Amide bond formation and peptide coupling
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Amide bond formation and peptide coupling Mgr. Juraj Dobiaš KOCH PRIF UK Ch. A. G. N., Montalbetti; V., Falque Tetrahedron 2005, 61, 10827–10852.
description
Amide bond formation and peptide coupling. Mgr. Juraj Dobia š KOCH PRIF UK. Ch. A. G. N . , Montalbetti ; V ., Falque Tetrahedron 2005 , 61 , 10827–10852 . Comparison to esterification. Activation methods. non-classical conditions : - microwave iradiation - enzymatic catalysis - PowerPoint PPT Presentation
Transcript of Amide bond formation and peptide coupling
Amide bond formation and peptide coupling
Mgr. Juraj DobiašKOCH PRIF UK
Ch. A. G. N., Montalbetti; V., Falque Tetrahedron 2005, 61, 10827–10852.
Comparison to esterification
R OH
OHO
R'R O
OR'
H+,
R OH
OH2N
R'R O
O
H3NR' R N
H
OR'
high temperatures - need acid activationmore basic
Activation methods
R LG
O
electrophilicity increase
better leaving group
R X
O
X = F, Cl, Bracid halides
R N3
O
acid azides
R
O
N N
acid imidazoles
R
O
O
O
R R
O
O
O
R'acid anhydrides
R O
OR'
OR'
good leaving group
acid esters
non-classical conditions:
- microwave iradiation- enzymatic catalysis- solid phase synthesis
Acid chloridesPreparation:
Coupling:
R
O
ClH2N
R'R N
H
OR' HCl
- amine protonization - base needed- moisture sensitive - too reactive
R
O
OH R
O
ClSO2 HCl
SOCl2
R
O
OH R
O
ClCO2 HCl
(COCl)2CO
cat. DMF
R
O
OH R
O
Cl
N NN ClCl
Cl
0.33 mol ekv
N N
N ClCl
Cl
problems with acid-labile protecting groups
OR
O
N N
N Cl
Cl
O
R O
Cl N N
N Cl
Cl
HO
Acid fluoridesPreparation:
Advantages over acid chlorides in coupling: - no base needed- less water sensitive- more electrophilic- less steric hindrance
R
O
OH R
O
F
N NN FF
F
R
O
OH R
O
F
N
NF
PF6
N
NO
stable urea formation
similar to cyanouric chloride
increased reactivity - izolated ion pair
Acid azidesPreparation:
Coupling:
R O
O NH2-NH2
R NH
ONH2
HNO2
R N3
O
R OH
O
R
O
R N3
OPPhOOPh
ON3
POPh
OOPh
N3
PPhOOPh
OOH
R N3
O NH2-R'
R NH
O
-N2R'
Side reaction: Curtius rearangement
R
O
NN
N -N2
R
O
Nnitrene
R
NC
ONu
mess
Acylimidazoles
N
O
N NN
R OH
O
N
O
N NHN
R O
O
O
N NOR
O
NHN
R N
O
N
CDI
Preparation:
Coupling:
- compatible also with amine salts – no additional base needed- one-pot synthesis
R N
O
NNH2-R'
R NH
OR'
NHN
free base generated as waste
N
O
N NN
2 TfO
more reactive coupling agent
Symetrical acid anhydrides
R OH
O CN
N
CHN
O N
O
R
R OH
O
R
O
O
O
R
NH
O
NH
DCC
Preparation:
Coupling:
R
O
O
O
R
H2NR'
R NH
OR'
R OH
O
- no base required- few commerialy acid anhydrides available- one equivalent of acid is wasted
Mixed acid anhydrides- cheap second carboxylic moiety – reduced waste but selectivity problem, solutions:Steric effect:
Electronic effect:
Other synthetic approach:
R O
O
OEt
O
Cl OEt
O
R OH
O
stabilized by resonance
R O
O O
bulky groupCl
O
R OH
O
R OH
ON O
EtO O
Et
R O
ON O
HEtO O
Et
N
EtO Oaromatization
R O
OR O
O
OEt
O
no HClN
good leaving group
Broadened concept of mixed anhydrides
ethoxyacetylene:
R OH
O
OEt
HR O
O
OEtmasked anhydride
H2NR' R N
H
OR'
OH
O
carbodiimines:
- HOBt overcomes problems with N-acylureas
R OH
O CN
N
CN
O NH
O
R
N
NH
R
O
O stable
slow
HOBt
fast R OBt
O H2NR'
R NH
OR'
HOBt
NN
N
HODIC
N C N N HCl
EDC - resulting in water soluble urea
Active esters
R
O
OR''
R'NH2
R
O
NR'
R''OH:
NO2HO
PNP
N
NN
N
HO
HOAt
NN
N
HO
HOBt
N
O
O
HO
HOSu
anion stabilization = electron acceptors, aromatic konjungation
NNN
N
O
RO N R'
H
H
aditional chelatation
examples:
- some available activated aminoacids- often not stable = in situ formation from other high-energy acid derivatives
Active esters – one-pot solutionsphosphonium salts:
R
O
OH
POBt
NNN
PF6
R
O
OPN
N
N
OBt
R
O
OBt
PO
NNN
uronium salts:
R
O
OH
R
O
OAt
NNN
N
ON
N PF6
HATU
R
O
O
N
N
NNN
N
O
N
O
N
Summarycommon mechanism of activation:- suppressing acidic properties- first step is nucleophilic attack of carboxylate- oxygen is taken to form low energy side productdesired reaction realization:- one-pot synthesis- easy separable, non-toxic and non-corrosive side products- water tolerant- no additional base needed- room temperature, high yields
