A. Alexakis et al.
With these good results at hand, we decided to test our
catalysts in the addition of aldehydes to vinyl sulfone,[13] re-
action recently developed in our group.[14] This reaction is
really interesting due to the versatility of the sulfonyl group
in organic chemistry.[15] Furthermore, moderate enantiocon-
trol had been achieved for the formation of compound 9d
(Table 3). 71% yield and 75% ee were obtained using
25 mol% of bipyrrolidine catalyst iPBP and only 55% ee
using bimorpholine derivatives.[58]
anone 10 with nitrostyrene 6, a classical model commonly
used (Table 4). Surprisingly, catalyst 4b, the less efficient
catalyst using aldehydes lead to a total conversion after 4 d
(entry 2). Furthermore this catalyst, the diastereoisomer of
the best catalyst for aldehyde, also gave the best results in
terms of enantioselectivity (ee 80%, entry 2). Catalyst 4a
and 4c gave much lower reactivity and a dramatic loss in
enantioselectivity (entries 1 and 3). Finally, the more hin-
dered catalysts 4d–f, highly reactive for aldehyde did not
catalyze the reaction (entries 4, 5 and 6).
Table 3. Conjugate addition of aldehydes 5c–i to vinylsulfone 8 catalyzed
by 4a.
Table 4. Catalyst screening for the addition of cyclohexanone 10 to nitro-
styrene 6 catalyzed by 4a.[a]
Entry R1, R2
Aldehyde equivalent, Reactions
Yield
[%][a]
ee
mol% 4a
conditions
[%][b]
Entry Cat. t [d] Conv (yield)[b] [%] dr (syn/anti)[c] ee (syn) [%][d]
1
2
3
4
5
6
7
nPr, H
(5c)
iPr, H
(5d)
iPr, H
(5d)
tBu, H
(5 f)
10 equiv, 10 mol%
À608C, 2h
87
90
86
96
84
74
85
85
75
77
1
2
3
4
4a
4b
4c
4d
4e
4 f
4b
4
4
4
4
4
5
3
60
100 (73)
85
0
13
0
100 (81)
95:5
90:10
95:5
–
>95:5
–
61
80
50
–
25
–
10 equiv, 10 mol%
2equiv, 5 mol%
2equiv, 10 mol%
2equiv, 10 mol%
À608C, 2h
À608C, 3 h
À608C, 4 h
À608C, 2h
À608C, 3 h
RT, 4 h
5
6
7[e]
92:8
87
allyl, H
(5g)
[a] Reactions were performed using 6 equivalents of ketone. [b] Conver-
sions were determined by 1H NMR of the crude product, isolated yields
are shown in brackets. [c] dr determined by 1H NMR of the crude prod-
uct. [d] ee determined by super fluid chromatography. [e] Reaction per-
formed in cyclohexane.
cHex, H 10 equiv, 10 mol%
(5h)
Ph, Me
(5i)
8291
84
10 equiv, 10 mol%
16
[a] Yield of isolated product after column chromatography on florisil.
[b] ee values determined by super fluid chromatography.
These results demonstrate how a slight modification in
the catalyst structure can totally change its properties. This
difference of reactivity relies on the different proposed tran-
sition state between ketones and aldehydes, where the ge-
ometry of the enamine plays a crucial role.[16] Finally a short
solvent and co-catalyst screening showed that the enantiose-
lectivity could be increased to 87% ee by using cyclohexane
instead of chloroform (entry 7).
In conclusion, a conceptually new family of chiral aminal–
pyrrolidine derivatives has been synthesized. From their
evaluation in diverse Michael additions, this family of cata-
lysts is highly modular since the catalytic properties toward
different substrates can easily be tuned by varying the sub-
stituents on the aminals. Finally, excellent results (ee up to
91%) have been obtained in the addition of aldehydes to
vinyl sulfones. This is to date the best published results on
such additions and represents a promising result.
Reactions performed using linear aldehydes gave excel-
lent results. Impressive reactivity (yield around 90%) and
good enantioselectivities were obtained with only 10 mol%
of catalyst 4a. More substituted aldehydes 5d and 5h gave
the best enantioselectivities (ee up to 91%, entries 1 and 6)
while less hindered ones gave slightly lower enantioselectivi-
ties (entries 1, 4 and 5). The more bulky 3,3-dimethylbutyr-
aldehyde 5 f gave only 75% ee probably due to a too strong
interaction between the tert-butyl group and the catalyst.
Impressively, only two equivalents of aldehydes could be
used with aldehydes 5d, 5 f and 5h (entries 3, 4 and 5) and
5 mol% was used with aldehyde 5d without loosing reactivi-
ty (entry 3). Unfortunately, poor enantiocontrol was ob-
served in the formation of the quaternary center with 5i
(entry 7). These results represent an impressive increase in
both reactivity and enantioselectivity compared with iPBP.
This good stereoselectivity can be explained by the same
transition state as proposed with iPBP. A strong interaction
of the sulfonyl group with the aminal associated with a good
control of the geometry of the enamine in the transition
state lead to this higher stereocontrol.
Investigations are currently under progress in our labora-
tory in order to improve those catalysts and toward a better
understanding of the influence of the various aminal groups
on the reactivity other different organocatalyzed reactions.
Keywords: asymmetric
catalysis
·
diversity-oriented
In order to study the reactivity of our catalysts with ke-
tones, their efficiency was tested in the reaction of cyclohex-
synthesis · enamines · Michael addition · organocatalysis
7506
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7504 – 7507