Boron-catalyzed Amide Formation

2018/03/02
B4 Koki Sasamoto1

Contents
1. Introduction
2. Boron-catalyzed amide condensation
1-1. Example of amide coupling using boronic acid
1-2. Amide coupling under mild conditions

1-3. Application to peptide synthesis
3. Reaction mechanism analysis

4. Summary2

Introduction
Importance of amide bond
Example of amide-containing drugs

25%of drugs
contain amide

16%

is amide formation
in medchem

A. K. Ghose et al. J. Comb. Chem. 1999, 1, 55.; S. D. Roughley et al. J. Med. Chem. 2011, 54, 3451.

3

IntroductionClassical Routepoor atom economy
typical coupling reagents and additives

4

Introduction
Nonclassical routes

5

Stoichiometric Amidation
Example of amidation using stoichiometric boron reagent

Inactive species

Not proceed catalytically

P. Nelson et al. J. Chem. Soc., 1965, 5142.

6

Catalytic Amidation

High yield

Low
Racemization
H. Yamamoto et al. J. Org. Chem. 1996, 61, 4196.

7

Catalytic Amidation
Plausible reaction mechanism

activatedaminolysis
H. Yamamoto et al. J. Org. Chem. 1996, 61, 4196.

8

Direct polycondensation

entry
12
3
4cat. 1(mol %)1010100solvent

yield (%)

MnMw

o -xylene/m -cresolo- xylene
toluene/m -cresol
toluene/m -cresol

858983046902680-22400
8330-M n the number-average molecular weight, Mw the weight-average molecular weight

H. Yamamoto et al. Macromolecules, 2000, 33, 3511.

9

Catalytic Amidation
Amidation for sterically demanding carboxylic acid
entry
12
3

catalyst
4a4b1

yield (%)
62
52
32

4B(OH)32

H. Yamamoto et al. Org. Lett., 2006, 8, 1431.

10Solid Phase Amidationrun
12
3time (h)162021yield (%)
95
95
97

B. Wang et al. Synthesis, 2001, 11, 1611.

11

Solid Phase Amidation
Amidation using fluorous bi-phasic catalyst

runconversion (%)

1>99

2>99

3>99

4>99

5>99

H. Yamamoto et al. Synlett, 2001, 9, 1371.

12

Solid Phase Amidation
MCF-supported boronic acids

Use of 8a
Yield (%)

191

294

3>98

4>98

5>98

6>98

MCF (mesocellular siliceous form)・ large and interconnected pores・ controlled micro-environments
L. Gu et al. Chem. Commun., 2014, 50, 7017.

13

Solid Phase AmidationDOWEX-bound boronic acid

Run Yield (%)
12345>99>99>99>99>99

RecoveryRecovery
Run Yield (%)
rate (%)
rate (%)>956>99>95>957>99>95>958>99>95>95
9>99>95>95
10>99>95
K. Ishihara et al. Asian J. Org. Chem., 2017, 6, 1191.

14

Solid Phase Amidation
Boronic acid-DMAPO or DMAP complex

entry
12catalyst
7a7a・DMAPyield (%)<592

Recovery rate (%)
95

37a・DMAPO

9985K. Ishihara et al. Asian J. Org. Chem. 2017, 6, 1191.

15

Amidation at Room TemperatureD. G. Hall et al. Angew. Chem. Int. Ed., 2008, 47, 2876.

16

Amidation at Room Temperature
Electron-donating group effects

D. G. Hall et al. J. Org. Chem., 2012, 77, 8386.

17

Amidation at Room Temperature
Plausible reaction mechanism
Decreased freedom

D. G. Hall et al. J. Org. Chem., 2012, 77, 8386.

18

Amidation at Room Temperature
Commercially available boronic acid

entry

Ar

yield (%)

1c2-I, 5-MeOC6H399

1g
1h2-furanyl
2-thiophenyl9992
synthesizedwith Ag2SO4

commercially available

E. K. W. Tam and A. Chen et al. Eur. J. Org. Chem., 2015, 1100.

19

Dipeptide synthesis
Dual boronic acid catalysts

Entry
1234

Carboxylic acid Ammonium salt
1115a
1115a1115b
1115bcat7555+4cat. Loading (X mol%) Yield (%)
25
13100
58100
<250 + 50
55

A. Whiting et al., Eur. J. Org. Chem. 2013, 5692–5700.

20

Dipeptide synthesis
Failure of coupling with amino acid

Complex was formed?

D. G. Hall et al., Green Chem, 2015, 17, 4016 .

21

Dipeptide synthesis
Boronic acid containing thiophene
Plausible mechanism
assist formation of A

break BJ. Blanchet et al., J. Org. Chem, 2015, 80, 4532.

22

Dipeptide synthesis
Ortho-substituted borinic acid

Selected Example of Peptide Synthesis
EntryAmino acid 12

Amino ester 10 Yields (%)

1

Boc-Phe-OH

H2N-Val-OMe

51

2

Boc-Phe-OH

H2N-Phe-OMe

61

3Z-Pro-OH

H2N-Phe-OMe

60

4Z-Pro-OH

H2N-Val-OBn59

No detective epimerization
J. Blanchet et al., Chem. Commun., 2015, 51, 16084.

23

Dipeptide synthesis
Plausible mechanism

J. Blanchet et al., Chem. Commun., 2015, 51, 16084.

24

Dipeptide synthesis
DATB (B3NO2) system

M. Shibasaki and N. Kumagai et al., Nat. Chem., 2017, 9, 571.

25

Dipeptide synthesis
Dipeptide coupling using DATB

M. Shibasaki and N. Kumagai et al., Nat. Chem., 2017, 9, 571.

26

Olygopeptide synthesis
Olygopeptide OGP(10-14) synthesis by using DATB

M. Shibasaki, N. Kumagai et al., Org. Lett. 2018, 20, 612.

27

Summary of Section 2
・ Boronic acid catalyzed amide condensation.

Hall first developed reactions at room temperature.

・ Recently, useful boronic acid catalysts developed for peptide synthesis.

・ Catalysts such as DATB, which makes the reactions proceed with a newmechanism attracted attentions.
28

Catalytic Amidation
Plausible reaction mechanism

1H NMR, IRH. Yamamoto et al. J. Org. Chem. 1996, 61, 4196.

29

Reaction mechanism analysis
Possibility of involving bis(acyloxy)boronate
ESI-MS

A. Whiting et al., Adv. Synth. Catal., 2006, 348, 813.

30

Reaction mechanism analysis
Overall mechanism of catalytic cycle

O-H···X bondrate-determining stepT. Marcelli, Angew. Chem. Int. Ed., 2010, 49, 6840.

31

Reaction mechanism analysis
Overrall mechanism of catalytic cycle

Marcelli

rate-determining step
Y. Fu et al., Org. Biomol. Chem., 2013, 49, 6840.

32

Reaction mechanism analysis
Performance of the ortho-halo-phenylboronic acids
no O-H···X interaction

stabilize TS

Key Transition State
Y. Fu et al., Org. Biomol. Chem., 2013, 49, 6840.

33

Reaction mechanism analysis
Boronic acids with amines

ESI, X-ray

X-ray

A. Whiting et al., Chem. Sci., 2018, 9, 1058.

34

Reaction mechanism analysis
Boronic acids with carboxylic acids

NMR, X-ray

A. Whiting et al., Chem. Sci., 2018, 9, 1058.

35

Reaction mechanism analysis
Boronic acid / carboxylic acid / amine systemdepend on order of addition

A. Whiting et al., Chem. Sci., 2018, 9, 1058.

36

Reaction mechanism analysis
Boronic acid / carboxylic acid / amine system

A. Whiting et al., Chem. Sci., 2018, 9, 1058.

37

Summary of Section 3・ The reaction intermediates of amide coupling by boronic acids havebeen thought to be mono(acyloxy)boronate or bis(acyloxy)boronate.
・ If dimers of boronic acid such as 11 and 12 are intermediates, boronic

acids which are easy to dimerize can be potential candidates.

38

Summary
・ Peptide synthesis achieved in recent years using boronic acids
derivatives.

・ Further mechanistic insights will provide valuable assistance for thedesign of more active boronic acids.

39