Highly diastereo-and enantioselective synthesis of monodifferentiated syn-1,2-diol derivatives through asymmetric transfer hydrogenation via dynamic kinetic resolution

Article abstract of DOI:10.1021/ol101451s

The first enantio-and diastereoselective approach to α-alkoxy- substituted syn-β-hydroxyesters through highly efficient catalytic asymmetric transfer hydrogenation via dynamic kinetic resolution reactions from the corresponding racemic β-ketoesters is described. In this atom-economical process, two contiguous stereogenic centers are generated simultaneously with an excellent diastereoselectivity (up to 99/1) and enantioselectivity (up to 99%), allowing a rapid access to a wide variety of aromatic and heteroaromatic monodifferentiated syn-1,2-diols.

Full text of DOI:10.1021/ol101451s

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3788-3791
Highly Diastereo- and Enantioselective
Synthesis of Monodifferentiated
syn-1,2-Diol Derivatives through
Asymmetric Transfer Hydrogenation via
Dynamic Kinetic Resolution
Damien Cartigny,† Kurt Pu¨ntener,‡ Tahar Ayad,† Michelangelo Scalone,‡ and
Virginie Ratovelomanana-Vidal*,†
Laboratoire Charles Friedel, UMR 7223, ENSCP Chimie ParisTech, 11 rue Pierre et
Marie Curie, 75231 Paris Cedex 05, France, and Process Research & Synthesis CoE
Catalysis, F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland
Virginie-Vidal@chimie-paristech.fr
Received June 24, 2010
ABSTRACT
The first enantio- and diastereoselective approach to r-alkoxy-substituted syn-ꢀ-hydroxyesters through highly efficient catalytic asymmetric
transfer hydrogenation via dynamic kinetic resolution reactions from the corresponding racemic ꢀ-ketoesters is described. In this atom-
economical process, two contiguous stereogenic centers are generated simultaneously with an excellent diastereoselectivity (up to 99/1) and
enantioselectivity (up to 99%), allowing a rapid access to a wide variety of aromatic and heteroaromatic monodifferentiated syn-1,2-diols.
Chiral 1,2-diols are important structural motifs present in
many natural products, such as carbohydrates, polyketides,
or alkaloids,1 and have found wide applications in organic
synthesis either as chiral ligands or auxiliaries.2 Several
efficient synthetic approaches to chiral 1,2-diols have already
been reported;3 however, most of them suffer from the fact
that the resulting two hydroxyl groups were not differenti-
ated. Thus, the synthesis of monodifferentiated diols remains
a challenge. In 2008, a catalytic glycolate aldol route to the
preparation of stereodefined differentiated 1,2-diols have been
reported by Denmark et al.4 Remarkably, both syn- and anti-
1,2-diols can be obtained under the same catalytic system.
However, conversion of the ester moiety to a more reactive
silyl ketene acetal as well as the need of a stoichiometric
amount of SiCl4 are an unavoidable necessity, which
significantly decreases the overall reaction efficiency. Myers
et al.5 have recently reported the synthesis of optically pure
(3) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (b) Shi, Y. Acc. Chem. Res. 2004, 37, 488. (c) Ikariya,
T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393. (d) Guillena,
G.; Najera, C.; Ramon, D. Tetrahedron: Asymmetry 2007, 18, 2249. (e)
Tanaka, F.; Barbas, C. F., III. In EnantioselectiVe Organocatalysis, Reaction
and Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007; pp 19-55. (f) Jiao, P.; Kawasaki, M.; Yamamoto, H. Angew. Chem.,
Int. Ed. 2009, 48, 1.
† ENSCP Chimie ParisTech.
‡ Hoffmann-La Roche.
(1) (a) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. ReV. 1995,
95, 1677. (b) Fu, G. C. In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley-VCH: Weinheim, 2000; pp 69-91.
(2) Seyden-Penn, J. In Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley-VCH: Weinheim, 1995.
(4) Denmark, S. E.; Chung, W.-J. Angew. Chem., Int. Ed. 2008, 47,
1890.
(5) Lim, S. M.; Hill, N.; Myers, A. G. J. Am. Chem. Soc. 2009, 131,
5763.
10.1021/ol101451s  2010 American Chemical Society
Published on Web 07/30/2010

cyclic anti-1,2-diol monosilyl ether derivatives in high
isolated yields and good to excellent selectivities using an
epoxidation-reduction sequence. However, this route has
some disadvantages that limits its practicality such as the
use of a high catalyst loading (30 mol %) combined with an
excess of reagents. In addition, this method remains es-
sentially restricted to cyclic silyl enol derivatives. Therefore,
the development of new catalytic highly enantio- and
diastereoselective transformations to access optically pure
monodifferentiated 1,2-diols with a high level of selectivity
and a high atom efficiency is still in great demand. We6 and
others7 have previously demonstrated that dynamic kinetic
resolution (DKR)8 in association with ruthenium-catalyzed
asymmetric hydrogenation turned out to be an elegant and
powerful synthetic tool to control two adjacent stereogenic
centers in one single chemical operation and with high atom
efficiency. We envisaged that the combination of DKR
techniques with the asymmetric transfer hydrogenation9 of
readily available racemic R-alkoxy-substituted ꢀ-ketoesters
could provide a conceptually new and straightforward route
to the preparation of stereodefined monodifferentiated 1,2-
diols units. To the best of our knowledge, such an approach
has never been reported in the literature.10
Our initial investigations concentrated on the evaluation
of various diamine-based Ru(II) catalysts 3a-h, in order to
identify the most suitable catalyst system for the asymmetric
transfer hydrogenation of racemic R-methoxy ꢀ-ketoester 1a
(Table 1). These preliminary experiments were carried out
Table 1. Screening of Diamine-Based Ru (II) Catalystsa
(6) (a) Genet, J.-P.; Mallart, S.; Juge, S. French Patent 8 911 159, 1989.
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Ratovelomanana-Vidal, V.; Genet, J.-P. Eur. J. Org. Chem. 2000, 3903.
(f) Lavergne, D.; Mordant, C.; Ratovelomanana-Vidal, V.; Genet, J.-P. Org.
Lett. 2001, 3, 1909. (g) Scalone, M.; Waldmeier, P. Org. Process Res. DeV.
2003, 7, 418. (h) Mordant, C.; Du¨nkelman, P.; Ratovelomanana-Vidal, V.;
Genet, J.-P. Chem. Commun. 2004, 1296. (i) Mordant, C.; Du¨nkelman, P.;
Ratovelomanana-Vidal, V.; Genet, J.-P. Eur. J. Org. Chem. 2004, 3017.
(j) Labeeuw, O.; Phansavath, P.; Genet, J.-P. Tetrahedron: Asymmetry 2004,
15, 1899. (k) Mordant, C.; Reymond, S.; Tone, H.; Lavergne, D.; Touati,
R.; Ben Hassine, B.; Ratovelomanana-Vidal, V.; Genet, J.-P. Tetrahedron
2007, 63, 6115. (l) Tone, H.; Buchotte, M.; Mordant, C.; Guittet, E.; Ayad,
T.; Ratovelomanana-Vidal, V. Org. Lett. 2009, 11, 1995. (m) Pre´vost, S.;
Gauthier, S.; Can˜o de Andrade, M. C.; Mordant, C.; Touati, A. R.; Lesot,
P.; Savignac, P.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V.; Genet,
J.-P. Tetrahedron: Asymmetry 2010, DOI: 10.1016/j.tetasy.2010.05.017.
(7) For selected references, see: (a) Noyori, R.; Ikeda, T.; Ohkuma, T.;
Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito,
T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134.
(b) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115,
144. (c) Mohar, B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.;
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Dalko, P. I. Tetrahedron Lett. 2001, 42, 5005. (e) Eustache, F.; Dalko, P. I.;
Cossy, J. Org. Lett. 2002, 4, 1263. (f) Eustache, F.; Dalko, P. I.; Cossy, J.
J. Org. Chem. 2003, 68, 9994. (g) Makino, K.; Goto, T.; Hiroki, Y.; Hamada,
Y. Angew. Chem., Int. Ed. 2004, 43, 882. (h) Makino, K.; Hiroki, Y.;
Hamada, Y. J. Am. Chem. Soc. 2005, 127, 5784. (i) Ito, M.; Kitahara, S.;
Ikariya, T. J. Am. Chem. Soc. 2005, 127, 6172. (j) Ros, A.; Magriz, A.;
Dietrich, H.; Ford, M.; Fernandez, R.; Lassaletta, J. M. AdV. Synth. Catal.
2005, 347, 1917. (k) Ros, A.; Magriz, A.; Dietrich, H.; Fernandez, R.;
Alvarez, E.; Lassaletta, J. M. Org. Lett. 2006, 8, 127. (l) Fernandez, R.;
Ros, A.; Magriz, A.; Dietrich, H.; Lassaletta, J. M. Tetrahedron 2007, 63,
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Tetrahedron 2007, 63, 7532. (n) Makino, K.; Iwasaki, M.; Hamada, Y.
Org. Lett. 2006, 8, 4573. (o) Arai, N.; Ooka, H.; Azuma, K.; Yabuuchi, T.;
Kurono, N.; Inoue, T.; Ohkuma, T. Org. Lett. 2007, 9, 939. (p) Hamada,
Y.; Koseki, Y.; Fujii, T.; Maeda, T.; Hibino, T. Chem. Commun. 2008,
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Asymmetry 2008, 19, 2816. (r) Limanto, J.; Krska, S. W.; Dorner, B. T.;
Vasquez, E.; Yoshikawa, N.; Tan, L. Org. Lett. 2010, 12, 512.
entry
Ru catalyst
convb (%)
dr syn/antib
ee sync (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
93
>99
>99
>99
7
>99
77
>99
90/10
85/15
82/18
88/12
91/9
55/45
93/7
95/5
>99
>99
>99
>99
nd
91
>99
>99
3g
3h
a Reactions were conducted using a 1 M solution of substrate (1 mmol).
Determined by H NMR of the crude reaction mixture. c Determined by
b
1
chiral stationary phase-supercritical fluid chromatography (CSP-SFC).
in dichloromethane at 30 °C for 20 h with a substrate to
catalyst molar ratio (S/C) of 200:1 using a 5:2 formic acid
and triethylamine azeotropic mixture as hydrogen source.
The results depicted in Table 1 clearly showed that the
stereochemical outcome of the reaction is strongly affected
by the structure of both the chiral diamine and the η6-arene
ligands. Indeed, transfer hydrogenation of 1a using Noyori’s
Ru(II)-TsDPEN11 catalyst 3a bearing p-cymene as η6-arene
provides the syn12 product 2a in 93% conversion with an
encouraging diastereoselectivity of 90/10 and an enantiomeric
excess up to 99% (Table 1, entry 1). Changing the arylsul-
fonyl group of the diamine ligand from p-toluenesulfonyl to
(9) (a) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045.
(b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (c) Everaere,
K.; Mortreux, A.; Carpentier, J.-F. AdV. Synth. Catal. 2003, 345, 67. (d)
Clapham, S. E.; Hadzovic, A.; Morris, R. H. Coord. Chem. ReV. 2004,
248, 2201. (e) Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006, 35, 226. (f)
Joseph, S. M.; Samec, J. S.; Ba¨ckvall, J.-E.; Andersson, P. G.; Brandt, P.
Chem. Soc. ReV. 2006, 35, 237. (g) Ikariya, T.; Blacker, A. J. Acc. Chem.
Res. 2007, 40, 1300.
(8) (a) Noyori, R.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36. (b)
Ward, R. S. Tetrahedron: Asymmetry 1996, 6, 1475. (c) Ratovelomanana-
Vidal, V.; Genet, J.-P. Can. J. Chem. 2000, 78, 5004. (d) Huerta, F. F.;
Minidis, A. B. E.; Ba¨ckvall, J.-E. Chem. Soc. ReV. 2001, 30, 321. (e)
Pellissier, H. Tetrahedron 2008, 64, 1563.
(10) So far, only one example has been reported by one of us: Scalone,
M. Roche Basel, 2008, private communication.
(11) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562.
Org. Lett., Vol. 12, No. 17, 2010
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Table 2. Optimization of the Reaction Conditions Using TsDPEN Ruthenium Catalysta
entry
solvent
Cb (mol L-1
)
temp (°C)
convb (%)
dr syn/antib
ee sync (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
1
30
30
30
30
50
10
30
30
30
30
30
30
30
30
30
>99
>99
>99
>99
>99
4
>99
>99
>99
>99
78
95/5
95/5
97/3
97/3
97/3
nd
97/3
96/4
91/9
95/5
87/13
92/8
96/4
95/5
97/3
>99
>99
>99
>99
>99
nd
>99
>99
>99
>99
>99
>99
>99
>99
>99
0.5
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Dioxane
Et2O
9
10
11
12
13
14
15d
Toluene
MeOH
i-PrOH
CH3CN
DMF
99
>99
>99
>99
CH2Cl2
a Reactions were conducted using a 1 mmol of substrate. Determined by H NMR of the crude reaction mixture. c Determined by chiral stationary
b
1
phase-supercritical fluid chromatography (CSP-SFC). d S/C ) 500.
a more electron-withdrawing group such as p-nitrobenzene-
sulfonyl (catalyst 3b) or 3,5-bis(trifluoromethyl)benzene-
sulfonyl (catalyst 3c) slightly increased the catalytic activity
in terms of conversion, giving 2a in 99% conversion with
up to 99% enantiomeric excess, but lower diastereoselectivity
(Table 1, entries 2 and 3). Similar results were obtained when
catalyst 3d, bearing a p-nitro group on the phenyl ring of
the N-tosyldiamine moiety, was employed (Table 1, entry
4). Modification of the η6-arene in the reference Ru(II)-
TsDPEN catalyst also significantly affected the stereochem-
ical outcome of the reaction (Table 1, entries 5-8). For
example, transfer hydrogenation of 1a using catalyst 3e
possessing η6-arene ) hexamethylbenzene afforded the
differentiated syn-1,2-diol 2a with an encouraging diaste-
reoselectivity of 91/9 but in only 7% conversion (Table 1,
entry 5). When the reaction was performed with catalyst 3f
(η6-arene ) benzene), full conversion into the desired product
2a was obtained. However, although the enantioselectivity
still remained high, the diastereoselectivity of the reaction
was very low (Table 1, entry 6). Changing the η6-arene ligand
from p-cymene to 1,4-dicyclohexylbenzene (catalyst 3b)
slightly increased the stereoselectivity, while conversion
dropped significantly (Table 1, entry 7). Finally, from this
survey, the Ts-DPEN ruthenium catalyst 3h possessing the
η6-arene ) mesitylene emerged as the best catalyst, yielding
the reduced product 2a in more than 99% conversion with a
diastereomeric ratio of 95/5 and perfect enantioselectivity
(Table 1, entry 8, ee >99%).
solvent aiming at improving the diastereoselectivity. The
results are summarized in Table 2. We found that the
diasteromeric ratio could be increased from 95/5 to 97/3
when the reaction was run under more diluted conditions
with no erosion of conversion and enantioselectivity (Table
2, entries 1-4). Increasing the temperature from 30 to 50
°C did not affect the stereochemical outcome of the reaction,
whereas a decrease in the reaction temperature from 30 to
10 °C resulted in almost no conversion (Table 2, entries 5
and 6). Further optimization focused on the solvent em-
ployed. With the exception of MeOH, conversions and ee
values greater than 99% with good to excellent diasteromeric
ratio ranging from 87/13 to 97/3 were achieved in all tested
solvents (Table 2, entries 7-14). From this survey, CH2Cl2
and THF proved to be the most suitable solvents with regard
to both selectivity and reactivity, providing the reduced
product 2a in a highly enantio- and diastereoselective manner
with, respectively, 99% ee and a dr ratio of 97/3 (Table 2,
entries 3, 5, and 7). Reducing the catalyst loading from S/C
200 to S/C 500 did not affect the catalytic efficiency, thus
giving the product 2a with similar high levels of stereose-
lectivity (Table 2, entry 15).
To assess the substrate scope, a full set of R-alkoxy-
substituted ꢀ-ketoester derivatives 1a-q were hydrogenated
under the optimized conditions using the TsDPEN ruthenium
complex 3h as catalyst. Examination of the results listed in
Table 3 shows that the reaction proceeded well in most cases,
giving aryl- and heteroaromatic-substituted products 2a-q
in full conversion with excellent diastereo- and enantiose-
lectivities, irrespective of the electronic nature of the
substitution pattern. For example, compounds 1 possessing
either electron-withdrawing or electron-donating groups at
Encouraged by these results, we then investigated the effect
of the following sequence: concentration, temperature and
(12) The absolute stereochemistry was confirmed by the X-ray single-
crystal structure (see the Supporting Information).
3790
Org. Lett., Vol. 12, No. 17, 2010

Similar good results in terms of both reactivity and
selectivity were obtained when the reaction was performed
with R-methoxy ꢀ-ketoester derivatives 1 containing electron-
rich as well as electron-poor substituents at the meta position
of the aromatic moiety (Table 3, entries 4, 6, and 8).
Although ortho substitution led to a decrease in the catalytic
efficiency, thus giving the product in moderate conversions
and diastereoselectivities, high enantioselectivities up to 99%
were still attained (Table 3, entries 3 and 7). This result could
be attributed to the unfavored steric hindrance between the
ortho-substituted group of the substrate and the catalyst
during the reaction. Heteroaromatic compounds can also be
used as partners, as demonstrated by the excellent results
obtained with thiophene (1l) and furan (1m) derivatives
(Table 2, entries 12 and 13). Similar impressive results were
obtained with the cinnamyl derivative 1n, providing the
expected product 2m in almost full conversion and perfect
selectivity (Table 3, entry 14). As showed in Table 3,
R-substituted ꢀ-ketoester derivatives 1o, 1p, and 1q bearing,
respectively, an ethoxy, a benzyloxy (Bn), and a p-meth-
oxybenzyloxy group (PMB) at the R position also proved to
be suitable substrates for this new process. Indeed, the
corresponding adducts 2o, 2p, and 2q were obtained in more
than 99% conversion with excellent diastereo- and enanti-
oselectivities (Table 3, entries 15-17). It should be noted
that Me, Bn, and PMB protecting groups could be removed
to provide the corresponding syn-1,2-diols.13,14
Table 3. Asymmetric Transfer Hydrogenation Catalyzed by
TsDPEN Ruthenium Catalyst 3ha
In conclusion, we have successfully achieved the first
example of a Ru-catalyzed asymmetric transfer hydrogena-
tion of readily available racemic R-alkoxy-substituted ꢀ-ke-
toesters via dynamic kinetic resolution. In this atom-
economical process, two contiguous stereogenic centers are
controlled simultaneously with excellent diastereoselectivity
(up to 99/1) and enantioselectivity (up to 99%), allowing
rapid access to a wide variety of aromatic as well as
heteroaromatic monodifferentiated syn-1,2-diols that are
otherwise difficult to prepare by asymmetric catalysis. The
scope of this reaction is currently under investigation, and
its application to the synthesis of natural products is
underway in our laboratory and will be reported in due
course.
Acknowledgment. D.C. is grateful to the Ministe`re de
l’Education Nationale et de la Recherche for financial support
(2007-2010).
Supporting Information Available: Experimental pro-
cedures and full characterization of new compounds and
copies of 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reactions were conducted using a 0.2 M solution of substrate 1 (1
mmol). b Determined by 1H NMR analysis of the crude product. c Determined
by chiral stationary phase supercritical-fluid chromatography (CSP-SFC).
d Reaction performed with S/C ) 100. e Substrate 1o bearing ethyl ester
group instead of methyl ester.
OL101451S
(13) (a) Green, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis; Wiley-VCH: Weinheim, 1999. (b) Denmark, S. E.; Chung, W.-
the para position on the phenyl rings gave uniformly high
enantioselectivities (98-99% ee) and diastereoselectivities
(96/4 to 97/3 dr) (Table 2, entries 2, 5, and 9-11).
J. J. Org. Chem. 2008, 73, 4582
.
(14) See the Supporting Information for details.
Org. Lett., Vol. 12, No. 17, 2010
3791