Selective Epimerization ofSugars Inspired by
Radical-Based Synthetic
Mechanisms
Literature Seminar
Ryo Kuroda
2022/6/9
1

Contents
1. Introduction
2. Representative Researches
ー Epimerization via Kinetic Control
ー Epimerization via Thermodynamic Control
ー Epimerization via Transient Thermodynamic Control
3. Summary

2

Contents
1. Introduction
2. Representative Researches
ー Epimerization via Kinetic Control
ー Epimerization via Thermodynamic Control
ー Epimerization via Transient Thermodynamic Control
3. Summary3

Importance of Synthesizing Rare Sugars

Carolyn E. Suh et al.
ACS Chem. 2021, 16,
1814−1828.

Rare Sugars
Glycosylated natural products
andPharmaceuticals

4

Synthesis Using Protecting Groups✔ Previous researchusing protecting groups
The use of protecting groups
is unnecessary synthetic steps

The direct transformation is efficient
But too difficult
Huang, Z. et al. Acc. Chem. 2017, 50(3), 465−471.

5

SAM ( Radical Enzymes )Radical SAM enzymes✔ Previous research using radical
SAM enzymes

MechanismMicrobial sugar biosynthesis has
diverse radical pathways

Broderick, W. E. et al. Acc. Chem. 2018, 51(11), 2611−2619.

6

Advantages and Challenges of Radical Pathways
Advantages✔ Reactivity at unconventional sites

Challenges
Reagents or harsh conditions✔ No unnecessary substrate activation✔ Easy translation from enzymatic tosynthetic systems
Prefunctionalization is necessary✔ Irreversible
7

Advantages and Challenges of Radical Pathways
Advantages✔ Reactivity at unconventional sites

Challenges
Reagents or harsh conditions✔ No unnecessary substrate activation✔ Easy translation from enzymatic tosynthetic systems
Prefunctionalization is necessary✔ Irreversible
8

Photochemistry

Carolyn E. Suh et al. ACS Chem. 2021, 16, 1814−1828.

Advantages of Photochemistry✔ No prefunctionalization✔ Mild conditions✔ Selective reaction✔ No reagents✔ Minimally Protecting groups
9Epimerization is Possible ??
✔ Alkylation and 1,2-radicalmigration is possible

Dimakos, V. et al. J. Am. Chem. 2019, 141(13), 5149−5153.

Dimakos, V. et al. Chemical Science. 2020, 11(6), 1531−1537.

Epimerization
Is Possible ??

10

Contents
1. Introduction
2. Representative Researches
ー Epimerization via Kinetic Control
ー Epimerization via Thermodynamic Control
ー Epimerization via Transient Thermodynamic Control
3. Summary11

Epimerization via Kinetic Control
Synthesis of rare sugar isomers through site-selective epimerization

Yong Wang et al. Nature. 2020, 578, 403−408.

✔ Kinetically controlled mechanism✔ High selectivity✔ Single step

✔ High yield✔ Site-selective12

Condition Optimization for Sugar Epimerization
ized
Optim n !!
oreactiYong Wang et al. Nature. 2020, 578, 403−408.

C3 selectivity↑
Hydrogen bond between 1a and the base
13

Substrate Scope of Protected Monosaccharides

This Strategy provides
rare sugars
1f, 1e ( pentose sugars )→ C3 and C2 epimerization
Yong Wang et al. Nature. 2020, 578, 403−408.

14Substrate Scope of Unprotected Monosaccharides

Epimerization of unprotected monosaccharides is successful
The only reaction of epimerization of 2-deoxygenated sugars

Yong Wang et al. Nature.
2020, 578, 403−408.

15

Substrate Scope of Oligosaccharides and Glycans

Yong Wang et al. Nature. 2020, 578, 403−408.

Epimerization of oligosaccharides and glycans is successful→ High selectivity, High functional group compatibility
16

Mechanistic Studies of Sugar Epimerizationa : No reverse epimerizationb : Hydrogen-atom abstraction is occurred↓Not simple equilibrium control
Yong Wang et al. Nature. 2020, 578, 403−408.

17

Mechanistic Studies of Photocatalyst and Quinuclidine
Quinuclidine

Graph:
Photocatalyst is quenched by quinuclidinec:
No thiol → No epimerization

Photocatalyst and quinuclidine :Sufficient for C-H cleavage (irreversible)
Insufficient for epimerization
Yong Wang et al. Nature. 2020, 578, 403−408.

Ad-SH

Constant Ad-SHandVariable Quinuclidine
18

Mechanistic Studies of Thiol Co-Catalyst
A : Productive epimerization conditions( Ad-SH )B : Non-productive conditions( 4BrPhSH )Yong Wang et al. Nature.
2020, 578, 403−408.

Fluorescence quenching (B) :Quinuclidine + 4BrPhSH >> Only Quinuclidine
Why ??

Oxidation of thiolate enhanced fluorescence quenching ??

19

Interaction between Quinuclidine and Thiol
Equilibrium Constant between
4-BrPhSH and Quinuclidine

Equilibrium Binding Curve between
4-BrPhSH and Quinuclidine

Equilibrium interaction between 4BrPhSH and Quinuclidine

Quinuclidine deprotonate acidic thiols
to form thiolate salts
Yong Wang et al. Nature. 2020, 578, 403−408.

20Interaction between Quinuclidine and Thiol
4-BrPhSNa

Quinuclidine

Yong Wang et al. Nature. 2020, 578, 403−408.

Fluorescence quenching :4-BrPhSHNa > Only Quinuclidine

Oxidation of thiolate enhanced fluorescence quenching21

Mechanistic Studies of Thiol Co-Catalyst
A : Productive epimerization conditions( Ad-SH )B : Non-productive conditions( 4BrPhSH )Yong Wang et al. Nature.
2020, 578, 403−408.

A ( Ad-SH ) : Sufficient acidic

B ( 4BrPhSH ) : Too acidic

Quenching of the photo-catalyst :Thiol < Quinuclidine↓C-H cleavage

Quinuclidine deprotonate acidic thiols to form thiolate salt↓
Quenching of the photo-catalyst :Thiolate salt > Quinuclidine↓Formation of thiyl radicals
22

Mechanistic Studies of Thiol Co-Catalyst

Thiyl radical≠ hydrogen-atom abstraction

Thiol co-catalyst= irreversible HAT to sugar radical( Second step )Yong Wang et al. Nature. 2020, 578, 403−408.

23

Mechanism of Sugar Epimerization

Yong Wang et al. Nature.
2020, 578, 403−408.

2 steps
1 : Hydrogen-atom abstraction by quinuclidinium radical cation
2 : HAT from thiolKinetically controlled↑
Irreversible and diastereoselective HAT from thiol

24

Short Summary
Synthesis of rare sugar isomers through site-selective epimerization

Yong Wang et al. Nature. 2020, 578, 403−408.

✔ Kinetic control✔ Sequential steps of HAT✔ HAT mediated by two distinct catalysts✔ Concise and potentially extensive access to rare sugars

25

Contents
1. Introduction
2. Representative Researches
ー Epimerization via Kinetic Control
ー Epimerization via Thermodynamic Control
ー Epimerization via Transient Thermodynamic Control
3. Summary26

Epimerization via Thermodynamic Control
A Change from Kinetic to Thermodynamic Control
Enables Trans-Selective Stereochemical Editing of Vicinal Diols

Yu-An Zhang et al. J. Am. Chem.
2022, 144, 599−605.

✔ Ph3SiSH as a HAT catalyst✔ Chemoselective✔ Thermodynamic✔ Mild condition✔ Broadly functional group tolerant✔ Concise access to trans-diol products27

Problem Presentationn!!
oit
caeThis rYu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

The access to cis- and trans-diaxial isomers→ Many methods
The access to trans-diequatorial isomers→ Limited

This research :Catalytic reaction to accesstrans-diequatorial vicinal
diols directly from cis-diols28Condition Optimization

2: Ph3SiSH is best thiol catalyst
3: No IrF, No Blue LED, No thiol→ No reaction
Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

29

Reaction Timecourse

The cis- / trans- isomer starting substrate→ Same final product ratio
The thiol catalyst dictates
the final equilibrium product ratio

PhSiSH > Ad-SH

Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

30

Comparison between Ph3SiSH and Quinuclidine

The interaction between
Ph3SiSH and Quinuclidine

No interaction between
Ad-SH and Quinuclidine
Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

31

Comparison between Ph3SiSH and Quinuclidine
Ph3SiSH

Ad-SH

Ph3SiSNa

Ph3SiSH
andDABCO (base)Single electron oxidation potential
Only Ph3SiSNa = Quinuclidine + Ph3SiSH

Single electron oxidation potential
Only Quinuclidine = Quinuclidine + AdSH

Fluorescence quenchingThiolate salt > DABCO (base)Fluorescence quenchingThiolate < Quinuclidine

Quinuclidine → BaseYu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

32

Comparison between Ph3SiSH and Quinuclidine
Optimization of base ( Ph3SiSH )

asebt
Bes

Ph3SiSH
Quinuclidine :replaced with DABCO, NaHCO3, orother basic additives↓Not HATAd-SH
Quinuclidine :Not replaced with DABCO, NaHCO3,or other basic additives

Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

33

Mechanism of the Epimerization

Ph3SiSH

Ad-SH

Ph3SiSH :Both H atom abstraction and donation↓The reaction is reversible↓Quinuclidine and Ad-SH:
Both H atom abstraction and donation↓Thermodynamic product !!

Kine2c product !!

Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

34

Optimization of Thiol in the Presence of DABCO
Optimization

Reaction timecourse

Electron-rich / -deficient thiophenol derivatives→ No reaction
Reaction speed : AcSH << Ph3SiSH
Equilibrium ratio : iPr3SiSH << Ph3SiSH↓
Ph3SiSH is Best !!
Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

35

Substrate Scope

Highly diastereoselectivity
Highly chemoselective( α-hydroxy C-H bond )Thermodynamicaly controlled

Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

36

Functional Group Compatibility

Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

37

Comparison with Previous Synthetic Strategies!!
pet
S
One

Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

Previous methods

This method✔ 4 steps✔ Cryogenic temperature✔ Stoichiometric oxidant / reductant✔ Use of protecting groups✔ Only 1 step
✔ No cryogenic temperature✔ No stoichiometric oxidant / reductant✔ No use of protecting groups
38

Substrate Scope of Sugars / Steroidnging
ChallesugareraRnrizatio
emoIshat bot xyroα-hyd ndsoC−H b

Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

39

Substrate Scope of Cis-Diol Mixtures

The reaction from mixtures of cis-diols to the only 1 desired trans-diequatorial diastereomer
is successful
Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

40Selectivity of α-hydroxy C-H BondBDE calculation→ C1~C3 is mostly same
Deuterium incorporation→ Only C1Both equatorial
and axial C−H bonds
undergo activation

Yu-An Zhang et al. J. Am. Chem. 2022, 144, 599−605.

41

Short Summary
A Change from Kinetic to Thermodynamic Control
Enables Trans-Selective Stereochemical Editing of Vicinal Diols

Yu-An Zhang et al. J. Am. Chem.
2022, 144, 599−605.

✔ Catalyst system of direct access from cis-vicinical to trans-diequatorial vicinial diols✔ Ph3SiSH promotes reversible HAT and thermodynamic control✔ Mild tools capable of tuning stereogenic centers
42

Contents
1. Introduction
2. Representative Researches
ー Epimerization via Kinetic Control
ー Epimerization via Thermodynamic Control
ー Epimerization via Transient Thermodynamic Control
3. Summary

43

Nobel Prize in Chemistry44

Epimerization via Transient Thermodynamic Control
Selective Isomerization via Transient Thermodynamic
Control: Dynamic Epimerization of trans to cis Diols

Christian, J. Oswood et al. J. Am. Chem.
2022, 144, 93−98.

✔ Boronic acid mediator✔ Selectivity✔ C2 site-selectivity✔ Epimerization of trans to cis Diols✔ Transient thermodynamic control
45

Problem Presentationn!!
oitcaeThis rChristian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

C1 stereocenter→ Many methods
Other stereocenters→ Limited

This research :New site-selectivity
46

Reaction Design of the Selective Epimerization

W10O324- : Radical generation by H atom abstraction
PhSH : Radical quenching by weak S-H bond
Equilibrium ratio :trans boronic ester ( ring strain ) > trans diol 1
cis boronic ester ( most stable ) < cis diol 3

cis boronic ester is predominant
Christian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

47

Optimization of the Selective EpimerizationtBes

S-S bonds homolyze with blue light
Disulfide → 2 × active thiophenol HAT catalyst→ More rate of W10O32 turnover→ (PhS)2 > PhSH(Bu4P)4W10O32 : Better soluble

Christian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

48

Optimization of the Selective EpimerizationtBes

S2 : (PhS)2, (Bu4P)4W10O32, MeB(OH)2, Light → Necessary
S3 : Boronic acid → trans - selectivity
Christian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

49

Substrate Scope of trans- 1,2-Diolsty )ng stabiliir
7all( smricStericSteeancrdhineancrdhineancrdniric hSteng
4 ri

Christian, J. Oswood et al.
J. Am. Chem. 2022, 144,93−98.

50

Substrate Scope of trans- 1,2-Diols

Acyclic diol :anti configuration is stable
Synthetic utility
20 :Human hormone
21 :diol- containing derivative of thepharmaceutical compound

Christian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

51

Substrate Scope of 1,3-Diols

Christian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

52

Substrate Scope of Glycosides
Site-selectivity ↑W10O32-4 abstract fromless sterically hindered
C−H sites
30 (Pharmaceuticals ) :β-configuration at C1↓
C3 epimerization (lesssterically hindered C−Hsites

Christian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

Kinetic selectivity !!
53

Short Summary
sed mop
Pro hanisc
Me

Selective Isomerization via Transient
Thermodynamic Control: Dynamic
Epimerization of trans to cis Diols✔ Epimerization of trans to cis Diols✔ Transient thermodynamic control✔ Methylboronic acid as a key chelating
additive✔ C2 site-selectivity

Christian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

54

Contents
1. Introduction
2. Representative Researches
ー Epimerization via Kinetic Control
ー Epimerization via Thermodynamic Control
ー Epimerization via Transient Thermodynamic Control
3. Summary55

Summary
Advantages of photoredox catalysis✔ No Prefunctionalization✔ No reagents✔ Mild conditions✔ Minimally Protecting groups✔ Selective reaction (site-, chemo-, diastereoselectivity)

Vision✔ Carbohydrate synthesis without protecting groups✔ New glycan synthesis

56Thank you for your attention !!

57

Appendix
58

The Integrated Photoreactor

Chi “Chip” Le et al. ACS Cent Sci. 2017, 3, 6, 647−653.

59

Optimization of Solvent

Christian, J. Oswood et al. J. Am. Chem. 2022, 144, 93−98.

60