Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional Ligands: Desymmetrization of Diarylmethanes via Ullman Cross-Coupling

Article abstract of DOI:10.1021/jacs.6b03444

We report the development of a new class of guanidine-containing peptides as multifunctional ligands for transition-metal catalysis and its application in the remote desymmetrization of diarylmethanes via copper-catalyzed Ullman cross-coupling. Through design of these peptides, high levels of enantioinduction and good isolated yields were achieved in the long-range asymmetric cross-coupling (up to 93:7 er and 76% yield) between aryl bromides and malonates. Our mechanistic studies suggest that distal stereocontrol is achieved through a Cs-bridged interaction between the Lewis-basic C-terminal carboxylate of the peptides with the distal arene of the substrate.

Full text of DOI:10.1021/jacs.6b03444

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Article
Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional
Ligands: Desymmetrization of Diarylmethanes via Ullman Cross-Coupling
Byoungmoo Kim, Alex J. Chinn, Daniel R Fandrick, Chris H. Senanayake, Robert A. Singer, and Scott J. Miller
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03444 • Publication Date (Web): 02 Jun 2016
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Journal of the American Chemical Society
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Distal Stereocontrol Using Guanidinylated Peptides as Multi-
functional Ligands: Desymmetrization of Diarylmethanes via
Ullman Cross-Coupling
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Byoungmoo Kim†, Alex J. Chinn†, Daniel R. Fandrick‡, Chris H. Senanayake‡, Robert A. Singer§, and
Scott J. Miller*,†
† Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States
‡ Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield,
Connecticut 06877-0368, United States
§ Chemical Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
Supporting Information Placeholder
Previous work: Desymmetrization of bis(phenol) via acylation (eq 1)
ABSTRACT: We report the development of a new class of
Me
Me
Me
Me
Me
Me
5 mol%
guanidine-containing peptides as multifunctional ligands for
transition-metal catalysis and its application in the remote
desymmetrization of diarylmethanes via copper-catalyzed Ullman
cross-coupling. Through design of these peptides, high levels of
enantioinduction and good isolated yields were achieved in the
long-range asymmetric cross-coupling (up to 93:7 er and 76%
yield) between aryl bromides and malonates. Our mechanistic
studies suggest that distal stereocontrol is achieved through a Cs-
bridged interaction between the Lewis-basic C-terminal
carboxylate of the peptides with the distal arene of the substrate.
Peptide 2
Ac2O
+
O
HO
OH
HO
O
O
Me
1a
1b
80% yield
95% ee
N
N
O
Ph
Me Me
Me
H
N
H
N
Ph
BocHN
N
H
O
N
H
O
O
NHTs
tBuO
2
NHTrt
This work: Long-range asymmetric Ullman cross-coupling (eq 2)
Me
*
Me
Me
Me
Me
Me
cat.
[Cu/Peptide*]
Br
Br
malonates
O
O
HN
N
HN
N
CF3
CF3
H
H
R
Br
3
4
O
O
Distal
stereocontrol
F3C
F3C
R = malonate
O
[Cu]
NHR
• Non-precious metal catalyst
• Multifunctional peptide ligand
• 'Drug-like' scaffold
Introduction
Peptide
Catalytic reactions that selectively create one or more new
chiral elements depend on close communication between the
catalyst and the substrate. In general, chirality is established by
the chiral catalyst as part of the bond forming process itself, or
commonly when the generated stereogenic center is proximal to
the newly constructed bond. Chirality can also be created over
longer ranges through bond-formation at enantiotopic sites which
are several bonds removed from the stereogenic center. However,
it is challenging to differentiate these distant enantiotopic sites,
and enzymes or catalysts of comparable dimensions are often
required.1 We reported one such case, employing short peptide
catalyst 2 to break symmetry in bis(phenol) 1a via O-acylation,
wherein the newly formed stereogenic center is five bonds away
from the site of bond formation, and the enantiotopic sites are
separated by nearly a full nanometer (eq 1).2 To date, only a few
examples using small molecule catalysts3 for remote
stereoinduction have been reported, and employment of
transition-metal catalysis for a related long-range asymmetric
induction has remained elusive.
a) Directs substrate
R
peptide
R
O
O
N
Multifunctional peptide ligand
for asymmetric, TM-catalyzed
remote functionalization
b) Bulky & electron-
rich guanidine
N
R
N
[M]
c) Ligand for metal
Asymmetric Hurtley reaction (eq 3)
R
R'O
O
20 mol% CuI
I
O
O
40 mol% Ligand
O
Me
R
+
R'O
Me
COMe
HO
N
H
CF3
O
R
Me
NHCOCF3
6
up to 82% yield
N
OH
5
H
up to 93% ee
would confer high activity to go along with any observed
enantioselectivity (eq 2). As boundary conditions for our study,
we wished to use abundant and inexpensive first-row transition
metal complexes as catalysts. We chose to focus on the Cu-
catalyzed Ullman cross-coupling reaction between malonate
derivatives and aryl halides (the Hurtley reaction; eq 3).4 Ma and
co-workers have established the enantioselective variant of the
process employing 2-methylacetoacetates and simple amino acid
ligands such as hydroxyproline.5 Herein, we report a new class of
peptide-based ligands that has culminated in efficient symmetry-
breaking cross-coupling reactions for the preparation of
enantioenriched, drug-like diarylmethane derivatives 4.6 As a
related system to eq 1, these processes fall into the category of
To accomplish such challenging processes, we endeavored to
develop new chiral ligands for transition-metals that would allow
distal stereocontrol in the desymmetrization of compound 3 (eq 2).
We questioned whether such asymmetric induction could be
achieved using simple peptides that closely interacted with the
substrate, and that housed a defined metal-binding moiety that
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reactions with distal pro-stereogenic elements, and our
experiments show that the peptide-based catalysts are well-suited
for these metal-catalyzed processes.
peptide capable of forming a secondary structure (e.g., a β-turn)
could be beneficial in terms of enhancing catalyst performance.16
Furthermore, we hypothesized that a C-terminal amide or a
carboxylate could interact with the substrate, perhaps through
hydrogen bonding (c.f., eq 2).17
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4
5
6
7
8
The ability to modulate ligands is essential to optimizing
asymmetric induction.7 We imagined that amino acids and
peptide-based metal complexes could be a suitable platform for
achieving long-range asymmetric induction (eq 2, a-c).8 We
proposed that the dimensions of the catalyst could be engineered
to adopt an optimal length and geometry (eq 2, a) such that
differentiation of the distal enantiotopic sites would be possible.
In order to fine-tune the Cu center, we speculated that bulky and
electron-rich guanidines (eq 2, b) could facilitate the Ullman
cross-coupling reaction under mild conditions. Despite many
well-known nitrogen-based ligands for asymmetric transition-
metal catalysts,9 there are few examples of fully substituted
guanidines as chiral ligands (eq 2, c).10 Notably, pentasubstituted
guanidines, unlike primary or secondary amines, should not
themselves be competitive substrates for Ullman-type reactions.11
Additionally, we were attracted to guanidine derivatives due to
their ease of synthesis and bench-stability.
Table 1. Elongation study of peptide ligandsa,b
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Results and Discussion
Catalyst optimization. Our studies began with an evaluation
of the desymmetrization reaction shown in Scheme 1. Treatment
of the symmetrical compound 3a with diethyl malonate (1.1
equiv) in the presence of CuI (20 mol%) and various ligands
provided an initial set of encouraging results.12 The use of proline
(L1) (Ma-type conditions) provided reasonable levels of
conversion, and a modest level of enantioselectivity for the
entry peptide
3ac
4ac
4a
7a
desired product 4a (41:59 er; Scheme 1).13
N,N-
% remaining % conv.
er
% conv.
Dimethylphenylalanine (L2) also provided good conversion, but a
nearly racemic product. In comparison, the application of the
pentasubstituted guanidine L3 led to a striking result, wherein the
product 4a could be isolated with an appreciable er of 89:11.
Unfortunately, when the
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8
41
34
26
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19
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26
47
48
43
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66
61
57
75:25
76:24
69:31
76:24
77:23
93:7
12
18
31
30
15
15
16
17
L5
L6
L7
L8
L9
Scheme 1. Evaluation of amino acid ligands14,15
L10
L11
L12
90:10
86:14
aReaction conditions: substrate (0.4 mmol), diethyl malonate (1.1 equiv), CuI (5 mol%), pep-
tide (10 mol%), Cs CO (3.2 equiv), and DMF (1.6 mL). bConversions were determined by 1H
2
3
NMR and enantiomeric ratios were determined by chiral high performance liquid chromatography
analysis, see supporting information for details. cContains 5-10% of inseparable impurity 8. See eq
4 and supporting information for details.
Table 1 lists the results of experiments in which the complexity
of the ligand was gradually increased. Catalysts with secondary
amide functionality at the C-terminal position of the ligand
(entries 1-4), exhibited only modest changes in selectivity, with
ers for the mono-functionalized product 4a ranging from 69:31 to
76:24. However, a significant enhancement in enantioselectivity
was observed with elongated catalysts in which the C-terminal
position was simply exchanged for a Li carboxylate (entries 5-8).
Notably, the catalyst derived from ligand L10 provided the
highest observed er (entry 6, 93:7), while also producing the
highest level of conversion to the product 4a (66%). In the
presence of a large excess Cs ions, the Li carboxylates seem likely
to undergo salt-exchange in situ to form Cs carboxylates.
catalyst loading was reduced to 5 mol%, the level of selectivity
declined to 58:42 er. Further studies revealed that asparagine
derivative L4 delivered er of 85:15 with 20 mol% of the catalytic
system, which diminished to only 72:28 er when 5 mol% was
used. We deemed the results to be sufficiently encouraging and
robust to stimulate further studies, on the basis of our ligand
design, through decoration of the side chain of L4 with peptide
residues.
During the course of these initial experiments, we discovered
that reaction efficiencies were compromised by the formation of a
persistent byproduct. While the mono-functionalized bromide 4a
As with many studies of peptide-based organocatalysts, we
imagined that incorporation of the metal-ligating residue into a
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could be isolated as the major product, a trace amount of the
corresponding iodide (eq 4) was also observed, which
resulted in noticeable decreases in both enantioselectivity (86:14,
1
2
3
4
5
6
7
8
8
89:11, respectively) and the 4a to 7a ratio. In accordance with
our initial hypothesis, the extensive studies of the peptide
sequence21 (which in turn affects the dimensions of the peptide
through its secondary structure) indicates that the peptides serve
multiple functions (c.f., eq 2), including a potential interaction
between the C-terminal carboxylate moiety of the peptide and the
substrate. Mechanistic studies regarding these aspects are
discussed in more detail in a following section.
presumably originated from cross-coupling of the pre-catalyst
iodide ligand and substrate 3a.18 Although 4a and 8 could be
analyzed as a mixture in a chiral HPLC analysis, isolated yields
were eroded. Based on the identification of this iodide byproduct,
we employed Cu(MeCN)4BF4 as the Cu source, as delineated in
Table 2.19 This straightforward solution completely eliminated
the byproduct, and allowed for less complicated reaction
optimization and purification.
Substrate scope. With an effective catalyst in hand, we turned
our attention to the scope of the reaction. As shown in Table 3,
simple variations to the malonate structure do not greatly impact
the reaction outcomes. Diethyl (entry 1), dimethyl (entry 2) di-iso-
propyl (entry 3) and dibenzyl (entry 4) malonates all deliver the
corresponding desymmetrized products 4a-4e with comparable
levels of conversion, isolated yield and er. However, the
introduction of an α-methyl group (entry 5) leads to a much
slower reaction, and only 12% isolated yield, although the er is
93:7 in this case.22 Gratifyingly after a single crystallization, the
functionalized diarylmethanes (4a and 4c) can be obtained in
essentially enantiopure forms with good recovery of material
(62% and 71%, respectively). Moreover, these enantioenriched
drug-like scaffolds contain synthetically versatile functional
groups (unreacted aryl bromide, malonate, anilines) that can be
easily modified to generate pharmaceutically-related motifs such
as N-heterocycles23 and aryl halides.24
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As shown in Table 2 (entry 1), the catalyst derived from
Cu(MeCN)4BF4 and L10 allowed for efficient conversion to the
desymmetrized product 4a, which exhibited a 91:9 er at 75%
conversion. As part of the optimization, we also determined that a
mixture of DMF/toluene was a suitable solvent system for the
reaction. Notably, a higher ratio of 4a to 7a was obtained under
the newly optimized conditions. After an extensive base screen,
we discovered that Cs2CO3 was essential for both reactivity and
selectivity.20 Moreover, alterations to the catalyst C-terminus
were evaluated. Exchange of the Li carboxylate (L10, entry 1) for
a methyl ester (L13, entry 2), or N-methyl amide (L6, entry 3)
Table 3. Malonate scopea,b
Table 2. Comparison of peptide's C-terminus capa,b
entry
1
Malonate
3a
4
4
7
% remain-
ing
%
er
%
conv.c
conv.c
11
4a, 76
92:8
7a, 13
(74)
After a single recrystallization
(62)d
>99:1
91:9
2
12
4b, 72
7b, 16
7c, 5
(70)
3
23
4c, 71
92:8
(68)
After a single recrystallization
(71)d
>99:1
4
15
4d, 72
10:90e
7d, 13
entry peptide
3a
4a
4a
7a
(70)
% remaining % conv.
er
% conv.
7:93e
-
1
2
3
13
13
12
75
65
66
91:9
86:14
89:11
12
22
22
L10
L13
L6
5
90
4e, 10
(3)
aReaction conditions: substrate (0.4 mmol), malonate (1.1 equiv), Cu(MeCN) BF (5 mol%),
4
4
peptide (10 mol%), Cs CO (3.2 equiv), DMF/Tol (0.5/1.1 mL). bConversions were determined by
aReaction conditions: substrate (0.4 mmol), diethyl malonate (1.1 equiv), Cu(MeCN) BF (5
2
3
4
4
1H NMR and enantiomeric ratios were determined by chiral high performance liquid chromatog-
mol%), peptide (10 mol%), Cs CO (3.2 equiv), DMF/Tol (0.5/1.1 mL). bConversions were
2
3
raphy analysis, see supporting information for details. cThe numbers in parentheses are isolated
determined by 1H NMR and enantiomeric ratios were determined by chiral high performance
liquid chromatography analysis, see supporting information for details.
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yields. dThe numbers in parentheses are % recovery yields. eCause of the reversed order of elution
number of substituents at the anilino nitrogen (eq 5). Notably,
of enantiomers undetermined.
1
2
3
4
5
6
7
8
both the trifluoroacetyl group and its amide proton proved to be
critical for reactivity. Neither acetamide 9 nor N-methyl amide 10
participates in the reaction, and no cross-coupled product is
observed under the optimized conditions (eq 5). It seems possible
that the presence of the amide proton is necessary for
deprotonation or hydrogen bonding and that there are stringent
electronic requirements for the proton, likely related to pKa or
hydrogen bonding capacity. With these results in mind, we
subjected the Cs-salt of the parent substrate (11) to the Cu-
catalyzed cross-coupling conditions (eq 6),27 which gave
essentially identical results as shown in Table 3, entry 2.
The scope of the diarylmethane starting material was also
evaluated, and provides fascinating results (Table 4). As with our
studies of desymmetrization through organocatalytic O-acylation,
the corresponding cross-coupling reactions respond dramatically
to alterations to the substituent located along the mirror plane of
the substrate.25 For example, whereas the tert-butyl substituent
gives the best result (entry 1, 92:8 er), decreasing steric size leads
to substrates that exhibit lower selectivity. Cyclohexyl (entry 2,
78:22 er) and methyl (entry 3, 52:48 er) typify this trend. Aryl-
substituted compounds also exhibit lower selectivity (entries 4–6).
In our previous studies of this substrate class, we proposed that
the molecule could exist in different “propeller like”
conformations that were influenced by the central substituent.
The presently reported data appear to follow this trend despite the
markedly different reaction mechanisms at play. The exact nature
of these substituent effects remains unknown. Yet, in the
mechanistic studies of the process shown in eq 1, the Sigman
group suggests that correlations between central substituents and
selectivity may be found in this class of substrate, and most
closely correspond to conventional steric parameterization 26
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Based on these results, we presumed that ionic-type
interactions are operative between the amides of the parent
substrate (deprotonated in situ) and both termini of Cu/peptide
complex (Figure 1a). Furthermore, taking into account the
importance of C-terminal carboxylate on the peptide L10 (Table
2), we specu-
Table 4. Diarylmethane scopea,b
lated that the long-range asymmetric induction could be achieved
through a Cs-ion bridged interaction between the C-terminal
entry
R"
3
4
4
7
carboxylate and
a distal deprotonated amide (Figure 1a,
% remainingc
%
er
%
highlighted in red). We thus designed mechanism-driven kinetic
resolution experiments to investigate these hypotheses (Figure 1b).
If both termini were participating in the formation of favorable
diastereomeric transition state (Figure 1a and 1b, Scenario 1), then
one could expect high krel values to be observed in kinetic
resolutions when racemic substrates possessing both terminal
amides were tested. However, in Scenario 2 (Figure 1b), this
requirement for multifunctionality would lead to a low krel value.
Unsymmetrical substrates 12a-c (Table 5) were prepared to
evaluate these limiting cases.
conv.c
conv.c
4a, 76
(74)
1
3a, 11
92:8
7a, 13
2d
3f, (52)
4f, (30) 78:22 7f, (16)
4g,
(50)
7g,
(18)
3d
4
3g, (32)
3h, 22
52:48
57:43
4h, 54
(45)
7h, 24
7i, 13
4i, 54
(39)
37:63
5
6
3i, 33
3j, 41
e
4j, 47
(47)
65:35
7j, 12
aReaction conditions: substrate (0.4 mmol), diethyl malonate (1.1 equiv), Cu(MeCN) BF (5
4
4
mol%), peptide (10 mol%), Cs CO (3.2 equiv), DMF/Tol (0.5/1.1 mL). bConversions were
2
3
determined by 1H NMR and enantiomeric ratios were determined by chiral high performance
liquid chromatography analysis, see supporting information for details. cThe numbers in parenthe-
ses are isolated yields. dProduct distributions are determined with isolated yields. eCause of the
reversed order of elution of enantiomers undetermined.
Figure 1. a) Proposed model for the interaction between C-
terminal carboxylate of the peptide L10 and distal amide of dia-
rylmethane. b) Prediction for mechanistically-driven kinetic reso-
lution studies
Mechanism-driven experiments.
With the goal of
understanding how elements of catalyst and substrate might
interact to afford the observed selectivity, we first examined a
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The unexpected results shown in Table 5 caused us to
used for selective extraction of Cs ions from nuclear waste.29
Based on the known binding energies for cation-π interactions,
the Cs-bridge between the peptide and the distal arene may be
delicate.30 However, utilization of weak coordination between
substrates and catalysts have been demonstrated to be fruitful in
asymmetric functionalization.31 Notably, substrate 12a is also
capable of this interaction, although the trifluoroacetamide may
introduce other deleterious effects. One possibility could be that
the trifluoroacetamide displaces the Cs ion from its ideal position
on the face of the arene, although this idea remains speculative.
Additionally, due to likely changes in both the geometry and pKa
of the trifluoroacetamide of substrate 12a, in comparison to
compound 3a, we speculate that the distal trifluoroacetamide is
less prone to deprotonation, which could modulate the interaction
(e.g., via H-bonding) with the peptide. As for the local arene
(shown in black, Figure 2), based on Yu and Musaev's
mechanistic details on Pd-catalyzed C(sp3)–H bond arylation, we
imagine that the Cs ion may remain bound between the carbonyl
oxygen of the amide and the arene which allows for
1
2
3
4
5
6
7
8
reevaluate our initial hypothesis. Under the optimized conditions
(entries 1, 3, 5), the unsymmetrical substrates exhibited a range of
selectivity, though contrary to our prediction (Figure 1b). While
we expected to obtain the highest krel with substrate 12a (bearing
both CF3COHN groups), this compound gives the lowest
selectivity in the series (krel = 5.3; entry 1). Instead, compounds
12b and 12c (lacking the distal CF3COHN group) exhibited
notably higher krel values of 11.3 (entry 3) and 10.3 (entry 5),
respectively. These trends were preserved, though the magnitudes
were reduced, when DMF alone was employed as the solvent
(entries 2, 4, 6). The results stimulated a new hypothesis, that a
remote arene-catalyst interaction might be responsible for the
asymmetric induction. Indeed, when the distal arene was replaced
with a simple methyl or cyclohexyl group (as in substrate 12d and
12e, respectively), selectivity in the kinetic resolution was
severely reduced (Scheme 2, krel = 1.6 and 1.2 based on 13d and
13e, respectively).
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10
11
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60
Table 5. Mechanistic studies via kinetic resolution of un-
symmetrical diarylmethanesa,b
Scheme 2. Kinetic resolution of racemic substrates that
lacks a distal arene (12d and 12e)
racemic substrate
entry
solvent
DMF/Tol
DMF
krel
5.3
N-coordination of the Cu center to facilitate oxidative addition
into the Ar–Br bond.32 It seems possible that in the parent
compound 3a, the distal trifluoroacetamide is capable of binding a
second Cs ion in a similar way (Figure 3a). It is also conceivable
that even a third Cs ion could be involved, although our
experiments do not resolve these possibilities.
1
2
3
4
5
3.5
DMF/Tol
DMF
11.3
6.9
Me
Me
Me
Cs
O
Br
Arene-directed
distal stereocontrol
N
F3
C
Cs
Br
O
O
O
[Cu]
O
Me
Me
N
O
O
Me2N
DMF/Tol
10.3
NH
NMe2
N
6
DMF
4.8
Figure 2. Arene-directed distal stereoinduction
aReaction conditions: racemic substrate (0.3 mmol), diethyl malonate (1.1 equiv),
In order to further understand the interactions between peptide
ligand and substrate, kinetic resolution studies were performed
using the same substrates as in Table 5, but with amide capped
peptide L6. One apparent difference between peptides L6 and
L10 is the C-terminal Lewis basicity, with the anionic carboxylate
being relatively basic compared to the neutral amide. An ionic
interaction between the catalyst and Cs ion would be relatively
strong in the case of the carboxylate (Figure 3a), while the weaker
amide interaction might be out-competed by Lewis basic solvent
molecules such as DMF (Figure 3b).33 If the Cs ion bridge
Cu(MeCN) BF (5 mol%), peptide (10 mol%), Cs CO (3.2 equiv), DMF/Tol (0.38/0.83 mL) or
4
4
2
3
DMF (1.2 mL). bConversions were determined by 1H NMR and enantiomeric ratios were deter-
mined by chiral high performance liquid chromatography analysis. See supporting information for
details. Results are reported as an average of two runs.
These findings, as well as the observations discovered during
our catalyst optimization (Tables 1 and 2), point to a possible non-
covalent interaction between the C-terminus of peptide L10 and
the distal arene, in which they are bridged by a Cs ion (Figure 2).
These ions are known to form various cation-π complexes with
arenes.28 For example, this type of molecular recognition has been
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Journal of the American Chemical Society
Page 6 of 8
mined by chiral high performance liquid chromatography analysis. See supporting information for
interaction proposed in Figure 2 is relevant for substrate-catalyst
recognition, then this interaction could be attenuated by altering
details. Results are reported as an average of two runs.
1
2
3
4
5
same type of interaction may be at play with both peptides L10
and L6, but to a lesser extent in the amide case. The combined
results of Tables 5 and 6 are in agreement with the model shown
in Figure 3b, where the C-terminus no longer interacts with the Cs
ion due to competing solvent molecule interactions.
6
7
8
Conclusion
9
In summary, we have developed a new peptide-based ligand
class for the enantioselective desymmetrization of diarylmethane-
based aryl bromides. Our design criteria of achieving remote
asymmetric induction in the Cu-catalyzed desymmetrizations
were satisfied through the development of a guanidinylated
peptide, which upon optimization of its dimensions and sequence,
allowed for the observation of substantial levels of selectivity.
The basis of the asymmetric induction proved to be a complex
interplay of effects, consistent with the critical role of each of the
components required to achieve the best results. Remote
interactions involving the catalyst and the arene that does not
undergo cross-coupling were found to be essential, and seem
embedded in an Cs-arene association. Evaluating the generality of
the guanidinylated peptides as ligands for various other
asymmetric reactions, including cross-couplings in complex
molecular settings,34 is one next step for this work, and we plan to
report on these studies in the near future.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Current proposed models for interactions between dif-
ferent C-termini of the peptide ligand and the diarylmethane
solvent conditions, as well.
Analysis of C-terminal amide-containing peptide L6 proved
consistent with these notions. As shown in Table 6, (entries 1, 3,
5), experiments with ligand L6 revealed incrementally lower krel
values in each of the cases examined. These effects were
exacerbated under conditions in pure DMF, in which competition
for non-covalent interactions would be expected to be greatest
(entries 2, 4, 6). These observations support the assertion that the
Table 6. Mechanistic studies via kinetic resolution of un-
symmetrical diarylmethanes with C-terminal amide pep-
tidea,b
ASSOCIATED CONTENT
Supporting Information
Additional figures, experimental details, characterization data for
all catalysts, substrates, and products, and crystallographic infor-
mation. X-ray data of 3a, SL1, SL2, SL11, SL20. The Supporting
Information is available free of charge on the ACS Publication
website.
AUTHOR INFORMATION
Corresponding Author
racemic substrate
entry
solvent
DMF/Tol
DMF
krel
3.3
1.6
8.4
1.8
Scott.miller@yale.edu
Notes
1
2
3
4
The authors declare no competing financial interests. Crystallo-
graphic data are deposited with the Cambridge Crystallographic
Data Centre under the accession number CCDC 1471490 (3a),
CCDC 1471491 (SL1), CCDC 1471492 (SL20), CCDC 1471493
(SL11), and CCDC 1471494 (SL2).
DMF/Tol
DMF
ACKNOWLEDGMENT
We thank the Boehringer-Ingelheim-Pfizer-Glaxo-Smith-Kline-
Abbvie Non-Precious Metal Catalysis Consortium for general
discussions in this area. We are grateful to Pfizer and Boehringer-
Ingelheim for partial support of this research. Additional support
from the National Institute of General Medical Science of the
National Institutes of Health (GM-068649) is gratefully acknowl-
edged.
5
6
DMF/Tol
DMF
7.5
1.8
aReaction conditions: racemic substrate (0.3 mmol), diethyl malonate (1.1 equiv),
REFERENCES
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4
4
2
3
DMF (1.2 mL). bConversions were determined by 1H NMR and enantiomeric ratios were deter-
1.
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At elevated temperatures the additional byproducts were ob-
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Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128,
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16050–16051.
6.
23.
(a) Maciver, E. E.; Knipe, P. C.; Cridland, A. P.; Thompson, A.
(a) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem.
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2013, 52, 9229–9233; (d) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang,
J.-Y.; Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc.
2013, 135, 1236–1239; (e) Laforteza, B. N.; Chan, K. S. L.; Yu, J.-Q.
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The amount of Cs2CO3 was adjusted to account for the number
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8.
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For reviews of peptide-metal complexes in asymmetric cataly-
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equiv of Cs2CO3 was required to match all acidic protons in the reaction
mixture (2 equiv from 3a, 1.1 equiv from diethyl malonate, 0.1 equiv from
L10). Subjecting substrate 3a under the optimized condition with <3.2
equiv of Cs2CO3 gave trace conversion which supports the hypothesis that
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tion was crucial for reactivity. Common N,N-bidendate ligands such as
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full details concerning conversion and product distribution see supporting
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14.
reaction conditions.
15.
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Absolute chemistry is currently unknown. Several attempts to
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ful.
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Page 8 of 8
1
2
Me
Me
Me
3
4
5
6
7
8
9
O
O
[Cu/peptide]
O
O
Me
O
+
Me
EtO
OEt
Me
Cs2CO3
F3
C
N
N
CF3
HN
O
H
H
O
Br
Me
Br
N
Li
Me
Me
Me
O
Me
Me
directs
substrate
Me
Me
O
N
Cs
O
Br
N
O
O
O
N
H
N
N
F3
C
Me
Cs
O
Br
F3C
N
N
CF3
ligand
for Cu
O
O
H
H
CF3
Br
[Cu]
EtO2
C
CO2Et
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Multifunctional peptide ligand
74% yield
92:8 er
(>99:1 er after single recrystallization)
Peptide
Distal stereocontrol
8
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