bar, entry 5) did not improve the e.e. (36%) and only a small
increase in enantioselectivity (52%) was observed when the
hydrogenation was carried out at 100 °C (entry 6).
displayed, under these optimized reaction conditions, an excellent
catalytic activity for all the substrates 3 considered, with high levels
of anti diastereoselectivity (86–99%) and enantioselectivity
(91–97%). Both anti (2S,3S)- and (2R,3R)-a-amino-b-hydroxy
esters could be easily synthesized with high diastereoisomeric and
enantiomeric excesses by judicious choice of the ligand configura-
tion. It is noteworthy that the diastereoisomeric excesses observed
seem linked to the nature of the side chain. The best results were
obtained with a long or ramified chain in the b-position (3c and 3d,
respectively).
Table 1 Hydrogenation reactiona of compounds 3c and 3d in alcoholic
solvent
In conclusion, the SYNPHOS® catalyzed hydrogenation affords
a general and efficient access to anti a-amino-b-hydroxy esters by
using configurationally labile a-NH2.HCl-b-keto esters. High
levels of enantiomeric and diastereoisomeric excesses are obtained
for a variety of alkyl b-keto esters under mild conditions via
dynamic kinetic resolution. This convenient method complements
the well-known hydrogenation of a-amido-b-keto esters which
provides the syn isomers as major products. This reaction is still
under investigation and the application of this strategy to the
synthesis of natural products and their analogues is currently
underway in our group.
Solvent P(H2)/
(RAOH) bar
d.e.b (%) e.e.b (%)
Entry
Substrate
T/°C anti
(2S,3S)
1
2
3
4
5
6
3d RNiPr
3d RNiPr
3d RNiPr
EtOH
EtOH
EtOH
12
50
100
12
50
12
50
50
50
50
50
98
98
98
93
90
93
87
87
87
39
36
52
3c RNC15H31 MeOH
3c RNC15H31 MeOH
3c RNC15H31 MeOH
100
We thank Dr R. Schmid and Dr M. Scalone (Hoffmann-La
Roche) for samples of (S)-MeO–BIPHEP = (S)-(2)-6,6A-dime-
a Conversions rates were determined by 1H NMR (MeOD) spectroscopy
before reprotection; all reactions were complete. b d.e. and e.e. were
determined by HPLC analysis after reprotection.
thoxy-2,2A-bis(diphenylphosphino)-1,1A-biphenyl.
A fellowship
from C.N.R.S./D.G.A. (C. M.) is gratefully acknowledged.
Based on these first results, the reaction solvent was changed to
slow down the reaction rate in order to favor a better discrimination
by the catalyst and improve the chiral induction. All hydro-
genations of the hydrochloride salts 3 were then conducted in
dichloromethane with a small percentage of alcoholic solvent (9%)
to maintain homogeneity. 2 mol% of catalyst [Ru(diphosphine)Br2]
were required to ensure complete conversions, the other conditions
remaining unchanged (i.e. under 12 bar of hydrogen at 50 °C for 24
h). This combination turned out to be the most appropriate to
achieve high anti diastereoselectivity and enantioselectivity for
both linear and branched a-amino-b-keto ester hydrochloride salts
3, regardless of the length or the hindrance of the side chain and
with good to excellent yields (Table 2). In all experiments, the
Ru(II)-catalysts were prepared in situ from (cod)Ru(2-methy-
lallyl)2, SYNPHOS® ligand recently developed by our group13,14
and methanolic HBr according to our convenient procedure.11 As
shown in Table 2, the Ru(II)-catalyst containing SYNPHOS®
Notes and references
1 Reviews: R. Noyori, M. Tokunaga and M. Kitamura, Bull. Chem. Soc.
Jpn., 1995, 68, 36; R. S. Ward, Tetrahedron: Asymmetry, 1995, 6, 1475;
V. Ratovelomanana-Vidal and J. P. Genet, Can. J. Chem., 2000, 78,
846; K. Faber, Chem. Eur. J., 2001, 7, 5005; H. Pellissier, Tetrahedron,
2003, 59, 8291–8327.
2 R. Noyori, T. Ikeda, T. Ohkuma, M. Widhalm, M. Kitamura, H. Takaya,
S. Akutagawa, N. Sayo, T. Saito, T. Taketomi and H. Kumobayashi, J.
Am. Chem. Soc., 1989, 111, 9134.
3 J. P. Genet, S. Mallart and S. Jugé, Fr. Pat. 8911159, 1989; J. P. Genet,
C. Pinel, S. Mallart, S. Jugé, S. Thorimbert and J. A. Laffitte,
Tetrahedron: Asymmetry, 1991, 2, 555.
4 K. Mashima, Y. Matsumura, K. Kusano, H. Kumobayashi, N. Sayo, Y.
Hori, T. Ishizaki, S. Akutagawa and H. Takaya, J. Chem. Soc., Chem.
Commun., 1991, 609; A. Girard, C. Greck, D. Ferroud and J. P. Genet,
Tetrahedron Lett., 1996, 37, 7967; E. Coulon, C. Caño de Andrade, V.
Ratovelomanana-Vidal and J. P. Genet, Tetrahedron Lett., 1998, 39,
6467; P. Phansavath, S. Duprat de Paule, V. Ratovelomanana-Vidal and
J. P. Genet, Eur. J. Org. Chem., 2000, 3903.
5 C. Caño de Andrade, V. Ratovelomanana-Vidal and J. P. Genet,
Tetrahedron Lett., 1995, 36, 2063; C. Mordant, C. Caño de Andrade, R.
Touati, V. Ratovelomanana-Vidal, B. Ben Hassine and J. P. Genet,
Synthesis, 2003, 2405.
Table 2 Hydrogenation of compounds 3 in optimized conditionsa
6 J. P. Genet, X. Pfister, V. Ratovelomanana-Vidal, C. Pinel and J. A.
Laffitte, Tetrahedron Lett., 1994, 35, 4559.
7 D. Lavergne, C. Mordant, V. Ratovelomanana-Vidal and J. P. Genet,
Org. Lett., 2001, 3, 1909.
8 J. S. Panek and C. E. Masse, J. Org. Chem., 1998, 63, 2382.
9 H. Azuma, R. Takao, H. Niiro, K. Shikata, S. Tamagaki, T. Tachibana
and K. Ogino, J. Org. Chem., 2003, 68, 2790.
10 A. Lei, S. Wu, M. He and X. Zhang, J. Am. Chem. Soc., 126, 126; After
submission of this manuscript, the stereoselective synthesis of anti b-
hydroxy-a-amino acids via DKR was reported: see K. Makino, T. Goto,
Y. Hiroli and Y. Hamada, Angew. Chem., Int. Ed., 2004, 43, 882.
11 J. P. Genet, C. Pinel, V. Ratovelomanana-Vidal, S. Mallart, X. Pfister,
C. Caño de Andrade and J. A. Laffitte, Tetrahedron: Asymmetry, 1994,
5, 675.
d.e.c (%)
anti
e.e.c (%)
(2S,3S)
Entry
Substrate
Yieldb (%)
1
2
3
4
5d
3a RNBnO-C4H8
3b RNC5H11
3c RNC15H31
3d RNiPr
94
85
83
90
96
92
93
96
99
98
92
91
96
97
96d
3d RNiPr
12 O. Hara, M. Ito and Y. Hamada, Tetrahedron Lett., 1998, 39, 5537.
13 S. Duprat de Paule, S. Jeulin, V. Ratovelomanana-Vidal, J. P. Genet, N.
Champion and P. Dellis, Eur. J. Org. Chem., 2003, 1931 and refs. cited
therein.
a Reaction conditions: 0.5 mmol of substrate in 2 mL of CH2Cl2 and 200 mL
of RAOH. b Yield over two steps. c d.e. and e.e. were determined by HPLC
analysis after reprotection. d Reaction conducted with (R)-SYNPHOS®, e.e.
of (2R,3R)-isomer.
14 J. P. Genet, Acc. Chem. Res., 2003, 36, 908.
C h e m . C o m m u n . , 2 0 0 4 , 1 2 9 6 – 1 2 9 7
1297