Asymmetric Organocatalytic Reactions under Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 84

O O O OH

3, 4
HSBM
4h, -20°C

+

H

R 3

R 3

R 1 R 2 R 1 R 2

1.0 equiv

1.1 equiv

O

Yield 62 - 94 %
dr 31:69 - 91:9
ee 55 - 95 %

H OMe

H

O

H O OMe

O H NH O

H 2 O

O

H

Cat. 3
(7 mol%)

N
H
O

N

H

NO 2

Yield 62 - 90 %
dr 40:60 - 98:2
ee 54 - 98 %

H 2 O

NH

O

OMe

H

PhCO 2 H (5 mol%)
H 2 O (1.1 equiv)

NH O

Cat. 4
(3 mol%)

Scheme 4.3 Asymmetric aldol reaction organocatalyzed by (S,S)-dipeptides 3 and 4
in a ball-mill, with benzoic acid and water as additives. 20,21

product in 62-94% yield, with high diastereoselectivity (up to 91 : 9) and
enantioselectivity ranging from 55% to 95% ee. With the use of additives
such as benzoic acid and water, it was possible to improve by more than
10 percentage units the enantioselectivity. Furthermore, the presence of
water molecules apparently induces the formation of chiral micelles in the
reaction medium, which results in a more rigid transition state and higher
stereoselectivities. Finally, the Brønsted acid effect may be explained in
terms of the protonated organocatalyst making the amide NH more acidic,
and e cient anchoring of the aldehyde substrate in the transition state
(Scheme 4.3). 20,21
Taking into consideration a possible stabilization of the transition state
by hydrogen bonding and p-p stacking interactions, 22 it was anticipated that
the presence of thioamide segments instead of amide segments in the
organocatalyst would give rise to more acidic N-H protons and therefore a
stronger hydrogen-bonding interaction between the organocatalyst and
the substrate, i.e., a more rigid transition state. 23 In the event, peptide
thioamides 5 and 6 led to the formation of aldol products with increased
diastereoselectivity, up to 98 : 2 anti : syn ratio. Nevertheless, the observed
enantioselectivity was essentially unchanged.
Thioamides 5 and 6 were also examined in aldol reactions with isatins as
substrates. 24 The products of this reaction are of significant interest in view
of

the biological activity exhibited by tertiary alcohols derived from