flavins: a bio-inspired approach to...

Me

Me N

N

NH

N O

O

R

Flavins: A Bio-Inspired Approach to Photocatalysis

Group Meeting: 3/02/2017

Steven Bloom

MacMillan Group


Outline

Photophysical properties of Flavins

Flavins in organic synthesis: PhotoredoxOxidationHalogenation

Introduction to Flavins: A Brief HistoryRole of Flavins in Biolgy and Basic Mechanisms

Energy transferSubstitution reactions


Riboflavin Biosynthesis

O

OH OH

NPPP OH2C

N

N

NH

O

NH2 O

OH OH

HNP OH2C

H2N

N

NH

O

NH2 O

OH OH

HNP OH2C

H2N

NH

NH

O

O

bacteria

H2CHN

H2N

NH

NH

O

O

HCHCHCCH2O

OHOHOH

P

H2CHN

H2N

NH

NH

O

O

HCHCHCCH2OH

OHOHOH

H3C

OCH2O

OH

P

CH2

N

NH

O

O

HCHCHCCH2OH

OHOHOH

N

N

Me

MeCH2

N

NH

O

O

HCHCHCCH2OH

OHOHOH

N

N

Me

Me

Riboflavin

GTP

H2O

GTPcyclohydrolase II deamination

condensationriboflavin synthase

Bachner,A.;Eberhardt,S.;Fischer,M.;Kis,K.;Richter,G.Annu.Rev.Nutr.2000,20,153-167.


Riboflavin Biosynthesis

CH2

N

NH

O

O

HCHCHC

CH2OH

OHOHOH

N

N

Me

Me

Riboflavin( vitamin B2)

post-modification

CH2

N

NH

O

O

HCHCHC

CH2O

OHOHOH

N

N

Me

Me

PO3H2

flavin mononucleotide(FMN)

CH2

N

NH

O

O

HCHCHC

CH2O

OHOHOH

N

N

Me

Me

PO2

O

O2P O O NN

HOOH

N

NNH2

flavin adenine dinucleotide(FAD)

CH3

N

NH

O

O

N

N

Me

Me

Lumiflavin(LF)

Bachner,A.;Eberhardt,S.;Fischer,M.;Kis,K.;Richter,G.Annu.Rev.Nutr.2000,20,153-167.


Flavoproteins

flavodoxin old yellow enzyme yeast FMO EpiD

90 Flavoproteins found in the human genome

84% contain FAD and 16% FMNlocated in the mitochondria90% perform redox reactions, 10% are transferases, lyases, isomerases, and ligases

FAD first isolated in 1879 from bovine milkFAD structure determined in 1934

Ghisla,S.;Massey,V.J.Biochem.1986,239,1-12.Fraaije,M.W.;Mattevi,A.TrendsBiochem.Sci.2000,25,126-132.


Conference19th International Symposium on Flavins and Flavoproteins

Organised by RUGDate Sun 2 July 2017 until Thu 6 July 2017

Venue Groningen

Newly discovered flavoproteinsFlavin-based chemistry

Flavoenzyme mechanisms & structuresFlavoenzyme engineering

Flavoproteins & lightFlavoenzymes & health

Flavoenzymes & industrial applications


Riboflavin Biochemistry

CH2

N

NH

O

O

HCHCHC

CH2OH

OHOHOH

N

N

Me

Me

Riboflavin

metabolism

( vitamin B2)

antioxidant

drug processing

- break down fats and carbohydrates-provides electrons for electrontransport chain

-neutralizes reactive oxygen speciesdirectly-activates glutathione reductase

-activates Cyt P450 for drugmetabolism

photochemical processes

-circadian rhythms-phototropism-phototaxis

Hemmerich,P.;Nagelschneider,G.F.E.B.S.Lett.1970,8,69-83.



CH2

N

NH

O

O

HCHCHC

CH2OH

OHOHOH

N

N

Me

Me

Riboflavin

metabolism

( vitamin B2)

antioxidant



Conrad,K.S.;Manahan,C.C.;Crane,B.R.Nat.Chem.Bio.2014,10,801-809.




CH2

N

NH

O

O

HCHCHC

CH2OH

OHOHOH

N

N

Me

Me

Riboflavin

metabolism

( vitamin B2)

antioxidant





oxidative catalysis

reductive catalysis



Riboflavin Photochemistry

CH2

N

NH

O

O

HCHCHC

CH2OH

OHOHOH

N

N

Me

Me


N

NH

O

O

N

N

Me

MeR

Halwer,M.J.Am.Chem.Soc.1951,73,4870-4874.



CH2

N

NH

O

O

HCHCHC

CH2OH

OHOHOH

N

N

Me

Me


1Riboflavin*0.67

3Riboflavin*

N

NH

O

O

N

N

Me

MeR

OISC

3RF*= 15 µs

Halwer,M.J.Am.Chem.Soc.1951,73,4870-4874.



CH2

N

NH

O

O

HCHCHC

CH2OH

OHOHOH

N

N

Me

Me


1Riboflavin*0.67

OISC

3Riboflavin*

pka of RF = 8.3

N

NH

O

O

N

N

Me

MeR

N

NH

O

O

N

N

Me

MeR

N

NH

O

O

N

N

Me

MeR

440 nmSET, H+

or

PCET

OISC

N

NH

O

O

HN

N

Me

MeR

*

3RF*/RFH = 1.5 V RFH/RF = -0.5 V

N

NH

O

O

N

N

Me

MeR

- e- H+

3RF*= 15 µs

Korvinson,K.A.;Hargenrader,G.N.;Stevanovic,J.;Xie,Y.;Joseph,J.Maslak,V.;Hadad,C.M.;Glusca,K.J.Phys.Chem.2016,120,7294-7300.



CH2

N

NH

O

O

HCHCHC

CH2OH

OHOHOH

N

N

Me

Me


N

NH

O

O

N

N

Me

Me

R

N

NH

O

O

N

N

Me

Me

SET to S1 (unproductive, ~ 50 ps)

SET to T1 (productive, ~ 15 µs)

heavy element substitutuion inreasesS1 to T1 ISC by spin-orbit coupling (100 x faster)

increases oxidation potential

RF = 1.5 V (ISC = ns), 3RF* = 15.0 µs

IRF = 1.65 V (ISC = ps), 3RF* = 5.8 µs

I

OH

OHHO

OH

H

intramolecular HAT from T1 competeswith SET

HAT from OH is 2x faster than α-C-H

N

NH

O

O

N

N

Me

Me

OR

ORRO

OR

H

R = OAc = OBu

acylation prevents HATand increases T1 lifetimes


Riboflavin Mechanisms

Monoamine oxidase (MAO)

Me

SEnz

N

N

NH

N

O

OR

R NH2

HMe

SEnz

NH

N

NH

N

O

OR

NH2

R

Me

SEnz

NH

N

NH

HN

O

OR

R NH2

Glucose oxidase

O

OH

HO

HO OH

OH O

OH

HO

HO OH

O

+




Glutathione reductase

Me

GR

N

N

NH

N

O

OR

Me

GR

NH

N

NH

N

O

OR

S

Me

GR

NH

N

NH

N

O

OR

NR

HH

NH2

O

NADH

NAD+

SSBH

SH

Me

GR

N

N

NH

N

O

OR

S

flavin-thiolatecharge-transfer

complex





p-Hydroxybenzoate

Me

GR

N

N

NH

N

O

OR

Me

GR

NH

N

NH

N

O

OR

OOH

3,4-hidroxybenzoate

H2O2

OHHO2C Base

Me

GR

NH

N

NH

N

O

OR

OH

OHHO2C

OH

-H2O



Me

Me

NH

N

NH

N

O

OR

OOH

O

O

NMe

RS

R RR

O

NOMe

RR

O

Last 50 years of research

many have now been demonstratedasymmetrically by H-bonding catalysis

RS

R

O

O

O

N-oxidation

epoxidation

lactonization

sulfoxidation

Massey,V.J.Biol.Chem.1994,269,22462-22462.

Nicewicz,D.A.;Nguyen,T.M.ACSCatal.2014,4,355-360.


RFRF*

RF

RF

oxidation

Ar NH2Ar OH

Ar SO

Me

Ar OAr O

Ar SO2

Me

O2

H2O2

reduction

flow of 2e- and 2H+

blue light

RF

RFHOH

oxidation

Ar NH2Ar OH

Ar SO

Me

Ar OAr O

Ar SO2

Me

-H2O

SLOW REACTION

Me

Me

NH

N

NH

N

O

OR

OOH

H2O2

RFOOH

reduction

RFflow of 1e- and 1H+

λmax = 440 nm

FAST REACTION

Me

Me

N

N

NH

N

O

OR

RFRF*

RFH2

oxidation

Ar NH2Ar OH

Ar SO

Me

Ar OAr O

Ar SO2

Me

O2

H2O2

reduction

blue lightRF

flow of 1e- and 1H+

λmax = 440 nm

FAST REACTION

Me

Me

N

N

NH

N

O

OR


Direct Benzylic oxidation

benzylic oxidationMe Me

Odirect

- first oxidation is difficult ( > 1.8 V)- catalyst deactivation by O2- competing O2 sensitization

air

simple benzylic oxidized product

Nicewicz,D.A.;Nguyen,T.M.ACSCatal.2014,4,355-360.



benzylic oxidationMe Me

Odirect

Me

Me N

N

NH

N O

O

R

RFλmax = 440 nm

air

simple benzylic oxidized product

E0

V vs SCE

1.67

2.06

2.25

2.45

3RF*

RFhυ

RF-Mg2+

RF-Yb3+

RF-Sc3+

p-OMe-toluene

p-Me-toluene

toluene

Sc3+

Sc3+

hυ

3RF*

Lewis acid coordination increasesreduction potential

Wolf,R.;Muhldorf,B.Chem.Commun.2015,51,8425-8428.



Me

O

MeCN, airsimple benzylic oxidized product

MeRiboflavin (10 mol%)

Sc(OTf)3 (20 mol%)

440 nm

CHO

no Sc, with Sc

0%, 71% 3%, 60%

Me

O

4%, 93%

Ph

OCHO

0%, 29%NC

CHO

0%, 15%MeO2C

0%, 49%MeO2C

Me

O

deactivated arenes




Me

O



Sc(OTf)3 (20 mol%)

440 nm

mechanistic proposal

Me RF-2Sc3+

PCETMe

O2 Me

OO

Me

Ohυ

RF-2Sc3+ O2

SLOWRF-2Sc3+ + H2O2




Me

O



Sc(OTf)3 (20 mol%)

440 nm Me

Me N

N

NH

N O

O

AcO

AcOOAc

OAc

Me

O

MeCN, H2O airsimple benzylic oxidized product


[Fe(TPA)(MeCN)2](ClO4)2

440 nm

N NN

NFe

LL

Fe(TPA)L2

Flavin catalyst

*disproportions H2O2 byproductWolf,R.;Muhldorf,B.Agnew.Chem.Int.Ed.2016,55,427-430.



Me

O



[Fe(TPA)(MeCN)2](ClO4)2 (2 mol%)

440 nm

OH

O

60%

overoxidation

Me

O

74% 70%

O

70%

O

66%

O

O

96%O

O

Wolf,R.;Muhldorf,B.Agnew.Chem.Int.Ed.2016,55,427-430.



Me

O



[Fe(TPA)(MeCN)2](ClO4)2 (2 mol%)

440 nm


Me RF-Fe(TPA)PCET

MeO2 Me

OO

Me

Ohυ

RF-Fe(TPA)O2

SLOWRF-Fe(TPA) + H2O2

Fe(TPA)

disproportionationN N

N

NFe

OOH

active for C-H oxidationWolf,R.;Muhldorf,B.Agnew.Chem.Int.Ed.2016,55,427-430.


HN

RHal

HN

RHal

Me

Me

hydroperoxyflavin

NH

N

NH

N O

O

R

OHO

Cl or Br

HOCl or HOBr

Wu,X.;Meng,C.;Yuan,X.;Jia,X.;Qian,X.;Ye,J.Chem.Commun.2015,51,11864-11867.


Decarboxylative Fluorination

SelectfluorCs2CO3

MeCN/H2O23 W CFL, rt

NTs

CO2H

NTs

F

photocatalyst

photocatalyst yield

Mes-Acr ClO4RiboflavinEosin Y

Rhodamine B

58%55%tracetrace

HN

RHal

HN

RHal

Me

Me

hydroperoxyflavin

NH

N

NH

N O

O

R

OHO



Selectfluor


Cs2CO3


NTs

CO2H

NTs

F

photocatalyst

photocatalyst yield


Rhodamine B

58%55%tracetrace

NTs

F

71%

NTs

F

36%

R

O F

N

O

OF

n n = 2, 35%n = 3, 40%n = 4, 39%n = 5, 42%

R = Ph, 73%R = tBu, 76%R = Br, 45%



Selectfluor


Cs2CO3


NTs

CO2H

NTs

F

photocatalyst

photocatalyst yield


Rhodamine B

58%55%tracetrace

NN

F

Cl

R COO

-CO2

R+ R F

NN

Cl

NN

Cl

RFRF*

RF



Energy Transfer [2+2] cycloaddition

400 nm LED

photocatalyst

O

Me

MeAr

MeCN O

H H

Ar MeMe

N

N

N

NMeO

MeOO

O

Me

ET = 59 kcal/mol-1

O

CH3

ET = 63 kcal/mol-1

photocatalyst λmax

Riboflavin (OH)4Riboflavin (OAc)4

450 nm450 nm

ET

50 kcal/mol-1 N

N

N

N

O

O

Bu

Me

alloxazine Me4

E0-0 = 69 kcal/mol-1

57 kcal/mol-1

yield

0%0%

Me

MeMe

Me

Alloxazine Me4 350 nm 59 kcal/mol-1 traceAlloxazine OMe2 400 nm 69 kcal/mol-1 87% (10 min)


Mojr,V.;Svobodova,Strakova,K.;Nevesely,T.;Chudoba,J.;Dvorakova,H.;Cibulka,R.Chem.Commun.2015,51,12036-12039.

Ir(ppy)3

Ir(ppy)2 4,4'-(MeO)2bpy

Ir(ppy)2 4,4'-Me2bpy

Ir(ppy)2 bpy

photocatalyst

Ru(bpy)3

Ir(ppy)2 4,4'-(CO2Me)2bpy

47.7

47.6

46.3

ET (kcal)

45.4

39.7

53.6



400 nm LED

photocatalyst

X

Me

MeAr

x = CH2, OMeCN X

H H

Ar MeMe

x = CH2, O

Me

ET = 59 kcal/mol-1

O

CH3

ET = 62 kcal/mol-1

Riboflavin (OH)4 50.0

Alloxazine OMe2 69.0

N

N

N

NMeO

MeO O

O

Bu

Me

Alloxazine OMe2

Ir[dFCF3ppy)]2dttbpy 61.0


Benzoquinone

Mesityl AcridiniumFluorenone

Riboflavin (OH)4

photocatalyst

FluoresceinEosin Y

55.053.050.0

ET (kcal)

47.045.0

69.0



400 nm LED

photocatalyst

X

Me

MeAr

x = CH2, OMeCN X

H H

Ar MeMe

x = CH2, O

Me

ET = 59 kcal/mol-1

O

CH3

ET = 62 kcal/mol-1

Naphthalene 61.0

Acetophenone 74.0

N

N

N

NMeO

MeO O

O

Bu

Me

Alloxazine OMe2

Alloxazine OMe2 69.0

Anthracene 43.0Rose bengal 41.0





400 nm LED

photocatalyst

O

Me

MeAr

MeCN O

H H

Ar MeMe

N

N

N

NMeO

MeOO

OBu

Me


O

H H

MeMe

R

R = OMe, 82% (>10:1)R = H, 87% (>10:1)R = Br, 76% (>10:1)R = CF3, 81% (>10:1)

H H

Ph

42% (7:1) 80%

H H

ArOC COAr

Ar = Ph, 70% (5:1)Ar = 4-OMePh, 67% (4:1)Ar = 4-CF3Ph, 58% (1:1)




400 nm LED

photocatalyst

O

Me

MeAr

MeCN O

H H

Ar MeMe

N

N

N

NMeO

MeOO

OBu

Me


O

Me

MeAr Energy Transfer

N

N

N

NMeO

MeOO

OBu

Me

*O

Me

MeAr *

O

H H

Ar MeMe[2+2]

Z

Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.


(E) to (Z) Isomerization

(-)-riboflavinhνO

HMeMe

Me

(E)

MeMe

Me

(Z)

Me

OH

Me Me

Me

Nature 1967, 215, 1483.retinal

the squalene conundrum

Me

Me

Me

Me

Me

Me

Me

Me

selective functionalization of polyenes

Scott Miller, Yale



(-)-riboflavinhνO

HMeMe

Me

(E)

MeMe

Me

(Z)

Me

OH

Me Me

Me

Nature 1967, 215, 1483retinal

O

OR(-)-riboflavin (5 mol%)

402 nmMeCN, rt

R R

ORO




O


402 nmMeCN, rt

R R

ORO

Me

OEtO

Z/E

quant., 99:1

Et

OEtO

quant., 95:5

OEtO

99%, 59:41

H

OEtO

quant., 95:5

Me

H3C OEtO

quant., 97:3

H

F3C




O


402 nmMeCN, rt

R R

ORO

N

Me

OEtO

Z/E

88%, 95:5

Me

OEtO

quant., 83:17

HO

quant., 87:13

Et

NO

quant, 96:4

Et

H3C OHO

24%, 99:1

Et

OMe

Me





O


402 nmMeCN, rt

R R

ORO

Z/E

Et

(-)-riboflavin (5 mol%)

402 nmMeCN, rt

OHO

24%, 99:1

Et

OH

O

O O

Et

57%

+





402 nmMeCN, MeOH (1:1) rt

R

OH

O

O O

RO2

O O

R

R = H, 79%

O O

R

R = Alkyl, 60-90%

O O

Me

R = OMe, 65%R = CF3, 48%R = Me, 60%

RO OMeO

herniarinhepatoprotectent




402 nmMeCN, MeOH (1:1) rt

R

OH

O

O O

RO2

R

OH

O


(E) to (Z)isomerization

(-)-riboflavin (RF) R

OHO

PCETR

OO

R

OO

RFH

RF

RFH2

PCET

O O

R

O2 RF

Merger of energy transfer and SET catalysis

ET

(E)-cinnamic acid coumarin





O


402 nmMeCN, rt

R R

ORO

Z/E

R

RO

R

R

O

mechanistic hypothesis

(-)-riboflavinhυ

R

R

O

(-)-riboflavinhυ

E ZisomerizationX

conjugated deconjugated(Z)




O


402 nmMeCN, rt

R R

ORO

Z/E

R

RO

R

R

O


E Z

1:1competition study


402 nmMeCN, rt RO

R

Z -(E) quenches 10x faster than (Z)

Stern Volmer quenching study




O


402 nmMeCN, rt

R R

ORO

Z/E

R

R

O


Etriplet sensitizer

RO

R

ZRiboflavinET = 50 kcal/mol-1

(E)ET ~ 34 kcal/mol (Z)ET ~ 60 kcal/mol-1

34 < ET < 60 kcal/mol-1

60 < ET < 74 kcal/mol-1

consistent with triplet energy transfer (ET) mechanism

X




O


402 nmMeCN, rt

R R

ORO

Z/E


R

R

O

isomerizationTol OEt

O

PhPh standardconditions

Tol

PhPh

OEtO

Tol

PhPh

OEtO

52%60:40

* No reaction without photocatalyst

scrambled



O


402 nmMeCN, rt

R R

ORO

Z/E


R

R

O

isomerization

standardconditions

52%60:40

Ar

O

R

R H F Me Et Pr

increasing Z/E ratio

consistent with radical stabilityMetternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.




O


402 nmMeCN, rt

R R

ORO

Z/E

R

RO

R

R

O


E Zvsdeconjugation induces selective excitation


402 nmMeCN, rt OEtO

Me

OOEtO

Me

S

reduced A 1,3 strain in (Z)-products(E) and (Z) are conjugated and planar

94%, 27:73 quant, 41:59




O


402 nmMeCN, rt

R R

ORO

Z/E

R

RO

R

R

O


E Zvs

deconjugation induces selective excitation


402 nmMeCN, rt OEtO

Me

introduction of allylic strain by ortho-fluoro

quant, 81:19

F

Marz,M.;Chudoba,J.;Kohout,M.;Cibulka,R.Org.Biomol.Chem.2017.


catalytic esterification

CO2H O

O

MeCN, O2 1 atmsimple carboxylic acids

and alcoholsester

Riboflavin (10 mol%)

PPh3 (2 equiv)

440 nm

R OHR

EtO2CHN

NH

CO2Et(10 mol%)

Mitsunobu conditions-typically performed with

stoichiometric azodicarboxylate

O2N O

O

R

R = H, 53%R = Me, 54%R = NO2, 60%R = OMe, 70%

O2N O

OPh

n = 1, 80%n = 7, 61%

nO p-Cl-Ph

32%

MeMe

O

O

58%

O

p-Cl-Ph




CO2H O

O


and alcoholsester


PPh3 (2 equiv)

440 nm

R OHR

EtO2CHN

NH

CO2Et(10 mol%)



65% 99:1 er

NO2

O

O

Ph

Me

59%, 99:1 er

NO2

O

O

Ph

Me

50%, 98:2 er

NO2

O

O

CO2Et

MeO2N

48%, 98:2 er

NO2

O

O

CO2Et

MeO2N


O2



CO2H O

O


and alcoholsester


PPh3 (2 equiv)

440 nm

R OHR

EtO2CHN

NH

CO2Et(10 mol%)




EtO2CHN

NH

CO2Et

(1.62 V vs SCE)RFH2

EtO2CN

NCO2Et

PPh3EtO2C

NNH

CO2EtPPh3

R OH

R OPPh3

R COOOPPh3R

O

O

R+

RF 1.67 V vs SCE


Concluding Remarks

Flavin photoredoxcatalysis is still under-ultized in synthetic organic chemistry

Flavin photocatalysis is an emerging field

Flavins serve an essential role in biochemistryThe unique photoredox properties of Flavins make them interesting photocatalyst

flavins: a bio-inspired approach to...

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