New chiral auxiliaries in enantioselective heterogeneous catalytic hydrogenations: (-) and (+)-dihydro-apovincaminic acid. Comparison with (-)- dihydro-apovincaminic acid ethyl ester. III

Article abstract of DOI:10.1016/S1381-1169(98)00140-X

The preparation, characterisation, use and comparison with (-)-dihydro- apovincaminic acid ethyl ester of (-) and (+)-dihydro-apovincaminic acid as chiral modifier in heterogeneous catalytic asymmetric hydrogenations are reported. The epimeric composition

Full text of DOI:10.1016/S1381-1169(98)00140-X

Ž
.
Journal of Molecular Catalysis A: Chemical 138 1999 123–127
New chiral auxiliaries in enantioselective heterogeneous
ž /
catalytic hydrogenations: y and
ž /
y -dihydro-apovincaminic acid ethyl ester. III
q -dihydro-apovincaminic acid. Comparison with
ž /
a
a
b
c
d
G. Farkas , K. Fodor , A. Tungler a,), T. Mathe , G. Toth , R.A. Sheldon
´ ´
´
a
Department of Chemical Technology, Technical UniÕersity of Budapest, H-1521 Budapest, Hungary
Organic Chemical Technology Research Group of the Hungarian Academy of Sciences, Budapest, Hungary
b
c
Technical Analytical Research Group of HAS, Dept. of General and Analytical Chemistry, Technical UniÕersity of Budapest,
Budapest, Hungary
d
Laboratory of Organic Chemistry and Catalysis, Delft UniÕersity of Technology, Delft, Netherlands
Received 18 February 1998; accepted 22 April 1998
Abstract
Ž .
The preparation, characterisation, use and comparison with y -dihydro-apovincaminic acid ethyl ester of y and
Ž
.
Ž
.
q -dihydro-apovincaminic acid as chiral modifier in heterogeneous catalytic asymmetric hydrogenations are reported. The
epimeric compositions were determined using NMR and HPLC methods. q 1999 Elsevier Science B.V. All rights reserved.
Keywords: Dihydro-apovincaminic acid; Hydrogenation; Enantioselectivity; Chiral auxiliary; Ethyl pyruvate; Isophorone
w x
tion of a-keto esters 2 . Both systems are
1. Introduction
Ž
.
effective ee’s up to 95% in the hydrogenation
of C5O double bonds in a specific class of
substrates. In order to find new chiral auxiliaries
with different or broader substrate specificity,
we have screened several vinca- and morphine-
type alkaloids in the hydrogenation of various
The known chiral auxiliaries for enantioselec-
tive hydrogenation can be classified into three
main groups: alkaloids, hydroxy and amino
acids. Notwithstanding the great number of chi-
ral compounds, which are used as chiral auxil-
iaries or chiral ligands, only a few of them are
effective in heterogeneous catalytic systems. The
most well known examples are Ni catalysts
modified with tartaric acid for the hydrogena-
w x
prochiral substrates 3 . A vinca-type alkaloid,
Ž
.
y -dihydro-apovincaminic acid ethyl ester
ŽŽ
.
.
y -DHVIN proved to be an effective chiral
additive in the hydrogenation of both C5C and
w x
tion of b-keto esters 1 and Pt catalysts modi-
fied with cinchona alkaloids for the hydrogena-
w x
C5O double bonds 4 . The starting unsaturated
Ž .
compound, apovincaminic acid ethyl ester I is
a synthetic molecule, which is used in the treat-
)
w x
ment of oxygen-deficiency of the brain 5 . Af-
Corresponding author.
1381-1169r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved.
Ž
.
PII: S1381-1169 98 00140-X

(
)
124
G. Farkas et al.rJournal of Molecular Catalysis A: Chemical 138 1999 123–127
D
w x
a
Ž
ter testing the effect of reaction parameters and
of the use of different catalysts on the perfor-
point: 210–2228C,
20 s y55,28 c s 1,
.
CHCl3 .
Ž
.
w
x
mance of y -DHVIN 6,7 , we tried to modify
the molecule in order to find out how it works
and perhaps to get a new chiral modifier with
even better effect.
Ethyl pyruvate and cinchonidine were sup-
plied by Merck. Apovincaminic acid ethyl ester
was supplied by Richter Gedeon.
2.1. Hydrogenation
2. Experimental
The hydrogenation of ethyl pyruvate and
isophorone was carried out at 258C and under
50 bar hydrogen pressure in a conventional
Pd black catalyst was prepared according to
the following procedure: 18 mmol 6.0 g
K2 PdCl4 was dissolved in 50 ml water and
Ž
.
apparatus or in a Buchi Bep 280 autoclave
¨
equipped with a magnetically driven turbine
stirrer and a gas-flow controlling and measuring
unit. Prior to hydrogenation the reaction mix-
tures were stirred under nitrogen for 15 min in
the reaction vessel.
Ž
.
reduced at boiling point with 74 mmol 5.0 g
Ž
.
Na HCOO dissolved in 20 ml water. When the
reduction was complete the pH of the suspen-
Ž
.
sion was basic pHs9 . The catalyst was fil-
tered and washed several times with distilled
water. Its BET surface area is 8 m2rg.
The reaction mixtures were analysed with a
gas chromatograph equipped with a b-cyclo-
Ž
Ž
Platinum on alumina catalysts E 4759, En-
dextrin capillary column analysis temperatures:
.
gelhard were heat-treated at 4008C for 3 h in
ethyl lactate at 908C, dihydroisophorone at
.
hydrogen flow under atmospheric pressure in a
glass reactor and subsequently cooled down to
room temperature and flushed with nitrogen.
1108C and FID. The chromatograms and peak
areas were recorded and peak areas were calcu-
lated with Chromatography Station for Win-
dows V1.6 DataApex, Prague . Enantiomeric
excess was defined as:
Ž
. Ž .
Ž
.
Apovincaminic acid ethyl ester 0.02 mol I
was dissolved in 60 ml 20% HCl solution and
boiled for 3 h. The pure HCl salt of II precipi-
ee % s R y S r R q S )100
Ž
.
Ž
.
Ž
.
Ž
.
tated yield 5 g, 75% . This salt was dissolved
in 100 ml water. After neutralisation with NaOH
solution and extraction with dichloromethane,
the organic phase was evaporated. The residue
2.1.1. HPLC chromatography
The analysis was carried out on a chiral AGP
column, at room temperature, the eluent was
Ž
.
consisted of yellow crystals II , melting point:
212–2408C. The hydrogenation reactions of a
80% Sorensen buffer and 20% acetonitrile. The
¨
adsorbance of the eluent was measured at 230
nm.
Ž
.
2% aqueous solution of apovincaminic acid II
HCl salt were carried out in an autoclave
equipped with a magnetic turbine stirrer, under
6 bar H2 pressure and at room temperature. The
2.1.2. NMR spectroscopy
Ž
The NMR spectra were recorded on a Bruker
Ac-500 spectrometer in CDCl3.
product composition ratio of IIrIIIHIV and
.
IIIrIV was determined with HPLC. The fil-
trate was neutralised with NaOH solution to
pHs7 and left to stand overnight at 58C in a
refrigerator. Compound IV crystallised and was
3. Results and discussion
Ž
.
filtered purity 90% , melting point: )2548C,
w x
a
D
20 sq55,08. The remaining filtrate was
partly evaporated and cooled, whereupon com-
pound III crystallised in 85% purity, melting
The naphthyl ester of dihydro-apovincaminic
acid seemed to be an appropriate derivative as
the necessity and usefulness of a naphthyl or

(
)
G. Farkas et al.rJournal of Molecular Catalysis A: Chemical 138 1999 123–127
125
Fig. 1. The reaction-scheme of the preparation of modifiers II, III, IV and V.
Ž
.
quinolyl group in modifiers for the enantioselec-
tive hydrogenation of ethyl pyruvate was veri-
II precipitated in pure form from the hydro-
chloric acid solution.
w x
Ž
.
Ž
.
fied 8 . However, the first route Fig. 1
The hydrogenation of this salt II HCl was
carried out in aqueous solution with PdrC cata-
stranded already at the second step, namely the
Ž
.
Ä
lyst. The resulting mixture of the epimers 70%
hydrolysis of y -DHVIN was incomplete and
Ž
.
Ž
.
Ž
.4
y -dihydro-apovincaminic acid could not be
a,a III and 30% a,b isomer IV could be
separated after partial neutralisation with NaOH.
The further conversion of the a,a-dihydro-
apovincaminic acid into optically pure naphthyl
isolated in pure form. The hydrolysis of the
unsaturated ester, in contrast, was facile, and the
hydrochloride salt of the apovincaminic acid
Table 1
The effect of different chiral auxiliaries on the ee of the hydrogenation of isophorone and ethyl-pyruvate
Solvent 50 cm3 MeOH, in the hydrogenation of isophorone 0.02 g modifiers, 0.2 g acetic acid, in the hydrogenation of ethyl pyruvate 0.1 g
modifiers, 0.1 g acetic acid.
)
Ž
.
Ž .
The modifier consists of ca. 80% y -DHVIN and 20% q -DHVIN.
) ) The modifier consists of ca. 70% III and 30% IV.
) ) ) Epimeric mixture.

(
)
126
G. Farkas et al.rJournal of Molecular Catalysis A: Chemical 138 1999 123–127
Ž .
lar to the structure of y -dihydro-apovinca-
ester was unsuccessful, however, owing to
epimerisation under the acylation conditions.
We compared the asymmetric induction of
w x
minic acid ethyl ester 4 . The –COOH and the
Ž
.
16-ethyl group are both in a position Fig. 2 .
Ž
.
Ž
.
w
x
y and q -DHVIN 6,7 with that of I, II, III
and IV in the Pd catalysed hydrogenation of
isophorone and in the Pt catalysed hydrogena-
4. Conclusions
Ž
.
tion of ethyl pyruvate see Table 1 .
w x
We previously reported 4 that Pd and Rh
Relation between structure, substituents of
the modifiers and their asymmetric effect in
hydrogenations.
are active catalysts for the hydrogenation of the
14,15 C5C double bond of I but that Pt is
inactive for this reaction. In the Pd catalysed
hydrogenation of I the a,a-epimer constitutes
ca. 80% of the product, while in the hydrogena-
Ž .
1
The difference between the effect of
a,a-isomers of saturated ester and acid is small
suggesting that the ester and the carboxyl group
have similar anchoring capabilities.
Ž
.
tion of II, the a,a-epimer III and the a,b-ep-
Ž
.
imer IV were produced in 70% and 30%,
respectively. Hence, during the hydrogenation
of isophorone with Pd catalyst, the unsaturated
modifiers I and II are hydrogenated in situ,
Ž .
2 The a,a-isomers of the saturated ester
and acid give a larger asymmetric induction
than that of the a,b-isomers, suggesting that an
equatorial position is preferred for the ester or
acid group.
Ž
.
Ž
.
giving a mixture of y - and q -DHVIN, or
of III and IV, respectively. The asymmetric
induction observed with the pure epimers of
DHVIN were very similar to those obtained
with the in situ generated epimeric mixtures
Ž .
3 Asymmetric induction solely due to the
Ž
.
unsaturated modifier compounds I, II could be
observed only in the Pt catalysed hydrogenation
of ethyl pyruvate, and was much smaller than
that of the saturated molecules. A possible ex-
planation for this difference can be that the ester
or acid groups can exert their anchoring effect
much better if they are not in the plane of the
ring they are attached to.
Ž
which contained mainly the a,a-epimers see
.
Table 1 .
In the Pt catalysed hydrogenation of ethyl
pyruvate, in contrast, there is a significant dif-
ference between the unsaturated and saturated
modifiers. In this reaction the true effect of the
unsaturated modifier molecules can really be
seen as Pt does not catalyse hydrogenation of
the 14,15 double bond of these vinca alkaloids.
Ž .
4 The difference in asymmetric induction
Ž
.
observed with the two epimeric esters y - and
Ž
.
q -DHVIN was much larger than that with the
Ž
.
acid epimers III and IV . This may be due to
the different size of the ester and carboxyl
groups.
(
)
3.1. Structure of y -dihydro-apoÕincaminic
acid
According to the NMR results the structure
Acknowledgements
Ž
.
of III, y -dihydro-apovincaminic acid is simi-
The authors gratefully acknowledge the fi-
nancial support of the Commission of European
Communities, COST PECO 12382 and the sup-
port of the Hungarian OTKA and Vargas Foun-
dations under No. T-015674. They are grateful
to Gedeon Richter for supplying apovincaminic
acid ethyl ester.
Ž
.
Fig. 2. The NMR dates of y -apovincaminic acid.

(
)
G. Farkas et al.rJournal of Molecular Catalysis A: Chemical 138 1999 123–127
127
I. Kollosvary, B. Herenyi, R.A. Sheldon, Tetrahedron Asym-
´
´
References
Ž
.
metry 6 1995 2395.
w x
1
Y. Izumi, M. Imaida, H. Fukawa, S. Akabori, Bull. Chem.
Soc. Jpn. 36 1963 21.
w x
5 Richter Gedeon, US Patent 4 035 370.
Ž
.
w x
6 T. Tarnai, A. Tungler, T. Mathe, J. Petro, R.A. Sheldon, G.
´ ´
´
w x
Ž
.
´
2
w x
3
Y. Orito, S. Imai, S. Niwa, J. Chem. Soc. Jpn. 8 1979 1118.
A. Tungler, T. Tarnai, T. Mathe, G. Vidra, J. Petro, R.A.
Ž
.
Toth, J. Mol. Catal. 102 1995 41.
´
w x
´ ´
7 A. Tungler, T. Mathe, K. Fodor, R.A. Sheldon, P. Gallezot, J.
´ ´
Sheldon, Proceedings of the 15th Conference of Organic
Reactions Catalysis Society, Phoenix, 1994, pp. 201–212.
Ž
.
Mol. Catal. 108 1996 145.
w x
8
G. Wang, T. Heinz, A. Pfaltz, B. Minder, T. Mallat, A.
w x
4
A. Tungler, T. Mathe, T. Tarnai, K. Fodor, G. Toth, J. Kajtar,
Ž
.
´ ´
´
´
Baiker, J. Chem. Soc. Chem. Commun. 1994 2047.