Strategies in Biomimetic Catalysis - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/sites/6/TMF... · Strategies in Biomimetic Catalysis Enzyme structure

Strategies in Biomimetic Catalysis

Tomer. M. FaraggiMacMillan Lab Group Meeting

November 29th 2016

O

Enzymes as an inspiration for reaction development

Regioselective hydroxylation in cholesterol biosynthesis

Me MeHO

■ Biochemical reactions are catalysed by enzymes with a high degree of precision, under mild conditions

Me

Me

Me

Me

Me MeHO

Me

Me

Me

OH

OH

O

NH2

OH

O

Asymmetric transamination in amino acid biosynthesis

■ There has been significant interest in mimicking the effect of enzymes in synthetic processes

Cys

S

Biocatalysis and Biomimetic catalysis

N

N N

N

FeO

Me

Me

Me

CO2HHO2C

Me

Biocatalysis:

The use of enzymes or whole cells as catalysts for synthetic chemistry

Biomimetic catalysis:

Chemical catalysis that mimics keyfeatures of enzymatic systems

Marchetti, L.; Levine, M. ACS Catal. 2011, 1 , 1090.


■ Enzyme structure consists of an active site surrounded by a protein superstructure

Binding site - Binds and orients substrateProvides control for selectivity of reactionUsually specific to a particular substrate

Catalytic site - Groups which catalyze reactionFor example groups of amino acid residues

Or metal cofactors bound by protein structure

Attempts made to mimic the effects of both sites


Cys

SN

N N

N

FeO

Me

Me

Me

CO2HHO2C

Me LN

N N

N

M

Ar

Ar

Ar

Ar

X

X X

X

X

XX

X

Metalloporphyrins - Development of new reactivity from an enzyme cofactor

Artificial enzymes - Use of supramolecular structures to mimic substrate binding


Cys

SN

N N

N

FeO

Me

Me

Me

CO2HHO2C

Me LN

N N

N

M

Ar

Ar

Ar

Ar

X

X X

X

X

XX

X



C–H functionalization inspired by oxidase enzymes

Holtmann, D.; Fraajie, M. W.; Arends, I. W. C. E.; Opperman, D. J.; Hollmann, F. Chem. Commun. 2014, 50, 13180Li, X-W.; Nay, B. Nat. Prod. Rep. 2014, 31, 533

■ Oxidase enzymes are integral in the biosynthesis of many natural products and metabolic processes

MeMeMe

H Me

Me

H

MeMeMe

OH OAc

Me

H

oxidative enzymes

HOOBz

O

O

HO OH

Taxadiene oxidation in the biosynthesis of taxol

■ A number of oxidase enzymes have been utilized in industrial scale processes

sugars

H

H

Me

Me

H

H

Me

CO2H

3 oxidationsteps O

OMe

H

OMe

H

H

OO

Me

Selective enzyme mediated oxygenation in the fermentation of artemisinic acid

ArtemisininArtemisinicacid

NH

N

NH

NR

Me

Me

O

OO

HO

peroxoflavin catalysts


Holtmann, D.; Fraajie, M. W.; Arends, I. W. C. E.; Opperman, D. J.; Hollmann, F. Chem. Commun. 2014, 50, 13180

Cys

SN

N N

N

FeO

Me

Me

Me

CO2HHO2C

Me

heme based catalysts

Cytochrome P450

OO

CuIICuII

NN

N

HN

NH

NH

His

His

His

N

NNHN

NH

NH

His

HisHis

non-heme metal based catalysts

Oxyhemocyanin

Reactive oxygenation agents at the active sites of some common oxidase enzymes

Gamez, P.; Aubel, P. G.; Driessen, W. L.; Reedijik, J. Chem. Soc. Rev. 2001, 30, 376

Monoamine Oxidases

NH

N

NH

NR

Me

Me

O

OO

HO

peroxoflavin catalysts


Holtmann, D.; Fraajie, M. W.; Arends, I. W. C. E.; Opperman, D. J.; Hollmann, F. Chem. Commun. 2014, 50, 13180

Cys

SN

N N

N

FeO

Me

Me

Me

CO2HHO2C

Me

heme based catalysts

Cytochrome P450

OO

CuIICuII

NN

N

HN

NH

NH

His

His

His

N

NNHN

NH

NH

His

HisHis

non-heme metal based catalysts

Oxyhemocyanin

Reactive oxygenation agents at the active sites of some common oxidase enzymes

Gamez, P.; Aubel, P. G.; Driessen, W. L.; Reedijik, J. Chem. Soc. Rev. 2001, 30, 376

Monoamine Oxidases

Cytochrome P450 class of enzymes

Nam, W. Acc. Chem. Res. 2007, 40, 522

Cys

SN

N N

N

FeIII

Me

Me

Me

CO2HHO2C

Me

■ Class of enzymes containing an iron heme cofactor, responsible for biological C–H oxidations

■ Mechanism proceeds through dioxygen activation and atom transfer via a high valent FeIV intermediate

■ Structure has inspired the development of a number of catalytic strategies based on high valent metals

O2

Cys

SN

N N

N

FeIV

OMe

Me

Me

CO2HHO2C

Me

Cytochrome P450 - Mechanism of action

Nam, W. Acc. Chem. Res. 2007, 40, 522

FeIII

S

O

Cys

O

FeII

SCys

RH

FeIV

S

O

Cys

FeIII

S

O

Cys

OH

FeIII

S

H2O

Cys

FeIII

S

HO

Cys

RH

RH

H+

H2O

RH

R

ROH

e-

O2

1. e-

2. H+

First synthetic reactions by Fe porphyrin complexes

Groves, J. T.; Nemo, T. E.; Myers, R. S. J. Am. Chem. Soc. 1979, 101 , 1032

N

N N

N

FeIII

ClPh

Ph

Ph

Ph

N

N N

N

FeIV

O

IO

Ph

Ph

Ph

Ph

Substrate products yield

Ph

Iodosyl benzene used togenerate active iron-oxo catalyst

Ph Ph

O

OH

OH

O

Epoxide: 55%

Alcohol: 15%

Ph

Cyclohexanol: 8%

Cyclohexanone: 0%

Cis isomer: 82%

Trans isomer: trace

Oxidation reactions utilizing metalloporphyrin catalysts

Che, C-M.; Lo, V.; Zhou, C-Y.; Huang, J-S. Chem. Soc. Rev. 2011, 40, 1950

N

N N

N

ML

Ar

Ar

Ar

Ar

Catalyst design by variation of porphyrin substituents, metal and axial ligand

Metals Axial ligands Terminal oxidants

Mn

Fe

Co

Ru

Os

Cl-

OH-

AcO-

CF3SO3-

MeOH

O2/air

H2O2

PhIO

NaClO

KHSO5X

X

X

X

X

X

X

X

■ In general more electron deficient porphyrin ligands lead to a more oxidising catalyst

■ Effects of axial ligand arise from trans effect - more electron donating ligand weakens M=O bond

■ Reaction mechanism has been adapted for unnatural reactions such as amination


Engelmann, X.; Monte-Pérez, I.; Ray, K. Angew. Chem. Int. Ed. 2016, 55, 7632

Effect of axial donation on the energies of the frontier orbitals of iron oxo complexes


Che, C-M.; Lo, V.; Zhou, C-Y.; Huang, J-S. Chem. Soc. Rev. 2011, 40, 1950

N

N N

N

ML

Ar

Ar

Ar

Ar


Mn

Fe

Co

Ru

Os

Cl-

OH-

AcO-

CF3SO3-

MeOH

O2/air

H2O2

PhIO

NaClO

KHSO5X

X

X

X

X

X

X

X

OH

OH

OHOH

catalyst

oxidant

C-H hydrocarbon oxidation has been a major focus of metalloporphyrin chemistry


Che, C-M.; Huang, J-S. Chem. Commun. 2009, 3996

N

N N

N

ML

Ar

Ar

Ar

Ar


Mn

Fe

Co

Ru

Os

Cl-

OH-

AcO-

CF3SO3-

MeOH

O2/air

H2O2

PhIO

NaClO

KHSO5X

X

X

X

X

X

X

X

S

catalyst

oxidant

Oxidation of other functionalities such as arenes and olefins has also been explored

OH

S

O

OH

O

O

Hydroxylation of unactivated C–H bonds by Fe porphyrins

In, J-H.; Park, S-E.; Song, R.; Nam, W. Inorg. Chimica. Acta 2003, 343, 373

N

N N

N

FeIII

ClAr

Ar

Ar

Ar

Catalyst (0.5 mol%)

PhI(OAc2)

H OH

Ar= F

F

F

F

F

Oxidation of other functionalities such as arenes and olefins has also been explored

Fluorinated aromatic on porphyrin core protects against oxidative degradation

Hydroxylation of unactivated C–H bonds by Fe porphyrins

In, J-H.; Park, S-E.; Song, R.; Nam, W. Inorg. Chimica. Acta 2003, 343, 373

Catalyst (0.5 mol%)

PhI(OAc2)

H OH

Substrate products yield

cyclohexanol: 37%

cyclooctanol: 47%

Both products: 17%

1,2 dMe: 10%

Me

Me

Me

Me

OH O

OH O

Me

Me

Me

Me

HO

OH

Me

Me

Me

Me

HO

OH

Me

Me

cyclooctanone: 7%

OH

cyclohexanone: 6%

2,3 and 3,4 dMe: 17%

Metalloporphyrin catalyzed C–H amination

Yang, J.; Weinberg, R.; Breslow, R. Chem. Commun. 2000, 531

N

N N

N

MnIII

ClAr

Ar

Ar

Ar

N

N N

N

MnIV

NTs

INTs

Ar

Ar

Ar

Ar

Me O

AcO

Me O

AcO

TsHNMn(TFPP)Cl

PhI NTs

■ First example of C-H amination on aromatic stereoid sybstrate

Ar=

F F

F

F F

47% yieldapprox 40 turnovers

Unlike corresponding oxidation process, no side reaction on aromatic ring


Yu, X-Q.; Huang, J-E.; Zhou, X-G.; Che, C-M. Org. Lett. 2000, 2, 2233

Mn(TFPP)Cl (1 mol%)

■ Conditions expanded to allow for the use of amines as aminating agent

NH2Ts

PhI(OAc)2

HNHTs

Substrate product yield

O O

NHTs

NHTs

NHTs

NHTs

81%

90%

83%

85%

Amination of unactivated C–H bonds

Chan, K-H.; Guan, X.; Lo, V. K-Y.; Che, C-M. Angew. Chem. Int. Ed. 2014, 53, 2982

■ Metal nitrene catalysts cannot functionalize unactivated hydrocarbons as readily as their oxo analogues

NHR

N

N N

N

RuIII

CO

Ar

Ar

Ar

Ar

N

N N

N

RuIII

LAr

Ar

Ar

Ar

L

N

N N

N

RuIV

NR

Ar

Ar

Ar

Ar

L

RN3

Ar= F L=N N MeMe

■ Use of an axial NHC ligand increases the reactivity of the Ru nitrene and carbene intermediates


Chan, K-H.; Guan, X.; Lo, V. K-Y.; Che, C-M. Angew. Chem. Int. Ed. 2014, 53, 2982

Catalyst (0.5 mol%)

■ Amination using aryl azides as nitrogen source

N3-C6F5

HNHTs

Substrate product yield

90%

92%

96%

96%

Me

NHC6F5

NHC6F5

NHC6F5

NHC6F5


Ruppel, J. V.; Kamble, R. M.; Zhang, X. P. Org. Lett. 2007, 9, 4889

[Co(TPP)] (0.5 mol%)

■ Intramolecular C–H amination with arylsulfonyl azide

SN3

O O

R R NHS

O O

R R

NHS

O OEt

EtMe

NHS

O OiPr

iPrMe Me

NHS

O O

Me Me

NHS

O O

NHS

O OMe

Me

90% 96%

Cy

iPr

NHS

O OO2N

Me

NHS

O OMe

Me

Me

Me

NHS

O O

BrMe

94% 96%

95% 87% 99% 93%

C–H amination using an engineered P450

McIntosh, J. A.; Coelho, P. S.; Farwell, C. C.; Wang, Z. J.; Lewis, J. C.; Brown, T. R.; Arnold, F. H. Angew. Chem. Int. Ed. 2013, 53, 9309

■ Intramolecular C–H amination with arylsulfonyl azide via "chemomimetic" enzyme modification

SN3

O O

NHS

O O

Et Me

Free Enzyme (0.1 mol%)

Wild type P450Modified P450

Fisrt example of a highly active enzyme catalyst for C–H amination

Et

Et

Enzyme

Turnovers %ee

Et

Et

2.1 nd383 73

Enzyme (E. Coli)

Wild type P450Modified P450

Turnovers %ee

5.1 nd430 87

% Yield

0.558

C–H halogenation via metalloporphyrin catalysis

Liu, W.; Huang, X. Y.; Cheng, M. J.; Nielsen, R. J.; Goddard, W. A.; Groves, J. T. Science 2012, 337, 1322

■ Use of strongly donating axial ligands stabilizes M-OH species, and slows down radical recombination

MnIV

F

O

MnIII

F

HO

MnIII

F

F

MnIII

F

PhIO

PhIO

R H

RAgF

R F

R

N

N N

N

MnIII

FAr

Ar

Ar

Ar

Ar= Me

Me

Me

■ Allows for substitution of fluoride onto metal center



Catalyst (6-8 mol%)

PhIO, AgF, TBAF

H F

Yield

49%

44%

51%

F

Me

OF3C

OHMe OHMe

F

Me

OF3C

F

dr= 8:1

dr=1.5:1

Substrate Product



Catalyst (6-8 mol%)

PhIO, AgF, TBAF

H F

YieldSubstrate Product

O

O

Me

MeMeH

MeH

OMe

H

H

Me

O

O

Me

MeMeH

MeH

OMe

H

H

Me

F

F

42%

α:β= 3.1

42%

α:β= 4.5



Catalyst (6-8 mol%)

PhIO, AgF, TBAF

H F

YieldSubstrate Product

O

O

Me

MeMeH

MeH

OMe

H

H

Me

O

O

Me

MeMeH

MeH

OMe

H

H

Me

16%

α:β= 7.8

23%

α:β= 6.2

F

F


Cys

SN

N N

N

FeO

Me

Me

Me

CO2HHO2C

Me LN

N N

N

M

Ar

Ar

Ar

Ar

X

X X

X

X

XX

X



Supramolecular complexes as enzyme mimics

Marchetti, L.; Levine, M. ACS Catal. 2011, 1 , 1090

■ "Artificial Enzymes" designed around an active site linked to a supramolecular scaffold

■ Structures contain well defined binding pockets capable of stabilizing reactive intermediates

■ Artificial enzymes display a range of binding modes, including H bonding, π−π Interactions, etc

■ Reactions isolated from the surrounding environment, allowing for enzyme-like selectivity

Raynal, M.; Ballester, P. Vidal-Ferran, A.; van Leeuwen, P. W. N. M. Chem. Soc. Rev. 2014, 43, 1734

Supramolecular complexes as enzyme mimics

Dong, Z.; Luo, Q.; Liu, J. Chem. Soc. Rev. 2012, 41, 7890

■ A range of scaffolds have been utilized as host structures for supramolecular enzyme models

Cyclodextrins as a scaffold for substrate binding


O

OHHO

OH

O

O

OH

HOOHO

OOH

OH

OH

O

O

OHOH

OH

OO

OH

OH

HOO

OOH

OHHO

O

OOH

HO

HO

O

β-Cyclodextrin Conical structure

■ Cyclodextrin family of compounds consists of a range of cyclic oligosaccarides

■ Hydrophobic cavity can accomodate a number of hydrophobic guest molecules

■ A numbe of isomers readily available, subject of many early reports on artificial enzymes

Catalytic systems using the cyclodextrin moiety


Initial report of an enzyme mimic

Breslow, R.; Overman, L. E. J. Am. Chem. Soc. 1970, 92, 1075

■ First description of an "artificial enzyme" for the hydrolysis of p-nitrophenyl acetate

O

O

NO

O

Ni2+ N

N-O

O

O2NO

Me OH

O2N

O

O-

■ Catalyst consists of metal complex covalently linked to β-cyclodextrin scaffold

■ Hydrolysis shows a 4x rate enhancement compared to the free metal complex alone

■ Rate acceleration attributed to substrate binding within hydrophobic cyclodextrin pocket

Artificial P450 enzyme for Stereoid Hydroxylation

Breslow, R.; Zhang, X.; Huang, Y. J. Am. Chem. Soc. 1997, 92, 1075

■ Artificial Cytochrome P450 enzyme to mimic selectivity seen in steroid biosynthesis

N

N N

N

MnIII

ClAr

Ar

Ar

Ar

SAr=

OR

O

Me

Me

H

H

HONH

OHO3S

tBu

Catalyst system based on metalloporphyrin core with appended cyclodextrin rings

OH

HO

Me

Me

H

H

H

1. Catalyst (10 mol%)

2. Hydrolysis

OH

■ Ester side chains required to facilitate binding to cyclodextrin groups on catalyst and control regioselectivity

■ Selective oxidation observed at C-6 position, without overoxidation to ketone

PhIO

40% yield


Yang, J.; Gabriele, B.; Belvedere, S.; Huang, Y.; Breslow, R. J. Org. Chem. 2002, 67, 5057


N

N N

N

MnIII

ClAr

Ar

Ar

Ar

SAr=

OR

O

Me

Me

H

H

HONH

OHO3S

tBu

Second generation catalyst contains fluorinated aromatic to prevent oxidative degradation

OR

RO

Me

Me

H

H

H

Catalyst (1 mol%)

OH

■ Selective oxidation observed with increased efficiency at C-6 position, without overoxidation to ketone

■ Substrates without both ester side chains give a mix of products

PhIO

quantitative yield

F

F F

F


Yang, J.; Gabriele, B.; Belvedere, S.; Huang, Y.; Breslow, R. J. Org. Chem. 2002, 67, 5057


N

N N

N

MnIII

ClAr

Ar

Ar

Ar

SAr=

Second generation catalyst contains fluorinated aromatic to prevent oxidative degradation

F

F F

F

NH

O

OR

R

Supramolecular enzyme mimic as an artificial peptidase

Milovic, N. M.; Badjic, J. D.; Kostic, N. M. J. Am. Chem. Soc. 2004, 126 , 696

■ Peptide bond cleavage is a major biological process, vatalyzed by a number of enzymes

protease

Internal X-Pro residues are difficult to cleave, with few enzymes that are able to do so

N

O

R

NHO

difficult cleavage

HN H2N

O

OR

RHN

OH

HN

O

R

NHO

OH

■ Stable Internal X-Pro linkages often used to protect proteins against degradation

■ Few enzyme class and synthetic methods known to cleave them specifically



■ Pd aqua complexes found to selectively cleave all X-Pro linkages

Arg-Pro-Pro-Gyl-Phe-Ser-Pro-Phe-Arg[Pd(H2O)4]2+

Arg-Pro Pro Gyl-Phe-Ser Pro-Phe-Arg

■ As Pro residues do not deprotonate, do not form metal amidate complex that supresses hydrolysis

■ However, sequence specific peptide avage often required for biochemical applications

S SPd2+ Me

H2O OH2

Cyclodextrin moiety intended to bind aromatic side chains

Thus specific to X-Pro-Ar sequences (Phe, Tyr and Trp)



■ Pd aqua complexes found to selectively cleave all X-Pro linkages

Arg-Pro-Pro-Gyl-Phe-Ser-Pro-Phe-ArgPd catalyst

Arg-Pro-Pro-Gyl-Phe-Ser Pro-Phe-Arg

■ With modified catalyst structure, selective peptide cleavage observed adjacent to Phe residue

■ Selectivity attributed to binding of aromatic ring inside cyclodextrin hydrophobic cavity

Self-assembled "Container" molecules


■ Non-covalent self assembled molecules have been used as "enzyme mimics" to encapsulate reactions

■ Container molecules made up of non-covalent linkages, eg. H-bonding, metal coordination, etc.

■ Well defined binding pocket, but present some flexibility when incorporating guest complexes

■ Easily prepared by combining components which assemble through complementary interactions


Yoshizawa, M.; Tamura, M.; Fujita, M. Science, 2006, 312, 251

■ Directing regioselectivity of Diels-Alder reaction by M6L4 molecular cage

N

O

O

R

OH NR

Diels-Alder of anthracene and phthalimide proceeds to yield adduct bridging at the center ring

Proposed to use host complexes to override the selectivity of uncatalyzed D-A reaction

HO

44%



■ Directing regioselectivity of Diels-Alder reaction in molecular hosts

N

O

O

Cy

OH

Use of supramolacular catalyst found to override selectivity in favor of terminal D-A adduct

Substrates without bulky group on phthalamide found to give bridging product

NCy

HO

98%Catalyst (10 mol%)

NCy

CO2H

NCy

CN

NCy

NCy

92% 88%

80% 55%



■ Directing regioselectivity of Diels-Alder reaction in molecular hosts

N

O

O

Cy

OH

Regioselectivity explained via fixed orientation of guest molecules prior to reaction

Bent structure of product leads to a lower affinity for host than substrates, allowing catalytic turnover

NCy

HO

98%Catalyst (10 mol%)

Supramolecular hosts for transition metal catalysis

Levin, M. D.; Kaphan, D. M.; Hong, C. M.; Bergman, R. G.; Raymond, K. M.; Toste, F. D. J. Am. Chem. Soc. 2016, 138 , 9682Brown, C. J.; Toste, F. D.; Bergman, R. G.; Raymond, K. M. Chem. Rev. 2015, 115 , 3012

■ M4L6 have a smaller aperture and an interior more segregated from bulk solution than M6L4

■ Encapsulation occurs with entropically favorable liberation of solvent molecules

■ Anionic host framework has a stabilizing effect on cationic guests and intermediates


Levin, M. D.; Kaphan, D. M.; Hong, C. M.; Bergman, R. G.; Raymond, K. M.; Toste, F. D. J. Am. Chem. Soc. 2016, 138 , 9682Kaphan, D. M.; Levin, M. D.; Bergman, R. G.; Raymond, K. M. Toste, F. D. Science 2014, 350, 1235

L-[M]

[M]R

XL

[M]R

R

[M+]R

RL

R-X

R-Nu

R-R

Merger of biomimetic envioronment control with unnatural mode of reactivity

Control of the rate of a step of a catalytic cycle via encapsulation rather than via ligand

One intermediate of a catalytic cycleSelectively encapsulated by host complex

L

X



■ Stoichiometric reductive elimination from dimethyl Au complex

Me3PAu

I

MeMe

10 mol%Me3PAu I Me Me

4000-fold rate acceleration seen with catalyst (20 weeks to 53 min)

Halide krel

IBr

Cl

15.7

6.5

Background reactivity measured using strongly binding Et4P+ to clock binding pocket

Me3PAu

I

MeMe

K1

Au+Me

MeMe3P

Au+Me

MeMe3P

k2

k-2

kcatMe3PAu I

Me Me

Proposed mechanismbased on pre- equilibrium between neutral and cationic substrates:

Kinetic invesigation indicates enzyme like mechanism following Michaelis-Menten like kinetics



■ Applied to stoichiometric sp3-sp3 coupling using a Pt catalyst

5 mol%Me3Sn Me

Me3PPt

Me

MeMe3P10 mol%

Me I Me Me

KF

Me3Sn F

KI

■ Efficient coupling observed only with both catalysts, deuteration indicates both starting materials incorporated

Pt+

Me

Me

Me

Me3P

Me3P

Modified catalyst allows forBetter incorporation ofMeI into host complex


Cys

SN

N N

N

FeO

Me

Me

Me

CO2HHO2C

Me LN

N N

N

M

Ar

Ar

Ar

Ar

X

X X

X

X

XX

X



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Strategies in Biomimetic Catalysis - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/sites/6/TMF... · Strategies in Biomimetic Catalysis Enzyme structure