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Catalysis by Small Peptidesan Introduction
Mario Wiesenfeldt
November 4th, 2020
Catalysis by Small Peptides
Enzyme catalysis
Xyl2P
PXyl2
RuNH2
H2N OMe
OMe
iPr
Catalysis by small peptides
2–20 amino acids
nonnatural amino acids – diverse reactivity
non-covalent interactions with substrates – high selectivity
modular and facile synthesis
design &understanding
diversereactivity
tailor-made non-covalent interactions
exceptionalselectivity
Catalysis by small molecules
Comparison between enzymes, transition metals, and small peptides: Lewis, C. J. ACS Catal. 2013, 3, 2954. (Selected) nobel lectures on asymmetric catalysis and directed evolution: Noyori, R. Angew. Chem., Int. Ed. 2019, 58, 14420 – Arnold, F. Angew. Chem., Int. Ed. 2002,
41, 2008.
Cl
Cl
NH
N
OO
HN
NH2
O
CO2H
Catalysis by Small Peptides
Enzyme catalysis
Xyl2P
PXyl2
RuNH2
H2N OMe
OMe
iPr
Catalysis by small peptides
2–20 amino acids
nonnatural amino acids – diverse reactivity
non-covalent interactions with substrates – high selectivity
modular and facile synthesis
design &understanding
enzyme-likeselectivity
directed evolution or mergerwith (photo-) catalysis
nonnaturalreactivity
Catalysis by small molecules
Nonnatural reactivity by photocatalysis: Biegasiewicz, K. F.; Cooper, S. J.; Gao, X.; Oblisnky, D.; Kim, J. H.; Garfinkle, S. E.; Joyce, L. A.; Sandoval, B.; Scholes, G. D.; Hyster, T. Science 2019, 364, 1166. Comparison between enzymes, transition metals, and small peptides:
Lewis, C. J. ACS Catal. 2013, 3, 2954. (Selected) nobel lectures on asymmetric catalysis and directed evolution: Noyori, R. Angew. Chem., Int. Ed. 2019, 58, 14420 – Arnold, F. Angew. Chem., Int. Ed. 2002, 41, 2008.
Cl
Cl
NH
N
OO
HN
NH2
O
CO2H
Small Peptides as Organocatalysts
Introduction
Catalytically relevant properties of small peptides
Small peptides as organocatalyst
Small peptides in Lewis acid and transition metal catalysis
Small peptides in photoredox catalysis
Summary
This group meeting does not cover the available literature comprehensively. Instead, selected keystudies are discussed in order to explain the underlying concepts.
Small Peptides as Organocatalysts
Introduction
Catalytically relevant properties of small peptides
Small peptides as organocatalyst
Small peptides in Lewis acid and transition metal catalysis
Small peptides in photoredox catalysis
Summary
This group meeting does not cover the available literature comprehensively. Instead, selected keystudies are discussed in order to explain the underlying concepts.
backbone
Structure of a Peptide Catalyst
Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem., Int. Ed. 2008, 47, 1871.
NH
N
OO
HN
NH2
O
CO2Hcatalytically activemoiety
substrate bindingmoiety
Structure of a Peptide Catalyst
Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem., Int. Ed. 2008, 47, 1871.
N
N
OO
HN
NH2
O
catalytically activemoiety
substrate bindingmoiety
backbone
O
O
HON
OR
R
complex three-dimensional geometry determined by primary and secondary protein structure
conformational flexibility due to high number of rotatable bonds
backbone serves as a tailor-made spacer between the catalytically active moiety and thesubstrate binding moiety
Design of the Secondary Structure
Review: Metrano, A. J.; Chinn, A. J.; Shugrue, C. R.; Stone, E. A.; Kim, B.; Miller, S. Chem. Rev. 2020, asap.
OOO
H H
α-helix
N
O
NHBoc
HO2C
O
HNO
MeOBn
HN
HNO
t-BuO MeO2C
O
NHTrt
Rigid unnatural amino acids
NH
CO2Me
Reiser
O
epoxidation catalyst (Miller)
Natural secondary structure motifs
Juliá-Collona epoxidationtype II β-turn
MeMe
HN
O
Burgess, Ortuno
NHO
Calmes, Amblard
NH
O
Schreiner
Peptide design is often centered around such structures with reduced conformational flexibility.
Design of the Secondary Structure
Lichtor, P. A.; Miller, S. J. J. Am. Chem. Soc. 2014, 136, 5301. Abascal, N. C.; Lichtor, P. A.; Giuliano, M. W.; Miller, S. J. Chem. Sci. 2014, 5, 4504.
N
O
NHBoc
HO2C
O
HNO
MeOBn
HN
HNO
t-BuO MeO2C
O
NHTrt
NMR &calculations
ensemble of closely relatedground-state conformations
type II β-turn epoxidation catalyst (Miller)
NNH
O
O
NHTrtHN
OPh
N
O
ONH
CO2MeONHTrt
O
NHBoc
HO2C
epoxidation catalyst (Miller) heterogeneous ensemble
NMR &calculations
highly regioselective in theepoxidation of farnesol
highly regio-and enantioselectivein the epoxidation of farnesol
Design of the Secondary Structure
Lichtor, P. A.; Miller, S. J. J. Am. Chem. Soc. 2014, 136, 5301. Abascal, N. C.; Lichtor, P. A.; Giuliano, M. W.; Miller, S. J. Chem. Sci. 2014, 5, 4504.
N
O
NHBoc
HO2C
O
HNO
MeOBn
HN
HNO
t-BuO MeO2C
O
NHTrt
NMR &calculations
ensemble of closely relatedground-state conformations
type II β-turn epoxidation catalyst (Miller)
NNH
O
O
NHTrtHN
OPh
N
O
ONH
CO2MeONHTrt
O
NHBoc
HO2C
epoxidation catalyst (Miller) heterogeneous ensemble
NMR &calculations
highly regioselective in theepoxidation of farnesol
highly regio-and enantioselectivein the epoxidation of farnesol
Even highly flexible, conformationally heterogeneous peptides may act as highly selective catalysts.
Facile synthesis of large peptide libraries by split and pool synthesis
split poolcouple split
couple
pool
Strategies for Library Screening
bead
amino acid peptide library
biased libraries by control the introduction of specific amino acids in each cycle
exponential increase of complexity with the number of cycles
Visualization of hits by co-immobilized fluorescent tags
Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123, 6496.
Strategies for Library Screening
HN
O
NHN
O
NHR
1
OH
R2
Ac2O
R1
OAc
R2 fluorescentnot fluorescent
peptide peptide
hit validationand sequencing
furtheroptimization
librarysynthesis
100,000 peptidesscreening of ca.1000 peptides
Lichtor, P.; Miller, S. J. ACS Comb. Sci. 2011, 13, 321.Krattiger, P.; McCarthy, C.; Pfaltz, A.; Wennemers, H. Angew. Chem., Int. Ed. 2003, 42, 1722.
Strategies for Library Screening
Co-immobilization of substrates
OH O
O
HN
dye
Me
OHN
Odye
H
O
ScreeningAnalysis
by GC/HPLC
Sorting of individual beads into individual vials
Related work has been reported by Jacobsen, Bradley, Barbas, Davies, Berkessel, Snapper, Hoveyda, and others.
Small Peptides as Organocatalysts
Introduction
Catalytically relevant properties of small peptides
Small peptides as organocatalyst
Small peptides in Lewis acid and transition metal catalysis
Small peptides in photoredox catalysis
Summary
This group meeting does not cover the available literature comprehensively. Instead, selected keystudies are discussed in order to explain the underlying concepts.
Krattinger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101.
Wennemers’ Tripeptide Catalyst
OH O
O
HN
dye
Me
OHN
Odye
H
O
NH
N
OO
HN
NH2
O
CO2H
H
O 10 mol%
acetone, −20 °CO2N
OH
O2N
Me
O
98%, 90% ee
Hit identification by library screening
Optimization in solution
Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem., Int. Ed. 2008, 47, 1871.
Wennemers’ Tripeptide Catalyst
3.7 Å
7.3 Å
lowest energy confi-guration of chiral peptide
lowest energy con-figuration of proline
O H
NO
O
RR
proline-catalyzedaldol reaction
N
N
OO
NH
NH2
O
O
O
HR
R
X Y
proposed conjugateaddition reaction
vs
H
O
R1 R2NO2
1–5 mol% chiral peptide
CHCl3/iPrOH, 25 °CH
O
R1
R2
NO2
H-Pro-Pro-Asp-NH2
chiral peptide syn/anti
H-D-Pro-Pro-Asp-NH2
96% 10:1 −85%
93% 25:1 95%
eeconversion
16 examples with >90% ee
reversal of selectivity byswitching the enantiomer
of a single amino acid
ONH NHO
HO2C
NH2
O
N
Siebler, C.; Maryasin, B.; Kuemin, M.; Erdmann, R. S.; Rigling, C.; Grünenfelder, C.; Ochsenfeld, C.; Wennemers, H. Chem. Sci. 2015, 6, 6725.Bächle, F.; Duschmalé, J.; Ebner, C.; Pfaltz, A.; Wennemers, H. Angew. Chem., Int. Ed. 2013, 52, 12619.
Wiesner, M.; Neuburger, M.; Wennemers, H. Chem. Eur. J. 2009, 15, 10103.
Wennemers’ Tripeptide Catalyst
N
R1
R2N
O
OO
OH
N
R1
OHO
R2NO2
H2O
H
O
R1
R2
NO2
rate- and enantioselectivitydetermining step
D-Pro-Pro moiety is critical
free carboxylic acid required
conformational flexibility in thebackbone tolerated
Ktrans/cis ratio influences selectivity
N
O
O
n π* interaction
NO
O
Ktrans/cis
cislower dipole moment
trans
structure activity relationship
R1 H
O
Schnitzer, T.; Wennemers, H. J. Am. Chem. Soc. 2017, 139, 15356.
Wennemers’ Tripeptide Catalyst
ONH
HN
O
CO2H
NH2
O
N
HN
O
CO2H
NH2
O
N
ONH
O
CO2H
NH2
O
N
ONH
10:1 trans/cis 46:1 trans/cis 71:1 trans/cis
H
OEt Ph
NO21 mol% chiral peptide
1 mol% NMM, 20 °C, 2 hH
O
Et
PhNO2
maj
or e
nant
iom
er [%
]
maj
or d
iast
ereo
mer
[%]
trans confomer [%] trans confomer [%]
9:1 CHCl3/MeOHMeOH
DioxaneTHF
MeCNDMF
Schnitzer, T.; Wennemers, H. J. Am. Chem. Soc. 2017, 139, 15356.
Wennemers’ Tripeptide Catalyst
ONH
HN
O
CO2H
NH2
O
N
HN
O
CO2H
NH2
O
N
ONH
O
CO2H
NH2
O
N
ONH
10:1 trans/cis 46:1 trans/cis 71:1 trans/cis
H
OEt Ph
NO21 mol% chiral peptide
1 mol% NMM, 20 °C, 2 hH
O
Et
PhNO2
maj
or e
nant
iom
er [%
]
maj
or d
iast
ereo
mer
[%]
trans confomer [%] trans confomer [%]
9:1 CHCl3/MeOHMeOH
DioxaneTHF
MeCNDMF
A higher proportion of the trans confomer leads to a higher enantio- and diastereoselectivity.
Schnitzer, T.; Wennemers, H. J. Am. Chem. Soc. 2017, 139, 15356.
Wennemers’ Tripeptide Catalyst
ONH
HN
O
CO2H
NH2
O
N
HN
O
CO2H
NH2
O
N
ONH
O
CO2H
NH2
O
N
ONH
10:1 trans/cis 46:1 trans/cis 71:1 trans/cis
H
OEt Ph
NO2
0.05 mol% NMM, 9:1CHCl3/iPrOH, 20 °C, 3 d
H
O
Et
PhNO2
Lowest catalyst loading of a secondary amine organocatalyst reported to date.
95%, 60.1 d.r., 99% ee
O
CO2H
NH2
O
N
ONH 0.05 mol%
Lewis, C. A.; Gustafson, J. L.; Chiu, A.; Balsells, J.; Pollard, D.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J., T. J. Am. Chem. Soc. 2008, 130, 16358. Lewis, C. A.; Chiu, A.; Kubryk, M.; Balsells, J.; Pollard, D.; Esser, C. K.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J., T. J. Am. Chem.
Soc. 2006, 128, 16454.
Remote Desymmetrization by Chiral Peptides
tBu
OAcHO
tBu
OHHO
tBu
OAcAcO
key intermediateat Merck (Rahway)
functional groups remotefrom stereocenter
5.8 Å
9.8 Å
Can this molecule be accessedby a desymmetrization?
enzymatichydrolysis
55% ee at lowconversion
peptide-catalyzedacylation
Lewis, C. A.; Gustafson, J. L.; Chiu, A.; Balsells, J.; Pollard, D.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J., T. J. Am. Chem. Soc. 2008, 130, 16358. Lewis, C. A.; Chiu, A.; Kubryk, M.; Balsells, J.; Pollard, D.; Esser, C. K.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J., T. J. Am. Chem.
Soc. 2006, 128, 16454.
Remote Desymmetrization by Chiral Peptides
tBu
OHHO
Design of the initial library
BocHNHN
ONH
OHN
O
NN
Me
NH
OHN
O
CO2Me
active moietypreviously identified
model: hexapeptide
i i+1 i+2 i+3 i+4 i+5aromatic aliphatic aromatic
Lewis, C. A.; Gustafson, J. L.; Chiu, A.; Balsells, J.; Pollard, D.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J., T. J. Am. Chem. Soc. 2008, 130, 16358. Lewis, C. A.; Chiu, A.; Kubryk, M.; Balsells, J.; Pollard, D.; Esser, C. K.; Murry, J.; Reamer, R. A.; Hansen, K. B.; Miller, S. J., T. J. Am. Chem.
Soc. 2006, 128, 16454.
Case Study 2: Remote Desymmetrization by Chiral peptides
Optimization workflow
42 peptides& reactionconditions
27%, 40% ee
1st generation
24 peptides,i+2 & i+3
varied
25%, 49% ee
2nd generation
24 peptides,i+1 varied – deleterious
25%, 49% ee
3rd generation
72%, 79% ee
4th generation
i+3–5 &lower
temperature
78%, 80% ee
5th generation
i+4,5 varied –
no influence
truncation totetrapeptide
BocHNHN
ONH
OHN
O
NN
Me
NH
O
O
NHTrt
MeMe
OtBuvariation ofC-terminus
Ph
NHTs
Ph
tBu
OAcHO
80%, 95% ee
Müller, C. E.; Zell, D.; Hrdina, R.; Wende, R. C.; Wanka, L. Schuler, S. M. M.; Schreiner, P. R. J. Org. Chem. 2013, 78, 8465.Müller, C. E.; Wanka, L.; Jewell, K.; Schreiner, P. R. Angew. Chem., Int. Ed. 2008, 47, 6180.
Schreiner’s Lipophilic Oligopeptide Catalyst
HN
ONH
O
NH
OMeO2C
Ph
HN OtBu
OMeN
N
OH
OH
trans, racemic
OH
OH
90% ee
chiralpeptide OH
OActoluene
rigid flexibleflexible
no secondary structure - centraladamantyl group separates both ends
adamantyl group holds the 3 stereocentersthat determine stereochemistry in place
H-bonding to second hydroxyl group
Dispersion interaction between hydrop-hobic substituents and substrate
Mechanistic information
second OH required – orthogonal to Miller’s previous system
Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443, 67.Müller, C. E.; Hrdina, R.; Wende, R. C.; Schreiner, P. R. Chem. Eur. J. 2011, 17, 6309.
Desymmetrization of cis-Diols
HN
ONH
O
NH
O
O
HN OtBu
OMeN
N
OH
OH
cis, meso
OAc
OH
acyl group migration
acylation OAc
O
Ph
HN
N
Me Me
MeMe
O
two catalyticallyactive species ona single peptide
oxidation
70%, 76% ee
Silyl protection
OH
OHn
OH
n
OH
N
MeN N
H
tBuHN
O
Me
tBu20–30 mol%
2 equiv. TBSCl, 1.3 equiv.DIPEA, 0.5–1 M in THF
OTBS
OHn
OTBS
n
OH10 examples, 87–96% ee
Diener, M. E.; Metrano, A. J.; Kusano, S.; Miller, S. J. J. Am. Chem. Soc. 2015, 137, 12369. Barrett, K. T.; Miller, S. J. J. Am. Chem. Soc. 2013, 135, 2963. Garand, E.; Kamrath, M. Z.; Jordan, P. A.; Wolk, A. B.; Leavitt, C. M.; McCoy, A. B.; Miller, S. J.; Johnson, M. A. Science 2012, 335, 694.
Gustafson, J. L.; Lim, D.; Miller, S. J. Science 2010, 328, 1251.
Atroposelective Bromination
CO2H
OH
CO2H
OH
Br Br
Br10 mol%
NO
BocHNNMe2
O
HNiPr
NMe2O
3 equiv. PhthNBr, 0.01 M in 97:3CHCl3/acetone, 25 °C, 18 h
ΔG‡(rac) = 7 kcal
N
BocHNN H
Me Me
O NH
H iPr
O
NMe2
Br
H
O
OH
O
O
ΔG‡(rac) = >30 kcal10 examples, 70–94% ee
N
OR
RBr
Br
Br
HO
11 examples, up to 92% ee
N
N
O
Me
BrBr
BrOMe
14 examples, up to 98% ee
reoptimized peptide backbones used
Related projects
Crawford, J. M.; Stone, E. A.; Mertrano, A. J.; Miller, S. J.; Sigman, M. S. J. Am. Chem. Soc. 2018, 140, 868. Mertrano, A. J.; Abascal, N. C.; Mercado, B. Q.; Paulson, E. K.; Hurtley, A. E.; Miller, S. J. J. Am. Chem. Soc. 2017, 139, 491. Mertrano, A. J.; Abascal, N. C.; Mercado, B. Q.; Paulson, E. K.;
Miller, S. J. Chem. Commun. 2016, 52, 4816.
Atroposelective Bromination
N
O
HN
NO
NMe2O
iPrO
NHBoc
Me2N
3 different confomers observedby x-ray crystallography
35 distinct peptide –53 crystal structures
N
O
HNR3
R2
HNO
R3
XO
O
NHBoc
R1 τH
wider τ-angle more flexible & more selective
type II’ β-turns type I’ β-turns
Crawford, J. M.; Stone, E. A.; Mertrano, A. J.; Miller, S. J.; Sigman, M. S. J. Am. Chem. Soc. 2018, 140, 868. Mertrano, A. J.; Abascal, N. C.; Mercado, B. Q.; Paulson, E. K.; Hurtley, A. E.; Miller, S. J. J. Am. Chem. Soc. 2017, 139, 491. Mertrano, A. J.; Abascal, N. C.; Mercado, B. Q.; Paulson, E. K.;
Miller, S. J. Chem. Commun. 2016, 52, 4816.
Atroposelective Bromination
N
O
HN
NO
NMe2O
iPrO
NHBoc
Me2N
3 different confomers observedby x-ray crystallography
35 distinct peptide –53 crystal structures
N
O
HNR3
R2
HNO
R3
XO
O
NHBoc
R1 τH
wider τ-angle more flexible & more selective
type II’ β-turns type I’ β-turns
Multiple confomers contribute to a transition state ensemble.
Yan, X. C.; Metrano, A. J.; Robertson, M. J.; Abascal, N. C.; Tirado-Rives, J.; Miller, S. J.; Jorgensen, W. L. ACS Catal. 2018, 8, 9968.
Atroposelective Bromination
5% vs 75%
NMe
Me
N
ON
ON
HNMe2
O
HONMe
Me
H NH
O
OtBu
H
iPr
type I’ β-turn
type II’ β-turn
only peptide –ground state
with
N
N
O
OH
Me
with
N
N
O
OH
CF3
94% ee 26% ee
75% vs 19% 51% vs 34%
opposite enantiomer opposite enantiomer
27% vs 43% 41% vs 36%
Yan, X. C.; Metrano, A. J.; Robertson, M. J.; Abascal, N. C.; Tirado-Rives, J.; Miller, S. J.; Jorgensen, W. L. ACS Catal. 2018, 8, 9968.
Atroposelective Bromination
5% vs 75%
NMe
Me
N
ON
ON
HNMe2
O
HONMe
Me
H NH
O
OtBu
H
iPr
type I’ β-turn
type II’ β-turn
only peptide –ground state
with
N
N
O
OH
Me
with
N
N
O
OH
CF3
94% ee 26% ee
75% vs 19% 51% vs 34%
opposite enantiomer opposite enantiomer
27% vs 43% 41% vs 36%
Substrate-association enforces a structural change of the peptide – induced fit.
Abascal, N. C.; Lichtor, P. A.; Giuliano, M. W.; Miller, S. J. Chem. Sci. 2014, 5, 4504. Lichtor, P. A.; Miller, S. J. J. Am. Chem. Soc. 2014, 136, 5301. Lichtor, P. A.; Miller, S. J. Nat. Chem. 2012, 4, 990.
Site-Selective Polyene Oxidation
One-bead-one-compound screening
Me
Me Me
OH
Me
farnesol
2,36,710,11
N
O
NH
HN
O
O
NHO
CO2MeTrtHNO
Ph
O
NHTrt
OBocHN
CH2O2H
Me
Me Me
OH
Me
>10011O
Me
Me Me
OH
Me
18.61.1
OptimizationOptimization
N
O
NHBoc
HO2C
O NH
O
Me
OBn
NH
NH
O
Ot-Bu
CO2Me
ONHTrt
O
Small Peptides as Organocatalysts
Introduction
Catalytically relevant properties of small peptides
Small peptides as organocatalyst
Small peptides in Lewis acid and transition metal catalysis
Small peptides in photoredox catalysis
Summary
This group meeting does not cover the available literature comprehensively. Instead, selected keystudies are discussed in order to explain the underlying concepts.
Key references: Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2002, 41, 1009. Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755. Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984. Luchaco-Cullis,
C. A.; Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem., Int, Ed. 2001, 40, 1456. Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284.
Pioneering Work on Peptides in Lewis Acid and Transition Metal Catalysis
N
tBuHN
O
Me
O
Snapper & Hoveyda: cyanation, alkylation
N
tBuHN
O
Me
N
N
tBuHN
O
Me
Hoveyda: copper-catalyzedallylic alkylation
LA
LA = Ti, Zr, Al
Hoveyda: copper-catalyzedconjugate additions
PPh2
Role of the peptide
creation of a chiralenvironment around
the metal catalyst
Samasivan, R.; Ball, Z. T. Angew. Chem., Int. Ed. 2012, 51, 8568.Samasivan, R.; Ball, Z. T. J. Am. Chem. Soc. 2010, 132, 9289.
Helical Peptide-Ligated Rhodium-“Paddlewheel” Complexes
Rh
R CO2Me
N2PhSiMe2SiH
R CO2Me
SiPhMe2
Enantioselective insertion into Si–H bonds
7 examples with>90% ee
Ph CO2Me
N2Rh CO2MePh
Enantioselective cyclopropanation
access to both enantiomersin >90% ee (7 examples)
Role of the peptide
creation of a chiralenvironment around
the metal catalyst
OO
RhOO
Rh
COR
AcHN ROC
NHAc
O
O O
O
OO
Popp, B. V.; Ball, Z. T. J. Am. Chem. Soc. 2010, 132, 6660.
Structure-Selective Protein Functionalization
RhOO
Rh
COR
AcHN ROC
NHAc
O
O O
O
RO2C Ph
FG
FGOO
RhOO
Rh
COR
AcHN ROC
NHAc
O
O O
O
helical peptide
RO2C
N2
Ph
E3/K3 coiled coil assembly places side chainin close proximity of the rhodium carbenoid
close proximity
NH
> 1000 rate enhancementcompared to Rh2(OAc)4
Although tryptophan is most reactive, selectivefunctionalization of E3-tyrosine or phenylalaninesoccurs even in presence of random tryptophane-
containing peptides.
K3
E3
Role of the peptide
substrate recognitionby non-covalent
interactions
Kim, B.; Chinn, A. J.; Fandrick, D. R.; Senayake, C. H.; Singer, R. A.; Miller, S. J. J. Am. Chem. Soc. 2016, 138, 7939.
Copper-Peptide-Mediated Cross-Coupling of Diarylmethanes
tBu
Br BrNH
NH
CF3
O
CF3
O
tBu
BrNH
NH
CF3
O
CF3
O
CO2EtEtO2C
74%, 84% ee
NNH
OLiO2C
MeMe
OHN
CO2
Me2NNMe2
identification of the substrate–peptide interaction
meso
tBu
BrNH
NH
CF3
O
CF3
O
tBu
Br BrNH
CF3
O
tBu
BrNH
CF3
O
tBu
BrNH
CF3
O Me
tBu
BrNH
CF3
O
Cu Cs2CO3, DMF/toluene
A high krel in the kinetic resolution of unsymmetrical substrates
indicates a substrate–peptide interaction
krel = 5.3 krel = 11.3
krel = 10.3 krel = 1.6 krel = 1.2
Kim, B.; Chinn, A. J.; Fandrick, D. R.; Senayake, C. H.; Singer, R. A.; Miller, S. J. J. Am. Chem. Soc. 2016, 138, 7939.
Copper-Peptide-Mediated Cross-Coupling of Diarylmethanes
tBu
Br BrNH
NH
CF3
O
CF3
O
tBu
BrNH
NH
CF3
O
CF3
O
CO2EtEtO2C
74%, 84% ee
NNH
OLiO2C
MeMe
OHN
CO2
Me2NNMe2
identification of the substrate–peptide interaction
meso
tBu
BrNH
NH
CF3
O
CF3
O
tBu
Br BrNH
CF3
O
tBu
BrNH
CF3
O
tBu
BrNH
CF3
O Me
tBu
BrNH
CF3
O
Cu Cs2CO3, DMF/toluene
A high krel in the kinetic resolution of unsymmetrical substrates
indicates a substrate–peptide interaction
krel = 5.3 krel = 11.3
krel = 10.3 krel = 1.6 krel = 1.2
Kim, B.; Chinn, A. J.; Fandrick, D. R.; Senayake, C. H.; Singer, R. A.; Miller, S. J. J. Am. Chem. Soc. 2016, 138, 7939.
Copper-Peptide-Mediated Cross-Coupling of Diarylmethanes
tBu
Br BrNH
NH
CF3
O
CF3
O
tBu
BrNH
NH
CF3
O
CF3
O
CO2EtEtO2C
74%, 84% ee
NNH
OLiO2C
MeMe
OHN
CO2
Me2NNMe2
identification of the substrate–peptide interaction
meso
Cu Cs2CO3, DMF/toluene
tBu
N Br N
Br
CF3
OCs
N NH
OMe
Me
ON
OCuO
NMe2
Me2N OO
CsO CF3
Proposed model
cation-π-interaction between substrate and ligated cesium
Role of the peptide
substrate recognitionby non-covalent
interaction
Kwon, Y.; Chinn, A. J.; Kim, B.; Miller, S. J. J. Am. Chem. Soc. 2018, 57, 6251.Chinn, A. J.; Kim, B.; Kwon, Y.; Miller, S. J. J. Am. Chem. Soc. 2017, 139, 18107.
Copper-Peptide-Mediated Cross-Coupling of Diarylmethanes
tBu
Br BrNH
NH
CF3
O
CF3
O
tBu
O BrNH
NH
CF3
O
CF3
O
14 alcohols, 84–99% ee
Cu K3PO4, MeCN
C–O coupling
C–N coupling and catalyst-controlled cyclodehydration
tBu
Br BrNH
NH
CF3
O
CF3
O
tBu
BrNH
CF3
O
18 examples, 84–99% eeall 4 diastereomers are accessible
Cu K3PO4, MeCN
chiral peptide
1) chiral peptide2) chiral phosphoric acid
NN
CF3
Small Peptides as Organocatalysts
Introduction
Catalytically relevant properties of small peptides
Small peptides as organocatalyst
Small peptides in Lewis acid and transition metal catalysis
Small peptides in photoredox catalysis
Summary
This group meeting does not cover the available literature comprehensively. Instead, selected keystudies are discussed in order to explain the underlying concepts.
Du, J.; Skubi, K. L.; Schultz, D. M.; Yoon, T. P. Science 2014, 344, 392.
Enantioselective [2+2] Photocycloaddition
R1
O
R2
O
R3 EuIr
OH
N
iPrN
OO NHnBu
R2
R1
O
R2
O
OH
NH
iPrN
OO NHnBu
R2
R1
O
R2
O
both diastereomers accessiblein high yields, d.r., and ee values
R1
O
R2
L*Eu Role of the peptide
creation of a chiral environmentaround the metal catalyst
via
two chiralco-catalysts
Shin, N. Y.; Ryss, J. M.; Zhang, X.; Miller, S. J.; Knowles, R. R. Science 2019, 366, 364.
Light-Driven Deracemization
IrNNR
2
O
R1R3
NNR2
O
R1R3
racemic enantioenriched
ET
PT HAT
PCET
Photoredox strategy for an out-of-equilibrium deracemization
ΔG > 0
N
O
HN
NO
Ph
NMe2O
O
BocN
HS
H
H
chiral peptide
OP
O
OO
NBu4
chiral phosphate
1-pyrene
1-pyrene
Role of the peptide
chiral hydrogenatom donor
Shin, N. Y.; Ryss, J. M.; Zhang, X.; Miller, S. J.; Knowles, R. R. Science 2019, 366, 364.
Light-Driven Deracemization
NNR2 R3
O
R1
NNR2 R3
O
R1
NNR2 R3
O
R1
NNR2 R3
O
R1
IrII
IrIII+
IrIII+*NNR
2 R3
O
R1
fastchiral
phosphate
slowchiral
phosphate
achiral
NNR2 R3
O
R1
NNR2 R3
O
R1
electron transfer enantioselectiveproton transfer(R) is depleted
enantioselectivehydrogen atom transfer
(S) is enriched
chiralpeptide
(R)
(R)
(S)
(S)
Summary
A diverse set of reactivity can be achieved using organocatalytic, organometallic, or merged activation modes.
Peptides may control selectivity in catalytic transformations using non-covalent interactions.
Control of the secondary structure is vital in order to place reactive groups in close proximity.
A variety of screening technologies may assist in the discovery process.
Thank you for your attention.Questions?