"Backdoor Induction" of chirality in asymmetric hydrogenation with rhodium(I) complexes of amino acid substituted triphenylphosphane ligands

Article abstract of DOI:10.1002/ejoc.201301011

This paper describes the synthesis and characterization of 5-(diphenylphosphanyl)isophthalic acid bioconjugates (Lig-[R]₂). In addition to symmetrically disubstituted conjugates with amino acids, peptides or amines, a convenient one-pot, two-step procedure for the synthesis of conjugates bearing two different substituents is reported. The 28 prepared phosphanes were used as monodentate ligands in the rhodium(I)-catalyzed hydrogenation of 2-acetamidoacrylate and (Z)-α-acetamidocinnamate. The ligand with the smallest side-chain substituents Lig-[Ala-OMe]₂ (1a) revealed the highest selectivity, with up to 84 % ee. The catalysts presented herein are models of artificial metalloenzymes in which the outer-coordination sphere controls the selectivity in catalysis. The chirality of distant hydrogen-bonded amino acids is transmitted by "backdoor induction" to the prochiral Rh^I center. Models of artificial metalloenzymes are presented in which the outer-coordination sphere controls the selectivity in catalysis. The chirality of distant hydrogen-bonded amino acids or amines is transmitted by "backdoor induction" to the prochiral Rh^I center. Copyright

Full text of DOI:10.1002/ejoc.201301011

FULL PAPER
DOI: 10.1002/ejoc.201301011
“Backdoor Induction” of Chirality in Asymmetric Hydrogenation with
Rhodium(I) Complexes of Amino Acid Substituted Triphenylphosphane Ligands
Zoran Kokan[a] and Srec´ko I. Kirin*[a]
Keywords: Amino acids / Metalloenzymes / Asymmetric catalysis / Hydrogenation / Supramolecular chemistry
This paper describes the synthesis and characterization of 5-
(diphenylphosphanyl)isophthalic acid bioconjugates (Lig-
[R]2). In addition to symmetrically disubstituted conjugates
with amino acids, peptides or amines, a convenient one-pot,
two-step procedure for the synthesis of conjugates bearing
two different substituents is reported. The 28 prepared phos-
phanes were used as monodentate ligands in the rhodium(I)-
catalyzed hydrogenation of 2-acetamidoacrylate and (Z)-α-
acetamidocinnamate. The ligand with the smallest side-
chain substituents Lig-[Ala-OMe]2 (1a) revealed the highest
selectivity, with up to 84% ee. The catalysts presented herein
are models of artificial metalloenzymes in which the outer-
coordination sphere controls the selectivity in catalysis. The
chirality of distant hydrogen-bonded amino acids is trans-
mitted by “backdoor induction” to the prochiral RhI center.
to the coordination sphere of the catalytic metal center is
widely accepted. Within our work, we challenge this funda-
mental principle and use a catalytically active metal center
that is only prochiral.[16] The chiral information is trans-
mitted by “backdoor induction” through hydrogen bonding
between distant pendant amino acids. An artificial C2-sym-
metrical peptide turn is formed that controls the chirality
of the catalytic metal coordination sphere. These catalysts
could be models of artificial enzymes with a functional
outer-coordination sphere. We and others have used “back-
door induction” in RhI complexes of amino acid tri-
phenylphosphane ligands I or II (Figure 1), and obtained
up to 68% ee in asymmetric hydrogenation.[16–18] In a sim-
ilar approach, instead of using chiral substituents -CO-
(Aa)n-OMe in II, van Leeuwen et al. attached achiral Schiff
bases; high selectivity in asymmetric hydrogenation was ob-
tained by the addition of a remote chiral diol through the
use of an assembly metal (Ti).[19] In this work, we present
a comprehensive study using amino acid substituted tri-
phenylphosphane bioconjugates III based on 5-(diphenyl-
phosphanyl)isophthalic acid as monodentate ligands in rho-
dium(I)-catalyzed asymmetric hydrogenation. When com-
Introduction
The catalysis of chemical reactions has an enormous im-
pact in industry, because the production of many important
chemicals involves at least one catalytic step.[1] Catalysis is
particularly important in the synthesis of chiral com-
pounds.[2] Among chiral industrial products, small-molecule
drugs hold a prominent place. In recent years, 80% of
small-molecule drugs approved by the US American
Federal Drug Agency (FDA) are chiral, and 75% are single
enantiomers.[3]
Nowadays, bioinspired catalysts composed of amino acid
or nucleotide building blocks are gaining growing impor-
tance.[4–7] Asymmetric hydrogenation is a particularly inter-
esting catalytic reaction, with emphasis on industrial appli-
cations.[8] Following the discovery of Wilkinson’s catalyst
[RhCl(PPh3)3], the use of chiral phosphane ligands in asym-
metric hydrogenation is well established.[9] Chelating bis-
(phosphane) ligands generally show higher selectivity when
compared with monodentate ligands, but moderate to excel-
lent selectivity in catalytic hydrogenation can also be
achieved with monodentate phosphane ligands.[10–15] The
advantages of monodentate ligands are easier synthesis and
more straightforward structural variations (ligand libraries)
for fine-tuning of catalytic properties.
Chiral metal complexes are very frequently used as
homogeneous asymmetric catalysts. The importance of the
incorporation of the chiral information as close as possible
[a] Rueer Bosˇkovic´ Institute,
Bijenicˇka 54, 10000 Zagreb, Croatia
E-mail: Srecko.Kirin@irb.hr
Figure 1. Amino acid substituted monodentate triphenylphosphane
ligands I and II reported previously,[16–18] and ligands III studied
in this paper; Aa = amino acid, Z = OMe or NH2, n = 1, 2 or 3.
www.irb.hr/eng/People/Srecko-Kirin
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301011.
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Asymmetric Hydrogenation with Rhodium(I) Complexes
pared with I or II, ligands III contain one additional amino the two corresponding symmetrical products 4a–g and 1a.
acid substituent, allowing more supramolecular interactions Ligands 5a–g were isolated in up to 29% yield, which is
that could stabilize the catalytic [Rh(III)2]+ complex and consistent with the results of previous work.[21]
display higher selectivity in catalysis.
Ligands 1–5 were characterized by 1H, 13C and 31P
NMR spectroscopy, and by ESI and MALDI mass spec-
trometry. It is interesting to note that proline-containing
peptides often show cis and trans isomers at the tert-amide
bond, which has some double-bond character and is
planar.[16,25] 13C NMR spectra (CDCl3) revealed traces of
the cis isomer for Lig-[Pro-OMe]2 (4g) and Lig-[Pro-OMe]-
[Ala-OMe] (5g), along with the dominant trans isomer. In
contrast, only the trans isomer was detected for Lig-[Gly-
Pro-Phe-OMe]2 (3b).
Results and Discussion
Ligands
Amino acid substituted monodentate triphenylphos-
phane ligands Lig-[Aa1-Z]2 (1a–f) (Z = OMe or NH2), Lig-
[Aa1–Aa2–OMe]2 (2a–f), and Lig-[Aa1–Aa2–Aa3–OMe]2
(3a–b) were synthesized in good yields[16] by treating 5-(di-
phenylphosphanyl)isophthalic acid[20] with N-unprotected
amino acids, dipeptides or tripeptides by using standard
peptide coupling conditions in solution (Scheme 1).
Precatalyst RhI Complexes
Unsymmetrically substituted ligands Lig-[NH-R][Ala-
Complexation of ligands 1–5 with [Rh(COD)(CH3CN)2]-
OMe] (5a–e) and Lig-[Aa1-OMe][Ala-OMe] (5f–g) were BF4 was performed in situ; the obtained precatalyst com-
prepared by starting from 5-(diphenylphosphanyl)iso- plexes were studied by ESI mass spectrometry, NMR and
phthalic acid using
a
one-pot, two-step approach CD spectroscopy.
The 2:1 ligand/metal stoichiometry was supported by
(Scheme 2).[21–23] First, 5-(diphenylphosphanyl)isophthalic
acid was activated with 1 equiv. of coupling reagent and strong [Rh(COD)(Lig-R)2]+ signals found in the ESI mass
treated with a mixture of 0.5 equiv. of an N-unprotected spectra. 31P NMR spectra featured, in some instances, one
amino acid or amine and 0.5 equiv. of H-Ala-OMe. In the doublet indicating the presence of one compound with
next step, this procedure was repeated. Activation with chemically equivalent phosphorus atoms, but in most cases
1 equiv. of coupling reagent was followed by reaction with a mixture of isomers was found (see the Supporting Infor-
a mixture of 0.5 equiv. of the same N-unprotected amino mation).[13a,19,26]
acid or amine and 0.5 equiv. of H-Ala-OMe. This one-pot
1H NMR spectra reveal the absence of amide resonances
procedure gave a mixture of three products, two symmetri- in [Rh(COD)(Lig-R)2]BF4 at δ Ͻ 7 ppm in a nonhydrogen-
cally substituted (4a–g and 1a) as well as one unsymmetri- bonding solvent (CDCl3), strongly indicating the presence
cally substituted (5a–g) (Scheme 2) with a 1:2:1 statistical of intramolecular hydrogen bonding. Such H-bonding is an
distribution in favor of the latter (5a–g).[21] The three prod- indication of a folded conformation of the studied square-
ucts could be separated by column chromatography when planar RhI complexes. In addition, a folded conformation
the employed amino acids or amines differed sufficiently in of the complexes is directed by the cis-bonded COD li-
polarity and hydrophobicity.[24] Seven one-pot reactions gand.[16,17] Further evidence for a folded conformation in
were performed. As expected, during chromatographic pu- solution is provided by CD spectroscopy of the rhodium
rification the unsymmetrical products 5a–g eluted between chromophore.[21,26] CD signals in the visible region strongly
Scheme 1. Synthesis of ligands Lig-[Aa1-Z]2 (1), Lig-[Aa1–Aa2–OMe]2 (2), and Lig-[Aa1–Aa2–Aa3–OMe]2 (3), Z = OMe or NH2. Reagents
and conditions: (a) TBTU/HOBt/DIPEA, CH2Cl2, r.t., 15 h; (b) H-Aa1-Z; (c) H-Aa1–Aa2–OMe, (d) H-Aa1–Aa2–Aa3–OMe.
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Z. Kokan, S. I. Kirin
FULL PAPER
Scheme 2. One-pot synthesis of ligands Lig-[NH-R or Aa1]2 (4), Lig-[NH-R or Aa1][Ala-OMe]2 (5) and Lig-[Ala-OMe]2 (1a). Reagents
and conditions: (a) HBTU (1 equiv.), HOBt (1 equiv.), DIPEA (4 equiv.), NH2-R or H-Aa1-OMe (0.5 equiv.) and H-Ala-OMe (0.5 equiv.),
CH2Cl2, r.t., 15 h; (b) HBTU (1 equiv.), HOBt (1 equiv.), DIPEA (4 equiv.), NH2-R or H-Aa1-OMe (0.5 equiv.) and H-Ala-OMe
(0.5 equiv.), CH2Cl2, r.t., 15 h. For an explanation of the non-standard three letter labels see the Experimental Section.
indicate an asymmetric coordination sphere of the RhI contains one β-turn involving two hydrogen bonds. Al-
metal ion and support the proposed “backdoor induction” though the two Aa strands adjacent to the phosphane
of chirality from the chiral amino acid substituents to the groups of [β2] are too far away for strong intramolecular H-
prochiral metal center. The sign and amplitude of the CD bonding to the neighboring Aa strands, weak H-bonding
signals could not, however, be correlated with enantio- interactions are possible, as found in closely related amino
selectivity obtained in catalysis.[9c,16,27]
acids based on 1,3,5-trisubsituted benzenes (see the Sup-
porting Information).[30,31] Interestingly, in all reported
cases so far, including ferrocene peptides, metallated phos-
phane peptides and 1,3,5-trisubstituted benzene peptides, l-
amino acids always induce (P)-helical chirality of the cen-
tral aromatic rings.
It is important to note that in asymmetric hydrogenation,
according to the stereochemical analysis proposed in Fig-
ure 2, an excess of the (R) product is expected when confor-
mations [β2]2 or [γ1]3 are dominant, whereas an excess of
the (S) product is expected when conformation [β2] is pre-
ferred. In addition, an excess of (R) product is expected
when the commercially available (R)-PhanePhos[32] is used
as hydrogenation catalyst (Figure 2).
Stereochemical Analysis
As shown previously,[16] the nomenclature initially devel-
oped for 1,nЈ-disubstituted ferrocene peptides[28,29] can be
used as a possible interpretation to explain the stereochemi-
cal outcome in asymmetric hydrogenation of methyl 2-acet-
amidoacrylate (S1) by using [(COD)Rh(Ph2P-C6H4-Aan)2]
BF4 complexes with meta or para substitution of the central
aromatic ring (Figure 2). The main secondary structures are
(i) a β-turn involving two hydrogen-bonded ten-membered
rings, Herrick conformation [β2], and (ii) a γ-turn involving
one hydrogen-bonded seven-membered ring, van Staveren
conformation [γ1].
Based on this interpretation, several folded conforma-
tions for RhI complexes derived from ligands 1–5 can be
proposed (see second row in Figure 2). The first conforma-
Asymmetric Catalysis
Supramolecular rhodium(I) complexes of monodentate
tion [β2]2 is based on two β-turns containing a total of four phosphane ligands 1–3 prepared in situ were tested as cata-
intramolecular hydrogen bonds, whereas the second confor- lysts in the asymmetric hydrogenation of methyl 2-acet-
mation [γ1]3 is based on three γ-turns and contains al- amidoacrylate (S1) in dichloromethane at three different
together three hydrogen bonds. The third conformation [β2] temperatures (room temp., –5 °C, and –20 °C; Table 1).
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Asymmetric Hydrogenation with Rhodium(I) Complexes
Figure 2. Proposed sterochemical analysis. Schematic representation (top view) of conformations in [Rh(Lig-R)2]+ complexes containing
ligands with various substitution patterns; (R)-PhanePhos is included for comparison. The upper central aromatic rings are indicated in
bold; the arrows indicate the sign of helical chirality between interacting interligand strands.
For Lig-[Aa1-Z]2 (1), the best results (up to 84% ee) were ids) as well as for ligands 4 and 5 (where the separation
obtained by using the ligand with the smallest side-chain of the three-component mixture strongly relies on favorable
substituent (Ala ester 1a) (Table 1, Entry 3). Introduction chromatographic properties).
of steric bulk by side-chain substitutions at the γ-position
Longer amino acid chains in Lig-[Aa1–Aa2–OMe]2 (2a–
(Phe derivatives 1c or 1f) and especially at the β-position f) and Lig-[Aa1–Aa2–Aa3–OMe]2 (3a–b) could induce more
(Val derivatives 1b or 1e) significantly lowered the selectiv- hydrogen bonding between neighboring monodentate li-
ity in catalysis.
gands, resulting in a more stable supramolecular complex
As expected, the selectivity was higher at lower tempera- [Rh(COD)(Lig-R)2]BF4 and higher selectivity in cataly-
ture when compared to room temperature; the Δee was, sis.[16,33] However, results obtained in catalysis with the
however, less than 10%. Decreasing the concentration in crowded RhI complexes derived from ligands 2 or 3 do not
CH2Cl2 by one order of magnitude revealed a small change support this reasoning (Table 1); smaller ligand 1a remains
in selectivity, Δee Յ 5% (Table 1, Entries 1 and 21), indicat- the most selective in the studied asymmetric hydrogenation.
ing the significance of intramolecular over intermolecular
Other selectivity trends obtained with ligands 1 could be
hydrogen bonds in the studied catalysts. In addition, the confirmed with ligands 2 or 3. A rather small improvement
catalysis was studied in methanol, a protic solvent. In this of selectivity was found at lower temperature. In addition,
case, generally, the selectivity in MeOH decreased, with the small amino acids Gly or Ala at the Aa1 position gave the
decrease being significant for 1a, 1c, 2b and 3b (about half best results (ligands 2a, 2b and 2d), whereas sidechain sub-
of the original value), but only small for 2a and 2d (Δee stitutions at the β- or γ-carbon atom of Aa1 cause a signifi-
10% or less). The relatively good selectivity in MeOH indi- cant decrease in selectivity (ligands 2e and 2f). A notable
cates stable secondary structures, particularly for 2a and 2d, exception is the low selectivity obtained for ligand Lig-[Gly-
comparable to peptides that can preserve their conforma- Phe-OMe]2 (2c) (up to 12% ee; Table 1, Entries 19 and 20),
tion even in a highly hydrogen-bond-competitive solvent despite having unsubstituted Gly at Aa1.
such as water.
Asymmetric hydrogenation of methyl (Z)-α-acet-
Similar results were obtained for the corresponding ester amidocinnamate (S2) was then examined by using ligands
or amide derivatives, with amides giving slightly higher Lig-[Aa1-Z]2 (1) (Table 2). Selectivity trends observed in hy-
selectivities. However, triphenylphosphane ligands with a drogenation of S1 were preserved with S2, and the highest
terminal amide group have the tendency to form gels[16] and selectivity was obtained with Ala derivatives 1a or 1d (up
are more difficult to purify by chromatography on silica due to 75% ee), albeit slightly lower than with S1. Elevated hy-
to their increased polarity. Therefore, only esters were drogen pressure (13 bar) was needed to obtain high chemi-
studied for ligands 2 and 3 with longer side chains (that are cal yields of P2 after 2 h; the yield of P2 obtained for catal-
already more polar due an increased number of amino ac- ysis performed at atmospheric pressure after 20 h was low.
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Table 1. RhI-catalyzed asymmetric hydrogenation of S1 by using
Table 2. RhI-catalyzed asymmetric hydrogenation of S2 by using
ligands 1.[a]
ligands 1–3.[a]
Entry Ligand Temp. [°C][b]
Conv. [%][c]
ee (S) [%][d]
Entry Ligand Press. [bar] Time [h] Conv. [%][b] ee (S) [%][c]
1
2
3
4
5
6
7
8
1a/1a
1a/1a
1a/1a
1b/1b
1b/1b
1c/1c
1c/1c
1d/1d
1d/1d
1d/1d
1e/1e
1e/1e
1f/1f
r.t.
–5
–20
r.t.
–5
r.t.
–5
r.t.
–5
–20
r.t.
–5
r.t.
–5
r.t.
–5
r.t.
–5
r.t.
–5
r.t.
–5
–20
r.t.
–5
r.t.
–5
r.t.
–5
r.t.
–5
Ͼ 98
Ͼ 98
65
Ͼ 98
Ͼ 98
Ͼ 98
94
98
48
4
Ͼ 98
85
Ͼ 98
76
Ͼ 98
98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
97
60
Ͼ 98
76
76 (80[e])/35[f]
1
2
3
4
5
6
7
8
9
1a/1a
1a/1a
1b/1b
1b/1b
1c/1c
1c/1c
1d/1d
1e/1e
1f/1f
1
13
1
13
1
13
13
13
13
20
2
20
2
20
2
2
20
Ͼ 98
4
Ͼ 98
37
Ͼ 98
47
Ͼ 98
72
77
75
39
39
59
59
77
37
66
80
84
25
26
54/19[f]
59
80
2
2
9
81
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
n.d.[g]
34
[a] Reaction conditions: [Rh]/ligand/substrate = 1:2.4:100, room
temp., CH2Cl2 (0.1 m substrate). [b] Determined by 1H NMR spec-
troscopic analysis. [c] Determined by GC analysis (l-Chirasil-Val).
41
63
70
1f/1f
2a/2a
2a/2a
2b/2b
2b/2b
2c/2c
2c/2c
2d/2d
2d/2d
2d/2d
2e/2e
2e/2e
2f/2f
72/63[f]
76
Table 3. RhI-catalyzed asymmetric hydrogenation of S1 by using
binary mixtures of ligands 1–4.[a]
68/35[f]
73
12
12
71 (76[e])/68[e]
78
80
Entry
L1/L2
nL1/nL2
Conv. [%][b]
ee (S) [%][c]
13 (R)
12 (R)
43 (R)
44 (R)
57
1
2
3
4
5
6
7
8
9
1a/4f
1e/4f
2e/4f
2c/4f
1a/1b
1a/1d
1a/2a
1a/3b
1a/4b
2a/2b
2a/2b
2a/2b
3:1
3:1
3:1
3:1
3:1
1:3
3:1
3:1
3:1
1:1
3:1
1:3
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
69
34
12
13
68
78
76
64
62
74
75
71
Ͼ 98
67
Ͼ 98
Ͼ 98
Ͼ 98
87
2f/2f
3a/3a
3a/3a
3b/3b
3b/3b
68
36/23[f]
47
[a] Reaction conditions: [Rh]/ligand/substrate = 1:2.4:100, p(H2) =
1 bar, CH2Cl2 (0.1 m substrate). [b] Reaction time: 2 h (r.t.), over-
night (–5 °C), or 3 d (–20 °C). [c] Determined by 1H NMR spectro-
scopic analysis. [d] Determined by GC analysis (Beta Dex 225).
[e] Diluted CH2Cl2 solution (10ϫ). [f] MeOH was used as solvent.
[g] n.d.: not determined.
10
11
12
[a] Reaction conditions: [Rh]/ligand/substrate = 1:2.4:100, p(H2) =
1 bar, room temp., 2 h, CH2Cl2 (0.1 m substrate). [b] Determined
by 1H NMR spectroscopic analysis. [c] Determined by GC analysis
(Beta Dex 225).
The selectivity obtained at atmospheric pressure is retained
at elevated pressure.
Binary mixtures of monodentate phosphane ligands can
lead to higher yields and selectivities in metal-catalyzed Lig-[Ala-Gly-OMe]2 (2a) and Lig-[Gly-Ala-OMe]2 (2b)
asymmetric reactions than the individual ligands alone.[34] were used in catalysis (Table 3, Entries 10–12), a small im-
In addition, by using an excess of the more selective ligand, provement was obtained in comparison to the results ob-
the formation of the less selective homo complex [ML2L2] tained by using only one ligand (Table 1, Enrties 15 and 17).
can be minimized. An increase in selectivity should be ob-
Products P1 or P2 with predominantly (S) configuration
served when the mixed-ligand complex is more selective. were obtained with most of the examined catalysts; the few
The asymmetric hydrogenation of S1 with RhI complexes exceptions being limited to Val or Phe derivatives with low
derived from binary mixtures is presented in Table 3.
selectivity. According to the stereochemical analysis de-
Binary mixtures with achiral ligand Lig-[Gly-OMe]2 (4f) scribed above, catalytic results support a preference for the
and a 3:1 excess of a chiral ligand did not exceed the selec- [β2] conformation. Our stereochemical analysis is further
tivity obtained with the corresponding chiral ligand alone supported by results obtained by using commercially avail-
(Table 3, Entries 1–4). In addition, a binary mixture of most able (R)-PhanePhos as ligand, yielding the expected (R)-P1
selective 1a with other chiral ligands did not improve the (Ͼ98% ee and Ͼ98% yield); reaction conditions are given
selectivity obtained by using only one single ligand (Table 3, in Table 1 (for chromatogram see the Supporting Infor-
Entries 5–9). However, when binary mixtures of ligands mation).
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Asymmetric Hydrogenation with Rhodium(I) Complexes
Finally, ligands 4a–g and 5a–g were evaluated in the rho-
Supramolecular RhI complexes [Rh(COD)-(Lig-R)2]BF4
dium(I)-catalyzed hydrogenation of S1 (Table 4). Some sub- prepared in situ with ligands Lig-R = 1–5 were used as cata-
stituents of ligands 4 and 5 lack the ester carbonyl group lysts in the asymmetric hydrogenation of methyl 2-acet-
(amine derivatives) and/or amide hydrogen atoms (Pro de- amidoacrylate (S1) or (Z)-α-acetamidocinnamate (S2). The
rivatives). Because, in these cases, not all hydrogen-bonding selectivity obtained depends strongly on the distant amino
patterns of the catalytically active complex are possible, the acid or amine substituents, spanning the range from 84% ee
obtained results can contribute to an understanding of the (1a; Table 1, Entry 3) to 4% ee (4b; Table 4, Entry 2),
stereochemical outcome. Diamines 4b–e lack the ester carb- strongly supporting the proposed “backdoor induction” of
onyl group, and the otherwise preferred [β2] conformation chirality. For the studied crowded complexes with ligands
cannot be formed. Consequently, the obtained selectivity is 1–5, highest selectivity was obtained for Lig-[Ala-OMe]2
rather low, being only up to 34% (Table 4, Entries 2–4). (1a) with small sidechain substituents. Attempts to use even
With proline derivative 4g, which contains no amide pro- smaller substituents did not improve the selectivity in catal-
tons, the selectivity was very low (10% ee; Table 4, Entry 6). ysis, as can be seen for example by using Lig-[Gly-OMe]-
Unsymmetrical ligands 5a–f are capable of forming [β2] [Ala-OMe] (5f) with small Gly at Aa1 or binary mixtures
conformations and induced moderate selectivity (47– of Lig-[Gly-OMe]2 (4f) and Lig-[Aa1-OMe]2 (1a) (Table 3,
68% ee; Table 4, Entries 7–12). Particularly interesting is Entries 1–4) or Lig-[Ala-Gly-OMe]2 (2a) and Lig-[Gly-Ala-
the rather low selectivity observed with derivative 5g OMe]2 (2b) (Table 3, Entries 10–12).
(29% ee; Table 4, Entry 13), for which the [β2] conformation
To obtain high selectivity, small-molecule catalysts typi-
can be formed, but without the weak supporting H-bond- cally need to incorporate the chiral information as close as
ing, due to the lack of Pro amide protons. As expected, possible to the catalytically active metal center. Herein, we
catalysis with achiral ligands 4a or 4f gave quantitative yield describe a series of relatively small supramolecular transi-
but without selectivity (Table 4, Entries 1 and 5).
tion-metal catalysts (ca. 1300 gmol–1) for which an ordered
chiral outer-coordination sphere allows the use of a prochi-
ral metal center. The presented catalysts are models of arti-
ficial metalloenzymes with a minimal functional outer-co-
ordination sphere.
Table 4. RhI-catalyzed asymmetric hydrogenation of S1 by using
ligands 4 and 5.[a]
Experimental Section
Entry
Ligand
Conv. [%][b]
ee (S) [%][c]
General Remark: Pure l-amino acids and (S)-amines were used ex-
cept for (R)-cyclohexylethylamine.
1
2
3
4
5
6
7
8
9
10
11
12
13
4a/4a
4b/4b
4c/4c
4d/4d[d]
4f/4f
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
0
4 (R)
18
34
0
10
47
67
68
60
51
54
29
Synthesis of Ligands 1–3. General Procedure: 5-(Diphenylphos-
phanyl)isophthalic acid (120 mg, 0.34 mmol), TBTU (212 mg,
0.68 mmol, 2 equiv.), HOBt (90 mg, 0.68 mmol, 2 equiv.) and DI-
PEA (175 µL, 1.05 mmol) were stirred at room temperature in
CH2Cl2 (50 mL). After 1 h, N-unprotected amino acid or peptide
(3–4 equiv.) was added to the reaction mixture, and stirring was
continued overnight (ca. 15 h). The reaction mixture was then
washed with satd. aq. NaHCO3, aq. citric acid (10%) and satd.
aq. NaCl, dried with Na2SO4, filtered, concentrated in vacuo, and
purified by automated flash chromatography on a prepacked silica
column.
4g/4g
5a/5a
5b/5b
5c/5c
5d/5d
5e/5e
5f/5f
5g/5g
[a] Reaction conditions: [Rh]/ligand/substrate = 1:2.4:100, p(H2) =
1 bar, room temp., 2 h, CH2Cl2 (0.1 m substrate). [b] Determined
by 1H NMR spectroscopic analysis. [c] Determined by GC analysis
(Beta Dex 225). [d] Catalysis by using enantiomer 4e yields (R)-P1
with 34% ee.
Catalytic Hydrogenation of Methyl 2-Acetamidoacrylate (S1). (a)
Catalysis at Room Temperature: An oven-dried, two-necked, round-
bottomed flask (10 mL) under nitrogen was charged with the li-
gand (6.6 μmol, 2.2 mol-%) dissolved in dichloromethane (3 mL;
distilled, degassed in an ultrasonic bath for 15 min), followed by
[(COD)Rh(CH3CN)2]-BF4 (1.25 mg, 3 μmol, 1 mol-%) dissolved in
dichloromethane (2 mL). Several experiments were performed in
diluted CH2Cl2 solution (total volume 50 mL instead of 5 mL) or
in methanol (total volume 5 mL); see Table 1 for more information.
The flask was then flushed with hydrogen, and the substrate
(45 mg, 0.3 mmol) was added in one portion and vigorously stirred
with a magnetic stirrer. After 2 h, 0.5 mL of the solution was eluted
through silica (150 mg) with ethyl acetate (5 mL), and the enantio-
meric excess (ee) was determined by chiral fused silica capillary
column [Beta Dex 225; isocratic 140 or 150 °C; 100 kPa head col-
umn pressure; eluting order: substrate, (R) product, (S) product].
(b) Catalysis at Low Temperature: According to the procedure for
Conclusions
This paper describes the solution-phase synthesis of
monodentate triphenylphosphane ligands disubstituted
with amino acids Lig-[Aa1-Z]2 (1) (Z = OMe or NH2), di-
peptides Lig-[Aa1–Aa2–OMe]2 (2) or tripeptides Lig-[Aa1–
Aa2–Aa3–OMe]2 (3). In addition, unsymmetrically disubsti-
tuted Lig-[NH-R or Aa1-OMe][Ala-OMe] (5) and their
symmetrically substituted analogues Lig-[NH-R or Aa1-
OMe]2 (4) have been prepared by using a convenient one-
pot, two-step protocol.
Eur. J. Org. Chem. 2013, 8154–8161
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8159

Z. Kokan, S. I. Kirin
FULL PAPER
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Catalytic Hydrogenation of Methyl (Z)-α-Acetamidocinnamate (S2).
(a) Catalysis at Atmospheric Pressure: The procedure described for
S1 was used with ligand (13.2 μmol, 2.2 mol-%), [(COD)-
Rh(CH3CN)2]BF4 (2.50 mg, 6 μmol, 1 mol-%) and S2 (70 mg,
0.3 mmol). Chiral fused silica capillary column [l-chirasil-Val; con-
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Catalysis at High Pressure: In an Eppendorf vial, Rh precursor and
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yellow solution was added to a 10 mL beaker containing the sub-
strate and CH2Cl2 (4 mL). This was tightly sealed in an autoclave
and purged three times with H2 (13 bar) and finally stirred at 13 bar
for 2 h. The product was analyzed as detailed above.
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Abbreviations: Amino acids are abbreviated by three or one letter
codes (for spectral assignation). The following non-standard ab-
breviations were used: H-BzA = H-NHCH2Ph (benzylamine), H-
PeA = H-NHCH(CH3)Ph (phenylethylamine), H-NeA = H-
NHCH(CH3)C10H7 (α-naphthylethylamine) and H-CeA = H-
NHCH(CH3)C6H11 (cyclohexylethylamine); see Scheme 2 for
structures.
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Supporting Information (see footnote on the first page of this arti-
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and complexes; gas chromatograms of catalytic products and de-
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These results are based on work financed by the Unity Through
Knowledge Fund (UKF) (36/08), the Croatian Science Foundation
(HrZZ) (02.04/23) and the Ministry of Science, Education and
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Published Online: November 5, 2013
Eur. J. Org. Chem. 2013, 8154–8161
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