Chemistry Reference
In-Depth Information
analysis of the resulting urea adducts. If this method is used to generate iso-
cyanates of peptides, then e
cient stirring is necessary to prevent epimerization of
the peptide isocyanates [315].
Typical procedure. Methyl (S)-2-isocyanato-3-phenylpropanoate (optical isomer of 452)
[315]:
A 250-mL, three-necked, round-bottomed flask was equipped with a me-
chanical stirrer and charged with dichloromethane (100 mL), saturated aqueous
sodium hydrogen carbonate solution (100 mL), and l-phenylalanine methyl ester
hydrochloride (5.50 g, 25.5 mmol). The biphasic mixture was cooled in an ice bath
and stirred mechanically while triphosgene (2.52 g, 8.42 mmol) was added in a
single portion. The reaction mixture was stirred in the ice bath for 15 min and
then poured into a 250-mL separatory funnel. The organic layer was collected, and
the aqueous layer was extracted with dichloromethane (3
15 mL). The combined
organic layers were dried (MgSO
4
), vacuum filtered, and concentrated at reduced
pressure in a rotary evaporator to leave a colorless oil. This oil was purified by
kugelrohr distillation (130
C, 0.05 mmHg) to afford 5.15 g (98%) of methyl (5)-2-
isocyanato-3-phenylpropanoate as a colorless oil. The optical purity of the product
was determined to be
99.5% by trapping with (S)-1-phenylethylamine and
1
H
NMR analysis of the resulting urea adduct, as described in reference [311].
Peptide isocyanates 454 have been prepared using triphosgene (0.7 mmol/mmol
peptide hydrochloride) 453 under milder reaction conditions, so as to minimize
the formation of hydantoins 455 and other side products [313].
>
R
2
R
2
O
O
(CCl
3
O)
2
CO
Cl
H
3
N
O
C
N
H
H
CH
2
Cl
2
, 0°C, 10 min
R
1
R
1
O
O
453
454
R
1
= PhCH
2
, R
2
=
i
-Bu Phenylalanylleucine methyl ester hydrochloride, Yield 91%
R
1
=
i
-Pr, R
2
= Me
Valylalanine methyl ester hydrochloride, Yield 67 %
O
Me
i-Pr
OMe
N
HN
O
O
455
Typical procedure. Valylalanine methyl ester isocyanate [313]: Reaction of valylalanine
methyl ester hydrochloride (123 mg, 0.515 mmol) with triphosgene (a solution of
112 mg in 1 mL of dichloromethane, 0.38 mmol) yielded 112 mg (95%) of the
crude isocyanate 454 as a colorless oily solid.
1
H NMR analysis of the product
revealed the presence of 8% of hydantoin 455 and 15% of an additional impurity.
For the preparation of many other peptide isocyanates, phosgene, either neat or
in toluene solution, rather than triphosgene was preferred.
