Efficient enantioselective synthesis of 3-aminochroman derivatives through ruthenium-synphos catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/ol201786q

A highly enantioselective asymmetric hydrogenation of various trisubstituted enamides derived from chroman-3-ones promoted by cationic Ru-Synphos catalysts is reported. This atom-economical and clean method provides an efficient route to optically active

Full text of DOI:10.1021/ol201786q

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3782–3785
Efficient Enantioselective Synthesis of
3-Aminochroman Derivatives Through
Ruthenium-Synphos Catalyzed
Asymmetric Hydrogenation
Zi Wu, Tahar Ayad,* and Virginie Ratovelomanana-Vidal*
Chimie ParisTech, Laboratoire Charles Friedel (LCF), 75005 Paris, France, and
CNRS, UMR 7223, 75005 Paris, France
tahar-ayad@chimie-paristech.fr; virginie-vidal@chimie-paristech.fr
Received April 26, 2011
ABSTRACT
A highly enantioselective asymmetric hydrogenation of various trisubstituted enamides derived from chroman-3-ones promoted by cationic Ru-
Synphos catalysts is reported. This atom-economical and clean method provides an efficient route to optically active 3-aminochroman derivatives,
which are important pharmacophores found in numerous drug candidates, in high chemical yields and enantiomeric excesses up to 96%.
The 3-aminochroman moiety I (3,4-dihydro-3-amino-
2H-1-benzopyrans) isanimportant structural unit thatcan
be found in numerous pharmaceutical drug candidates
used for the treatment and/or prevention of neuropsychia-
tric disorders, neurodegenerative disorders, pain, and sex-
ual dysfunction.1 Representative examples of this impor-
tant class of compounds include Robalzotan (NAD-299)2
and Alnespirone ((þ)-S20499),3 which display very high
affinity and good selectivity for the 5-HT1A serotonin
receptor and are today under clinical development for
the treatment of anxiety and depression (Figure 1). Com-
Figure 1. Structure of biologically active compounds containing
the 3-aminochroman moiety I.
pound II is a potent, nontoxic, and peripherally selective
inhibitor of dopamine-β-hydroxylase, which can be used
for the treatment of certain cardiovascular disorders such
However, despite the obvious practical potential of
aminochroman derivatives, only limited success has been
achieved for the synthesis of the pharmaceutically inter-
esting 3-aminochroman moiety I. To date, the most
as hypertension and chronic heart failure.4
(1) (a) Anderson, B. R.; Carlsson, P. A. E.; Svensson, K. A. I.;
Wikstron, H. V.; Hallberg, A. R. WO90/12795, 1990. (b) Cook, A.;
Miller, D. C. WO2006/056850, 2006. (c) Hatzenbuhler, N. T.; Baudy, R.;
Evrard, D. A.; Failli, A.; Harrison, B. L.; Lenicek, S.; Mewshaw, R. E.; Saab,
A.; Shah, U.; Sze, J.; Zhang, M.; Zhou, D.; Chlenov, M.; Kagan, M.;
Golembieski, J.; Hornby, G.; Lai, M.; Smith, D. L.; Sullivan, K. M.;
Schechter, L. E.; Andree, T. H. J. Med. Chem. 2008, 51, 6980.
(2) Ross, S. B.; Thorberg, S.-O.; Jerning, E.; Mohell, N.; Stenfors, C.;
Wallsten, C.; Milchert, I. G.; Ojteg, G. A. CNS Drug Rev. 1999, 5, 213.
(3) (a) Curle, P. F.; Mocaer, E.; Renard, P.; Guardiola, B. Drug Dev.
(4) Learmonth, D. A.; Soares Da Silva, P. M. V.; Beliaev, A.
WO2004/033447, 2004.
(5) (a) Holmberg, P.; Tedenborg, L.; Rosqvist, S.; Johansson, A. M.
Bioorg. Med. Chem. Lett. 2005, 15, 747. (b) Holmberg, P.; Sohn, D.;
Leideborg, R.; Caldirola, P.; Zlatoidsky, P.; Sverker, H.; Mohell, N.;
Rosqvist, S.; Nordvall, G.; Johansson, A. M.; Johansson, R. J. Med.
Chem. 2004, 47, 3927. (c) Zhou, D.; Hatzenbuhler, N. T.; Gross, J. L.;
Harrison, B. L.; Evrard, D. A.; Chlenov, M.; Golembiesky, J.; Hornby,
G.; Schechter, L. E.; Smith, D. L.; Andree, T. H.; Stack, G. P. Bioorg.
Med. Chem. Lett. 2007, 17, 3117.
ꢀ
Res. 1994, 32, 183. (b) MacSweeney, C. P.; Lesourd, M.; Gandon, J.-M.
Eur. J. Pharmacol. 1998, 345, 133.
r
10.1021/ol201786q
Published on Web 07/14/2011
2011 American Chemical Society

commonly used approach relies on the resolution of
racemic mixtures of I through diastereomeric salt
formation.1,5 Viaud-Massuard and Guillaumet et al.6
have described the preparation of 3-aminochroman
derivatives by radical cyclization using L-serine deriva-
tives as chiral starting materials. Although excellent
enantioselectivity up to 99% was obtained, this route
has some disadvantages that limit its practicality, such as
the use of a large excess of highly toxic tin reagent
combined with a long reaction sequence. In addition,
this method remains essentially restricted to 5-substi-
tuted-3-aminochroman derivatives. In 2010, Sachetti
et al.7 reported a biocatalytic approach resulting in
the synthesis of the (R)-5-methoxy-3-aminochroman, a
key precursor to the antidepressant drug Robalzotan
with a moderate ee of 51%. Consequently, the deve-
lopment of catalytic enantioselective methods that
would allow practical access to the 3-aminochroman
moiety, with high selectivity, is highly desirable. Asym-
metric hydrogenation8 of trisubstituted enamides de-
rived from chromanone derivatives9 would be the most
atom-economical approach to these molecules. As far as
asymmetric hydrogenation of enamides derived from
3-chromanone is concerned, and to the best of our
knowledge, only rare examples of such an approach
have been described in the literature. Bruneau, Dixneuf
et al.10 reported low to high ee values, ranging from
5 to 92%, for the asymmetric hydrogenation of
some ene carbamate10a and enamide10a,b derivatives
using Ru-based catalysts with a substrate scope mostly
limited to the synthesis of 5-methoxy-3-aminochro-
man as a model substrate. Recently, one additional
example concerning the enantioselective synthesis of
(R)-6,8-difluorochroman-3-ylamine has been revealed
in a patent using Ru- and Rh-complexes with enan-
tioselectivities from 5 to 93% ee.11 In connection with
our ongoing research program toward the use of metal-
catalyzed asymmetric hydrogenation for the synthesis of
biologically relevant active compounds,12 we report herein
the efficient enantioselective synthesis of various 3-amino-
chroman derivatives 2 through ruthenium-Synphos cata-
lyzed asymmetric hydrogenation of trisubstituted enamides
1 derived from chroman-3-ones.
We preliminarily screened a series of cationic ruthenium
complexes in the asymmetric hydrogenation of the readily
available N-acetyl enamide 1a10 as a model substrate. Four
atropisomeric diphosphine ligands, including the mile-
stone (S)-Binap L1,13 and the (S)-MeO-Biphep L214 as
well as the (S)-Synphos L3,15 and the (S)-Difluorphos L416
developed in ourgroup, wereemployedinthis study. Initial
hydrogenation experiments were conducted at 50 bar of
hydrogen pressure and 50 °C in methanol with 1 mol %
of Ru-catalyst for 20 h. The results depicted in Table 1
clearly showed that the stereochemical outcome of the
reaction was strongly dependent on the nature of the
complexes used. Indeed, the in situ generated RuBr2
[diphosphine] catalysts were prepared according to our
convenient procedure,17 by mixing Ru(cod)(η3-methy-
lallyl)2 with the required diphosphines in the presence of
methanolic hydrobromic acid, which gave the 3-amino-
chroman derivative 2a in moderate to good yields and
selectivities ranging from 61 to 78% ee (Table 1, entries
1ꢀ4, 44ꢀ82% yields). Similar catalytic activity was
achieved with the cationic monohydride ruthenium
(6) (a) Usse, S.; Pave, G.; Guillaumet, G.; Viaud-Massuard, M.-C.
Tetrahedron: Asymmetry 2001, 12, 1689. (b) Pave, G.; Usse-Versluys, S.;
Viaud-Massuard, M.-C.; Guillaumet, G. Org. Lett. 2003, 23, 4253.
(7) Fuganti, C.; Sacchetti, A. J. Mol. Catal. B: Enzym. 2010, 66, 276.
(8) (a) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asym-
metric Synthesis, 2nd ed.; Ojima, I., Ed.; John Wiley & Sons: New York,
2000; pp 1ꢀ110. (b) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (c)
Shang, G.; Li, W.; Zhang, X. In Catalytic Asymmetric Synthesis, 3rd ed.;
Ojima, I., Ed.; John Wiley & Sons: New York, 2010; pp 343ꢀ436. (d) Genet,
J.-P. Acc. Chem. Res. 2003, 36, 908. (e) de Vries, A.-G., Elsevier, C. J.,
Eds. Handbook of Homogeneous Hydrogenation; Wiley-VCH: Weinheim,
Germany, 2006.
(9) (a) Zhang, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Zhang, X. J. Org.
Chem. 1999, 64, 1774. (b) Tang, W.; Chi, Y.; Zhang, X. Org. Lett. 2002,
4, 1696. (c) Bernsmann, H.; Van Der Berg, M.; Hoen, R.; Minnard, A. J.;
Mehler, G.; Reetz, M. T.; De Vries, J. G.; Feringa, B. L. J. Org. Chem.
2005, 70, 943.
(10) (a) Dupau, P.; Bruneau, C.; Dixneuf, P. H. Tetrahedron: Asym-
metry 1999, 10, 3467. (b) Dupau, P.; Le Gendre, P.; Bruneau, C.;
Dixneuf, P. H. Synlett 1999, 11, 1832. (c) Renaud, J. L.; Dupau, P.;
Hay, A.-E.; Guingouain, M.; Dixneuf, P. H.; Bruneau, C. Adv. Synth.
Catal. 2003, 345, 230.
(11) Learmonth, D. A.; Gerosa, A. Z.; Grasa, G. A.; Beliaev, A.
US2010/0036127, 2010.
(13) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi., K.; Ito, T.;
Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932.
(14) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.;
€
Foricher, J.; Lalonde, M.; Muller, R. K.; Scalone, M.; Schoettel, G.;
Zutter, U. Pure Appl. Chem. 1996, 68, 131.
(15) (a) Duprat de Paule, S.; Champion, N.; Ratovelomanana-Vidal,
V.; Genet, J.-P.; Dellis, P. French Patent 2830254, 2001. (b) Duprat de
Paule, S.; Champion, N.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Dellis, P.
WO Patent 03029259, 2003. (c) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-
Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P. Eur. J. Org. Chem. 2003,
1931. (d) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genet,
J.-P.; Champion, N.; Deschaux, G.; Dellis, P. Org. Process Res. Dev. 2003, 7,
399.
(16) (a) Jeulin, S.; Duprat de Paule, S.; V. Ratovelomanana-Vidal,
V.; Genet, J.-P.; Champion, N. Angew. Chem., Int. Ed. 2004, 43, 320. (b)
Jeulin, S.; Duprat de Paule, S.; V. Ratovelomanana-Vidal, V.; Genet,
J.-P.; Champion, N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5799.
(12) (a) Mordant, C.; Reymond, S.; Tone, H.; Lavergne, D.; Touati,
R.; Ben Hassine, B.; Ratovelomanana-Vidal, V.; Genet, J.-P. Tetrahe-
dron 2007, 63, 6115. (b) Blanc, D.; Madec, J.; Popowyck, F.; Ayad, T.;
Phansavath, P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Adv. Synth.
Catal. 2007, 349, 942. (c) Jeulin, S.; Ayad, T.; Ratovelomanana-Vidal,
V.; Genet, J.-P. Adv. Synth. Catal. 2007, 349, 1592. (d) Deport, C.;
Buchotte, M.; Abecassis, K.; Tadaoka, H.; Ayad, T.; Ohshima, T.;
Genet, J.-P.; Mashima, K.; Ratovelomanana-Vidal, V. Synlett 2007,
2743. (e) Pautigny, C.; Jeulin, S.; Ayad, T.; Genet, J.-P.; Ratovelomanana-
Vidal, V. Adv. Synth. Catal. 2008, 350, 2525. (f) Tone, H.; Buchotte, M.;
Mordant, C.; Guittet, E.; Ayad, T.; Ratovelomanana-Vidal, V. Org. Lett.
2009, 11, 1995. (g) Tadaoka, H.; Cartigny, D.; Nagano, T.; Gosavi, T.;
Ayad, T.; Genet, J.-P.; Ohshima, T.; Ratovelomanana-Vidal, V.; Mashima,
K. Chem.;Eur. J. 2009, 15, 9990. (h) Cartigny, D.; Nagano, T.; Ayad, T.;
Genet, J.-P.; Ohshima, T.; Mashima, K.; Ratovelomanana-Vidal, V. Adv.
(17) Genet, J. P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart, S.;
~
Pfister, X.; Cano de Andrade, M. C.; Laffitte, J. A. Tetrahedron:
Asymmetry 1994, 5, 665.
ꢁ
Synth. Catal. 2010, 358, 1886. (i) Prevost, S.; Gauthier, S.; Cano de
Andrade, M. C.; Mordant, C.; Touati, A. R.; Lesot, P.; Savignac, P.;
Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Tetra-
hedron: Asymmetry 2010, 21, 1436. (j) Pautigny, C.; Debouit, C.; Vayron,
P.; Ayad, T.; Ratovelomanana-Vidal, V. Tetrahedron: Asymmetry 2010,
21, 1382.
(18) (a) Dobbs, D. A.; Vanhessche, K. P. M.; Brazi, E.;
Rautenstrauch, V.; Lenoir, J. Y.; Genet, J. P.; Wiles, J. A.; Bergens,
S. H. Angew. Chem., Int. Ed. 2000, 39, 1992. (b) Wiles, J. A.; Bergens,
S. H.; Vanhessche, K. P. M.; Dobbs, D. A.; Rautenstrauch, V. Angew.
Chem., Int. Ed. 2001, 40, 914.
Org. Lett., Vol. 13, No. 15, 2011
3783

Table 1. Ruthenium Catalyzed Asymmetric Hydrogenation of Chromanone 1aa
entry
Ru-catalyst
conversion (%)b
yield (%)c
ee (%)d
1
Ru(cod)(η3-Methylallyl)2 þ (S)-Binap L1 þ HBr (2.2 equiv)
Ru(cod)(η3-Methylallyl)2 þ (S)-MeO-Biphep L2 þ HBr (2.2 equiv)
Ru(cod)(η3-Methylallyl)2 þ (S)-Synphos L3 þ HBr (2.2 equiv)
Ru(cod)(η3-Methylallyl)2 þ (S)-Difluorphos L4 þ HBr (2.2 equiv)
Ru(cod)(η3-Methylallyl)2 þ (S)-Binap L1 þ HBF4 (1.1 equiv)
Ru(cod)(η3-Methylallyl)2 þ (S)-MeO-Biphep L2 þ HBF4 (1.1 equiv)
Ru(cod)(η3-Methylallyl)2 þ (S)-Synphos L3 þ HBF4 (1.1 equiv)
Ru(cod)(η3-Methylallyl)2 þ (S)-Difluorphos L4 þ HBF4 (1.1 equiv)
{[RuCl((S)-Binap L1)]2(μ-Cl)3}ꢀ[NH2Me2]þ
80
82
75
78
82
44
71
76
70
38
86
88
93
86
90
88
96
85
74
78
76
61
77
78
80
72
79
81
83
78
72
74
84
77
2
3
84
4
54
5
78
6
84
7
86
8
43
9
98
10
11
12
13
14
15
16
{[RuCl((S)-MeO-Biphep L2)]2(μ-Cl)3}ꢀ[NH2Me2]þ
{[RuCl((S)-Synphos L3)]2(μ-Cl)3}ꢀ[NH2Me2]þ
>99
>99
92
{[RuCl((S)-Difluorphos L4)]2(μ-Cl)3}ꢀ[NH2Me2]þ
[RuCl((S)-Binap L1)(p-cym)]þClꢀ
94
[RuCl((S)-MeO-Biphep L2)(p-cym)]þClꢀ
>99
>99
90
[RuCl((S)-Synphos L3)(p-cym)]þClꢀ
[RuCl((S)-Difluorphos L4)(p-cym)]þClꢀ
a All reactions were performed using 1 mmol of substrate 1 in methanol for 20 h, at 50 °C and 50 bar with 1 mol % of Ru-catalyst. b Determined by 1H
NMR of the crude product. c Isolated yield after flash chromatography. d Determined by chiral stationary phase-supercritical fluid chromatography
(CSP-SFC). Absolute configuration was determined to be S by comparison of the specific rotation with reported data.
complex [Ru(H)(η6-cot)Diphosphine]þBF4ꢀ, which was
previously successfully used for the industrial synthesis of
(þ)-cis-methyldihydrojasmonate18 (entries 5ꢀ8, 38ꢀ76%
yields, and 72ꢀ80% ee). When the reaction was carried out
with the preformed dimeric [{RuCl((S)-Diphosphine)}2(μ-
Cl)3]ꢀ[NH2Me2]þ complexes (entries 9ꢀ12) or the cationic
[RuCl{(p-cym)(S)-Diphosphine}]þClꢀ catalysts (entries
13ꢀ16), a significant increase in terms of both conversions
and yields was observed. With these catalytic systems, the
selectivity of the reaction proved to be sensitive to the
nature of the diphosphine used, since, among all the ligands
tested, the electron-rich Synphos15 ligand L3 gave the
higher enantioselectivity, with 83% and 84% ee, respec-
tively(entries11and15). Finally,from thisinitial screening,
the cationic [RuCl{(p-cym(S)-Synphos}]þClꢀ complex
emerged as the best catalyst, providing the 3-aminochro-
man product 2a in more than 99% conversion and 96%
isolated yield, with an encouraging enantiomeric excess of
84% (Table 1, entry 15).
With this encouraging result in hand, we next studied the
effects of the solvent, temperature, and hydrogen pressure
using 1 mol % of the [RuCl{(p-cym)(S)-Synphos}]þClꢀ
catalyst. As outlined in Table 2, the reaction could be
performed in all solvents examined, either protic or apro-
tic, providing the hydrogenated product 2a in good to
excellent yields, ranging from 83 to 96%. Polar solvents
tend to give higher enantioselectivities (Table 2, entries
1ꢀ4, 79ꢀ84% ee) than nonpolar solvents (entries 5ꢀ8,
73ꢀ77% ee), the most efficient one being methanol,
which allowed the isolation of the 3-aminochroman
derivative 2a in 96% yield and 84% ee (entry 1). The data
in Table 2 also illustrated that a substantial change in
hydrogen pressure and reaction temperature did not
significantly affect the stereochemical outcome of the
reaction, since excellent catalytic activity was still main-
tained (Table 2, entries 9ꢀ12, 94ꢀ96% yields, and
82ꢀ84% ee). Through these screenings, the best reaction
conditions for asymmetric hydrogenation of 1a were
therefore set as the following: 1 mol % of [RuCl
{(p-cym)(S)-Synphos}]þClꢀ as catalyst, methanol as
solvent, under 50 bar of H2 at 50 °C for 20 h.
Next, we evaluated the possibility of extending the scope
of this transformation. Toward this end, several enamide
derivatives were prepared according to known procedures19
and subsequently hydrogenated under our optimized reac-
tion conditions (Table 3). In most cases, substrates 1aꢀp
were fully converted to their corresponding 3-aminochro-
man derivatives 2aꢀp in high isolated yields and good to
excellent enantioselectivities up to 96%. As shown in
Table 3, both reactivity and enantioselectivity were influ-
enced by the nature of the amide moiety. Indeed, when
comparing the results obtained with the N-acetyl enamide
1a, the hydrogenation of enamides 1bꢀe bearing an Et, Pr,
t-Bu, and Ph group provides the hydrogenated products
2bꢀe in lower enantioselectivities ranging from 76 to
80% (Table 3, compare entry 1 vs entries 2ꢀ5). A lower
catalytic activity was observed for the hydrogenation of the
(19) (a) Velkov, J.; Mincheva, Z.; Bary, J.; Boireau, G.; Fujier, C.
Synth. Commun. 1997, 27, 375. (b) Alami, M.; Peyrat, J.-F.; Belachmi,
ꢀ
L.; Brion, J.-D. Eur. J. Org. Chem. 2001, 4207. (c) Pave, G.; Chalard, P.;
Viaud-Massuard, M. C.; Troin, Y.; Guillaumet, G. Synthesis 2004, 121.
3784
Org. Lett., Vol. 13, No. 15, 2011

ene benzyl carbamate 1f, probably as a result of electronic
and steric factors (Table 3, entry 6).
Table 3. Asymmetric Hydrogenation of Substrates 1aꢀpa
Table 2. Optimization of the Reaction Conditions for Asym-
metric Hydrogenation of 1aa
temp
P
conv
(%)b
yield
(%)c
ee
(%)d
entry
solvent
MeOH
(°C)
(bar)
1
50
50
50
50
50
50
50
50
70
30
50
50
50
50
50
50
50
50
50
50
50
50
70
20
>99
>99
>99
>99
>88
>93
>99
>99
>99
>99
>99
>99
96
96
93
91
83
89
93
92
95
94
96
94
84
80
79
79
73
77
76
77
83
83
84
82
2
EtOH
3
i-PrOH
EtOAc
CH2Cl2
THF
4
5
6
7
1,4-dioxane
toluene
MeOH
MeOH
MeOH
MeOH
8
9
10
11
12
a All reactions were performed using 1 mmol of substrate 1a with
1 mol % of Ru-catalyst. b Determined by 1H NMR of the crude product.
c Isolated yield after flash chromatography. d Determined by chiral
stationary phase-supercritical fluid chromatography (CSP-SFC).
The data of Table 3 also revealed that the selectivity of
the reaction was strongly dependent on the substitution
pattern of the aromatic ring. A modest enantioselectivity
of 34% was preliminarily obtained with the 5-methoxy
substituted enamide 1g, which was in agreement with the
results of Bruneau, Dixneuf et al.10 (Table 3, entry 7).
This result could be attributed to the unfavorable steric
hindrance between the ortho-substituted group of the
substrate and the catalyst during the reaction. A better
enantiofacial discrimination up to 74% was observed for
the 7-methoxy substituted substrate 1h (Table 3, entry 8).
Pleasingly, for 8-substituted enamides 1iꢀk, the desired
products 2iꢀk were obtained in excellent yields and selec-
tivities, irrespective of the nature of the substituents,
although electron-withdrawing groups tend to give slightly
higher enantioselectivities compared to electron-donating
groups (Table 3, entries 9ꢀ11, 92ꢀ97% yields, 91ꢀ93% ee).
The same trend was observed for the reduction of enamides
1lꢀp. Indeed, although the yields were essentially the same,
the selectivity was influenced by the substituents of the
phenyl ring, with higher enantioselectivities being obtained
with an electron-withdrawing group (Table 3, entries
12ꢀ16, 92ꢀ95% yields, 91ꢀ96% ee).
a All reactions were performed using 1 mmol of substrate 1 with
1 mol % of Ru-catalyst. In all cases, complete conversions were achieved.
b Isolated yield after flash chromatography. c Determined by chiral sta-
tionary phase HPLC analysis or by chiral stationary phase-supercritical
fluid chromatography (CSP-SFC) (see Supporting Information).
and attractive strategy for the preparation of the im-
portant 3-aminochroman moiety. Application to the
synthesis of pharmaceutically active products is under-
way and will be reported in due course.
Acknowledgment. Z.W. thanks the CNRS and the Min-
ꢂ
istere de l’Education et de la Recherche for financial support.
In conclusion, we have successfully achieved the first
general and efficient enantioselective Ru-Synphos cata-
lyzed asymmetric hydrogenation of readily available
trisubstituted enamides derived from 3-chromanones.
This atom-economical protocol offers several advan-
tages, including operational simplicity, high chemical
yields, and enantioselectivities. This makes it a useful
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
3785