strategies in biomimetic catalysis - princeton...
TRANSCRIPT
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.
Strategies in Biomimetic Catalysis
■ 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
Strategies in Biomimetic Catalysis
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
Strategies in Biomimetic Catalysis
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
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
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, 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
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, 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
Oxidation reactions utilizing metalloporphyrin catalysts
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
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
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
OH
OH
OHOH
catalyst
oxidant
C-H hydrocarbon oxidation has been a major focus of metalloporphyrin chemistry
Oxidation reactions utilizing metalloporphyrin catalysts
Che, C-M.; Huang, J-S. Chem. Commun. 2009, 3996
N
N N
N
ML
Ar
Ar
Ar
Ar
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
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
Metalloporphyrin catalyzed C–H amination
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
Metalloporphyrin catalyzed C–H amination
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
Metalloporphyrin catalyzed C–H amination
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
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
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
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
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
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
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
Strategies in Biomimetic Catalysis
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
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
Dong, Z.; Luo, Q.; Liu, J. Chem. Soc. Rev. 2012, 41, 7890
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
Dong, Z.; Luo, Q.; Liu, J. Chem. Soc. Rev. 2012, 41, 7890
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
Artificial P450 enzyme for Stereoid Hydroxylation
Yang, J.; Gabriele, B.; Belvedere, S.; Huang, Y.; Breslow, R. J. Org. Chem. 2002, 67, 5057
■ 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
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
Artificial P450 enzyme for Stereoid Hydroxylation
Yang, J.; Gabriele, B.; Belvedere, S.; Huang, Y.; Breslow, R. J. Org. Chem. 2002, 67, 5057
■ Artificial Cytochrome P450 enzyme to mimic selectivity seen in steroid biosynthesis
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
Supramolecular enzyme mimic as an artificial peptidase
Milovic, N. M.; Badjic, J. D.; Kostic, N. M. J. Am. Chem. Soc. 2004, 126 , 696
■ 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)
Supramolecular enzyme mimic as an artificial peptidase
Milovic, N. M.; Badjic, J. D.; Kostic, N. M. J. Am. Chem. Soc. 2004, 126 , 696
■ 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
Dong, Z.; Luo, Q.; Liu, J. Chem. Soc. Rev. 2012, 41, 7890
■ 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
Self-assembled "Container" molecules
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%
Self-assembled "Container" molecules
Yoshizawa, M.; Tamura, M.; Fujita, M. Science, 2006, 312, 251
■ 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%
Self-assembled "Container" molecules
Yoshizawa, M.; Tamura, M.; Fujita, M. Science, 2006, 312, 251
■ 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
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 , 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
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 , 9682Kaphan, D. M.; Levin, M. D.; Bergman, R. G.; Raymond, K. M. Toste, F. D. Science 2014, 350, 1235
■ 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
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 , 9682Kaphan, D. M.; Levin, M. D.; Bergman, R. G.; Raymond, K. M. Toste, F. D. Science 2014, 350, 1235
■ 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