'backdoor Induction' of chirality: Asymmetric hydrogenation with rhodium(I) complexes of triphenylphosphane-substituted β-turn Mimetics

Article abstract of DOI:10.1021/om5005385

Bioconjugate bidentate ligands 2-10 were obtained by tethering triphenylphosphanecarboxylic acid to amino acid substituted spacers with different flexibility, ranging from a rigid enediyne-based β-turn inducer to flexible linear aliphatic chains with up to eight carbon atoms. The 21 synthesized ligands revealed up to 81% ee selectivity in rhodium-catalyzed asymmetric hydrogenation of α,β-unsaturated amino acids. The key feature of the catalysts is the prochiral coordination sphere of the catalytic metal while the chirality is transmitted by 'backdoor induction' from distant hydrogen-bonded amino acids. DFT calculations were applied to study the structure and relative stability of the precatalytic organometallic Rh(I) complexes, with particular emphasis on hydrogen-bonded secondary structures.

Full text of DOI:10.1021/om5005385

Article
pubs.acs.org/Organometallics
“Backdoor Induction” of Chirality: Asymmetric Hydrogenation with
Rhodium(I) Complexes of Triphenylphosphane-Substituted β‑Turn
Mimetics
Zoran Kokan, Zoran Glasovac, Maja Majeric Elenkov, Matija Gredicak, Ivanka Jeric, and Srecko I. Kirin*
́
̌
́
́
Ruđer Bosk
̌
ovic
́
Institute, Bijenick
̌
a cesta 54, HR-10000 Zagreb, Croatia
S
* Supporting Information
ABSTRACT: Bioconjugate bidentate ligands 2−10 were
obtained by tethering triphenylphosphanecarboxylic acid to
amino acid substituted spacers with different flexibility, ranging
from a rigid enediyne-based β-turn inducer to flexible linear
aliphatic chains with up to eight carbon atoms. The 21
synthesized ligands revealed up to 81% ee selectivity in
rhodium-catalyzed asymmetric hydrogenation of α,β-unsatu-
rated amino acids. The key feature of the catalysts is the
prochiral coordination sphere of the catalytic metal while the
chirality is transmitted by “backdoor induction” from distant
hydrogen-bonded amino acids. DFT calculations were applied to study the structure and relative stability of the precatalytic
organometallic Rh(I) complexes, with particular emphasis on hydrogen-bonded secondary structures.
bridged with a rigid cis-enediyne moiety have predefined
turnlike conformation while maintaining enough flexibility to
adjust upon addition of metal ions.7 Moreover, the close
resemblance with one class of β-turn geometry was found when
applying geometric analysis on Cα surrogates in our templates
(Chart 1b).
Recently, we have used triphenylphosphane amino acid
bioconjugates as bioinspired monodentate ligands in Rh(I)-
catalyzed asymmetric hydrogenation of α,β-unsaturated amino
acids.8−12 Those [Rh(COD)(Lig)2]BF4 complexes feature a
prochiral catalytically active metal; the chirality is transmitted
by “backdoor induction” from distant hydrogen-bonded amino
acids (Chart 2).8,13 Herein, we tether monodentate ligands to
rigid or flexible linkers that allow different spatial arrangements
of hydrogen bond donor and acceptor groups (of the amino
acids) and as a consequence different phosphane−rhodium−
INTRODUCTION
■
β-Turns are among three main secondary structural motifs
found in peptides and proteins.1 Mimetics with turnlike
structures are involved in various interactions between
biomolecules;2 therefore, new scaffolds able to act as β-turn
initiators are highly desirable. Generally, turnlike structures are
known to be stabilized by the presence of conformational
constraints, additional hydrogen bond donating and accepting
groups, or peptide bond trans−cis isomerization.3−5
A rather general model which may be used for efficient β-
turn template screening is based on geometric analysis of the
distances between Cα atoms in various β-turn fragments.6 A
cluster analysis of tetraalanyl peptide segments, constructed by
using torsion angles of different idealized β-turn types,
identified clear patterns with a triangle relationship (Chart
1a). We have reported that templates based on amino acids
Chart 1. Triangle Relationship of (a) Cα atoms (Solid
Squares) in a Near-Isosceles Pattern Found in β-Turns5 and
(b) Cα Surrogates (Open Squares) in Peptide Mimetics
Described Herein, Calculated for the Bis-N-Acetyl
Chart 2. Side View (Left) and Top View (Right) of Meta-
Substituted [Rh(COD)(Lig)2]BF4 Complexes
a
a
Derivative using B3LYP/6-31G(d)
a
The upper central aromatic ring is indicated in boldface; the arrows
indicate the sign of helical chirality.
a
Received: May 19, 2014
Published: July 30, 2014
Distances are given in Å.
© 2014 American Chemical Society
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phosphane bite angles14 and study the influence of the various
linkers on the selectivity in asymmetric hydrogenation.
Catalytic hydrogenation of Boc-9 using Pd/C in MeOH gave
Boc derivatives Boc-10. Ligand bioconjugates 9 and 10 were
obtained by N-terminal deprotection of Boc-9 and Boc-10
(TFA/DCM), followed by coupling with triphenylphosphanes
I or II under standard conditions (TBTU/HOBt/DIPEA).
Asymmetric Hydrogenation. Organometallic precatalyst
complexes [Rh(COD)Lig]BF4 with bidentate ligands, Lig = 2−
10, prepared in situ were used in asymmetric hydrogenation of
α,β-unsaturated amino acids S1 and S2 (Scheme 4). Their
catalytic activity was compared to that of in situ prepared
complexes [Rh(COD)(Lig)2]BF4 with monodentate ligands,
Lig = 1A, 1Ap; the results are collected in Tables 1 and 2.
All examined Rh complexes proved to be efficient hydro-
genation catalysts with excellent conversion of the substrate to
the product. Thus, optimal conditions for hydrogenation of S1
are 2 h at room temperature and ambient pressure, while
optimal conditions for S2 are 2 h at room temperature and
elevated H2 pressure (13 bar).
In particular, rigid enediyne ligands 9 generally show higher
selectivity than supramolecular ligand 1 or derivatives 10 with a
more flexible linker. The best result with up to 81% ee was
obtained using the meta-substituted alanine ligand 9A with a
small side chain (Table 1, run 6). Catalysis with previously
reported diphenlyphosphane−isophthalic acid based ligands
also gave the highest selectivity if alanine derivatives were
used.8a
RESULTS AND DISCUSSION
■
Synthesis and Characterization. Monodentate ligand
amino acid bioconjugates 1A and 1Ap were prepared by
standard peptide coupling in solution (TBTU/HOBt/DIPEA),
reacting Boc-Ala-OH with meta- or para-substituted
(diphenylphosphane)benzoic acid I or II, respectively (Scheme
1).15
a
Scheme 1.
a
Reagents and conditions: (a) Boc-Ala-OMe, TBTU/HOBt/DIPEA,
DCM, room temperature, 15 h.
Bidentate ligand bioconjugates 2A−8A, 4AA, and 5AA were
synthesized according to Scheme 2. First, the N-Boc-protected
derivatives Boc-2A−Boc-8A, Boc-4AA, and Boc-5AA were
prepared using 2 equiv of Boc-Ala-OH and 1 equiv of diamines
NH2-(CH2)n-NH2 with different chain lengths, n = 2−8. In the
second step, the Boc derivatives were deprotected under
standard conditions (TFA/DCM) and further coupled with
meta-substituted triphenylphosphanecarboxylic acid II via the
TBTU/HOBt/DIPEA protocol to give ligand amino acid or
dipeptide bioconjugates 2A−8A, 4AA, and 5AA.
The synthesis of bidentate ligand bioconjugates 9 and 10 is
highlighted in Scheme 3. Sonogashira coupling of alanine,
leucine, valine, or phenylalanine N-propargyl amides16 and 1,2-
diiodobenzene was performed in THF in the presence of
piperidine, Pd(PPh3)4, and CuI to yield Boc-enediynes Boc-9.
A significant difference in selectivity was obtained for meta-
and para-substituted ligands. Meta-substituted ligands 9 and 10
revealed moderate to good selectivity, mostly above 50% ee for
both substrates. In contrast, for all para-substituted ligands 1Ap,
9Ap, 9Lp, 10Ap, and 10Lp, the selectivity in catalysis was
generally below 20% ee (see Table S1, Supporting
Information). The favorable displaced stacking of the central
aromatic rings in meta-substituted ligands (see (i) in Chart 3)
can be used to explain the significantly higher selectivity in
catalysis, as opposed to the less favorable face-to-face stacked
a
Scheme 2.
a
Reagents and conditions: (a) TBTU/HOBt/DIPEA, DCM, room temperature, 15 h; (b) TFA/DCM (1/1); (c) Boc-Ala-OMe, TBTU/HOBt/
DIPEA, DCM, room temperature, 15 h; (d) Ph2P-mC6H4-CO2H/TBTU/HOBt/DIPEA, DCM, room temperature, 15 h.
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a
Scheme 3.
a
Reagents and conditions: (a) piperidine (2 equiv), Pd(PPh3)4 (0.01 equiv), CuI (0.1 equiv)/THF; (b) Pd/C/MeOH; (c) TFA/DCM (1/1); (d)
Ph2P-C6H4-CO2H/TBTU/HOBt/DIPEA, DCM, room temperature, 15 h.
a
Scheme 4.
Table 1. Rh(I)-Catalyzed Asymmetric Hydrogenation of S1
or S2 by using Meta-Substituted Ligands 1, 9, and 10
a
conversn
b
c
run
ligand substrate t (h) p (bar)
(%)
ee (R) (%)
e
1
1A/1A
1A/1A
1A/1A
9A
S1
S2
S2
S1
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
2
20
2
1
1
>98
47
56 (S)/3 (S)
58 (S)
2
a
3
13
1
>98
>98
>98
89
61 (S)
Reagents and conditions: (a) [Rh(COD)Lig]BF4/H2/DCM (0.1 M
e
substrate), room temperature; [Rh]/Lig/substrate = 1/1.1/100.
4
2
75/56
d
5
9A
2
1
73
6
9A
20
2
1
81
53
58
63
35
61
70
49
53
61
40
44
60
16
45
36
7
7
9A
13
1
90
aromatic rings in the para-substituted ligands ((ii) in Chart
3).17
8
9V
2
>98
63
9
9V
20
2
1
The opposite stereochemical outcome of the catalytic
reaction was obtained for meta-substituted bidentate ligands
9 and 10, in comparison to monodentate ligand 1A (Table 1).
Using monodentate ligand 1A, the catalysis resulted in up to
61% ee in favor of (S)-P1 or (S)-P2; this result is in agreement
with our previous stereochemical analysis.8b,13 However, if
meta-substituted bidentate ligands 9 and 10 are used, an excess
of (R)-P1 or (R)-P2 is obtained in catalytic hydrogenation.
Next, in an attempt to investigate the importance of
structural rigidity in catalysis, instead of the rigid enediyne
(in ligands 9), aliphatic chains with varying length (up to eight
carbon atoms) were incorporated in bidentate phosphane
ligands 2A−8A. Meta substitution of the ligand and amino acid
building block alanine were retained, because meta-substituted
alanine ligands were the most selective catalysts so far. In the
2A−8A series of ligands, the highest selectivity in the studied
asymmetric hydrogenation was 72% ee (R) for the optimal
spacer length of n = 5 (Table 2, entry 10). Adding one amino
acid per chain in 4AA and 5AA did not improve the selectivity
(Table 2, entries 22−27). Interestingly, for a series of ligands
8A, 10A, and 9A, all with an eight-carbon-atom spacer, the
selectivity significantly increases upon constraining the spacer
by means of a phenyl ring and/or triple bonds (Chart 4),
indicating that complexes with rigid spacers give more
structurally defined intermediates in the catalytic cycle.
10
11
12
13
14
15
16
17
18
19
20
21
22
9V
13
1
81
9L
2
>98
78
9L
20
2
1
9L
13
1
>98
>98
63
9F
2
9F
20
2
1
9F
13
1
87
10A
10A
10A
10L
10L
10L
2
>98
>98
>98
>98
>98
>98
20
2
1
13
1
2
20
1
2
13
a
b
Reaction according to Scheme 4. Determined by 1H NMR
c
spectroscopic analysis. Determined by GC analysis: BetaDex 225
for S1/P1 and L-Chirasil-Val for S2/P2. Reaction performed at −5
°C. MeOH was used as solvent.
d
e
At ambient pressure, the selectivity of the catalysts for both
S1 and S2 is mostly similar, often with slightly higher ee values
in the asymmetric hydrogenation of S2. Catalysis under
increased hydrogen pressure resulted in a significant decrease
of selectivity for S2 using bidentate meta ligands 9 and 10,
while it had almost no effect on para ligands (Table S1,
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selectivity with 3A and 8A (Table 2, entries 5, 6 and 20, 21),
and an inversion of selectivity with 6A (Table 2, entries 14, 15).
When the solvent is changed from dichloromethane to
methanol (Tables 1 and 2), the quantitative yield of the
catalytic hydrogenation is retained, while the selectivity
decreases. In the case of ligands 1A and 4A, the selectivity is
completely lost: 56% to 3% ee (Table 1, entry 1) and 51% to
8% ee (Table 2, entry 8), respectively. However, if 9A is used as
ligand in Rh(I)-catalyzed hydrogenation, moderate selectivity is
retained (Table 1, entry 4, 75% to 56% ee). These results reveal
the importance of hydrogen bonds for inducing selectivity, as
shown in our previous work.8a
Chart 3. Different Stacking of the Central Aromatic Rings:
(i) Meta- and (ii) Para-Substitution Pattern
a
a
The lower ring is indicated with a dashed line.
Table 2. Rh(I)-Catalyzed Asymmetric Hydrogenation of S1
a
or S2 by using Ligands 2−8
b
c
run ligand substrate t (h) p (bar) conversn (%)
ee (R) (%)
Precatalyst Rh(I) Complexes. Spectroscopy. Rh(I)
complexes with ligands 1−10, with 2:1 phosphorus donor to
metal stoichiometry, were prepared in situ and studied by NMR
and CD spectroscopy. The absence of amide proton resonances
1
2A
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
S1
S2
S2
2
20
2
1
1
>98
92
8
2
2A
1
3
2A
13
1
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
4
1
4
3A
2
22
8
below δ 7 ppm in H NMR spectra of Rh(I) complexes in a
5
3A
20
2
1
non-hydrogen-bonding solvent (CDCl3) indicates the involve-
ment of amide protons in hydrogen bonding, suggesting an
ordered structure of the metal complexes in solution (see the
Supporting Information). CD spectra of the Rh(I) complexes
further support an ordered structure in CH2Cl2 solution (Chart
5). In particular, CD signals of the Rh chromophore strongly
support efficient “backdoor induction” of chirality from the
chiral amino acids to the prochiral rhodium.8,18−20
6
3A
13
1
24
d
7
4A
2
51/8
8
4A
20
2
1
47
9
4A
13
1
19
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
5A
2
65
5A
20
2
1
72
5A
13
1
39
6A
2
16
6A
20
2
1
22
Chart 5. CD Spectra of Selected Organometallic Precatalytic
Complexes [Rh(COD)(Lig)]BF4 in CH2Cl2
6A
13
1
12 (S)
48
7A
2
7A
20
2
1
55
7A
13
1
6
8A
2
13 (S)
9 (S)
23 (S)
29 (S)
22 (S)
12 (S)
39
8A
20
2
1
8A
13
1
4AA
4AA
4AA
5AA
5AA
5AA
2
20
2
1
13
1
2
20
2
1
48
13
23
a
b
Reaction according to Scheme 4. Determined by 1H NMR
c
spectroscopic analysis. Determined by GC analysis: BetaDex 225
for S1/P1 and L-Chirasil-Val for S2/P2. MeOH was used as solvent.
d
Chart 4. Spacers Incorporated in Ligands 8A, 10A, and 9A in
Comparison to the Selectivity Obtained in Catalysis of S1
a
(Upper Row) or S2 (Lower Row)
Computational Study. Relative energies of Rh(I) precatalyst
complexes were calculated using two theoretical methods. First,
the widely accepted general purpose B3LYP approach was
employed (M1 method), which has been used earlier for
investigation of the gas-phase chemistry of metal complexes.21
The second calculation method, M2, using the M06-L density
functional is parametrized against a training set containing
noncovalent interactions including π−π interactions and was
recommended for calculation of metal complexes.22
In our study, supramolecular complexes with monodentate
ligands [Rh(COD)(1Lig)2]+ as well as complexes with
bidentate ligands [Rh(COD)(9Lig)]+ were calculated; amino
acid substituents were achiral glycine or chiral L-alanine.
Geometry optimization of all investigated structures led to a
square-planar rhodium coordination, as found in X-ray crystal
structures of [Rh(COD)(PPh3)2]+ derivatives.23 Since the
tetrafluoroborate anion does not coordinate to the metal,
a
Constrained carbon atoms are highlighted in red.
Supporting Information). Monodentate ligand 1A (Table 1,
entries 2 and 3) exhibited only a slight change in selectivity for
S2 at higher pressure, which is in accordance with our previous
work.8a Ligands with an alkyl spacer reveal an increase of
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only the cations were calculated; the anion was left out for
simplicity.
For each metal complex, several conformers based on
different hydrogen-bonding patterns between the two parallel
amino acid strands were considered (Chart 6). The conformers
Table 3. Relative Energies (Erel) of Several Conformers of
the Achiral (Lig = G) and Chiral (Lig = A) Precatalytic
Complexes Calculated Using Theoretical Models M1 and
a
M2
Erel/kJ mol−1
Lig = A
Chart 6. Different Hydrogen Bonding Patterns: Conformers
a, b, c1, and c2 Exemplified at the Amino Acid Substituted
Enediyne Backbone
b
b
conformer
Lig = G M-1,2′
P-1,2′
a
[Rh(COD)(1Lig)2]+
[Rh(COD)(9Lig)]+
a1
M1
0.0
(0.0)
8.4
0.0
(0.0)
28.0
17.3
(M2)
M1
(5.4)
12.3
a2
b
(M2)
M1
(9.6)
25.0
(41.9)
0.0
(12.2)
30.6
(12.4)
37.9
(M2)
M1
(44.4)
0.0
(44.9)
30.9
a1
a2
b
(M2)
M1
(0.0)
6.6
(0.0)
30.4
(28.8)
6.2
(M2)
M1
(4.7)
10.8
(28.2)
(25.5)
8.5
(13.1)
43.1
(M2)
(26.3)
(46.9)
a
Relative energies (Erel) were calculated by either the B3LYP (M1
model) or M06-L (M2 model) density functional method at the same
optimized geometries. The most stable conformation was used as the
b
reference structure. Configuration of the Rh metallacycle; see Chart 7
for an explanation.
Chart 7. Different Substitution Patterns a1 and a2 of the
a
,
Meta-Disubstituted Rings in the Rh(I) Complexes25
a
Hydrogen bonds are indicated by dashed lines; Bernstein−Davis
notation is indicated in red, according to ref 24.
can be distinguished by looking at the carbonyl oxygen atoms
directly attached to the triphenylphosphane moiety: the
“Herrick conformer” a features both carbonyl oxygen atoms
directly attached to the triphenlyphosphane moiety pointing
away from the cleft formed by the two amino acids. In the “van
Staveren conformer” b, one carbonyl oxygen atom points
toward the cleft and the other carbonyl oxygen points away,
̌
while in the “Gredicak conformer” c both carbonyl oxygen
atoms point inward. If the Bernstein−Davis classification is
applied,24 the conformers differ in the number of atoms
involved in the hydrogen-bonded rings: R22(10) for a, R22(12)
for b, R22(14) for c1 with interstrand hydrogen bonds, and an
additional hydrogen bond with S(7) notation is possible in
conformer b. On the other hand, conformer c2 contains two
S(7) intrastrand hydrogen bonds.
The relative energies of the various conformers are collected
in Table 3. Slightly different results with the two theoretical
methods could be expected; our calculations show, however,
that both methods predict the same trend of stabilities for the
studied conformers.
a
For a detailed stereochemical analysis see the Supporting
Information.
optimization, interstrand hydrogen bonds cleaved and intra-
strand hydrogen bonds were established, ending up in the c2
conformer that is, however, 50 kJ mol−1 above the most stable
conformer a1. Additional attempts to optimize the c1
conformer starting from c1-like initial geometries were not
successful. Therefore, only conformers a and b were studied in
detail, while the least stable conformer c2 was abandoned.
The achiral supramolecular complex [Rh(COD)(1G)2]+ was
studied first (Table 3). In this case, the conformers differ in the
number of hydrogen bonds: conformers a1 and a2 each contain
two hydrogen bonds, while conformer b has one such bond.
Both applied theoretical models M1 and M2 predicted “Herrick
conformer” a1 to be the most stable (Table 3). The highest
stability of “Herrick conformer” a is expected, since this
conformer is found in the single crystal of [Pt(1VA)2Cl2],9d
and a is also present in the ferrocene peptides.13,26 However,
while a1 is significantly more stable than b (ΔErel > 25 kJ
mol−1), the relative energies of the crowded conformer a2 are
For the “Herrick conformer” two different substitution
patterns of π−π stacked meta-disubstituted phenyl rings were
considered: stretched conformer a1 and crowded conformer a2
(Chart 7). It is important to note that the same helical chirality
of the hydrogen-bonded amino acid substituents, for example P
in Chart 7, induces opposite chirality at the metal coordination
sphere, M for a1 and P for a2. For the “van Staveren
conformer” b, geometrical optimization surprisingly predicts
π−π stacking between one meta-disubstituted phenyl ring and
̌
one monosubstituted phenyl ring. “Gredicak conformer” c1
with interstrand hydrogen bonds was not identified as a
minimum on the potential energy surface (PES). During
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rather close to those of a1 (ΔErel = 6.6 (M1) and 4.7 kJ mol−1
(M2)) (Table 3).
that controls the chirality of the prochiral catalytic metal in
asymmetric catalysis. The results obtained herein clearly show
that the chiral information far away from the catalytic metal has
a significant impact on enantioselectivity in the studied
hydrogenation reaction.
It is important to point out that subtle changes to the
architecture of our L-amino acid substituted ligands allow access
to both enantiomers of the catalytic product: while
monodentate ligand 1A yields an excess of the S product,
introducing a linker in the most selective bidentate ligands 9A
and 5A results in predominant formation of the R product. In
order to explain this turnover in selectivity and predict the
configuration of the major product in catalysis, detailed
experimental and computational data on the reaction
mechanism are necessary.12 Work along these lines is in
progress in our laboratories.
Next, the achiral macroyclic complex [Rh(COD)(9G)]+ was
calculated. Including the β-turn mimicking building block
introduces two more amide protons capable of hydrogen
bonding. Again, the conformers differ in the number of
hydrogen bonds: conformers a1 and a2 contain two hydrogen
bonds each, and conformer b has three H bonds. The results
obtained reveal that “Herrick conformer” a1 is the most stable
for [Rh(COD)(9G)]+ as well, followed by a2 and b, but the
energy difference between a1 and b is only 10.8 kJ mol−1 (by
M2) (Table 3).
Complexes [Rh(COD)(1A)2]+ and [Rh(COD)(9A)]+ con-
taining the chiral amino acid alanine have also been calculated.
In these chiral derivatives, interstrand hydrogen bonding
between the two amino acids induces helical chirality at the
stacked phenyl rings, leading to different stereoisomers (Table
3). The trends found for achiral glycine derivatives apply also
for chiral alanine analogues: (i) “Herrick conformers” a are
more stable than the “van Staveren” conformers b and (ii) the
difference between a and b is larger for the supramolecular
complex [Rh(COD)(1A)2]+ than for the bidentate complex
[Rh(COD)(9A)]+. However, only small energetic differences
were calculated for conformers with different helical chiralities
of the rhodium coordination sphere that would lead to opposite
configurations of the product in catalysis. For the chiral
supramolecular complex [Rh(COD)(1A)2]+ ΔErel between
1,2′-M a1 and 1,2′-P a1 is only 5.4 kJ mol−1 (by the M2
theoretical model). In addition, for chiral bidentate complex
[Rh(COD)(9A)]+, three conformers of different helical
chiralities are found to be within 10 kJ mol−1: 1,2′-P a2 and
1,2′-M b are only 6.2 and 8.5 kJ mol−1 (using M1 theoretical
model) less stable than 1,2′-M a1. From the small energy
differences calculated for the studied conformers of precatalytic
complexes, it is not possible to predict a general trend for the
configuration of the preferred product in catalysis.
EXPERIMENTAL SECTION
■
General Methods. Reactions were carried out in ordinary
glassware, and chemicals were used as purchased from commercial
suppliers without further purification. Pure L-amino acids were used.
Reactions were monitored by TLC on silica gel 60 F254 plates and
detected with a UV lamp (254 nm) or ninhydrin; compounds were
purified using automated flash chromatography equipped with a UV
detector (254 nm) and prepacked silica columns. For reactions at low
temperature, a cryostat device was used.
Mass spectra were measured on a HPLC-MS system coupled with
6410 triple-quadrupole mass spectrometer, operating in a positive ESI
mode. High-resolution mass spectra were obtained on a MALDI TOF-
TOF instrument using a CHCA matrix. CD spectra were recorded on
a spectropolarimeter in 1 cm quartz Suprasil cells. NMR spectra were
obtained on spectrometers operating at 300.13 or 600.13 MHz for 1H,
75.47 or 150.92 MHz for 13C, and 242.93 MHz for 31P nuclei.
Chemical shifts, δ (ppm), indicate a downfield shift from the internal
standard tetramethylsilane (TMS) for 1H NMR, H3PO4 (85%) for 31
P
NMR, or residual solvent signal for 13C NMR (77.16 ppm for CDCl3
or 39.52 ppm for DMSO-d6). Coupling constants, J, are given in Hz.
Enantiomeric excesses were determined on a gas chromatograph (FID
detector) using chiral fused silica capillary columns Beta Dex 225 (30
m × 0.25 mm × 0.25 μm) or Permabond L-Chirasil-Val (25 m × 0.25
mm).
CONCLUSION
■
Bidentate triphenylphosphane amino acid ligands Lig contain-
ing β-turn inducing linkers with different flexibilities have been
synthesized and characterized. Precatalytic organometallic
rhodium(I) complexes [Rh(COD)(Lig)]BF4 adopt an ordered
structure in non-hydrogen-bonding solvents, as shown by NMR
and CD spectroscopy. The structure and relative stability of
selected precatalytic complexes was studied by DFT calcu-
lations using the two theoretical models B3LYP and M06-L and
showed that stretched “Herrick conformer” a1 is the most
stable, but the difference in stability from that of the crowded
“Herrick conformer” a2 can be rather small: ΔErel < 10 kJ
mol−1.
Computational Details. All calculations were performed using the
Gaussian09 program package.28 Geometries were optimized using the
B3LYP hybrid density functional29 in conjunction with the Ahlrichs
SVP basis set30 for the first-row elements and TZVP basis set for
phosphorus, while the LanL2DZ effective core potential31 was
employed for rhodium. Electronic energies were recalculated using
two different density functionals, indicated throughout the text as the
calculation models M1 and M2. The first model (M1) encompasses a
B3LYP hybrid density functional in conjunction with LanL2DZ ECP
for rhodium and TZVP basis set for other elements. Alternatively,
model M2 was constructed by choosing the M06-L density
functional,22 in combination with Pople’s 6-311++G(3df,2p) (C, H,
O, N, and P) and LanL2DZ (Rh) basis sets. The nature of the
stationary points was verified by vibrational analysis at the optimized
geometries, and no imaginary frequencies were obtained. Total
energies (Etot) were obtained by summing M1 or M2 electronic
energies with zero-point vibrational energies (EZPV) without any
scaling of the latter. Visualization of the optimized structures was done
by MOLDEN 5.0.32
The rhodium complexes were used as catalysts in asymmetric
hydrogenation of α,β-unsubstituted amino acids. Bidentate
ligands described in this study yielded more selective catalysts
than their monodentate analogues (61% ee (S) with
monodentate ligand 1A). The nature of the linker in the
bidentate ligands has a major influence on the selectivity in
catalysis. In particular, enantioselectivities up to 81% ee (R)
were obtained with ligand 9A, containing the most favorable
rigid enediyne linker. Within the series of ligands with different
lengths of the flexible −NH(CH2)nNH− linker, the best result
was obtained with ligand 5A: n = 5, 72% ee (R). The presented
catalysts are enzyme models where an artificial chiral β-turn
serves as a minimal but functional outer coordination sphere
Ligands. Peptide Coupling: General Procedure. 5-
(Diphenylphosphino)isophthalic acid, TBTU, HOBt, and DIPEA
were stirred at room temperature in DCM. After 1 h, amino acid or
peptide was added to the reaction mixture and stirring was continued
overnight (approximately 15 h). The reaction mixture was then
washed with NaHCO3 (saturated aqueous), citric acid (10%,
aqueous), and NaCl (saturated aqueous), dried over Na2SO4, filtered,
4010
dx.doi.org/10.1021/om5005385 | Organometallics 2014, 33, 4005−4015

Organometallics
Article
evaporated under vacuum, and purified by automated flash
chromatography on a prepacked silica column.
167.3 (7), 173.0 (A1). ESI-MS (m/z): 793.3 (M + H+, 100%).
MALDI-HRMS (m/z): calcd 793.3067 (C47H46N4O4P2 + H+), found
793.3071.
Boc Protecting Group Removal. The corresponding Boc-protected
amino acid or peptide was dissolved in DCM/trifluoroacetic acid (1/1,
5 mL) and the solution stirred for 2 h at room temperature. The
volatiles were evaporated under reduced pressure, and the viscous
residue was dissolved in 15 mL of DCM. The residual trifluoroacetic
acid was neutralized with excess DIPEA (0.5 mL). This solution was
used for further peptide synthesis.
4A. 3-(Diphenylphosphino)benzoic acid (132.3 mg, 0.43 mmol),
HOBt (62.8 mg, 0.46 mmol), TBTU (135.1 mg, 0.42 mmol), DIPEA
(0.145 mL, 0.88 mmol), Boc-4A (92.8 mg, 0.22 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.18,
DCM/MeOH 10/0.5). Yield: 93.6 mg (54%). 1H NMR (CDCl3,
300.13 MHz) δ/ppm: 1.29−1.42 (m, 4H), 1.43 (d, 6H, J = 7 Hz),
2.92−3.03 (m, 2H), 3.22−3.33 (m, 2H), 4.69−4.78 (m, 2H), 7.04 (d,
2H, J = 8 Hz), 7.08 (dd, 2H, J1 = 6 Hz, J2 = 5 Hz), 7.24−7.36 (m,
22H), 7.70 (dt, 2H, J1 = 7.5 Hz, J2 = 1.5 Hz), 7.79 (dt, 2H, J1 = 8 Hz,
J2 = 1.5 Hz). 13C NMR (CDCl3, 150.92 MHz) δ/ppm: 18.8 (β), 26.4
(b), 39.2 (a), 49.5 (α), 127.4 (4), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 128.8
(d, 3JCP = 6 Hz, 5), 129.1, 129.1 (4′, 4″), 132.8 (d, 2JCP = 24.5 Hz, 2),
1A. 3-(Diphenylphosphino)benzoic acid (126.9 mg, 0.41 mmol),
HOBt (53.39 mg, 0.40 mmol), TBTU (132.1 mg, 0.41 mmol), DIPEA
(0.140 mL, 0.85 mmol), H-Ala-OMe·HCl (61.7 mg, 0.44 mmol),
DCM (50 mL). Chromatography on silica (12 g), EtOAc/hexane
gradient (TLC: Rf = 0.60, EtOAc/hexane 1/1). Yield: 109.1 mg
1
(67%). H NMR (600,14 MHz, CDCl3) δ/ppm: 1.48 (d, 3H, J = 7
2
2
Hz), 3.77 (s, 3H), 4.73−4.77 (m, 1H), 6.59 (d, 1H, J = 7 Hz), 7.29−
133.9 (d, JCP = 19 Hz, 2′), 133.9 (d, JCP = 20.5 Hz, 2″), 134.0 (d,
1 1
7.42 (m, 12H), 7.76−7.78 (m, 2H). 13C NMR (CDCl3, 75.48 MHz)
3JCP = 6 Hz, 3), 136.5 (d, JCP = 11 Hz, 1′), 136.6 (d, JCP = 10.5 Hz,
3
1″), 136.8 (d, 2JCP = 15 Hz, 6), 138.7 (d, JCP = 14 Hz, 1), 167.3 (7),
1
δ/ppm: 18.7 (β), 48.7 (α), 52.7 (OMe), 127.7 (4), 128.8 (d, JCP = 7
3
2
173.0 (A1). 31P NMR (CDCl3, 242.93 MHz) δ/ppm: −5.09. ESI-MS
(m/z): 829.4 (M + Na+, 43%). MALDI-HRMS (m/z): calcd 807.3223
(C48H48N4O4P2 + H+), found 807.3227.
Hz, 3′, 3″), 128.9 (d, JCP = 6 Hz, 5), 129.2 (4′, 4″), 132.3 (d, JCP
=
2
3
25 Hz, 2), 133.9 (d, JCP = 20 Hz, 2′, 2″), 134.3 (d, JCP = 8 Hz, 3),
136.6, 136.6 (d, 1JCP = 11 Hz, 1′, 1″), 136.8 (d, 2JCP = 15 Hz, 6), 138.7
(d, 1JCP = 13 Hz, 1), 166.6 (7), 173.7 (A1). ESI-MS (m/z): 392.2 (M
+ H+, 100%). MALDI-HRMS (m/z): calcd 392.1410 (C23H22NO3P +
H+), found 392.1402.
4AA. 3-(Diphenylphosphino)benzoic acid (104.7 mg, 0.34 mmol),
HOBt (48.0 mg, 0.36 mmol), TBTU (105.6 mg, 0.33 mmol), DIPEA
(0.150 mL, 0.91 mmol), Boc-4AA (91.1 mg, 0.16 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.26,
DCM/MeOH 9.5/0.5). Yield: 112.4 mg (69%). 1H NMR (DMSO-d6,
600.14 MHz) δ/ppm: 1.18 (d, 6H, J = 7 Hz), 1.31 (d, 6H, J = 7 Hz),
1.33−1.35 (m, 4H), 2.93−2.99 (m, 2H), 3.01−3.06 (m, 2H), 4.18−
4.23 (m, 2H), 4.39−4.43 (m, 2H), 7.24−7.27 (m, 8H) 7.29−7.32 (m,
2H), 7.39−7.42 (m, 12H), 7.48−7.50 (m, 2H), 7.70 (t, 2H, J = 5.5
Hz), 7.88−7.93 (m, 6H), 8.57 (d, 2H, J = 7 Hz). 13C NMR (CDCl3,
150.92 MHz) δ/ppm: 17.6, 18.3 (1,2β), 26.2 (b), 38.1 (a), 48.1, 49.2
1Ap. 4-(Diphenylphosphino)benzoic acid (117.8 mg, 0.39 mmol),
HOBt (43.1 mg, 0.32 mmol), TBTU (97.1 mg, 0.30 mmol), DIPEA
(0.200 mL, 1.21 mmol), H-Ala-OMe·HCl (48.5 mg, 0.35 mmol),
DCM (50 mL). Chromatography on silica (12 g), EtOAc/hexane
gradient (TLC: Rf = 0.46, EtOAc/hexane 1/1). Yield: 84.1 mg (71%).
1H NMR (600,14 MHz, CDCl3) δ/ppm: 1.51 (d, 3H, J = 7 Hz), 3.79
(s, 3H), 4.77−4.82 (m, 1H), 6.69 (d, 1H, J = 7 Hz), 7.29−7.37 (m,
12H), 7.74 (dd, 2H, J1 = 8 Hz, J2 = 1 Hz). 13C NMR (CDCl3, 150.92
3
MHz) δ/ppm: 18.8 (β), 48.7 (α), 52.7 (OMe), 127.1 (d, JCP = 6.5
(1,2α), 128.0 (4), 128.6 (d, 3JCP = 5 Hz, 5), 128.8 (d, 3JCP = 7 Hz, 3′,
Hz, 3, 6), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 129.2 (4′, 4″), 133.7 (d, 2JCP
=
=
3″), 129.0, 129.1 (4′, 4″), 132.7 (d, 2JCP = 26 Hz, 2), 133.2 (d, JCP
=
2
19 Hz, 2, 6), 134.0 (d, 2JCP = 20 Hz, 3, 5), 134.1 (4), 136.5 (d, 1JCP
20 Hz, 2′), 133.2 (d, JCP = 19.5 Hz, 2″), 134.2 (d, JCP = 8 Hz, 3),
2
3
1
2
1
1
11 Hz, 1′, 1″), 142.7 (d, JCP = 14 Hz, 1), 166.6 (7), 173.7 (A1). 31P
NMR (CDCl3, 242.93 MHz) δ/ppm: −5.08. ESI-MS (m/z): 430.4 (M
+ K+, 53%). MALDI-HRMS (m/z): calcd 392.1410 (C23H22NO3P +
H+), found 392.1415.
135.6 (d, JCP = 14 Hz), 136.2 (d, JCP = 11 Hz, 1′), 136.2 (d, JCP =
11.5 Hz, 1″), 137.1 (d, 1JCP = 13 Hz, 1), 165.8 (7), 171.8 (1,2A1). ESI-
MS (m/z): 949.4 (M + H+, 100%). MALDI-HRMS (m/z): calcd
949.3965 (C54H58N6O6P2 + H+), found 949.3981.
2A. 3-(Diphenylphosphino)benzoic acid (133.2 mg, 0.43 mmol),
HOBt (61.7 mg, 0.46 mmol), TBTU (134.5 mg, 0.42 mmol), DIPEA
(0.145 mL, 0.88 mmol), Boc-2A (84.9 mg, 0.21 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.20,
DCM/MeOH 10/0.5). Yield: 76.7 mg (45%). 1H NMR (CDCl3,
300.13 MHz) δ/ppm: 1.40 (d, 6H, J = 7 Hz), 3.20−3.30 (m, 2H),
3.42−3.54 (m, 2H), 4.48−4.57 (m, 2H), 6.82 (d, 2H, J = 7 Hz), 6.92
(t, 2H, J = 4 Hz), 7.24−7.35 (m, 22H), 7.69 (dt, 2H, J1 = 7.5 Hz, J2 =
1.5 Hz), 7.79 (dt, 2H, J1 = 8 Hz, J2 = 1.5 Hz). 13C NMR (CDCl3,
150.92 MHz) δ/ppm: 18.3 (β), 39.6 (a), 49.9 (α), 127.6 (4), 128.8 (d,
5A. 3-(Diphenylphosphino)benzoic acid (126.6 mg, 0.41 mmol),
HOBt (60.0 mg, 0.44 mmol), TBTU (131.2 mg, 0.41 mmol), DIPEA
(0.145 mL, 0.88 mmol), Boc-5A (94.6 mg, 0.21 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.21,
DCM/MeOH 9.5/0.5). Yield: 66.0 mg (39%). 1H NMR (CDCl3,
600.14 MHz) δ/ppm: 1.16−1.21 (m, 2H), 1.40−1.49 (m, 4H), 1.45
(d, 6H, J = 7 Hz), 2.98−3.02 (m, 2H), 3.32−3.37 (m, 2H), 4.71−4.76
(m, 2H), 6.92 (dd, 2H, J1 = 6.5 Hz, J2 = 4 Hz), 7.21−7.33 (m, 24H),
7.69 (dt, 2H, J1 = 8 Hz, J2 = 1.5 Hz), 7.81 (dt, 2H, J1 = 8 Hz, J2 = 1.5
Hz). 13C NMR (CDCl3, 75.48 MHz) δ/ppm: 18.2 (β), 23.0 (c), 28.2
(b), 38.8 (a), 49.3 (α), 127.4 (4), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 128.9
(d, 3JCP = 8 Hz, 5), 129.1 (4′, 4″), 133.0 (d, 2JCP = 26 Hz, 2), 133.9 (d,
2JCP = 20 Hz, 2′, 2″), 134.0 (d, 3JCP = 8 Hz, 3), 136.6 (d, 1JCP = 11 Hz,
1′, 1″), 136.8 (d, 2JCP = 14 Hz, 6), 138.6 (d, 1JCP = 13.5 Hz, 1), 167.4
(7), 173.1 (A1). 31P NMR (CDCl3, 242.93 MHz) δ/ppm: −5.07. ESI-
MS (m/z): 821.3 (M + H+, 43%). MALDI-HRMS (m/z): calcd
821.3380 (C49H50N4O4P2 + H+), found 821.3361.
3
3JCP = 7 Hz, 3′, 3″), 128.9 (d, JCP = 5.5 Hz, 5), 129.2 (4′, 4″), 132.7
2
2
2
(d, JCP = 25 Hz, 2), 133.9 (d, JCP = 19 Hz, 2′), 133.9 (d, JCP = 19
3
1
Hz, 2″), 134.0 (d, JCP = 8 Hz, 3), 136.6 (d, JCP = 11 Hz, 1′), 136.6
1
2
1
(d, JCP = 11 Hz, 1″), 136.8 (d, JCP = 14.5 Hz, 6), 138.8 (d, JCP
=
13.5 Hz, 1), 167.3 (7), 173.5 (A1). ESI-MS (m/z): 801.3 (M + Na+,
100%). MALDI-HRMS (m/z): calcd 779.2910 (C46H44N4O4P2 + H+),
found 779.2906.
3A. 3-(Diphenylphosphino)benzoic acid (137.1 mg, 0.45 mmol),
HOBt (63.4 mg, 0.47 mmol), TBTU (141.3 mg, 0.44 mmol), DIPEA
(0.145 mL, 0.88 mmol), Boc-3A (92.8 mg, 0.22 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.20,
5AA. 3-(Diphenylphosphino)benzoic acid (93.9 mg, 0.31 mmol),
HOBt (47.6 mg, 0.35 mmol), TBTU (101.6 mg, 0.32 mmol), DIPEA
(0.150 mL, 0.91 mmol), Boc-5AA (93.3 mg, 0.16 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.27,
1
1
DCM/MeOH 9.5/0.5). Yield: 107.9 mg (61%). H NMR (CDCl3,
DCM/MeOH 9.5/0.5). Yield: 92.8 mg (63%). H NMR (DMSO-d6,
600.14 MHz) δ/ppm: 1.42 (d, 6H, J = 7 Hz), 1.64−1.68 (m, 2H),
3.09−3.14 (m, 2H), 3.42−3.47 (m, 2H), 4.58−4.63 (m, 2H), 6.78 (d,
2H, J = 7 Hz), 7.10 (t, 2H, J = 6 Hz), 7.27−7.35 (m, 22H), 7.74 (dt,
600.14 MHz) δ/ppm: 1.17−1.22 (m, 2H), 1.18 (d, 6H, J = 7 Hz), 1.31
(d, 6H, J = 7 Hz), 1.32−1.37 (m, 4H), 2.93−3.04 (m, 4H), 4.18−4.23
(m, 2H), 4.38−4.43 (m, 2H), 7.24−7.27 (m, 8H) 7.29−7.32 (m, 2H),
7.39−7.42 (m, 12H), 7.48−7.51 (m, 2H), 7.66 (t, 2H, J = 5.5 Hz),
7.89−7.93 (m, 6H), 8.58 (d, 2H, J = 7 Hz). 13C NMR (CDCl3, 75.48
MHz) δ/ppm: 17.6, 18.2 (1,2β), 23.5 (c), 28.6 (b), 38.4 (a), 48.1, 49.3
(1,2α), 128.0 (4), 128.6 (d, 3JCP = 5 Hz, 5), 128.8 (d, 3JCP = 7 Hz, 3′,
2H, J1 = 7 Hz, J2 = 1.5 Hz), 7.80 (dt, 2H, J1 = 8 Hz, J2 = 1.5 Hz). 13
C
NMR (CDCl3, 150.92 MHz) δ/ppm: 18.4 (β), 29.0 (b), 37.1 (a), 49.8
(α), 127.6 (4), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 128.9 (d, 3JCP = 6 Hz, 5),
129.2 (4′, 4″), 132.7 (d, 2JCP = 26 Hz, 2), 133.9 (d, 2JCP = 20 Hz, 2′),
133.9 (d, 2JCP = 19 Hz, 2″), 134.1 (d, 3JCP = 8 Hz, 3), 136.6 (d, 1JCP
=
3″), 129.1 (4′, 4″), 132.7 (d, JCP = 26 Hz, 2), 133.2 (d, JCP = 19.5
Hz, 2′), 133.3 (d, 2JCP = 19.5 Hz, 2″), 134.2 (d, 3JCP = 8 Hz, 3), 135.7
2
2
11 Hz, 1′, 1″), 136.8 (d, 2JCP = 14 Hz, 6), 138.7 (d, 1JCP = 13.5 Hz, 1),
4011
dx.doi.org/10.1021/om5005385 | Organometallics 2014, 33, 4005−4015

Organometallics
Article
(d, 2JCP = 14 Hz), 136.2 (d, 1JCP = 11 Hz, 1′), 136.2 (d, 1JCP = 11 Hz,
+ H+, 100%). MALDI-HRMS (m/z): calcd 903.3223 (C56H48N4O4P2
+ H+), found 903.3233.
1
1″), 137.1 (d, JCP = 13 Hz, 1), 165.8 (7), 171.7, 171.8 (1,2A1). ESI-
MS (m/z): 963.4 (M + H+, 100%). MALDI-HRMS (m/z): calcd
963.4122 (C55H60N6O6P2 + H+), found 963.4124.
9Ap. 4-(Diphenylphosphino)benzoic acid (145.4 mg, 0.48 mmol),
HOBt (67.4 mg, 0.50 mmol), TBTU (151.3 mg, 0.47 mmol), DIPEA
(0.235 mL, 1.42 mmol), Boc-9A (125.8 mg, 0.24 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.21,
EtOAc/hexane 1/1). Yield: 105.3 mg (49%). 1H NMR (CDCl3,
600.14 MHz) δ/ppm: 1.52 (d, 6H, J = 7 Hz), 4.04 (dd, 2H, J1 = 17.5
Hz, J2 = 4.5 Hz), 4.33 (dd, 2H, J1 = 17.5 Hz, J2 = 6.5 Hz), 4.90−4.95
(m, 2H), 7.18−7.22 (m, 6H), 7.25−7.27 (m, 8H), 7.29−7.33 (m,
14H), 7.49 (d, 2H, J = 8 Hz), 7.62 (dd, 2H, J1 = 6 Hz, J2 = 4.5 Hz),
7.72 (dd, 2H, J1 = 8 Hz, J2 = 1 Hz). 13C NMR (CDCl3, 75.48 MHz) δ/
ppm: 18.2 (β), 30.3 (a), 49.2 (α), 81.6 (b), 88.9 (c), 125.9 (d), 127.3
(d, 3JCP = 6.5 Hz, 3,5), 128.2 (f), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 129.2
6A. 3-(Diphenylphosphino)benzoic acid (148.0 mg, 0.48 mmol),
HOBt (67.0 mg, 0.50 mmol), TBTU (154.0 mg, 0.48 mmol), DIPEA
(0.160 mL, 0.97 mmol), Boc-6A (116.1 mg, 0.25 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.24,
1
DCM/MeOH 10/0.5). Yield: 111.01 mg (55%). H NMR (CDCl3,
300.13 MHz) δ/ppm: 1.11−1.28 (m, 4H), 1.33−1.41 (m, 4H), 1.44
(d, 6H, J = 7 Hz), 2.92−3.03 (m, 2H), 3.18−3.29 (m, 2H), 4.65−4.75
(m, 2H), 6.82 (t, 2H, J = 5.5 Hz), 7.21 (d, 2H, J = 8 Hz), 7.24−7.34
(m, 22H), 7.74 (dt, 2H, J1 = 7 Hz, J2 = 1.5 Hz), 7.82 (dt, 2H, J1 = 8
Hz, J2 = 1 Hz). 13C NMR (CDCl3, 75.48 MHz) δ/ppm: 18.3 (β), 25.4
3
2
(c), 28.8 (b), 38.7 (a), 49.4 (α), 127.5 (4), 128.8 (d, JCP = 7 Hz, 3′,
(4′, 4″), 131.7 (e), 133.5 (d, JCP = 19 Hz, 2,6), 133.7 (4), 134.0 (d,
3″), 128.8 (d, 3JCP = 4 Hz, 5), 129.1 (4′, 4″), 132.9 (d, 2JCP = 24.5 Hz,
2), 133.8 (d, 2JCP = 19.5 Hz, 2′, 2″), 134.1 (d, 3JCP = 6.5 Hz, 3), 136.6
(d, 1JCP = 11 Hz, 1′, 1″), 136.8 (d, 2JCP = 14 Hz, 6), 138.6 (d, 1JCP = 13
Hz, 1), 167.2 (7), 172.7 (A1). ESI-MS (m/z): 835.4 (M + H+, 100%).
MALDI-HRMS (m/z): calcd 835.3536 (C50H52N4O4P2 + H+), found
835.3558.
1
2JCP = 20 Hz, 2′, 2″), 136.4, 136.4 (d, JCP = 11 Hz, 1′, 1″), 142.6 (d,
1JCP = 14 Hz, 1), 167.5 (7), 173.0 (A1). ESI-MS (m/z): 941.3 (M +
K+, 5%). MALDI-HRMS (m/z): calcd 925.3043 (C56H48N4O4P2 +
H+), found 925.3026.
9V. 3-(Diphenylphosphino)benzoic acid (114.1 mg, 0.37 mmol),
HOBt (49.7 mg, 0.37 mmol), TBTU (119.6 mg, 0.37 mmol), DIPEA
(0.130 mL, 0.79 mmol), Boc-9V (110.0 mg, 0.19 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.41,
EtOAc/hexane 1/1). Yield: 84.8 mg (47%). 1H NMR (CDCl3, 300.14
MHz) δ/ppm: 0.97 (d, 6H, J = 6.5 Hz), 0.98 (d, 6H, J = 6.5 Hz),
2.15−2.27 (m, 2H), 3.95 (dd, 2H, J1 = 17.5 Hz, J2 = 4.5 Hz), 4.35 (dd,
2H, J1 = 17.5 Hz, J2 = 6.5 Hz), 4.60 (dd, 2H, J1 = J2 = 8.5 Hz), 7.17−
7.35 (m, 30H), 7.71−7.78 (m, 6H). 13C NMR (CDCl3, 75.48 MHz)
δ/ppm: 19.0, 19.5 (γ), 30.0 (a), 31.0 (β), 59.5 (α), 81.3 (b), 89.0 (c),
125.8 (d), 127.6 (4), 128.0 (f), 128.7 (5, under the 3′ peak), 128.7 (d,
7A. 3-(Diphenylphosphino)benzoic acid (123.6 mg, 0.40 mmol),
HOBt (55.5 mg, 0.41 mmol), TBTU (124.8 mg, 0.39 mmol), DIPEA
(0.145 mL, 0.88 mmol), Boc-7A (94.9 mg, 0.20 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.27,
DCM/MeOH 9.5/0.5). Yield: 84.4 mg (49%). 1H NMR (CDCl3,
600.14 MHz) δ/ppm: 1.13 (s, 1H), 1.24−1.30 (m, 2H), 1.46 (d, 6H, J
= 7 Hz), 2.87−2.92 (m, 2H), 3.23−3.28 (m, 2H), 4.75−4.80 (m, 2H),
6.96 (t, 2H, J = 5.5 Hz), 7.26−7.34 (m, 24H), 7.77 (dt, 2H, J1 = 7.5
Hz, J2 = 1.5 Hz), 7.85 (dt, 2H, J1 = 8 Hz, J2 = 1.5 Hz). 13C NMR
(CDCl3, 105.92 MHz) δ/ppm: 18.4 (β), 25.7 (c), 27.7 (d), 28.3 (b),
39.3 (a), 49.2 (α), 127.6 (4), 128.7 (5, overlapped with 3′ peak), 128.8
2
3JCP = 7 Hz, 3′, 3″), 129.1 (4′, 4″), 131.8 (e), 132.9 (d, JCP = 24 Hz,
2
2
2), 133.9 (d, JCP = 20 Hz, 2′), 133.9 (d, JCP = 20 Hz, 2″), 134.2 (d,
3JCP = 7 Hz, 3), 136.6 (d, 1JCP = 10.5 Hz, 1′), 136.6 (d, 1JCP = 10.5 Hz,
3
2
(d, JCP = 7 Hz, 3′, 3″), 129.1 (4′, 4″), 133.1 (d, JCP = 26 Hz, 2),
133.9 (d, 2JCP = 20 Hz, 2′), 133.9 (d, 2JCP = 19 Hz, 2″), 134.1 (d, 3JCP
= 8 Hz, 3), 136.6 (d, 1JCP = 11 Hz, 1′, 1″), 136.8 (d, 2JCP = 14.5 Hz, 6),
1″), 136.8 (d, 2JCP = 16 Hz, 6), 138.5 (d, JCP = 13 Hz, 1), 167.6 (7),
1
1
172.0 (V1). ESI-MS (m/z): 981.4 (M + Na+, 22%). MALDI-HRMS
(m/z): calcd 959.3849 (C60H56N4O4P2 + H+), found 959.3851.
9L. 3-(Diphenylphosphino)benzoic acid (90.3 mg, 0.30 mmol),
HOBt (40.4 mg, 0.30 mmol), TBTU (93.0 mg, 0.29 mmol), DIPEA
(0.100 mL, 0.61 mmol), Boc-9L (83.7 mg, 0.14 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.28,
EtOAc/hexane 1/1). Yield: 51.1 mg (38%). 1H NMR (CDCl3, 600.14
MHz) δ/ppm: 0.88 (d, 6H, J = 6 Hz), 0.90 (d, 6H, J = 6 Hz), 1.62−
1.76 (m, 6H), 3.85 (dd, 2H, J1 = 17.5 Hz, J2 = 4.5 Hz), 4.27 (dd, 2H, J1
= 17.5 Hz, J2 = 6.5 Hz), 4.83−4.87 (m, 2H), 7.11 (d, 2H, J = 8 Hz),
7.17−7.19 (m, 2H), 7.22 (t, 2H, J = 7.5 Hz), 7.25−7.34 (m, 20H),
7.69 (d, 2H, J = 8 Hz), 7.76 (d, 2H, J = 8 Hz), 7.79 (pseudo-t, 2H, J =
5.5 Hz). 13C NMR (CDCl3, 75.48 MHz) δ/ppm: 22.2, 23.1 (δ), 25.0
(γ), 30.1 (a), 41.0 (β), 52.3 (α), 81.3 (b), 89.0 (c), 125.6 (d), 127.5
138.5 (d, JCP = 13 Hz, 1), 167.2 (7), 172.8 (A1). ESI-MS (m/z):
849.4 (M + H+, 100%). MALDI-HRMS (m/z): calcd 849.3693
(C51H54N4O4P2 + H+), found 849.3696.
8A. 3-(Diphenylphosphino)benzoic acid (148.2 mg, 0.48 mmol),
HOBt (71.0 mg, 0.53 mmol), TBTU (156.7 mg, 0.49 mmol), DIPEA
(0.160 mL, 0.97 mmol), Boc-8A (107.4 mg, 0.22 mmol), DCM (50
mL). Chromatography (DCM/MeOH gradient; TLC, Rf = 0.15,
EtOAc/hexane 7/3). Yield: 124.09 mg (59%). 1H NMR (CDCl3,
300.13 MHz) δ/ppm: 1.14 (s, 8H), 1.29−1.37 (m, 4H), 1.44 (d, 6H, J
= 7 Hz), 2.91−3.03 (m, 2H), 3.23−3.34 (m, 2H), 4.66−4.76 (m, 2H),
6.81 (t, 2H, J = 5.5 Hz), 7.07 (d, 2H, J = 8 Hz), 7.25−7.36 (m, 22H),
7.73−7.77 (m, 2H), 7.81 (d, 2H, J = 8 Hz). 13C NMR (CDCl3, 75.48
MHz) δ/ppm: 18.6 (β), 25.9 (c), 28.4 (d), 29.1 (b), 39.4 (a), 49.4 (α),
3
3
127.5 (4), 128.8 (d, JCP = 7 Hz, 3′, 3″), 128.8 (d, JCP = 5 Hz, 5),
3
2
2
(4), 127.9 (f), 128.7 (d, JCP = 7 Hz, 3′, 3″), 128.8 (5, under the 3′
129.1 (4′, 4″), 132.8 (d, JCP = 24.5 Hz, 2), 133.9 (d, JCP = 19.5 Hz,
2
2′, 2″), 134.1 (d, 3JCP = 8 Hz, 3), 136.5 (d, 1JCP = 11 Hz, 1′, 1″), 136.7
peak), 129.1, 129.1 (4′, 4″), 131.8 (e), 132.8 (d, JCP = 23 Hz, 2),
2
2
2
1
133.9 (d, JCP = 19.5 Hz, 2′), 133.9 (d, JCP = 19.5 Hz, 2″), 134.0 (d,
(d, JCP = 14 Hz, 6), 138.6 (d, JCP = 13.5 Hz, 1), 167.1 (7), 172.5
(A1). ESI-MS (m/z): 885.3 (M + Na+, 14%). MALDI-HRMS (m/z):
calcd 863.3849 (C52H56N4O4P2 + H+), found 863.3835.
1
1
3JCP = 7 Hz, 3), 136.6 (d, JCP = 11 Hz, 1′), 136.6 (d, JCP = 11 Hz,
1″), 136.8 (d, 2JCP = 16.5 Hz, 6), 138.4 (d, 1JCP = 13 Hz, 1), 167.5 (7),
172.9 (L1). ESI-MS (m/z): 1009.4 (M + Na+, 29%). MALDI-HRMS
(m/z): calcd 987.4162 (C62H60N4O4P2 + H+), found 987.4164.
9Lp. 4-(Diphenylphosphino)benzoic acid (80.4 mg, 0.26 mmol),
HOBt (37.5 mg, 0.28 mmol), TBTU (85.4 mg, 0.27 mmol), DIPEA
(0.090 mL, 0.55 mmol), Boc-9L (75.9 mg, 0.12 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.33,
EtOAc/hexane 1/1). Yield: 36.7 mg (30%). 1H NMR (CDCl3, 600.14
MHz) δ/ppm: 0.93 (d, 6H, J = 6 Hz), 0.95 (d, 6H, J = 6 Hz), 1.52−
1.56 (m, 2H), 1.71−1.78 (m, 4H), 3.92 (dd, 2H, J1 = 17.5 Hz, J2 = 4
Hz), 4.30 (dd, 2H, J1 = 17.5 Hz, J2 = 7 Hz), 4.86−4.90 (m, 2H), 7.25−
7.20 (m, 8H), 7.26−7.35 (m, 26H), 7.66−7.67 (m, 6H). 13C NMR
(DMSO-d6, 75.48 MHz) δ/ppm: 21.2, 23.0 (δ), 24.4 (γ), 28.9 (a),
40.3 (β), 51.7 (α), 80.0 (b), 90.9 (c), 124.8 (d), 127.7 (d, 3JCP = 7 Hz,
3, 5), 128.4 (f), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 129.2 (4′, 4″), 131.8 (e),
9A. 3-(Diphenylphosphino)benzoic acid (76.7 mg, 0.25 mmol),
HOBt (39.2 mg, 0.29 mmol), TBTU (81.3 mg, 0.25 mmol), DIPEA
(0.165 mL, 1.00 mmol), Boc-9A (60.2 mg, 0.11 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.49,
EtOAc/hexane 7/3). Yield: 33.6 mg (33%). 1H NMR (CDCl3, 300.14
MHz) δ/ppm: 1.49 (d, 6H, J = 7 Hz), 4.02 (dd, 2H, J1 = 17.5 Hz, J2 =
4.5 Hz), 4.30 (dd, 2H, J1 = 17.5 Hz, J2 = 6 Hz), 4.83−4.93 (m, 2H),
7.19−7.38 (m, 28H), 7.65 (pseudo-t, 2H, J = 5 Hz), 7.75 (dt, 2H, J1 =
7.5 Hz, J2 = 1 Hz), 7.86 (d, 2H, J1 = 7.5 Hz, J2 = 1 Hz). 13C NMR
(CDCl3, 150.92 MHz) δ/ppm: 18.2 (β), 30.3 (a), 49.3 (α), 81.6 (b),
88.9 (c), 125.9 (d), 127.6 (4), 128.1 (f), 128.8 (d, 3JCP = 7 Hz, 3′, 3″),
128.8 (5, under the 3′ peak), 129.1 (4′, 4″), 131.7 (e), 133.1 (d, 2JCP
=
2
2
26 Hz, 2), 133.9 (d, JCP = 19 Hz, 2′), 133.9 (d, JCP = 19 Hz, 2″),
133.9 (d, 3JCP = 6 Hz, 3), 136.6 (d, 1JCP = 11 Hz, 1′, 1″), 136.8 (d, 2JCP
1
2
2
= 14 Hz, 6), 138.6 (d, JCP = 14 Hz, 1), 167.4 (7), 172.9 (A1). 31P
132.7 (d, JCP = 19 Hz, 2), 133.3 (d, JCP = 20 Hz, 2′, 2″), 134.3 (4),
136.0 (d, 1JCP = 11 Hz, 1′), 136.1 (d, 1JCP = 11 Hz, 1″), 140.7 (d, 1JCP
NMR (CDCl3, 242.93 MHz) δ/ppm: −5.13. ESI-MS (m/z): 903.3 (M
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Article
= 13 Hz, 1), 166.0 (7), 172.1 (L1). ESI-MS (m/z): 1009.4 (M + Na+,
2), 133.8 (d, 2JCP = 20 Hz, 2′), 134.0 (d, 2JCP = 20 Hz, 2″), ≈ 133.9 (3,
not observable because overlap), 136.5 (d, 1JCP = 11 Hz, 1′), 136.5 (d,
1JCP = 11 Hz, 1″), 136.9 (d, 2JCP = 18 Hz, 6), 138.7 (d, 1JCP = 13.5 Hz,
1), 139.8 (d), 167.3 (7), 172.8 (A1). 31P NMR (CDCl3, 242.93 MHz)
δ/ppm: −4.96. ESI-MS (m/z): 1033.5 (M + K+, 23%). MALDI-
HRMS (m/z): calcd 1033.4374 (C62H68N4O4P2 + K+), found
1033.4388.
18%). MALDI-HRMS (m/z): calcd 1009.3982 (C62H60N4O4P2
+
Na+), found 1009.3978.
9F. 3-(Diphenylphosphino)benzoic acid (98.6 mg, 0.32 mmol),
HOBt (47.5 mg, 0.35 mmol), TBTU (103.7 mg, 0.32 mmol), DIPEA
(0.200 mL, 1.21 mmol), Boc-9F (101.6 mg, 0.15 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.47,
EtOAc/hexane 1/1). Yield: 69.7 mg (44%). 1H NMR (CDCl3, 600.14
MHz) δ/ppm: 3.11 (dd, 2H, J1 = 14 Hz, J2 = 8 Hz), 3.20 (dd, 2H, J1 =
14 Hz, J2 = 7 Hz), 3.90 (dd, 2H, J1 = 17.5 Hz, J2 = 4.5 Hz), 4.20 (dd,
2H, J1 = 17.5 Hz, J2 = 6 Hz), 5.02−5.06 (m, 2H), 7.09−7.33 (m, 40H),
7.49 (t, 2H, J = 5.5 Hz), 7.61 (d, 2H, J = 7.5 Hz), 7.72 (d, 2H, J = 8
Hz). 13C NMR (CDCl3, 75.48 MHz) δ/ppm: 30.1 (a), 38.5 (β), 55.1
(α), 81.5 (b), 88.8 (c), 125.7 (d), 127.0 (ζ), 127.6 (4), 128.1 (f), 128.6
(δ), 128.7 (5, under the 3′ peak), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 129.1
(4′, 4″), 129.4 (ε), 131.8 (e), 132.8 (d, 2JCP = 24 Hz, 2), 133.9 (d, 2JCP
10Lp. 4-(Diphenylphosphino)benzoic acid (110.1 mg, 0.36 mmol),
HOBt (49.8 mg, 0.37 mmol), TBTU (114.2 mg, 0.36 mmol), DIPEA
(0.120 mL, 0.73 mmol), Boc-10L (105.0 mg, 0.17 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.47,
EtOAc/hexane 1/1). Yield: 63.5 mg (36%). 1H NMR (CDCl3, 600.14
MHz) δ/ppm: 0.94 (d, 6H, J = 6 Hz), 0.95 (d, 6H, J = 6.5 Hz), 1.49−
1.60 (m, 4H), 1.67−1.77 (m, 6H), 2.35−2.46 (m, 4H), 2.85−2.90 (m,
2H), 3.48−3.54 (m, 2H), 4.90−4.93 (m, 2H), 6.98−7.00 (m, 2H),
7.03−7.05 (m, 2H), 7.20 (d, 2H, J = 9 Hz), 7.23−7.35 (m, 24H), 7.68
(dd, 2H, J1 = 8.5 Hz, J2 = 1 Hz), 7.84 (dd, 2H, J1 = 8 Hz, J2 = 4 Hz).
13C NMR (CDCl3, 75.48 MHz) δ/ppm: 22.4, 23.0 (δ), 25.1 (γ),29.7
(c), 31.1 (b), 39.3 (a), 41.3 (β), 52.5 (α), 81.6 (b), 88.9 (c), 126.2 (f),
127.2 (d, 3JCP = 6.5 Hz, 3,5), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 129.1 (e),
3
1
= 20 Hz, 2′, 2″), 133.9 (d, JCP = 7.5 Hz, 3), 136.6 (d, JCP = 11 Hz,
1′), 136.6 (d, 1JCP = 11 Hz, 1″), 136.8 (γ), 136.8 (d, 2JCP = 15.5 Hz, 6),
1
138.5 (d, JCP = 13.5 Hz, 1), 167.5 (7), 171.7 (F1). ESI-MS (m/z):
1055.2 (M + H+, 39%). MALDI-HRMS (m/z): calcd 1055.3849
(C68H56N4O4P2 + H+), found 1055.3872.
2
2
129.2 (4′, 4″), 133.5 (d, JCP = 19 Hz, 2), 133.8 (4), 134.0 (d, JCP
=
20 Hz, 2′, 2″), 136.4 (d, 1JCP = 11 Hz, 1′, 1″), 139.6 (d), 142.7 (d, 1JCP
10A. 3-(Diphenylphosphino)benzoic acid (66.4 mg, 0.22 mmol),
HOBt (29.4 mg, 0.22 mmol), TBTU (69.6 mg, 0.22 mmol), DIPEA
(0.145 mL, 0.88 mmol), Boc-10A (100.0 mg, 0.19 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.21,
EtOAc/hexane 7/3). Yield: 26.6 mg (27%). 1H NMR (DMSO-d6,
300.13 MHz) δ/ppm: 1.31 (d, 6H, J = 7 Hz), 1.57−1.67 (m, 4H),
2.52−2.56 (m, 4H, solvent overlapped), 3.03−3.15 (m, 4H), 4.36−
4.46 (m, 2H), 7.05−7.13 (m, 4H), 7.22−7.31 (m, 10H), 7.38−7.42
(m, 11H), 7.45−7.51 (m, 3H), 7.89−7.95 (m, 6H), 8.54 (d, 2H, J1 =
7.5 Hz, J2 = 1 Hz). 13C NMR (DMSO-d6, 75.48 MHz) δ/ppm: 18.0
(β), 29.1 (c), 30.7 (b), 38.4 (a), 49.1 (α), 125.8 (f), 128.0 (4), 128.6
(d, 3JCP = 6 Hz, 5), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 128.9 (e), 129.1, (4′,
= 14 Hz, 1), 167.5 (7), 172.9 (A1). ESI-MS (m/z): 1033.4 (M + K+,
10%). MALDI-HRMS (m/z): calcd 1017.4608 (C62H68N4O4P2
+
Na+), found 1017.4615.
Precatalytic Rh(I) Complexes. NMR Measurements. [Rh-
(COD)(CH3CN)2]BF4 (1 mg, 2.6 μmol, 1 equiv) and ligand (2
equiv) were each dissolved in CDCl3 (300 μL). Rhodium solution was
added to the ligand solution, and NMR spectra were recorded shortly
thereafter.
CD Measurements. Visible region (c = 0.15−0.44 mmol dm−3):
[Rh(COD)(CH3CN)2]BF4 (1 equiv) and the ligand (2 equiv) were
each dissolved in 2 mL of distilled, degassed CH2Cl2. These solutions
were then mixed, and the mixture was diluted to 5.0 mL. UV region (c
= 0.01−0.03 mmol dm−3): 300 μL of the solution for visible
measurements was diluted to 5.0 mL.
2
2
4″), 132.7 (d, JCP = 26 Hz, 2), 133.2 (d, JCP = 20 Hz, 2′), 133.2 (d,
2JCP = 20 Hz, 2″), 134.3 (d, 3JCP = 8 Hz, 3), 135.6 (d, 2JCP = 14 Hz, 6),
136.2 (d, 1JCP = 11 Hz, 1′), 136.2 (d, 1JCP = 11 Hz, 1″), 137.0 (d, 1JCP
= 12.5 Hz, 1), 139.4 (d), 165.5 (7), 172.1 (A1). ESI-MS (m/z): 911.4
(M + H+, 34%). MALDI-HRMS (m/z): calcd 911.3849
(C56H56N4O4P2 + H+), found 911.3828.
Catalysis. Catalytic Hydrogenation of Methyl 2-Acetamidoacry-
late (S1). Catalysis at Room Temperature. An oven-dried, two-
necked, round-bottomed flask (10 mL) under nitrogen was charged
with the ligand (6.6 μmol, 2.2 mol %) dissolved in CH2Cl2 (3 mL;
distilled, degassed in an ultrasonic bath for 15 min), followed by
[Rh(COD)(CH3CN)2]BF4 (1.25 mg, 3 μmol, 1 mol %) dissolved in
CH2Cl2 (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). The flask was then flushed with hydrogen, and
S1 (45 mg, 0.3 mmol) was added in one portion and the mixture
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 enantiomeric excess (ee) was determined with a chiral fused
silica capillary column (Beta Dex 225; isocratic 140 or 150 °C; 100
kPa head column pressure; eluting order substrate, R product, S
product).
10Ap. 4-(Diphenylphosphino)benzoic acid (66.0 mg, 0.22 mmol),
HOBt (67.4 mg, 0.50 mmol), TBTU (70.0 mg, 0.22 mmol), DIPEA
(0.145 mL, 0.88 mmol), Boc-10A (100.0 mg, 0.19 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.24,
EtOAc/hexane 7/1). Yield: 58.2 mg (59%). 1H NMR (DMSO-d6,
300.13 MHz) δ/ppm: 1.32 (d, 6H, J = 7 Hz), 1.59−1.69 (m, 4H),
2.52−2.57 (m, 4H), 3.07−3.15 (m, 4H), 4.39−4.48 (m, 2H), 7.05−
7.13 (m, 4H), 7.23−7.31 (m, 12H), 7.39−7.43 (m, 12H), 7.88 (dd,
4H, J1 = 8 Hz, J2 = 1 Hz), 7.94 (pseudo-t, 2H, J = 5.5 Hz), 8.46 (d, 2H,
J = 7.5 Hz). 13C NMR (DMSO-d6, 75.48 MHz) δ/ppm: 18.0 (β), 29.2
3
(c), 30.7 (b), 38.4 (a), 49.1 (α), 125.8 (f), 127.7 (d, JCP = 6.5 Hz,
3,5), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 128.9 (e), 129.2 (4′, 4″), 132.7 (d,
2JCP = 19 Hz, 2), 133.3 (d, 2JCP = 19.5 Hz, 2′, 2″), 133.4 (4), 136.1 (d,
1
1JCP = 11 Hz, 1′, 1″), 139.4 (d), 140.65 (d, JCP = 13.5 Hz, 1), 165.6
Catalysis at Low Temperature. According to the procedure for
reactions at room temperature before substrate addition, the reaction
flask was placed in a thermo-container filled with technical ethanol (or
2-propanol), cooled by a cryostat device to −5 °C, and the mixture
was stirred vigorously overnight.
(7), 172.1 (A1). ESI-MS (m/z): 925.4 (M + H+, 32%). MALDI-
HRMS (m/z): calcd 925.3043 (C56H48N4O4P2 + Na+), found
925.3026.
10L. 3-(Diphenylphosphino)benzoic acid (109.2 mg, 0.36 mmol),
HOBt (50.7 mg, 0.38 mmol), TBTU (113.4 mg, 0.35 mmol), DIPEA
(0.120 mL, 0.73 mmol), Boc-10L (105.0 mg, 0.17 mmol), DCM (50
mL). Chromatography (EtOAc/hexane gradient; TLC, Rf = 0.47,
EtOAc/hexane 1/1). Yield: 57.8 mg (33%). 1H NMR (CDCl3, 600.14
MHz) δ/ppm: 0.89 (d, 6H, J = 6.5 Hz), 0.90 (d, 6H, J = 6.5 Hz),
1.42−1.57 (m, 4H), 1.61−1.70 (m, 6H), 2.28−2.33 (m, 2H), 2.42−
2.47 (m, 2H), 2.66−2.70 (m, 2H), 3.48−3.54 (m, 2H), 4.86−4.90 (m,
2H), 6.86 (d, 2H, J = 9 Hz), 6.97−7.00 (m, 2H), 7.04−7.07 (m, 2H),
7.25−7.34 (m, 22H), 7.39−7.41 (m, 2H), 7.67−7.69 (m, 2H), 7.71−
7.73 (m, 2H), 7.97−7.98 (m, 2H). 13C NMR (CDCl3, 75.48 MHz) δ/
ppm: 22.4, 22.9 (δ), 25.0 (γ), 29.5 (c), 31.4 (b), 39.1 (a), 41.4 (β),
52.6 (α), 126.1 (f), 127.2 (4), 128.8 (d, 3JCP = 7 Hz, 3′, 3″), 128.8 (d,
2JCP = 6 Hz, 5), 129.2, 129.2 (4′, 4″), 129.3 (e), 132.6 (d, 2JCP = 21 Hz,
Catalytic Hydrogenation of Methyl (Z)-α-Acetamidocinnamate
(S2). Catalysis at Atmospheric Pressure. The procedure described for
S1 was used with ligand (13.2 μmol, 2.2 mol %), [Rh(COD)-
(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; conditions
22 min at 170 °C, 40 °C min−1 to 190 °C, 60 kPa head column
pressure; tR = 18.30 (R), 18.75 (S), 32.39 (substrate) min).
Catalysis at High Pressure. In an Eppendorf vial, Rh precursor and
the ligand were dissolved in CH2Cl2 (0.5 mL each) and mixed. The
yellow solution was placed in a 10 mL beaker containing the substrate
and CH2Cl2 (4 mL). The beaker 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.
4013
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7908. (d) Deuss, P. J.; Heeten, R.; Laan, W.; Kamer, P. C. J. Chem. Eur.
J. 2011, 17, 4680−4698.
ASSOCIATED CONTENT
* Supporting Information
■
S
(12) (a) Gridnev, I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633−
644. (b) Tangand, W.; Zhang, X. Chem. Rev. 2003, 103, 3029−3069.
(c) Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746−1754.
(d) Imamoto, T.; Tamura, K.; Zhang, Z.; Horiuchi, Y.; Masashi Sugiya,
M.; Kazuhiro Yoshida, K.; Akira Yanagisawa, A.; Gridnev, I. D. J. Am.
Chem. Soc. 2012, 134, 1754−1769.
Text, a table, figures, and xyz files giving synthetic procedures
for the precursors Boc-2−Boc-10, catalytic asymmetric hydro-
genation using para-substituted ligands, NMR and CD spectra,
GC chromatograms, visualized calculated structures of various
conformers and stereochemical analysis, and Cartesian
coordinates for all computed molecules collected in a single
separate text file readable by the program Mercury (version 3.3
or later)33 for visualization and analysis. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Kirin, S. I.; Kraatz, H.-B.; Metzler-Nolte, N. Chem. Soc. Rev.
2006, 35, 348−354.
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AUTHOR INFORMATION
Corresponding Author
*E-mail for S.I.K.: Srecko.Kirin@irb.hr.
Notes
■
(15) Herd, O.; Heβler, A.; Hingst, M.; Tepper, M.; Stelzer, O. J.
Organomet. Chem. 1996, 522, 69−76.
(16) Gredica
194.
̌ ́ ́
k, M.; Kolonic, A.; Jeric, I. Amino Acids 2008, 35, 185−
The authors declare no competing financial interest.
(17) (a) Martinez, C. R.; Iverson, B. L. Chem. Sci. 2012, 3, 2191−
2201. (b) Lee, E. C.; Kim, D.; Jurecka, P.; Tarakeshwar, P.; Hobza, P.;
Kim, K. S. J. Phys. Chem. A 2007, 111, 3446−3457. (c) Meyer, E. A.;
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(18) For CD spectra of [Rh(COD)(PPh3)2] derivatives see ref 8 and:
Yu, J.; Rajan Babu, T. V.; Parquette, J. R. J. Am. Chem. Soc. 2008, 130,
7845−7847.
ACKNOWLEDGMENTS
■
These materials 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 Sports (MSES, 098-0982904-2946, 098-
0982933-2908 and 098-0982933-2936). We thank COST
Action CM1105 for financial support.
(19) For CD spectra of ferrocene peptides [Fe(C5H4CO-Aan-R)2]
(Herrick conformation) see ref 13 and: Kirin, S. I.; Schatzschneider,
U.; Koster, S. D.; Siebler, D.; Metzler-Nolte, N. Inorg. Chim. Acta
2009, 362, 894−906.
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