Impact of the β-turn hydrogen bond on the trans/cis ratio and the performance of the peptide catalyst H-DPro-Pro-Glu-NH2

Article abstract of DOI:10.1016/j.tet.2020.131184

The effect of the β-turn hydrogen bond on the trans/cis conformer ratio and the catalytic performance of the peptidic catalyst H-DPro-Pro-Glu-NH₂ was investigated. Different electron withdrawing and donating substituents at the C-terminus of peptide analogues caused changes in the trans/cis ratio and the enantioselectivities of the peptides in conjugate addition reactions of aldehydes to nitroolefins. The results imply that the β-turn H-bond contributes but is not critical for the catalytic performance of H-DPro-Pro-Glu-NH₂ and related peptidic catalysts.

Full text of DOI:10.1016/j.tet.2020.131184

Journal Pre-proof
Impact of the β-turn hydrogen bond on the trans/cis ratio and the performance of the
peptide catalyst H-dPro-Pro-Glu-NH
2
Tobias Schnitzer, Rudolf L. Ganzoni, Helma Wennemers
PII:
S0040-4020(20)30319-7
https://doi.org/10.1016/j.tet.2020.131184
TET 131184
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 March 2020
Revised Date: 2 April 2020
Accepted Date: 5 April 2020
Please cite this article as: Schnitzer T, Ganzoni RL, Wennemers H, Impact of the β-turn hydrogen bond
on the trans/cis ratio and the performance of the peptide catalyst H-dPro-Pro-Glu-NH , Tetrahedron
2
(2020), doi: https://doi.org/10.1016/j.tet.2020.131184.
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Impact of the β-turn hydrogen bond on the
trans/cis ratio and the performance of the
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peptide catalyst H-DPro-Pro-Glu-NH2
Tobias Schnitzer, Rudolf L. Ganzoni, Helma Wennemers
Laboratory of Organic Chemistry, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland.
H
Ar:
N
CO H
2
X
N
trans
NH
Kt/c
Enantioselectivity
O
O
O
HN
Ar
β
-turn
X: EWG Kt/c
X: EDG Kt/c

1
Tetrahedron
journal homepage: www.elsevier.com
Impact of the β-turn hydrogen bond on the trans/cis ratio and the performance
of the peptide catalyst H- Pro-Pro-Glu-NH2
D
*
*
Tobias Schnitzer, Rudolf L. Ganzoni, and Helma Wennemers
Laboratory of Organic Chemistry, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland.
ARTICLE INFO
ABSTRACT
Article history:
Received
The effect of the
performance of the peptidic catalyst H-
β
-turn hydrogen bond on the trans/cis conformer ratio and the catalytic
Pro-Pro-Glu-NH was investigated. Different electron
D
2
Received in revised form
Accepted
withdrawing and donating substituents at the C-terminus of peptide analogues caused changes
in the trans/cis ratio and the enantioselectivities of the peptides in conjugate addition reactions
Available online
of aldehydes to nitroolefins. The results imply that the
β
-turn H-bond contributes but is not
critical for the catalytic performance of H-
D
Pro-Pro-Glu-NH and related peptidic catalysts.
2
Keywords:
Peptide catalysis
2
009 Elsevier Ltd. All rights reserved.
Conjugate addition reaction
Conformational analysis of peptides
Trans/cis isomerization
β-turn peptides
1
.
Introduction
a)
b)
O
H
N
Various peptides have been developed in the last 20 years as
catalysts for asymmetric transformations, including transfer
hydrogenations, acylations, and C–C bond formations.
of these peptides adopt a turn-like structure that is stabilized by
one or more intramolecular hydrogen bonds (H-bonds).
Peptides of the type H-Pro-Pro-Xaa (Xaa: any amino acid) are
examples of such catalysts. These tripeptides are highly reactive
and stereoselective catalysts for aldol reactions and related
NH2
N
O
[
1,2]
O
O
Many
NH
1
CO H
2
[
1-12]
c)
CO H
CO H
2
2
H
N
H
N
[
4]
N
N
Ktrans/cis
[
5-7]
[8]
cis
trans
NH
Pro-Pro-Glu-NH
O
conjugate addition reactions to nitroolefins,
maleimide and
dicyanoolefins. For example, only 0.1 mol% of the tripeptide
H- Pro-Pro-Glu-NH2 1 suffices to catalyze the conjugate
addition reaction of aldehydes to nitroolefins in excellent yields
CONH2
[
9]
H N
O
O
O
β
H
D
HN
-turn
[
6]
Scheme 1: a) Peptide catalyst H-
D
2
(1). b) Calculated
and stereoselectivities (Scheme 1a).
NMR spectroscopic,
computational, and crystallographic analyses revealed that 1
adopts a type I β-turn structure with a H-bond between the C-
structure of 1, confirmed by NMR spectroscopic analysis, ref. 9. c)
Equilibrium between trans and cis conformers of 1.
terminal amide-NH and the
D
Pro-Pro amide C=O group
This intramolecular β-turn H-bond can only
Pro-Pro amide bond is trans and not cis
configured (Scheme 1c). Recent studies on H- Pro-Pro-Glu-NH2
showed, that the trans/cis conformer ratio of the Pro-Pro amide
bond directly correlates with the stereoselectivity of conjugate
2
[
10]
Herein, we used analogues of H-DPro-Pro-Glu-NH 1 bearing
2
(Scheme 1b).
different para-substituted phenyl moieties at the C-terminal
amide to probe the effect of the β-turn H-bond on the trans/cis
ratio and stereoselectivity of these peptidic catalysts. The
stereoselectivity was assessed in the conjugate addition reaction
of butanal to (E)-nitrostyrene. We show that a stronger
intramolecular H-bond enhances the population of the trans
conformer and the enantioselectivity of the catalyst. Yet, our
studies also show, that the effect is comparatively small,
implying that this β-turn H-bond is important but is not the only
contributor for the catalytic efficiency of the peptidic catalyst.
form when the
D
D
D
[
11]
addition reactions of aldehydes to nitroolefins.
hypothesized that a stronger β-turn H-bond should stabilize the
trans conformer and thereby improve the stereoselectivity of the
Hence, we
tripeptidic catalyst H-DPro-Pro-Glu-NH 1.
2

2
Tetrahedron
2
.
Results and discussion
conformation of 1 and 2a–2e is essentially identical, a hypothesis
1
that was supported by the H NMR spectra in CDCl /CD OH 9:1,
3
3
To study the effect of the β-turn hydrogen bond on the
which show similar trans/cis ratios of ~96:4 for all of the
peptides. Note, the conformation of the enamines derived from
the peptidic catalysts is key for their stereoselectivity since the
trans/cis ratio and catalytic performance of H- Pro-Pro-Glu-NH2
1
C-terminal amide. We envisioned that phenyl groups bearing
electron-donating substituents (e.g., OMe, Me) should weaken
whereas electron-withdrawing substituents (e.g., F, CF ) should
D
we used analogues with para-substituted phenyl moieties at the
enamine is involved in the rate- and enantioselectivity-
determining step.
[15]
Enamines bearing a CO H group are,
2
3
however, highly reactive, in particular in protic solvents, and
their conformation is therefore difficult to analyze. Since
previous studies showed that the relative trend of the trans/cis
ratio observed for the ground state remained the same for the
respective peptide-enamines, we also compared here the trans/cis
strengthen the intramolecular H-bond of the peptides (Scheme
2
a). Importantly, the C-terminal substituent should point away
from the active site of the peptide and should therefore only
affect the β-turn H-bond but not the overall secondary structure
of the peptides (Scheme 2b).
[10a,11]
ratios of the ground state peptides.
Table 1. Comparison of the trans/cis amide bond ratio and the catalytic
i
performance of peptides 2a–2e in CHCl
3
/ PrOH.
a
b
b
c
Catalyst
trans/cis ratio
Conv. (%)
d.r.
ee (%)
1
98:2
67
73
79
72
73
35:1
35:1
35:1
35:1
35:1
35:1
97
2
2
a
96:4
96
b
96:4
96
2
c
95:5
96
2
d
95:5
96
d
2
e
96:4
47
97
Scheme 2: a) Analogues 2a–2e with C-terminal para-substituted phenyl
moieties. b) Structure of 1 with a cartoon depiction of position of the C-
terminal aromatic moiety. c) Solution phase synthesis of 2a–2e (note the yield
of 2e was lower due to solubility issues).
a
1
Determined by
H
b
NMR spectroscopic analysis of the peptide in
1
CDCl
3
/CD
3
OH 9:1. Determined by H NMR spectroscopic analysis of the
c
crude reaction mixture. Determined by chiral stationary phase SFC analysis.
d
Low, due to low solubility of 2e. Data for 1 taken from reference 11a
We prepared peptide analogues 2a–2e using a convergent
Apolar and aprotic solvents compete less for H-bonds than
synthetic route in solution phase (Scheme 2c). Boc-
DPro-Pro-OH
[
16]
polar protic solvents.
We therefore reasoned that the
was obtained by coupling of Boc- Pro-OH with H-Pro-OMe
D
[
12]
t
substituent of the C-terminal phenyl group should have a bigger
influence on the β-turn H-bond and thus the catalytic
performance of the tripeptidic catalysts in solvents such as THF
and dioxane than in a protic solvent. We therefore evaluated the
peptidic catalysts 1 and 2a–2e in THF and dioxane, solvents in
which the peptides are still sufficiently soluble (Table 2).
followed by saponification.
Coupling of Cbz-Glu(O Bu)-OH
with the corresponding anilines and hydrogenation yielded the
t
glutamic acid building block H-Glu(O Bu)-NHAr with different
phenyl moieties (Ar). The trifluoroacetic acid (TFA) salts of the
tripeptides 2a–2e were obtained after coupling of the two
building blocks and global deprotection with TFA.
NMR spectroscopic analyses of 1 and 2a–2e revealed
trans/cis ratios in the range of 78:22–82:18 in d -dioxane
1
D and 2D NMR spectra, including nuclear Overhauser
8
effects (NOEs), of peptide 2c in CDCl /CD OH 9:1 are similar to
that of 1.
group of 2a–2e points indeed away from their reactive amino and
carboxylic acid groups (Figure 1).
3
3
[
10]
(
9
Table 2, top). Similarly small difference in the range of 88:12–
This finding suggests that the C-terminal phenyl
8
1:9 were observed in the NMR spectra in d -THF (Table 2,
bottom). These values show that the relative energy differences
between the trans conformers of peptides 2a–2e are very small.
We started to evaluate the catalytic performance of peptides
a–2e in CHCl / PrOH 9:1 (Table 1), the solvent that had
emerged as the best for conjugate addition reactions between
aldehydes and nitroolefins when using parent peptide 1 as
catalyst. The reaction between butanal and (E)-nitrostyrene
served to compare peptide analogues 2a–2e with 1. Since protic
solvents such as PrOH compete for H-bonding, we envisioned
that the reactivity and stereoselectivity of the examined peptides
should be similar in the CHCl / PrOH mixture. Indeed, γ-
nitroaldehyde 3 was obtained with comparable stereoselectivity
d.r. ~35:1 syn/anti, 97% ee) in the presence of all six peptides
and also the conversion of the starting materials to the product
70%) was similar after 2 h.
Peptides 2d and 2e with electron withdrawing F- and CF -groups
3
i
2
3
at the C-terminal phenyl group have in both solvents the highest
trans-conformer content. Peptides 2a and 2b with electron
donating OMe- and Me-groups at the C-terminal phenyl group
have the lowest trans-conformer content. These results show that
electron withdrawing substituents enhance and electron donating
substituents reduce the trans/cis ratio and thus the strength of the
β-turn H-bond. The subtle yet noticeable effect exerted by the
different substituents is also reflected in the chemical shifts of the
[
5]
i
i
3
1
C-terminal amide NHAr signal observed in the H NMR spectra.
(
The NHAr signal of 2d and 2e appears significantly more
downfield than those of 2a and 2b (Table 2).
[
13,14]
(
These findings suggest that the

3
Table 2. Comparison of the trans/cis amide bond ratio and the catalytic
performance of peptides 2a–2e in dioxane and THF.
differences in the enantioselectivity of less than 5% ee. These
findings show that the conformation and thus the catalytic
activity of peptide 1 and related peptides is not only defined by
the intramolecular H-bond. Rather, a synergistic ensemble of
features such as the conformational preorganization by the
DPro-
Pro motive and the interactions arising from the side chain of
[
10,11]
Glu
enable compensation of a remote perturbation to
a
b
b
c
Catalyst Solvent
trans/cis
Chemical shift
NHAr (ppm)
Conv.
(%)
d.r.
ee
preserve high catalytic activity and stereoselectivity.
a
ratio
(%)
85
87
87
87
88
90
1
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
80:20
78:22
79:21
80:20
81:19
82:18
-
20
17:1
10:1
11:1
11:1
10:1
10:1
4
.
Experimental section
2
a
8.65
8.69
8.81
8.85
9.16
~15
~15
~10
~15
~15
Reagents and materials were of the highest commercially
available grade and used without further purification. Reactions
were monitored by thin layer chromatography using Merck silica
gel 60 F254 glass sheets. Visualization of the compounds was
achieved by UV light or ninhydrin stain. Flash chromatography
was performed on a CombiFlash EZ Prep from Teledyne Isco
2
b
2
c
2
d
2
e
1
13
using RediSep Normal-phase Silica Flash Columns. H and
C
NMR spectra were recorded on a Bruker DRX 400, a Bruker AV
III 400 (400 MHz/100 MHz) or a Bruker AV III 600 (600
MHz/150 MHz). All spectra were recorded at 25 °C. Only signals
of the major trans conformer are reported. Chemical shifts (δ) are
reported in parts per million (ppm) relative to the signal of
tetramethylsilane (TMS) using the residual solvent signals. SFC
analyses were performed on an analytical SFC with a diode array
detector ACQUITY-UPLC- PDA from Waters using the AD
chiral stationary phase column (150 mm x 30 mm) from Waters
under the reported conditions. High-resolution MALDI spectra
were acquired on a Bruker solariX 94 (ESI/MALDI-FT-ICR) and
a Bruker Ultra-Flex II (MALDI-TOF) spectrometer. The
1
THF
THF
THF
THF
THF
89:11
88:12
88:12
89:11
90:10
91:9
-
~5
31:1
16:1
15:1
15:1
14:1
14:1
84
84
84
85
85
88
2
2
a
8.61
8.85
8.96
8.98
9.30
~10
~10
~10
~10
~10
b
2
c
2
d
2
e
THF
a
1
Determined by H NMR spectroscopic analysis of the peptide in the
b
1
corresponding deuterated solvent. Determined by H NMR spectroscopic
c
analysis of the crude reaction mixture. Determined by chiral stationary phase
synthesis of Boc-
DPro-Pro-OH was performed according to ref
SFC analysis. Data for 1 taken from reference 11a.
1
2, the synthesis of H-
D
Pro-Pro-Glu-NH 1 according to ref 5.
2
Next, we examined the reactivity and stereoselectivity of
a–2e in the conjugate addition reaction in THF and dioxane. As
Synthesis of Z-Glu(OtBu)-NHAr, exemplified for Ar = Ph
Z-Glu(OtBu)-OH (1.25 equiv., 0.89 mmol, 300 mg), aniline
2
expected from previous studies, the reactions proceeded slower in
i
[11]
(
1.0 equiv., 0.71 mmol, 63 µL), EDC•HCl (1.25 equiv., 0.89
mmol, 170 mg), and HOBt (1.4 equiv., 1.00 mmol, 153.0 mg)
were suspended in dry CH Cl (10 mL). Hünig‘s base (1.25
these solvents than in CHCl / PrOH 9:1.
In comparison to
3
parent peptide 1 peptides 2a–2e are less diastereoselective, likely
due to unfavorable π-π-interactions between the C-terminal
phenyl ring and nitrostyrene. The enantioselectivity of 2a–2e is,
however, comparable to that of 1 and, most notable, reflects the
trend expected from the electronic differences at their C-termini.
Peptides 2d and 2e, bearing electron withdrawing substituents at
the C-terminal phenyl group, form the γ-nitroaldehyde 3 with
higher enantioselectivity (2d: 88% ee, 2e: 90% ee in dioxane; 2d:
2
2
equiv., 0.89 mmol, 85 µL) was added and the solution was stirred
overnight until TLC monitoring showed full consumption of
aniline. The reaction mixture was diluted with EtOAc, washed
with aqueous HCl (0.1 M), 5% aqueous Na CO and brine. The
2
3
organic layer was dried over Na SO4 and the solvent was
2
removed under reduced pressure. The resulting colorless solid
was dissolved in MeOH/CH Cl 3:1 (10 mL). Pd/C (10% w/w,
8
5% ee, 2e: 88% ee in THF) than 2a–2c bearing electron
2
2
2
0 mg) was added and the mixture was stirred under a hydrogen
donating substituents at the C-terminal phenyl group (87% ee in
dioxane; 84 or 85% ee in THF). These subtle differences in the
enantioselectivities correlate with the similarly small differences
in the trans/cis ratios. These findings underscore that the
intramolecular β-turn H-bond stabilizes the trans conformer and
thereby enhances the stereoselectivity of the peptidic catalyst.
atmosphere (1 atm) for 24 h. The reaction mixture was filtered
over a small pad of silica. Removal of the solvent under reduced
pressure gave H-Glu(OtBu)-NHPh as a colorless solid, which
was used without further purification (198 mg, 0.71 mmol,
quant.).
Synthesis of H-DPro-Pro-Glu-NHAr 2a–2e, exemplified for
3
.
Conclusion
2
c
In conclusion, our study shows that the β-turn H-bond
between the C-terminal amide NH and the N-terminal C=O of the
Boc-
DPro-Pro-OH (1.0 equiv., 0.65 mmol, 202.0 mg),
EDC•HCl (1.1 equiv., 0.71 mmol, 136 mg), HOBt (1.5 equiv.,
.97 mmol, 148.5 mg) and Hünig‘s base (1.0 equiv., 0.71 mmol,
8 µL) were suspended in dry CH Cl . H-Glu(OtBu)-NHPh (1.0
equiv. 0.71 mmol, 198 mg) was added and the reaction mixture
was stirred over night until TLC monitoring showed full
consumption of the glutamate derivative. The reaction mixture
was diluted with EtOAc, washed with aqueous HCl (0.1 M), 5%
tripeptidic catalyst H-
DPro-Pro-Glu-NH2 stabilizes the trans
0
6
conformer of the Pro-Pro amide bond. C-terminal electron
D
2
2
withdrawing groups enhance this intramolecular H-bond and
increased the enantioselectivity of the tripeptidic catalyst. The
effect of electron withdrawing or donating groups installed at a
C-terminal phenyl group was, however, comparatively small with

4
Tetrahedron
aqueous Na CO and brine. The organic layer was dried over
H-DPro-Pro-Glu-NH(p-CF -C H ) (2e)
3 6 4
2
3
Na SO and the solvent was removed under reduced pressure.
2
4
1
Colorless solid, (29 mg, 0.06 mmol, 8% overall yield). H
The crude product was dissolved in TFA/triisopropyl silane/H O
2
NMR (500 MHz, D O) δ = 7.75 (dd, J = 8.3, 1.1 Hz, 2H), 7.69 –
2
9
5:2.5:2.5 (10 mL) and stirred for 1 h. Removal of all volatiles
7
8
1
2
.63 (m, 2H), 4.66 (dd, J = 8.8, 7.0 Hz, 1H), 4.51 (ddd, J = 22.1,
.7, 4.8 Hz, 2H), 3.80 – 3.69 (m, 1H), 3.63 (dt, J = 10.5, 7.1 Hz,
H), 3.45 (ddt, J = 36.3, 11.6, 7.2 Hz, 2H), 2.68 – 2.50 (m, 3H),
.41 – 2.30 (m, 1H), 2.30 – 2.20 (m, 1H), 2.19 – 1.95 (m, 7H).
C NMR (126 MHz, D O) δ = 177.4, 174.03, 172.0, 168.1,
39.5, 131.6, 126.3, 121.3, 114.2 (q, J = 206.2 Hz), 113.4, 60.7,
under reduced pressure followed by precipitation and thorough
washing with Et O afforded peptide 2c as its TFA salt. The
2
peptide was redissolved in MeCN/H O 1:1, dried by
2
lyophilization and used without further purification (153 mg,
1
3
2
0
.37 mmol, 52% yield).
1
5
(
9.3, 54.0, 47.6, 46.6, 30.3, 29.5, 28.0, 26.2, 24.2, 23.9. HRMS
ESI): m/z calcd. for [M + H] C H F N O : 485.2006; found:
+
+
22 28 3 4 5
H-
DPro-Pro-Glu-NH(p-MeO-C H ) (2a)
6 4
4
85.1998.
Colorless solid, (140 mg, 0.31 mmol, 44% overall yield).
H NMR: (600 MHz, CDCl /CD OH 9:1) δ = 8.97 (s, 1H), 8.73
1
3
3
(d, J = 7.3 Hz, 1H), 7.55 – 7.47 (m, 2H), 6.90 – 6.79 (m, 2H),
NMR Spectroscopic analysis of the trans/cis ratios
4
4
1
.76 (dd, J = 8.8, 6.5 Hz, 1H), 4.54 (dd, J = 8.7, 2.9 Hz, 1H),
.50 (td, J = 7.8, 3.2 Hz, 1H), 3.88 (ddd, J = 9.8, 7.6, 3.7 Hz,
1
H NMR spectra of peptides 1 and 2a–2e were recorded at
13
concentrations of ~5 mM, the concentration of the peptide in the
conjugate addition reaction. In case of low solubility of the
peptide, a saturated solution of less than 5 mM was used. No
evidence for aggregation was observed. The samples were
equilibrated for at least 2 h and no changes of the trans/cis ratios
over time were observed. The trans/cis ratios of the peptides
depend strongly on the solvent polarity, hence dry solvents were
used. The trans/cis ratios were determined by manual integration
of baseline separated signals of the two spin systems.
H), 3.80 (s, 3H), 2.61 – 2.46 (m, 3H), 2.34 – 1.89 (m, 9H).
C
NMR (151 MHz, CDCl /CD OH 9:1) δ = 178.4, 170.9, 169.3,
1
4
3
3
69.1, 156.7, 130.9, 122.1, 114.1, 61.7, 59.1, 55.6, 53.9, 47.6,
6.8, 30.3, 29.2, 28.8, 25.8, 24.9, 24.5. HRMS (MALDI): m/z
+
+
calcd. for [M + H] C H N O : 447.2238; found: 447.2229.
22
31
4
6
H-DPro-Pro-Glu-NH(p-Me-C H ) (2b)
6 4
1
Colorless solid, (121 mg, 0.28 mmol, 39% overall yield). H
NMR (600 MHz, CDCl /CD OH 9:1) δ = 8.96 (s, 1H), 8.76 (d, J
=
3
3
Conjugate Addition Reaction
7.3 Hz, 1H), 7.53 – 7.44 (m, 2H), 7.15 – 7.06 (m, 2H), 4.77
(
1
3
dd, J = 8.8, 6.5 Hz, 1H), 4.59 – 4.48 (m, 2H), 3.98 – 3.87 (m,
H), 3.59 – 3.47 (m, 2H), 3.43 – 3.35 (m, 1H), 2.60 – 2.47 (m,
13
H), 2.31 (d, J = 0.8 Hz, 3H), 2.30 – 1.93 (m, 9H). C NMR
The peptide TFA salt (1 mol%) was added to a solution of N-
methylmorpholine (1 mol%), (E)-nitrostyrene (1 equiv., 250
μmol, 37.3 mg) and butanal (1.5 equiv., 375 μmol, 33.8 μL) in
the respective solvent (0.5 mL). The reaction mixture was stirred
at room temperature. The conversion and diastereoisomeric ratio
(151 MHz, CDCl /CD OH 9:1) δ = 178.4, 170.8, 169.3, 169.1,
3 3
1
2
35.1, 134.4, 129.5, 120.4, 61.6, 59.1, 53.8, 47.6, 46.8, 30.2,
9.2, 28.9, 25.8, 24.9, 24.5, 20.9. HRMS (MALDI): m/z calcd.
1
were determined by H NMR spectroscopic analysis of the crude
+
+
for [M + H] C H N O : 431.2289; found: 431.2287.
22
31
4
5
mixture by comparison of the aldehyde R-CHO signals. The
enantiomeric excess was determined by chiral stationary phase
SFC (AD-3, 5% MeOH, 2.0 mL/min, 40 °C, 214 nm, 1.00 min
H-
DPro-Pro-Glu-NHPh (2c)
(syn, minor), 1.21 min (syn, major).
1
Colorless solid, (153 mg, 0.37 mmol, 52% overall yield). H
NMR (600 MHz, CDCl /CD OH 9:1) δ = 9.19 (s, 1H), 8.67 (d, J
3
3
=
7.3 Hz, 1H), 7.62 – 7.58 (m, 2H), 7.34 – 7.29 (m, 2H), 7.15 –
5. References and notes
7
6
2
.01 (m, 1H), 4.74 (dd, J = 8.8, 6.7 Hz, 1H), 4.52 (tdd, J = 8.1,
1
.
For reviews, see: (a) Colby Davie, E. A.; Mennen, S. M.; Xu, Y.;
Miller Chem. Rev. 2007, 107, 5759–5812. (b) Shugrue, C. R.;
Miller, S. J. Chem. Rev. 2017, 117, 11894–11951. (c) Wennemers,
H. Chem. Commun. 2011, 47, 12036–12041. (d) Lewandowski,
B.; Wennemers, H. Curr. Opin. Chem. Biol. 2014, 22, 40–46.
.6, 3.5 Hz, 2H), 3.56 – 3.46 (m, 2H), 3.43 – 3.36 (m, 2H), 2.57 –
13
.47 (m, 3H), 2.36 – 1.91 (m, 9H). C NMR (151 MHz,
CDCl /CD OH 9:1) δ = 178.1, 171.3, 169.9, 169.0, 137.9, 129.0,
1
2
3
3
24.8, 120.5, 61.6, 59.2, 54.1, 47.6, 46.7, 30.4, 29.3, 28.8, 26.1,
+
2. For examples, see: (a) Gustafson, J. L.; Lim, D.; Miller, S. J.
Science 2010, 328, 1251–1255. (b) Lichtor, P. A.; Miller, S. J.
Nat. Chem. 2012, 4, 990–995. (c) Barrett, K. T.; Metrano, A. J.;
Rablen, P. R.; Miller, S. J. Nature 2014, 509, 71–75. (d) Shugrue,
C. R.; Miller, S. J. Angew. Chem. Int. Ed. 2015, 54, 11173–11176.
4.8, 24.6. HRMS (MALDI): m/z calcd. for [M + H]
+
C H N O : 417.2132; found: 417.2141.
22
29
4
5
(
e) Hsieh, S.-Y.; Tang, Y.; Crotti, S.; Stone, E. A.; Miller, S. J. J.
H-DPro-Pro-Glu-NH(p-F-C H ) (2d)
6 4
Am. Chem. Soc. 2019, 141, 18624–18629. (f) Müller, C. E.; Zell,
D.; Schreiner, P. R. Chem. Eur. J. 2009, 15, 9647–9650. (g)
Wende, R. C.; Seitz, A.; Niedek, D.; Schuler, S. M. M.; Hofmann,
C.; Becker, J.; Schreiner, P. R.; Angew. Chem. Int. Ed. 2016, 55,
1
Colorless solid, (153 mg, 0.43 mmol, 61% overall yield). H
NMR (600 MHz, CDCl /CD OH 9:1) δ = 9.11 (s, 1H), 8.71 (d, J
3
3
=
7.3 Hz, 1H), 7.69 – 7.54 (m, 2H), 7.11 – 6.96 (m, 2H), 4.76
2
719–2723. (h) Akagawa, K.; Kudo, K. Angew. Chem. Int. Ed.
(
7
dd, J = 8.8, 6.6 Hz, 1H), 4.58 – 4.42 (m, 2H), 3.88 (ddd, J = 9.9,
.6, 3.7 Hz, 1H), 2.62 – 2.45 (m, 3H), 2.35 – 1.91 (m, 9H). C
2012, 51, 12786–12789. (h) Martin, H. J.; List, B. Synlett 2003,
12, 1901–1902. (i) Valerio, D’E.; Zwicknagl, A. H.; Reiser, O.
Org. Lett. 2008, 73, 3262–3265. (j) Cortes-Clerget, M.; Gager, O.;
Monteil, M.; Pirat, J. L.; Migianu-Griffoni, E.; Deschamp, J.;
Lecouvey, M. Adv. Synth. Catal. 2016, 358, 34–40. (k) Hsieh, S.-
Y.; Tang, Y.; Crotti, S.; Stone, E. A.; Miller, S. J. J. Am. Chem.
Soc. 2019, 141, 18624–18629. (l) Girvin, Z. C.; Andrews, M. K.;
Liu, X.; Gellman, S. H. Science 2019, 366, 1528–1531.
13
NMR (151 MHz, CDCl /CD OH 9:1) δ = 178.3, 171.0, 169.6,
1
6
HRMS (MALDI): m/z calcd. for [M + H] C H FN O :
4
3
3
69.1, 160.4, 158.8, 133.9 (d, J = 2.9 Hz), 122.1 (d, J = 7.9 Hz),
1.6, 59.1, 53.9, 47.6, 46.8, 30.3, 29.2, 28.8, 25.8, 24.8, 24.5.
+
+
21
28
4
5
35.2038; found: 435.2033.

5
3
4
.
.
Metrano, A. J.; Abascal, N. C.; Mercado, B. Q.; Paulson, E. K.;
Hurtley, A. E.; Miller, S. J. J. Am. Chem. Soc. 2017, 139, 492–
5
16.
(a) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers,
H. Org. Lett. 2005, 7, 1101–1103. (b) Schnitzer, T.; Wiesner, M.;
Krattiger, P.; Revell, J. D.; Wennemers, H. Org. Biomol. Chem.
2
017, 15, 5877–5881.
5
.
(a) Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem. Int.
Ed. 2008, 47, 1871–1874. (b) Wiesner, M.; Neuburger, M.;
Wennemers, H. Chem. Eur. J. 2009, 15, 10103–10109.
6
7
.
.
Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J. Am.
Chem. Soc. 2010, 132, 6–7.
(a) Wiesner, M.; Revell, J. D.; Tonazzi, S.; Wennemers, H. J. Am.
Chem. Soc. 2008, 130, 5610–5611. (b) Duschmalé, J.;
Wennemers, H. Chem. Eur. J. 2012, 18, 1111–1120. (c) Kastl, R.;
Wennemers, H. Angew. Chem. Int. Ed. 2013, 52, 7228–7232. (d)
Schnitzer, T.; Möhler, J. S.; Wennemers, H. Chem. Sci. 2020, 11,
1
943–1947. (e) Schnitzer, T.; Budinská, A.; Wennemers, H. Nat.
Catal. 2020, 3, 143–147.
8
.
.
Grünenfelder, C. E.; Kisunzu, J. K.; Wennemers, H. Angew.
Chem. Int. Ed. 2016, 55, 8571–8574.
Schnitzer, T.; Wennemers, H. Synlett 2017, 28, 1282–1286.
9
1
0. (a) Rigling, C.; Kisunzu, J. K.; Duschmalé, J.; Häussinger, D.;
Wiesner, M.; Ebert, M.-O.; Wennemers, H. J. Am. Chem. Soc.
2
018, 140, 10829–10838. (b) Schnitzer, T.; Wennemers, H. Helv.
Chim. Acta 2019, hlca.201900070. (c) Grünenfelder, C. E.;
Kisunzu, J. K.; Trapp, N.; Kastl, R.; Wennemers, H. Peptide
Science 2017, 108:e22912.
1
1. (a) Schnitzer, T.; Wennemers, H. J. Am. Chem. Soc. 2017, 139,
1
5
5356–15362. (b) Schnitzer, T.; Wennemers, H. Synthesis 2018,
0, 4377–4382.
1
1
2. Duschmalé, J.; Kohrt, S.; Wennemers, H. Chem. Commun. 2014,
0, 8109–8112.
3. The reaction was monitored after 2 h since epimerization at C(2)
5
or 3 reduced the d.r. over time. Full conversion was reached after
1
2–48 h.
1
1
4. An equimolar amount of N-methylmorpholine (NMM) was used
to liberate the free secondary amine. Note that previous studies
had shown that the presence of TFA/NMM does not affect the
performance of the peptidic catalyst 1; see, for example ref 15a
5. (a) Duschmalé, J.; Wiest, J.; Wiesner, M.; Wennemers, H. Chem.
Sci. 2013, 4, 1312. (b) Bächle, F.; Duschmalé, J.; Ebner, C.;
Pfaltz, A.; Wennemers, H. Angew. Chem. Int. Ed. 2013, 52,
1
2619. (c) Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J.
Am. Chem. Soc. 2010, 132, 6–7.
1
6. (a) Spencer, J. N.; Allott, K. N.; Chanandin, S.; Enders, B. G.;
Grushow, A.; Kneizys, S. P.; Mobley, D.; Naghdi, J.; Patti, L. M.;
Salata, J. S. J. Sol. Chem. 1988, 17, 287–296. (b) Spencer, J. N.;
Campanella, C. L.; Harris, E. M.; Wolbach, W. S. J. Phys. Chem.
1
985, 89, 1888–1891. (c) Reynisson, J.; McDonald, E. J. Comput.
Aided. Mol. Des. 2004, 18, 421–431.
Acknowledgments
We thank the Fonds der Chemischen Industrie (Germany) for
a Kekulé Fellowship for T. S. and the Swiss National Science
Foundation (Grant No. 200020_188729) for financial support.

TET 131184
To whom it may concern,
I herewith confirm that there is no competing interest.
Best regards
Helma Wennemers