Stereoselective Synthesis of Optically Active α-hydroxy Ketones and anti-1,2-diols via Asymmetric Transfer Hydrogenation of Unsymmetrically Substituted 1,2-diketones

Article abstract of DOI:10.1021/ol0002572

Formula Represented A well-defined chiral Ru catalyst RuCl(N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine)(η⁶-arene) effectively promotes asymmetric transfer hydrogenation of 1-aryl-1,2-propanedione with HCOOH/N(C₂H₅)₃, leading preferentially to optically active 1-aryl-2-hydroxy-1-propanone with up to 99% ee and 89% yield at 10°C. The reaction at 40°C gives anti-1-aryl-1,2-propanediol with up to 95% ee and 78% yield. This is a highly efficient procedure for the synthesis of optically active anti-diols.

Full text of DOI:10.1021/ol0002572

ORGANIC
LETTERS
2
000
Vol. 2, No. 24
833-3836
Stereoselective Synthesis of Optically
Active r-Hydroxy Ketones and
anti-1,2-Diols via Asymmetric Transfer
Hydrogenation of Unsymmetrically
Substituted 1,2-Diketones
3
Takashi Koike, Kunihiko Murata, and Takao Ikariya*
Graduate School of Science and Engineering, Tokyo Institute of Technology and
CREST, Japan Science and Technology Corporation, 2-12-1 O-okayama,
Meguro-ku, Tokyo 152-8552, Japan
tikariya@o.cc.tilech.ac.jp
Received September 5, 2000
ABSTRACT
6
A well-defined chiral Ru catalyst RuCl(N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine)(η -arene) effectively promotes asymmetric transfer
2 5 3
hydrogenation of 1-aryl-1,2-propanedione with HCOOH/N(C H ) , leading preferentially to optically active 1-aryl-2-hydroxy-1-propanone with up
to 99% ee and 89% yield at 10 °C. The reaction at 40 °C gives anti-1-aryl-1,2-propanediol with up to 95% ee and 78% yield. This is a highly
efficient procedure for the synthesis of optically active anti-diols.
Optically active R-hydroxy ketones are useful building blocks
for the synthesis of biologically active compounds, natural
products, and medicines, as well as chiral auxiliaries or
tions, versatile methods include the enzymatic kinetic resolu-
tion of R-hydoxyketones and the asymmetric oxidation of
7
enolates or enol ethers using a stoichiometric amount of
1
2
3
ligands for asymmetric synthesis. This important class of
chiral N-sulfonyloxaziridines, (salen)Mn catalysts, or Sharp-
2-6
4
compounds has been prepared by means of oxidative and
less dihydroxylation catalysts.
nonoxidative7 methods. Among these effective transforma-
,8
Although the asymmetric catalytic reduction of readily
available 1,2-diketones would be a promising approach, no
practical reduction systems have been reported except for
(
1) (a) Gala, D.; DiBenedetto, D. J.; Clark, J. E.; Murphy, B. L.;
Schumacher, D. P.; Steinman, M. Tetrahedron Lett. 1996, 37, 611-614.
b) Girijavallabhan, V. M.; Ganguly, A. K.; Pinto, P. A.; Sarre, O. Z. Bioorg.
8
the enzymatic reduction systems because there is a lack of
(
suitable catalyst systems. Recently, we have developed a
practical asymmetric synthesis of optically active diols via
an asymmetric transfer hydrogenation of 1,2-diketones with
Med. Chem. Lett. 1991, 1, 349-352. (c) Konishi, T.; Miyaoka, T.; Tajima,
Y.; Oida, S. Chem. Pharm. Bull. 1991, 39, 2241-2246.
(2) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919-934 and
references therein.
3) Adam, W.; Fell, R. T.; Stegmann, V. R.; Saha-M o¨ ller, C. R. J. Am.
Chem. Soc. 1998, 120, 708-714.
4) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992,
7, 5067-5068.
5) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819-
822.
6) Adam, W.; Fell, R. T.; Saha-M o¨ ller, C. R.; Zhao, C.-G. Tetrahe-
dron: Asymmetry 1998, 9, 4117-4122.
6
9
(
a chiral Ru(II) catalyst, RuCl(Tsdpen)(η -arene) (1;
TsDPEN, N-(p-toluenesulfonyl)-1,2-diphenylethylenedi-
(
5
(
(7) Adams, W.; Diaz, M. T.; Fell, R. T.; Saha-M o¨ ller, C. R. Tetrahe-
dron: Asymmetry 1996, 7, 2207-2210.
(8) Kawai, Y.; Hida, K.; Tsujimoto, M.; Kondo, S.; Kitano, K.;
Nakamura, K.; Ohno, A. Bull. Chem. Soc. Jpn. 1999, 72, 99-102.
7
(
1
0.1021/ol0002572 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

amine). In this synthesis, an efficient dynamic kinetic
resolution of the R-hydoxy ketone intermediate, benzoin, led
to the formation of optically active 1,2-diols in almost
quantitative yields.10 Here, we report the stereoselective
synthesis of both optically active R-hydroxy ketones and anti-
Table 1. Asymmetric Transfer Hydrogenation of 1,2-Diketones
to R-Hydroxyketones Catalyzed by Chiral Ru(II) Catalysts with
Formic Acida
product, 3 and 4
1,2-diols by this chiral Ru(II)-catalyzed asymmetric transfer
Ru
temp yield
ee
(%)c
hydrogenation of unsymmetrically substituted 1,2-diketones.
ketone catalyst S/C (°C) (%)b
3:4b
configd
A well-defined chiral catalyst RuCl[(S,S)-Tsdpen](p-
cymene) (1c) has proven to effect the asymmetric reduction
of 1-phenyl-1,2-propanedione (2a) with a substrate/catalyst
molar ratio (S/C) of 300 using 1 molar equiv of formic acid
2
2
2
2
2
2
2
2a
2a
2
2
2
a
a
a
a
a
a
a
(S,S)-1c
(S,S)-1c
(S,S)-1ce 300
(S,S)-1cf 300
(S,S)-1cg 300
(S,S)-1a
(S,S)-1b 500
(S,S)-1d 500
300
500
10
10
10
10
20
10
10
10
10
0
30
40
10
10
30
99
95
79
72
99
95
85
88
99
26
87
82
60
87
79
89:11 99, 12
80:20 97, 6
77:23 97, 12
71:29 96, 21
86:14 97, 49
51:49 87, 43
73:27 98, 36
61:39 93, 50
84:16 97, 27
77:23 96, 67
71:29 82, 35
48:52 24, 29
57:43 95, 60
100:0 92,0
S,S
S,R
S,R
S,R
S,R
S,R
S,R
S,R
S,S
S,R
S,R
S,R
2 5 3
to 2a (2a:HCOOH:N(C H ) ) 1:1.1:0.65) at 10 °C, giving
a 9:1 mixture of 1-phenyl-2-hydroxy-1-propanone, (S)-3a,
with 99% ee and 1-phenyl-1-hydroxy-2-propanone, (S)-4a,
with 12% ee with an overall yield of 99% (Scheme 1). Table
500
1
lists some representative examples.
(S,S)-1e
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
500
500
500
500
500
500
a
a
a
Scheme 1
2b
2
2
c
d
Si
S,R
(S,S)-1ch 200
27:73 >99, 47
a
The reaction of 1,2-diphenyl-1,2-propanedione (0.84 mmol) was carried
out with a diketone/HCOOH/N(C2H5)3 molar ratio of 1/1.1/0.65 at 10 °C
b
for 24 h, unless otherwise noted. Yields and molar ratio of 3 to 4 were
1
determined by H NMR using 1,3,5-trimethoxybenzene as a internal
standard. c Determined by HPLC analysis using a Daicel Chiralcel OB
column or GLC analysis using a Chirasil-DEX CB column (25 m).
d
Determined by GLC or HPLC analysis in comparison to the authentic
sample. 0.1 M in CH3CN. 0.1 M in CH2Cl2. g 0.1 M in DMSO.
e
f
h
Diketone/HCOOH/N(C2H5)3 molar ratio ) 1/4.4/2.6, 24 h, 0.1 M in
i
CH2Cl2. Determined from the sign of rotation of the isolated product.
almost 1:1 ratio and 60% yield. The marked decrease in the
regioselectivity can possibly be attributed to steric factors.
Noticeably, diketone 2c, bearing an electron-donating meth-
oxy group at the para position on the phenyl group, was
exclusively converted to (S)-1-(4′-methoxyphenyl)-2-hy-
droxy-1-propanone 3c with 92% ee in 87% yield because
of the decrease in the reactivity of the benzoyl group
compared with that in unsubstituted 2a. However, diketone
The reduction occurred at the less hindered carbonyl group
in 2a. A mixture of formic acid and triethylamine acts as
both a hydrogen source and a reaction medium to attain
excellent catalyst performance compared with the results
attained in other organic solvents (Table 1). At higher
temperatures, the enantioselectivity and regioselectivity
significantly decreased. The stereochemical outcomes are also
delicately influenced by the structures of the Ru complex as
well as the thermodynamic and kinetic parameters of the
ketonic substrates, although 4a formation is thermodynami-
2
d with electron-withdrawing fluoro atoms gave mainly 4d
with 47% ee in addition to 3d with an excellent enantiomeric
excess, >99% (3d:4d ) 1:2.7 in 79% yield); compound 3d
is a key intermediate of the antifungal agent Sch 42427 (SM
1a
9
164).
11
cally favorable compared with 3a. The TsCYDN-based Ru
complex RuCl[(S,S)-Tscydn](p-cymene) (1e; (S,S)-TsCYDN,
(1S,2S)-N-(p-toluenesulfonyl)-1,2-cyclohexanediamine) ex-
hibited stereoselectivity similar to that attained with 1c albeit
with somewhat lower reactivity. The molar ratio of products
3a to 4a depended on the choice of arene ligand on the
catalyst, decreasing in the order of p-cymene > p-xylene >
mesitylene > benzene. The p-cymene and p-xylene com-
plexes displayed excellent enantioselection in the formation
of 3a.
The general sense of the enantioface discrimination of each
carbonyl group in 2a observed with (S,S)-1c in this asym-
metric reduction is well compared with the results obtained
in the reduction of acetophenone derivatives with the same
catalyst, indicating that the adjacent carbonyl function does
not play any significant role, as was observed in the
In a similar manner, the asymmetric reduction of 1-phenyl-
1,2-butanedione 2b under otherwise identical conditions gave
a mixture of 3b with 95% ee and 4b with 60% ee in an
3834
Org. Lett., Vol. 2, No. 24, 2000

Scheme 2
1
0
11
asymmetric reduction of benzils or acetyl pyridines. Note
that, as exemplified in Table 1, excellent levels of enantio-
selection were observed with formation of the alcohols 3,
but alcohols 4 had lower ee values possibly because of
intrinsic properties of R-hydroxy carbonyl units. In fact,
treatment of optically active (R)-4a (92% ee) in a mixture
2 5 3
N(C H ) ) 3.1/2.6 catalyzed by (S,S)-1c at 40 °C led
preferentially to anti-(1R,2S)-1-phenyl-1,2-propanediol,
(1R,2S)-5a, with >99% ee in 82% yield together with syn-
(1R,2R)-1-phenyl-1,2-propanediol, (1R,2R)-5a, with 45% ee
in 18% yield. In a similar manner, (R)-3a was reduced to
afford mainly syn-(1R,2R)-5a with 96% ee in 86% yield
(Table 2). In contrast, the reaction of racemic 4a with a
2 5 3
of HCOOH/N(C H ) without Ru catalyst at 40 °C resulted
in a rapid racemization along with the formation of 12% of
racemic 3a after 24 h. Experimental results as well as
thermodynamic data12 show that the equilibrium ratio of 4a
Table 2. Asymmetric Transfer Hydrogenation of
R-Hydroxyketones and 1,2-Diketones to 1,2-Diols Catalyzed by
Chiral Ru(II) Complex with Formic Acida
to 3a at 40 °C in CD
optically active 3a (89% ee) did racemize and isomerize to
a to some extent under identical conditions at 40 °C,
CN is ca. 80:20.13 On the other hand,
3
4
product, anti- and syn-5b
14
although it did not change significantly at 10 °C. Therefore,
long exposure of the products in the HCOOH/N(C
yield
(%)
ee,
configc,
2
5 3
H )
ketone
S/C
anti:syn (%)anti,syn
anti, syn
mixture containing Ru catalyst at higher temperature should
be avoided in order to obtain the optically active R-hy-
drokyketones with high enantiomeric purities.
Thanks to characteristic properties of these R-substituted
hydroxy ketones under the reaction conditions, stereoselective
formation of optically active 1,2-diols can be achieved.
Transfer hydrogenation of (S)-3a (89% ee) with a HCOOH/
(
(
S)-3a
R)-3a
200
200
100
100
91
82:18
14:86
19:81
>99, 45
64, 96
74, 83
(1R,2S) (1R,2R)
(1R,2S) (1R,2R)
(1R,2S) (1R,2R)
rac- 4a 500
a
The reaction of 1,2-diphenyl-1,2-propanedione (1.5 mmol) was carried
out with a Ru catalyst (S,S)-1c, ketone/HCOOH/N(C2H5)3 molar ratio )
b
1
/3.1/2.6 at 40 °C, unless otherwise noted. Yield and a anti/syn molar
1
ratio of 5 were determined by H NMR using 1,3,5-trimethoxybenzene as
a internal standard, and the ee values were determined by GLC analysis
using a Chirasil-DEX CB column (25 m) of the acetonide derivative of 5.
c
(9) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J.
Determined from the GLC analysis in comparison to the authentic samples.
Am. Chem. Soc. 1995, 117, 7562-7563. (b) Takehara, J.; Hashiguchi, S.;
Fujii, A.; Inoue, S.; Ikariya, T.; Noyori, R. J. Chem. Soc., Chem. Commun.
1
1
996, 233-234. (c) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics
996, 15, 1087-1089. (d) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya,
T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-2522. (e) Uematsu, N.;
Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996,
configurationally labile stereogenic center under the condi-
tions mentioned in Table 2 gave mainly syn-(1R,2R)-5a with
1
18, 4916-4917. (f) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, A.;
8
3% ee in 74% yield via the dynamic kinetic resolution of
Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285-288. (g) Hashiguchi,
S.; Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 288-290. (h) Matsumura, K.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738-8739. (i)
Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102. (j) Murata,
K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186-2187.
racemic 4a.
Optically active 1,2-diols are readily accessible from the
one-pot reaction of 1,2-diketones by using this practical
asymmetric transfer hydrogenation method. The reaction of
(10) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.; Ikariya,
2
a with a S/C molar ratio of 200 in a HCOOH/N(C
mixture (4.4/2.6) at 40 °C for 24 h gave anti-(1R,2S)-5a with
5% ee and in 78% yield together with syn-(1R,2R)-5a as a
2 5 3
H )
T. Org. Lett. 1999, 1, 1119-1121.
(
(
11) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett., in press.
12) Elphimoff-Felkin. I.; Verrier. M. Bull. Soc. Chim. Fr. 1967, 1052-
9
1
057.
(
13) The treatment of 3a or 4a in a mixture of HCOOH/N(C2H5)3 (3a
or 4a:HCOOH/N(C2H5)3 ) 1:3.1:2.6, 0.1 M in CD3CN) at 40 °C gave a
:1 equilibrium mixture of 4a and 3a after 10 days.
14) Treatment of (R)-3a with 89% ee with a mixture of HCOOH/
minor product as shown in Scheme 2. Optically active 5a is
generated mainly from the enantioselective reduction of the
intermediate 3a and partly from the minor intermediate via
a dynamic kinetic resolution (Scheme 3). Diketone 2c bearing
a methoxy group on the aromatic ring was reduced with high
stereoselectivity to give anti-(1R,2S)-1-(4′-methoxyphenyl)-
4
(
N(C2H5)3 (3a:HCOOH/N(C2H5)3 ) 1:3.1:2.6) at 40 °C for 24 h resulted in
a racemization to 77% ee accompanied with a formation of 14% of 4a.
Reaction of (R)-4a under identical conditions resulted in a complete
racemization with a formation of 12% of racemic 3a.
Org. Lett., Vol. 2, No. 24, 2000
3835

Scheme 3
1
,2-propanediol, anti-5c, which is a major metabolites of
of regio-, diastereo-, and enantioselectivity. The coordina-
tively saturated nature of the Ru(II) complexes 1, as well as
the structural and electronic factors of the substrate, is
responsible for the excellent stereoselective outcome of the
asymmetric reduction.
15
trans-anethole in the rat, with 98% ee and in 90% yield.
This work presents the first successful reductive transfor-
mation of unsymmetrically substituted 1,2-diketones to
1
6
optically active R-hydroxy ketone and anti-1,2-diols. The
reaction is characterized by high stereoselectivity in terms
Acknowledgment. This work was financially supported
by grant-in-aid (12305057) from the Ministry of Education,
Science, Sports and Culture of Japan.
(
15) (a) Ishida, T.; Bounds, S. V. J.; Caldwell, J.; Drake, A.; Takeshita,
T. Tetrahedron: Asymmetry 1996, 7, 3113-3118. (b) Sy, L.-K.; Brown,
G. D. J. Nat. Prod. 1998, 61, 987-992.
(16) Although optically active syn-1,2-diols with extremely high ee’s
are readily accessible using the Sharpless AD reaction of trans-disubstitued
olefins, anti-diols can be obtained with moderate to good ee’s from the
AD reaction of cis-olefins (syn-1-phenyl-1,2-propanediol 5b with 97% ee
vs anti-1-phenyl-1,2-propanediol 5a with 72% ee). (a) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483-
2547. (b) Kolb, H. C.; Sharpless, K. B. Tetrahedron Lett. 1992, 50, 10515-
10530. (c) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568-
7570.
Supporting Information Available: Experimental pro-
cedure for the transfer hydrogenation reaction and analytical
data for the reaction, This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0002572
3836
Org. Lett., Vol. 2, No. 24, 2000