Synthesis of novel chiral diamino alcohols and their application in copper-catalyzed asymmetric allylic oxidation of cycloolefins

Article abstract of DOI:10.5012/bkcs.2014.35.7.1989

The small library of new enantiomerically pure (S,S)-diamino alcohols 1 and their hydroxyldiamide precursors 2 were conveniently synthesized on a gram scale from inexpensive and commercially chiral pool amino acids. The catalytic and induced asymmetric ef

Full text of DOI:10.5012/bkcs.2014.35.7.1989

Synthesis of Novel Chiral Diamino Alcohols and Their Application
Bull. Korean Chem. Soc. 2014, Vol. 35, No. 7 1989
http://dx.doi.org/10.5012/bkcs.2014.35.7.1989
Synthesis of Novel Chiral Diamino Alcohols and Their Application in
Copper-Catalyzed Asymmetric Allylic Oxidation of Cycloolefins
Laleh Faraji, Saadi Samadi, Khosrow Jadidi,* and Behrouz Notash
Department of Chemistry, Shahid Beheshti University, G.C. Tehran 1983963113, Iran. *E-mail: k-jadidi@sbu.ac.ir
Received December 18, 2013, Accepted March 8, 2014
The small library of new enantiomerically pure (S,S)-diamino alcohols 1 and their hydroxyldiamide precursors
2 were conveniently synthesized on a gram scale from inexpensive and commercially chiral pool amino acids.
The catalytic and induced asymmetric effects of the chiral ligands 1 in the asymmetric allylic oxidation of
cycloolefins were investigated.
Key Words : Chiral diamino alcohols, Chiral hydroxyldiamides, Asymmetric allylic oxidation, Small chiral
libraries, Chiral pool amino acids
Introduction
Optically active amino alcohols are one of the important
classes of compounds because of their presence in the
1
natural products. They have also found applications as
chiral ligands and auxiliaries for a variety of asymmetric
2,3
4
reactions. Furthermore, diamino alcohols and their hydr-
5
oxyldiamide precursors, in particular, are core units in many
medicinal compounds such as HIV protease inhibitors
5f
5g-i
5j
A80987 (3), A77003 (4) and lacosamide (5) (Scheme
1). Due to the importance and high efficiency of chiral
4g
hydroxyldiamide, chiral amino alcohols and their methoxy
analogy, our attention was focused on the development of a
simple and efficient method to produce a small library of
enantiomerically pure diamino alcohols 1 and their hydrox-
yldiamide precursors 2 from readily available starting materials.
Although the asymmetric synthesis of vicinal amino alcohols
has been extensively studied, however, there have been a
few reports of asymmetric synthesis to diamino alcohols,
Scheme 1
which may become precursors of new kinds of amino alcohol
4d-g
compounds.
The chiral hydroxyldiamides 2, which ap-
terms of long reaction times, unsatisfactory yields, or low
enantioselectivities. Apparently, yields and ees achieved in
this work are superior for the allylic oxidation of cyclo-
olefins in comparison with other works that used chiral
amino alcohols as ligands.
pear structurally similar to molecules 3-5, can be expected to
provide more opportunities for the development of bio-
5
logically active compounds. Moreover, the chiral diamino
alcohols, 1, can be used in the asymmetrical reactions as a
catalyst to increase reaction rate and as a chiral auxiliary or
chiral ligand to induce the chirality in the synthesis of chiral
Experimental
2,3
products. Enantioselective allylic oxidation of olefins
using copper chiral complexes have been the subject of great
interest during the last decade. This reaction provides an
access to chiral allylic alcohols, which are the key inter-
General Information. Melting points were measured on
an Elecrtothermal 9100 apparatus and are uncorrected.
Optical rotations were measured with a Perkin-Elmer 341
6,7
1
13
mediates in natural products synthesis. Since the use of
polarimeter at 589 nm. H and C NMR spectra were record-
ed on a BRUKER DRX-300 AVANCE spectrometer at
300.13 and 75.47 MHz in CDCl3 and DMSO-d6 using TMS
(δ = 0.0 ppm) as internal standard. IR spectra were recorded
on a Bomen FT-IR-MB-series instrument. Mass spectra were
recorded on a FINNIGAN-MAT 8430 spectrometer operat-
ing at an ionization potential of 70 eV. Enantiomeric excess
(ee) of the allylic esters 9 were determined by HPLC analysis
chiral amino alcohol ligands has been less studied on asym-
8
metric Kharasch reaction, our increasing interest was con-
centered on the demonstration of catalytic and asymmetric
effects of the chiral tridentate diamino alcohols 1 in the
asymmetric copper-catalyzed allylic oxidation of cyclo-
9
olefins. To the best of our knowledge, all the reported
allylic oxidations suffer from at least one disadvantage in

1990 Bull. Korean Chem. Soc. 2014, Vol. 35, No. 7
Laleh Faraji et al.
20
o
using EC 250/4.6 Nucleocel Alpha S column. All reactions
were performed under an atmosphere of dry, oxygen-free
nitrogen. All reagents were purchased from Aldrich, Merk,
Alfa Acer or Acros. N-protected amino acids 7 and amino
(921 mg, 80%). mp 78 C. [α]D = +250 (c = 0.04, CH2Cl2).
1
H NMR (300 MHz, CDCl3) δH 0.87 (d, 6H), 1.18-1.46 (m,
2H), 1.46-1.62 (m, 1H), 2.85 (br s, 1H), 3.38-3.47 (br dd,
2H), 3.91-4.09 (br s, 1H), 5.07 (s, 2H), 5.11-5.29 (br s, 1H),
10,
13
alcohols 8 were prepared according to literature procedure.
6.28-6.43 (m, 2H) 7.32 (br s, 10H). C NMR (75.46 MHz,
11
Olefins were distilled from calcium hydride before use.
CDCl3) δC 22.2, 23.0, 24.8, 39.8, 50.3, 59.0, 65.0, 67.1,
127.1, 128.1, 128.2, 128.4, 128.5, 129.0, 136.1, 137.9, 156.0,
All solvents were of reagent grade and were dried and di-
stilled immediately before use as follows: acetonitrile and
acetone from P2O5, methylene chloride from calcium hydride,
tetrahydrofuran and diethyl ether from sodium and methanol
from magnesium. Column chromatography was performed
using silica gel 60 (230 400 mesh) eluting with ethyl
acetate: n-hexane. TLC was performed using silica gel 60
F256 plates with visualization by UV.
−1
170.4. FT-IR (KBr, cm ) 3316, 2960, 2905, 1720, 1659,
+
1521, 1237, 1050, 733, 698. MS (m/z) = 384 (M ); Anal.
calcd for C22H28N2O4: C 68.73, H 7.34, N 7.29; found C
68.84, H 7.40, N 7.23.
Benzyl ((S)-2-(((S)-1-Hydroxy-3-phenylpropan-2-yl)-
amino)-2-oxo-1-phenylethyl)carbamate (2d): White solid
(1.152 g, 92%). mp 156 C. [α]D = +30 (c = 0.5, DMSO).
20
o
1
2
General Procedure for the Synthesis of Chiral Hydr-
oxyldiamide 2. To a cold solution of N-protected amino acid
H NMR (300 MHz, DMSO) δH 2.61-2.68 (dd, J = 13.2 Hz,
3J = 8.3 Hz, 1H ), 2.82-2.88 (dd, J = 13.2 Hz, J = 5.3 Hz,
1H), 3.21-3.31 (m, 2H), 3.79- 3.90 (m, 1H), 4.83 (t, J = 5.3
Hz, 1H), 5.03 (s, 2H), 5.22 (d, J = 8.6 Hz, 1H), 7.26-7.35 (m,
2
3
o
7 (3 mmol) in dry THF (10 mL) at −15 C under N2 were
added 4-methylmorpholine (0.33 mL, 3 mmol) followed by
addition of isobutyl chloroformate (0.39 mL, 3 mmol). The
reaction mixture was allowed to stir for 5 minutes and then,
a THF solution of chiral amino alcohol 8 (3 mmol) was
13
15H), 7.82 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H). C
NMR (75.46 MHz, DMSO) δC 36.8, 53.3, 62.2, 63.4, 67.2,
126.7, 127.2, 128.2, 128.3, 128.6, 128.6, 128.7, 128.8,
o
−1
added to the reaction flask at −15 C. The reaction was
129.2, 136.0, 137.4, 137.6, 155.8, 170.0. FT-IR (KBr, cm )
warmed to room temperature and stirred for 16 h at rt. The
reaction mixture was concentered and dissolved in 15 mL of
ethyl acetate and 3 mL of water. After separation of layers,
The ethyl acetate layer was washed with 1 N HCl (12 mL),
water (3 mL), 5% NaHCO3 (12 mL), water (6 mL), and then
with saturated NaCl. The organic layer was concerted to
afford chiral hydroxyldiamide 2 as a white solid after
crystallization in ethylacetate/hexane.
3379, 2881, 1694, 1663, 1468, 1278, 1189, 1108, 892, 863.
+
MS (m/z) = 418 (M ); Anal. calcd for C25H26N2O4: C 71.75,
H 6.26, N 6.69; found C 71.79, H 6.31, N 7.09.
Benzyl ((S)-1-(((S)-1-Hydroxy-3-phenylpropan-2-yl)-
amino)-1-oxo-3-phenylpropan-2-yl)carbamate (2e): White
20
o
solid (1.242 g, 96%). mp 160 C. [α]D = +12.76 (c = 0.4,
1
CH2Cl2). H NMR (300 MHz, DMSO) δH 2.61-2.73 (br dd,
2H), 2.82-2.93 (m, 2H), 3.20-3.36 (br s, 3H), 3.78-3.88 (br
dd, 1H), 4.17-4.24 (m, 1H), 4.93 (s, 2H), 7.15-7.32 (m, 15H),
Benzyl ((S)-2-(((S)-2-Hydroxy-1-phenylethyl)amino)-2-
oxo-1-phenylethyl)carbamate (2a): White solid (1.077 g,
13
7.44 (d, J = 8.7 Hz, 1H), 7.92 (br s, 1H). C NMR (75.46
MHz, DMSO) δC 36.7, 36.9, 53.4, 62.8, 63.4, 67.5, 126.8,
20
o
89% yield). mp 206 C. [α]D = –23.52 (c = 0.42, DMSO).
1
H NMR (300 MHz, DMSO) δH 3.47-3.54 (br dd, 2H), 4.74-
127.4, 128.2, 128.3, 128.4, 128.6, 128.8, 128.9, 129.1,
−1
4.81 (dd, 1H), 4.86 (t, J = 5.4 Hz, 1H), 5.02 (s, 2H), 5.36 (d,
J = 8.7 Hz, 1H), 7.22-7.33 (m, 13H), 7.44 (d, 2H), 7.91 (d, J
= 8.5 Hz, 1H), 8.62 (d, J = 7.9 Hz, 1H). C NMR (75.46
MHz, DMSO) δC 31.1, 55.6, 64.9, 66.0, 127.3, 127.4, 127.6,
136.1, 137.4, 137.6, 156.1, 170.2. FT-IR (KBr, cm ) 3281,
2937, 1690, 1653, 1534, 1286, 1247, 1041, 747, 697. MS
13
+
(m/z) = 432 (M ); Anal. calcd for C26H28N2O4: C 72.20, H
6.53, N 6.48; found C 72.28, H 6.57, N 6.50.
128.0, 128.1, 128.2, 128.5, 128.7, 128.8, 137.3, 139.2,
Benzyl ((S)-1-(((S)-1-Hydroxy-3-methylbutan-2-yl)amino)-
3-methyl-1-oxobutan-2- yl)carbamate (2f): White solid
−1
141.3, 156.6, 169.9. FT-IR (KBr, cm ) 3306, 2966, 1694,
20
o
1651, 1561, 1529, 1250, 1048, 748, 700. MS (m/z) = 404
(816 mg, 81%). mp 160 C. [α]D = +81.8 (c = 0.2, CH2Cl2).
+
1
(M ); Anal. calcd for C24H24N2O4: C 71.27, H 5.98, N 6.93;
H NMR (300 MHz, DMSO) δH 0.80-0.86 (m, 12H), 1.79-
found C 71.35, H 6.08, N 6.90.
1.88 (m, 1H), 1.88-1.97 (m, 1H), 3.35-3.43 (br s, 2H), 3.54-
3.60 (m, 1H), 3.84 (t, 1H), 4.59 (br t, 1H), 5.03 (s, 2H), 7.27-
7.30 (br d, 1H), 7.30-7.38 (m, 5H), 7.50 (d, J = 8.9 Hz, 1H).
Benzyl ((S)-2-(((S)-1-Hydroxy-3-methylbutan-2-yl)amino)-
2-oxo-1-phenylethyl)carbamate (2b): White solid (1.032
20
o
1
13
g, 93%). mp 130 C. [α]D = +360 (c = 0.1, DMSO). H
NMR (300 MHz, DMSO) δH 0.82 (t, 6H), 1.73-1.87 (m, 1H),
3.48-3.53 (m , 2H), 4.6 (br t, 1H), 5.04 (s, 2H), 5.31 (d, J =
8.7 Hz, 1H), 7.25-7.34 (m, 10H), 7.91 (d, J = 8.2 Hz, 2H).
C NMR (75.46 MHz, DMSO) δC 18.6, 18.8, 20.0, 20.1,
28.7, 28.9, 56.4, 58.9, 61.4, 66.0, 127.5, 128.2, 128.8, 137.4,
−1
156.09, 170.11. FT-IR (KBr, cm ) 3284, 2977, 2875, 1691,
1646, 1532, 1247, 1043, 1024, 746, 699. MS (m/z) = 336
13
+
C NMR (75.46 MHz, DMSO) δC 18.5, 20.0, 28.6, 56.2,
(M ); Anal. calcd for C18H28N2O4: C 64.26, H 8.39, N 8.33;
58.8, 61.5, 66.0, 127.5, 127.8, 128.1, 128.2, 128.6, 128.8,
found C 64.35, H 8.42, N 8.29.
−1
137.4, 139.3, 156.1, 170.2. FT-IR (KBr, cm ) 3318, 2954,
Benzyl ((S)-1-(((S)-1-Hydroxy-4-methylpentan-2-yl)-
amino)-4-methyl-1-oxopentan-2-yl)carbamate (2g): White
2856, 1690, 1650, 1529, 1250, 1226, 1050, 854, 699. MS
20
+
o
(m/z) = 370 (M ); Anal. calcd for C21H26N2O4: C 68.09, H
7.07, N 7.56; found C 68.3, H 7.14, N 7.49.
solid (939 mg, 86%). mp 101 C. [α]D = +41.25 (c = 1.4
1
CH2Cl2). H NMR (300 MHz, DMSO) δH 0.80-0.87 (m,
Benzyl ((S)-2-(((S)-1-Hydroxy-4-methylpentan-2-yl)-
amino)-2-oxo-1-phenylethyl)carbamate (2c): White solid
12H), 1.28-1.35 (m, 2H), 1.35-1.44 (m, 2H), 1.55-1.61 (m,
2H), 3.17-3.20 (m, 1H), 3.28-3.31 (m, 1H), 3.71- 3.78 (m,

Synthesis of Novel Chiral Diamino Alcohols and Their Application
Bull. Korean Chem. Soc. 2014, Vol. 35, No. 7 1991
−1
1H), 3.97-4.04 (m, 1H), 4.65 (t, 1H), 5.02 (s, 2H), 7.34-7.37
172.9. FT-IR (KBr, cm ) 3294, 2958, 2844, 1662, 1636,
13
+
(m, 6H), 7.50 (d, J = 8.6 Hz, 1H). C NMR (62.89 MHz,
DMSO) δC 26.8, 27.1, 27.3, 28.0, 28.2, 28.7, 29.3, 29.5,
1538, 1266, 1073, 1031, 695. MS (m/z) = 334 (M ); Anal.
calcd for C19H30N2O3: C 68.23, H 9.04, N 8.38; found C
53.8, 58.5, 68.1, 69.0, 132.8, 133.0, 133.6, 142.4, 161.1,
68.29, H 9.09, N 8.32.
−1
177.1. FT-IR (KBr, cm ) 3304, 2967, 2864, 1691, 1653,
N-((S)-1-(((S)-1-Hydroxy-3-methylbutan-2-yl)amino)-
4-methyl-1-oxopentan-2-yl)benzamide (2l): White solid
+
1552, 1235, 1118, 1035, 751, 737. MS (m/z) = 364 (M ,
100). Anal. calcd for C20H32N2O4: C 65.91, H 8.85, N 7.69;
20
o
(797 mg, 83%). mp242 C. [α]D = –100.26 (c = 0.08, CH2Cl2).
1
found C 66.04, H 8.89, N 7.75.
H NMR (300 MHz, CDCl3) δH 0.83-0.86 (m, 12H), 1.31-
Benzyl ((S)-1-(((S)-1-Hydroxy-3-phenylpropan-2-yl)-
amino)-4-methyl-1-oxopentan-2-yl)carbamate (2h): White
1.44 (m, 2H), 1.51-1.76 (m, 2H), 3.50-3.68 (m, 2H), 3.89-
4.10 (br s, 1H), 4.63-4.79 (br s, 1H), 7.25-7.60 (m, 5H), 7.81
20
o
13
solid (979 mg, 82%). mp 130 C. [α]D = –25.71 (c = 1.1,
(d, J = 6.6 Hz, 2H). C NMR (62.89 MHz, CDCl3) δC 26.8,
27.2, 27.3, 28.1, 28.2, 29.4, 29.5, 50.1, 52.3, 65.5, 127.4,
1
CH2Cl2). H NMR (300 MHz, CDCl3) δH 0.89 (br s, 6H),
−1
1.41-1.51 (m, 1H), 1.60-1.75 (m, 2H), 2.86 (d, J = 6 Hz,
2H), 3.49-3.72 (m, 2H), 4.15 (br s, 2H), 5.09 (s, 2H), 5.41
128.6, 131.8, 133.6, 163.9, 172.6. FT-IR (KBr, cm ) 3298,
2960, 2873, 1638, 1582, 1295, 1069, 695. MS (m/z) = 320
(M ); Anal. calcd for C18H28N2O3: C 67.47, H 8.81, N 8.74;
13
+
(br s, 1H), 6.70 (br s, 1H), 7.21-7.35 (m, 10H). C NMR
(62.89 MHz, CDCl3) δC 20.6, 21.4, 23.2, 35.4, 39.7, 51.5,
52.4, 62.0, 65.7, 125.1, 126.6, 126.8, 127.1, 127.1, 127.8,
found C 67.52, H 8.85, N 8.70.
General Procedure for the Synthesis of Diamino Alcohol
1. To suspension of LiAlH4 (263 mg, 7 mmol) in THF (15
−1
134.6, 136.3, 155.0, 171.2. FT-IR (KBr, cm ) 3451, 2958,
o
2925, 2870, 1712, 1652, 1541, 1273, 1163, 1114, 717, 690.
mL) at 0 C under N2 atmosphere was added 2 (1 mmol).
+
o
MS (m/z) = 398 (M ); Anal. calcd for C23H30N2O4 : C 69.32,
H 7.59, N 7.03; found C 69.28, H 7.65, N 7.11.
The suspension was reflux for 24 h, cooled to 0 C and
treated with 5 mL THF and 1 mL water. After filtration of
the resulting suspension, the water layer was extracted with
CH2Cl2, dried over MgSO4. After removal of the solvent, the
residue was chromatographed on silica gel (hexane/ethyl
acetate = 30:3 to 1:30) to afford the product as a pale yellow
oil (78-95%).
N-((S)-1-(((S)-1-Hydroxy-3-phenylpropan-2-yl)amino)-
4-methyl-1-oxopentan-2-yl)benzamide (2i): White solid
20
o
(883 mg, 80%). mp 148 C. [α]D = –123.5.0 (c = 0.3,
1
C2H5OH). H NMR (300 MHz, DMSO) δH 0.82-0.88 (m,
2
6H), 1.38-1.50 (m, 1H), 1.50-1.69 (m, 2H), 2.61-2.68 (dd, J
3
2
3
= 13.5 Hz, J = 8.1 Hz, 1H), 2.80-2.86 (dd, J = 13.5Hz, J =
4.9 Hz, 1H), 3.30-3.36 (dd, 2H), 3.89 (br d, 1H), 4.48 (br s,
1H), 4.87 (t, 1H), 7.11-7.25 (m, 5H), 7.44-7.54 (m, 3H), 7.75
(d, J = 8.1Hz, 1H), 7.86 (d, J = 6.9 Hz, 2H), 8.38 (d, J = 8.2
(S)-2-(((S)-2-(Methylamino)-2-phenylethyl)amino)-2-
phenylethanol (1a): Light yellow oil (216 mg, 80%). [α]D20
1
= +102 (c = 0.9, CH2Cl2). H NMR (300 MHz, CDCl3) δH
2.28 (s, 3H), 1.94-2.61 (br s, 3H), 2.69 (d, 2H), 3.50-3.90
13
13
Hz, 1H). C NMR (75.46 MHz, DMSO) δC 20.3, 21.4, 23.1,
(m, 4H), 7.24-7.38 (m, 10H). C NMR (75.46 MHz, CDCl3)
35.3, 39.6, 51.40, 52.3, 61.8, 127.1, 128.1, 128.2, 128.4,
δC 34.2, 53.6, 64.4, 64.9, 67.0, 127.0, 127.2, 127.4, 127.6,
−1
128.5, 128.5, 140.6, 141.6. FT-IR (KBr, cm ) 3340, 3063,
−1
128.6, 128.9, 136.2, 137.6, 167.01, 171.19. FT-IR (KBr, cm )
3308, 2951, 2867, 1655, 1632, 1536, 1288, 1150, 1042, 679.
2936, 1649, 1547, 1278, 1111, 1073, 759, 701. MS (m/z) =
270 (M ); Anal. calcd for C17H22N2O: C 75.52, H 8.20, N
+
+
MS (m/z) = 368 (M ); Anal. calcd for C22H28N2O3: C 71.71,
H 7.66, N 7.60; found C 71.79, H 7.71, N 7.52.
10.36; found C 75.59, H 8.28, N 10.34.
N-((S)-1-(((S)-2-Hydroxy-1-phenylethyl)amino)-4-methyl-
1-oxopentan-2-yl)benzamide (2j):White solid (849 mg,
(S)-3-Methyl-2-(((S)-2-(methylamino)-2-phenylethyl)
amino)butan-1-ol (1b): Yellow oil (210 mg, 89%). [α]D20
=
20
o
1
1
80%). mp 174 C. [α]D = –60 (c = 0.1, CH2Cl2). H NMR
(300 MHz, DMSO) δH 0.88 (d, J = 5.7 Hz, 6H), 1.48-1.80
(m, 3H), 3.68 (m, 2H), 4.51-4.66 (br s, 1H), 4.81 (br d, 1H),
4.92 (t, 1H), 7.22-7.30 (m, 5H), 7.45-7.47 (m, 3H), 7.86 (d, J
= 6.6 Hz, 2H), 8.27 (d, J = 7.9 Hz, 1H), 8.47 (d, J = 8.1 Hz,
+38.75 (c = 4, CH2H5OH). H NMR (300 MHz, CDCl3) δH
0.85 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 1.67-1.78
(m, 1H), 2.28 (s, 3H), 2.32-2.38 (m, 1H), 2.69 (br s, 3H),
3.30-3.64 (dd, 1H), 3.56-3.61 (m, 2H), 7.22-7.35 (m, 5H).
13
C NMR (75.46 MHz, CDCl3) δC 18.6, 19.3, 29.3, 34.0,
13
1H). C NMR (75.46 MHz, DMSO) δC 20.3, 21.4, 23.1,
53.9, 61.4, 64.7, 65.1, 127.2, 127.4, 128.5, 141.5. FT-IR
−1
35.3, 51.4, 52.3, 61.8, 127.1, 128.1, 128.2, 128.4, 128.6,
(KBr, cm ) 3330, 2957, 2872, 2793, 1142, 1109, 1036, 759,
−1
+
128.9, 136.2, 137.6, 167.0, 171.2. FT-IR (KBr, cm ) 3303,
701. MS (m/z) = 236 (M ); Anal. calcd for C14H24N2O: C
2966, 2941, 2881, 1659, 1633, 1539, 1275, 1078, 1036, 698.
71.14, H 10.23, N 11.85; found C 71.22, H 10.40, N 11.79.
(S)-4-Methyl-2-(((S)-2-(methylamino)-2-phenylethyl)
amino)pentan-1-ol (1c): Light yellow oil (237 mg, 95%).
+
MS (m/z) = 354 (M ); Anal. calcd for C21H26N2O3: C 71.16,
H 7.39, N 7.90; found C 71.12, H 7.48, N 7.99.
[α]2D0 = +75 (c = 0.13, CH2Cl2). H NMR (300 MHz, CDCl3)
1
N-((S)-1-(((S)-1-Hydroxy-4-methylpentan-2-yl)amino)-
4-methyl-1-oxopentan-2-yl)benzamide (2k): White solid
δH 0.87 (d, J = 6.5 Hz, 6H), 1.21-1.31 (m, 2H), 1.56-1.63 (m,
20
o
2
(821 mg, 82%). mp134 C. [α]D = –115.40 (c = 0.12, CH2Cl2).
1H), 2.33 (s, 3H), 2.73-2.77 (m, 1H), 2.87-2.92 (dd, J =
1
3
2
3
H NMR (300 MHz, CDCl3) δH 0.83-0.91 (m, 12H), 1.31-
12.7 Hz, J = 4.3 Hz, 1H), 2.98-3.03 (dd, J = 12.7 Hz, J =
2
3
1.44 (m, 2H), 1.51-1.76 (m, 4H), 3.52-3.72 (m, 2H), 3.92-
4.19 (br s, 1H), 4.67-4.88 (br s, 1H), 7.22-7.57 (m, 5H), 7.79
9.2 Hz = 1H), 3.31-3.37 (dd, J = 11.1Hz, J = 7.6 Hz, 1H),
3.60-3.65 (dd, J = 11.2 Hz, J = 3.4 Hz , 1H), 3.75-3.82 (dd,
2
3
13
13
(d, 2H). C NMR (62.89 MHz, CDCl3) δC 22.4, 23.0, 24.9,
1H), 7.27-7.39 (m, 5H). C NMR (75.46 MHz, DMSO) δC
39.9, 50.2, 52.4, 65.7, 127.3, 128.6, 131.9, 133.8, 163.4,
21.7, 23.7, 24.6, 30.6, 31.2, 47.4, 58.3, 58.9, 59.5, 129.4,

1992 Bull. Korean Chem. Soc. 2014, Vol. 35, No. 7
Laleh Faraji et al.
−1
129.6, 130.2, 132.6. FT-IR (KBr, cm ) 3403, 2956, 2859,
22.4, 23.2, 24.9, 31.7, 38.3, 39.8, 48.3, 58.7, 60.9, 63.3,
+
−1
1564, 1364, 1144, 1056, 759, 701. MS (m/z) = 250 (M );
Anal. calcd for C15H26N2O: C 71.95, H 10.47, N 11.19;
126.3, 128.6, 129.2, 138.8. FT-IR (KBr, cm ) 3367, 2956,
2927, 2860, 1564, 1139, 1040, 744, 700. MS (m/z) = 264
(M ); Anal. calcd for C16H28N2O: C 72.68, H 10.67, N 10.59;
+
found C 71.99, H 10.44, N 11.26.
(S)-2-(((S)-2-(Methylamino)-2-phenylethyl)amino)-3-
phenylpropan-1-ol (1d): Light yellow iol (232 mg, 82%).
found C 72.75, H 10.71, N 10.54.
(S)-2-(((S)-2-(Benzylamino)-4-methylpentyl)amino)-3-
phenylpropan-1-ol (1i): Light yellow oil (275 mg, 81%).
[α]2D0 = +12.l5 (c = 4, CH2Cl2). H NMR (300 MHz, CDCl3)
1
[α]2D0 = +22 (c = 0.2, CH2Cl2). H NMR (300 MHz, CDCl3)
1
δH 2.25 (s, 3H), 2.68 (t, 2H), 2.81 (d, 2H), 2.93 (m, 4H),
3.31-3.37 (dd, 1H), 3.55-3.59 (m, 2H), 7.23-7.32 (m, 10H).
δH 0.88 (t, J = 6.6 Hz, 6H), 1.10-1.21 (m, 1H), 1.31-1.46 (m,
1H), 1.51-1.68 (m, 1H), 2.41-2.49 (m, 1H), 2.66-2.76 (m,
13
C NMR (75.46 MHz, CDCl3) δC 34.0, 38.1, 52.6, 63.1,
2
3
64.8, 65.0, 127.0, 127.2, 127.5, 127.6, 128.1, 128.5, 140.7,
4H), 2.83-2.87 (m, 1H), 3.33-3.38 (dd, J = 10.7 Hz, J = 5.6
−1
2
3
141.2. FT-IR (KBr, cm ) 3389, 2958, 2920, 2851, 1262,
Hz, 1H), 3.59-3.63 (dd, J = 10.7 Hz, J = 3.8 Hz, 1H), 3.63-
3.72 (m, 2H), 7.19-7.35 (m, 10H). C NMR (75.46 MHz,
+
13
1035, 800, 701. MS (m/z) = 284 (M ); Anal. calcd for
C18H24N2O: C 76.02, H 8.51, N 9.85; found C 76.11, H 8.59,
CDCl3) δC 18.5, 18.9, 20.7, 37.8, 38.5, 45.8, 46.6, 50.1, 60.4,
62.5, 122.7, 123.0, 133.2,124.0, 124.3, 124.9, 136.1, 136.7.
N 9.79.
−1
(S)-2-(((S)-2-(Methylamino)-3-phenylpropyl)amino)-3-
phenylpropan-1-ol (1e): Light yellow oil (238 mg, 80%).
FT-IR (KBr, cm ) 3336, 3031, 2998, 2945, 1458, 1035, 742,
+
700. MS (m/z) = 340 (M ); Anal. calcd for C22H32N2O: C
[α]2D0 = +230.76 (c = 0.23, CH2Cl2). H NMR (300 MHz,
77.60, H 9.47, N 8.23; found C 77.65, H 9.45, N 8.28.
(S)-2-(((S)-2-(Benzylamino)-4-methylpentyl)amino)-2-
phenylethanol (1j): Light yellow oil (283 mg, 87%). [α]D20
1
CDCl3) δH 2.19 (d, J = 6 Hz, 2H), 2.37 (s, 3H), 2.55-2.93 (m,
2
3
7H), 3.31-3.37 (dd, J = 10.5 Hz, J = 6.5 Hz, 1H), 3.56-3.60
2
3
13
1
(dd, J = 10.5 Hz, J = 3.1 Hz, 1H), 7.09-7.29 (m, 10H). C
NMR (75.46 MHz, CDCl3) δC 28.6, 29.3, 33.8, 53.5, 61.5,
64.7, 65.0, 126.9, 127.2, 127.3, 127.5, 128.4, 128.6, 141.3,
= +56.07 (c = 0.9, CH2Cl2). H NMR (300 MHz, CDCl3) δH
0.85-0.90 (dd, 6H), 1.10-1.23 (m, 1H), 1.32-1.48 (m, 1H),
2
1.48-1.64 (m, 1H), 2.12-2.34 (br s, 3H), 2.38-2.45 (dd, J =
11.7 Hz, J = 7.7 Hz, 1H), 2.56-2.61 (dd, J = 11.7 Hz, J =
3.6 Hz, 1H), 2.63-2.78 (m, 2H), 3.49-3.63 (m, 1H), 3.63-
−1
3
2
3
141.4. FT-IR (KBr, cm ) 3337, 3025, 2932, 2846, 1564,
+
1135, 1033, 744, 701. MS (m/z) = 298 (M ); Anal. calcd for
C19H26N2O: C 76.47, H 8.78, N 9.39; found C 76.57, H 8.85,
13
3.82 (m, 3H), 7.19-7.36 (m, 10H). C NMR (75.46 MHz,
N 9.36.
CDCl3) δC 18.4, 18.9, 20.7, 37.9, 45.9, 46.5, 50.2, 60.3, 62.6,
123.0, 133.2, 124.0, 124.2, 124.3, 124.9, 136.1, 136.7. FT-IR
(S)-3-Methyl-2-(((S)-3-methyl-2-(methylamino)butyl)-
amino)butan-1-ol (1f): Light yellow oil (158 mg, 78%).
−1
(KBr, cm ) 3350, 3016, 2958, 1458, 1374, 1208, 1031, 752,
[α]2D0 = –107 (c = 0.23, CH2Cl2). H NMR (300 MHz, CDCl3)
700. MS (m/z) = 326 (M ); Anal. calcd for C21H30N2O: C
1
+
δH 0.85 (t, J = 5.8 Hz, 6H), 0.92 (d, J = 6.4 Hz, 6H), 1.67-
1.79 (m, 1H) 1.79-1.89 (m, 1H), 2.33 (br s, 1H), 2.37 (s,
3H), 2.49 (t, 1H), 2.71 (br d, 1H), 3.35 (t, 1H), 3.58-3.61 (m,
77.26, H 9.26, N 8.58; found C 77.33, H 9.29, N 8.51.
(S)-2-(((S)-2-(Benzylamino)-4-methylpentyl)amino)-4-
methylpentan-1-ol (1k): Colorless oil (269 mg, 88%). [α]D20
13
1
4H). C NMR (75.46 MHz, CDCl3) δC 18.8, 18.9, 19.5,
= −44 (c = 0.5, CH2Cl2). H NMR (300 MHz, CDCl3) δH
19.6, 29.3, 29.6, 33.9, 53.9, 61.6, 64.7, 65.4. FT-IR (KBr,
0.89 (d, J = 5.8 Hz, 12H), 1.10-1.30 (m, 4H), 1.56-1.78 (m,
2H), 2.39-2.75 (m, 6H), 3.20-3.30 (m, 1H), 3.54-3.58 (dd,
−1
+
cm ) 3359, 2959, 2874, 1567, 1048. MS (m/z) = 202 (M );
Anal. calcd for C11H26N2O: C 65.30, H 12.95, N 13.84;
found C 65.28, H 12.98, N 13.90.
13
1H), 3.74-3.78 (dd, 2H), 7.23-7.31 (m, 5H). C NMR (75.46
MHz, CDCl3) δC 18.4, 18.5, 18.7, 18.9, 20.6, 20.7, 35.6, 35.8,
37.9, 51.6, 50.7, 60.4, 62.3, 123.0, 133.2,124.0, 124.2. FT-IR
(S)-4-Methyl-2-(((S)-4-methyl-2-(methylamino)pentyl)
amino)pentan-1-ol (1g): Light yellow oil (193 mg, 84%).
−1
(KBr, cm ) 3336, 3025, 2961, 2859, 1367, 1161, 1029, 740,
[α]2D0 = +30 (c = 0.5, CH2Cl2). H NMR (300 MHz, CDCl3)
699. MS (m/z) = 306 (M ); Anal. calcd for C19H34N2O: C
1
+
δH 0.89 (d, J = 6.3 Hz, 12H), 1.08-1.46 (m, 4H), 1.46-1.66
(m, 2H), 2.39 (s, 3H), 2.51-2.70 (m, 3H), 3.23-3.33 (m, 3H),
74.46, H 11.18, N 9.14; found C 74.53, H 11.15, N 9.19.
(S)-2-(((S)-2-(Benzylamino)-4-methylpentyl)amino)-3-
methylbutan-1-ol (1l): Colorless oil (248 mg, 85%). [α]D20
13
3.54-3.59 (dd, 1H). C NMR (75.46 MHz, CDCl3) δC 21.7,
1
21.9, 23.7, 23.8, 24.6, 24.5, 30.6, 31.2, 33.1, 54.5, 61.9, 65.3,
= +90 (c = 0.8, CH2Cl2). H NMR (300 MHz, CDCl3) δH
−1
66.3. FT-IR (KBr, cm ) 3409, 2951, 2858, 2795, 1207,
0.88-0.99 (m, 12H), 1.24-1.28 (m, 1H), 1.40-1.50 (m, 1H),
1.63-1.65 (m, 1H), 1.75-1.91 (m, 1H), 2.33 (br s, 1H), 2.44-
2.56 (m, 1H), 2.67-2.70 (br d, 2H), 3.25-3.49 (m, 1H), 3.59-
+
1044. MS (m/z) = 230 (M ); Anal. calcd for C13H30N2O: C
67.77, H 13.12, N 12.16; found C 67.87, H 13.18, N 12.14.
(S)-2-(((S)-4-Methyl-2-(methylamino)pentyl)amino)-3-
phenylpropan-1-ol (1h): Light yellow oil (205 mg, 78%).
13
3.67 (m, 1H), 3.78 (br s, 2H), 7.33 (br s, 5H). C NMR
(75.46 MHz, CDCl3) δC 18.3, 18.4, 18.7, 18.9, 20.5, 35.4,
35.5, 37.6, 51.4, 50.4, 60.3, 62.0, 123.2, 133.5, 124.5, 124.6.
[α]2D0 = +85.71 (c = 0.1, CH2Cl2). H NMR (300 MHz, CDCl3)
1
−1
δH 0.88 (d, J = 6.5 Hz, 6H), 1.04-1.19 (m, 1H), 1.30-1.43 (m,
1H), 1.43-1.62 (m, 1H), 2.28 (t, 1H), 2.34 (s, 3H), 2.48 (t,
1H), 2.52-2.61 (m, 1H), 2.63-2.68 (dd, 1H), 2.70-2.73 (d, J =
6.9 Hz, 2H), 2.79-2.90 (m, 1H), 3.32-3.38 (dd, J = 10.8 Hz,
3J = 6.4 Hz, 1H), 3.57-3.62 (dd, J = 10.8 Hz, J = 3.6 Hz,
FT-IR (KBr, cm ) 3389, 3033, 2967, 2869, 1365, 1104, 1048,
+
740, 699. MS (m/z) = 292 (M ); Anal. calcd for C18H32N2O:
C 73.92, H 11.03, N 9.58; found C 73.99, H 11.08, N 9.55.
Synthesis of (S)-N2-((S)-1-Hydroxy-3-methylbutan-2-
yl)-N1-methyl-1-phenylethane-1,2-diaminium Chloride:
To a solution of diamine 1b (1 mmol) in dry diethyl ether (5
2
2
3
13
1H), 7.18-7.32 (m, 5H). C NMR (75.46 MHz, CDCl3) δC

Synthesis of Novel Chiral Diamino Alcohols and Their Application
Bull. Korean Chem. Soc. 2014, Vol. 35, No. 7 1993
mL) was added dropwise, at 0 °C, a 1 N anhydrous HCl/
methanol solution (2 mmol, 2 equiv). A white precipitate
was immediately formed. After 10 min of stirring, the solvent
was evaporated to afford the corresponding chlorhydrate
of diamine in quantitative yield. [α]2D0 = +40.25 (c = 2.5,
iso-propyl alcohol/hexanes; 99.5:0.5; flow rate 0.5 mL/min;
tR = 31.2 min (R), 33.8 min (S)) (maximum ee = 19% (R)).
(R)-Cyclopent-2-en-1-yl 4-nitrobenzoate (9b)6j: mp 77-
79 °C. [α]2D0 = +10° (c = 1.0, CHCl3). H NMR (300 MHz,
1
CDCl3) δH 1.97-2.04 (m, 1H), 2.38-2.50 (m, 2H), 2.59-2.63
1
CH2H5OH). H NMR (300 MHz, DMSO) δH 0.95 (d, J = 6.4
(m, 1H), 5.98 (m, 2H), 6.22 (m, 1H), 8.20 (d, J= 8.5 Hz,
−1
Hz, 6H), 2.14-2.20 (m, 1H), 2.31 (s, 3H), 2.96-3.08 (br s,
1H), 3.58-3.62 (m, 1H), 3.63-3.78 (br s, 2H), 3.87-4.03 (m,
1H), 4.68-4.93 (br s, 1H), 7.40-7.68 (m, 5H), 9.27-9.49 (br d,
2H), 8.28 (d, J = 8.5 Hz, 2H). IR (KBr, cm ) 1109, 1268,
1520, 1706, 2846. The enantiomeric excess was determined
by chiral HPLC (EC 250/4.6 Nucleocel Alpha S column,
iso-propyl alcohol/hexanes; 99.5:0.5; flow rate 0.4 mL/min;
tR = 36.5 min (R), 38.4 min (S)) (maximum ee = 8% (R)).
(R)-Cyclohept-2-en-1-yl 4-nitrobenzoate (9c)6j: mp 72-
13
1H), 10.23-10.44 (br d, 1H). C NMR (75.46 MHz, DMSO)
δC 17.5, 19.9, 27.8, 30.7, 49.1, 57.4, 59.6, 65.8, 129.3, 129.7,
−1
130.3, 132.9. FT-IR (KBr, cm ) 3330, 2957, 2872, 2793,
1142, 1109, 1036, 759, 701. MS (m/z) = 236 (M-2Cl ); Anal.
calcd for C14H26Cl2N2O: C 54.37, H 8.47, N 9.06; found C
75 °C. [α]2D0 = +8° (c = 1.0, CHCl3). H NMR (300 MHz,
−
1
CDCl3) δH 1.66-1.72 (m, 4H), 2.02-2.12 (m, 2H), 2.07-2.40
54.46, H 8.51, N 9.01.
(m, 2H), 5.58-5.64 (m, 1H), 5.75-5.82 (m, 1H), 5.92-5.98
−1
Synthesis of tert-Butyl 4-Nitrobenzoperoxoate6j: p-Nitro-
benzoyl chloride (3.2 g, 17.2 mmol) was dissolved in a 100
mL round bottom flask containing CH2Cl2 (35 mL). The
(m, 1H), 8.22-8.28 (m, 4H). IR (KBr, cm ) 1106, 1273,
1528, 1709, 2893. The enantiomeric excess was determined
by chiral HPLC (EC 250/4.6 Nucleocel Alpha S column,
iso-propyl alcohol/hexanes; 99.5:0.5; flow rate 0.4 mL/min;
tR = 28.7 min (R), 32.6 min (S)) (maximum ee = 3% (R)).
(R)-Cyclooct-2-en-1-yl 4-nitrobenzoate (9d)6j: mp 71-74
o
solution was cooled to –20 C and stirred under nitrogen for
15 min. Pyridine (1.7 mL, 20.0 mmol) was added and the
reaction mixture was stirred for 10 min. Next, tert-butyl
hydroperoxide (3.5 mL, 20.0 mmol) was added dropwise to
°C. [α]2D0 = +13° (c = 1.0, CHCl3). H NMR (300 MHz,
1
o
the reaction at −20 C, and stirred for 4 h. Then the reaction
CDCl3) δH 1.46-1.72 (m, 7H), 2.07-2.40 (m, 3H), 5.60-5.66
solution was diluted with CH2Cl2 (20 mL), and washed with
water. The organic layer was separated, dried over MgSO4,
and evaporated to obtained crude yellow solid product.
Purification using flash chromatography (n-hexane: EtOAc;
90:10) afforded the light yellow solid product. (3.9 g, 98%
(m, 1H), 5.73-5.82 (m, 1H), 5.92-5.96 (m, 1H), 8.22-8.32
−1
(m, 4H). IR (KBr, cm ) 1108, 1281, 1527, 1718, 2853. The
enantiomeric excess was determined by chiral HPLC (EC
250/4.6 Nucleocel Alpha S column, iso-propyl alcohol/
hexanes; 99.5:0.5; flow rate 0.4 mL/min; tR = 20.9 min (R),
23.1 min (S)) (maximum ee = 15% (R)).
1
yield). mp 75-78 ºC. H NMR (300 MHz, CDCl3) δH 1.45 (s,
9H), 8.14-8.35 (m, 4H).
General Procedure for the Enantioselective Allylic
Oxidation of Cycloolefins using tert-Butyl 4-Nitrobenzo-
peroxoate. To a flame-dried round bottom flask (25 mL), a
light yellow solution of the diamino alcohol ligand 1 (0.065
mmol) and copper salt (0.55 mmol) were stirred in CH3CN
(4 mL) and stirred for 3 h at ambient temperature. After
addition of phenyl hydrazine (6 µL, 0.06 mmol) color of the
solution was changed from blue green to red. Then, 10 mg of
4 Å molecular sieves were added. After a few min, cyclo-
olefin (5 mmol) was added. The reaction mixture was cooled
Results and Discussion
A series of (S,S)-diamino alcohol ligands 1 were conv-
eniently prepared by a three-steps procedure with minimal
purification of intermediates in high overall yields and
excellent enantiomeric excess from the readily available (S)-
amino acids. Table 1 describes a small library of novel
ligands 1 and (S,S)-hydroxyldiamide precursors 2. For syn-
thesis of these molecules, at first, the amino acids were
protected by one of the two kinds of protecting groups, the
o
10
to −10 C and then tert-butyl 4-nitrobenzoperoxoate (0.203
carbobenzoxy (Cbz) or benzoyl (Bz) groups. Then, hydrox-
g, 0.85 mmol) was added dropwise to the reaction solution
under nitrogen atmosphere. The mixture was kept at room
temperature until TLC showed to complete disappearance of
perester. The reaction mixture was dissolved in 10% NH4OH,
extracted with EtOAc and dried over MgSO4. Removal of
solvent in vacuo afforded a yellow residue that was
chromatographed over silica gel to provide the pure white
solid product.
yldiamide precursors 2 were obtained in 80-96% yields from
coupling of protected amino acids with chiral amino alcohols
8, which were easily prepared from the reduction of amino
11
acids. Afterwards, the hydroxyldiamide 2 were reduced
easily with lithium aluminum hydride to provide the chiral
tridentate ligands 1 in the range of 78-95% yields. The diver-
sity of chiral amino acids, chiral amino alcohols and the
protecting groups make it possible to create a library of
chiral diamido and diamino alcohols 2 and 1.
(R)-Cyclohex-2-en-1-yl 4-nitrobenzoate (9a)6j: mp 68-
71 °C. [α]2D0 = +29° (c =1.5, CHCl3). H NMR (300 MHz,
The structures of products 1 and precursors 2 were assign-
ed by their elemental and spectroscopic analysis including,
1
CDCl3) δH 1.76-2.14 (m, 6H), 5.54 (m, 1H), 5.84 (d, J = 9.8
13
1 13
IR, H NMR, C NMR and mass spectral data. As expected,
Hz, 1H), 6.04 (d, J = 9.8 Hz, 1H), 8.21-8.31 (m, 4H).
NMR (300 MHz, CDCl3) δC 18.8, 25.0, 28.2, 69.8, 123.4,
C
1
13
the H NMR and C NMR spectrum of the precursor 2, and
ligand 1 clearly showed the presence of only (S,S)-dia-
stereomer. In order to confirm further that no racemization
occurs, the diaminium chloride of 1b was prepared and its
−1
125.0, 130.7, 133.6, 136.2. IR (KBr, cm ) 1107, 1278,
1525, 1713, 2928. The enantiomeric excess was determined
by chiral HPLC (EC 250/4.6 Nucleocel Alpha S column,

1994 Bull. Korean Chem. Soc. 2014, Vol. 35, No. 7
Laleh Faraji et al.
Table 2. Asymmetry allylic oxidation of cycloolefins in the present
of chiral diamino alcohols 1
Entry
n
Ligand
Time (h)
Yield (%)
eea (%)
1
2
2
2
2
2
2
2
2
1
3
4
4
2
2
2
2
2
2
2
2
2
2
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
40
40
30
180
38
50
85
60
40
40
40
75
72
64
70
84
83
60
65
63
50
63
9a (95)
9a (95)
9a (70)
9a (50)
9a (80)
9a ( 80)
9a (60)
9b (90)
9c (90)
9d (90)
9d (90)
9a (87)
9a (90)
9a (95)
9a (90)
9a (80)
9a (75)
9a (90)
9a (85)
9a (80)
9a (92)
9a (80)
19
17b
8c
Traced
19e
Tracef
Traceg
9
3
4
5
6
7
8
9
3
Figure 1. The ORTEP diagram of diaminium chloride of 1b.
Thermal ellipsoids are at 30% probability level.
10
11
12
13
14
15
16
17
18
19
20
21
22
15
10b
Trace
Trace
17
absolute configuration was determined by single-crystal X-
12
ray analysis (Figure 1).
In order to evaluate the potential of new chiral diamino
alcohols 1 in the catalytic asymmetric reaction, we tested
chiral tridentate ligands 1 in the copper-catalyzed allylic
oxidation of cycloolefins using tert-butyl p-nitroperbenzoate
as an oxidant at room temperature in the presence of various
copper complexes ([Cu(CH3CN)4]PF6, CuOTf and Cu(OTf)2)
and in three different solvents. The reactions were monitored
by TLC for consumption of the perester and stopped at the
given time. The results are summarized in Table 2. The best
results were achieved in oxidation of cyclohexene in aceto-
nitrile with 10 mol % 1a-CuPF6 complex in the presence of
molecular sieves, which afforded 2-cyclohexenyl-p-nitro-
10
5
1g
1h
1i
3
12
3
1j
5
1k
1l
10
5
aEnantiomeric excess (ee) of the allylic esters were determined by HPLC
analysis using an EC 250/4.6 Nucleocel Alpha S column. b15% CuPF6 as
c
a source of Cu was used. 10 mol % Cu(OTf)2 as a source of Cu was
used. dCuOTf was used as a source of Cu. eThe reaction was carried out
at 0 oC. fAcetone was used as solvent. gCH2Cl2 was used as solvent
Table 1. Synthesis of chiral diamino alcohols 1 from N-protected
chiral amino acids
benzoate 9a in 95% yield 19% ee (entry 1 in Table 2). To the
best of our knowledge, this enantioselectivity and yield in
entry 1 are the highest for the allylic oxidation of cyclo-
olefins so far in contrast to 48% yield and 11% ee of
products, which were obtained when chiral amines or other
9
amino alcohols were used as ligands in this reaction. Most
likely, the presence of additional coordinating group might
promote catalysis in this case.
Entry
R1
R2
R3
2 (Yield%)
1 (Yield%)
1
2
Ph
Ph
Ph
Ph
Bn
PhCH2O
PhCH2O
Ph
2a (89)
2b (93)
2c (80)
2d (92)
2e (96)
2f (81)
2g (86)
2h (82)
2i (80)
2j (80)
2k (82)
2l (83)
1a (80)
1b (89)
1c (95)
1d (82)
1e (80)
1f (78)
1g (84)
1h (78)
1i (81)
1j (87)
1k (88)
1l (85)
Increasing or decreasing the catalyst loading led to decrease
of the enantioselectivity (entries 1 vs. 2 in Table 2). Reduc-
ing the reaction temperature resulted in a decrease in reac-
tivity without any significant increase in enantioselectivity
(entries 1 vs. 5 in Table 2). Higher enantioselectivity was
observed in acetonitrile, and the reactivity was also found to
be dependent on solvent. The reactions that carried out in
acetonitrile proceed faster than those in dichloromethane and
slightly better than those in acetone (entries 1 vs. 6-7 in
Table 2). Finally, for comparison, the reaction was carried
out in the absence of ligands and low yield of the desired
product was obtained after 40 h.
i-Pr
3
PhCH2O i-Bu
4
PhCH2O
PhCH2O
Bn
Bn
5
6
i-Pr PhCH2O
i-Pr
7
i-Bu PhCH2O i-Bu
8
i-Bu PhCH2O
Bn
Bn
9
i-Bu
i-Bu
i-Bu
i-Bu
Ph
Ph
Ph
Ph
10
11
12
Ph
i-Bu
i-Pr

Synthesis of Novel Chiral Diamino Alcohols and Their Application
Bull. Korean Chem. Soc. 2014, Vol. 35, No. 7 1995
4762-4773. (b) Salomé, C.; Salomé-Grosjean, E.; Stables, J. P.;
Kohn, H. J. Med. Chem. 2010, 53, 3756-3771. (c) Jungheim, L.
N.; Shepherd, T. A.; Baxter, A. J.; Burgess, J.; Hatch, S. D.;
Lubbehusen, P.; Wiskerchen, M.; Muesing, M. A. J. Med. Chem.
1996, 39, 96-108. (d) King, A. M.; Salomé, C; Dinsmore, J.;
Salomé-Grosjean, E.; De Ryck, M.; Kaminski, R.; Valade, A.;
Kohn, H. J. Med. Chem. 2011, 54, 4815-4830. (e) Wang, G. T.; Li,
S.; Wideburg, N.; Krafft, G. A.; Kempf, D. J. J. Med. Chem. 1995,
38, 2995-3002. (f) Kempf, D. J.; Marsh, K. C.; Fino, L. C.; Bryant,
P.; Craig-Kennard, A.; Sham, H. L.; Zhao, C.; Vasavanonda, S.;
Kohlbrenner, W. E.; Wideburg, N. E.; Saldivar, A.; Green, B. E.;
Herrin, T.; Norbeck, D. W. Bioorg. Med. Chem. 1994, 2, 847-858.
(g) Erickson, J.; Neidhart, D. J.; Van Drie, J.; Kempf, D. J.; Wang,
X. C.; Norbeck, D. W.; Plattner, J. J.; Rittenhouse, J. W.; Turon,
M.; Wideburg, N.; Kohlbrenner, W. E.; Simmer, R.; Helfrich, R.;
Paul, D. A.; Knigge, M. Science 1990, 249, 527-533. (h) Erickson,
J.; Kempf, D. J.; Arch. Virol. 1994, 9, 19-29. (i) Jadhav, P. K.;
Woener, F. J. Bioorg. Med. Chem. Lett. 1992, 2, 353-356. (j) Choi,
D.; Stables, J. P.; Kohn, H. J. Med. Chem. 1996, 39, 1907-1916.
6. (a) Kharasch, M. S.; Fono, A. J. Org. Chem. 1958, 23, 324-324.
(b) Kharasch, M. S.; Fono, A. J. Org. Chem. 1958, 23, 324-325.
(c) Kharasch, M. S.; Fono, A. J. Org. Chem. 1958, 23, 325-326.
(d) Kharasch, M. S.; Sosnovsky, G.; Yang, N. C. J. Am. Chem.
Soc. 1958, 80, 756-756. (e) Kharasch, M. S.; Sosnovsky, G.; Yang,
N. C. J. Am. Chem. Soc. 1959, 81, 5819-5824. (f) Eames, J.;
Watkinson, M. Angew. Chem. Int. Ed. 2001, 40, 3567-3571. (g)
Andrus, M. B.; Lashley, J. C. Tetrahedron 2002, 58, 845-866. (h)
Andrus, M. B.; Argade, A. B.; Chen, X.; Pamment, M. G. Tetra-
hedron Lett. 1995, 36, 2945-2948. (i) Gokhale, A. S.; Minidis, A.
B. E.; Pfaltz, A. Tetrahedron Lett. 1995, 36, 1831-1834. (j) Andrus,
M. B.; Zhou, Z. J. Am. Chem. Soc. 2002, 124, 8806-8807.
7. (a) Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.;
Teplý, F.; Meghani, P.; Kočovský, P. J. Org. Chem. 2003, 68,
4727-4742. (b) Lee, W.-S.; Kwong, H.-L.; Chan, H.-L.; Choi, W.-
W.; Ng, L.-Y. Tetrahedron: Asymmetry 2001, 12, 1007-1013. (c)
Hoang, V. D. M.; Reddy, P. A. N.; Kim, T. J. Organometallics
2008, 27, 1026-1027.
Conclusion
In summary, we have synthesized the small library of new
enantiomerically pure (S,S)-diamino alcohols 1, and their
hydroxyldiamide precursors 2 derived from the commer-
cially chiral pool amino acids. The applicability of the chiral
tridentates diamino alcohols 1 as ligands to the copper-cata-
lyzed asymmetric allylic oxidation reaction of cycloolefins
were demonstrated. The best result in the oxidation of
cyclohexene was achieved with 1a-CuPF6 complex in
acetonitrile to afford the product in 95% yield and 19% ee.
These values in ee and yields are the highest so far in the
allylic oxidation of cycloolefins. Although the enantioselec-
tivity of the reactions is still low, we are confident that
improvements in the reaction condition will result in an
increase of asymmetric induction that is in progress in our
laboratory. Efforts to improve the enantioselectivity in this
reaction and extend the scopes of the reaction using these
ligands are in progress.
Acknowledgments. Publication cost of this paper was
supported by the Korean Chemical Society.
References
1. (a) Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38,
1532-1568. (b) Heightman, T. D.; Vasella, A. T. Angew. Chem.,
Int. Ed. 1999, 38, 750-770. (c) Carbohydrate Mimics; Chapleur,
Y., Ed.; Wiley-VCH: Weinheim, Germany, 1998. (d) Hauser, F.
M.; Ellenberger, S. R. Chem. Rev. 1986, 86, 35-67.
2. (a) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107,
767-796. (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835-875. (c) Pu, L.; Yu, H-B. Chem. Rev. 2001, 101,
757-824. (d) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2756.
(e) Reetz, M. T. Chem. Rev. 1999, 99, 1121-1162. (f) Reetz, M. T.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1531-1546.
8. Samadi, S.; Jadidi, K.; Notash, B. Tetrahedron: Asymmetry 2013,
24, 269.
9. Rispens, M. T.; Zondervan, C.; Feringa, B. L. Tetrahedron: Asym-
metry 1995, 6, 661-664.
3. (a) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed.
2005, 44, 3881-3884. (b) Li, Y.; He, B.; Qin, B.; Feng, X.; Zhang,
G. J. Org. Chem. 2004, 69, 7910-7913. (c) Nakano, H.; Kumagai,
N.; Matsuzaki, H.; Kabuto, C.; Hongo, H. Tetrahedron: Asymmetry
1997, 8, 1391-1401. (d) Solà, L.; Vidal-Ferrán, A.; Moyano, A.;
Pericás, M.; Riera, A. Tetrahedron: Asymmetry 1997, 8, 1559-
1568. (e) Wilken, J.; Gröger, H.; Kossenjans, M.; Martens, J.
Tetrahedron: Asymmetry 1997, 8, 2761-2771.
4. (a) Wittenberger, S. J.; Baker, W. R.; Donner, B. G. Tetrahedron
1993, 49, 1547-1556. (b) Kempf, D. J.; Norbeck, D. W.; Codacovi,
L.; Wang, X. C.; Kohlbrenner, W. E.; Wideburg, N. E.; Paul, D.
A.; Knigge, M. F.; Vasavanonda, S.; Craig-Kennard, A.; Saldivar,
A.; Rosenbrook, Wm., Jr.; Clementt, J. J.; Plattner, J. J.; Erickson,
J. J. Med. Chem. 1990, 33, 2687-2689. (c) Kempf, D. J.; Sowin, T.
J.; Doherty, E. M.; Hannick, S. M.; Codavoci, L.; Henry, R. F.;
Green, B. E.; Spanton, S. G.; Norbeck, D. W. J. Org. Chem. 1992,
57, 5692-5700. (d) Bernardi, L.; Bonini, B. F.; Dessole, G.; Fochi,
M.; Franchini, M.; Gavioli, S.; Ricci, A.; Varchi, G. J. Org. Chem.
2003, 68, 1418-1425. (e) Leclerc, E.; Vrancken, E.; Mangeney, P.
J. Org. Chem. 2002, 67, 8928-8937. (f) Gmeiner, P.; Junge, D.;
Kartner, A. J. Org. Chem. 1994, 59, 6766-6776. (g) Shin, S.; Han,
Y. E.; Sun Park, C.; Lee, W.; Ha, H. J. Tetrahedron: Asymmetry
2000, 11, 3293-3301.
10. (a) Smith, C. S.; Brown, A. E. J. Am. Chem. Soc. 1941, 63, 2605-
2606. (b) Duguet, N.; Donaldson, A.; Leckie, S. M.; Kallström, E.
A.; Campbell, C. D.; Shapland, P.; Brown, T. B.; Slawin, A. M. Z.;
Smith, A. D. Tetrahedron: Asymmetry 2010, 21, 601-616.
11. McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3568-
3571.
12. X-ray data for diaminium chloride of 1b: C14H26N2Cl2O, M =
309.27, triclinic system, space group P1, a = 7.1264(14), b =
10.864(2), c = 12.215(2) Å; α = 67.22(3), β = 81.67(3), γ =
3
−3
76.53(3)º; V = 846.4(3) Å , Z = 2, Dcalcd = 1.214 g cm , μ(Mo-
−1
Kα) = 0.379 mm , crystal dimension of 0.35 × 0.2 × 0.17 mm.
The X-ray diffraction measurement was made on a STOE IPDS-II
diffractometer with graphite monochromated Mo-Kα radiation.
The structure was solved by using SHELXS. The Data reduction
and structure refinement was carried out with SHELXL using the
13
X-STEP32 crystallographic software package. The non-hydro-
gen atoms were refined anisotropically by full matrix least-
squares on F2 values to final R1 = 0.1148, wR2 = 0.2726 and S =
0.979 with 327 parameters using 4924 independent reflection (θ
range = 2.94-25.00º). Hydrogen atoms were added in idealized
positions. The crystallographic information file has been deposit-
ed with the Cambridge Data Centre, CCDC 928537.
13. X-STEP32 Version 1.07b, Crystallographic Package; Stoe & Cie
GmbH: Darmstadt, Germany, 2000.
5. (a) Le Tiran, A.; Stables, J. P.; Kohn, H. J. Med. Chem. 2002, 45,