Ruthenium-catalyzed asymmetric reduction of 1,3-diketones using transfer hydrogenation

Article abstract of DOI:10.1016/S0040-4039(01)00906-6

1,3-Diketones were reduced to 1,3-diols by using RuCl[N-(tosyl)-1,2-(diphenylethylenediamine) (η⁶-arene)] in the presence of formic acid and triethylamine. 1,3-Diols were obtained in good chemical yields and with high ee when symmetrical diketo

Full text of DOI:10.1016/S0040-4039(01)00906-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5005–5007
Ruthenium-catalyzed asymmetric reduction of 1,3-diketones using
transfer hydrogenation
Janine Cossy,* Florence Eustache and Peter I. Dalko
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 7 May 2001; accepted 26 May 2001
Abstract—1,3-Diketones were reduced to 1,3-diols by using RuCl[N-(tosyl)-1,2-(diphenylethylenediamine) (h6-arene)] in the
presence of formic acid and triethylamine. 1,3-Diols were obtained in good chemical yields and with high ee when symmetrical
diketones were reduced. © 2001 Elsevier Science Ltd. All rights reserved.
Catalytic asymmetric hydrogenation using chiral ruthen-
ium complexes is a powerful method of producing
chiral alcohols and amines with excellent enantioselec-
tivity.1 Highly efficient chiral diamine-based Ru(II) cat-
alysts such as RuCl[N-(arylsulfonyl) cyclohexyl-
1,2-diamine) (h6-arene)] or RuCl[N-(arylsulfonyl)-1,2-
(diphenylethylenediamine) (h6-arene)] complexes have
been developed either for catalytic hydrogenation under
H2 pressure or transfer hydrogenation using 2-propanol
or formic acid.2 Here, we report a practical asymmetric
reduction of 1,3-diketones to the corresponding 1,3-
diols with good diastereo- and enantioselectivities,
using a catalytic amount of RuCl[(N-arylsulfonyl)-1,2-
diamine (p-cymene)] complexes A–D in the presence of
Et3N and formic acid (Schemes 1 and 2).
The reduction of 1,3-diphenyl-1,3-propanedione 1a (R1
and R2=Ph) with catalyst A (0.05 equiv.) in the pres-
ence of Et3N (2.0 equiv.) and formic acid (5.0 equiv.) in
CH2Cl2, DMF or under solvent free conditions
afforded an inseparable mixture of anti- and syn-1,3-
diols 2a and 3a. The products were transformed to the
corresponding ketals 4a and 5a that were separated.
The enantiomeric purity of ketal 4a, and consequently
of diol 2a, was established by chiral HPLC.3 The
absolute configurations of the newly formed stereocen-
ters were determined by X-ray diffraction of the corre-
sponding Mosher’s esters.4 According to these results
the (S,S)-A complex gives rise to the (S,S)-diol 2a. The
results are summarized in Table 1.
The influence of solvent and temperature on the selec-
tivity of the reaction was examined using catalyst A
(Table 1). Best results were obtained in CH2Cl2 at 25°C
(entry 2) and 50°C (entry 3). When the reaction was
performed either in DMF (entry 4) or without solvent
(entry 5), diols 2a and 3a were obtained in poor to
modest yields. Although the rate of the reaction
increased with the temperature (entries 1–3), the com-
R
N
Tf
N
Ph
Ph
B R = Tf
C R = Mes
D R = Ts
A
Ru
Ru
N
H2
N
H2
Cl
Cl
Scheme 1.
OMe
+
OMe
,
H
OH OH
R2
OH OH
R2
O
O
O
O
O
O
RuClLn* (5%)
R1
R1
R2
R1
R2
R2
R1
HCO2H
Et3N
R1
3
2
1
4
5
solvent
Scheme 2.
Keywords: 1,3-diketones; 1,3-diols; reduction; ruthenium; catalyst.
* Corresponding author. Fax: +33 (01)1 4079 46 60; e-mail: janine.cossy@espci.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00906-6

5006
J. Cossy et al. / Tetrahedron Letters 42 (2001) 5005–5007
Table 1. Reduction of 1,3-diketone 1a in the presence of catalyst A
Entry
Solvent
T (°C)
Time
Yield (%)5 (2a+3a)
dr (2a:3a)
ee (%) (4a)
1
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
DMF
0
25
50
40
25
4 days
5 days
6 h
3 days
3 days
0
79
80
12
63
–––
–––
96
95
95
96
83:17
76:24
73:27
71:29
None
Table 2. Reduction of 1,3-diketone 1a using catalysts (S,S)-B, C or D
Entry
Catalyst
T (°C)
Time (h)
Yield (%)5 (2a+3a)
dr (2a:3a)
ee (%) (4a)
Config. (4a)
1
2
3
4
5
B
B
C
D
D
25
50
25
25
50
48
3.5
72
48
4
96
91
48
95
83
97:3
86:14
98:2
95:5
98.5:1.5
99.0
99.0
99.7
99.7
99.8
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
bined yields of 2a/3a as well as the diastereo- and
enantioselectivity of the reaction were not affected con-
siderably. According to these results, optimum condi-
tions for the reduction of ketone 1a (dr=76/24; ee for
the (d,l) compound 2a=95%) are the use of CH2Cl2 at
a temperature of 50°C. Hoping to improve the
Table 3. Reduction of ketones 1b–e using catalyst (S,S)-D. Reaction conditions: CH2Cl2 at 50°C for 6 h
Products
Anti/Syn
Yield
(%)
Starting material
Entry
(ee)
OH OH
O
O
OH OH
95/5
85
O
O
O
O
O
O
1
(S)
(S)
*
1b
2b
3b
OH OH
O
O
OH OH
58/42
79
2
(S) (R)
1c
2c
3c
(ee = 83%)
OH OH
OH OH
O
O
91
57/43
3
(R)
(S)
2d
*
1d
3d
OH OH
OH OH
O
O
2e/3e/3e'
3e
70 /15/15
4
(S) (S)
OH OH
1e
2e
(ee = 94.5%)
3e'
* ee not determined.

J. Cossy et al. / Tetrahedron Letters 42 (2001) 5005–5007
5007
diastereomeric ratio, we examined catalysts B, C and D
in CH2Cl2 at 25 and 50°C. The results are reported in
Table 2.
As chiral 1,3-diols are useful building blocks, their
transformation to biologically active compounds is
under investigation and the results will be reported in
due course.
As observed previously, the chemical yield as well as
the diastero- and the enantioselectivity of the reduction
of 1a were not affected considerably by the tempera-
ture. The best dr and ee values were obtained using
catalyst D in CH2Cl2 at 50°C (entry 5) (dr=98.5/1.5, ee
(2a)=99.8%). Consequently the enantioselective reduc-
tion of 1,3-diketones was generalized to substrates 1b–
1e under these conditions. The results are summarized
in Table 3.
Acknowledgements
F.E. would like to thank Rhodia for a grant.
References
When the reduction of 1b was effected with catalyst D,
diols 2b and 3b were obtained in a ratio of 95/5 and
with a yield of 85% (entry 1). Unfortunately, the ee of
2b could not be determined at the diol stage or by
transforming them to their corresponding ketals as they
polymerized under acidic conditions. In the case of
compound 1c, diols 2c and 3c were isolated as a 58/42
mixture in 79% yield. The enantioselectivity of 2c was
measured from the corresponding ketals3 (83%) and the
absolute configuration (S,R) of the newly created cen-
ters were assigned by comparing the optical rotation
with the literature data.6
1. For a recent review, see: (a) Noyori, R.; Ohkuma, T.
Angew. Chem., Int. Ed. 2001, 40, 40–73. See also (b) Pai,
C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S. C.
J. Am. Chem. Soc. 2000, 122, 11523–11514; (c) Geneˆt,
J.-P.; Ratovelomanana-Vidal, V.; Pinel, C. Synlett 1993,
478–480; (d) Ohkuma, T.; Doucet, H.; Pham, T.; Mikami,
K.; Korenaga, T.; Terada, M.; Noyori, R. J. Am. Chem.
Soc. 1998, 120, 1086–1087; (e) Halle, R.; Schulz, E.;
Spagnol, M.; Lemaire, M. Synlett 2000, 680–682; (f)
Krasik, P.; Alper, H. Tetrahedron 1994, 50, 4347–4354; (g)
Schwink, L.; Ireland, T.; Pu¨ntener, K.; Knochel, P. Tetra-
hedron: Asymmetry 1998, 9, 1143–1163; (h) Ohkuma, T.;
Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori, R. J. Org.
Chem. 1996, 61, 4872–4873; (i) Everaere, K.; Scheffler,
J.-L.; Montreux, A.; Carpentier, J.-F. Tetrahedron Lett.
2001, 42, 1899–1901; (j) Jung, H.; Koh, J. H.; Kim, M.-J.;
Park, J. Org. Lett. 2000, 2, 2487–2490.
When dione 1d was transformed to diols 2d and 3d
using catalyst D, the products were obtained in high
yield (91%) but the diastereoselectivity was low (dr=
57/43). When 1e was reduced using catalyst D under
standard conditions three products, 2e, 3e and 3e%, were
isolated in 55% combined yield, in a ratio of 70/15/15.
The enantiomeric excess of 2e was measured from the
corresponding ketal 4e (ee=94.5%) using chiral
HPLC.3 The absolute configuration of the newly cre-
ated stereogenic centers were determined by X-ray dif-
fraction of the corresponding Mosher’s ester.4
2. (a) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675–
678; (b) Koike, T.; Murata, K.; Ikariya, T. Org. Lett.
2000, 2, 3833–3836.
3. Columns: Daicel CHIRALCEL OJ and OD-H; solvents:
hexane/2-propanol 50:50–99:1; flow rate: 0.2–0.6 mL/min;
detection UV at 220 nm.
4. The Mosher’s esters were prepared using (COCl)2 activa-
tion: Bergeron, R. J.; Mu¨ller, R.; Bussenius, J.; McManis,
J. S.; Merriman, R. L.; Smith, R. E.; Yao, H.; Weimar, W.
R. J. Med. Chem. 2000, 43, 224–235.
It is worth noting that the reduction of symmetrically
substituted 1,3-diaryl-1,3-diketones afforded diols of
reasonably high dr and ee (up to 90%) compared to
unsymmetrically substituted 1,3-diketones (i.e. when
alkyl and aromatic group were present in the a-posi-
tions). The diastereomeric ratios of diols from these
reductions were considerably lower (57/43 and 58/42).
5. Isolated yields. Satisfactory analytical data (1H NMR, 13C
NMR, MS) were obtained for all compounds.
6. Chan, T. H.; Nwe, K. T. J. Org. Chem. 1992, 57, 6107–
6111.
.