Chiral calix[4]arene-based diphosphites as ligands in the asymmetric hydrogenation of prochiral olefins

Article abstract of DOI:10.1002/ejic.200700764

Chiral calixarene-based diphosphite ligands 3a-d have been obtained via lower-rim functionalisation of the p-tert-butylcalix[4]arene core. High enantiomeric excesses (up to 94%) and good activities were obtained in the rhodium-catalyzed asymmetric hydroge

Full text of DOI:10.1002/ejic.200700764

SHORT COMMUNICATION
DOI: 10.1002/ejic.200700764
Chiral Calix[4]arene-Based Diphosphites as Ligands in the Asymmetric
Hydrogenation of Prochiral Olefins
Angelica Marson,[a] Zoraida Freixa,[b] Paul C. J. Kamer,*[c] and
Piet W. N. M. van Leeuwen*[a]
Keywords: Homogeneous catalysis / Stereoselective catalysis / Asymmetric hydrogenation / Calixarenes / Diphosphites
Chiral calixarene-based diphosphite ligands 3a–d have been
obtained via lower-rim functionalisation of the p-tert-butyl-
calix[4]arene core. High enantiomeric excesses (up to 94%)
and good activities were obtained in the rhodium-catalyzed
asymmetric hydrogenation of prochiral olefins with
TADDOL-containing diphosphites 3c,d. This is the first
example of chiral calix[4]arene-modified ligands that induce
high enantioselectivity in metal-catalysed asymmetric reac-
tions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
mimicking enzymes, impose steric confinement on metal
and substrates in addition to the well-explored ligand ef-
fects.
Introduction
Asymmetric reactions catalysed by transition metals are
among the most efficient methods for preparing a wide
range of enantiomerically pure compounds.[1] The tremen-
dous achievements in organometallic chemistry have re-
sulted in fundamental understanding of elementary steps
and consequently in many examples of rational ligand de-
sign.[2] Still, the rates and selectivity of enzymatic catalysis
are seldom equalled by transition metal catalysis. Chemical
transformations catalyzed by enzymes often operate via
complicated mechanisms and require large and sophisti-
cated protein structures that have been obtained after mil-
lions of years of evolution. Although nowadays enzymes
are applied successfully in many chemical conversions, their
substrate specificity can be too high in certain cases and the
biological reaction conditions might be not wanted. This is
why the majority of industrial processes is based on man-
made catalysts. Many attempts are being made to obtain
efficient catalysts that can compete with enzymes in sub-
strate-selectivity and activity, such as incorporation of tran-
sition metal complexes in proteins and antibodies.[3] To
bridge the gap between enzyme and transition metal cata-
lysts it is important to develop new catalyst systems that,
Calixarenes form a suitable scaffold for the development
of new bulky and structurally well-defined ligands.[4] The
combination of calixarene cavities with catalytic centres
might lead to shape-selective catalysts, adding this success-
fully exploited feature of biological systems to transition
metal catalysis. Although the number of successful applica-
tions of the shape selectivity of calixarene-based catalysts is
growing,[5] high selectivities in asymmetric catalysis have
not been achieved so far.[6]
From the different functionalities that one can consider,
phosphite ligands proved their adequacy in many transition
metal-catalysed reactions such as hydrogenation, hydrofor-
mylation, hydrocyanation and allylic alkylation.[2]
Results and Discussion
Here we report on the asymmetric hydrogenation of pro-
chiral olefins, as model reaction, using enantiopure ca-
lix[4],BINOL- and calix[4],TADDOL-containing diphos-
phites. The effective formation of a shape defined active site
is achieved by directly attaching three of the hydroxy groups
of the calix[4]arene through µ3-bridging phosphorus atom.
[a] Van’t Hoff Institute for Molecular Sciences, University of Am-
sterdam,
Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Nether- In this way, these new C1-symmetric bidentate ligands,
lands
which combine the intrinsic steric bulk of the calix[4]arene
Fax: +31-20-525-5604
scaffold with a stereocentre located on a phosphite pendent
arm linked to the lower rim of the calix[4]-cavity, represent
the first class of chiral calix[4]arene-modified ligands to be
reported in literature and successfully applied in metal-cata-
lysed asymmetric reactions. In order to gain information
about the potential of such type of ligands, we carried out
some preliminary investigations on two different types of
E-mail: pwnm@science.uva.nl
[b] Institute of Chemical Research of Catalonia (ICIQ),
Av. Països Catalans 16, 43007 Tarragona, Spain
[c] School of Chemistry, University of St Andrews,
St. Andrews, Fife, KY16 9ST, United Kingdom
Fax: +44-1334-467285
E-mail: pcjk@st-and.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
Eur. J. Inorg. Chem. 2007, 4587–4591
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A. Marson, Z. Freixa, P. C. J. Kamer, P. W. N. M. van Leeuwen
SHORT COMMUNICATION
chiral moieties and by comparing the role of the stereocen- strongly affects the product distribution. As expected, the
tre, we evaluated the efficacy of the ligand systems and their more sterically hindered fragments (i.e. TADDOL-PCl c,d)
catalytic performances.
afford mainly monofunctionalised products, while with the
Chiral diphosphite ligands 3a–d were prepared through bare BINOL derivatives a,b the two fractions are obtained
a two-step synthesis according to reported calixarenes- in a 1:1 ratio. Nevertheless, no further purification was car-
phosphorylation procedures (Scheme 1).[5g] Since the se- ried out on the isolated crude products, which were treated
quence in which the two steps are followed is crucial in or- in the second step with an excess of PCl3/NEt3 to give, after
der to obtain diphosphites in the appropriate cone confor- chromatographic separation, the pure chiral diphosphite
mation,[5d,7] p-tert-butylcalix[4]arene 1 was firstly treated products 3a–d. Thus, the resulting calix[4],BINOL- (3a,b)
with one equivalent of nBuLi in THF at room temperature and calix[4],TADDOL-based diphosphites 3c,d are charac-
and then reacted with one equivalent of chiral phosphor- terised by the presence of one phosphorus atom, acting as
ochloridites (a–d),[8,9] affording the monofunctionalised ca- a triple µ3-O,O,O bridge, at the lower rim of the calix[4]-
lix[4]arene intermediates 2a–d. In the present study, we fo- cavity and a second phosphorus atom on a pendent chiral
cused our attention on chiral units derived from commer- unit.
cially available diols such as (R)- and (S)-BINOL [(R)-, (S)-
The 31P NMR spectra show in all cases two distinctive
2,2Ј-dihydroxy-1,1Ј-binaphthyl] and (R,R)- and (S,S)- singlets for the two non-equivalent phosphite moieties of
TADDOL [(R,R)-, (S,S)-2,2-dimethyl-α,α,αЈ,αЈ-tetraphen- each ligand: one at δ = 104 ppm for the µ3-bridging phos-
yldioxolane-4,5-dimethanol] which allow an economically phorus atom and one for the chiral fragment-containing
attractive preparative method of bidentate ligands and a phosphite (δ = 147 ppm for BINOL derivatives 3a,b; δ =
fast and efficient preliminary investigation of the catalytic 140 ppm for TADDOL derivatives 3c,d respectively). Both
performances of the corresponding metal complexes.
chemical shifts fall into the expected ranges for calix[4]-
based µ3-bridging phosphites,[5d,5g] and for TADDOL- or
BINOL-based phosphite ligands.[10] Also in the corre-
sponding 1H NMR spectra, ligands 3a–d show similar spec-
troscopic features. The four tert-butyl signals and the four
AB patterns for the bridging methylene units (ArCH2Ar),
with AB separations larger than 1 ppm, clearly prove the
C1 symmetry of these structures and the overall cone con-
formation of the calix[4]arene backbone This geometry was
further confirmed by the 13C NMR spectra in which some
of the signals for the ArCH2Ar fall into the expected range
for syn-oriented phenolic neighbours (ca. 35–36 ppm),
while others fall in an intermediate range of values (ca. 36–
37 ppm).[5g,11] It should be recalled that, due to the strain
imposed by the very short µ3-bridging phosphite unit, the
observation of signals with an intermediate chemical shift
might be interpreted in terms of partial flattening of the
calixarene core.
Investigations have been carried out to define the coordi-
nation chemistry of diphosphites 3a,d and assess their che-
lating abilities towards square planar RhI precursors. The
complexation reaction of ligands 3a,c with one equivalent
of [Rh(nbd)2BF4] (nbd = 2,5-norbornadiene) in dichloro-
methane solution proceeds rapidly. Displacement of one
molecule of 2,5-norbornadiene occurs after 30 minutes at
room temperature whilst stirring, affording complexes
[Rh(nbd)(P1ʝP2)][BF4] (4a,c). The corresponding 31P
NMR spectra showed two distinctive double doublets as a
result of phosphorus–rhodium and phosphorus–phospho-
rus couplings [1J(Rh,P1) = 274 Hz, 1J(Rh,P2) = 265 Hz and
1
1
2J(P1,P2) = 83 Hz (4a); J(Rh,P1) = 265 Hz, J(Rh,P2) =
249 Hz and J(P1,P2) = 81 (4c)].
2
Scheme 1. Synthesis of chiral calix[4]arene-based diphosphites 3a–d.
The observed rhodium–phosphorus coupling constants
are very similar to those reported for [Rh(diolefin)(P1ʝP2)]+
The first reaction step is not very selective towards rhodium complexes with coordinated diphosphite ligands,
monofunctionalisation and gives rise to the formation of while the coupling constants between the two non-equiva-
by-products, like 1,3-disubstituted calix[4]arenes. We ob- lent phosphorus atoms are larger than expected.[12] Coup-
served that the steric bulk of the phosphorochloridites ling constants between 27 and 50 Hz are generally observed
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Asymmetric Hydrogenation of Prochiral Olefins
ane, was chosen as the test reaction and the activity and
the enantioselectivity of the catalyst precursors evaluated at
different reaction conditions (Table 1). Initially the ligand
to rhodium ratio was kept constant at 1.5 (entries 1 and 6),
then the reaction time and the substrate/rhodium ratios
were changed from 20 h to 4 h (entries 2 and 7) and from
100 to 1000 (entries 3 and 8), respectively.
(1)
Table 1. Asymmetric hydrogenation of prochiral olefins with
[Rh(nbd)2BF4] and ligands 3a–d.[a]
Entry
Ligand Substrate % Conv. (t [h])[b] % ee (config.)[c]
1
2
3a
3a
3a
3a
3a
3c
3c
3c
3c
3c
3b
3d
A
A
A
A
B
A
A
A
A
B
A
A
100 (20)
100 (4)
100 (4)
60 (20)
100 (20)
100 (20)
100 (4)
100 (4)
100 (20)
100 (20)
100 (20)
100 (20)
74 (R)
74 (R)
76 (R)
20 (S)
32 (R)
92 (R)
92 (R)
94 (R)
92 (R)
94 (R)
75 (S)
92 (S)
3[d]
4[e]
5
6
7
8[d]
9[f]
10
11
between the two non-equivalent phosphorus atoms in rela-
tive cis positions. Lowering the temperature to 193 K did
not result in any additional splitting of the 31P NMR sig-
nals, which indicates that, for both rhodium complexes 4a,c, 12
only one isomer is present in solution. Clearly, this might
represent an advantage in terms of enantioselectivity when
these complexes are employed as catalysts in asymmetric
transformations.
Chiral diphosphites 3a–d were tested as ligands in the
asymmetric rhodium-catalysed hydrogenation and of pro-
chiral olefins using [Rh(nbd)2BF4] as metal precursor. Cata-
[a] Standard conditions: [Rh] = 1 m; [ligand]/[Rh] = 1.5; [sub-
strate]/[Rh] = 100; solvent = CH2Cl2 (2.0 mL); p = 5 bar; T = 25 °C;
catalyst precursors prepared in situ. [b] Percent conversion mea-
sured by GC. [c] Percent enantiomeric excess measured by chiral
GC. [d] [substrate]/[Rh] = 1000. [e] Solvent: CH2Cl2/toluene, 1:3.
[f] [ligand]/[Rh] = 5.
The results summarised in Table 1 show that the catalytic
lytic experiments were run in a parallel manner using an systems obtained with diphosphites 3a,c are very active in
autoclave equipped with 5, 8, or 15 mini-reactors (see Sup- the hydrogenation of dimethyl itaconate (A) and, although
porting Information for details). The catalyst precursors a standard reaction time of 20 h was chosen, complete con-
were formed in situ by mixing metal complexes with ligands version was already reached after 4 h. The increase of the
3a–d under inert atmosphere. The autoclave was purged ligand to rhodium ratio or the substrate to rhodium ratio
four times with hydrogen and then charged with the appro- does not have a negative effect on the activity of the re-
priate gas pressure.
ported catalytic systems, which still afford high enantio-
The rhodium-catalysed hydrogenation, carried out under selectivities (ee up to 94%) and full conversions after 4 h
mild conditions (25 °C, 5 bar H2), was examined as model reaction time. In one case (entry 4) the solvent of the reac-
reaction employing dimethyl itaconate (A) and α-(acyl- tion was changed to a mixture of dichloromethane/toluene
amino)acrylate (B) as representative substrates. Parallel ex- (1:3) showing that the efficiency of the process depends
periments were run employing a standard substrate/rho- strongly on the nature of solvent employed, and that the
dium ratio of 100 and using catalyst precursors formed in catalyst performance, both in terms of activity and enantio-
situ by mixing ligands 3a,c with [Rh(nbd)2BF4]. The forma- selectivity, was best when pure dichloromethane was used.
tion of the active species [Rh(P1ʝP2)(solvent)2][BF4], gener- Interestingly, opposite stereoinduction was observed in this
ated by removal of the diolefin, is generally faster when it case. It should be noted that rhodium-catalysed asymmetric
involves the hydrogenation of the more reactive norbornad- hydrogenation reactions are commonly performed in meth-
iene rather than that of cyclooctadiene.[13] Different out- anol, but since phosphite ligands are known to decompose
comes have been observed, regarding both the activity and in protic solvents,[14] further hydrogenation reactions were
the selectivity of the catalytic process, depending on the na- studied using dichloromethane.
ture of the substrate and of the diphosphite used.
Ligand 3c, which contains the bulky TADDOL moiety,
The hydrogenation of dimethyl itaconate providing di- affords the best catalyst, reaching enantioselectivities
methyl methylsuccinate [A; Equation (1)], in dichlorometh- around 92% in all experiments. The results obtained with
Eur. J. Inorg. Chem. 2007, 4587–4591
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4589

A. Marson, Z. Freixa, P. C. J. Kamer, P. W. N. M. van Leeuwen
SHORT COMMUNICATION
Supporting Information (see also the footnote on the first page of
this article): Catalyst preparation, synthetic and catalytic pro-
cedures.
ligand 3a follow the same trend as observed for ligand 3c,
but the enantioselectivities are somewhat lower. As it would
be expected by less bulky ligands, the asymmetric induc-
tions with precursors containing ligand 3a are lower than
those with ligand 3c. Besides ligands 3a,c, which were used
extensively in these catalytic investigations, their enantio-
mers, namely ligands 3b,d, were also employed in analogous
hydrogenation experiments showing, as expected, identical
results but with opposite stereoinduction (entries 11,12).
We also studied the hydrogenation of α-(acylamino)acry-
lates [Equation (2)] under standard reaction conditions. Hy-
drogenation of methyl α-acetamidoacrylate [B; Equation
(2)] giving the alanine derivative afforded high enantio-
selectivity (ee = 94%) with ligand 3c, while a low value of
32% was obtained with ligand 3a. In both cases complete
conversion was reached after 20 h reaction time (entries
5,10).
Acknowledgments
This research was financed by the Division of Chemical Sciences
of the Netherlands Organization for Scientific Research (NWO-
CW).
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Conclusions
We have synthesized novel chiral diphosphite ligands
built up on calix[4]arene backbones and characterised by a
C1 symmetry. We employed these ligands in the rhodium-
catalysed hydrogenation of prochiral olefins, reaching excel-
lent activities and enantioselectivities in the hydrogenation
of dimethyl itaconate and methyl α-acetamidoacrylate. The
best enantioselectivities have been obtained for both sub-
strates with the same, most bulky, ligand. These preliminary
investigations demonstrated for the first time that calix[4]-
arene-based C1-symmetric diphosphites can be successfully
applied in metal-catalysed asymmetric transformations.
Due to their ease of preparation, different classes of chiral
bidentates can be generated, for example, by systematic
variation of the steric and electronic properties of the ste-
reocentre linked to the lower rim of the calix[4]-cavity. Thus,
the results reported herein have to be considered as an im-
portant starting point and further study of this promising
type of ligands in homogeneous catalysis is in progress.
Experimental Section
Experimental details for all compounds and procedures are given
in the Supporting Information.
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Asymmetric Hydrogenation of Prochiral Olefins
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Received: July 19, 2007
Published Online: September 4, 2007
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