Activation by One
Electron Oxidation
B4 Kimihiro Miyauchi
2021/12/17

1Introduction
Examples of one electron oxidation• Initiating cycloaddition

Ishihara, K. et al. J. Am. Chem. Soc. 2019, 141, 1877-1881•Bioconjugation

Francis, M. et al. J. Am. Chem. Soc. 2011, 133, 16970–16976
2

Contents

nMesolytic Cleavage of Radical Cation
nOxidative SNAr Pathway
nApplication to BiomolecularnSummary3

Contents

nMesolytic Cleavage of Radical Cation
nOxidative SNAr Pathway
nApplication to BiomolecularnSummary

4

Mesolytic Cleavage of Radical Cation• Conventional Alkylation Strategies
ØStrong acids or Lewis acids required for generating carbocation。

R2R
3R1

R2Lewis Acid / Strong Acid

R3X
Ø

R1Alkylation reagents are very reactive.
XO O
MeS
F3CO

MeH 2CIMeNN

MeO BF4
Me5

Mesolytic Cleavage of Radical Cation• Previous works

Knowles, R. et al. Angew. Chem. Int. Ed. 2016, 55, 9969-9973.

N[O]O
Me-e-NOMeTEMPO

MeCiampi, S., Coote, M. et al. J. Am. Chem. Soc. 2018, 140, 766–774.

Ø Generating carbocation by mesolytic cleavage of radicalcation
Ø Under mild conditions without Lewis/strong acid6

Electrochemically activated methylation

Ø Stable and unreactive in neutral form without electrochemical stimuli.

Coote, M., et al. J. Am. Chem. Soc. 2019, 141, 15450–15455
7

Optimization

Coote, M., et al. J. Am. Chem. Soc. 2019, 141, 15450–15455
8

Optimization
No reaction
OO

OHOMe

N OMe

No reaction
OOOH

N OMe

OMe

• Neither stoichiometric oxidants nor PC facilitated methylation
Ø Electrochemistry is crucial for this reaction

Coote, M., et al. J. Am. Chem. Soc. 2019, 141, 15450–15455
9

Substrate scopeØ Methylation achieved in moderate
to high yieldØ Bearing functional groups
susceptible to reduction→ divided cells
10Coote, M., et al. J. Am. Chem. Soc. 2019, 141, 15450–15455

Mechanism

Solid line: Scan 1
Dotted line: Scan 2

11Coote, M., et al. J. Am. Chem. Soc. 2019, 141, 15450–1545

Short SummaryØ Electrochemically activated methylation under mild condition.
Ø TEMPO-Me is stable in neutral form.
Ø There is still some room for improvement of the substrate scope andthe reactivity of the donor.
Coote, M., et al. J. Am. Chem. Soc. 2019, 141, 15450–15455
12

Contents

nMesolytic Cleavage of Radical Cation
nOxidative SNAr Pathway
nApplication to BiomolecularnSummary

13

Oxidative SNAr Pathway• Common SNAr pathway
EWG
X

EWG
NuX

Nu

EWG
Nu

Meisenheimer complex

X = F, Cl

Cannot be applied to electron-rich arenes• Attempts to facilitate SNAr with electron neutral/rich arenes
F HN
MeNN

210 C˚
K3PO4N
MeHigh temperature is needed
Diness, F. & Fairlie, D. Angew. Chem. Int. Ed. 2012, 51, 8012-8016
14

Oxidative SNAr Pathway• Previous reports
Ø Substitution at C–OMe

Nicholas. T., & Nicewicz. D. J. Am. Chem. Soc. 2017, 139, 16100–16104

Ø Defluorinative substitution

5 equiv.

1 equiv.

Required excess amount of fluoroarene

Huang, H., & Lambert, T. H. Angew. Chem. Int. Ed. 2020, 59, 658-662

15

Oxidative SNAr Pathway

Electron neutral ~ rich arene

Ø SNAr reaction with electron rich or neutral arene under mild condition
Ø Amine or carboxylic acid can be used as nucleophile

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194
16

Optimization (Heteroarene)

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194
17

Optimization (Heteroarene)

Using HFIP as solvent gave higher yield

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194
18

Substrate Scope (Heteroarene)

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194
19

Optimization (Amine, Carboxylic acid)• Xanthylium salt catalyst is not compatible with amine as nucleophile
ArAr
H2N-R1
RORRN
R1R

Nicewicz, D. et al. Synlett. 2019, 30, 827-832• Using acridinium salt catalyst (Catalyst B) instead

20

Optimization (Amine, Carboxylic acid)21

Substrate Scope (Amine, Carboxylic acid)

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194
22

Substrate Scope (Amine, Carboxylic acid)23

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194

Substrate Scope (Amine, Carboxylic acid)Ø Modification without racemizing→ 46~48
Ø Applicable to drug compound, but resulted in low to moderate yield.

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194
24

Proposed Mechanism

J. Am. Chem. Soc. 2017, 139, 16100–16104

25

Rational for regioselectivity

B3LYP/6-31+G(d,p)

Positive charge resides on C-F

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194
26

Short Summary

Electron neutral ~ rich arene

Ø Reverse the reactivity of electron-rich arene with single-electronoxidation.
Ø Late-stage functionalization of pharmaceutical compounds

Nicewicz, D. et al. J. Am. Chem. Soc. 2020, 142 , 17187-17194
27

Contents

nMesolytic Cleavage of Radical Cation
nOxidative SNAr PathwaynApplication to BiomolecularnSummary28

Application to Biomolecular•Previous reports
Ø Decarboxylative C term modification

Ø Ligand directed Tyr modification

MacMillan, D. et al. Nat. Chem. 2018, 10, 205–211

Sato, S., & Nakamura, H. Angew. Chem. Int. Ed. 2013, 52, 8681-8684
29

Site-selective Tyr Modification

Ø Tyrosine selective modification
Ø Further functionalization with versatile handle
MacMillan, D. et al. Nat. Chem. 2021, 13, 902–908
30

Optimization

MacMillan, D. et al. Nat. Chem. 2021, 13, 902–908
31

Substrate Scope of Peptide or Protein

Ø Site-selective Tyr modification was achieved
32MacMillan, D. et al. Nat. Chem. 2021, 13, 902–908

Rational for Site-selectivity

Ø A residue surface-exposed and activated is modified.
Ø Sterically hindered or deactivated Tyr did not react.
Ø Cation-𝜋 interaction reduces 𝜋 electron density.
MacMillan, D. et al. Nat. Chem. 2021, 13, 902–908
33

Proposed MechanismØ From excited state absorption,
flavin oxidates phenoxiazine not Tyr.

MacMillan, D. et al. Nat. Chem. 2021, 13, 902–908
34

Further Functionalization

Organic dyeHandles for click reaction

Ø Aldehyde selective and one-pot transformation

MacMillan, D. et al. Nat. Chem. 2021, 13, 902–908
35

Influence on Protein StructureØ 78% of the native activity was retained.

36

MacMillan, D. et al. Nat. Chem. 2021, 13, 902–908

Influence on Protein Structure• CD spectra of native and modified protein

Ø Secondary structures were generally retained
37

MacMillan, D. et al. Nat. Chem. 2021, 13, 902–908

Short SummaryØ Reactive Tyr residue is functionalized selectively.
Ø Further functionalization with various biorthogonal moieties
Ø Retaining 3D structure or enzymatic activities
38

Summary• Reaction proceeds generally under mild condition• Reversing reactivity of the substrates unreactive inconventional pathways• Applicable to biomolecular modification

39