A new enantioselective synthesis of glycidates via dynamic kinetic resolution of racemic 2-chloro-3-keto esters using chiral Ru (II) complexes

Article abstract of DOI:10.1016/0040-4039(95)00182-C

2-chloro-3-keto esters were quantitatively hydrogenated to syn and anti 2-chloro-3-hydroxyester by asymmetric hydrogenation with chiral ruthenium (II) catalysts prepared in-situ from (COD)Ru(2-methylallyl)₂ in presence of atropisomeric ligands such as MeO-Biphep and Binap, giving enantioselectivity up to 99%, 2-chloro-3-hydroxy esters were treated with different bases to give (E)-and (Z)-2,3-epoxyalkanoates in 65-90% yields with 84-97% ee.

Full text of DOI:10.1016/0040-4039(95)00182-C

Tetrahedron
Vol. 36, No.
1995
Science Ltd
Printed in Great Britain
A New Enantioselective Synthesis of Glycidates Via Dynamic Kinetic
Resolution of Racemic
Chiral Ru (II) Complexes
esters using
Jean-Pierre
M. C.
de Andrade, V. Ratovelomanana-Vidal
de
Organique,
au C.N.R.S.,
75231 Paris
Nationale
05, France.
de Chimie de
11 rue P. et M. Curie,
Key Words: Asymmetric Hydrogenation, Chiral Ruthenium (11) Catalysts, Dynamic Kinetic
Resolution,
esters were quantitatively
by asymmetric hydrogenation with
in presence of atropisomeric
enantioselectivity up to 99%. esters
and in
to
and
(II) catalysts
in-situ from
and Binap, giving
such as
with different bases to give
with
cc.
Optically active epoxy acids or esters are an extremely important class of compounds for biologically
active products synthesis. In particular, optically active glycidate 2 is an
efficient and practical intermediate’ for the synthesis of dilthiazem hydrochloride 1, which is a potent channel
blocker used for the treatment of angina pectoris and hypertension. Taxol and the semisynthetic taxotere are
currently considered as the most exciting compounds in cancer chemotherapy.3 The importance of taxol and
taxotere’s C-13 side chains to these drugs was noted in the very earliest biological studies on these remarkable
molecules. In several efficient approaches of the
and taxotere side chains
having threo
The
substituants, 3R) methyl-3-(phenyl) glycidate 4 was used as key
phenylglycidate 5 also provided an efficient route to the taxol side chain 3.5
0
Ar = p-methoxyphenyl
a : R = P h
b:
3
2
There is still a need for developing efficient processes for the preparation of
and in their
enantiomerically pure form. In view of the excellent enantiodifferentiating ability of the ruthenium catalysts
developed in our laboratory for the reduction of olefins and keto groups, and the powerful synthetic so-called
2063

2064
dynamic resolution of racemic 2-substituted keto esters,
the enantioselective reduction of
esters* seemed to be an obvious and facile approach to the above optically active molecules.
In this paper, we wish to describe a new and efficient synthesis of optically active
hydroxyesters using chiral ruthenium (II) catalysts (scheme 1) and their conversion to the corresponding chiral
glycidates.
OR’
or
OR’
R
Cl
7
Cl
a R= Ph
OR’
OR’
6 b R= p-l&O-Ph,
6
R=Me,
9
Cl 10
Scheme 1
Table 1 Hydrogenation of
esters 6 with
Conditions
complexes
S o l v e n t
Entry trate
Catalyst
atm
h
27
2 0
5 0 6 0
90
6a
+
50
80
60
3
90
64
3
6a
6a
4
86
+
+
50
80
27
80
16
6b
6b
(R)-binap
(S)-binap
(R)-binap
(R)-binap
80
30
90
6
17
2 0
5
90
+
7
8
+
+
6c
(a) Chemical yields were determined by
NMR (b) and (c) d. e. and
columns] and
determined by G. C. analysis of
with racemic materials prepared by reduction with
Acid
0-acetyl esters [DB
et
(d) all
(e) Ruthenium complexes catalysts were
diphospines and the upon
from a mixture of
The absolute configurations of
was determined by comparison of their optical
of authentic samples
with
in
with
Our results are summarized in table 1. We first investigated the hydrogenation of racemic ethyl
chloro-3-phenyl-3-oxopropionate 6a. In principle reduction should provide a mixture of the four possible
stereoisomers,
(X=
9a and
This study revealed that the stereochemical course of the reduction with
or Br) was noticeably influenced by the structures of the substrates, choice of
solvents and the catalyst. Hydrogenation of 6a in ethanol
by (R)-binapRuBr2 (prepared
conducted under quite mild conditions (30 atm. of hydrogen, 27 “C), proceeded with a good syn
diastereoselectivity (81% de), but with a very low enantioselectivity (5 and 31% ee, entry 1). Using the
catalyst
+
or (R)-MeO-biphep
hydrogenation proceeded with poor anti diastereoselectivity (35 and 44 % de
entries 2 and 3). Interestingly, use of only 0.5%
in
under 60 atm.
of hydrogen pressure, at 50
respectively), but with good enantioselectivity (up to

2065
of the catalyst
+
under higher pressure and temperature (86 atm.,
resulted
in better anti diastereoselectivity and enantioselectivity (92% de, entry 4). Reduction of
selectivity with poor enantiofacial discrimination when hydrogenation was conducted in a
also gave syn
solvent and
(all)2 +
under mild conditions (5 atm., 50
entry 5). Finally using the same catalyst as for 6a
(S)-binap
asymmetric hydrogenation resulted in full conversion to 7b with 92% de and 94% ee
having an alkyl chain using in ethanol under moderate
6). Reduction of
+
conditions (30 atm., 27 “C), resulted in very low anti diastereoselectivity (4% de), but high enantioselectivity
(93% ee, entry 7). However, when high pressure and temperature were used (90 atm.,
hydrogenation
proceeded with very high enantio- and diastereoselectivity (entry
enantiomeric excess.
giving almost exclusively with 99% of
Table 2 Synthesis of chiral glycidates from a-Chloro-P-Hydroxyesters
Conditions
Yield
(%)
Epoxides
0
Substrate a-Chloro-P-Hydroxyester
e.e.(%)
(%)
H O
1
85
Ph
94%
84%
Ph
0
2
3
9 0
90
Ph
7
p-An
94%
Cl
0
4
99%
a)
were determined by chiral
on Chiracel OD Daicel column 25 x 0.46;
Chmmpack capillary column chromatography
(entry 2, Table 1) were separated by MPLC column chromatography, eluent:
and 9b (entry 6, Table 1) were separated by Flash column chromatography, eluent:
pm; b) e.e were
by GC on a
c) The chlomhydroxyesters
d) The
and
c) From entry 8, Table
The optically
epoxy
obtained from
chlorohydroxyesters.
When syn
chlorohydroxyester
was treated with
in a DMF-water
epoxide was formed in 85% yield without detection of
treatment of with DBU in optically active trans
phenylglycidate (entry 1). However by
phenylglycidate was obtained with 84% ee,
in 90% yield (entry 2). Interestingly, upon the same conditions, 7b led to
90% yield (entry 3). When the crude chlorohydroxyester was treated with
pure methylglycidate was obtained with 97% ee in moderate yield of 65% (entry 4).
The efficiency of this technology was shown in the synthesis of both enantiomers of
epoxy ester with 95% ee in
in
the optically
methylglycidate
+ (S) or (R)
from the common racemic
atropisomeric ligands
ester 11 using the catalyst system
(scheme 2). The reduction of 11 conducted with (S)-MeO-Biphep as chiral
methylglycidate 12 with
96% ee, in 90% overall yield. Inversely, use of (R)-MeO-biphep, under the above reduction and cyclization
conditions, produced the enantiomer 13 with the same ee and overall yield.
ligand at
atm.,
for 4 h, and then treated with base (DBU), afforded the

2066
+
DBU,
Scheme 2
a)
were determined by chiral HPLC on Chiralcel OD Daicel column 25 x 0.46 cm,
In summary, we have established the optimal conditions for the kinetic dynamic resolutions of racemic
esters to produce both
enantiomers of glycidates with very high enantioselectivity (up to
This technic
97% ee) using chiral Ru complexes prepared in-situ from
offers news opportunities for the preparation of biologically active products and these studies are currently
under investigation.
Acknowledgements : We thank
(Brazil) for a grant to M. C.
de Andrade. We also thank Dr M.
Y.
Petit and 0.
thank Dr. E.
for helpful discussions. We are also very grateful to Y.
and Dr. R.
for technical assistance (HPLC analysis). We
=
(Hoffman La
and
glycidate.
for samples of
We thank Dr.
Rossey
for providing us analytical
data of the
References and notes
a) Rossey.
L.; Wick, A. E. E.P. 049712; b) Rossey,
Kanerva, L.T.; Sundholm, 0. J. Chem.
K.; Oh-lshi, T. Pharm. Bull. 1993.41.
A.; Inoue, H.; Takeda, M. Chem. Pharm. Bull. 643-648.
a) Nagao, T.; M.; Nakajima, H. Chem. Pharm. Bull. 1973,
a) Guenard, D.; Gueritte-Vogelein, F.; Potier, P.
G.N.; Drugs. 519; c)
M.; Guenard, D. Gueritte-Voegelin, F. Potier, P.
Zard, L.; Wick, A. E. chiral 92 Proc eedings
Manchester U.K. 1992.51;
Inoue, H.;
Trans
d)
e) Marsuki, K.;
2.
3.
Res. 1993.26, 160-167; b) Sclichenmyer, W.J.;
S. Chem. Eng. News.
Put. Appli. E.P.
d) For
4.
a)
L.; Jacobsen, E. N. J. Org. Chem.
43204323; b) Dcnis, J.-N.;
A.; Greene,
J. Org.
Chem. 1991.56, 6939-6942;
J.-N.;
A.: Greene, A.E. J. Org. Chem. 1990.57, 1957-1959; d)
J.-N.; Greene, A.E.;
approach to
A.A.;
M.-J. J. Org.
e) Review total and semi synthetic
Tetrahedron symposia-in-print,
1992.48, 6953-6964; For recent the first total
Synthesis of
R.A.;
C.; Kim, H.-B.; Liang, F.;
R.J.; Boatman, P.D.;
M.;
Smith,
Kim, S.;
Liu, J.H.; J. Am.
a) Bunnage, M.E.; Davies, S.G.; Goodwin, C.J. J.
H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K.K.; Gentile, L.N.;
1994,116, and
5.
6.
Trans 1993, 13, 1375-1376; b)
Asymmetry. 43-46; b)
Liu. Y.C.: Chen, C.S. J. Org.
a) J.-P.; S.;
1993.58,
S.
C.
J.-P.;
S.; Caihlol, N.; Laffitte J.A. Tetrahedron
5343-5346; c)
de Andrade, M.C.: Laffitte, J.A.
J.-P.; Pinel. C.: Ratovelomanana-Vidal. V.;
S.; Galopin, C.; Lalfitte, J.A. Tetrahedron Asymmetry.
S.; S., Patent 8911159 (August 1989); b)
S.; Thorimbert, S.; Laffitte, J.A. Tetrahedron 1991.2, 555-567; c)
Ratovelomanana-Vidal, V.; Pinel, C.; J.A.
this area see: Noyori, R.;
T.; Takemoti. T.: Kumobayashi, H. J. Am. Chem.
M.; Noyori, R. J. Am. Chem. 1993,115,
a) For microbial asymmetric reduction of
0.;
J.-P.; Pinel,
Ratovelomanana-Vidal, V.:
S;
X.;
: Asymmetry.
1994.5, 665-674:
Andrade, MC.;
S.; Pfister, X.; Bischoff, L.; Cairo de
7.
a)
J.-P.:
J.-P.; Pinel, C.;
J.-P.;
S.;
X.;
d) For leading references in
T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa,
N.;
1989,111, 9134-9135 and Kitamura, M.; Tokunaga,
8.
esters see
M.; Buisson, D.;
H.; Ikari, Y.; Oishi, T. Synthesis.
H.; Matsukura, H.; Oishi, T.; Tetrahedron
R.
H.;
R.;
9.
General procedure of hydrogenation:
esters (1 mmol) dissolved in 2 ml of anhydrous solvent were.
into a ml Schlenck tube filled with argon
by
a
times cycle of vacuum/argon at R.T.. This solution was
atmosphere containing
(1
and the chiral diphosphine (1.3
3 times with hydrogen and
The reaction mixture
was immediately placed into an autoclave which was
available from
10
(Received in France 8 December 1994; accepted 25 January 1995)