Access to optically active linear ketones by one-pot catalytic deprotection, decarboxylation, asymmetric tautomerization from racemic benzyl β-ketoesters

Article abstract of DOI:10.1039/b009828k

Benzyl 2-benzoyl-2-phenylpropanoate 1b subjected to heterogeneous hydrogenolysis conditions in the presence of catalytic amounts of commercially available cinchonia alkaloids as chiral protic source, led to (R)-1,2-diphenylpropanone with up to 71% ee, through a cascade reaction involving deprotection, decarboxylation and asymmetric tautomerization of enolic species.

Full text of DOI:10.1039/b009828k

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Access to optically active linear ketones by one-pot catalytic deprotection,
decarboxylation, asymmetric tautomerization from racemic benzyl b-ketoesters
Olivier Roy, Mira Diekmann, Abdelkhalek Riahi, Françoise Hénin* and Jacques Muzart
Unité Mixte de Recherche «Réactions Sélectives et Applications», CNRS – Université de Reims Champagne-Ardenne,
BP 1039, 51687 Reims Cedex 2, France. E-mail: francoise.henin@univ-reims.fr
Received (in Liverpool, UK) 1st December 2000, Accepted 25th January 2001
First published as an Advance Article on the web 26th February 2001
Benzyl 2-benzoyl-2-phenylpropanoate 1b subjected to het-
erogeneous hydrogenolysis conditions in the presence of
catalytic amounts of commercially available cinchonia
alkaloids as chiral protic source, led to (R)-1,2-diph-
enylpropanone with up to 71% ee, through a cascade
reaction involving deprotection, decarboxylation and asym-
metric tautomerization of enolic species.
(2)
In the first experiments, we applied the conditions previously
defined from cyclic substrates:15 to an acetonitrile solution of
substrate 1a† and chiral aminoalcohol (0.3 eq.) was added
palladium on charcoal (0.025 eq., Ref. 5011 from Engelhard
Company), then, H2 was continuously bubbled into the mixture
for the time indicated in Table 1. From the results assembled in
Numerous diastereoselective methods exist in enol chemistry to
prepare linear ketones bearing an a-stereogenic centre: they use
various protecting groups as chiral auxiliaries1,2 or an alkylating
reagent having a chiral leaving group.3,4 Another efficient way
involves the asymmetric protonation of metal enolates gen-
erated from ketones5 or ketenes6 by stoichiometric quantities of
a chiral protic source. In some cases, these latter methods
become catalytic in chiral inducing entity,7,8 but meticulous
adjustments of the experimental conditions are then required.
The development of catalytic methods in asymmetric protona-
tion of open chain ketone enolates can be complicated by two
main factors: i) in contrast to ester or amide derivatives, these
simple enolates have no additional chelation sites able to
enhance the rigidity of a transition state in coordinating the
chiral protic source9 and ii) Z- and E-enolates can provide
similar10 or opposite4 enantiomers. Currently no rule can
predict the olefin configuration effect; thus, the preparation of a
single enol geometrical isomer is required and is difficult to
achieve.
Table 1 Enantioselective hydrogenolysis–decarboxylation–tautomerization
from 1a
2a
3a
AH*
ee
Run 0.3 eq. T °C Timea/h Yieldb(%) (config.)c Yiledb (%)
1
2
3
4
5
6
7
8
4
4
4
5
5
5
6
6
6
7
22
22
50
22
50
80
0
22
50
22
0.25
1
79
71
58
74
60
62
19
89
81
82
2 (S)
4 (S)
6 (S)
17
22
11
n.d.d
n.d.d
n.d.d
n.d.d
n.d.d
n.d.d
n.d.d
0.25
0.5
0.25
0.17
7e
1
0.37
1.1
5 (S)
10 (S)
10 (S)
16 (S)
10 (S)
9 (S)
9
10
We have shown that 2-carboxy-2-methyltetralone provided
optically active 2-methyltetralone in a two step reaction
consisting of a decarboxylation and an asymmetric protonation
of the resulting enolic species assisted by catalytic amounts of
enantiopure aminoalcohols.11 In acyclic series, a similar
methodology has been studied by Brunner’s group and was also
effective starting from malonic substrates12 [eqn. (1)]; fur-
5 (R)
a Reaction time to reach full conversion of the substrate, as indicated by
TLC. b Isolated yields of purified products. c Enantiomeric excess deter-
mined by HPLC (column Daicel, Chiralcel OD; n-hexane–i-PrOH = 99+1,
0.6 mL min21, tr (R) = 14.1 min, tr (S) = 15.5 min, a = 1.2); configuration
determined by optical rotation comparison:2,17 [a]D20 = +5 (c 1 CHCl3,
eeHPLC = 10%). d Not determined. e Conversion: 35%.
Table 1, it appears that ketone 2a was obtained with good
chemical yields but usually accompanied by alcohol 3a,16
which corresponds to an over-reduction of 2a, the amount of 3a
increasing slowly with the reaction time (runs 1 and 2). As
aminoalcohols, we used (2)-ephedrine (4) and aminoborneol
(5) which gave satisfying results from cyclic substrates,15 and
also cinchonia alkaloids 6 or 7 which afforded good enantio-
selectivities from malonic substrates.12–14 However these chiral
inducing entities led to poor enantioselectivities even in varying
the reaction temperature (Table 1); the results were not
improved by modifying the nature of the supported palladium
catalyst or the solvent (toluene and THF instead of acetoni-
trile).
Then we examined substrate 1b† where the benzyl group in
the 2-position was replaced by a phenyl substituent capable of
stabilizing the enolic species (Table 2). From this substrate
compared to 1a, the chemical yield of ketone 2b increased since
alcohol 3b was not produced. Again the use of 4 and 5 led to no
or low enantioselectivity (runs 11 and 12). In contrast, the
enantiomeric excess of 2b increased dramatically with cincho-
(1)
thermore, this has been applied to the preparation of optically
active naproxen derivatives, the selectivity being higher,
starting from 2-cyano-2-arylpropionic acid13 than from
2-ethoxycarbonyl-2-arylpropionic acid.14
Using this methodology, we envisaged to prepare aliphatic
non racemic ketones. Since we have observed that solutions of
2-carboxy-2-methyltetralone where the acidic group is tertiary
were not stable at rt,11 we decided to start from protected b-
ketoacids. The acidic group was protected as benzylic ester as
the reductive cleavage of the benzyl group would allow a
gradual generation of the acid and of the enolic species. The
in situ generation of the intermediates under palladium–
aminoalcohol catalysis15 could improve both chemical and
optical yields. We present here our results [eqn. (2)].
DOI: 10.1039/b009828k
Chem. Commun., 2001, 533–534
This journal is © The Royal Society of Chemistry 2001
533

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Thus we have shown that, in spite of their non-fixed
geometry, enolic species corresponding to open chain ketones
could be asymmetrically protonated in using a catalytic amount
of commercial cinchonine, the one pot procedure starting from
1 being easily carried out.
We thank Eva Berssen for a few experiments and Socrates
Institution for financial support to M. D. and E. B. who were on
leave from Oldenburg University, Germany. Part of this work
has been carried out in the framework of the COST D12/
0028/99 program. We are grateful to the “Ministère de la
Recherche et de la Technologie” for a PhD studentship to O. R.
and to Engelhard Company for a loan of Pd catalysts.
References and notes
† Selected data for 1: 1a: dH (250 MHz, CDCl3) 7.7–7.8 (m, 2H), 6.9–7.4
(m, 13H), 5.09 (br s, 2H, OCH2Ph), 3.44 (d, 1H, CHHPh, J = 13.7 Hz), 3.35
(d, 1H, CHHPh, J = 13.7 Hz), 1.50 (s, 3H, CH3). 1b: dH (250 MHz, CDCl3)
7.62–7.66 (m, 2H), 7.06–7.50 (m, 13H), 5.16 (d, 1H, OCHHPh, J = 12.6
Hz), 5.08 (d, 1H, OCHHPh, J = 12.6 Hz), 1.94 (s, 3H, CH3).
Table 2 Enantioselective cleavage–decarboxylation–tautomerization from
1b at room temperature
2b
Run Solvent AH* (eq.)
Timea/h Yielda (%) ee (config.)b
1 Reviews: J. S. McCallum and L. S. Liebeskind, in Stereoselective
Synthesis (Houben-Weyl), ed. G. Helmchen, R. W. Hoffmann, J. Mulzer
and E. Schaumann, Thieme Verlag: New York, 1996, p. 916. P. Fey and
W. Hartwig, ibid, p. 969. P. Fey, ibid, p. 1030.
2 W. Oppolzer, C. Darcel, P. Rochet, S. Rosset and J. De Brabander, Helv.
Chim. Acta, 1997, 80, 1319.
3 P. Duhamel, in Stereoselective Synthesis (Houben-Weyl), ed. G.
Helmchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Thieme
Verlag: New York, 1996, p. 1101.
4 C. Fehr and J. Galindo, J. Am. Chem. Soc., 1988, 110, 6909.
5 K. Ishibara, H. Nakamura and H. Yamamoto, J. Am. Chem. Soc., 1999,
121, 7720.
6 For examples: Ref. 4; J. Pracejus and H. Mätje, J. Prakt. Chem., 1964,
24, 195; Y. Nakamura, S. Takeuchi, Y. Ohgo, M. Yamaoka, A. Yoshida
and K. Mikami, Tetrahedron, 1999, 55, 4595.
7 C. Fehr and J. Galindo, Angew. Chem., Int. Ed. Engl., 1994, 33,
1888.
8 Y. Nakamura, S. Takeuchi, A. Ohira and Y. Ohgo, Tetrahedron Lett.,
1996, 37, 2805; S. Takeuchi, Y. Nakamura, Y. Ohgo and D. P. Curran,
Tetrahedron Lett., 1998, 39, 8691; B. L. Hodous, J. C. Ruble and G. C.
Fu, J. Am. Chem. Soc., 1999, 121, 2637.
9 C. Fehr, Angew. Chem., Int. Ed. Engl., 1996, 35, 2566.
10 F. Hénin, S. Létinois and J. Muzart, Tetrahedron: Asymmetry, 2000, 11,
2037 and references cited therein.
11
12
13
14
15
16
17
MeCN
4 (0.3)
5 (0.3)
6 (0.3)
7 (0.3)
7 (0.5)
7 (0.1)
Adsorbedc
7 (0.3)
7 (0.3)
7 (0.3)
7 (0.05)
Adsorbedc
7 (0.3)
1
97
85
70
94
100
100
0
”
”
”
”
”
”
0.5
0.5
1
1
1
16 (S)
49 (S)
56 (R)
56 (R)
61 (R)
7
17
1
2
95
85
100
100
64 (R)
52 (R)
71 (R)
68 (R)
18
19
20
21
THF
AcOEt
”
”
8
49d
70 (R)
a See Table 1. b Enantiomeric excess determined by HPLC (column Daicel,
Chiralcel OD; n-hexane–i-PrOH = 99+1, 0.6 mL min21, tr (R) = 11.8 min,
tr (S) = 13.9 min, a = 1.46); configuration determined by optical rotation
comparison:2,18 [a]D20
= +167 (c 1.2 CHCl3, eeHPLC =
71%). c The
suspension is prepared as following: the palladium on charcoal is added to
a solution of 7 in chloroform; then the solvent is evaporated under reduced
pressure and replaced by the solution of the substrate in MeCN or AcOEt.
d Only 49% of conversion.
11 F. Hénin, J. Muzart, M. Nedjma and H. Rau, Monatsh. Chem., 1997,
128, 1181.
12 H. Brunner, J. Müller and J. Spitzer, Monatsh. Chem., 1996, 127,
845.
nia aminoalcohols; indeed we observed 49 and 56% ee with
cinchonidine (6) (run 13) and cinchonine (7) (run 14) re-
spectively. As these latter chirality inductors were insoluble in
acetonitrile, we studied the effects of the amount of 7 and of its
distribution in the medium. As expected, increasing the amount
of 7 from 0.3 (run 14) to 0.5 eq. (run 15) did not change the
selectivity. Dropping to 0.1 eq. the amount of 7 was not
detrimental to both chemical yield and ee (run 16). Adsorbing 7
on the supported catalyst by its dissolution in chloroform
followed by a solvent exchange allowed a slight increase of the
enantioselectivity, but a concomitant decrease of the reaction
rate (run 17). Switching from acetonitrile to THF led to a slower
reaction and a decreased ee (run 18). The best solvent for both
yield and ee was ethyl acetate, since ee could reach 71% for a
quantitative chemical yield (runs 19); even in the presence of
only 0.05 eq. of 7, ee remained high (68%, run 20). In this
solvent however, the adsorption of 7 on palladium on charcoal
was detrimental to the conversion without change of the ee.
13 H. Brunner and P. Schmidt, Eur. J. Org. Chem., 2000, 2119.
14 H. Brunner and P. Schmidt, Z. Naturforsch., 2000, 55b, 369.
15 J. Muzart, F. Hénin and S. Jamal Aboulhoda, Tetrahedron: Asymmetry,
1997, 8, 381; S. Jamal Aboulhoda, I. Reiners, J. Wilken, F. Hénin, J.
Martens and J. Muzart, Tetrahedron: Asymmetry, 1998, 9, 1847.
16 A syn relative configuration has been determined for the diastereomer in
slight excess (around 55±3%) which could be compared with analogous
values observed for 3a resulting of the hydride reduction of 2a: C.
Alvarez Ibarra, F. Fernandez Gonzalez, M. L. Quiroga Feijoo and J.
Santoro, An. Quim., 1978, 74, 449; C. Alvarez Ibarra, R. Pérez-Ossorio,
M. L. Quiroga, M. S. Arias Pérez and M J. Fernandez Dominguez,
J. Chem. Soc., Perkin Trans. 2, 1988, 101.
17 T. Izawa, Y. Terao and K. Suzuki, Tetrahedron: Asymmetry, 1997, 8,
2645.
18 A. I. Meyers, D. R. Williams, S. White and G. W. Erickson, J. Am.
Chem. Soc., 1981, 103, 3088.
534
Chem. Commun., 2001, 533–534