyrrole backbone. Therefore,
these amino alcohols were expected to serve as new ligands in
enantioselective reactions.
Bifunctionalized atropisomeric biaryls are widely used in dif-
ferent enantioselective reactions as chiral ligands, auxiliaries,
or optically active organocatalysts.1 2,2´-Disubstituted 1,1´-
binaphtalenes and 1,1´-biphenyls, both with C2 symmetry, are
classical representatives of these compounds.2,3 Most fre-
quently, they have two hydroxyl, amino, or phosphino groups
in the C2 and C2´ positions.1 Simultaneous or separate modifi-
cations of the chemically identical groups of these biaryls are
simple, applying the reactants in suitable molar ratios. Similarly,
the simultaneous transformation of both functional groups of a
bifunctionalized chiral compound of C1 symmetry is relatively
easy. For example, the dimethyl ester, two tetrasubstituted diol
derivatives, and two pyrrolobenzoxazepine derivatives of
optically active 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-
pyrrole-2-carboxylic acid (1) were prepared in our laboratory,
using the reagents in excess.4 The selective modification of
one functional group of the two identical ones in atropisomeric
compounds with C1 symmetry, such as dicarboxylic acid 1,
requires a different strategy. With a careful selection of the
reagents and conditions, however, the reactivity differences
between the two carboxylic acid functions can be exploited.
In the present study, which was a part of our ongoing
project on the chemistry of atropisomeric 1-phenylpyrrole
derivatives, our aim is to develop a synthesis for new chiral
amino alcohols, starting from dicarboxylic acid 1. Optically
active amino alcohols are among the most frequently applied
compounds in enantioselective reactions. Recently, several
papers have been published on the synthesis and application
of b-amino alcohols,5,6 and promising results have been
published about the application of 1,4-amino alcohols7 as
chiral additives in enantioselective reactions.
For an efficient synthesis for the target molecules to be
found, detailed experimental studies were carried out in our
laboratory.
EXPERIMENTAL
General
All commercial starting materials were purchased from Sigma Aldrich
Kft. (Budapest, Hungary) and Merck Kft. (Budapest, Hungary) and were
used without further purification. Tetrahydrofuran was obtained anhy-
drous by distillation from sodium wire, after the characteristic blue color
of the in situ generated sodium diphenylketyl had been found to persist.
The organometallic reactions and the reductions were carried out in
Schlenk flasks under a dry nitrogen atmosphere. Thin-layer chromatogra-
phy (TLC) was carried out on Kieselgel 60 F254 (Merck) sheets (visuali-
zation of the products was made by exposing the plate to UV radiation or
by staining it with the aqueous solution of (NH4)6Mo7O24, Ce(SO4)2, and
sulphuric acid. Routine 1H, 13C and 19F NMR spectra were recorded in
CDCl3, acetone-d6 and DMSO-d6 solution on a Bruker AV 300 or DRX 500
spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany). Proton
chemical shifts are reported in ppm relative to the internal standard
(dTMS = 0 ppm) or solvents (dAcetone = 2.05, dDMSO = 2.50 ppm), and car-
bon chemical shifts are reported in ppm relative to the solvents
(dChloroform = 77.00). The enantiomeric ratios of the optically active
samples of 12a were determined from the 1H spectra recorded at
Contract grant sponsor: National Development Agency, New Hungary Devel-
opment Plan. Project title: “Development of quality-oriented and harmonized
R + D + I strategy and functional model at BME”.; Contract grant number:
TÁMOP-4.2.1/B-09/1/KMR-2010-0002.
*Correspondence to: Ferenc Faigl, Department of Organic Chemistry and
Technology, Budapest University of Technology and Economics, Budafoki
út 8., H-1111 Budapest, Hungary. E-mail: ffaigl@mail.bme.hu
Received for publication 1 December 2011; Accepted 11 March 2012
DOI: 10.1002/chir.22049
Published online in Wiley Online Library
(wileyonlinelibrary.com).
In the designed new amino alcohols, the amino and the
hydroxyl groups are separated by a six-atom chain, yet, they
must be close in space, because they are both attached to
© 2012 Wiley Periodicals, Inc.

FAIGL ET AL.
25 ꢀC on a Varian Inova400 spectrometer in the presence of (R)-1. The
3099, 2977, 2952, 1738, 1616, 1544, 1479, 1330, 1289. 1H NMR
(CDCl3, 300 MHz) dH 8.13 (1H, dd, J = 7.8, 1.5 Hz), 7.87 (1H, dd,
J = 7.5, 1.5 Hz), 7.57 (1H, t, J = 8.1 Hz), 6.78 (1H, br s), 6.55 (1H, dd,
J = 3.6, 1.5 Hz), 6.30 (1H, dd, J = 3.6, 3.0 Hz), 3.67 (3H, s), 3.52
(2H, m), 3.39 (2H, m), 1.12 (6H, t, J = 5.4 Hz). 13C NMR (CDCl3,
75 MHz) dC 164.84, 162.02, 139.06 (d, J = 1.6 Hz), 133.86, 132.22,
129.69 (q, J = 5.2 Hz), 128.64 (q, J = 31 Hz), 128.18, 127.56, 122.93
(q, J = 273 Hz), 111.59, 107.68, 52.49, 41.00, 40.43, 13,27. 19F
NMR (CDCl3, 282 MHz) dF ꢂ60.02. HRMS (EI) m/z calcd. for
enantiomeric ratios of the optically active samples of 2 and 13a–c
were determined by high-performance liquid chromatography (HPLC)
measurements carried out on Phenomonex (Torrance, USA) Lux
Cellulose-2 or Amylose-2 columns (5 mm, 250 ꢁ 4.6 mm) (eluent
hexane/ethanol). Infrared (IR) spectra were recorded on an appliance
type PerkinElmer (Waltham, USA) 1600 with a Fourier Transformer.
Data are given in cmꢂ1. Specific rotation of the optically active
samples was determined on a PerkinElmer 245 MC polarimeter using
sodium lamp (589 nm). Melting points were determined in capillary
tubes, using a Gallenkamp (Loughborough, UK) melting point appara-
tus. Computations were performed at the AM1 semiempirical level
implemented in the MOPAC (Stewart Computational Chemistry,
Colorado Springs, USA) package of InsightIIW commercial software.
High-resolution mass spectra (HRMS) were recorded on Waters (Waters
Kft., Budapest, Hungary) LCT Premier XE spectrometer in electrospray
ionization (ESI, 2.5 kV) mode, using water (0.035% trifluoroacetic acid)/
acetonitrile (0.035% trifluoroacetic acid) as eluent in gradient elution (5–95%
acetonitrile); samples were made up in acetonitrile.
C18H19F3N2O3 (M)+: 368.1366, found 366.1348. ½aꢃ25 =ꢂ88.9 (c 1.0; EtOH).
D
N,N-Diisopropyl-(S )-1-[2-methoxycarbonyl-6-(trifluoromethyl)phe-
nyl]-1H-pyrrole-2-carboxamide ((S )-6b).
After the addition of
diisopropyl amine, the reaction mixture was stirred for 24 h at 25 ꢀC
and was monitored by TLC (hexane/ethyl acetate = 3/1, Rf = 0.40).
After general work-up, pure (S)-6b was yielded as white solid
(1.24 g, 98%). Mp: 76–78 ꢀC (from toluene). IR (KBr, cmꢂ1): 3099,
3009, 2973, 2933, 1748, 1614, 1540, 1438, 1246, 1211. 1H NMR
(CDCl3, 500 MHz) dH 8.14 (1H, d, J = 8.0 Hz), 7.87 (1H, d, J = 8.0 Hz),
7.56 (1H, t, J = 8.0 Hz), 6.73 (1H, s), 6.45 (1H, dd, J = 3.5, 1.5 Hz),
6.27 (1H, t, J = 3.3 Hz), 5.80–2.40 (2H, br s), 3.67 (3H, s), 1.27
(6H, d, J = 6.5 Hz), 1.21 (6H, d, J = 6.5 Hz). 13C NMR (CDCl3,
75 MHz) dC 165.05, 161.91, 139.27 (d, J = 1.4 Hz), 134.27, 132.38,
129.94 (q, J = 5.1 Hz), 128.76 (q, J = 30.3 Hz), 128.31, 127.11, 123.19
(q, J = 274.2 Hz), 110.81, 107.59, 52.63, 21.08, 20.99. 19F NMR (CDCl3,
Synthesis
(S)-1-[2-Methoxycarbonyl-6-(trifluoromethyl)phenyl]-1H-pyrrole-
2-carboxylic acid ((S)-2).
(S)-1-[2-Carboxy-6-(trifluoromethyl)
phenyl]-pyrrole-2-carboxylic acid (1, 16.7 mmol, 5.00 g, ee 99.8%) was
dissolved in methanol (75 ml), and the solution was cooled down to
0 ꢀC. Then thionyl chloride (116.9 mmol, 8.53 ml) was added dropwise
into it, and the reaction mixture was stirred at room temperature for
48 h. The reaction was monitored by TLC (ethyl acetate/methanol =
3/1) until 1 was consumed. The solvent was evaporated in vacuo,
and hexane (40 ml) was poured to the residue. The mixture was
refluxed for an hour, and the solid was filtered off, washed with
hexane to yield monoester (S)-2 as white crystalline material
(4.19 g, 80%, ee 99.8%). mp 159–160 ꢀC (from hexane). IR (KBr,
cmꢂ1): 3434, 1735, 1664, 1540, 1484. 1H NMR (CDCl3, 300 MHz)
dH 8.16 (1H, d, J = 8.5 Hz), 7.92 (1H, d, J = 8.5 Hz), 7.64 (1H, t,
J = 8.5 Hz), 7.14 (1H, dd, J = 3.9, 1.8 Hz), 6.85 (1H, br s), 6.34 (1H,
dd, J = 3.9, 3.0 Hz), 3.64 (3H, s). 13C NMR (CDCl3, 75 MHz) dC
164.64, 164.60, 134.09, 131.51, 131.25, 130.02 (q, J = 5 Hz), 129.17
(q, J = 31 Hz), 128.96, 128.83, 125.10, 122.65 (q, J = 272 Hz), 119.42,
109.68, 52.68. 19F NMR (CDCl3, 282 MHz) dF ꢂ60.47. Anal. Calcd
for C14H10F3NO4 (313.23): C, 53.68; H, 3.22; N, 4.47. Found: C,
282 MHz) dF ꢂ59.64. ½aꢃ2D5 = ꢂ83.9 (c 1.0; EtOH).
N-Isopropyl-(S)-1-[2-methoxycarbonyl-6-(trifluoromethyl)phenyl]-
1H-pyrrole-2-carboxamide ((S)-6c).
The reaction was monitored
by TLC (hexane/ethyl acetate = 1/1, Rf = 0.45). Pure (S)-6c is a white
solid (1.11 g, 98%). Mp: 133–134 ꢀC (from toluene). IR (KBr, cmꢂ1):
3323, 3275, 2974, 1733, 1628, 1551, 1484. 1H NMR (CDCl3,
300 MHz) dH 8.15 (1H, d, J = 7.8 Hz), 7.91 (1H, d, J = 7.8 Hz), 7.60
(1H, t, J = 8.0 Hz), 6.75 (1H, br s), 6.63 (1H, dd, J = 3.75, 1.5 Hz), 6.30
(1H, t, J = 3.0 Hz), 5.60 (1H, d, J = 7.8 Hz), 4.03 (1H, octet, J = 6.9 Hz)
3.67 (3H, s), 1.13 (3H, d, J = 1.5 Hz), 1.11 (3H, d, J = 1.5 Hz). 13C
NMR (CDCl3, 75 MHz) dC 164.64, 159.80, 139.40, 133.94, 131.38,
129.94 (q, J = 5.1 Hz), 129.32, 128.79 (q, J = 30.4 Hz), 128.34, 122.85
(q, J = 274.0 Hz), 110.45, 108.55, 96.12, 52.50, 40.90, 22.92, 22.90. 13C
DEPT (CDCl3, 75 MHz) dC 133.94, 129.94 (q, J = 5.1 Hz), 128.34,
110.45, 108.55, 52.50, 40.90, 22.92, 22.90. 19F NMR (CDCl3, 282MHz)
dF ꢂ60.33. HRMS (EI) m/z calcd. for C17H17F3N2O2 (M)+: 354.1201,
54.01; H, 3.78; N 4.60. ½aꢃ2D5 = ꢂ55.5 (c 1.2; EtOH). Ee was determined after
the quantitative conversion into their dimethyl esters4 (3) by HPLC
analysis using a chiral stationary phase, Phenomonex Lux Cellulose-2
column (5 mm, 250 ꢁ 4.6 mm), eluent hexane/ethanol = 97/3, 0.8 ml/
min, UV detector 256 nm, 20 ꢀC, retention time for (S)-3: 12.2 min., for
(R)-3: 13.6 min.
found 354.1191. ½aꢃ2D5 = ꢂ69.6 (c 0.78; EtOH).
N-Benzyl-(S )-1-[2-methoxycarbonyl-6-(trifluoromethyl)phenyl]-1H-
pyrrole-2-carboxamide ((S )-6d).
The reaction was monitored by
TLC (hexane/ethyl acetate = 1/1, Rf = 0.50). Pure (S)-6 d is a white
solid (1.31 g, 98%). Mp: 123–125 ꢀC (from toluene). IR (KBr, cmꢂ1):
3352, 3288, 1735, 1637, 1558, 1482. 1H NMR (CDCl3, 500 MHz) dH
8.17 (1H, d, J = 8.0 Hz), 7.93 (1H, d, J = 7.5 Hz), 7.61 (1H, t,
J = 8.0 Hz), 7.31–7.16 (5H, m) 6.78 (1H, br s), 6.67 (1H, dd, J = 3.5,
1.5 Hz), 6.31 (1H, dd, J = 4.0, 3.0 Hz), 6.09 (1H, br s), 4.42 (2H, d,
J = 5.5 Hz), 3.66 (3H, s). 13C NMR (CDCl3, 75 MHz) dC 164.62,
160.39, 139.30, 138.46, 134.03, 131.32, 130.02 (q, J = 5.0 Hz), 128.88
(q, J = 31 Hz), 128.74, 128.59, 128.46, 127.60, 127.35, 122.85
(q, J = 274 Hz), 111.07, 108.74, 52.54, 43.02. 19F NMR (CDCl3,
282 MHz) dF ꢂ60.24. HRMS (EI) m/z calcd. for C21H17F3N2O3 (M)+:
General Procedure for the Synthesis of Amides 6a–f
(S)-1-[2-Methoxycarbonyl-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-
carboxylic acid ((S)-2, 3.2 mmol, 1.00 g, ee 99.8%) was dissolved in
dry toluene (10 ml) and thionyl chloride (3.84 mmol, 0.28 ml), and
one drop dry dimethylformamide was added dropwise. The reac-
tion mixture was stirred at 80 ꢀC for 2 h. The solvent was evapo-
rated in vacuo. The residue was dissolved in dry toluene (10 ml).
A
solution of the respected amine (8.0 mmol) in dry toluene
(5 ml) was added dropwise at 0 ꢀC, and the mixture was stirred
for 15 min. 1-M solution of hydrogen chloride (10 ml) was added,
the phases were separated, and the organic solution was washed
with water (5 ml), then brine (5 ml) before drying over sodium sulfate
and concentrated in vacuo.
402.1187, found 402.1191. ½aꢃ2D5 = ꢂ45.5 (c 0.7; EtOH).
N-[(R)-1-phenylethyl]-(S)-1-[2-methoxycarbonyl-6-(trifluoromethyl)
phenyl]-1H-pyrrole-2-carboxamide ((S)-6e).
The reaction was
N,N-Diethyl-(S )-1-[2-methoxycarbonyl-6-(trifluoromethyl)phenyl]-
1H-pyrrole-2-carboxamide ((S )-6a).
The reaction was monitored
monitored by TLC (hexane/ethyl acetate = 1/1, Rf =0.75). Pure (S)-6e is a
white solid (1.31 g, 99%). Mp: 132–134 ꢀC (from toluene). IR (KBr, cmꢂ1):
3316, 1735, 1722, 1627, 1482, 1147. 1H NMR (CDCl3, 300MHz) dH 8.12
by TLC (hexane/ethyl acetate = 1/1, Rf = 0.45). Pure (S)-6a is a white
solid (1.16 g, 99%). Mp: 57–58 ꢀC (from toluene). IR (KBr, cmꢂ1):
Chirality DOI 10.1002/chir

NEW ATROPISOMERIC AMINO ALCOHOLS
(1H, d, J=7.8Hz), 7.91 (1H, d, J= 7.2 Hz), 7.58 (1H, t, J=7.8Hz), 7.32–7.21 (5H,
m), 6.76 (1H, br s), 6.76 (1H, dd, J= 3.9, 1.5 Hz), 6.29 (1H, t, J= 3.3 Hz), 6.03 (1H,
d, J= 8.4 Hz), 5.09 (1H, quint, J= 7.4 Hz), 3.58 (3H, s), 1.45 (3H, d, J=6.9Hz). 13
is a white solid (1.06 g, 96%). Mp: 143–146 ꢀC (from diethyl ether). IR
(KBr, cmꢂ1): 3304, 3001, 2970, 2936, 2879, 1590, 1466, 1323, 1164,
1126. 1H NMR (CDCl3, 500 MHz) dH 7.78 (1H, d, J = 7.5 Hz), 7.65
(1H, d, J = 8.0 Hz), 7.54 (1H, t, J = 7.5 Hz), 6.65 (1H, s), 6.46 (1H, dd,
J = 2.5 Hz), 6.29 (1H, t, J = 3.0 Hz), 5.77 (1H, d, J = 7.5, 3.0 Hz), 4.68
(1H, br s), 4.27–4.20 (2H, m), 3.42 (1H, br s), 1.32 (6H, d, J = 6.5 Hz),
1.18 (6H, s). 13C NMR (CDCl3, 75 MHz) dC 163.11, 142.31, 137.02
(d, J = 1.5 Hz), 134.64, 129.69, 129.23, 127.40, 127,27 (q, J = 30.1 Hz),
125.69 (q, J = 5.2 Hz), 119.63 (q, J = 273.7 Hz), 110.98, 107.91, 60.62,
C
NMR (CDCl3, 75MHz) dC 164.84, 159.92, 143.54, 139.42 (d, J= 1.5), 134.21,
131.63, 130.16 (q, J= 5.1 Hz), 129.23, 128.95 (q, J= 30.5 Hz), 128.82, 128.72,
128.63, 127.34, 126.29, 123.28 (q, J= 274.1 Hz), 111.19, 108.87, 52.67, 48.19,
21.96. 19F NMR (CDCl3, 282MHz) dF ꢂ60.23. ½aꢃ25 = +27.2 (c 0.85; EtOH).
D
(S)-1-[2-Methoxycarbonyl-6-(trifluoromethyl)phenyl]-1H-pyrrole-
25
50.50, 46.47, 20.75, 19.95. 19F NMR (CDCl3, 282 MHz) dF ꢂ60.30. ½aꢃD
2-carboxamide ((S)-6f).
To the solution of the acid chloride in dry
toluene (10ml) aqueous ammonia (15M, 8.0mmol, 1.88 ml) was added
at 0 ꢀC, then the mixture was stirred for 15 min. The reaction was
monitored by TLC (pure ethyl acetate, Rf = 0.42). 1-M solutions of
hydrogen chloride (10ml) and toluene (40ml) were added, the phases
were separated, and the organic solution was washed with water (10ml),
then brine (10ml) before drying over sodium sulfate and concentrated
in vacuo to yield pure (S)-6f as white solid (0.97 g, 98%). Mp: 104–105 ꢀC
(from toluene). IR (KBr, cmꢂ1): 3497, 3428, 3355, 2952, 1741, 1729,
1635, 1608, 1483, 1448. 1H NMR (CDCl3, 300 MHz) dH 8.15 (1H, d,
J = 7.4 Hz), 7.92 (1H, d, J = 7.8Hz), 7.60 (1H, t, J = 8.0Hz), 6.79 (1H, s),
6.74 (1H, dd, J= 3.9, 1.5 Hz), 6.32 (1H, t, J= 3.3 Hz), 5.38 (1H, br s), 3.67 (3H, s).
13C NMR (CDCl3, 75MHz) dC 164.88, 162.24, 139.39 (d, J= 1.7 Hz), 134.23,
131.57, 130.23 (q, J = 5.1 Hz), 129.52, 129.10 (q, J= 30.6Hz), 128.70, 128.09,
123.05 (q, J= 274.2 Hz), 112.92, 109.11, 52.80. 19F NMR (CDCl3, 282 MHz)
dF ꢂ60.32. HRMS (ESI) m/z calcd. for C14H12F3N2O3 (M + H)+: 313.2513,
= ꢂ163.4 (c 0.5; EtOH).
N-Isopropyl-(S)-1-[2-hydroxymethyl-6-(trifluoromethyl)phenyl]-
1H-pyrrole-2-carboxamide ((S)-7c).
The reaction was monitored
by TLC (hexane/ethyl acetate = 1/1, Rf = 0.32). Pure (S)-7c is a white,
amorphous material (0.93 g, 95%). IR (KBr, cmꢂ1): 3323, 2976, 2935,
2878, 1635, 1552, 1481, 1322, 1165, 1133. 1H NMR (CDCl3, 300 MHz)
dH 7.79 (1H, d, J = 7.2 Hz), 7.67 (1H, d, J = 7.5 Hz), 7.55 (1H, t,
J = 7.8 Hz), 6.69 (1H, br s), 6.63 (1H, dd, J = 3.6, 1.5 Hz), 6.29
(1H, t, J = 3.0 Hz), 5.97 (1H, br s), 4.39 (1H, br s), 4.26 (2H, m), 4.01
(1H, octet, J = 7.1 Hz), 1.14 (3H, d, J = 6.6 Hz), 1.09 (3H, d, J = 6.6 Hz).
13C NMR (CDCl3, 75 MHz) dC 161.50, 141.50, 136.83 (d, J = 1.7 Hz),
133.75, 129.31, 129.22, 128.66, 127.28 (q, J = 30.3 Hz), 125.86
(q, J = 5.2 Hz), 123.09 (q, J = 273.7 Hz), 111.50, 108.74, 60.35, 41.34,
22.57, 22.47. 19F NMR (CDCl3, 282 MHz) dF ꢂ60.74. HRMS (EI) m/z
25
calcd. for C16H17F3N2O2 (M)+: 326.1260, found 326.1242. ½aꢃD = ꢂ71.6
found 313.2504. ½aꢃ2D5 =ꢂ60.0 (c 0.5; EtOH).
(c 0.86; EtOH).
N-Benzyl-(S)-1-[2-hydroxymethyl-6-(trifluoromethyl)phenyl]-1H-
General Procedure for the Synthesis of Primary
pyrrole-2-carboxamide ((S)-7d).
The reaction was monitored by
Alcohols 7a–f
TLC (hexane/ethyl acetate = 1/1, Rf = 0.36). Pure (S)-7d is a white,
amorphous material (1.03 g, 92%). IR (KBr, cmꢂ1): 3422, 2925, 1639,
1552, 1480, 1321, 1130. 1H NMR (CDCl3, 500 MHz) dH 7.82 (1H, d,
J = 7.5 Hz), 7.70 (1H, d, J = 8.0 Hz), 7.58 (1H, t, J = 7.5 Hz), 7.33–7.21
(5H, m), 6.74 (1H, br s), 6.69 (1H, d, J = 3.75 Hz), 6.31 (1H, t, J = 3.0 Hz),
6.27 (1H, br s), 4.44 (2H, sym m), 4.29 (2H, s), 4.04 (1H, br s). 13C NMR
(CDCl3, 75 MHz) dC 162.39, 143.31, 141.81, 137.97, 137.04, 134.23, 129.67,
129.53, 129.05, 128.98, 127.86, 127.74 (q, J= 29.4 Hz), 126.34 (q, J = 5.0 Hz),
123.39 (q, J = 273.9 Hz), 112.28, 109.25, 60.80, 43.67. 19F NMR (CDCl3,
282 MHz) dF ꢂ60.69. HRMS (EI) m/z calcd. for C20H17F3N2O2
Compound (S)-6a–f (3.0 mmol) was dissolved in dry tetrahydrofuran
(9 ml) under nitrogen atmosphere, and well-powdered sodium
tetrahydridoborate (4.50 mmol, 0.17 g) and ethanol (1 ml) were added.
The reaction mixture was stirred at room temperature for 48–72 h.
The reaction was monitored by TLC (hexane/ethyl acetate) until 6a–f
was consumed. The solvent was evaporated in vacuo. The residue
was dissolved in diethyl ether (20 ml), and 1-M solution of hydrogen
chloride (10 ml) was added at 0 ꢀC. The phases were separated, and
the organic solution was washed with water (5 ml), then brine (5 ml)
before drying over sodium sulfate and concentrated in vacuo.
(M)+: 374.1233, found 374.1242. ½aꢃ2D5 = ꢂ63.2 (c 1.0; EtOH).
N,N-Diethyl-(S)-1-[2-hydroxymethyl-6-(trifluoromethyl)phenyl]-1H-
pyrrole-2-carboxamide ((S)-7a).
The reaction was monitored by TLC
N-[(R)-1-phenylethyl]-(S)-1-[2-hydroxymethyl-6-(trifluoromethyl)
(hexane/ethyl acetate = 1/1, Rf = 0.35). Pure (S)-7a is a white solid (0.97 g,
95%). Mp: 121–123 ꢀC (from diethyl ether). IR (KBr, cmꢂ1): 3332, 1600,
1542, 1482, 1320. 1H NMR (CDCl3, 500MHz) dH 7.79 (1H, dd, J=7.2,
0.5 Hz), 7.65 (1H, dd, J= 7.5, 1.0 Hz), 7.55 (1H, t, J= 7.5 Hz), 6.69 (1H, br s),
6.54 (1H, dd, J=3.75, 1.5Hz), 6.31 (1H, dd, J= 3.75, 3.0 Hz), 5.37 (1H, br s),
4.27 (2H, s), 3.90–3.26 (4H, m), 1.28–1.03 (6H, m). 13C NMR (CDCl3,
75 MHz) dC 163.46, 142.18, 136.97, 134.63, 129.40, 128.24, 127.70, 127.44
(q, J= 32 Hz), 125.83 (q, J= 6.0 Hz), 123.21 (q, J= 273 Hz), 111.69, 108.26,
60.74, 43.24, 39.41, 14.10, 12.15. 19F NMR (CDCl3, 282 MHz) dF ꢂ60.62.
HRMS (EI) m/z calcd. for C17H19F3N2O (M)+: 340.1418, found 340.1399.
phenyl]-1H-pyrrole-2-carboxamide ((S)-7e).
The reaction was
monitored by TLC (hexane/ethyl acetate= 2/1, Rf = 0.22). Pure (S)-7e is
a colorless oil (1.11 g, 99%). IR (KBr, cmꢂ1): 3315, 3063, 2976, 2930, 1633,
1548, 1481, 1416, 1321, 1154. 1H NMR (CDCl3, 300 MHz) dH 7.81
(1H, dd, J = 7.6, 0.5 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.58 (1H, t, J = 7.8Hz),
7.39–7.27 (5H, m), 6.72 (1H, s), 6.67 (1H, dd, J = 3.9, 1.5 Hz), 6.30
(1H, dd, J = 3.7, 2.9Hz), 6.17 (1H, d, J = 8.0 Hz), 5.16–5.03
(1H, quintet, J = 7.5 Hz), 4.25 (2H, s), 3.98 (1H, br s), 1.45 (3H, d,
J = 6.9 Hz). 13C NMR (CDCl3, 75 MHz) dC 161.74, 142.96, 141.85, 137.01
(d, J = 1.8), 134.25, 129.66, 129.35, 129.33, 128.98, 127.71, 127.69
(q, J = 30.4Hz), 126.32 (q, J = 5.2Hz), 126.31, 123.41 (q, J = 273.7 Hz),
112.03, 109.19, 60.78, 48.82, 21.92. 19F NMR (CDCl3, 282 MHz)
½aꢃ2D5 = ꢂ173.3 (c 0.86; EtOH).
A selected single crystal (0.4 ꢁ 0.3 ꢁ 0.2 mm) of (R)-7a was mounted
on a Rigaku (Rigaku Europe SE, Berlin, Germany) R-AXIS RAPID diffrac-
tometer (graphite monochromator Cu Ka radiation, l = 1.54187 Å). CCDC
846790 contains the supplementary crystallographic data for this article.
These data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre website at www.ccdc.cam.ac.uk/data_request/cif.
dF ꢂ60.78. ½aꢃ25 = ꢂ56.8 (c 0.4; CHCl3).
D
(S)-1-[2-Hydroxymethyl-6-(trifluoromethyl)phenyl]-1H-pyrrole-
2-carboxamide ((S)-7f).
The reaction was monitored by TLC
(pure ethyl acetate, Rf = 0.35). Pure (S)-7f is a white solid (0.81 g, 95%).
Mp: 160–161 ꢀC (from diethyl ether). IR (KBr, cmꢂ1): 3516, 3375, 3172,
3115, 1668, 1623, 1484, 1435, 1320, 1134. 1H NMR (CDCl3, 300MHz) dH
7.83 (1H, d, J= 6.9 Hz), 7.68 (1H, d, J= 6.3 Hz), 7.62 (1H, t, J = 7.7Hz), 7.49
(1H, br s), 6.99 (1H, dd, J= 3.9, 1.5 Hz), 6.82 (1H, s), 6.74 (1H, br s), 6.27
Chirality DOI 10.1002/chir
N,N-Diisopropyl-(S)-1-[2-hydroxymethyl-6-(trifluoromethyl)
phenyl]-1H-pyrrole-2-carboxamide ((S)-7b).
The reaction was
monitored by TLC (hexane/ethyl acetate = 3/1, Rf = 0.25). Pure (S)-7b

FAIGL ET AL.
(1H, t, J = 3.3 Hz), 5.25 (1H, t, J = 5.4Hz), 4.10 (1H, dd, J= 14.9, 5.4 Hz), 3.93
148.32, 140.07, 136.64, 131.62, 131.11 (q, J = 29.5 Hz), 130.16, 129.90,
129.56, 129.24, 128.87, 128.76, 128.49, 128.29, 128.17 (q, J = 5.6 Hz),
125.28 (q, J = 273.9 Hz), 113.37, 108.33, 82.68, 43.08, 23.76, 23.46. 19F
NMR (acetone-d6, 282 MHz) dF ꢂ60.93. HRMS (ESI) m/z calcd.
(1H, dd, J= 14.9, 5.4Hz). 13C NMR (CDCl3, 75 MHz) dC 164.33, 144.74,
137.78 (q, J = 1.7Hz), 132.28, 129.26, 129.12, 129.06, 127.37 (q, J= 29.9Hz),
125.51 (q, J = 5.3Hz), 124.42 (q, J= 273.1 Hz), 114.62, 110.48, 60.92. 19F
25
for C28H26F3N2O2 (M+ H)+: 479.1946, found 479.1944. ½aꢃD = ꢂ86.0
NMR (CDCl3, 282 MHz) dF ꢂ58.85. HRMS (ESI) m/z calcd. for
25
C
13H12F3N2O2 (M + H)+: 285.2412, found 285.2419. ½aꢃD = ꢂ94.0 (c 0.65;
(c 0.4; EtOH).
acetone).
Reaction of Primary Amide (S)-6f with Grignard’s Reagent
Phenylmagnesium bromide (4.8 mmol, 0.87 g) was prepared in dry
diethyl ether (10 ml) by the addition of bromobenzene to magnesium
General Procedure for the Synthesis of Tertiary
Alcohols 8a–c
turnings.
A solution of (S)-1-[2-methoxycarbonyl-6-(trifluoromethyl)
A solution of bromobenzene (9.5 mmol, 1.5 g) in dry tetrahydrofuran
(15 ml) was cooled down to ꢂ75 ꢀC, and a hexane solution of butyllithium
(9.5 mmol, 14.2 ml, 1.5 mol/L solution) was added into the stirred solution
under nitrogen atmosphere. Compound (S)-6a–c (3.0 mmol) was added
to the stirred reaction mixture for 15 min, and the stirring was continued
for an additional 30 min at ꢂ75 ꢀC. At room temperature, saturated
aqueous ammonium chloride solution (15 ml) and diethyl ether (30 ml)
were added into it. The phases were separated, the aqueous phase was
washed with diethyl ether (2 ꢁ 25 ml), the collected organic solutions
were washed with brine (25 ml), dried over sodium sulfate, concentrated
in vacuo, and the residue was purified by column chromatography
(Kieselgel, eluent hexane/ethyl acetate).
phenyl]-1H-pyrrole-2-carboxamide ((S)-6f, 1.6 mmol, 0.5 g, ee 99.8%) in
dry tetrahydrofuran (5 ml) was added into the stirred solution at 0 ꢀC
under nitrogen atmosphere. The reaction mixture was stirred for 30 min
at 0 ꢀC. When the mixture warmed to room temperature, saturated
aqueous ammonium chloride solution (15 ml) and diethyl ether (30 ml)
were added, the phases were separated, the aqueous phase was washed
with diethyl ether (15 ml), the collected organic solutions were washed
with brine (25 ml), dried over sodium sulfate, concentrated in vacuo,
and the residue was purified by column chromatography (Kieselgel,
eluent hexane/ethyl acetate = 1/1) to yield (S)-10 and (R,S)-11.
(S)-1-[2-Benzoyl-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-
carboxamide ((S)-10).
White solid (0.26 g, 45%, Rf = 0.3). Mp:
N,N-Diethyl-(S)-1-[2-diphenylhydroxymethyl-6-(trifluoromethyl)
181–183 ꢀC (from ethyl acetate). IR (KBr, cmꢂ1): 3466, 3300, 3189,
1661, 1610, 1475, 1444, 1333, 1286, 1116. 1H NMR (DMSO, 500 MHz)
dH 7.99 (1H, dd, J = 8.0, 1.0 Hz), 7.73 (1H, t, J = 7.8 Hz), 7.70–7.66
(3H, m), 7.60 (1H, t, J = 7.5 Hz), 7.42 (2H, t, J = 7.8 Hz), 7.32 (1H, br s),
6.87 (1H, s), 6.78 (1H, dd, J = 3.5, 1.5 Hz), 6.66 (1H, br s), 6.04 (1H, t,
J = 3.2 Hz). 13C NMR (DMSO, 75 MHz) dC 193.27, 161.32, 139.79, 137.17
(q, J= 1.8 Hz), 135.70, 133.52, 131.82 129.76 129.70, 128.57, 128.16, 128.00
(q, J = 5.1 Hz), 127.08 (q, J = 30.1 Hz), 122.97 (q, J = 274.1 Hz), 112.96,
phenyl]-1H-pyrrole-2-carboxamide ((S)-8a).
monitored by TLC, and the residue was purified by column chromatogra-
phy (hexane/ethyl acetate = 4/1, Rf = 0.6). Pure (S)-8a is white,
The reaction was
a
amorphous material (1.42 g, 96%). IR (KBr, cmꢂ1): 3196, 2984, 1593,
1542, 1466, 1316, 1285, 1166, 1133, 1110. 1H NMR (CDCl3, 500 MHz) dH
8.14 (1H, s), 7.63 (1H, d, J = 7.5 Hz), 7.32 (1H, t, J = 7.5 Hz), 7.30–7.20
(8H, m), 7.16 (2H, m), 7.12 (1H, d, J = 8.0 Hz), 6.47 (1H, d, J = 2.5 Hz),
5.79 (1H, t, J = 3.3 Hz), 5.55 (1H, s), 3.97 (1H, br s), 3.52 (1H, br s), 3.32
(2H, sextet, J = 7.0 Hz), 1.28 (3H, br s), 1.07 (3H, br s). 13 C NMR (CDCl3,
75 MHz) dC 164.46, 148.94, 147.63, 146.33, 137.50 (d, J = 1.4 Hz), 134.98,
129.31, 129.22 (q, J = 29.3 Hz), 128.40, 127.79, 127.60, 127.44, 127.30,
127.04, 126.86, 126.75, 126.01 (q, J = 5.5 Hz), 123.22 (q, J = 272.6 Hz),
112.18, 106.27, 81.19, 43.07, 39.28, 14.09, 12.21. 19F NMR (CDCl3,
282 MHz) dF ꢂ60.48. HRMS (ESI) m/z calcd. for C29H28F3N2O2
25
107.84. 19F NMR (DMSO, 282 MHz) dF ꢂ54.22. ½aꢃD = ꢂ17.4 (c 0.9;
EtOH, ee 24%). Ee was determined by HPLC analysis using a chiral
stationary phase (Phenomonex Lux Cellulose-2 column (5mm,
250 ꢁ 4.6 mm), eluent hexane/ethanol = 85/15, 1.0 ml/min, UV detector
256 nm, 20 ꢀC, retention time for (S)-10: 19.2 min, for (R)-10: 29.5 min.
(ꢄ)-1-[2-Aminocarbonyl-6-(trifluoromethyl)phenyl]-2-benzoyl-1H-
(M + H)+: 493.2103, found 493.2089. ½aꢃD25 = ꢂ130.8 (c 6.0; CHCl3).
N,N-Diisopropyl-(S)-1-[2-diphenylhydroxymethyl-6-(trifluoro-
pyrrole ((R,S)-11).
White solid (0.17 g, 30%, ee 0%, Rf = 0.2). Mp:
195–197 ꢀC (from ethyl acetate). IR (KBr, cmꢂ1): 3405, 3163, 3127,
1689, 1622, 1314, 1156, 1129, 726. 1H NMR (DMSO, 500 MHz) dH
7.93 (1H, d, J = 7.5 Hz), 7.80 (1H, d, J = 7.0 Hz), 7.74 (1H, t, J = 7.8 Hz),
7.70 (2H, d, J = 7.5Hz), 7.60 (1H, t, J= 7.5 Hz), 7.50 (2H, t, J = 7.5 Hz),
7.42 (1H, s), 7.33 (1H, s), 7.26 (1H, s), 6.79 (1H, dd, J= 4.0, 1.5 Hz), 6.37
(1H, t, J = 3.3Hz). 13C NMR (DMSO, 75MHz) dC 183.97, 166.89, 138.33,
138.27, 135.47 (q, J = 1.7Hz), 133.05, 132.89, 131.77, 131.74, 129.01,
128.81, 128.14, 127.23 (q, J= 5.1 Hz), 126.39 (q, J = 30.0 Hz), 123.01
(q, J= 273.9 Hz), 121.36, 109.28. 19F NMR (DMSO, 282 MHz) dF ꢂ54.28.
methyl)phenyl]-1H-pyrrole-2-carboxamide ((S)-8b).
The reac-
tion was monitored by TLC, and the residue was purified by column
chromatography (hexane/ethyl acetate = 4/1, Rf = 0.65). Pure (S)-8b is a
white solid (1.47 g, 94%). Mp: 148–149 ꢀC (from ethyl acetate). IR
(KBr, cmꢂ1): 3190, 2973, 2937, 2872, 2792, 1587, 1538, 1465, 1317, 1165.
1H NMR (CDCl3, 500 MHz) dH 8.50 (1H, s), 7.64 (1H, d, J = 8.0 Hz), 7.33
(1H, t, J = 8.0 Hz), 7.30–7.21 (8H, m), 7.16–7.12 (3H, m), 6.41 (1H, dd,
J = 3.5, 1.5 Hz), 5.81 (1H, t, J = 6.5 Hz), 5.55 (1H, s), 4.77 (1H, br s), 3.46
(1H, br s), 1.42–1.12 (12H, m). 13C NMR (CDCl3, 75MHz) dC 164.54,
149.87, 148.01, 146.58, 137.78 (d, J = 1.3Hz), 135.32, 129.38 (q, J= 29.0Hz),
129.19, 128.74, 128.60, 128.43, 128.04, 127.66, 127.03, 126.96, 126.00
(q, J = 5.5 Hz), 123.56 (q, J = 274.3Hz), 50.54, 46.66, 21.63, 21.39, 20.86,
½aꢃ2D5 = 0 (c 1.0; EtOH).
10-Trifluoromethyl-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,6-
dione (9).
To a solution of KOtBu (1.1 mmol, 0.12 g) in dry
tetrahydrofuran (3 ml), (S)-1-[2-methoxycarbonyl-6-(trifluoromethyl)
phenyl]-1H-pyrrole-2-carboxamide ((S)-6f, 1.0 mmol, 0.31 g) was added
at 0 ꢀC. After stirring for 10 min, 1-M solution of hydrogen chloride
(5 ml) and ethyl acetate (15 ml) were added, the phases were separated,
and the organic solution was washed with water (5 ml), then brine (5 ml)
before drying over sodium sulfate and concentrated in vacuo to yield
pure 9 as white solid (0.25 g, 90%, Rf = 0.9 in pure ethyl acetate). Mp:
207–208 ꢀC (from tehtrahydrofuran). IR (KBr, cmꢂ1): 3463, 3417, 3363,
3159, 2991, 1735, 1643, 1610, 1480, 1387. 1H NMR (acetone-d6,
300 MHz) dH 10.24 (1H, s), 8.29 (1H, dd, J = 7.8, 1.2 Hz), 8.19 (1H, dd,
J = 8.1, 1.5 Hz), 7.80 (1H, t, J = 7.8 Hz), 7.38 (1H, quint, J = 1.5 Hz), 7.13
(1H, dd, J = 3.8, 1.8 Hz), 6.54 (1H, t, J = 3.3 Hz). 13 C NMR (acetone-d6,
20.05. 19F NMR (CDCl3, 282 MHz) dF ꢂ60.08. ½aꢃ25 = ꢂ124.3 (c 1.0; EtOH).
D
N-Isopropyl-(S)-1-[2-diphenylhydroxymethyl-6-(trifluoromethyl)
phenyl]-1H-pyrrole-2-carboxamide ((S)-8c).
The reaction was
monitored by TLC, and the residue was purified by column chromatogra-
phy (hexane/ethyl acetate = 4/1, Rf = 0.58). Pure (S)-8c is a white solid
(1.33 g, 93%). Mp: 127–129 ꢀC (from ethyl acetate). IR (KBr, cmꢂ1):
3313, 3130, 3066, 3026, 2975, 2768, 1602, 1550, 1464, 1315. 1H NMR
(acetone-d6, 300 MHz) dH 7.77 (1H, d, J = 7.8 Hz), 7.57 (1H, s), 7.53
(2H, t, J = 7.2 Hz), 7.35–7.17 (11H, m), 6.60 (1H, s), 5.65 (1H, s), 5.60
(1H, s), 4.10 (1H, octet, J = 6.8 Hz), 1.22 (3H, d, J= 6.6 Hz), 1.11 (3H, d,
J=6.6Hz). 13 C NMR (acetone-d6, 75MHz) dC 164.03, 150.65, 149.48,
Chirality DOI 10.1002/chir

NEW ATROPISOMERIC AMINO ALCOHOLS
(S)-N-Isopropyl-2-aminomethyl-1-[2-hydroxymethyl-6-(difluoro-
methyl)phenyl]-1H-pyrrole ((S)-12c). The reaction was moni-
75 MHz) dC 166.86, 160.03, 137.81, 136.68 (d, J = 1.4 Hz), 134.79
(q, J = 5.3 Hz), 132.99, 132.61 (q, J = 4.5 Hz), 130.50, 129.76, 126.42
(q, J = 31.4 Hz), 125.28 (q, J = 273.1 Hz), 122.67, 113.13. 19F NMR
(acetone-d6, 282 MHz) dF ꢂ56.54.
tored by TLC, and the residue was purified by column chromatography
(hexane/ethyl acetate = 1/1, Rf = 0.05–0.2). Pure (S)-12c is a colorless
oil (0.38 g, 82%, ee 99.8%). IR (KBr, cmꢂ1): 3261, 3106, 2968, 2871,
1596, 1486, 1321. 1H NMR (CDCl3, 300 MHz) dH 7.82 (1H, d,
J = 7.5 Hz), 7.72 (1H, d, J = 7.5 Hz), 7.58 (1H, t, J = 7.5 Hz), 6.61 (1H, br
s), 6.26 (1H, t, J = 3.3 Hz), 6.22 (1H, m), 4.14 (1H, d, J = 12.0 Hz), 3.89
(1H, d, J = 12.0Hz), 3.66 (1H, d, J = 12.9 Hz), 3.02 (1H, d, J = 12.9Hz), 2.72
(1H, sextet, J = 6.3 Hz), 1.02 (3H, d, J = 6.3 Hz), 0.78 (3H, d, J = 6.3 Hz). 13C
NMR (CDCl3, 75MHz) dC 144.52, 135.35 (q, J = 1.7 Hz), 135.25, 133.42,
129.47, 128.59 (q, J = 30Hz), 125.81 (q, J= 5.1Hz), 124.34, 123.03
(q, J = 273.7 Hz), 108.52, 108.39, 58.64, 48.40, 41.13, 22.88, 20.90. 19F NMR
(CDCl3, 282MHz) dF ꢂ60.87. HRMS (ESI) m/z calcd. for C16H20F3N2O
General Procedure for the Synthesis of Amino Alcohols
12a–f and 13a–c
Compound (S)-7a–f or (S)-8a–c (1.5 mmol) was dissolved in dry
toluene (4 ml), and borane dimethysulfide complex (3.0 mmol, 0.285 ml)
was added dropwise. The reaction mixture was stirred at 80 ꢀC for 72 h
in case of primary alcohols or for 2 h in case of tertiary alcohols. Methanol
(2 ml) was added slowly dropwise at 0 ꢀC; the solvent was evaporated in
vacuo. The residue was dissolved in methylene chloride (1 ml), and 5-M
solution of hydrogen chloride (2 ml) was added. The mixture was
stirred for 30 min. Then methylene chloride (5 ml) and aqueous sodium
hydroxide (5-M, 5 ml) were added, the phases were separated, and the
aqueous phase was washed with methylene chloride (5 ml), whereas
the collected organic phases were dried over sodium sulfate and
concentrated in vacuo. The crude residue was purified by column
cromatography.
(M+ H)+: 313.3375, found 313.3366. ½aꢃ2D5 = +52.9 (c 1.07; EtOH).
N-benzyl-(S)-2-aminomethyl-1-[2-hydroxymethyl-6-(trifluoromethyl)
phenyl]-1H-pyrrole ((S)-12d).
The reaction was monitored by TLC,
and the residue was purified by column chromatography (hexane/ethyl
acetate= 1/1, Rf = 0.1–0.25). Pure (S)-12d is a colorless oil (0.35 g, 64%, ee
99.8%). IR (KBr, cmꢂ1): 3294, 3064, 2927, 2849, 1597, 1486, 1321, 1163,
(S)-N,N-Diethyl-2-aminomethyl-1-[2-hydroxymethyl-6-(trifluoro-
1
1132. H NMR (CDCl3, 300 MHz) dH 7.83 (1H, d, J= 7.5 Hz), 7.70 (1H, d,
methyl)phenyl]-1H-pyrrole ((S)-12a).
The reaction was moni-
J = 7.5 Hz), 7.59 (1H, t, J = 8.0 Hz), 7.29–7.17 (5H, m), 6.60 (1H, br s), 6.26
(1H, t, J = 3.0 Hz), 6.23 (1H, dd, J = 2.1, 1.5Hz), 4.17 (1H, d, J = 12.0 Hz),
3.91 (1H, d, J = 12.0 Hz), 3.71 (1H, d, J= 13.0 Hz), 3.69 (1H, d, J = 13.5 Hz),
3.63 (1H, d, J = 13.0 Hz), 3.10 (1H, d, J = 13.5Hz). 13C NMR (CDCl3,
75MHz) dC 144.34, 137.99, 135.34 (d, J= 1.5Hz), 135.16, 132.73, 129.56,
128.63 (q, J= 30.2 Hz), 128.57, 128.33, 127.38, 125.91 (q, J= 5.2 Hz), 124.55,
122.98 (q, J = 273.9Hz), 109.19, 108.53, 58.85, 53.12, 43.11. 19F NMR (CDCl3,
282 MHz) dF ꢂ60.90. HRMS (EI) m/z calcd. for C20H19F3N2O (M)+:
tored by TLC, and the residue was purified by column chromatography
(hexane/ethyl acetate = 1/1, Rf = 0.10–0.45). Pure (S)-12a is a white
solid (0.37 g, 75%, ee 99.8%). Mp: 62–63 ꢀC (from ethyl acetate). IR
(KBr, cmꢂ1): 3362, 1486, 1321. 1H NMR (CDCl3, 300 MHz) dH 7.81
(1H, d, J = 7.5 Hz), 7.73 (1H, d, J = 7.5Hz), 7.58 (1H, t, J = 7.5 Hz), 6.64
(1H, br s), 6.24 (2H, d, J = 9.6 Hz), 4.13 (1H, d, J= 11.4Hz), 3.93 (1H, d,
J= 11.4Hz), 3.21 (1H, d, J = 14.1 Hz), 3.07 (1H, d, J = 14.1 Hz), 2.71
(2H, m), 2.20 (2H, m), 0.76 (6H, t, J = 7.2 Hz). 13 C NMR (CDCl3, 75 MHz)
dC 144.34, 135.59, 135.36, 131.09, 129.46, 128.60 (q, J = 30Hz), 125.89
(q, J = 5 Hz), 124.59, 123.01 (q, J = 274 Hz), 111.10, 108.10, 59.24, 53.39,
49.97, 45.89, 9.82. 19F NMR (CDCl3, 282 MHz) dF ꢂ63.27. HRMS
360.1442, found 360.1449. ½aꢃ2D5 = +52.7 (c 0.73; EtOH).
N-[(R)-1-phenylethyl]-(S)-2-aminomethyl-1-[2-hydroxymethyl-6-
25
(EI) m/z calcd. for C17H21F3N2O (M)+: 326.1611, found 326.1606. ½aꢃD
(trifluoromethyl)phenyl]-1H-pyrrole ((S)-12e).
The reaction was
= ꢂ75.6 (c 0.8; EtOH).
monitored by TLC, and the residue was purified by column chroma-
tography (hexane/ethyl acetate = 2/1, Rf = 0.05–0.3). Pure (S)-12e is
a white solid (0.49 g, 87%, ee 99.8%). Mp: 98–103 ꢀC (from ethyl acetate).
(S)-N,N-Diethyl-2-aminomethyl-1-[2-hydroxymethyl-6-(difluoro-
1
IR (KBr, cmꢂ1): 3312, 2960, 2852, 1594, 1487, 1321, 1157, 1129. H NMR
methyl)phenyl]-1H-pyrrole
((S)-12a´).
1H
NMR
(CDCl3,
(CDCl3, 300 MHz) dH 7.89 (1H, t, J= 4.7 Hz), 7.60–7.58 (2H, m), 7.12–7.09
(3H, m), 6.98–6.95 (2H, m), 6.59 (1H, s), 6.25 (1H, t, J = 3.3Hz), 6.22
(1H, dd, J = 3.5, 1.6 Hz), 4.21 (1H, d, J = 11.7 Hz), 3.96 (1H, d, J = 11.7 Hz),
3.81 (1H, q, J= 6.6 Hz), 3.45 (1H, d, J = 13.2 Hz), 2.87 (1H, d,
J = 13.2 Hz), 1.28 (3H, d, J = 6.9 Hz). 13C NMR (CDCl3, 75 MHz) dC
144.05, 142.73, 135.13, 133.15, 129.39, 128.56 (q, J = 30.1 Hz), 128.37,
126.98, 126.50, 125.87 (q, J= 5.3 Hz), 124.55, 122.82 (q, J = 273.7 Hz),
109.30, 108.45, 59.10, 58.07, 41.68, 24.15. 19F NMR (CDCl3, 282MHz)
dF ꢂ59.68. HRMS (ESI) m/z calcd. for C21H22F3N2O (M + H)+:
300 MHz) dH 7.81 (1H, d, J = 7.5 Hz), 7.73 (1H, d, J = 7.5 Hz), 7.58 (1H, t,
J = 7.5 Hz), 6.64 (1H, br s), 6.24 (2H, d, J = 9.6 Hz), 5.76 (1H, t,
J = 54.5 Hz, –CHF2), 4.13 (1H, d, J = 11.4 Hz), 3.93 (1H, d, J = 11.4 Hz),
3.21 (1H, d, J = 14.1 Hz), 3.07 (1H, d, J = 14.1 Hz), 2.71 (2H, m), 2.20
(2H, m), 0.76 (6H, t, J = 7.2 Hz). 19F NMR (CDCl3, 376 MHz) dF ꢂ110.47
2
2
2
(1F, dd, JFF = 309.1 Hz, JHF = 55.1 Hz), ꢂ114.82 (1F, dd, JFF = 309.1 Hz,
2JHF = 55.1 Hz).
(S )-N,N-Diisopropyl-2-aminomethyl-1-[2-hydroxymethyl-6-
375.4068, found 375.4060. ½aꢃ2D5 = +74.7 (c 0.7; EtOH).
(difluoromethyl)phenyl]-1H-pyrrole ((S)-12b).
The reaction was
monitored by TLC, and the residue was purified by column chromatog-
raphy (hexane/ethyl acetate = 1/1, Rf = 0.05–0.2). Pure (S)-12b is a
white solid (0.36 g, 68%, ee 99.8%). Mp: 78–80 ꢀC (from ethyl acetate).
IR (KBr, cmꢂ1): 3374, 3110, 2970, 2938, 2889, 1597, 1487, 1321, 1182,
1163. 1H NMR (acetone-d6, 500 MHz) dH 7.94 (1H, d, J = 7.5 Hz), 7.80
(1H, d, J = 7.5 Hz), 7.71 (1H, t, J = 7.8 Hz), 6.64 (1H, s), 6.17 (2H, s), 4.87
(1H, br s), 4.22 (1H, d, J = 13.5 Hz), 4.16 (1H, d, J = 13.5 Hz), 3.41
(1H, d, J = 14.5 Hz), 3.22 (1H, d, J = 14.5 Hz), 3.09 (2H, sextet,
J = 6.6 Hz), 0.90 (6H, d, J = 6.5 Hz), 0.72 (6H, d, J = 6.5 Hz). 13C NMR (ace-
tone-d6, 75 MHz) dC 146.52, 137.21 (q, J = 1.8 Hz), 134.78, 134.20, 131.15,
129.72 (q, J = 29.9 Hz), 127.17 (q, J = 5.3 Hz), 125.43 (q, J = 273.3 Hz),
125.02, 111.99, 109.79, 60.74, 48.07, 41.03, 22.25, 19.78. 19F NMR (ace-
tone-d6, 282 MHz) dF ꢂ60.52. HRMS (ESI) m/z calcd. for C19H26F3N2O
(S)-2-Aminomethyl-1-[2-hydroxymethyl-6-(trifluoromethyl)phe-
nyl]-1H-pyrrole ((S)-12f).
The reaction was monitored by TLC,
and the residue was purified by column chromatography (pure ethyl
acetate, Rf = 0.05–0.25). Pure (S)-12f is a white solid (0.29 g, 71%, ee
99.8%). Mp: 97–98 ꢀC (from ethyl acetate). IR (KBr, cmꢂ1): 3360, 3188,
3111, 2924, 2850, 1596, 1570, 1486, 1320, 1134. 1H NMR (CDCl3,
300 MHz) dH 7.83 (1H, d, J = 7.5 Hz), 7.72 (1H, d, J = 7.8 Hz), 7.59 (1H, t,
J = 7.7 Hz), 6.61 (1H, s), 6.28–6.24 (2H, m), 4.18 (1H, d, J = 12.0 Hz), 3.95
(1H, d, J = 13.5 Hz), 3.29 (1H, d, J = 12.0 Hz), 3.14 (1H, d, J = 13.5 Hz),
2.99 (3H, br s). 13C NMR (CDCl3, 75 MHz) dC 144.38, 135.35 (d,
J = 1.5 Hz), 135.14, 134.60, 129.58, 128.69 (q, J = 30.0 Hz), 125.92 (q,
J = 5.3 Hz), 124.56, 123.01 (q, J = 273.9 Hz), 108.56, 108.42, 58.65, 35.91.
19F NMR (CDCl3, 282 MHz) dF ꢂ60.89. HRMS (ESI) m/z calcd.
Chirality DOI 10.1002/chir
(M + H)+: 355.1997, found 355.1991. ½aꢃ2D5 = +34.2 (c 0.5; EtOH).

FAIGL ET AL.
25
25
for C13H14F3N2O (M + H)+: 271.2577, found 271.2588. ½aꢃD = +22.6
465,5292. ½aꢃD = +51.7 (c 0.9; CHCl3). Ee was determined by HPLC
(c 1.0; EtOH).
analysis using a chiral stationary phase, Phenomonex Lux Amylose-2
column (5 mm, 250 ꢁ 4.6 mm), eluent hexane/ethanol = 98.5/1.5,
0.5 ml/min, UV detector 222 nm, 15 ꢀC, retention time for (R)-13c:
13.6 min, for (S)-13c: 16.2 min.
N,N-Diethyl-(S)-2-aminomethyl-1-[2-diphenylhydroxymethyl-6-
(trifluoromethyl)phenyl]-1H-pyrrole ((S)-13a).
The reaction was
monitored by TLC, and the residue was purified by column chromatogra-
phy (hexane/ethyl acetate= (8/1, Rf = 0.05–0.25). Pure (S)-13a is a white
solid (0.53 g, 74%, ee 99.8%). Mp: 113–114 ꢀC (from ethyl acetate). IR
(KBr, cmꢂ1): 3100, 3086, 2978, 2881, 2825, 1589, 1481, 1449, 1315, 1165.
1H NMR (CDCl3, 500 MHz) dH 8.32 (1H, br s), 7.74 (1H, d, J= 7.5Hz),
7.36 (1H, t, J = 8.0 Hz), 7.28 (2H, t, J = 7.3 Hz), 7.24–7.19 (6H, m), 7.14
(1H, d, J = 8.0 Hz), 7.05 (2H, m), 6.08 (1H, s), 5.77 (1H, t, J = 3.0 Hz),
5.41 (1H, s), 3.27 (1H, d, J = 14.5 Hz), 3.05 (1H, d, J = 14.5 Hz), 2.81
(2H, hextet, J = 7.0 Hz), 2.29 (2H, sextet, J = 7.0 Hz), 0.83 (3H, t,
J = 7.0 Hz). 13 C NMR (CDCl3, 75 MHz) dC 148.98, 148.93, 147.13,
137.19 (d, J = 1.4 Hz), 135.12, 131.13 (q, J = 29.2 Hz), 130.40, 128.22,
127.80, 127.68, 127.45, 127.23, 126.80, 126.69, 126.49 (q, J = 5.5 Hz),
125.43, 129.99 (q, J = 274.5 Hz), 109.80, 105.77, 80.73, 48.33, 45.95,
10.13. 19F NMR (CDCl3, 282 MHz) dF ꢂ60.75. HRMS (ESI) m/z calcd.
General Procedure for the Enantioselective Addition of
Diethyl Zinc to Benzaldehyde using Chiral Amino Alcohol
(S)-13c
Optically active amino alcohol (S)-13c (0.01 mmol, 5 mg, ee 99.8%) was
dissolved in dry toluene (1 ml), a solution of diethyl zinc in hexane
(1 mol/L, 0.4 mmol, 0.4 ml) was added, and the mixture was stirred for
an hour at room temperature. After the addition of benzaldehyde
(0.2 mmol, 20 ml), the mixture was stirred overnight. Saturated aqueous
ammonium chloride solution (5 ml) and toluene (10 ml) were added,
and the phases were separated. The aqueous phase was washed with
toluene (5 ml), and the collected organic phases were dried over
sodium sulfate and concentrated in vacuo. The crude residue was
purified by column chromatography (hexane/ethyl acetate = 5/1) to
yield (S)-1-phenylpropanol (15, 21.6mg, 80%) with 86% enantiomeric
excess. The ee was determined by gas chromatography analysis on an
Agilent (Santa Clara, USA) 4890 D instrument equipped with a BETA-
DEXPTMP 120 fused silica capillary column (0.25nm/0.25 mm, 30 m,
Supelco, Sigma-Aldrich, 70 to 140 ꢀC, 10 ꢀC/min, retention time for (R)-
15: 17.4 min, for (S)-15: 17.7min). The absolute configuration of 15 was
25
for C29H30F3N2O (M + H)+: 479.2310, found 479.2301. ½aꢃD = +81.3 (c 0.5;
CHCl3). Ee was determined by HPLC analysis using a chiral stationary
phase, Phenomonex Lux Amylose-2 column (5 mm, 250 ꢁ 4.6 mm),
eluent hexane/ethanol = 98.5/1.5, 0.5 ml/min, UV detector 222 nm, 15ꢀC,
retention time for (R)-13a: 9.5 min, for (S)-13a: 12.0 min.
25
determined by the specific rotation of the product (ee 86%, ½aꢃD = ꢂ40.9
(c 1.25; CHCl3),11: ½aꢃD25 = ꢂ47.5 (c 1; CHCl3) for the pure S enantiomer).
N,N-Diisopropyl-(S)-2-aminomethyl-1-[2-diphenylhydroxymethyl-
6-(trifluoromethyl)phenyl]-1H-pyrrole ((S)-13b).
The reaction
RESULTS AND DISCUSSION
Synthesis of the Key Compound Monoester (2) by Selective
Esterification of (S)-1
was monitored by TLC, and the residue was purified by column chromatog-
raphy (hexane/ethyl acetate= 5/1, Rf = 0.15–0.35). Pure (S)-13b is a white
solid (0.67 g, 88%, ee 99.8%). Mp: 113–114 ꢀC (from ethyl acetate). IR
(KBr, cmꢂ1): 3089, 3057, 2965, 2879, 2750, 1590, 1480, 1458, 1312,
1162. 1H NMR (acetone-d6, 500 MHz) dH 7.91 (1H, d, J = 8.0 Hz), 7.58
(1H, t, J = 8.0 Hz), 7.39–7.33 (4H, m), 7.29–7.21 (5H, m), 7.06–7.05 (2H,
m), 6.91 (1H, s), 6.02 (1H, s), 5.63 (1H, t, J = 6.0 Hz), 5.35 (1H, s), 3.47
(1H, d, J = 14.5 Hz), 3.35 (2H, sextet, J = 6.5 Hz), 3.23 (1H, d,
J = 14.5 Hz), 1.01 (6H, d, J = 6.5 Hz), 0.87 (6H, d, J = 6.5 Hz). 13C NMR
(acetone-d6, 75 MHz) dC 150.50, 150.01, 149.63, 138.93 (d, J = 1.2 Hz),
137.04, 133.10, 132.81 (q, J = 29.1 Hz), 130.24, 129.62, 129.29, 128.87,
128.86 (q, J = 5.5 Hz), 128.61, 126.46, 125.19 (q, J = 274,1 Hz), 111.93,
107.89, 82.63, 48.05, 40.78, 22.82, 19.11. 19F NMR (acetone-d6,
282 MHz) dF ꢂ60.90. HRMS (ESI) m/z calcd. for C31H34F3N2O
The synthesis of the desired atropisomeric amino alcohols
was performed using (S)-1 as starting material, via 2, the
monomethyl ester of the dicarboxylic acid 1. The key
compound 2 was obtained in high selectivity by the esterifica-
tion of the carboxylic group connected to the phenyl ring in
dicarboxylic acid 1. This monoesterification was carried out
with thionyl chloride in methanol (Scheme 1). The formation
of the monoester and the diester (compounds 2 and 34) are
consecutive reactions, for which the optimal conditions had
to be determined. Varying the reaction conditions systemati-
cally, we found that the optimal amount of the thionyl chloride
is 7 eq. The usage lower amounts of thionyl chloride resulted
in lower monoester/diester product ratios and increased the
reaction time as well. Higher temperatures favored the
25
(M + H)+: 507.2623, found 507.2634. ½aꢃD = +73.4 (c 0.5; EtOH). Ee
was determined by HPLC analysis using a chiral stationary phase,
Phenomonex Lux Amylose-2 column (5mm, 250 ꢁ 4.6 mm), eluent
hexane/ethanol = 98.5/1.5, 0.5ml/min, UV detector 222 nm, 15ꢀC,
retention time for (R)-13b: 7.6 min, for (S)-13b: 7.9 min.
N-Isopropyl-(S)-2-aminomethyl-1-[2-diphenylhydroxymethyl-6-
(trifluoromethyl)phenyl]-1H-pyrrole ((S)-13c).
The reaction was
monitored by TLC, and the residue was purified by column chromatogra-
phy (hexane/ethyl acetate = 3/1, Rf = 0.05–0.25). Pure (S)-13c is a white
solid (0.55 g, 79%, ee 99.8%). Mp: 117–119 ꢀC (from ethyl acetate). IR
(KBr, cmꢂ1): 3422, 3298, 3086, 2965, 2751, 1587, 1481, 1447, 1315, 1137.
1H NMR (CDCl3, 300 MHz) dH 7.74 (1H, dd, J = 7.9, 1.3 Hz), 7.38 (1H, t,
J = 7.9 Hz), 7.33–7.13 (9H, m), 7.05 (2H, dd, J = 6.7, 3.0 Hz), 6.10 (1H, dd,
J = 3.3, 1.5 Hz), 5.82 (1H, t, J = 3.2 Hz), 5.48 (1H, s), 3.77 (2H, br s), 3.68
(1H, d, J = 13.7 Hz), 3.18 (1H, d, J = 13.7 Hz), 2.77 (sextet, J = 6.3 Hz), 1.09
(3H, d, J = 6.3 Hz), 0.82 (3H, d, J = 6.2 Hz). 13 C NMR (CDCl3,75 MHz,)
dC 210.99, 148.65, 147.00, 137.21 (d, J = 1.3 Hz), 135.42, 132.97, 131.25
(q, J = 29.4 Hz), 128.53, 128.00, 127.83, 127.77, 127.43, 127.17, 127.10,
126.65 (q, J = 5.5 Hz), 125.21, 123.23 (q, J = 274.5 Hz), 108.10, 106.65,
81.55, 48.24, 41.82, 23.24, 21.62. 19F NMR (CDCl3, 282 MHz) dF ꢂ60.67.
HRMS (ESI) m/z calcd. for C28H28F3N2O (M + H)+: 465,5299, found
Chirality DOI 10.1002/chir
Scheme 1. Selective monoesterification of (S)-1.

NEW ATROPISOMERIC AMINO ALCOHOLS
formation of the dimethyl ester. After 48 h, a 85:15 mixture of
because the decomposition of the reducing agent was faster
than the formation of the target compounds.
Tertiary alcohols (S)-8a–c were prepared by the addition of
Grignard’s reagents or phenyl lithium to the benzoic acid
ester derivatives (S)-6a–c (Scheme 4) in excellent yields.
The reactions were carried out at low temperature, and
in situ formed organolithium reagents were used.
In one case, when (S)-6f was used as starting material, the
aforementioned tertiary alcohol formation reaction failed.
With the use of 3 Eq of Grignard’s reagent, two main products
10 and 11 were obtained (in 1.5/1.0 ratio).
The anticipated product 10 was obtained in only 24% ee,
whereas the unexpected compound 11 in racemic form,
despite the enantiopure starting material. The supposed routes
of formation of the two ketones can be seen in Scheme 5.
Our hypothesis was that compound 11 could be formed
through an imide derivative (9). Compound 9 should be the
product of the ring closure reaction of the functions in (S)-
6f´, and this latter compound could serve as an intermediate
for 10 as well. To confirm the formation of 9, a separate
reaction was carried out in which the starting material (S)-
6f was treated with potassium tert-butoxide. Compound 9
was isolated after an acidic work-up procedure in excellent
(95%) yield, but in racemic form. This phenomenon explains
the observed low optical activities of products 10 and 11.
The rotational energy barrier around the C–N bond has to
be much smaller in 9 than in 10 and 11, hence the stereo-
chemically labile intermediate is the reason for the formation
of racemic products.
monomethyl and dimethyl esters was obtained using optimal
conditions. The formation of the other possible monoester
4—by the esterification of the carboxylic group connected
to the pyrrole ring—was not detected in the crude product
because of the big difference between the electron densities
on the carbonyl carbon atoms connected to the phenyl and
the pyrrole rings (Fig. 1). That difference is caused by two
effects: the electron withdrawing CF3 group connected to
the phenyl ring and the electron excessive heterocyclic
pyrrole ring, which decreases the electron deficiency on the
carbonyl carbon atom connected to the a carbon atom of
the ring. Pure (ꢂ)-(S)-2 was obtained after recrystallization
of the crude product from hexane in 80% yield.
The positions of the methoxycarbonyl and the carboxylic
groups in (S)-2 were proved by single crystal X-ray diffraction
studies based on the structure of its mirror image derivative
(+)-(R)-7a (Fig. 3). The latter compound was synthesized
from (+)-(R)-2. The positions of the amide and the hydroxy-
methyl functions in (R)-7a have certified the structure of
(R)-2 and, consequently, confirmed the constitution of (S)-2.
The free carboxylic group of compound (S)-2 was con-
verted into an acid chloride (S)-5 followed by acid amide
formation ((S)-6, Scheme 2).
Preparation of Optically Active Amino Alcohol
Derivatives of (S)-1
The method could be applied for a wide range of amines.
We prepared primary, secondary, and tertiary amides as well
with excellent yields in all cases (>95%). The formation of the
alcoholic function from the ester groups was implemented in
two ways. First, primary alcohols (S)-7a–f were synthesized
by the reduction of the benzoic acid ester moiety by using
sodium tetrahydridoborate (Scheme 3).
It was found that the mixture of tetrahydrofuran and etha-
nol is the most suitable solvent for the reduction. When 10%
ethanol was used, the reaction was complete after 72 h and
the usage of 1.5 Eq reducing agent was found enough. In pure
alcoholic solvents, the reduction was never complete, even
when sodium tetrahydridoborate was applied in large excess,
It has to mentioned that the observed side reaction, namely
formation of compound 11 from 6f, represents an interesting,
unexpected amino group migration from the pyrrole-bonded
carboxamide group into the methoxycarbonyl substituent of
the benzene ring in the presence of phenylmagnesium
bromide. The structure of 11 was confirmed by 2D NMR
spectroscopic measurements. The results can be seen in
Figure 2a and b. First, the 1H–1H COSY (correlation spectros-
copy) experiment was performed (Fig. 3), and the proton sig-
nals were separated into four spin systems: namely, (a) the
pyrrole ring protons between 6.37 and 7.26 ppm, (b) the pro-
ton signals of the trisubstituted phenyl ring between 7.71
and 7.93 ppm, and (c) the signals of the phenyl ring between
7.50 and 7.70 ppm. The two amide hydrogen signals appear
separately at 7.42 and 7.33 ppm, and although these broad
signals do not show any splitting, on the basis of the COSY
spectrum, they form the fourth (AB) spin system. After the
1
full assignment of the H NMR spectrum, the structure can
be postulated via the HMBC experiment. We have two
carbonyl signals in the 13C spectrum, one at 183.97 ppm, the
other at 166.89 ppm. The former should belong to an unsatu-
rated ketone, and the latter is in the range of amide carbonyl
signals. In the HMBC spectrum, the signal at 189.97 ppm
Fig. 1. Relative electron deficiencies on the carbonyl carbon atoms
connected to the rings of (S)-1.
Scheme 2. Preparation of amides (S)-6a–f.
Chirality DOI 10.1002/chir

FAIGL ET AL.
shows correlations with the pyrrole 3-H (6.79 ppm) and the
2,6-H (ortho) signal (7.70 ppm) of the monosubstituted phenyl
ring, whereas the signal at 166.89 ppm correlates with the two
amide protons and the 3-H (7.80 ppm) signal of the trisubsti-
tuted phenyl ring. These correlations give unambiguous proof
for the structure of compound 11.
The synthesis of amino alcohols was completed by the
reduction of the amide groups of (S)-7a–f and (S)-8a–c.
When lithium tetrahydridoaluminate was chosen as reduc-
ing agent, a defluorination side reaction was observed
(Scheme 6). The usual purification attempts to produce pure
12a have failed; therefore, the structure of compound 12a´
Scheme 3. Chemoselective reduction of the benzoic acid ester moiety of
(S)-7a–f.
1
was determined from the H and 19F NMR spectra of the
mixture of 12a and 12a´. Brabander and co-workers ob-
served a similar phenomenon, using lithium tetrahydridoalu-
minate for the reduction of CF3 group containing compounds.8
The formation of the undesired side product could be avoided
by using borane complexes.
The reduction rates of the amides containing primary
alcohol function, using borane dimethysulfide complex,
was moderate. After a 2-day reaction time, the optically ac-
tive bifunctional atropisomeric derivatives ((S)-12a–f ) were
obtained as precipitates, in excellent (up to 90%) yields
(Scheme 7).
Scheme 4. Transformation of the benzoic acid ester functions of (S)-6a–c
into tertiary alcohols ((S)-8a–c).
The similar reduction of amides (8a–c) containing tertiary
alcoholic functions proved to be much easier: the starting
materials consumed within 2 h (Scheme 8).
Single-Crystal X-Ray Diffraction Studies
On the basis of previous X-ray studies of (+)-1ꢅ(R)-1-
phenylethylamine salt, it is known that the absolute configura-
tion of (+)-1 is R.
We could also prepare single crystals from (+)-7a for X-ray
studies by crystallization from diethyl ether. The structure of
(+)-(R)-7a is shown in Figure 3. The structure is in agreement
with the configuration of its starting material (+)-(R)-1. There
is a well-defined intramolecular hydrogen bond between the
oxygen atom of the amide group and the hydrogen of the hy-
droxyl group (Fig. 3). This sterically favorable intramolecular
hydrogen bridge may be among the reasons for the unusual
low reactivity of the primary hydroxyl group containing
amides (7a–f) during the reduction with borane complexes.
Scheme 5. Unexpected side reactions during the transformation of the
benzoic acid ester moiety of (S)-6f.
Fig. 2. 2D NMR spectra of 11. 1H-1H COSY spectrum and the main part of the HMBC spectrum.
Chirality DOI 10.1002/chir

NEW ATROPISOMERIC AMINO ALCOHOLS
is often a method of choice when other chiral selectors (e.g.,
lanthanide shift reagents or cyclodextrins) fail to work
properly. For the determination of the optical purity of amino
alcohol 12a, we employed its parent compound, dicarboxylic
acid 1. In a previous study, the effective application of 1-[2-
carboxy-6-(trifluoromethly)phenyl]-2-carboxylic acid (R)-1
was described as a chiral shift reagent for the determination
of the enantiomeric ratio of oxetanes and cis-but-2-ene-1,4-diol
derivatives, too.10 Figure 4 shows the enantiomeric splitting of
Pyr–CH2–N (in 12a) in the presence of (R)-1. Other
resonances did not show enantiomeric splitting, but the
signals of Pyr–CH2–N (both enantiomer at ~3.65 ppm) were
found to be adequate for the determination of ee. The signal
ratio of the racemic form is 1:3, which means 1 and 1 + 2
protons (for the two enantiomers). From the ratio of the
signals, the enantiomeric purity can be calculated.
Scheme 6. Reduction of amide (S)-7a with LiAlH4.
Further measurements were carried out from the enantio-
merically pure amino alcohol 12a and from the enantiomeric
mixture made by the addition of a small amount of the
racemic form to the enantiopure compound (Fig. 5). The
results have confirmed that the synthesis of the amino
alcohol 12a occurred without any racemization.
Scheme 7. Preparation of amino alcohols (S)-12a–f.
Recently, we have described the determination of the
activation energy of rotation around the C–N bonds for
compound 1.4 Molecular modeling calculations were carried
out, with a parallel experimental determination of DG#. We
found that DG# = +31.6 kcal/mol for compound 1. The theo-
retically and the experimentally determined DG# values were
in good agreement. To obtain more information about the
optical stability of the target compounds, further computa-
tional studies were performed. The activation energy values
were estimated using AM1 semiempirical quantum chemical
method. The geometries of the transition states of 6a and
12a model compounds are visualized in Figure 6, whereas
the calculated and experimentally determined activation
energy values are collected in Table 1.
Scheme 8. Preparation of amino group containing tertiary alcohols (S)-13a–c.
By viewing the growing order of the activation energies
1 < 6a < 12a, one can generally state that the increased size
of the transformed carboxylic acid functions causes higher
steric resistance. By reduction of the carboxylic acid deriva-
tive, the relative space filling of the formed groups will be
greater because of their increased freedom of movement.
Fig. 3. X-ray crystal structure and solid-state conformation of (+)-(R)-7a.
Determination of the Ee Values and the Rotational
Energy Barriers
1
A solution H NMR spectroscopic method has been devel-
oped to assess the enantiomeric composition of 12a. The
enantiomeric purity was determined with the help of a well-
established methodology9: by adding an optically active chiral
solvating agent to the solution of 12a in apolar aprotic
solvents. The application of chiral solvating agents in NMR
Fig. 4. 1H NMR signals of methylene protons of amino alcohol 12a in the
presence of a molar equivalent chiral dicarboxylic acid (+)-(R)-1.
Chirality DOI 10.1002/chir

FAIGL ET AL.
TABLE 1. Calculated and experimentally determined activa-
tion energies for isomerisation of compounds 1, 6a, and 12a
Compound
DG#
(kcal/mol)
DG#
(kcal/mol)
measured
calculated
1
6a
12a
32.9
42.4
64.5
31.6
–
–
Scheme 9. Enantioselective addition of diethyl zinc to benzaldehyde using
chiral amino alcohol (S)-13c.
Fig. 5. Determination of the ee values for compound 12a by 1H NMR anal-
ysis. Spectra were recorded in the presence of (R)-1. The racemate was added
to the solution in one case (middle spectrum) to check the validity of the NMR
method and to confirm the chemical shift and the enantiomeric purity.
primary amide nitrogen of 6f could easily attack the carbonyl
carbon atom of the ester group to form compound 9.
A smaller difference between the reactivities of the two
carbonyl groups was observed during the reaction of 9 with
phenylmagnesium bromide, where ketones 10 and 11 were
formed in the same order of magnitude. Finally, a highly
selective addition of phenyllithium to the aforementioned
ester group could also be achieved in the cases of 6a-c to
yield the new optically active compounds 8a–c.
The relative stereochemical stabilities of the prepared
compounds were in accordance with the relative values of
rotational energy barriers, calculated for the starting material
(1) and two new products (6a and 12a). The height of the
rotational energy barrier for 1 was also determined by NMR
spectroscopic experiments, which produced a value close to
the calculated one.
The enantioselective addition of diethylzinc to benzaldehyde
in the presence of a catalytic amount of (S)-13c demonstrated
on the first occasion that the prepared new atropisomeric amino
alcohols ((S)-12a–f and (S)-13a–c) can be used as efficient
catalysts in such reactions.
Until now, chiral b-aminoalcohols has been known from the
literature as good ligands; therefore, it is important to men-
tion that the synthesized new atropisomeric amino alcohols
represent the first examples of such chiral aminoalcohols in
which the two functions are connected to each other across
a six-atom long chain.
Fig. 6. Transition state geometries of 6a and 12a calculated by AM1
method (red: oxygen, blue: nitrogen, green: fluoro atom).
The optical stability of amino alcohol 12a is twice as high as
that of compound 1.
Application of Optically Active Amino Alcohol Derivative
(S)-13c as Catalyst
The addition of diethylzinc to benzaldehyde was chosen to
test the utility of the prepared new chiral amino alcohols as
enantioselective organocatalysts. Herein, we report the first
successful example for the application of (S)-13c as an
efficient catalyst of the aforementioned addition reaction.
The (S) enantiomer of 1-phenylpropanol was obtained in a
good (80%) yield and with 86% enantiomeric excess by using
5 mol% amino alcohol (S)-13b (Scheme 9).
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