Chemistry Reference
In-Depth Information
Tab. 4.39.
N-Carboxy-a-amino acid anhydrides prepared with triphosgene [894].
NCA 1212
Yield
(%)
NCA 1212
Yield
(%)
l-valine
75
l-phenylalanine
75
O
g
-benzyl-l-glutamic acid
O-benzyl-l-tyrosine
65
72
O-benzyl-l-threonine
66
glycine
83
N-Boc-l-lysine
73
times in excess of 5 h lead to discoloration, which complicates NCA purification.
The NCA was recrystallized from THF/hexane until a constant melting point was
reached.
A facile one-pot method for the formation of NCAs at room temperature em-
ploying triphosgene has been reported [894]. In a typical reaction, the N-Boc-
amino acid 1210 and triphosgene are stirred in ethyl acetate at room temperature.
Addition of triethylamine to the solution is accompanied by an instantaneous pre-
cipitation of triethylamine hydrochloride to give the intermediate 1211. Thereafter,
the progress of the reaction can be readily followed by measuring CO
2
evolution
with a manometer connected to the flask. The requisite amount of CO
2
forms
within 2-20 h depending on the nature of the amino acid. Ethyl acetate is used as
solvent since triethylamine
HCl is marginally soluble in this solvent at room tem-
perature. Triethylamine
95% yield by filtration of the sus-
pension obtained. The NCAs listed in Table 4.39 were each prepared by this
procedure.
HCl is recovered in
>
Cl
O
Cl
CO
2
O
OR
OO
O
(CCl
3
O)
2
CO
O
OH
H
N
O
H
O
Et
3
N
O
H
R
O
R
1210
1211
1212
The chemical conversion of N-Boc-amino acids to NCAs is invariably quantitative,
as judged by the degree of CO
2
evolution. The losses in the overall yields are a
consequence of the low solubility of NCAs in most organic solvents, including
ethyl acetate. At times, some NCAs contain a trace of triethylamine hydrochloride
as an impurity (easily detected and quantified by
1
H NMR). The last traces of tri-
ethylamine hydrochloride can be precipitated from the solution by chilling the re-
action mixture in ice/water for 5-10 min prior to filtration. However, this proce-
dure results in somewhat lower yields of the desired NCA. If the potential
contamination of the NCA by traces of triethylamine
HCl can be tolerated, the use
of a larger volume of solvent in the reaction improves the recovery of NCAs.
