β-Hydroxyamide-based ligands and their use in the enantioselective borane reduction of prochiral ketones

Article abstract of DOI:10.1002/chir.22254

Hydroxyamide-based ligands have occupied a considerable place in asymmetric synthesis. Here we report the synthesis of seven β-hydroxyamide-based ligands from the reaction of 2-hydroxynicotinic acid with chiral amino alcohols and test their effect on the enantioselective reduction of aromatic prochiral ketones with borane in tetrahydofuran (THF). They produce the corresponding secondary alcohols with up to 76% enantiomeric excess (ee) and good to excellent yields (86-99%). Chirality 26:21-26, 2013. 2013 Wiley Periodicals, Inc.

Full text of DOI:10.1002/chir.22254

CHIRALITY 26:21–26 (2014)
β-Hydroxyamide-Based Ligands and Their Use in the Enantioselective
Borane Reduction of Prochiral Ketones
MURAT AZIZOGLU, ASLI ERDOGAN, NEVIN ARSLAN, AND YILMAZ TURGUT*
Chemistry Department, Science Faculty, Dicle University, Diyarbakir, Turkey
ABSTRACT
Hydroxyamide-based ligands have occupied a considerable place in asymmetric
synthesis. Here we report the synthesis of seven β-hydroxyamide-based ligands from the reaction
of 2-hydroxynicotinic acid with chiral amino alcohols and test their effect on the enantioselective
reduction of aromatic prochiral ketones with borane in tetrahydofuran (THF). They produce the
corresponding secondary alcohols with up to 76% enantiomeric excess (ee) and good to excellent
yields (86-99%). Chirality 26:21–26, 2013. © 2013 Wiley Periodicals, Inc.
KEY WORDS: hydroxyamide; prochiral ketones; asymmetric borane reduction
INTRODUCTION
EXPERIMENTAL SECTION
General Methods
The synthesis of optically active compounds has become an
important area of research for pharmaceutical industries and
research academic institutions, as it is frequently observed
that individual enantiomers of a chiral drug molecule display
All glassware was oven-dried for several hours at 120°C, assembled
while hot, and cooled in a stream of dry nitrogen gas. All chemicals were
reagent grade unless otherwise specified. Solvents were dried according
to established procedures by distillation under argon atmosphere from
the appropriate drying agent. Silica gel 60 (Merck, Darmstadt, Germany;
1
,2
contrasting biological activities. This has forced organic
chemists to develop efficient and highly selective catalysts
for the synthesis of single enantiomers through asymmetric
reactions. Among the variety of asymmetric reactions leading
to enantiomerically pure alcohols, the enantioselective reduc-
tion of prochiral ketones with borane in the presence of a
0
(
.040–0.063 mm) and silica gel / thin-layer chromatography (TLC)-cards
F254) were used for flash column chromatography and TLC. Melting
points were determined with a Gallenkamp Model apparatus with open
capillaries. Infrared spectra were recorded on a Mattson 1000 FTIR model
spectrometer. Elemental analyses were performed with a Carlo-Erba
1108 model apparatus. Optical rotations were taken on a Perkin Elmer
3
chiral ligand has received considerable attention. Optically
active secondary alcohols are widely used in the preparation
of chiral liquid crystal materials and other chiral optical
1
13
(Boston, MA) 341 model polarimeter. H (400 MHz) and C (100 MHz)
nuclear magnetic resonance (NMR) spectra were recorded on a Bruker
(Billerica, MA) AV400 High Performance Digital FT-NMR Spectrometer.
The chemical shifts (δ) and coupling constants (J) are expressed in parts
per million and Hertz, respectively.
4
,5
materials.
Apart from transition metal complexes, many researchers
started working with hydride donors like aluminum and
boron complexes. Among them, oxazaborolidine synthesized
The enantiomeric excess (ee) value determination was carried out
using chiral high-performance liquid chromatography (HPLC) on a
Daicel Chiralcel OD-H and Chiralcel AS-3 column on aBioRad (Hercules,
CA) model 2800 pump and BioRad UV-detector. The absolute configura-
tion of the major enantiomer was assigned according to the sign of the
specific rotation.
3,6
by Itsuno et al. from L-valine gave high enantioselectivity
for prochiral ketone reduction. This method was further
7
–11
developed by Corey et al.
which is generally known as
the CBS method.
In addition to the CBS system, other catalysts such as
12–16
17–19
Preparation of the β-Hydroxyamide-Based Ligands 1–7
hydroxyl-amides,
sulphonamides,
and phosphina-
20–23
24
mides,
prolinol-squaramide have also been developed
2-Hydroxy-N-[(1S)-2-hydroxy-1-phenylethyl]pyridine-3-carboxamide
1. 2-Hydroxynicotinic acid (958mg, 6.9 mmol) was dissolved
in dry dimethylformamide (DMF). The mixture was cooled to
À15°C. Then N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
hydrochloride (EDCl) (1321 mg, 6.9 mmol) and HOBt
(1056 mg, 6.9 mmol) were added to this solution at the same
temperature. The solution of (2S)-2-amino-2-phenylethanol
(904mg, 6.6 mmol) in dry DMF (15 mL) was introduced into
the solution dropwise over a period of 0.5 h under an argon
atmosphere at the same temperature. After the addition was
completed, the mixture was allowed to the warm to room
temperature and stirred for an appropriate time (monitored by
TLC). When the reaction was completed, the DMF was
as efficient catalysts for the asymmetric reduction of ketones.
As important intermediates in the preparation of chiral
2
5
26,27
oxazoline ligands, thiazoline ligands
ligands,
and imidazoline
28,29
many chiral β-hydroxyamides have been synthe-
sized from carboxylic acids and amino alcohols. In addition to
developing versatile chiral catalysts, Liu and colleagues
reported the synthesis of prolinol-based C -symmetric amino al-
2
cohols with multicoordination groups and their application in
the catalytic borane-mediated reduction of prochiral ketones.30
Considering the potential coordination and H-bond donation
ability of β-hydroxyamides, some of them have been applied to
1
5
asymmetric catalysis as ligands or catalysts. There is a
continuing interest in the development of new tridentates
chiral ligands to be tested in the borane enantioselective reduc-
tion of prochiral ketones. In order to obtain tridentate chiral
ligands, we synthesized β-hydroxyamide ligands 1–7 from
Additional Supporting Information may be found in the online version of this
article.
Correspondence to: Y. Turgut, Chemistry Department, Science Faculty,
Dicle University, 21280 Diyarbakir, Turkey. E-mail: yturgut@dicle.edu.tr
Received for publication 17 June 2013; Accepted 31 August 2013
DOI: 10.1002/chir.22254
Published online 6 November 2013 in Wiley Online Library
(wileyonlinelibrary.com).
*
2
-hydroxynicotinic acid and commercially available amino alco-
hols and tested their catalytic activity for the enantioselective
borane reduction of prochiral ketones.
©
2013 Wiley Periodicals, Inc.

2
2
AZIZOGLU ET AL.
removed under reduced pressure. Water (10 mL) was then
added to quench the reaction. The mixture was extracted with
CHCl (2 x 10mL) and dried over anhydrous Na SO . After-
wards the organic phase was evaporated under reduced pres-
sure to give the crude product, which was purified by column
chromatography through silica gel, eluted with 10:1 ethyl ace-
(CH ) ), 58.25 (CH-NH), 81.59 (alph.C), 106.38 (Ar- C),
3 2
121.04 (Ar-C), 126.18 (Ar-C), 126.52 (Ar-C), 126.56 (Ar-C),
126.66 (Ar-C), 127.85 (Ar-C), 128.40 (Ar-C), 139.53 (Ar-C),
144.38 (Ar-C), 147.37 (Ar-C), 147.51 (Ar-C), 162.51 (Ar-C-OH),
163.66 (C=0). Anal. Calcd. for C H N O (mw: 376 g/mol):
3
2
4
23 24 2 3
C, 73.40; H, 6.38; N, 7.45. Found: C, 73.43; H, 6.40; N, 7.48.
tate/methanol solvent mixture (TLC R =0.37), to give the pure
f
2
-Hydroxy-N-[(1S)-2-hydroxy-1,2,2-triphenylethyl)pyridine-3-
yield 1 as a white solid in 90% (1540 mg) yield. M.p:
31.6-134°C,[α]2 = À107.4 (c 1, tetrahydofuran, THF). IR
0
carboxamide 4. This compound was prepared as described
above for 1 starting from 2-hydroxynicotinic acid (487 mg,
3.5 mmol),
1
(
1
D
KBr): 3232, 3178, 3029, 2920, 2853, 1684, 1613, 1548, 1470,
-
1
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
322, 1235, 1073, 1034, 912, 778, 701, 570 cm . 1H NMR
hydrochloride (EDCl) (670mg, 3.5 mmol), HOBt (535.5 mg,
(
DMSO-d ): δ (ppm) 3.68 (s, 2H, CH ), 5.06 (q, J=5.4 Hz, 2H,
6
2
3
3
.5 mmol), and (S)-(À)-2-amino-1,1,2-triphenylethanol (950 mg,
.3 mmol). The crude product was purified by recrystallizing
OH and PhCH), 6.48 (t, J=6.6Hz, 1H, Ar-H), 7.23-7.33 (m, 5H,
Ar-H), 7.72 (d, J=5.5Hz, 1H, Ar-H), 8.32 (d, J=7.0 Hz, 1H,
Ar-H), 10.42 (d, J=8.0 Hz, 1H, NH), 12.51 (s, 1H, Ar-OH). 13
from ethyl acetate to give 4 (1120 mg, 75%) as a white solid.
C
M.p: 250.2-252.1 °C, [α]2 = À295.6 (c 1, THF). IR (KBr): 3433,
0
D
NMR (DMSO-d ): δ(ppm) 55.23 (PhCH), 65.19 (CH OH),
6
2
3
1
235, , 3060, 3026, 2969, 1659, 1604, 1551, 1483, 1323, 1237,
149, 1059, 774, 698 cm , H NMR (DMSO-d ): δ (ppm) 6.02
1
06.71 (Ar- C), 120.9 (Ar-C), 127.28 (Ar-2C, overlapped, from
HETCOR,), 128.64 (Ar-C), 139.9 (Ar-C), 141.64 (Ar-C), 144.46
Ar-C), 162.80 (Ar-C-OH), 163.32 (C=0). Anal. Calcd. for
C H N O (mw:258 g/mol): C, 65.12; H, 5.4; N, 10.85. Found:
-1 1
6
(
d, J=9.3Hz, 1H, CH-NH), 6.24 (s, 1H, OH), 6.40 (t, J=6.7 Hz,
Ar-H ), 7.04-7.65 (m, 16H, Ar-H), 8.23-8.26 (m, 1H, Ar-H),
0.81 (d, J=9.3Hz, 1H, NH), 12.35 (s, 1H, Ar-OH). 13C NMR
DMSO-d ): δ(ppm) 59.15 (CH), 80.69 (alph.C), 106.49 (Ar- C),
(
1
4 14 2 3
1
(
C, 65.20; H, 5.5; N, 10.90.
6
1
1
1
1
1
20.77 (Ar-C), 126.70 (Ar-C), 126.80 (Ar-C), 126.92 (Ar-C),
26.93 (Ar-C), 127.06 (Ar-C), 127.33 (Ar-C), 127.77 (Ar-C),
28.04 (Ar-C), 129.79 (Ar-C), 139.86 (Ar-C), 140.49 (Ar-C),
44.40 (Ar-C), 146.18 (Ar-C), 146.50 (Ar-C), 162.53 (Ar-C-OH),
62.66 (C=0). Anal. Calcd. for C H N O (mw: 410 g/mol):
2
-Hydroxy-N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]pyridine-3-
carboxamide 2. This compound was prepared as described
above for 1 starting from 2-hydroxynicotinic acid (958mg,
6
.9 mmol),
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
26 22 2 3
hydrochloride (EDCl) (1321 mg, 6.9 mmol), HOBt (1056 mg,
C, 76.10; H, 5.36; N, 6.83. Found: C, 76.13; H, 5.40; N, 6.80.
6
6
.9 mmol), and (2S)-2-amino-3-phenyl-1-propanol (996.6 mg,
.6 mmol). The crude product was purified by recrystallizing
2
3
-Hydroxy-N-[(2S)-1-hydroxy-1,1,3-triphenylpropan-2-yl]pyridine-
-carboxamide 5. This compound was prepared as described
from methanol to give 2 (1060 mg, 58%) as a yellow solid. M.
2
0
o
p.: 166.4-168.1°C,[α]D = À114.4 (c 1, THF). IR (KBr): 3397,
above for 1 starting from 2-hydroxynicotinic acid (500 mg,
.6 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
hydrochloride (EDCl) (689.4 mg, 3.6 mmol), HOBt (550.8 mg,
.6 mmol), and (S)-(À)-2-amino-1,1,3-triphenyl-1-propanol
1000 mg, 3.6 mmol). The crude product was purified by crys-
3
1
226, 3108, 3070, 2999, 2928, 1673, 1587, 1549, 1470, 1326,
233, 896, 752, 692, 572 cm . H NMR (DMSO-d ): A part of
3
-
1 1
6
AB spin system: δ (ppm) 2.78 (dd, J=7.4 and 13.6 Hz, 1H,
PhCH ), B part of AB spin system: 2.92 (dd, J=6.2 and
3
2
(
1
1
7
3.2 Hz, 1H, PhCH ), 3.45 (m, 2H, CH OH), 4.15 (d, J=5.8Hz,
H, CH-NH), 4.95 (s, 1H, OH), 6.45 (t, J=6.6 Hz, Ar-H ),
.17-7.26 (m, 5H, Ar-H), 7.68 (d, J=5.7Hz, 1H, Ar-H), 8.30
2 2
tallizing from ethyl acetate to give 5 (1300 mg, 85%) as an open
20
yellow solid. M.p. 226.1-228.4 °C,[α]D = À157.5 (c 1, THF). IR
(
KBr): 3358, 3263, 3058, 2966, 1659, 1539, 1488, 1445, 1326,
(
d, J=7.0 Hz, 1H, Ar-H), 9.92 (d, J=8.0Hz, 1H, NH), 12.44
-1 1
1
058, 773, 697, 567 cm , H NMR (DMSO-d ): δ (ppm) 2.72
6
(
s, 1H, Ar-OH). 13C NMR (DMSO-d ): δ(ppm) 37.40 (PhCH ),
6
2
(
d, J= 6.7 Hz, 2H, -CH ), 5.33-5.39 (m, 1H, CH-NH), 6.29-6.40
2
5
1
1
2.71 (BnCH), 62.37 (CH OH), 106.61 (Ar-C), 120.88 (Ar-C),
26.51 (Ar-C), 128.64 (Ar-C), 129.65 (Ar-C), 139.27 (Ar-C),
39.72 (Ar-C), 144.30 (Ar-C), 162.69 (Ar-C-OH), 163.31 (C=0).
2
(
m, 2H, Ar-H and OH), 7.05-8.03 (m, 17H, Ar-H), 10.05
13
(
d, J= 9.8 Hz, 1H, NH), 11.40 (s, 1H, Ar-OH). C NMR
(
DMSO-d ): δ(ppm) 37.20 (CH ), 57.19 (CH), 80.69 (alph.-C),
6
2
Anal. Calcd. for C H N O (mw:272 g/mol) C, 66.18; H,
15 16 2 3
1
1
1
1
1
06.35 (Ar-C), 120.57 (Ar-C), 126.20 (Ar-C), 126.24 (Ar-C),
26.48 (Ar-C), 126.52 (Ar-C), 126.89 (Ar-C), 127.80 (Ar-C),
28.29 (Ar-C), 128.63 (Ar-C), 129.45 (Ar-C), 139.52 (Ar-C),
39.70 (Ar-C), 144.20 (Ar-C), 146.61 (Ar-C), 146.98 (Ar-C),
62.45 (Ar-C-OH), 163.11 (C=0). Anal. Calcd. for C H N O
5
.88; N, 10.29. Found: C, 66.20; H, 5.94; N, 10.30.
2-Hydroxy-N-[(2S)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl]pyri-
dine-3-carboxamide 3. This compound was prepared as
described above for 1 starting from 2-hydroxynicotinic
acid (584.2 mg, 4.2 mmol), N-(3-dimethylaminopropyl)-N-
ethylcarbodiimide hydrochloride (EDCl) (804.3 mg, 4.2 mmol),
HOBt (642.6 mg, 4.2 mmol), and (2S)-(À)-2-amino-3-methyl-
27 24 2 3
(
mw: 424 g/mol): C, 76.40; H, 5.66; N, 6.60. Found: C, 76.40;
H, 5.67; N, 6.61.
2-Hydroxy-N-[(1S,2R)-2-hydroxy-1,2-diphenylethyl]pyridine-3-
carboxamide 6. This compound was prepared as described
above for 1 starting from 2-hHydroxynicotinic acid (695 mg,
5.0 mmol),
hydrochloride (EDCl) (957.5 mg, 5.0 mmol), HOBt (765 mg,
5.0 mmol), and (1S,2R)-(+)-2-amino-1,2-diphenylethanol
(1000 mg, 4.7 mmol). The crude product was purified by
crystallizing from ethyl acetate to give 6 (1100 mg, 70%) as a
white solid. M.p. 238.2-240.4 °C,[α] = +117.3 (c 1, THF).IR
1
,1-diphenyl-1-butanol (1000 mg, 3.9 mmol). The crude product
was purified by recrystallizing from ethyl acetate to give
(1100 mg, 75%) as a white solid. M.p: 242.1-243.6°C,[α]
3
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
2
0
=
À72.9 (c 1, THF), IR (KBr): 3391, 3285, 3119, 3067, 2956,
D
2
5
3
926, 2853, 1663, 1626, 1546, 1480, 1324, 1240, 1060, 776, 699,
58 cm-1 , H NMR (DMSO-d ): δ (ppm) 0.76 (d, J=6.8 Hz,
1
6
H, -CH ), 0.86 (d, J=6.7 Hz, 3H, -CH ), 1.76-1.82 (m, 1H,
3
3
2
0
CH(CH ) ), 5.03 (d, J=10.0 Hz, 1H, CH-NH), 5.97 (s, 1H,
3
2
D
-1
OH), 6.41 (t, J=6.6 Hz, Ar-H ), 7.04-8.29 (m, 12H, Ar-H),
(KBr, cm ): 3347, 3217, 3080, 2969, 1669,1592, 1473,
1329,696. H NMR (DMSO-d ): δ (ppm) 4.97 (m, 1H,-CH-NH ),
1
3
1
1
0.07 (d, J=10 Hz, 1H, NH), 12.31 (s, 1H, Ar-OH). C NMR
6
(
DMSO-d ): δ(ppm) 18.45 (CH ), 23.50 (CH ), 29.17 (ÀCH
5.24 (q, 1H, CH-OH), 5.71 (d, 1H, J = 4.12 Hz, OH), 6.43-6.46
6
3
3
Chirality DOI 10.1002/chir

β-HYDROXYAMIDE-BASED LIGANDS
23
(
m, 1H, Ar-H), 7.05-7.21 (m, 10H, Ar-H), 7.70-7.71 (m, 1H,
The process usually requires activation of a carboxylic acid
moiety in the presence of coupling reagents. Activation con-
sists of the replacement of the hydroxyl group of the carbox-
ylic acid with a leaving group, as the acid would otherwise
simply form salts with the amine. The reaction of the acti-
vated intermediate and the amine is known as the coupling
Ar-H),8.25-8.27 (m, 1H, Ar-H),10.65 (d, 1H, J = 8.6 Hz, -NH) ).
13
C NMR (DMSO-d ): δ(ppm) 59.22 (CH-OH, 75.31( CH-NH),
6
1
06.67 (Ar-C), 120.74 (Ar-C), 127.07(Ar-C), 127.15(Ar-C),127.40
(Ar-C), 127.91(Ar-C), 127.93(Ar-C), 128.50(Ar-C), 139.94
(Ar-C), 140.02 (Ar-C), 142.51 (Ar-C), 144.34 (Ar-C, 162.87
(Ar-C-OH), 162.98 (C=0). Anal. Calcd. for C H N O (mw:
3
34
reaction and the activators are coupling reagents.
N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide
20 18 2 3
34 g/mol): C, 71.86; H, 7.69; N,8.38. Found: C, 72.02; H, 7.74;
hydro-
N, 8.40.
chloride (EDCl)/HOBt reagents have been widely used in
amide synthesis to improve yields, because they show a
moderate activity and they are reasonably cheap. When
dicyclohexylcarbodiimide (DCC) was employed in the syn-
thesis of the amides, the removal of dicyclohexylurea by prod-
uct necessitated lengthy chromatography procedures. To
avoid this, we preferred using N-(3-dimethylaminopropyl)-N-
ethylcarbodiimide hydrochloride (EDCl) as the coupling
agent. This afforded a water-soluble urea byproduct which
was easily removed by aqueous washes. As well as simplify-
ing the work-up procedure, this modification also signifi-
cantly increased the yields of the amides formed. Use of
acid chlorides proved to be problematic since significant
amounts of bisacylated product were formed under these
conditions.
Considering the potential coordination and H-bond donation
ability of β-hydroxyamide-based ligands, some of them have
been applied to asymmetric catalysis as ligand or catalyst. With
this analogy in mind, A series of novel chiral β-hydroxyamide li-
gands 1–7 with multicoordination groups were easily prepared
from 2-hydroxynicotinic acid and commercially available amino
alcohols (Scheme 1). Treatment of 2-hydroxynicotinic acid with
N-(3-dimethylaminopropyl)-N-ethylcarbodiimidehydrochloride
2
-Hydroxy-N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]pyr-
idine-3-carboxamide 7. This compound was prepared as
described above for 1 starting from 2-hydroxynicotinic
acid (973 mg, 7.0 mmol), N-(3-dimethylaminopropyl)-N-
ethylcarbodiimide
hydrochloride
(EDCl)
(1340 mg,
7
.0 mmol), HOBt (1071 mg, 7.0 mmol), and (1R,2S)-(+)-cis-1-
amino-2-indanol (1000 mg, 6.71 mmol). The crude product
was purified by crystallizing from ethyl acetate to give
7
D
(1300 mg, 70%) as a white solid. M.p.247.7-249°C,[α]
2
0
=
+8.2 (c 0.5, THF). IR (KBr): 3326, 3126, 3067, 2928, ,
1
7
680, 1626, 1566, 1523, 1436, 1311, 1243, 1088, 1054, 893,
74, 673, 578 cm , H NMR (DMSO-d ): δ (ppm) A part of
-
1 1
6
AB system: 2.82 (d, J = 16 Hz, 1H ), B part of AB system,
.10 (dd, J= 4.8 and 16 Hz, 1H), 4.47 (s, 1H, -CH-OH), 5.22
3
(
(
(
1
s, 1H, OH), 5.39 (q, J= 5.0 and 8.3 Hz, 1H, CH-NH), 6.49
t, J= 6.7 Hz, Ar-H ), 7.16-7.27 (m, 4H, Ar-H), 7.70-7.72
m, 1H, Ar-H), 8.42-8.45 (m, 1H, Ar-H), 10.26 (d, J= 8.4 Hz,
1
3
H, NH), 12.43 (s, 1H, Ar-OH). C NMR (DMSO-d ):
6
δ(ppm) 40.46 (CH , (from DEPT135 spect.)), 57.53 (ÀCNH),
2
72.45 (ÀC-OH), 106.52 (Ar-C), 121.07 (Ar-C), 124.36 (Ar-C),
125.39 (Ar-C), 126.82 (Ar-C), 127.71 (Ar-C), 139.87 (Ar-C),
141.18 (Ar-C), 143.14 (Ar-C), 144.49 (Ar-C), 162.65 (Ar-C-OH),
163.92 (C=0). Anal. Calcd. for C H N O (mw: 270 g/mol):
(
EDCl) and 1-hydroxybenzotriazole hydrate (HOBt) using
1
5 14 2 3
amino alcohols in DMF afforded the corresponding chiral
β-hydroxyamide ligands 1–7 as solid in 58-90% yields.
Structures of all novel compounds were confirmed by spectral
and elemental analyses.
C, 66.60; H, 5.18; N, 10.37. Found: C, 66.65; H, 5.20; N, 10.40.
General Procedure for the Enantioselective Reduction of
Ketones With Borane-Dimethyl Sulfide in the Presence of
β-hydroxyamides 1–7
It is known that the ee is sensitive to the solvent, amount of
the catalyst, the catalyst generation period, and the reaction
A 25-mL two-necked flask was charged with β-hydroxyamide 1–7
0.05 mmol, 10%) in dry and fresh THF (3 mL), equipped with a magnetic
35
temperature. In our previous studies we reported the opti-
mization conditions for ee in the asymmetric borane reduction
of prochiral ketone. Under optimized reaction conditions
from our previous studies, we tested β-hydroxyamides 1–7
(
stirrer and a connection to the combined nitrogen/vacuum line, and
closed with a septum. The air in the flask was replaced by nitrogen.
The β-hydroxyamides 1–7 were dissolved in THF (3 mL) under stirring
3 2
and a solution of BH .SMe (0.5 mmol, 10M) complex was added at 0°C
by a syringe. After the mixture was stirred for 1 h at 65°C, the freshly
distilled ketone (0.5 mmol) in dry and fresh THF (2mL) was added over a
period of 1.5 h by a syringe at the same temperature. The reaction mixture
was kept stirring at the 65°C until the ketone was completely consumed.
After stirring a further 30min at room temperature, the reaction mixture
was quenched by the addition of MeOH (2mL) and extracted with CH
three times. The combined organic extracts were washed with brine and
dried over MgSO . After evaporating the solvent under reduced pressure,
2 2
Cl
4
the product was purified by column chromatography on silica gel using
petroleum ether/EtOAc (5:1; for 4-nitroacetophenone: 5/3) as eluent.
The ee value was determined by HPLC with Chiralcel AS-3 or Chiralcel
OD-H columns.
RESULTS AND DISCUSSION
Amide bonds play a major role in the elaboration and
composition of biological systems, representing, for example,
the main chemical bonds that link amino acid building blocks
3
1,32
together to give proteins.
Peptides and proteins play an important role in modern
biology. A key step in peptide production is the formation of
the peptide bond, which involves amide bond formation.
33
Scheme 1. Synthesis of β-hydroxyamide-based ligands 1–7.
Chirality DOI 10.1002/chir

2
4
AZIZOGLU ET AL.
Chirality DOI 10.1002/chir

β-HYDROXYAMIDE-BASED LIGANDS
25
in the asymmetric borane reduction of different substituted
aromatic prochiral ketones; the results are summarized in
Table 1.
In the asymmetric reduction studies for catalysts 1 and 2,
which contain a primary alcohol moiety, one chiral center,
and a phenyl and benzyl moiety in the stereogenic center,
the reduction yield is very high (from 90 to 99%), although
enantioselectivity is very low. Absolute configurations of the
products were found to be R, while those of the alcohols
formed by the reduction of isopropyl phenyl ketone,
From the above results obtained for the enantioselective
prochiral reduction catalyzed by series of chiral
a
β-hydroxyamides 1–7, it was found that chiral β-hydroxyamides
6 and 7 gave the best enantioselectivity, and the results are
shown Table 1.
CONCLUSION
In conclusion, we have synthesized chiral β-hydroxyamide
ligands 1–7 from 2-hydroxynicotinic acid and commercially
available amino alcohols, for enantioselective ketone reduc-
tion with borane dimethyl sulfide as a reducing agent. Differ-
ent prochiral ketones were reduced up to 76% ee and 99%
yield. One can see that especially that ligand 7, which is more
rigid, has two chiral centers, and contains indanol ring and a
secondary alcohol, as well as ligand 6, which has also two
chiral centers, and carries two phenyl groups in the chiral
centers, exhibit better catalytic activity than the other ligands.
2
-bromoacetophenone, and 2,2,2-trifluoroacetophenone were
opposite (S) configuration.
In the asymmetric reduction studies with catalyst 3, the
best enantioselectivity was found for S isomer alcohol of
2
-bromoacetophenone (25% ee) (Table 1, cat. 3). For the
examined ketones, the catalyst gave very low
3
enantioselectivities, but high chemical yields (Table 1, cat. 3).
Catalyst 3 contains an isopropyl moiety and a tertiary alcohol
carbon in the stereocenter and has two phenyl groups.
As can be seen in Table 1, when catalysts 1 and 2 are
compared in enantioselectivity and yield, it can be stated that
ACKNOWLEDGMENTS
We would like to thank the Scientific and Technological
Research Council of Turkey (TUBITAK) for financially
supporting this research (Project No: 110 T 809).
catalyst 2, which is far from the stereocenter as a CH - group,
2
is a better catalyst. This may be due to fact that the phenyl
group is slightly further to the stereocenter during the forma-
tion of oxazaborolidine between catalyst 2 and boron. In
Table 1, it is seen that catalyst 3, which contains a secondary
alcohol moiety and two stereogenic centers, is a good reduc-
tion catalyst in both enantioselectivity and yield.
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Chirality DOI 10.1002/chir