Amino Acids and Peptides in Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 133

100%

90%

80%

70%

60%

30Hz
R 2 = 0,97685
y = 0,0631x - 0,0388
20 Hz
R 2 = 0,97258
y = 0,033x + 0,0167
10 Hz
R 2 = 0,9853
y = 0,0165x - 0,0102

50%

40%

30%

20%

10%

0%

0 20 45 70 95 120 145 170 195 220 245 270 295

Time (min)

Figure 6.2 Conversion of Boc-Phe-NCA into Boc-Phe-Ala-OMe as a function of time.

to a plateau at 3 bar that lasted 15 min, until the reactor was opened
(t ¼ 60 min). This pressure increase is in complete accordance with the
formation of CO 2 that occurs during the reaction. Opening the jar to follow
completion of the reaction resulted in a pressure drop to atmospheric
pressure. An additional hour of agitation at 350 rpm resulted in an
insignificant rise in pressure and temperature indicating the end of the
reaction, which could be confirmed by 1 H NMR analysis of the crude.
This approach was then applied to the synthesis of the dipeptide aspar-
tame, a nutritive sweetener that is produced at the multi-ton scale every
year. After preparation of Boc-Asp(OtBu)-NCA, the latter was treated with
phenylalanine methyl ester hydrochloride during 1 h milling at 30 Hz
to produce Boc-Asp(OtBu)-Phe-OMe with an excellent yield of 97%
(Scheme 6.16). Boc and tBu protecting groups were then removed by gaseous
HCl treatment in the absence of any solvent to furnish aspartame hydro-
chloride in quantitative yield. Notably, these two first reactions are per-
formed with a close to quantitative global yield while producing either
volatile or water-soluble side-products (CO 2 , isobutylene and NaCl). Finally,
aspartame hydrochloride was solubilized in water and neutralization to the
isoelectric point (pH 5.0) with an aqueous solution of Na 2 CO 3 furnished
aspartame as a white powder in 84% yield.

6.3.3 Synthesis of a,b- and b,b-Dipeptides
By using a very similar method, Juaristi and coworkers published a year later
the solvent-free, ball-mill mediated synthesis of a,b- and b,b-dipeptides. 44
Indeed, b-UNCAs were used in place of the a-UNCAs utilized by Lamaty and