Asymmetric Organocatalytic Reactions under Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 82

reduction of heating time, which implies energy savings, and (4) the
frequent observation of reduced reaction times.
In this context, an important goal in this area is the application of HSBM
in asymmetric organocatalysis, 9 i.e., the aim here is to make organocatalysis
even more sustainable. 10 Indeed, the high concentration of reactants
achieved under solvent-free conditions, the increased mixing eciency, and
lower activation energies are all factors that improve the eciency of the
reaction by decreasing the reaction time and simultaneously improving the
enantioselectivity of the reaction.
4.2 Asymmetric Organocatalysis and the Ball Milling
Technique
4.2.1 Asymmetric Aldol Reaction
Since the emergence of the organocatalysis, aldol reactions have been widely
used as test reaction. 9 One reason for the great interest in the study of
asymmetric aldol reactions lies in the feasibility of enantioselective prepar-
ation of b-hydroxyketones through C-C bond formation, with the concomi-
tant generation of one or more stereogenic centers. Indeed, a great diversity
of molecules presenting the b-hydroxycarbonyl moiety are present in
bioactive molecules that are of great importance in the pharmaceutical
industry. 11,12
Aldol reactions are carried out employing various strategies, including
metal catalysis, 13 enzymatic catalysis, 14 and more recently by means of small
organic molecules in the absence of metals - that is by means of organocata-
lysts. 9 In this regard, the success of (S)-proline (1) as organocatalyst in
asymmetric intra- or intermolecular aldol reactions 15 has led to the study
of the reaction under solvent-free conditions. 16 In particular, Bolm and co-
workers reported the first successful asymmetric aldol reaction organocata-
lyzed by (S)-proline (1) under HSBM, demonstrating the advantages of this
technique when compared with other reaction conditions. 17 With this study,
Bolm et al. made a revolutionary contribution to organocatalysis: the reaction
was performed under solvent-free reaction conditions. Various aldehydes and
ketones were evaluated and the anticipated aldol products were obtained in
good to excellent yields (42-99%), high diastereoselectivity (up to 99 : 1) and
moderate to excellent enantiomeric excess (45-99% ee) (Scheme 4.1). 17,18
Today, various chiral organocatalysts are used to carry out asymmetric
aldol reactions. Indeed, the most successful organocatalysts in solution
conditions have been evaluated under solvent-free conditions employing the
HSBM technique.
While solvents help homogenize reaction parameters such as tempera-
ture, the use of HSBM presents important advantages such as the fact
that reagents are generally used in stoichiometric amounts, reaction times
are short compared with conventional solution reactions with traditional
stirring, and the reactions are much cleaner. It is worth mentioning that