Asymmetric hydrogenation of α-hydroxy ketones catalyzed by MsDPEN-Cp*Ir(III) complex

Article abstract of DOI:10.1021/ol070964w

Asymmetric hydrogenation of a series of α-hydroxy aromatic ketones in methanol catalyzed by Cp*Ir(OTf)(MsDPEN) (MsDPEN = N-(methanesulfonyl)-1, 2-diphenylethylenediamine) affords the 1-aryl-1,2-ethanediols in up to 99% ee. The reaction can be conducted with a substrate-to-catalyst molar ratio at high as 6000 under 10 atm of H_2-1-Hydroxy-2-propanone is also hydrogenated with high enantioselectivity.

Full text of DOI:10.1021/ol070964w

ORGANIC
LETTERS
2
007
Vol. 9, No. 13
565-2567
Asymmetric Hydrogenation of
-Hydroxy Ketones Catalyzed by
2
r
MsDPEN−Cp*Ir(III) Complex
Takeshi Ohkuma,*,† Noriyuki Utsumi, Masahito Watanabe, Kunihiko Tsutsumi,
‡
‡
‡
†
‡
Noriyoshi Arai, and Kunihiko Murata
DiVision of Chemical Process Engineering, Graduate School of Engineering, Hokkaido
UniVersity, Sapporo 060-8628, Japan, and Central Research Laboratory, Technology
and DeVelopment DiVision, Kanto Chemical CO., Inc., Soka, Saitama 340-0003, Japan
ohkuma@eng.hokudai.ac.jp
Received April 25, 2007
ABSTRACT
Asymmetric hydrogenation of
a series of r-hydroxy aromatic ketones in methanol catalyzed by Cp*Ir(OTf)(MsDPEN) (MsDPEN )
N-(methanesulfonyl)-1,2-diphenylethylenediamine) affords the 1-aryl-1,2-ethanediols in up to 99% ee. The reaction can be conducted with a
2
substrate-to-catalyst molar ratio as high as 6000 under 10 atm of H . 1-Hydroxy-2-propanone is also hydrogenated with high enantioselectivity.
Exploitation of synthetic procedures for useful chiral building
blocks is one of the main subjects in the area of organic
chemistry. Recently, practical asymmetric syntheses of
biologically active compounds using chiral 1-aryl-1,2-
the asymmetric hydrogenation of 1-hydroxy-2-alkanones to
afford chiral 1,2-diols in high enantiomeric excess (ee).7
However, reaction of R-hydroxyacetophenone (3a) with the
BINAP-Ru(II) catalyst gave the 1,2-diol 4a in only 66%
-9
1
ethanediols as key intermediates have been reported. Enan-
(2) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
tioselective dihydroxylation of styrene derivatives with AD-
mix reagents is a representative method to produce this
important class of compounds.1 Asymmetric hydrogenation
Hartung, J.; Jeong, K-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768-2771. (b) Crispino, G. A.;
Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Sharpless, K. B. J. Org.
Chem. 1993, 58, 3785-3786. (c) Becker, H.; King, S. B.; Taniguchi, M.;
Vanhessche, K. P. M.; Sharpless, K. B. J. Org. Chem. 1995, 60, 3940-
3941. (d) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
,2
of R-hydroxy aromatic ketones is another reliable procedure
for this purpose (Scheme 1).3-5 However, this asymmetric
3
5, 448-451.
transformation is still difficult even with modern, well-
(3) For asymmetric hydrogenation of R-chloro aromatic ketones with
6
chiral arene-Ru(II) complex 2, see: Ohkuma, T.; Tsutsumi, K.; Utsumi,
N.; Arai, N.; Noyori, R.; Murata, K. Org. Lett. 2007, 9, 255-257. See
also: Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval, C.;
Noyori, R. J. Am. Chem. Soc. 2006, 128, 8724-8725.
designed molecular catalysts. For example, RuX
(
2
(BINAP)
polymeric form) (X ) Cl, Br)7,8 and its analogues catalyze
†
‡
Hokkaido University.
Kanto Chemical CO., Inc.
(4) For asymmetric transfer hydrogenation of R-hydroxyacetophenone,
see: (a) Cross, D. J.; Kenny, J. A.; Houson, I.; Campbell, L.; Walsgrove,
T.; Wills, M. Tetrahedron: Asymmetry 2001, 12, 1801-1806. (b) Matharu,
D. S.; Morris, D. J.; Kawamoto, A. M.; Clarkson, G. J.; Wills, M. Org.
Lett. 2005, 7, 5489-5491. (c) Matharu, D. S.; Morris, D. J.; Clarkson, G.
J.; Wills, M. Chem. Commun. 2006, 3232-3234.
(5) Asymmetric hydrogenation of vinyl bis(boronates) followed by an
oxidative treatment with a basic H2O2 gave the chiral diol in high ee. See:
Morgan, J. B.; Morken, J. P. J. Am. Chem. Soc. 2004, 126, 15338-15339.
(1) (a) Pye, P. J.; Rossen, K.; Weissman, S. A.; Maliakal, A.; Reamer,
R. A.; Ball, R.; Tsou, N. N.; Volante, R. P.; Reider, P. J. Chem.sEur. J.
2
2
002, 8, 1372-1376. (b) Haukaas, M. H.; O’Doherty, G. A. Org. Lett.
002, 4, 1771-1774. (c) Singh, A. K.; Prasad, J. S.; Delaney, E. J. In
Asymmetric Catalysis on Industrial Scale: Challenges, Approaches, and
Solutions; Blaser, H. U., Schmidt, E., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; pp 335-348.
1
0.1021/ol070964w CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/23/2007

high as 6000 under 10 atm of H
1
2
2
, affording a series of 1-aryl-
,2-ethanediols in up to 99% ee. The reaction of 1-hydroxy-
-propanone, an aliphatic R-hydroxy ketone, is also dis-
Scheme 1
cussed.
Cp*Ir(OTf)[(S,S)-MsDPEN] [(S,S)-1a] and Cp*Ir(OTf)-
1
6,17
[
(S,S)-TsDPEN] [(S,S)-1b]
fonyl)-1,2-diphenylethylenediamine) (Scheme 1) were pre-
pared from commercially available [Cp*IrCl in two steps
see the Supporting Information). The iridium complex
reacted with (S,S)-MsDPEN or (S,S)-TsDPEN in a basic
O-CH Cl two phase system to give the 16-electron amide
complex Cp*Ir[(S,S)-MsDPEN] or Cp*Ir[(S,S)-TsDPEN].
Dropwise addition of TfOH in CH Cl to the CH Cl solution
(TsDPEN ) N-(toluenesul-
2 2
]
(
H
2
2
2
16b
2
2
2
2
of the amide complex formed (S,S)-1a or (S,S)-1b in good
3
yield.
First, we selected R-hydroxyacetophenone (3a)18 as a
typical substrate for the screening of chiral catalysts and
reaction conditions (Scheme 1). When hydrogenation of 3a
(
1.63 g, 12.0 mmol) using (S,S)-1a (1.5 mg, 2.0 µmol, S/C
6000) as a precatalyst in methanol (4.8 mL) under 10 atm
of H at 60 °C was conducted for 15 h, (R)-1-phenyl-1,2-
ethanediol [(R)-4a] was produced in 96% ee and 97% yield
Table 1). The reactivity was reduced when the reaction was
)
2
(
ee.10 trans-RuCl
2
(XylBINAP)(DAIPEN) with an alkaline
base effects asymmetric hydrogenation of R-methoxyaceto-
Table 1. Asymmetric Hydrogenation of
phenone, affording 2-methoxy-1-phenyl-1-ethanol in 97%
R-Hydroxyacetophenone (3a)a
11-14
ee.
However, the hydroxy ketone 3a was not reduced
conditions
(R)-4a
yield
%c
97 (94) 96
with the catalyst owing to instability of the ketonic substrate
under such basic conditions.15 We report herein for the first
time, asymmetric hydrogenation of R-hydroxy aromatic
ketones with the newly devised Cp*Ir(OTf)(MsDPEN) (1a)
temp
°C
H2
ee
%
S/Cb
6000 CH3OH
6000 C2H5OH
6000 i-C3H7OH
6000 CH3OH
solvent
atm
d
catalyst no.
(S,S)-1a
(S,S)-1a
60
60
60
50
70
60
60
60
10
10
10
10
10
1
(
Cp* ) pentamethylcyclopentadienyl, TfO- ) trifluoro-
36
67
50
65
96
95
97
96
(S,S)-1a
(S,S)-1a
(S,S)-1a
(S,S)-1a
(S,S)-1b
(S,S)-2
methanesulfonate, MsDPEN ) N-(methanesulfonyl)-1,2-
diphenylethylenediamine). The hydrogenation proceeded
smoothly with a substrate-to-catalyst molar ratio (S/C) as
6000 CH3OH
e
200
CH3OH
97 (94) 96
6000 CH3OH
6000 CH3OH
10
10
12
85
(
6) (a) Ohkuma, T.; Noyori, R. In ComprehensiVe Asymmetric Catalysis;
<1
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 1, pp 199-246. (b) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
a
Unless otherwise stated, reactions were conducted using 12 mmol of
a (2.0 M) in solvent containing 1 or 2 (2.0 µmol, 0.33 mM) in a silanized
3
2
000; pp 1-110. (c) Ohkuma, T.; Noyori, R. In Transition Metals for
b
glass autoclave. Reaction time was 15 h. Substrate/catalyst molar ratio.
Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; Vol. 2, pp 29-113. (d) Ohkuma, T.; Noyori,
R. In The Handbook of Homogeneous Hydrogenation; de Vries, J. G.,
Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, Germany, 2007; pp 1105-
c
d
e
1
Determined by H NMR analysis. Isolated yield is stated in parentheses.
Determined by chiral HPLC analysis (DAICEL CHIRALCEL OB).
Reaction using 0.80 mmol of 3a (0.067 M) with 1a (4.0 µmol, 0.33 mM).
1
163.
7) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988,
10, 629-631.
8) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1994.
(
carried out in ethanol or 2-propanol, while a high level of
enantioselectivity was preserved. An optimal yield was
attained in the reaction at 60 °C. The catalytic species may
have a short life at a higher temperature. The hydrogenation
1
(
(9) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264-267.
(
(
10) Ohkuma, T. Ph.D. Thesis, Nagoya University, 1991.
11) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.;
2
proceeded smoothly even under 1 atm of H at an S/C of
Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 13529-13530.
(16) For asymmetric transfer hydrogenation of ketones catalyzed by
TsDPEN-Cp*Ir complexes, see: (a) Mashima, K.; Abe, T.; Tani, K. Chem.
Lett. 1998, 1199-1200. (b) Mashima, K.; Abe, T.; Tani, K. Chem. Lett.
1998, 1201-1202. (c) Murata, K.; Ikariya, T.; Noyori, R. J. Org. Chem.
1999, 64, 2186-2187.
(
12) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40-73.
(13) For asymmetric hydrogenation of arylglyoxal dialkylacetals, see:
Arai, N.; Ooka, H.; Azuma, K.; Yabuuchi, T.; Kurono, N.; Inoue, T.;
Ohkuma, T. Org. Lett. 2007, 9, 939-941.
+
(14) For asymmetric hydrogenation of amino ketones catalyzed by chiral
(17) Reaction of [Cp*Ir(TsDPEN)] with H2 gave the IrH species. See:
Ru complexes, see: Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am.
Chem. Soc. 2000, 122, 6510-6511.
Heiden, Z. M.; Rauchfuss, T. B. J. Am. Chem. Soc. 2006, 128, 13048-
13049.
(
15) See for example: Edmonds, J. S.; Morita, M.; Turner, P.; Skelton,
(18) Martin, R. Handbook of Hydroxyacetophenones; Springer: Berlin,
Heidelberg, New York, 2005.
B. W.; White, A. H. Steroids 2006, 71, 34-41.
2566
Org. Lett., Vol. 9, No. 13, 2007

2
00 without loss of enantioselectivity. The catalyst feature
reaction conditions, while the hydrogenation of 3d substituted
by an electron-attracting CN group at the 4′ position
proceeded smoothly. Complete conversion was achieved with
a high level of enantioselectivity in the hydrogenation of 4′-
F- and 4′-Cl-substituted ketones, 3g and 3i, at an S/C of 3000
under otherwise identical conditions. Reaction of 3′-Cl-
substituted ketone 3h afforded the chiral alcohol 4h in 95%
ee, while the fluorinated ketone 3f at the 2′ position was
reduced with moderate enantioselectivity. Disubstituted
was significantly affected by the N-sulfonate substituents.
When the reaction was conducted with Cp*Ir(OTf)[(S,S)-
TsDPEN] [(S,S)-1b] (S/C ) 6000, 10 atm H
2
, 60 °C, 15 h),
(R)-4a was obtained in only 12% yield and 85% ee (Table
6
1). It is worth noting that Ru(OTf)(TsDPEN)(η -p-cymene)
(2), which is an efficient catalyst for asymmetric hydrogena-
3
tion of R-chloro aromatic ketones, was virtually inert for
the reaction of the electronically related R-hydroxy ketones.
The catalyst system was applied to the asymmetric
hydrogenation of a series of R-hydroxy ketones 3, and the
3
ketone 3j with a CF group at the 3′ and 5′ positions was
hydrogenated in the presence of (S,S)-1a to yield (R)-4j in
96% ee. The antipode of the product, that is, (S)-4j, is a key
intermediate for the synthesis of substance P inhibitors.1a
results are shown in Table 2. Hydrogenation of the 4′-CH
3
-
2
-Thienyl ketone 3k was converted to the chiral alcohol 4k
Table 2. Asymmetric Hydrogenation of R-Hydroxy Ketonesa
with nearly perfect enantioselectivity, leaving the hetero-
1
9
aromatic ring intact. Interestingly, (S,S)-1a efficiently
catalyzed the hydrogenation of 1-hydroxy-2-propanone (3l),
the simplest aliphatic R-hydroxy ketone, producing (R)-1,2-
ketone
no.
conditions
alcohol
ee
H2
time
yield
%c
catalyst S/Cb atm
d
configne
7-9
h
%
propanediol [(R)-4l] in 80% ee (Table 2). Again, the chiral
3
af
arene-Ru complex 2 showed poor activity and enantio-
3
3
3
3
3
3
3
3
3
3
3
3
3
(S,S)-1a 6000 10
(S,S)-1a 1000 10
(S,S)-1a 1000 10
(S,S)-1a 1000 10
(S,S)-1a 1000 10
(S,S)-1a 1000 10
(S,S)-1a 3000 10
(S,S)-1a 1000 10
(S,S)-1a 3000 10
(S,S)-1a 1000 10
(S,S)-1a 1000 10
(S,S)-1a 1000 10
15
15
15
15
15
15
15
15
15
15
15
15
15
97 (94)
96
R
R
R
R
b
c
d
e
f
>99 (89) 94
>99 (94) 97
>99 (94) 94
<1
>99 (89) 74
>99 (93) 96
selectivity for this reaction.
In summary, we have described the first example of highly
enantioselective hydrogenation of R-hydroxy aromatic ke-
tones catalyzed by the newly devised MsDPEN-Cp*Ir(III)
triflate 1a. The closely related catalysts, TsDPEN-Cp*Ir(III)
triflate 1b and arene/TsDPEN-Ru(II) triflate 2, as well as
several other known catalysts, are not effective for this
transformation. A series of 1-aryl-1,2-ethanediols and the
heteroaryl analogues are quantitatively obtained in up to 99%
ee by hydrogenation with the Ir catalyst 1a. A simple 1,2-
propanediol is also available in high stereoselectivity. Thus,
this method provides a new, efficient pathway to produce
synthetically useful chiral 1,2-diols.
Rg
R
R
R
R
h
g
h
89 (80)
95
h
i
>99 (91) 96
>99 (91) 96
>99 (97) 99
97 (90)
35
j
k
l
g
S
80i
10i
R
R
l
(S,S)-2
1000 10
a
Unless otherwise stated, reactions were conducted using 2.0 mmol of
ketone (0.33 M) in methanol containing 1a or 2 (2.0 µmol, 0.33 mM) at 60
°
C in a silanized glass autoclave. Substrate/catalyst molar ratio. c Deter-
b
1
mined by H NMR analysis. Isolated yield is stated in parentheses.
Determined by chiral HPLC analysis. Determined by the sign of rotation.
Acknowledgment. This work was supported by a Grant-
in-Aid from the Japan Society for the Promotion of Science
d
f
e
g
Reaction with 12.0 mmol of 3a (2.0 M). See Supporting Information.
h
Reaction with 6.0 mmol of 3 (1.0 M). i Determined by chiral GC analysis
(JSPS) (Grant No. 18350046).
after conversion to the acetone cyclic acetal.
Supporting Information Available: Preparative methods
and properties of chiral Ir complexes 1, procedures for
asymmetric hydrogenation of R-hydroxy ketones, NMR and
substituted ketone 3b in the presence of (S,S)-1a with an
S/C of 1000 at 60 °C under 10 atm of H
diol (R)-4b in 94% ee quantitatively. An excellent optical
yield of 97% was achieved in the reaction of 3′-CF
2
afforded the chiral
D
HPLC behavior of products, [R] values and absolute-
configuration determination. This material is available free
of charge via the Internet at http://pubs.acs.org.
3
-
substituted ketone 3c. The reactivity was markedly influenced
by the electronic properties of the substrates. Thus, a hydroxy
OL070964W
ketone 3e bearing an electron-donating CH
3
O group at the
(
19) Due to the group priority in nomenclature, (R)-4a-j,l and (S)-4k
4′ position was not converted at all under the standard
have the same â configuration in Scheme 1.
Org. Lett., Vol. 9, No. 13, 2007
2567