Amino Acids and Peptides in Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 131

R 1

EDC·HCl(1.0 equiv), DMAP (2.0 equiv)
MeNO 2 (0.25

O R 1

O

L/mg)

BocHN μ

+

BocHN

OH

N
H

H 2 N

Ball-mill, 30 min, 30Hz

R 1 = OMe (87%), Cl (88%) Boc-Ala-OH R 1 = OMe, Cl

Scheme 6.12 EDC-mediated mechanosynthesis of amides.

This approach was applied to the coupling of various a-UNCAs with
a-aminoesters, furnishing numerous a,a-dipeptides with high yields
(Table 6.1). When starting from Boc-Phe-NCA with alanine or leucine esters
as the nucleophiles, high conversions and yields were obtained (Table 6.1,
entries 1-3). Under the same conditions, treatment of Boc-Phe-NCA with
phenylalanine methyl ester hydrochloride salt gave a low conversion of 58%,
which was supposed by the authors to be related with the physicochemical
state of the reaction mixture (Table 6.1, entry 4). Indeed, due to its insolubility
in water, Boc-Phe-Phe-OMe could be recovered as pure material by simple
trituration in aqueous media followed by filtration and drying. It was isolated
in 55% yield, which can be considered as very satisfying compared to the
relatively low conversion. Notably, the production of Boc-Phe-Phe-OMe under
these conditions fits particularly well the 12 principles of Green Chemistry 42
as it was produced without the use of any organic solvent from the reaction to
the product recovery. In addition, aminoesters can also be used as their
acetate salt as AcOH H-Gly-OtBu was transformed into Boc-Phe-Gly-OtBu
with high conversion and yield (Table 6.1, entry 5). Bulky electrophiles such
as Boc-Val-NCA can also lead eciently to the corresponding dipeptides with
yields ranging from 85% to 100% (Table 6.1, entries 6-10). The urethane
protecting group can also be switched to the widely used Fmoc group as
treating Fmoc-Val-NCA with various amino-esters furnished the corres-
ponding dipeptides with high conversions (Table 6.1, entries 11-15).
The same approach is applicable to the synthesis of tripeptides as reacting
the dipeptide HCl H-Ala-Gly-OMe with Boc-Val-NCA produced Boc-Val-Ala-
Gly-OMe in 89% yield (Scheme 6.14).

6.3.2 Scale-up of Peptide Synthesis
The scalability of this approach was also studied. While the reaction con-
ditions were optimized for a vibrating ball-mill, performing the synthesis of
a dipeptide on a large scale was realized on a planetary ball-mill by using a
250 mL jar equipped with an in-line temperature and pressure monitoring
system. The latter was filled with 3.85 g of Boc-Phe-NCA, 1.84 g of HCl H-
Ala-OMe and 1.7 g of NaHCO 3 and agitated for 2 h in the planetary ball-mill
at 350 rpm, furnishing 4.3 g of the dipeptide Boc-Phe-Ala-OMe in an excel-
lent yield of 94% (Scheme 6.15). 43
Measurement of the temperature indicated a slow but regular increase
from 26 to 33 1C during the first 60 min of the reaction (Figure 6.3). In
addition, the pressure increased during 50 min from atmospheric pressure