Amino Acids and Peptides in Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 117

PG-AA 1 -OH (xs)

PG-AA 2 -OH (xs)

Deprotection

FG PG-AA 1 H-AA 1

PG-AA 2 AA 1

Anchoring
Washing

Washing Coupling reagent (xs)

Washing

Deprotection
Washing

Cleaving PG-AA 3 -OH (xs)

H-AA 2 AA 1

H-AA 3 AA 2 AA 1 X PG-AA 3 AA 2 AA 1

Washing

Coupling reagent (xs)
Washing

Tripeptide

= insoluble resin FG = Functional Group PG = protecting group

Scheme 6.1 Schematic synthesis of a tripeptide on solid-phase.

6.2 Mechanochemical Synthesis and Derivatization
of Amino Acids
Amino acids are interesting targets for solid-state reactions, due to their
intrinsic properties such as their zwitterionic nature and high melting
points. However, their reactivity and uses in mechanochemical processes
have not yet been fully explored and exploited.

6.2.1 Synthesis of Amino Acid Derivatives
Historically, the first example of their use in organic mechanochemistry dates
back to 2000, when L- cysteine 12-14 (1) (together with its hydrochloride mono-
hydrate derivative) and L- proline 13 (3) were tested for their solid-state reactivity
in the presence of stoichiometric quantities of paraformaldehyde (Scheme 6.2).
Solid paraformaldehyde (HCOH) n (6) polymer is a handling-friendly and
convenient alternative to access gaseous formaldehyde monomer (7) ( formed
in situ during mechanochemical milling by complete breakage of the weak
polymer chain bonds). Thus, the solid-state condensation in the ball-mill
with amino (or ammonium) group led to the corresponding methylene imi-
nium salts, 15 (R)-1 HCl and (S)-5 quantitatively. However, they are extremely
reactive and they can be easily trapped by nucleophiles, such as the thiol
group on L- cysteine 12 (1) - leading to L -thiazolidine (or its hydrochloride) 12
(R)-2 after removing in vacuo the water of the reaction - or water, 13 leading to
large-scale quantities (200 g) 16 of stable N/O-hemiacetal (S)-4. 16,17
(S)-Proline (3) also served for the waste free, large scale and quantitative
synthesis of azomethine ylide 11 14,16,18 using stoichiometric milling with
ninhydrin, via a three-step solid-state cascade reaction (substitution/elim-
ination/decarboxylation) without the need of purification, 17 outperforming
the synthesis in solution (82% yield) (Scheme 6.3).

6.2.2 Oxidation Reactions
As an alternative to a plethora of methods for the synthesis of disulfides in
solution, the aerobic solid-state oxidation of thiol to symmetrical organo-
disulfides under ball milling was achieved using L- cysteine (1) with iodine