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O
O
BocN
BocHN
OMe
O
H
NaHCO
3
(1.5 equiv)
OMe
+
CO
2
+
NaCl
HCl·
H
2
N
O
Planetary ball-mill
250 mL jar
350 rpm, 2 h
O
O
Boc-Phe-NCA
3.85 g
HCl·H-Ala-OMe
1.84 g
Boc-Phe-Ala-OMe
4.3 g
94% yield
Scheme 6.15
Synthesis of Boc-Phe-Ala-OMe on a 4.3 g scale.
3.5
80
3.0
70
Opening of the jar
2.5
60
Pressure
2.0
50
1.5
40
1.0
30
0.5
Temperature
0.0
20
0 0 0 0 0 0 0 0 0 0 0 0 0
Time (min)
Figure 6.3 Temperature and pressure measurement during the synthesis of Boc-
Phe-Ala-OMe at the 4.3 g scale.
coworkers. While known to present slightly lower reactivity in solution than
a-UNCAs, b-UNCAs could be easily transformed into a,b- and b,b-dipeptides,
showing the high versatility and capacity of the ball-milling approach.
Indeed, treating Boc-b-Ala-NCA with a-aminoester hydrochlorides such as
glycine, alanine, leucine, or phenylalanine methyl ester hydrochlorides in
the presence of NaHCO
3
in a vibrating ball-mill during 2 h furnished the
corresponding a,b-dipeptides with yields ranging from 83% to 88% yield
(Scheme 6.17). Utilizing bulkier nucleophiles such as valine or isoleucine
methyl ester hydrochlorides did not hamper the reaction as Boc-b-Ala-Val-
OMe and Boc-b-Ala-Ile-OMe were isolated in 82% and 80% respectively.
Starting from Boc-b-Ala-NCA also allowed the synthesis of a precursor of the
natural
L-
carnosine (H-b-Ala-His-OH), a mammalian dipeptide presenting
biological activity.
44
Indeed, when 2HCl
H-His-OMe was reacted in a ball-
mill with Boc-b-Ala-NCA, Boc-b-Ala-His-OMe was produced in 91% yield.
Finally, substituted b-UNCA could also be used as substrates under the
above conditions as Boc-protected (S)-b
3
-carboxyhomoglycine N-carboxy
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