RuCl3/PPh3: An efficient combination for the preparation of chiral 1,3-anti-diols through catalytic hydrogenation

Article abstract of DOI:10.1021/ol062631p

(Chemical Equation Presented) An efficient economical alternative to the commonly used Evans' reagent for the diastereoselective reduction of β-hydroxy ketones is reported. Thus, ruthenium-mediated hydrogenation of enantioenriched β-hydroxy ketones using

Full text of DOI:10.1021/ol062631p

ORGANIC
LETTERS
2007
Vol. 9, No. 1
105-108
RuCl3/PPh3: An Efficient Combination
for the Preparation of Chiral
1,3-anti-Diols through Catalytic
Hydrogenation
Olivier Labeeuw, Christophe Roche, Phannarath Phansavath,* and
Jean-Pierre Geneˆt*
Laboratoire de Synthe`se Se´lectiVe Organique et Produits Naturels UMR 7573 CNRS,
ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
jean-pierre-genet@enscp.fr
Received October 26, 2006
ABSTRACT
An efficient economical alternative to the commonly used Evans’ reagent for the diastereoselective reduction of
â-hydroxy ketones is reported.
Thus, ruthenium-mediated hydrogenation of enantioenriched
â-hydroxy ketones using RuCl3 associated to achiral monophosphines allowed
the preparation of a series of 1,3-anti-diols in good yields and with a high level of diastereoselectivity. A short screening of ligands pointed
out PPh3 as the most effective phosphine, and PCy3 afforded the 1,3-diols with an unexpected moderate syn selectivity.
The stereoselective synthesis of 1,3-diols is of particular
interest due to the prominence of this motif within many
classes of natural products.1 Among the procedures developed
for the obtention of acyclic 1,3-diols,2 metal hydride reduc-
tion of 1,3-diones3 and transition-metal-catalyzed hydrogena-
tion reactions of 1,3-diketones4 and 3,5-dioxoesters5 have
been reported. Apart from these methods, the diastereose-
lective reduction of â-hydroxy ketones is particularly attrac-
tive because both syn- and anti-1,3-diols can be prepared
depending on the hydride reagents and the reaction condi-
tions. The most commonly used methods for the reduction
to syn-diols involve either the Bu3B/NaBH4 combination
developed by Narasaka and Pai6 or the modified Et2BOMe/
(4) Ru catalysts: (a) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am.
Chem. Soc. 1988, 110, 629. (b) Kawano, H.; Ishii, Y.; Saburi, M.; Uchida,
Y. J. Chem. Soc., Chem. Commun. 1988, 87. (c) Mezzetti, A.; Tschumper,
A.; Consiglio, G. J. Chem. Soc., Dalton Trans. 1995, 49. (d) Brunner, H.;
Terfort, A. Tetrahedron: Asymmetry 1995, 6, 919. (e) Blanc, D.; Ratovelo-
manana-Vidal, V.; Marinetti, A.; Geneˆt, J.-P. Synlett 1999, 480. (f) Stritzke,
K.; Schulz, S.; Nishida, R. Eur. J. Org. Chem. 2002, 3884. (g) Cossy, J.;
Eustache, F.; Dalko, P. I. Tetrahedron Lett. 2001, 42, 5005. (h) Poss, C.
S.; Rychnovsky, S. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 3360.
(i) Mezzetti, A.; Consiglio, G. J. Chem. Soc., Chem. Commun. 1991, 1675.
(j) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. J. Org.
Chem. 1991, 56, 5161. (k) Pini, D.; Mandoli, A.; Iuliano, A.; Salvadori, P.
Tetrahedron: Asymmetry 1995, 6, 1031. Ni catalysts: (l) Ito, K.; Harada,
T.; Tai, A.; Izumi, Y. Chem. Lett. 1979, 1049. (m) Ito, K.; Harada, T.; Tai,
A. Bull. Chem. Soc. Jpn. 1980, 53, 3367. (n) Sugimura, T.; Yoshikawa,
M.; Yoneda, T.; Tai, A. Bull. Chem. Soc. Jpn. 1990, 63, 1080. (o) Tai, A.;
Kikukawa, T.; Sugimura, T.; Inoue, Y.; Osawa, T.; Fujii, S. J. Chem. Soc.,
Chem. Commun. 1991, 795.
(1) (a) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021. (b) Schneider, C.
Angew. Chem., Int. Ed. 1998, 37, 1375.
(2) For reviews on stereoselective synthesis of 1,3-diols, see: (a) Bode,
S. E.; Wolberg, M.; Mu¨ller, M. Synthesis 2006, 557. (b) Oishi, T.; Nakata,
T. Synthesis 1990, 635.
(3) (a) Maier, G.; Roth, C.; Schmitt, R. K. Chem. Ber. 1985, 118, 704.
(b) Maier, G.; Schmitt, R. K.; Seipp, U. Chem. Ber. 1985, 118, 722. (c)
Barluenga, J.; Resa, J. G.; Olano, B.; Fustero, S. J. Org. Chem. 1987, 52,
1425. (d) Ravikumar, K. S.; Sinha, S.; Chandrasekaran, S. J. Org. Chem.
1999, 64, 5841. (e) Bartoli, G.; Bosco, M.; Bellucci, M. C.; Dalpozzo, R.;
Marcantoni, E.; Sambri, L. Org. Lett. 2000, 2, 45. (f) Ohtsuka, Y.; Kubota,
T.; Ikeno, T.; Nagata, T.; Yamada, T. Synlett 2000, 535. (g) Benedetti, F.;
Berti, F.; Donati, Y.; Fregonese, M. Chem. Commun. 2002, 828.
(5) (a) Blandin, V.; Carpentier, J.-F.; Mortreux, A. Eur. J. Org. Chem.
1999, 1787. (b) Blandin, V.; Carpentier, J.-F.; Mortreux, A. Eur. J. Org.
Chem. 1999, 3421. (c) Blandin, V.; Carpentier, J.-F.; Mortreux, A. New J.
Chem. 2000, 24, 309. (d) Shao, L.; Seki, T.; Kawano, H.; Saburi, M.
Tetrahedron Lett. 1991, 32, 7699. (e) Shao, L.; Kawano, H.; Saburi, M.;
Uchida, Y. Tetrahedron 1993, 49, 1997.
10.1021/ol062631p CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/10/2006

NaBH4 system reported by Prasad.7 On the other hand, 1,3-
anti-diols are most usually prepared from the corresponding
â-hydroxy ketones by reaction with the mild reducing agent,
tetramethylammonium triacetoxyborohydride (commonly
named Evans’ reagent).8 Although good to excellent dias-
tereoselectivities can be achieved with this method, the use
of boron reagents remains prohibitive on a preparative scale
due to economic and environmental concerns.
Herein, we report an operationally simple and waste-free
method for diastereoselective hydrogenation9 of â-hydroxy-
ketones into 1,3-anti-diols, using an inexpensive RuCl3/
phosphine combination.10
Initial studies of the influence of reaction conditions were
carried out with 1a as the standard substrate and PPh3 as a
ligand. The hydrogenation reaction was first examined in
methanol using 2 mol % of RuCl3 and 4 mol % of PPh3
(Table 1).
conversion was actually achieved at 50 °C and under 10 bar
of hydrogen pressure (entry 3). Under these conditions, high
anti diastereoselectivity (91% de) was obtained. Decreasing
the hydrogen pressure to 4 bar afforded low conversion (entry
4).
A short screening of solvents showed that MeOH was the
solvent of choice for the hydrogenation reaction in terms of
both conversion and selectivity because, using the optimized
reaction parameters, we obtained low conversions and
unsatisfactory diastereomeric excesses in CH2Cl2, hexane,
or toluene (entries 5-7).
To increase the selectivity of the reaction, we next focused
our attention on the influence of the monophosphine ligands
in the hydrogenation of 1a using various phosphines under
the optimized conditions (Table 2).
Table 2. Hydrogenation of 1a in the Presence of RuCl3/PR3
a
Table 1. Hydrogenation of 1a in the Presence of RuCl3/PPh3
θ
conversion
(%)c
de
b
entry
phosphinea
PPh3
P(p-MeC6H4)3
(°)b
pKa
(%)d
time
(h)
P
(bar)
temp
(°C)
conversion
(%)b
de
1
2
3
4
5
6
7
8
9
145
145
2.73
3.84
4.59
1.03
100
80
77
100
78
5-10
50
91 (anti)
90 (anti)
89 (anti)
74 (anti)
90 (anti)
ndf
83 (anti)
23 (anti)
27 (syn)
entry
solvent
(%)c
P(p-MeOC6H4)3 145
1
2
3
4
5
6
7
MeOH
MeOH
MeOH
MeOH
CH2Cl2
hexane
toluene
72
72
24
48
24
24
24
10
100
10
4
10
10
10
25
25
50
50
50
50
50
30
88
100
35
61
16
ndd
83
91
ndd
44
P(p-ClC6H4)3
P(m-MeC6H4)3
P(o-MeC6H4)3
PPh2Cy
PPhCy2
PCy3
145
148
178
153
162
170
3.30
e
-
5.05
e
-
30
75
59
62
9.70
10
a In the absence of phosphine, no reduction was observed. b Values of
cone angles (θ) and pKa are taken from the literature.12 c Conversions were
determined by 1H NMR spectroscopy of the crude product. d de determined
by HPLC analysis. e Unknown. f de not measured.
a Conditions: 1a (0.5 mmol), solvent (2 mL), RuCl3 (10 µmol), PPh3
(20 µmol). b Conversions were determined by 1H NMR spectroscopy of
the crude product. c de determined by HPLC analysis, chiralcel OD-H
column, hexane/iPrOH 95:5, flow rate of 1 mL/min. An authentic sample
of the 1,3-anti-diol 2a was obtained by reduction of 1a with Me4NBH(OAc)3,
and an authentic sample of the 1,3-syn-diol was prepared by reduction with
Et2BOMe/NaBH4. The identities of the diastereomers were established on
the correspoding acetonides using the protocol reported by Rychnovsky.11
d de not measured.
A comparison of various triarylphosphines has first been
studied (entries 1-6). Phosphines such as P(p-MeC6 H4)3,
P(p-MeOC6 H4)3, and P(m-MeC6 H4)3 afforded high diaste-
reoselectivities albeit lower conversions (77-80% conver-
sion, 89-90% de, entries 2, 3, and 5), whereas P(o-Me C6
H4)3 led to very poor conversion presumably due to the
higher steric hindrance (entry 6). On the other hand, the less
electron-rich phosphine P(p-ClC6H4)3 yielded complete
conversion but lower diastereomeric excess (74% de, entry
4). For phosphines bearing the same cone angle value (145°),
an increase of the pKa values has no effect on the diaste-
reoselectivity (entries 1-3). Indeed, for basic phosphines
such as P(p-MeC6H4)3 and P(p-MeOC6H4)3, the diastereo-
selectivity of the hydrogenation (89-90% de) remains similar
to that obtained with PPh3. On the contrary, a less basic
When the reaction was run at room temperature, conver-
sions were incomplete under either low or high pressures of
hydrogen (10 or 100 bar, respectively, entries 1 and 2). Full
(6) (a) Narasaka, K.; Pai, F. C. Chem. Lett. 1980, 1415. (b) Narasaka,
K.; Pai, F. C. Tetrahedron 1984, 40, 2233.
(7) (a) Kathawala, F. G.; Prager, B.; Prasad, K.; Repic, O.; Shapiro, M.
J.; Stabler, R. S.; Widler, L. HelV. Chim. Acta 1986, 69, 803. (b) Chen, K.
M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Chem. Lett. 1987, 1923. (c) Chen, K. M.; Hardtmann, G. E.; Prasad,
K.; Repic, O.; Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.
(8) (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939.
(b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
110, 3560.
(9) For reviews on asymmetric hydrogenation, see: (a) Noyori, R.;
Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40. (b) Ohkuma, T.; Kitamura,
M.; Noyori, R. Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley: VCH,
2000. (c) Geneˆt, J.-P. Acc. Chem. Res. 2003, 36, 908.
(11) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511.
(10) For an initial report on asymmetric hydrogenation of â-keto esters
using RuCl3/chiral diphosphines, see: Madec, J.; Pfister, X.; Phansavath,
P.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P. Tetrahedron 2001, 57, 2563.
(12) (a) Rahman, M. M.; Liu, H.-Y.; Eriks, K.; Prock, A.; Giering, W.
P. Organometallics 1989, 8, 1. (b) Woska, D.; Prock, A.; Giering, W. P.
Organometallics 2000, 19, 4629.
106
Org. Lett., Vol. 9, No. 1, 2007

phosphine such as P(p-ClC6H4)3 afforded a lower diastereo-
meric excess (74% de, entry 4).
methylallyl)2 and the diphosphine. Thus, using dppe (1,2-
bis(diphenylphosphino)ethane) or dppb (1,4-bis(diphenylphos-
phino)butane) as achiral diphosphines, the reaction proceeded
quantitatively and delivered the corresponding 1,3-anti-diols
with good diastereoselectivities (91% de in both cases).
The hydrogenation reaction of compound 1a was also
examined with monophosphines bearing one or more alkyl
substituents, namely, PPh2Cy, PPhCy2, and PCy3. Given the
steric hindrance brought by the cyclohexyl group, the
reduction of 1a with the aforementioned phosphines afforded
the corresponding diol with only moderate conversions, up
to 75% (entries 7-9). In the case of PPh2Cy, the formal
exchange of a phenyl ring by a cyclohexyl group led to a
decrease in diastereoselectivity (from 91% de for PPh3 to
83% de for PPh2Cy, anti isomer, entries 1 and 7). Further-
more, a considerable decrease of diastereoselectivity was
observed when switching from PPh2Cy to PPhCy2 (from 83
to 23% de, anti isomer, entries 7 and 8). Even more
remarkable is the reversal of stereoselectivity observed with
PCy3 because in this case the 1,3-syn-diol was the major
product of the reaction (27% de for the 1,3-syn-diol, entry
9). From these data, an increase in the cone angle values
results in a decrease of the diastereoselectivity.
Finally, in an attempt to establish the scope of the RuCl3/
PPh3-promoted hydrogenation, a series of â-hydroxy ketones
1a-g bearing various substitution patterns were synthe-
sized.14 These compounds were subjected to hydrogenation
reactions under the established standard conditions, and good
to high diastereoselectivities were achieved (Table 3). Thus,
Table 3. Diastereoselective Hydrogenation of Compounds
1a-f in the Presence of RuCl3/PPh3
A correlation between the cone angles and the stereo-
chemical issues of the hydrogenation reactions of compound
1a with PPh3, PPh2Cy, PPhCy2, and PCy3 is best visualized
in Figure 1. Such a significant decrease in selectivity upon
moving from PPh3 to PCy3 is unclear at present.
Figure 1. Correlation between the cone angles and the diastereo-
selectivity of the catalytic hydrogenation with PPh3, PPh2Cy,
PPhCy2, and PCy3.
a For the determination of the de, samples of diastereomerically enriched
1,3-syn-diols 2 were prepared by reduction of 1 with Et2BOMe/NaBH4.
b de determined by HPLC analysis. c de obtained after reduction of 1 with
tetramethylammonium triacetoxyborohydride. d de determined by GC analy-
sis on the corresponding Mosher diesters.
Achiral diphosphines have been used as well in the
hydrogenation reaction of compound 1a. However, the
RuCl3/diphosphine combination failed to afford complete
conversion owing to the lower activity of the relevant
ruthenium complex. The hydrogenation reactions of 1a were
therefore conducted under the above-mentioned standard
conditions using the more active [Ru(PP)Br2] complexes,13
prepared in situ from commercially available (COD)Ru(2-
a series of variously substituted 1,3-anti-diols 2a-g have
been prepared through this procedure.15 High yields were
obtained in the hydrogenation of â-hydroxy ketones 1a-e
(13) For preparation of the [Ru(P*P)Br2] complexes using chiral diphos-
phines, see: Genet, J.-P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart,
S.; Can˜o de Andrade, M. C.; Laffite, J. A. Tetrahedron: Asymmetry 1994,
5, 665.
(14) Compounds 1a-g were prepared from the corresponding enantio-
merically pure â-hydroxyesters, through addition of alkyllithium reagents
on the related Weinreb amides.
Org. Lett., Vol. 9, No. 1, 2007
107

bearing phenyl or benzyloxy groups as well as linear and
branched alkyl substituents (entries 1-5). The diastereose-
lectivities observed for the corresponding 1,3-anti-diols were
uniformly high (91-97% de). Starting from â-hydroxy
ketone 1f, the enantiomer of 1a, the corresponding anti-diol
2f was obtained in high yield and, as could be expected,
with comparable diastereoselectivity (89% de, entry 6 vs 91%
de, entry 1). The presence of a methyl substituent in the R
position had no effect on the hydrogenation reaction because
high anti selectivity was obtained in the reduction of
compound 1g (94% de, entry 7). For comparison, a number
of â-hydroxy ketones have also been reduced using tetram-
ethylammonium triacetoxyborohydride. In all cases, the
RuCl3/PPh3-mediated hydrogenation afforded the 1,3-anti-
diols with comparable selectivities (entries 1, 2, and 4) or
even significantly higher de’s (97% vs 80%, entry 3).
In conclusion, we have shown that monodentate achiral
phosphine ligands can be used efficiently for the ruthenium-
catalyzed diastereoselective hydrogenation of â-hydroxy
ketones. This catalytic procedure, involving the RuCl3/PPh3
combination, is highly preparative in nature, avoids the use
of expensive tetramethylammonium triacetoxyborohydride,
and tolerates varied hydroxyketone structures. This method
should be an interesting alternative to boron reagents for the
preparation of 1,3-anti-diols and is particularly suitable for
large-scale reactions.
Acknowledgment. O.L. and C.R. are grateful to the
Ministe`re de l’Education Nationale et de la Recherche for a
grant (2001-2004 and 2005-2008, respectively). This work
was partially supported by a grant from CPER (2000-2006
action 10040 ‘Poˆle Chimie du Vivant’) and from SESAME
(2003-2006, E1767 ‘De´veloppement du Poˆle Chimie du
Vivant a` l’ENSCP: de la chimie mole´culaire a` la biotech-
nologie’).
(15) Typical procedure for the hydrogenation reaction: hydroxyketone
1 (0.5 mmol) was purged by three vacuum/argon cycles, dissolved in
degassed methanol (2 mL), and transferred via cannula to a round-bottomed
tube containing a degassed mixture of RuCl3 (2.1 mg, 10 µmol) and PPh3
(5.2 mg, 20 µmol). The reaction vessel was placed in a stainless steel
autoclave which was purged with hydrogen and pressurized to 10 bar. The
autoclave was heated to 50 °C by circulating thermostated water in the
double wall, and magnetic stirring was started as soon as the required
temperature was reached. After stirring for 24 h, the autoclave was cooled
to room temperature. Hydrogen was vented, and the reaction mixture was
concentrated in vacuo.
Supporting Information Available: Complete spectro-
scopic data for compounds 2a-g. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL062631P
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