SUPRAphos-based palladium catalysts for the kinetic resolution of racemic cyclohexenyl acetate

Article abstract of DOI:10.1039/b700156h

High-throughput screening of the SUPRAphos library revealed a palladium catalyst based on supramolecular ligands that gave fast and highly efficient kinetic resolution of cyclohexenyl acetate with an S-value up to 12. The Royal Society of Chemistry.

Full text of DOI:10.1039/b700156h

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SUPRAphos-based palladium catalysts for the kinetic resolution of
racemic cyclohexenyl acetate{
Xiao-Bin Jiang, Piet W. N. M. van Leeuwen and Joost N. H. Reek*
Received (in Cambridge, UK) 5th January 2007, Accepted 8th February 2007
First published as an Advance Article on the web 6th March 2007
DOI: 10.1039/b700156h
High-throughput screening of the SUPRAphos library revealed
a palladium catalyst based on supramolecular ligands that gave
fast and highly efficient kinetic resolution of cyclohexenyl
acetate with an S-value up to 12.
The palladium catalyzed asymmetric allylic alkylation for the
formation of C–C and C–heteroatom bonds is an intensively
1
explored reaction that finds application in organic synthesis.
Numerous chiral catalysts reported in the literature provide the
product in high enantioselectivities (ee’s), especially when 1,3-
1
diphenylpropenyl acetate is used as the model substrate. Interest-
ingly, for other substrates such as 1,3-dimethylpropenyl acetate and
cyclic ones (5–7 membered rings), there is only a limited number of
Scheme 1 Schematic representation of a supramolecular bidentate
ligand and a typical example from the SUPRAphos library that forms
via a zinc(II) porphyrin–pyridyl interaction.
1,2
chiral catalysts available that induce high enantioselectivity.
3
Palladium catalysts can also be used for kinetic resolution, a
process in which one of the enantiomers of the racemic starting
material is converted to the desired product while the other
enantiomer is recovered unchanged. Kinetic resolution can be very
powerful because extremely high enantiopurities can be achieved,
3
albeit at the cost of the yield in less favourable cases. In most
Scheme 2 Schematic representation of kinetic resolution of rac-1.
examples in which metal catalysts are used both enantiomers of the
3–6
substrate show some reactivity towards the catalyst. While the
palladium catalyzed allylic substitution reaction has been widely
studied, relatively few catalysts have been reported in the literature
kinetic resolution of rac-1 (Table 1). We simultaneously monitored
the conversion, the ee of substrate 1, and that of product 2. Hot
spots for high conversions and ee’s are displayed in red in Table 1.
It should be noted that for kinetic resolution we aim for 50%
conversion (100% of one enantiomer).
7–9
for kinetic resolution. A plausible mechanism for the kinetic
resolution of cyclohexenyl acetate using palladium bisphosphine
8
ligands was reported in 1998.
10,11
We,
The SUPRAphos library contains phosphine–phosphite as well
as bisphosphite type ligands and in control experiments we also
used L91–L94 as chiral, monodentate ligands (the last column of
Table 1). Inspection of Table 1 reveals that a few catalysts based
on heterobidentate supramolecular ligands give rise to kinetic
resolution of rac-1; four catalysts provide substrate 1 in 99% ee at a
12
and others, have recently introduced a new class of
bidentate ligands which form via self-assembly of two mono-
dentate ligands (Scheme 1). We have used the zinc(II)porphyrin–
pyridine interaction as an assembly motif to generate bidentate
phosphorus-based ligands. With the use of a small number of
building blocks a large library of (hetero-)bidentate phosphorus
1
0b,d
ligands
formylation,
allylic alkylation.
was generated that was successfully used in hydro-
1
0a,b,c
10d
asymmetric hydrogenation, and asymmetric
10c,d
Here we report for the first time a
combinatorial approach to search for novel catalysts for the
kinetic resolution of cyclohexenyl acetate rac-1 (Scheme 2), using
the SUPRAphos ligand library (building blocks L91–L94, Fig. 1
and L1–L15, Fig. 2).
We screened the catalysts library based on SUPRAphos ligands
L91–L94 (Fig. 1) and L1–L15 (Fig. 2) in the palladium catalyzed
Supramolecular and Homogeneous Catalysis, van’t Hoff Institute for
Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht
1
66, Amsterdam, 1018 WV, The Netherlands.
E-mail: reek@science.uva.nl; Fax: +31 20 5255604; Tel: +31 20 5256437
Electronic supplementary information (ESI) available: experimental
{
details and catalysis results. See DOI: 10.1039/b700156h
Fig. 1 Structures of porphyrin functionalized phosphites (L9n).
Chem. Commun., 2007, 2287–2289 | 2287
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Fig. 3 Kinetic resolution of rac-1 with Pd(L91/L5) in CH
2 2
Cl . For
general conditions see footnote.
substrate increases with time (and conversion) whereas that of the
product remains the same (Fig. 3). After 30 min the conversion
reached 69%, and the ee of the remaining 31% substrate (S)-1
reached 99%, equivalent to an S-value of 12. In contrast to what is
usually found for kinetic resolution experiments, the ee of the
product (R)-2 is only moderate (31%) and, as usual, of the
opposite enantiomeric form.
Fig. 2 Structures of N-containing phosphorus ligands (Ln).
conversion between 69 and 84%. As second best result we obtained
3
6% ee only for the substrate. The four best catalysts had in com-
We have explored various reaction conditions to optimize the
selectivity and activity of the system. In other solvents such
mon that the ligand consisted of L91 and an ortho-pyridyl func-
tionalized phosphine and we decided to study these in more detail.
We monitored the progress of the reaction with time at room
as THF, EtOAc and CH CN the kinetic resolution was lower than
3
that found in CH Cl and the reaction times required in THF,
2
2
temperature in CH Cl
2
2
using SUPRAphos ligand L91/L5 and
EtOAc and CH CN are much longer (16 h). A result comparable
3
3
Pd(g -C
[
3
H
5
)Cl]
2
as the palladium precursor (1 mol%), rac-1 as the
to that in CH Cl was found in toluene (see supporting informa-
2
2
substrate and dimethyl malonate as the nucleophile. We obtained
curves that are typical of kinetic resolution; the ee of unreacted
tion for details). The lower rates may be due to (1) the much lower
solubility of porphyrin–phosphite L91 in these solvents compared
2 2
to CH Cl or (2) to solvent coordination to palladium or zinc.
Table 1 Kinetic resolution of rac-1 using palladium catalysts based
on various SUPRAphos ligands L9n/Ln
Upon changing the metal/ligands ratios of Pd/L91/L5, the
reactivity and enantioselectivity varied substantially, but results
could not be improved (see supporting information for details). A
ratio of 1/1.5/1.2 gave the highest kinetic resolution. In the presence
of an excess of achiral ligand L5, catalysis by the complexes of
a
2
Pd(L5) species becomes dominant and no enantioselectivity is
obtained. With substoichiometric amounts of ligands, e.g. a ratio
of 1/0.5/0.45, the reaction becomes extremely slow and non-
enantioselective. Lower temperatures did not lead to better results.
Elevating the temperature to 40 uC accelerated the reaction and
after 10 min the conversion reaches 75% with 99% ee of (S)-1
2
1
21
(
TOF 450 mol?mol ?h ). We also investigated the influence of
the palladium precursors on the kinetic resolution (see supporting
3
information for details). [Pd(g -C H )Cl] gave the fastest reaction
3 5 2
and the highest resolution. The use of Pd(0) species led to forma-
tion of the active catalyst, but, due to slow exchange of dba by
phosphorus ligands and substrate, the reaction is much slower.
a
3
General conditions: [Pd(g -C
Ln 1/1.5/1.2 with respect to Pd, 20 eq. dipea
diisopropylethylamine), 1 mmol (0.25 mM) of rac-1 in CH Cl
unless otherwise noted, 3 mmol dimethyl malonate, 3 mmol
3 5 2
H )Cl] , 1 mol% Pd, Pd/L9n/
5
2
The combination of Pd(COD)Cl and L91/L5 did not lead to any
(
2
2
,
conversion.
13
BSA, catalytic amount of KOAc, RT, inert conditions (dried
). The ee of the substrate and conversion of the reaction were
determined by ultra fast GC on chiral column (Diethyl
Terbutyl Silyl Beta in PS086), Interscience , t
5 9.1 min, the absolute configuration was compared with the
We also studied the scope of nucleophiles that can be used; the
size of the nucleophiles has been varied systematically by replacing
the methyl groups of the malonate ester for larger ones (Me, Et,
i-Pr, t-Bu, Bn). The palladium catalyst based on L91/L5 was
reasonably tolerant to these changes as with all nucleophiles,
except for the t-butyl ester (60% ee at 70% conversion), a high ee
N
2
a
1
S
1 5 8.5 min,
t
R
7
f,8
literature.
GC, b-Dex column, t
configuration was compared with the literature.
The ee (%) of the product was determined by chiral
R
5 69.9 min, t 5 70.8 min, the absolute
S
7
f,8
S 5 K
5 ln(1 2 C)(1 2 E)/ln(1 2 C)(1 + E), C 5 conv%/100,
ee%/100. In the last column the results of control
R
/
(99%) for the substrate was observed at conversions between 69
K
S
E
5
and 80%. An increase of the steric bulk of the nucleophiles (Me,
Et, i-Pr, t-Bu, Bn) leads to a small decrease of the resolution and a
lower rate of reaction was observed (see supporting information
experiments are displayed in which the ligands have been used as
monodentates (L9n : Pd 5 2.2).
2
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Compared to m-pyridyl phosphine L2, that in combination with
L91 provides a palladium catalyst that shows no kinetic resolution,
the o-pyridyl phosphines L3, L5–7 (providing selective catalysts
with L91) interact more weakly with Zn-porphyrin. Indeed, UV–
Vis measurements for the complexes of Pd/L91/L3, L5–L6 and Pd/
L91 and Pd/L91/L2 showed that pyridyl coordination of L3, L5
and L6 to the zinc porphyrin of L91 is not complete, leaving the
pyridyl function partly in the free state. The weaker interaction,
and thus the partly free pyridyl, may be responsible for the peculiar
enantioselective behaviour of the catalysts described in this paper
that give rise to kinetic resolution. It is important to note that the
5 Recent reviews on non-enzymatic catalysts in kinetic resolution, see: (a)
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7
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F. Gerhards, M. Frank and G. Raabe, Tetrahedron: Asymmetry, 1998,
3
palladium catalyst based on PPh and L91 gives rise to low ee of
the substrate and the product, demonstrating that the weak
interaction between the two ligands in Pd(L91)(L3) is important for
its performance.
9
3
2
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511; (d) H.-J. Gais, N. Spalthoff, T. Jagusch, M. Frank and G. Raabe,
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ee’s of the S enantiomer above conversions of 60% at high rates
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2
1
21
TOF 450 mol?mol ?h ), but the ee of the product is low (30%)
(
5435; (g) T. Okauchi, K. Fujita, T. Ohtaguro, S. Ohshima and
and opposite, albeit constant during the reaction. The combination
of a high kinetic resolution and a low ee of the product is
remarkable as usually a catalyst will lead to acceptable ee’s of the
product and a poor kinetic resolution. The currently accepted view
is that the transition state for the oxidative addition is similar to
that of the nucleophilic attack, explaining why usually high kinetic
resolution is accompanied by high ee of the product. The main
difference between the current system and those previously
reported is the dynamic character of the ligand, enabling the
catalyst to change its coordination sphere during the various
reaction steps. For instance, a decoordination of the achiral
pyridylphosphine ligands from the zinc is envisaged, which could
either result in coordination to palladium or cause deracemization
of the substrate attached to the palladium. Future research will
study these processes in more detail and we will explore this type of
adaptive supramolecular catalysts in other reactions to see if this
principle can be generalized.
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8
9 Examples of palladium mediated kinetic resolution of acyclic substrates
via allylic alkylation, see: (a) B. M. Trost, R. C. Bunt, R. C. Lemoine
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1
NWO and DSM are gratefully acknowledged for financial
support.
Notes and references
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2
3
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4
Recent reviews on kinetic resolution with enzymes, see: (a) A. Archelas
and R. Furstoss, Curr. Opin. Chem. Biol., 2001, 5, 112; (b) A. Steinreiber
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