Supramolecular PhanePhos-analogous ligands through hydrogen-bonding for asymmetric hydrogenation

Article abstract of DOI:10.1039/b716529c

PhanePhos-analogous phosphorous ligands have been generated via self-assembly through hydrogen-bonding, and studied in rhodium-catalyzed asymmetric hydrogenation (up to 99% ee). The Royal Society of Chemistry.

Full text of DOI:10.1039/b716529c

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Supramolecular PhanePhos-analogous ligands through hydrogen-bonding
for asymmetric hydrogenationw
Andy Ch. Laungani and Bernhard Breit*
Received (in Cambridge, UK) 26th October 2007, Accepted 30th November 2007
First published as an Advance Article on the web 18th December 2007
DOI: 10.1039/b716529c
PhanePhos-analogous phosphorous ligands have been generated
via self-assembly through hydrogen-bonding, and studied in
rhodium-catalyzed asymmetric hydrogenation (up to 99% ee).
meta-substituted arene rings which resembles the planar chiral
element found in PhanePhos.
Herein, we report the preparation of ligands 1–2, their self-
assembly properties and structures in solution and the solid-
state as well as on their application to rhodium(I)-catalyzed
asymmetric hydrogenation.
In the past 30 years the field of asymmetric transition metal
catalysis has been dominated by chiral bidentate ligands.1
However, the work of Feringa, de Vries et al.,2 Reetz and
Mehler,3 and Pringle et al.4 has demonstrated that monoden-
tate phosphorus-based ligands can be successfully applied as
well.5 Monodentate ligands are particularly attractive due to
their relative ease of preparation in comparison with their
bidentate counterparts.
A prominent chelating ligand system for highly enantio-
selective rhodium-catalyzed asymmetric hydrogenation is the
PhanePhos ligand developed by Pye and Rossen et al.6 Un-
fortunately, access to this system requires a multistep synth-
esis. We7 and others8 recently demonstrated that bidentate
ligands can be constructed by a self-assembly process of
monodentate ligands mediated through hydrogen-bonding.9
Thus, we wondered whether a simple monodentate ligand
could be designed that would self-assemble in the presence
of a transition metal center to provide a planar chiral Phane-
like structure. Inspection of molecular models suggested that
meta-carboxypeptidyl substituted triarylphosphines (Do =
PPh2) or phosphites (Do = OP(OAr)2) might be suitable
candidates. An interligand helical hydrogen-bonding network
as indicated in Scheme 1 could be expected. This in turn might
induce a planar chiral p-stacking arrangement of the two
The synthesis of the ligands was straightforward, employing
conventional solution-phase peptide synthesis procedures10,11
(for details see ESIw).
Coordination properties of ligands 1 and 2 were investigated
upon reaction with cis-[Cl2Pt(cod)] and [Rh(cod)2]BF4. The
1
thus-formed complexes were studied by 2D H, 31P and 13C
NMR spectroscopy and ESI-MS, which in all cases proved the
formation of cis-[Cl2PtL2] and [Rh(cod)L2]BF4 species (see
ESIw). Suitable single crystals for X-ray crystal-structure
analysis could be obtained for cis-[Cl2Pt(1b ꢀ 1b)]. As shown
in Fig. 1, the cis-coordinated phosphine ligands are linked by
pairs of interligand N–Hꢀ ꢀ ꢀOQC hydrogen bonds of the
peptidyl side chain which adopt a helical conformation.
Interestingly, the meta-substituted arene rings of the two
neighbouring phosphine ligands adopt
a planar chiral
Phane-type conformation. This p–p interaction (B3.30 A) is
also expected to additionally contribute to the stabilization of
the supramolecular metal-induced ligand assembly.12 Addi-
tionally,
a hydrogen-bonding intermolecular network is
formed between the homodimeric complexes in the crystalline
state.
Scheme 1 Schematic representation of ‘‘SupraPhanePhos’’.
NMR spectra indicate that a similar geometry is prevalent
in solution in aprotic solvents such as CDCl3 as well. Thus, the
1JP,Pt = 3659 Hz obtained from the 31P NMR spectrum is
typical for the cis-coordination of two phosphines at the
platinum center.14 The proton NMR spectrum of the complex
displays well-resolved sharp resonances, which rules out the
Institut fur Organische Chemie und Biochemie, Albert-Ludwigs-
¨
Universitat Freiburg, Albertstr. 21, 79104 Freiburg, Germany. E-mail:
¨
bernhard.breit@organik.chemie.uni-freiburg.de; Fax: (+49) 761-203-
8715; Tel: (+49) 761-203-6051
w Electronic supplementary information (ESI) available: Experimental
details, synthesis and characterization of ligands and complexes. See
DOI: 10.1039/b716529c
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Table 1 Rh-catalyzed enantioselective hydrogenation of substrates
3–5a
Entry Ligands Substrate Time/h Conv.b (%) eec (%) (S)
1
2
3
4
5
6
7
1a ꢀ 1a
1b ꢀ 1b
1c ꢀ 1c
2a ꢀ 2a
2b ꢀ 2b
2b ꢀ 2b
2c ꢀ 2c
3
3
3
3
3
3
3
o6
o6
o6
24
100
100
100
98
100
100
100
51
32
32
90 (R)
99
2.5
o6
77d
82
o6
Fig. 1 PLATON13 plot of cis-[Cl2Pt(1b ꢀ 1b)] in the solid-state at
100 K.z Selected interatomic distances (A) and angles (1) of one
independent complex in the asymmetric unit: Pt2–P3 2.268(2),
Pt2–P4 2.244(2), N5ꢀ ꢀ ꢀO14 2.926(8), O10ꢀ ꢀ ꢀN7 2.913(9), N4ꢀ ꢀ ꢀO9
2.856(9), O5ꢀ ꢀ ꢀN6 2.890(9), O13ꢀ ꢀ ꢀN2 2.872(9), N8ꢀ ꢀ ꢀO1 2.836(9);
P3–Pt2–P4 98, N5–Hꢀ ꢀ ꢀO14 159, N7–Hꢀ ꢀ ꢀO10 167, N4–Hꢀ ꢀ ꢀO9 159,
O5ꢀ ꢀ ꢀH–N6 177, O13ꢀ ꢀ ꢀH–N2 166, N8–Hꢀ ꢀ ꢀO1 168. O1 and N2
belong to the 2nd independent complex in the asymmetric unit,
whereas N4 and O5 belong to the 2nd independent complex in an
adjacent cell (symmetry operation: x + 1, y, z). Pt green, C dark gray,
H light gray, N blue, P orange, O red, Cl yellow. Irrelevant H atoms
bound to C atoms and disordered ethyl acetate solvent molecules in
the lattice were omitted for clarity.
8
9
10
11
12
13
1a ꢀ 1a
1b ꢀ 1b
1c ꢀ 1c
2a ꢀ 2a
2b ꢀ 2b
2c ꢀ 2c
4
4
4
4
4
4
o6
o6
o6
27
100
100
100
18
100
100
46
30
39
85 (R)
98
75
o6
o6
14
15
16
17
18
19
a
1a ꢀ 1a
1b ꢀ 1b
1c ꢀ 1c
2a ꢀ 2a
2b ꢀ 2b
2c ꢀ 2c
5
5
5
5
5
5
19
o6
o6
20
6
o6
79
100
100
25
44
100
13 (R)
15 (R)
3 (R)
82
85 (R)
97 (R)
Reaction conditions: [Rh] : L1 : L2 : substrate = 1 : 1.2 : 1.2 : 100,
b
p(H2) 1 bar, CH2Cl2 (0.1 M substrate), room temperature. Conver-
1
c
sion determined by H NMR spectroscopy. ees for products of 3, 5
and 4 determined by chiral GC (Hydrodex-b-TBDAc and GT-A,
trifluoroacetyl-g-cyclodextrin) and chiral HPLC (Chiralpak AD),
formation of large, disordered aggregates and suggests the
formation of well-defined supramolecular species with a dis-
tinct predominant conformation. Analysis of the solution
structures of peptides 1 before and after coordination of PtII
confirm a change in the chemical shifts and in the NH,CaH-
coupling constants of the amide protons on complexation, and
indicate a conformational change induced by the metal.w
Compared with the free ligand, the observed significant low
field shift of the N–H proton of the amino acid attached to the
P-aryl moiety (e.g. for 1a: Dd = 1.43 ppm) is indicative of
strong H-bonding.15 In contrast, the amide proton of the
terminal amino acid did not show a significant downfield shift
(e.g. for 1a: Dd = 0.15 ppm). Both observations suggest that
the relatively rigid helical structure and p-stacking of the self-
assembled peptide-based complexes is maintained, but the
intercomplex hydrogen-bonding network pattern found in
the crystalline state is not persistent in solution.
d
respectively. MeOH as solvent.
amidites.2 Therefore we expected that replacement of the
achiral phosphine functionality (Do = PPh2) with a chiral
BINOL-based phosphite group (Do = OP(OAr)2) may
enhance asymmetric induction of the catalyst when a matching
between the chirality of the peptide backbone and the chirality
of the phosphite moiety is reached. Thus, the peptidyl phos-
phite ligands 2a–c were studied next. Ligand 2c is unable to
form the self-assembly structure through hydrogen bonding.
Hence, results obtained with this ligand would provide infor-
mation on the role of the self-assembly structure with respect
to the ligands’ ability to induce enantioselectivity.
In order to obtain some information on the potential of
these supramolecular complexes as chiral catalysts, Rh-cata-
lyzed enantioselective hydrogenation of methyl N-acetyl de-
hydro-amino acids (3, 4) and dimethyl itaconate (5) was
investigated in CH2Cl2 at room temperature under 1 atm of
H2 (Table 1). All rhodium–phosphine complexes
[Rh(cod)(1 ꢀ 1)]BF4 were catalytically active (full conversions
after less than six hours, entries 1–3, 8–10 and 15–16).
However, the enantioselectivities remained moderate (up to
51% ee, entry 1).
Hydrogenation of methyl 2-N-acetamido acrylate (3), with
[Rh(cod)(2a ꢀ 2a)]BF4, gave the (R)-hydrogenation product
with 90% ee (entry 4). Conversely, on employing the dia-
stereomeric phosphite ligand 2b under identical conditions the
reaction was faster (100% conversion after 2.5 h) and gave the
(S)-configured hydrogenation product in quantitative yield
and an excellent ee of 99% (entry 5). Hence, 2b represents
the ‘‘matched’’ peptidyl phosphite ligand. On the other hand,
control phosphite 2c gave an ee of only 82%, which clearly
indicates the importance of the peptidyl side chains for
enantioinduction. The same conclusion can be drawn from
the result of the hydrogenation experiment with ligand 2b in a
H-bond disrupting solvent such as methanol (entry 6).
It has been shown that some of the results obtained with
chelating phosphines can be matched by the use of bidentate
phosphinites,16 phosphonites,17 phosphites,18 or phosphoro-
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Similar good results were obtained for the phenylalanine
precursor 4 (entries 8–13, up to 98% ee). Conversely, in the
case of dimethyl itaconate (5), the classical monodentate
phosphite ligand 2c performed with best results (97% ee, entry
19). This again proves that there exists no ideal catalyst for all
substrates.
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In conclusion, a new class of supramolecular PhanePhos-
analogous ligands formed through self-assembly via hydrogen-
bonding between peptidyl side chains was successfully applied
in rhodium-catalyzed asymmetric hydrogenation. Both the
reactivity and enantioselectivity observed are comparable to
the best results obtained with common monodentate or bi-
dentate Rh–phosphite catalysts,1 and match the results
achieved by PhanePhos-type ligands.6,19
(d) J. N. H. Reek, M. Roder, P. E. Goudriaan, P. C. J. Kamer, P.
¨
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Taken together, our experimental findings support the con-
clusion that helical secondary structures are important ele-
ments for significant catalyst activity and enantioselectivity. In
summary, salient features of these catalysts, such as their ease
of preparation from readily accessible and modular building
blocks, the inherent combinatorial possibilities of this supra-
molecular approach, as well as the excellent levels of stereo-
control, render these ligand systems attractive for practical
asymmetric synthesis.
H. Jiao, D. Michalik, J. Holz, R. Paciello, B. Breit and A. Borner,
¨
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N. H. Reek, Dalton Trans., 2006, 3385.
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11 For other phosphorus-containing peptidyl ligands which have been
applied in catalysis, see: (a) S. R. Gilbertson and X. Wang, J. Org.
Chem., 1996, 61, 434; (b) S. R. Gilbertson, X. Wang, G. S. Hoge,
C. A. Klug and J. Schaefer, Organometallics, 1996, 15, 4678; (c) S.
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This work was supported by the Fonds der Chemischen
Industrie, DFG (Int. Research Training Group GRK 1038),
the Alfried Krupp Award for young university teachers of the
Krupp Foundation (to BB), and BASF.
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846 | Chem. Commun., 2008, 844–846