Parallel synthesis and screening of polymer-supported phosphorus- stereogenic aminophosphane-phosphite and -phosphinite ligands

Article abstract of DOI:10.1002/anie.200801689

(Chemical Equation Presented) Bound to Ps: An efficient, rapid, parallel solid-phase synthesis of a series of resin-bound P-stereogenic aminophosphane-phosphinite and -phosphite ligands is developed (see scheme).The ligands form active hydrogenation catal

Full text of DOI:10.1002/anie.200801689

Communications
DOI: 10.1002/anie.200801689
Immobilized Catalysts
Parallel Synthesis and Screening of Polymer-Supported Phosphorus-
Stereogenic Aminophosphane–Phosphite and –Phosphinite Ligands**
RenØ den Heeten, Bert H. G. Swennenhuis, Piet W. N. M. van Leeuwen, Johannes G. de Vries,
and Paul C. J. Kamer*
In the past there has been a renewed interest in developing
polymer-bound ligands and the corresponding catalysts. The
primary advantages of polymer-supported ligands are the
ease of purification during the synthesis and the ability to
[1]
recover and reuse both the transition metal and the ligand.
Resin-bound chiral ligands have proven their efficiency in
Scheme 1. Modular synthesis of aminophosphane ligands.
[
2]
asymmetric catalysis. The combinatorial synthesis and
screening of chiral ligand libraries is an efficient method for
[3]
finding enantioselective catalysts and a number of successful
However, these types of ligands have all been developed in
the traditional synthetic way requiring troublesome and
laborious ligand optimization. A generally applicable combi-
natorial approach has not been developed yet because the
synthetic methodology is still lacking. To assemble libraries of
these chiral ligands the development of an efficient solid-
phase methodology is pivotal, not only to allow automated
synthesis but also to circumvent work-up and purification
problems, inherent to solution-phase synthesis.
[
4,5]
approaches have been reported.
Although solid-phase
organic synthesis (SPOS) has proven its efficiency in high-
speed routes towards chemical libraries, surprisingly, exam-
ples in which SPOS is applied in the combinatorial synthesis
[
6]
and screening of phosphorus ligands are rare. Recently, we
reported the solid-phase parallel synthesis of a variety of
[
7]
phosphites and phosphoramidites. Herein, we report an
efficient route for the parallel synthesis of polymer-supported
phosphorus-stereogenic aminophosphane–phosphite and
aminophosphane–phosphinite bidentate ligands, as well as
their application in rhodium-catalyzed asymmetric hydro-
genation.
Following the general synthetic route developed by JugØ
[
8]
and co-workers (Scheme 1), we developed the following
[
10]
route towards supported analogues.
The reaction of
1
oxazaphospholidine borane 1a (R = phenyl) with the lithi-
[11]
P-stereogenic aminophosphane–phosphite and amino-
phosphane–phosphinite ligands (3, Scheme 1) have success-
ated analogue 5 (Scheme 2)
of 4-bromo functionalized
polystyrene 4 yielded a white resin that, based on the
[8]
fully been applied in asymmetric hydrogenation and hydro-
chemical shift of the relatively sharp resonance signal
[
9]
31
[12]
formylation. As a result of the modular structure of this class
of ligands, there is an enormous potential for ligand fine-
observed in its gel-phase
P NMR
spectrum (d =
71.4ppm), was identified as 2a (Scheme 2). To create
structural diversity, we synthesized oxazaphospholidine bor-
anes 1a–f and the subsequent reaction with 5 yielded
aminophosphane boranes 2a–f. Oxazaphospholidine boranes
1b, 1c, and 1d were obtained using a method described by
1
2
3
tuning (R , R , and R ), which makes them ideal candidates
for the parallel synthesis of (supported) ligand libraries.
[*] Prof. Dr. P. C. J. Kamer
[13]
EaStCHEM, School of Chemistry
University of St. Andrews
St. Andrews, Fife, KY16 9ST (United Kingdom)
Fax: (+44)-1334-463808
JugØ et al. for the synthesis of 1a (route A, Scheme 2).
Based on a procedure developed by Ziao et al., 1 f was
[14]
synthesized analogously to 1e (route B).
E-mail: pcjk@st-andrews.ac.uk
Homepage: http://chemistry.st-and.ac.uk/eastchem/profiles/sta/
kamer.html
R. den Heeten, B. H. G. Swennenhuis,
Prof. Dr. P. W. N. M. van Leeuwen
van’t Hoff Institute for Molecular Sciences
University of Amsterdam
Nieuwe Achtergracht 166, 1018 WV Amsterdam (The Netherlands)
Prof. Dr. J. G. de Vries
DSM Pharmaceutical Products—Advanced Synthesis
Catalysis & Development
P.O. Box 18, 6160 MD Geleen (The Netherlands)
[
**] This work was supported by the NWO Combinatorial Chemistry
program and DSM. J. M. Ernsting is acknowledged for assistance
with NMR data analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801689.
Scheme 2. Synthesis of resin-bound aminophosphane boranes 2a–f.
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Since purification of the resins is accomplished by a simple
washing procedure, the oxazaphospholidine boranes 1 can be
applied in excess (> 1.5 equiv) without compromising the
purity of the resulting immobilized aminophosphanes 2.
3
1
Elemental analysis and P gel-phase NMR spectroscopy
indicated that the polymer-supported aminophosphane bor-
anes 2a–f were formed in excellent yield and purity with high
[
15]
diastereoselectivity (diastereomeric ratio > 96:4).
The
Scheme 4. Structure of supported ligand 12, and of non-supported 22
and 23.
hydroxy-functionalized resins 2a–f proved suitable starting
materials for resin-bound aminophosphane-based bidentate
ligands. For instance, reaction of 2d with an excess
(>1.3 equiv) chlorodiphenylphosphane (10; Scheme 3) in
of ClPPh and subsequent treatment with Et NH gave, after
2
2
the presence of a base, gave the corresponding aminophos-
purification by column chromatography, 22 in 38% yield.
The resin-bound ligands were used in the rhodium-
catalyzed asymmetric hydrogenation of methyl a-acetamido-
cinnamate (I), methyl a-acetamidoacrylate (II), and dimethyl
itaconate (III). For this purpose the ligands were dispersed in
methylene chloride in the presence of 1 equivalent of [Rh-
(cod) ]BF (cod = cyclooctadiene). After stirring for 2 h the
resins were separated from the solution phase by filtration
and subsequently washed. The resulting yellow solids (orange
for the ferrocenyl containing resins), were applied as catalysts
phane–borane–phosphinite 15·BH cleanly, as shown by the
3
3
1
P NMR spectrum which displayed typical resonance signals
for the phosphinite (d = 113 ppm) and aminophosphane–
borane (d = 69 ppm) moieties. The borane was straightfor-
wardly removed using neat Et NH, yielding chelating ligand
2
1
5 (Scheme 3) as was confirmed by an upfield shift of Dd =
2
4
3
1
1
2 ppm of the phosphorus amide signal in the P NMR
spectrum. The (stereo)chemical purity of more than 92% is
[
3f,g]
sufficient for parallel screening of a library of catalysts.
(
Table 2). Both activity and enantioselectivity depended
1
3
strongly on the structure of substituents R and R . Con-
Table 2: Results of asymmetric hydrogenation.
[
a]
[b]
[c]
Entry
Ligand
Substrate
Solvent
CH Cl
C6H6
C6H6
C6H6
Conv.[%]
ee [%]
Scheme 3. Solid-phase synthesis of ligands 12–21.
1
2
3
4
5
6
7
8
9
12
12
13
14
16
16
17
17
18
20
22
23
12
13
14
16
16
17
17
17
17
18
16
17
20
I
I
I
I
I
I
I
I
I
I
I
I
II
II
II
II
II
II
II
II
II
II
III
III
III
31
17
4
18
>99
53
51
13
14
98
62
98
>99
39
58
79
64
>99
52
46
49 (R)
59 (R)
17 (R)
32 (R)
42 (S)
69 (S)
65 (S)
73 (S)
<2 (S)
55 (S)
79 (R)
87 (S)
10 (R)
6 (R)
2
2
Following this facile synthetic route, we synthesized ten
resin-bound bidentate ligands in good purity by reaction of
resins 2a–f, with 10 or 11 (2,2’-biphenol phosphorochloridite).
CH
C6H
Cl
2
2
2
6
[
16]
CH Cl
2
The structures of the resins are summarized in Table 1. The
synthesis of a larger library by application of other chloro-
phosphorus reagents is currently underway.
C6H6
C6H6
C6H6
C6H6
C6H6
1
1
1
0
1
2
[
d]
Table 1: Parallel-synthesized supported ligands.
13
CH
2
Cl
2
2
2
2
1
1
4
5
CH Cl
1
3
1
3
2
Ligand
R
R
Ligand
R
R
CH Cl
7 (S)
2
12
13
14
15
16
ferrocenyl
o-anisyl
phenyl
methyl
ferrocenyl
diphenyl
diphenyl
diphenyl
diphenyl
biphenol
17
18
19
20
21
o-anisyl
2-biphenyl
methyl
2-naphthyl
phenyl
biphenol
biphenol
biphenol
biphenol
biphenol
16
17
18
19
21
CH
2
Cl
19 (S)
44 (S)
74 (S)
89 (S)
85 (S)
81 (S)
35 (S)
79 (R)
n.d.
C H
6
6
CH
Cl
2
2
C
C
H
H
6
6
[
[
e]
e]
6
6
22
23
24
25
26
C6H6
C6H6
C6H6
C6H6
C6H6
39
44
70
<1
17
Waldmann et al. demonstrated that ligand optimization
on solid support mirrored the results obtained with the
47 (R)
[
17]
[a] Conditions: [Rh]=2.5 mm, Rh/substrate=1:30, p(H
)=15 bar, T=
2
analogues ligands in homogeneous solution. To investigate
the catalytic behavior of the homogeneous counterparts of
our resin-bound ligands, we synthesized aminophosphane
phosphinite 22 (Scheme 4). The reaction of oxazaphospholi-
dine borane 1 f with phenyllithium, followed by the addition
258C, t=20 h, 0.5 mL solvent. [b] Percentage conversion of substrate,
determined by GC. [c] Enantiomeric excess of product, determined by
chiral GC (absolute configuration drawn in parenthesis). [d] Data taken
from Ref. [8b], t=47 h. [e] The reaction was carried out with Rh-loaded
17 recovered from the previous run. n.d.=not determined.
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Communications
versions varied between < 1 and > 99%, while the enantio-
meric excess (ee) ranged from < 2 up to 89%. In general, the
phite ligands. The solid-phase procedures allow the rapid
synthesis and screening of the new resin-bound ligands. The
ligands form active hydrogenation catalysts, displaying mod-
erate to good enantioselectivities. Studies to expand the
structurally diversity of our resin-bound chelating ligands are
currently in progress. Furthermore we have demonstrated the
importance of the configuration of the chiral ephedrine
backbone on the product chirality.
activity of the resin-bound catalysts was higher in CH Cl than
2
2
in benzene, although in the latter solvent higher enantiose-
lectivities were observed.
Resin-bound 12 and its non-supported analogue 22 gave
comparable reaction rates in the rhodium-catalyzed hydro-
genation of cinnamate I and both formed predominately the
R-enantiomer. The enantioselectivity observed for the poly-
mer-bound ligand 12 was however lower than that for the
corresponding non-supported ligand 22, 59% versus 79% ee,
respectively (Table 2, entries 2 and 11).
Received: April 10, 2008
Revised: May 26, 2008
Published online: July 21, 2008
The related non-supported ligand 23 (Scheme 4) is
derived from (+)-ephedrine and has been applied by JugØ
and co-workers in the asymmetric hydrogenation of
a-acetamidocinnamate I under identical reaction conditions,
allowing a comparison with (the performance of) 22. The
inversed order of introduction of the substituents at the
aminophosphane P-atom in the synthesis of 22 compared to
the reported analogue 23 will provide the same configuration
of the P-stereogenic phosphorus for both 22 and 23, and thus
the ligands differ merely in the configuration of the carbon
backbone. Interestingly, by altering the configuration of the
ephedrine moiety, the enantiomeric excess of the hydro-
genation product switched from 87% (S) with ligand 23 to
Keywords: asymmetric catalysis · combinatorial chemistry ·
immobilized catalysts · P ligands · solid-phase synthesis
.
[
8b]
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2
with the decisive influence of substituent R and the config-
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[8]
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Finally, we tested the recycling of the resin-bound catalyst
in the asymmetric hydrogenation of acrylate II, for which we
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subsequent catalytic hydrogenation (Table 2, entries 19–21).
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activity (52–39%) and enantioselectivity (89–81% ee). These
results demonstrate that in addition to the easy parallel solid-
phase preparation, the supported ligands offer the advantage
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hydrogenation reactions.
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