Kinetic resolution of vic-amino alcohols catalyzed by a chiral Cu(II) complex

Article abstract of DOI:10.1016/j.tetlet.2006.09.049

Kinetic resolution of N-benzoylated vic-amino alcohols was achieved by benzoylation in the presence of copper triflate and (R,R)-Ph-BOX as catalysts. The observed enantioselectivity was moderate to high. The method was applied to a kinetic resolution of r

Full text of DOI:10.1016/j.tetlet.2006.09.049

Tetrahedron Letters 47 (2006) 8073–8077
Kinetic resolution of vic-amino alcohols catalyzed
by a chiral Cu(II) complex
Masaru Mitsuda, Tomoaki Tanaka, Toshimitsu Tanaka, Yosuke Demizu,
Osamu Onomura and Yoshihiro Matsumura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 21 August 2006; revised 8 September 2006; accepted 12 September 2006
Available online 2 October 2006
Abstract—Kinetic resolution of N-benzoylated vic-amino alcohols was achieved by benzoylation in the presence of copper triflate
and (R,R)-Ph-BOX as catalysts. The observed enantioselectivity was moderate to high. The method was applied to a kinetic reso-
lution of racemic prolinol and piperidinemethanol derivatives as well as an asymmetric desymmetrization of 2-amino-1,3-diol
derivatives.
ꢀ 2006 Published by Elsevier Ltd.
Kinetic resolution has long continued to attract much
interest in asymmetric synthesis because of its simple
process for preparation of enantiomerically enriched
compounds from an easily available racemic mixture.1,2
We recently explored an efficient method for kinetic res-
olution of 1,2-diols 1, which is based on a recognition of
the 1,2-diol moiety with copper ion associated with some
chiral ligand L* such as (R,R)-Ph-BOX to afford the
activated 1,2-diol intermediates 2 followed by mono-
benzoylation (Eq. 1).3–5 In continuing the study, we
report herein kinetic resolution of vic-amino alcohols 4
affording optically active amino alcohols 5 (Eq. 2).2d,j,6
In advance of the kinetic resolution of 4, we first tried
the benzoylation of N-protected amino alcohol 6a as a
model compound to see whether it behaved in a similar
way as that of 1,2-diols 1. The result showed that the
reaction of 6a with BzCl afforded 7a in 96% yield, while
22% yield of 7a was observed in a reaction without cop-
per triflate and the chiral ligand (Eq. 3), suggesting that
H
Bz
O
O
Cu2+
L*
OH
OH
O
O
BzCl
base
-HCl
Cu2+ L*
+ Cu2+ L*
N
N
R
R
O
H
ð1Þ
ð2Þ
R
O
H
Ph
R,R)-Ph-Box
Ph
L*
(
1
2
3
OH
OBz
BzCl
Cu(OTf)2
R
NH
Z
R
NH
Z
chiral ligand
K2CO3
4
5
Keywords: Kinetic resolution; vic-Amino alcohol; Monobenzoylation; Chiral copper complex.
*
Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819 2476; e-mail: matumura@net.nagasaki-u.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.09.049

8074
M. Mitsuda et al. / Tetrahedron Letters 47 (2006) 8073–8077
6a might be recognized with copper ion/L* in a similar
manner to the kinetic resolution of 1.
Table 1. Competitive benzoylation reaction between N-protected
ethanol amines 6a–ea
Entry
6b–e
Protecting group
Products 7a–e
Ratio of 7a:7b–e
1
2
3
4
6b
6c
6d
6e
CO2t-Bu
100:0
100:0
100:0
100:0
Bz
OH
O
CO2CH2Ph
SO2Php-Me
COMe
O
O
BzCl (0.5 eq)
HN
HN
K2CO3 (1.5 eq)
THF, rt, 3 h
a The competitive reaction was carried out under the following con-
ditions: 6a (0.5 mmol), 6b–e (0.5 mmol), BzCl (0.1 mmol), Cu(OTf)2
and (R,R)-Ph-Box (0.015 mmol), K2CO3 (0.5 mmol), THF (2 mL), at
rt for 3 h.
ð3Þ
6a
7a
in the presence of Cu(OTf)2 (0.03 eq)
and ( )-Ph-Box (0.03 eq)
R,R
96% based on BzCl
22% based on BzCl
in the absence of Cu(OTf)2
and ( )-Ph-Box
Table 2. Competitive benzoylation reaction of 6a with alcohols 8a–da
R,R
Entry
8a–d
R
Products 7a, 9a–d
Ratio of 7a:9a–d
Further data about the reactivity of 6a for the benzoyl-
ation were obtained in the competitive reactions be-
tween 6a with 6b–e (Eq. 4, Table 1).
1
2
3
4
8a
8b
8c
8d
OH
OBz
OEt
Et
11:89
100:0
100:0
100:0
a The competitive reaction was carried out under the following con-
ditions: 6a (0.5 mmol), 8a–d (0.5 mmol), BzCl (0.1 mmol), Cu(OTf)2
and (R,R)-Ph-BOX (0.015 mmol), K2CO3 (0.5 mmol), THF (2 mL),
at rt for 3 h.
The results shown in Table 1 indicate that other protect-
ing groups than the benzoyl group were entirely ineffec-
tive as N-protecting groups of vic-amino alcohols to be
benzoylated.
Furthermore, N-benzoylated aminoethanol 6a was sub-
jected to competitive reactions with a variety of alcohols
having a substituent at the b-position (Eq. 5). The re-
sults are shown in Table 2, which shows that 6a was less
Bz
Bz
OH
O
O
OH
O
BzCl (0.2 eq)
HN
O
HN
NH
PG
NH
PG
Cu(OTf)2 (0.03 eq)
)-Ph-Box (0.03 eq)
ð4Þ
ð5Þ
(R,R
K2CO3 (1.0 eq)
THF, rt, 3 h
6a
7b-e
6b-e
7a
Bz
Bz
OH
O
O
O
OH
O
BzCl (0.2 eq)
HN
HN
R
R
Cu(OTf)2 (0.03 eq)
(R,R)-Ph-Box (0.03 eq)
K2CO3 (1.0 eq)
THF, rt, 3 h
9a-d
8a-d
6a
7a
OBz
O
OH
OH
O
HN
HN
HN
O
BzCl (0.5 eq)
ð6Þ
Cu(OTf)2 (0.03 eq)
R
R
R
(
R,R)-Ph-BOX (0.03 eq)
K2CO3 (1.0 eq)
THF, rt, 3 h
(
S)-5ap-at
recovered (R)-4ap-at
4ap-at

M. Mitsuda et al. / Tetrahedron Letters 47 (2006) 8073–8077
8075
R
R
R
OH
OBz
OH
O
HN
O
HN
HN
O
BzCl (0.5 eq)
OMe
OMe
OMe
Cu(OTf)2 (0.03 eq)
(R,R)-Ph-BOX (0.03 eq)
K2CO3 (1.0 eq)
THF, rt, 3 h
recovered (R)-4bt-ft
4bt-ft
(S)-5bt-ft
ð7Þ
R=Me
s
=29
5bt; 34% yield, 89% ee 4bt; 62% yield, 54% ee
5ct; 41% yield, 86% ee 4ct; 42% yield, 68% ee
R=Et
s
=28
R=Ph
5dt; 26% yield, 85% ee 4dt; 62% yield, 36% ee
5et; 33% yield, 87% ee 4et; 51% yield, 80% ee
s
=18
=35
s
R=p-ClPhCH2
R=p-MeOPhCH2
5ft; 32% yield, 85% ee
4ft; 65% yield, 30% ee
s=16
Table 3. Kinetic resolution of amino alcohols 4ap–at
Entry
Compounds
R
Products (S)-5ap–at
Recovered (R)-4ap–at
Selectivity (s)a
4ap–at
Yield (%)
% ee
Yield (%)
% ee
1
2
3
4
5
4ap
4aq
4ar
4as
4at
H
p-Cl
o-Cl
p-OMe
o-OMe
5ap
5aq
5ar
5as
5at
26
30
20
45
36
78
46
77
83
93
4ap
4aq
4ar
4as
4at
62
73
72
53
59
32
16
30
62
55
11
3
10
20
50
a Ref. 1a.
reactive than 1,2-diol 8a but it was more reactive than
benzoyloxy-, ethoxyl- or ethyl-substituted ethanols
(8b–d).
Our attention was then focused on a kinetic resolution
of N-alkylated N-benzoylethanolamine derivatives 10
because there have been known numerous naturally
occurring compounds having an N-alkylethanolamine
moiety.
On the basis of those results, we tried a kinetic resolu-
tion of dl-valinol derivatives 4ap–at by benzoylation in
which copper triflate and (R,R)-Ph-BOX were present.
The results are shown in Table 3.
H
O
R
Cu2+ L*
O
OH
O
N
N
R'
R
A moderate enantioselectivity (78% ee) was observed
in the case of N-benzoylated valinol 4ap (entry 1), but
o-MeO-phenylcarbonylated valinol 4at gave the best
result (entry 5) among those examined (entries 1-5).
The s value1a was 50.
R'
10
2'
The other examples of kinetic resolution are shown in
Eq. 7.
So, we tried a competitive reaction between 6a and 6b to
afford a mixture of 7a and 7b with a ratio of 50/50 (Eq.
OBz
OBz
OH
OH
BzCl (0.2 mmol, 0.1 eq)
Cu(OTf)2 (0.03 eq)
N
O
N
O
HN
O
Me
HN
O
Me
+
+
(
R,R)-Ph-BOX (0.03 eq)
ð8Þ
K2CO3 (1.0 eq)
THF, rt, 3 h
6a
1.0 mmol
7a
6b
1.0 mmol
7b
50
:
50
~100% based on BzCl

8076
M. Mitsuda et al. / Tetrahedron Letters 47 (2006) 8073–8077
OBz
OH
OH
S
R
(0.5 eq)
BzCl
N
N
N
+
Cu(OTf)2 (0.03 eq)
R,R)-Ph-BOX (0.03 eq)
O
O
O
(
K2CO3 (1.0 eq)
rt. 3 h
ð9Þ
(R)-11
dl-11
(S
)-12
95% ee
49% yield
43% yield
94% ee
97% ee
s
=118
44% yield
in THF
in Et2O
57% yield 84% ee
s=174
R
S
OBz
OH
(0.5 eq)
BzCl
OH
N
N
N
+
Cu(OTf)2 (0.03 eq)
R,R)-Ph-BOX (0.03 eq)
O
O
O
(
K2CO3 (1.0 eq)
rt. 3 h
ð10Þ
(R)-12
dl-12
(S)-13
40% yield
49%yield
95% ee
95% ee
48% yield 79% ee
50% yield 98% ee
s
=95
in THF
in Et2O
s=177
Me
*
BzCl (1.0 eq)
OH
OBz
Me
O
OH
OH
HN
HN
Cu(OTf)2 (0.03 eq)
R,R)-Ph-BOX (0.03 eq)
K2CO3 (1.0 eq)
THF, rt, 3 h
O
(
ð11Þ
ð12Þ
(-)-14
13
97% yield 95%ee
OH
OH
OH
(1.0 eq)
BzCl
*
N
N
OBz
Cu(OTf)2 (0.03 eq)
R,R)-Ph-BOX (0.03 eq)
O
O
(
K2CO3 (1.0 eq)
THF, rt, 3 h
15
(-)-16
88% yield 94%ee
8), indicating that 6b had similar reactivity to 6a for the
benzoylation, and suggesting an intermediary formation
of intermediates 20,7 which corresponded to 2 derived
from diols 1.
our method is very simple and easy in operation in com-
parison with the reported methods. The mechanistic
details and an application of asymmetric desymmetriza-
tion are now under investigation.
On the basis of this result, dl-prolinol (dl-11) and dl-
piperidinemethanol (dl-13) were subjected (Eqs. 9 and
10) to kinetic resolution under conditions similar to
those for 4ap–4ft.8
Acknowledgement
Y.M. thanks the Japan Society for the Promotion of Sci-
ence for Scientific Research (B) (17350051) for financial
support.
Also, 2-amino-1,3-diols 13 and 15 were asymmetrically
desymmetrized by benzoylation to afford optically active
14 and 16 in 97% yield with 95% ee and 88% yield with
94% ee, respectively (Eqs. 11 and 12).9
References and notes
The results shown in this paper are useful for the prep-
1. Some reviews of kinetic resolution: (a) Kagan, H. B.; Fiaud,
aration of optically active vic-amino alcohols, because
J. C. Top. Stereochem. 1988, 18, 249–330; (b) Pamies, O.;

M. Mitsuda et al. / Tetrahedron Letters 47 (2006) 8073–8077
8077
Baeckvall, J.-E. Chem. Rev. 2003, 103, 3247–3261; (c)
Ghanem, A.; Aboul-Enein, H. Y. Chirality 2005, 17, 1–15.
2. Recent examples of kinetic resolution of alcohols: (a)
Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125,
4166–4173; (b) Priem, G.; Pelotier, B.; Macdonald, S. J. F.;
Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003, 68,
3844–3848; (c) Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey,
S. G.; Jarvest, R. L. Tetrahedron 2004, 60, 4513–4525; (d)
Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc.
2004, 126, 12212–12213; (e) Terakado, D.; Koutaka, H.;
Oriyama, T. Tetrahedron: Asymmetry 2005, 16, 1157–1165;
(f) Yamada, S.; Misono, T.; Iwai, Y. Tetrahedron Lett.
2005, 46, 2239–2242; (g) Gissible, A.; Finn, M. G.; Reiser,
O. Org. Lett. 2005, 7, 2325–2328; (h) Boren, L.; Martin-
Matute, B.; Xu, Y.; Cordova, A.; Baeckvall, J.-E. Chem.
Eur. J. 2006, 12, 225–232; (i) Akai, S.; Tanimoto, K.;
Kanao, Y.; Egi, M.; Yamamoto, T.; Kita, Y. Angew.
Chem., Int. Ed. 2006, 45, 2592–2595; (j) Mazet, C.;
Roseblade, S.; Ko¨hler, V.; Pfaltz, A. Org. Lett. 2006, 8,
1879–1882.
3. (a) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O.
J. Am. Chem. Soc. 2003, 125, 2052–2053; (b) Matsumura,
Y.; Maki, T.; Tsurumaki, K.; Onomura, O. Tetrahedron
Lett. 2004, 45, 9131–9134.
4. Kinetic resolution of 1,2-diols with chiral tin catalyst: (a)
Iwasaki, F.; Maki, T.; Nakashima, W.; Onomura, O.;
Matsumura, Y. Org. Lett. 1999, 1, 969–972; (b) Iwasaki, F.;
Maki, T.; Onomura, O.; Nakashima, W.; Matsumura, Y. J.
Org. Chem. 2000, 65, 996–1002.
Chem., Int. Ed. 1996, 35, 2813–2817; Asymmetric reduction
of a-amino ketones: (h) Ohkuma, T.; Ishii, D.; Takeno, H.;
Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510–6511;
Asymmetric a-hydroxyamination of aldehyde: (i) Kano, T.;
Ueda, M.; Takai, J.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 6046–6047.
7. A kinetic resolution of dl-N-benzyl-a-piperidinemethanol
under conditions similar to those for 4ap–4ft proceeded to
afford the corresponding benzoate in 21% yield with 62%
ee. This result supports an intermediary formation of
intermediates 20.
8. Typical procedure for kinetic resolution: Into a solution of
Cu(OTf)2 (5.4 mg, 0.015 mmol) and (R,R)-Ph-Box (5.0 mg,
0.015 mmol) in THF (2 mL) were added dl-12 (110 mg,
0.5 mmol), K2CO3 (69.1 mg, 0.5 mmol) and benzoyl chlo-
ride (0.029 mL, 0.25 mmol). After being stirred for 3 h at rt,
into the reaction mixture water (10 mL) was added. The
organic portion was extracted with AcOEt (20 mL · 3).
The combined organic layer was dried over MgSO4 and the
solvent was removed in vacuo. The residue was chromato-
graphed on SiO2 (n-hexane–AcOEt = 1:2) to afford (S)-13
(64.9 mg, 40% yield, 95% ee) and (R)-12 (53.0 mg, 48%
yield, 79% ee). Optical purities of product (S)-13 and
recovered (R)-12 were determined by chiral HPLC: Daicel
Chiralcel OD column (4.6 mm B, 25 cm), n-hexane–iso-
propanol = 20:1, wavelength: 254 nm, flow rate: 1.0 mL/
min, retention time for 13: 19.7 min ((S)-(ꢀ)-13), 22.9 min
((R)-(+)-13). retention time for 12: 18.1 min ((S)-(ꢀ)-12),
20.2 min ((R)-(+)-12).
5. Representative desymmetrization of meso-1,2-diols: (a)
Mizuta, S.; Sadamori, M.; Fujimoto, T.; Yamamoto, I.
Angew. Chem., Int. Ed. 2003, 42, 3383–3385; (b) Mazet, C.;
Ko¨hler, V.; Pfaltz, A. Angew. Chem., Int. Ed. 2005, 44,
4888–4891.
9. The absolute stereoconfigurations of 14 and 16 have not yet
been determined. Compound 14: 1H NMR (300 MHz,
CDCl3) d 1.54 (s, 3H), 3.79 (d, J = 12.3 Hz, 1H), 3.88 (d,
J = 12.3 Hz, 1H), 4.42 (br s, 1H), 4.61 (d, J = 11.7 Hz, 1H),
4.69 (d, J = 11.4 Hz, 1H), 6.79 (br s, 1H), 7.40–7.64 (m,
6H), 7.77 (d, J = 6.9 Hz, 2H), 8.06 (d, J = 7.2 Hz, 2H).
HPLC: Daicel Chiralcel OD column (4.6 mm B, 25 cm), n-
hexane/isopropanol = 20:1, wavelength: 254 nm, flow
rate: 1.0 mL/min, retention time: 31.7 min ((ꢀ)-isomer),
6. Recent representative methods for the catalytic prepa-
ration of optically active vic-amino alcohols: Asym-
´
´
metric O-acylation (a) Sanchez-Sancho, F.; Herradon, B.
´
Tetrahedron: Asymmetry 1998, 9, 1951–1965; (b) Gonzalez-
26:5
´
Sabın, J.; Gotor, V.; Rebolledo, F. Tetrahedron: Asymme-
36.7 min ((+)-isomer). ½aꢁD ꢀ19.7 (c 2.0, CHCl3).
try 2004, 15, 1335–1341; (c) Pelotier, B.; Priem, G.;
Macdonald, S. J. F.; Anson, M. S.; Upton, R. J.; Campbell,
I. B. Tetrahedron Lett. 2005, 46, 9005–9007; (d) Cowley, A.
R.; Bhalay, G.; Linney, I. D. J. Org. Chem. 2006, 71, 6298–
6301; (e) Angione, M. C.; Miller, S. J. Tetrahedron 2006, 62,
5254–5261; Aminolytic kinetic resolution of epoxide: (f)
Kim, S. K.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl.
2004, 43, 3952–3954; Asymmetric aminohydroxylation of
olefin: (g) Li, G.; Angert, H. H.; Sharpless, K. B. Angew.
Compound 16: 1H NMR (300 MHz, CDCl3) d 1.75–2.02
(m, 3H), 2.18–2.28 (m, 1H), 3.40–3.60 (m, 2H), 3.95–4.02
(m, 2H), 4.81 (d, J = 11.1 Hz, 1H), 4.95 (d, J = 11.4 Hz,
1H), 5.63 (br t, J = 5.7 Hz, 1H), 7.28–7.52 (m, 7H), 7.56–
7.63 (m, 1H), 8.07 (d, J = 7.2 Hz, 2H). HPLC: Chiralpak
AD column (4.6 mm B, 25 cm), n-hexane/isopropa-
nol = 5:1, wavelength: 254 nm, flow rate: 1.0 mL/min.
retention time: 10.9 min ((+)-isomer), 14.4 min ((ꢀ)-iso-
28:0
mer). ½aꢁD ꢀ50.4 (c 0.85, CHCl3).