catalysis by small peptides an introduction...modular and facile synthesis design & understanding...

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.

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


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.


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


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.


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.


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.


Introduction





Summary


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



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.


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.


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



ONH

HN

O

CO2H

NH2

O

N

HN

O

CO2H

NH2

O

N

ONH

O

CO2H

NH2

O

N

ONH


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.



ONH

HN

O

CO2H

NH2

O

N

HN

O

CO2H

NH2

O

N

ONH

O

CO2H

NH2

O

N

ONH


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


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


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.


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.


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.


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.


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


Introduction





Summary


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.


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.


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


Introduction





Summary


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?

catalysis by small peptides an introduction...modular and facile synthesis design & understanding...

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