L Le ev ve el l 2 2 C Ca as se e 2 26 6
2 2- -C Ch hl lo or ro o- -1 1, ,3 3, ,5 5- -t tr ri ia az zi in ne es s a as s A Ac ct ti iv va at ti in ng g G Gr ro ou up ps s o of f
C Ca ar rb bo ox xy yl li ic c A Ac ci id ds s i in n t th he e F Fo or rm ma at ti io on n o of f P Pe ep pt ti id de e
B Bo on nd ds s
K Ke ey y p po oi in nt t: : K Ki Ki Ki K Ki Ki K Kin i in in in i i e et ti ti ti t ti ti t tic ic ic ic i i i is is i is is is i iso ot to to to to to t top op op pe e e ef ff f ff ff f ff f f e
fe f fe f fe fe f fec ct ts ts t ts ts ts ts t t . .
C Co on nc ce er rt t t
r rte te t te te te te t ted d v ve ve v ve ve ve ve v ver rs rs r rs rs rs rs r r u us s s st te te t te te te te t tep ep ep pw wi wi wi w wi wi w wis is i is is
is i i e e m me ec ch ha an ni is is i is is is i i m m
N
N
N
Cl
R
R
N
R 1
R
1
R 1
R 2 COOH
R 3 NH 2
R 2 CONHR 3
?
2 2- -C Ch hl lo or ro o- -1 1, ,3 3, ,5 5- -t tr ri ia az zi in ne es s a as s A Ac ct ti iv va at ti in ng g G Gr ro ou up ps s o of f
C Ca ar rb bo ox xy yl li ic c A Ac ci id ds s i in n t th he e F Fo or rm ma at ti io on n o of f P Pe ep pt ti id de e B Bo on nd ds s
2-Chloro-4,6-disubstituted-1,3,5-triazines 1 have been widely used in the activation of carboxylic acids in the formation of peptide bonds. The reaction requires
the presence of a tertiary amine in the reaction medium and the participation of
quaternary triazinyl ammonium salts 2 as intermediates of the reaction has been
demonstrated. The role of these species in the activation of the carboxylic acid involves substitution of the amine-leaving group in 2 by the carboxylate ion, to afford triazine super active esters 3, the reagents employed in the peptide bond formation step (Scheme 26.1).
N
N
N
Cl
R
R
N
R 1
R 1
R 1
N
N
N
N
R
R
R 1
R 1
R 1
Cl
R 2 COOH
N
N
N
O
R
R
R 2
O
R 3 NH 2
R 2 CONHR 3
0 o C, Et 2 O
or benzene
1
2
3
Scheme 26.1
The common trend of intermediates 2 is to decompose rapidly at room temperature. Nevertheless, triazinyl ammonium derivative 4, obtained from 2-chloro-4,6dimethoxy-1,3,5-triazine 5 (CDMT) and N-methylmorpholine N N
6, resulted to be
sufficiently stable to be studied (Scheme 26.2).
2 2- -C Ch hl lo or ro o- -1 1, ,3 3, ,5 5- -t tr ri ia az zi in ne es s a as s A Ac ct ti iv va at ti in ng g G Gr ro ou up ps s o of f
C Ca ar rb bo ox xy yl li ic c A Ac ci id ds s i in n t th he e F Fo or rm ma at ti io on n o of f P Pe ep pt ti id de e
B Bo on nd ds s
K Ke ey y p po oi in nt t: : K Ki Ki Ki K Ki Ki K Kin i in in in i i e et ti ti ti t ti ti t tic ic ic ic i i i is is i is is is i iso ot to to to to to t top op op pe e e ef ff f ff ff f ff f f e
fe f fe f fe fe f fec ct ts ts t ts ts ts ts t t . .
C Co on nc ce er rt t t
r rte te t te te te te t ted d v ve ve v ve ve ve ve v ver rs rs r rs rs rs rs r r u us s s st te te t te te te te t tep ep ep pw wi wi wi w wi wi w wis is i is is
is i i e e m me ec ch ha an ni is is i is is is i i m m
N
N
N
Cl
R
R
N
R 1
R
1
R 1
R 2 COOH
R 3 NH 2
R 2 CONHR 3
?
2 2- -C Ch hl lo or ro o- -1 1, ,3 3, ,5 5- -t tr ri ia az zi in ne es s a as s A Ac ct ti iv va at ti in ng g G Gr ro ou up ps s o of f
C Ca ar rb bo ox xy yl li ic c A Ac ci id ds s i in n t th he e F Fo or rm ma at ti io on n o of f P Pe ep pt ti id de e B Bo on nd ds s
2-Chloro-4,6-disubstituted-1,3,5-triazines 1 have been widely used in the activation of carboxylic acids in the formation of peptide bonds. The reaction requires
the presence of a tertiary amine in the reaction medium and the participation of
quaternary triazinyl ammonium salts 2 as intermediates of the reaction has been
demonstrated. The role of these species in the activation of the carboxylic acid involves substitution of the amine-leaving group in 2 by the carboxylate ion, to afford triazine super active esters 3, the reagents employed in the peptide bond formation step (Scheme 26.1).
N
N
N
Cl
R
R
N
R 1
R 1
R 1
N
N
N
N
R
R
R 1
R 1
R 1
Cl
R 2 COOH
N
N
N
O
R
R
R 2
O
R 3 NH 2
R 2 CONHR 3
0 o C, Et 2 O
or benzene
1
2
3
Scheme 26.1
The common trend of intermediates 2 is to decompose rapidly at room temperature. Nevertheless, triazinyl ammonium derivative 4, obtained from 2-chloro-4,6dimethoxy-1,3,5-triazine 5 (CDMT) and N-methylmorpholine N N
6, resulted to be
sufficiently stable to be studied (Scheme 26.2).