Enantioselective organocatalytic conjugate addition of aldehydes to vinyl sulfones and vinyl phosphonates as challenging michael acceptors

Article abstract of DOI:10.1002/chem.200801892

Chiral amines with a pyrrolidine framework catalyze the enantioselective conjugate addition of a broad range of aldehydes to various vinyl sulfones and vinyl phosphonates in high yields and with enantioselectivities up to >99% ee. This novel process provides synthetically useful chiral γ-gem-sulfonyl or phosphonyl aldehydes which can be widely functionalized with retention of the enantiomeric excess. Mechanistic insights including DFT calculations are explored in detail.

Full text of DOI:10.1002/chem.200801892

DOI: 10.1002/chem.200801892
Enantioselective Organocatalytic Conjugate Addition of Aldehydes to Vinyl
Sulfones and Vinyl Phosphonates as Challenging Michael Acceptors
Sarah Sulzer-Mossꢀ,[a] Alexandre Alexakis,*[a] Jiri Mareda,[a] Guillaume Bollot,[a]
Gerald Bernardinelli,[b] and Yaroslav Filinchuk[c]
Abstract: Chiral amines with a pyrrolidine framework catalyze the enantioselec-
tive conjugate addition of a broad range of aldehydes to various vinyl sulfones and
Keywords: aldehydes
asymmetric synthesis
Michael addition · organocatalysis
·
amines
·
·
vinyl phosphonates in high yields and with enantioselectivities up to >99% ee.
This novel process provides synthetically useful chiral g-gem-sulfonyl or phosphon-
yl aldehydes which can be widely functionalized with retention of the enantiomeric
excess. Mechanistic insights including DFT calculations are explored in detail.
Introduction
bonyl,[7f,9] and ester,[7i,10] groups, have been successfully ex-
ploited in aminocatalysis. Nevertheless, expanding the scope
of Michael acceptors still remains an important challenge.
In this context, after developing efficient 2,2’-bipyrrolidine
and 3,3’-bimorpholine derivatives for ACA of aldehydes and
ketones to nitroolefins,[8] we focused on less extensively ex-
plored vinyl sulfones and vinyl phosphonates due to their
easy access from commercial sources and their potential for
offering highly tunable chiral intermediates. In the past, con-
siderable efforts have been devoted to the development of
ACA to vinyl sulfones.[11,12] Although the reaction of pre-
formed enamines with vinyl sulfones has been known for
some time,[13] only sporadic examples lead to enantioen-
riched adducts,[14] and the use of organocatalysis in this area
remains elusive.[15] Moreover, despite the great interest in
vinyl phosphonates,[16] few reports describe the formation of
chiral g-phosphonate carbonyl compounds through ACA.[17]
With a view to generalizing the scope of pyrrolidine-based
catalysis, we have recently communicated the first enantio-
selective organocatalytic conjugate addition of aldehydes to
vinyl sulfones[18] and to vinyl phosphonates[19] (Scheme 1).
Herein, we describe improved conditions and catalysts for
these ACA, which result in higher yields and enantioselec-
Besides transition-metal complexes and enzymes, organoca-
talysis is now well-recognized as a powerful tool for the
preparation of optically active compounds.[1,2] The pioneer-
ing reports of the proline intermolecular aldol reaction[3]
and iminium ion catalysisꢀ concept[4] set the stage for an ex-
plosion of aminocatalysis over the last few years. Chiral sec-
ondary amines have proven to be effective aminocatalysts
by covalently activating the carbonyl partners either via nu-
cleophilic enamine or electrophilic iminium species.[5]
Among the wide variety of methods available, the asymmet-
ric conjugate addition (ACA) catalyzed by pyrrolidine ana-
À
logues is of considerable importance for stereoselective C C
bond forming reactions.[6] Direct Michael addition of car-
bonyl donors via enamine activation represents a particular-
ly attractive route, affording versatile functionalized adducts
in an atom-economical manner. Several electron-withdraw-
ing groups on the Michael acceptor, including nitro,[7,8] car-
[a] S. Sulzer-Mossꢁ, Prof. A. Alexakis, Dr. J. Mareda, G. Bollot
Department of Organic Chemistry, University of Geneva
30 Quai Ernest Ansermet, 1211 Geneva (Switzerland)
Fax : (+41)22-379-3215
E-mail: alexandre.alexakis@unige.ch
[b] Dr. G. Bernardinelli
Laboratoire de Cristallographie, University of Geneva
24 Quai Ernest Ansermet, 1211 Geneva (Switzerland)
[c] Dr. Y. Filinchuk
Swiss-Norwegian Beam Lines, ESRF, BP-220
6, rue Jules Horowitz, 38043 Grenoble (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801892.
Scheme 1. ACA of aldehydes to vinyl sulfones and vinyl phosphonates
catalyzed by chiral amines.
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FULL PAPER
tivities for a broad range of aldehydes. In addition, the syn-
thetic utility of optically active Michael adducts as useful
chiral synthons is exemplified by various functionalizations.
We also present mechanistic insights including DFT calcula-
tions for the N-iPr-(2S,2’S)-bipyrrolidine (iPBP) catalyst.
sion was achieved in 30 minutes with vinyl bisACTHNGUTER(NNUG sulfone) 4 in
moderate yield (entry 4). This suggested that the reactivity
of pyrrolidine-catalyzed conjugate addition of aldehydes re-
quires geminal bisACTHNUGRTENUNG(sulfonyl) groups on the olefin.
In view of the investigation of the diastereoselectivity of
the reaction, we were interested in b-substituted vinyl bis-
AHCTUNGTRENNUNG
Results and Discussion
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
The vinyl sulfones and vinyl phosphonates used for this
study are compiled in Figure 1. Some of these compounds
(1, 2, 3, 6) were purchased from commercial suppliers;
others (4, 5, 7) were prepared according to literature proce-
dures (see Supporting Information).[20–22]
a phenyl appendage at the b-position through a modified
Knoevenagel procedure.[24] Surprisingly, under pyrrolidine
catalysis, b-phenyl bisACTHNUGRTENUNG(sulfone) 5 underwent a retro-Knoeve-
nagel reaction, releasing bis(phenylsulfonyl)methane anion
16 which reacted with isovaleraldehyde 8a to give allylic bis-
AHCTUNGTREG(NNUN sulfone) 14 after suitable isomerization (Table 1, entry 5,
Scheme 2).
Scheme 2. Mechanism of formation of allylic bisACHTNUTRGNE(NUG sulfone) 14.
Figure 1. Vinyl sulfones 1–5 and vinyl phosphonates 6, 7 studied.
Reactivity—mono-activated vs bis-activated vinyl sulfones:
At the outset of our studies, we evaluated the reactivity of
vinyl sulfones 1–5 towards catalytic conjugate addition. Iso-
valeraldehyde 8a was selected as our model substrate due to
its low tendency to do a self-aldol reaction and 25 mol% of
pyrrolidine was used as the organocatalyst (Table 1). A
large excess of aldehyde (10 equiv) was employed to force
an equilibrium to favor the Michael adduct. Inspired by our
previous work on nitroolefins,[8] chloroform was used as the
solvent.
We therefore focused our attention on vinyl bisACTHNGUTRENNU(G sulfone) 4
and performed an extensive screen of reaction conditions.
ACA of aldehydes to vinyl sulfones—Optimization of reac-
tion conditions: The modest yield obtained previously
(53%, Table 1, entry 4) could be explained by the formation
of tetrasulfone by-product 17, arising from 1,4-addition of
bis(phenylsulfonyl)methane anion 16, generated in situ, to
vinyl bisACTHNUTRGENUG(N sulfone) 4 (Table 2 and Section on Mechanistic In-
sights) (Table 1, entry 4 vs Table 2, entry 1). Moreover, the
sensitivity of g-sulfonyl aldehyde 12a also accounts for the
precedent modest yield. Indeed, purification on silica gel
(53% yield) gave unsatisfactory results whereas a significant
improvement was observed by using Florisil (75% yield)
Table 1, entry 4 vs Table 2, entry 1).
No or scarcely any reaction occurred with mono-activated
vinyl sulfones 1–3 (entries 1–3) whereas complete conver-
Table 1. Reactivity of vinyl sulfones 1–5.
The stereochemical outcome was next examined by test-
ing a range of pyrrolidine-core organocatalysts for the Mi-
chael reaction of isovaleraldehyde 8a with vinyl bisACHTUNGTRENNUNG(sulfone)
4, with the results summarized in Table 2. We first found
that decreasing the temperature to À608C gave higher enan-
tioselectivity (entries 2–3 vs entry 4). It was also apparent
that the selectivity of 2,2’-bipyrrolidine derivatives 18a–f
relies on the steric hindrance of the tertiary amine (en-
tries 4–9). Either a primary group on the nitrogen such as
N-Bn 18c (entry 6) and N-Me 18d (entry 7) or a too bulky
group such as N-cHex 18b (entry 5) and N-3-pentyl 18e
(entry 8) were revealed to be unselective. Surprisingly, hy-
drochloride salt 18 f did not catalyze the reaction (entry 9).
Moreover, the smaller the group, the higher the quantity of
by-product 17. Significantly, the proportion of tetrasulfone
17 becomes lower as the substituent becomes bulkier. Ac-
tually, the most interesting result from the 2,2’-bipyrrolidine
Entry Vinyl sulfone
t
Product Conv.[a] [%] Yield[b] [%]
1
2
3
4
5
1
2
3
4
5
4 d
4 d
4 d
7a
8a
9a
0
0
<10
–
–
–
30 min 10a
100
100
53
–
30 min 14[c]
[a] Determined by 1H NMR of the crude material. [b] Isolated yields
after purification by column chromatography on silica gel. [c] For the for-
mation of 14, see Scheme 2.
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3205

A. Alexakis et al.
Table 2. ACA of isovaleraldehyde 8a to vinyl bisACTHNUTRGNE(NUG sulfone) 4; catalyst
screening.
Table 2. (Continued)
Entry Catalyst
Reaction condi- Conv.[a]
Yield[b]
[%]
ee[c]
[%]
tion
[%]
14
À608C, 2 h
0
–
–
Entry Catalyst
Reaction condi- Conv.[a]
Yield[b]
[%]
ee[c]
[%]
[a] Determined by 1H NMR on the crude material. [b] Isolated yields
after purification by column chromatography on Florisil. [c] ee values
were determined by SFC. [d] Proportion of tetrasulfone by-product 17
determined by H NMR of the crude material. [e] The reaction was slug-
gish and led to many by-products. [f] Not determined.
tion
[%]
1
1
2
RT, 30 min
RT, 30 min
100
100
75 (19)[d]
–
65 (18)[d] 57
62 (16)[d] 63
71 (13)[d] 75
derivatives was obtained with the secondary iPr group 18a
(71% yield, 75% ee) (entry 4). Replacement of the bicyclic
five-membered ring by a six-membered ring prevented the
formation of tetrasulfone 17 which improved the yield from
71 to 79% but also decreased the enantioselectivity (entry 4
vs 10). Interestingly, mono-substituted pyrrolidinylmethyl di-
amines 18h, and 18i provided only traces of by-product 17
which stems from their low tendency to add to vinyl bis-
3
4
À308C, 1 h
À608C, 2 h
100
100
5
6
À608C, 2 h
100
100
43 (17)[d] 58
AHCTUNGTREG(NNNU sulfone) 4 (entries 11–12). However, diamines 18h and 18i
gave Michael adduct 12a in low yield (entries 11–12). In this
series, the tertiary amine had to be composed of a morpho-
line moiety to achieve good enantioselectivity (entry 11 vs
entry 12). Moreover, neither l-proline nor diphenylprolinol
18j afforded the desired Michael adduct 12a (entries 13–
14). From these results, iPBP 18a was found to be the best
catalyst for the reaction (Table 2, entry 4).
Influence of the solvent as well as catalyst loading were
next evaluated (Table 3). Chlorinated solvent (CHCl3,
CH2Cl2) achieved the highest yields and enantioselectivities
(entries 1–3). The use of anhydrous CHCl3 decreased the
amount of by-product 17 with respect to purum CHCl3
(entry 2 vs entry 1). All other solvents tested were rather
disappointing. No conversion was obtained with anhydrous
CH3CN (entry 5), whilst MeOH (entry 4) or anhydrous THF
(entry 6) provided lower yields and ee values in comparison
to anhydrous CHCl3 which gave the best results (entry 2). It
should be emphasized that the enantioselectivity and chemi-
cal yield including proportion of by-product 15 depends on
the catalyst loading. The greater the quantity of iPBP 18a
employed, the better the enantioselectivity and the yield
(entries 2, 7–11). Hence, 25 mol% of iPBP 18a in CHCl3
was the best compromise with regard to selectivity and reac-
tivity (entry 2).
À608C, 2 h
27 (31)[d] 45
7
8
À608C, 2 h
À608C, 2 h
100
100
23 (50)[d] 54
69 (6)[d]
47
–
9
À608C, 2 h
À608C, 2 h
À608C, 2 h
0
–
10
100
100
79 (0)[d]
55
19
11[e]
25 (4)[d]
Other experiments concerning the concentration of alde-
hyde 8a and sequence of reagent addition were conducted
(Table 4). As widely described,[1,2] the larger the concentra-
tion of aldehyde, the cleaner the reaction and the better the
enantioselectivity (entry 1 vs entries 3–4). The excess of al-
dehyde forces an equilibrium favouring the Michael adduct,
and consequently restricting side reactions. The requirement
of a large excess of aldehyde was confirmed by the slow ad-
dition of isovaleraldehyde 8a which led to many by-products
12
À608C, 2 h
À608C, 2 h
100
38 (2)[d]
53
13[e]
n.d.[f]
n.d.[f]
n.d.[f]
(entry 2). Finally, the slow addition of vinyl bisACTHNUTRGENUG(N sulfone) 4
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Enantioselective Organocatalysis
FULL PAPER
Table 3. Effect of solvent and catalyst loading.
Table 4. Effect of aldehyde concentration and sequence of reagent addi-
tion.
Entry Catalyst loading
[mol%]
Solvent
T
[8C]
Yield[a]
[%]
ee[b]
[%]
Entry
Equivalent aldehyde 8a
Yield[a] [%]
ee[b] [%]
1
10
10
2
5
10
71 (13)[c]
n.d.[e]
75
1[c]
2[e]
3
4
5
6
7
8
9
25
25
25
25
25
25
5
10
15
30
40
CHCl3 À60
CHCl3 À60
CH2Cl2 À78
MeOH À60
CH3CN À45
71 (18)[d]
71 (13)[d]
50 (23)[d]
65 (18)[d]
n.d.[f]
75
75
66
35
2[d]
3
n.d.[e]
45
43 (33)[c]
53 (25)[c]
78 (0)[c]
4
58
63
5[f]
n.d.[f]
15
THF
À78
15 (19)[d]
15 (4)[d]
40 (13)[d]
68 (11)[d]
70 (19)[d]
70 (20)[d]
[a] Isolated yields after purification by column chromatography on Flori-
sil. [b] eeꢀs were determined by chiral SFC. [c] Proportion of tetrasulfone
by-product 17 determined by H NMR of the crude material. [d] Slow ad-
dition of isovaleraldehyde 8a (1 h30). [e] Not determined (sluggish reac-
CHCl3 À60
CHCl3 À60
CHCl3 À60
CHCl3 À60
CHCl3 À60
34
34
52
75
1
10
11
tion). [f] Slow addition of vinyl bisACTHNUTRGNEUNG(sulfone) 4 (1 h 30 min).
80
[a] Isolated yields after purification by column chromatography on Flori-
sil. [b] eeꢀs were determined by chiral SFC. [c] Purum CHCl3 without
prior purification. [d] Proportion of tetrasulfone by-product 17 deter-
mined by 1H NMR of the crude material. [e] CHCl3 extra dry, with mo-
lecular sieves, filtered over basic alumina. [f] Not determined.
organocatalyst led to a,a-dimethyl-g,g-sulfonyl aldehyde 12 f
in good yield (entry 6). The differentiation between methyl
and ethyl in 3-methylbutyraldehyde 8g was obviously not
enough to provide good stereocontrol (entry 7). Finally, 2-
phenylpropionaldehyde 8h reacted very slowly with no se-
lectivity, probably due to the enolizable benzylic protons
under basic catalysis (entry 8).
suppressed the formation of by-product 17, but with a de-
crease of enantiomeric excess (entry 5).
ACA of aldehydes to vinyl sulfones catalyzed by iPBP—
Scope of aldehydes: With the optimized conditions in hand
for iPBP 18a catalyst, we next enlarged the scope of the re-
action with a variety of aldehydes (Table 5). Overall, the
asymmetric induction depended on the steric bulk of the al-
dehyde partner. Isovaleraldehyde 8a and 2-cyclohexylacetal-
dehyde 8b afforded their respective adducts 12a and 12b in
good yields and enantioselectivities (entry 1–2). The best
asymmetric outcome was at-
Improved conditions and catalyst for ACA of aldehydes to
vinyl sulfones—Diphenylprolinol silyl ether: Although we
have demonstrated the efficiency of the first organocatalytic
ACA of aldehydes to vinyl sulfones in terms of yield and re-
activity, the previous set of reaction conditions was substrate
dependent and ee values higher than 80% could not be
reached using iPBP 18a (Table 5). With a view to improving
our methodology, we were interested in (S)-diphenylprolinol
tained using bulkier 3,3-dime-
Table 5. ACA of aldehydes 8a–h to vinyl bisACTHUNRGTNE(NUG sulfone) 4 catalyzed by iPBP 18a.
thylbutyraldehyde 8c, with
80% ee (entry 3). Linear alde-
hyde such as valeraldehyde 8d
produced adduct 12d in good
yield but with moderate enan-
tiomeric excess (entry 4). Al-
though substrate 8e showed
similar reactivity, no stereose-
lectivity
was
observed
Entry
Aldehyde/Product
R1
R2
Reaction conditions
Yield[a] [%]
ee[b] [%]
(entry 5). This methodology
was also applied to the chal-
lenging formation of quaterna-
ry carbon centers with a,a-dis-
ubstituted aldehydes but re-
quired a higher temperature
(RT) for complete conversion
(entries 6–8). Thus, the reac-
tion of isobutyraldehyde 8 f as
nucleophile and pyrrolidine as
1
2
3
4
8a/12a
8b/12b
8c/12c
8d/12d
8e/12e
8 f/12 f
8g/12g
8h/12h
iPr
H
H
H
H
À608C, 2 h
À608C, 2 h
À608C, 2 h
À608C, 2 h
À608C, 2 h
RT, 1 h
71
71
78
76
72
73
59
75 (+)[c]
70 (+)[c]
80 (+)[c]
53 (+)[c]
0[d]
cHex
tBu
nPr
Me
Me
Et
5
H
6[e]
7
Me
Me
Me
–
RT, 4 h
RT, 7 h
12 (+)[c]
0
8
Ph
14 (15)[f]
[a] Isolated yields after purification by column chromatography on Florisil. [b] eeꢀs were determined by chiral
SFC. [c] Sign of the optical rotation. [d] ee determined on the corresponding primary alcohol 31e. [e] Reaction
performed with 50 mol% of pyrrolidine. [f] Conversion determined by H NMR of the crude material.
1
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A. Alexakis et al.
silyl ether 18k for promoting ACA of isovaleraldehyde 8a
to vinyl bis(sulfone) 4 (Table 6). Indeed, catalyst 18k was
could be reduced to 10 mol% or even to 5 mol%, without
compromising both yield and enantioselectivity (entries 7–
8). Due to the fact that we were interested in performing
these reactions on a large scale, it was pleasing to find that
only 1 mol% of (S)-diphenylprolinol silyl ether 18k was re-
quired to provide Michael adduct 12a in 90% yield and
with 86% ee (entry 9). Finally, it is worthy of note that the
reaction could also be performed using only 2 equivalents of
isovaleraldehyde 8a with still high yield and ee (entry 10).
To probe the scope of the improved methodology, a broad
range of aldehydes was next considered (Table 7). Extensive
variation in steric demands of the aldehyde substituent can
be realized, affording g-gem-sulfonyl aldehydes 12a–e, i–j in
good yields (77–90%) and with high enantioselectivities
(76–98% ee; entries 1–7). Once again, hindered aldehydes
accessed the highest ee values, with up to 98% ee for 3,3-di-
methylbutyraldehyde 8c (entries 1–3). Not only branched al-
dehydes (entries 1–3) but also linear aldehydes, such as va-
leraldehyde 8d and propionaldehyde 8e can also be em-
ployed to reach good enantioselectivity (entries 4–5). Inter-
estingly, the allyl moiety can be introduced with good level
of stereocontrol (entry 6). From a synthetic point of view,
(Z)-undec-8-enal (8j), bearing a cis double bond, gave the
Michael adduct 12j in good yield and with 93% ee
(entry 7).
ACHTUNGTRENNUNG
extensively explored by Jørgensen in various organocatalytic
reactions,[25] and innovatively reported by Hayashi as an ex-
ceptional catalyst for the Michael reaction of aldehydes to
nitroolefins.[7f] Pleasingly, (S)-diphenylprolinol silyl ether
18k was found to induce particularly high stereocontrol for
the ACA of isovaleraldehyde 6a to vinyl bisACTHNURGTNE(NUG sulfone) 4.
Thus, the Michael adduct 12a was obtained in high yield
(88%), with excellent enantioselectivity and without the for-
mation of tetrasulfone by-product 17 (93% ee; Table 6,
entry 1). (S)-Diphenylprolinol silyl ether 3a was revealed to
be an especially active catalyst owing to its bulky substitu-
ents. It is worth noting that (S,S)-iPBP 18a and (S)-diphe-
nylprolinol silyl ether 18k afforded the same major enantio-
mer (+)-(S)-12a which involves the same facial selectivity
according to steric shielding (See Section on DFT Calcula-
tions).
Table 6. ACA of isovaleraldehyde 8a to vinyl bis
ACHTUNGERTN(NUNG sulfone) 4 catalyzed by
(S)-diphenylprolinol silyl ether 18k; optimisation of reaction conditions.
Table 7. ACA of aldehydes 8a–e, i–j to vinyl bis
(S)-diphenylprolinol silyl ether 18k.
ACHTUNGERTN(NUNG sulfone) 4 catalyzed by
Entry Equivalent al- Cat. loading Solvent
T
Yield[a] ee[b]
dehyde 8a
[mol%]
[8C] [%]
[%]
1
10
25
CHCl3
À60 88
93
(+)[c]
87
2
3
4
5
6
10
10
10
10
10
25
25
25
25
25
hexane
toluene
toluene
CHCl3
H2O/EtOH RT 45
(95:5)
À60 81
À60 87
À78 87
RT 83
93
92
90
72
Entry
Aldehyde/Product
R1
Yield[a] [%]
ee[b] [%]
7
8
9
10
10
10
10
2
10
5
1
CHCl3
CHCl3
CHCl3
CHCl3
À60 90
À60 89
À60 90
À60 89
92
91
86
89
1
2
3
4
5
6
6a/10a
6b/10b
6c/10c
6d/10d
6e/10e
6i/10i
iPr
90
86
90
87
85
88
92
83
98
85
76
92
cHex
tBu
nPr
Me
10
[a] Isolated yields after purification by column chromatography on Flori-
sil. [b] ee values were determined by chiral SFC. [c] Sign of the optical ro-
tation.
allyl
7
6j/10j
77
93
Our next task was optimize the reaction conditions for
catalyst 18k (Table 6). A short solvent survey revealed the
suitability of nonpolar solvents (entries 1–3). The best re-
sults in terms of yields and enantioselectivity were achieved
with both chloroform (entry 1) and toluene (entry 3). When
the reaction in toluene was performed at a lower tempera-
ture (À788C), no improvement was observed (entry 3 vs 4).
For practical purposes, chloroform was chosen as the solvent
in the subsequent studies. To our delight, the reaction in
chloroform could also be carried out at room temperature
with conservation of high yield and enantioselectivity
(entry 1 vs 5). However, changing chloroform to a mixture
of H2O/EtOH (95:5)[26] drastically decreased either yield or
enantiomeric excess (entry 5 vs 6). The catalyst loading
[a] Isolated yields after purification by column chromatography on Flori-
sil. [b] eeꢀs were determined by chiral SFC.
(S)-Diphenylprolinol silyl ether 18k also proved to be an
efficient catalyst for the straightforward construction of
chiral quaternary carbon centers with a,a-disubstituted alde-
hydes (Table 8). Despite the unfruitful preliminary result
with 3-methylbutyraldehyde 8g (entry 1), we anticipated
that higher differenciation between the a-substituents would
provide better stereoinduction. Pleasingly, 2-phenylpropio-
naldehyde[27] 8h underwent reaction with vinyl bis
4 in good yield and with promising enantiomeric excess de-
ACHTUNGTRENNUNG(sulfone)
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Enantioselective Organocatalysis
FULL PAPER
Table 8. ACA of aldehydes 8g–h, k–l to vinyl bis
(S)-diphenylprolinol silyl ether 18k.
ACHTUNGERTN(NUNG sulfone) 4 catalyzed by
enantiopure (S)-citronellal 8m, the Michael adduct (2S,3S)-
12m is obtained in nearly pure form [>99% ee, Scheme 3,
Equation (2)].[28] It is worth noting that a higher enantiose-
lectivity for Michael adduct (S,S)-12m was observed when
the reaction is performed with pure (S)-citronellal 8m and
(S)-18k catalyst in comparison with racemic (Æ)-citronellal
8m [Scheme 3, Equation (2) vs (1). This can be considered
as a match situation between (S)-citronellal and (S)-18k cat-
alyst. From the result obtained with racemic (Æ)-citronellal
8m, it seems that (R)-citronellal 8m and the same catalyst
does not afford as high diastereoselectivity. In this mismatch
combination, the formation of the minor (R,R)-diastereomer
12m affects the optical purity of of (S,S)-12m obtained from
(S)-citronellal 8m. Therefore, the observed ee of (S,S)-12m
obtained from the racemic citronellal is lower than expect-
ed, and this can also explain the 40:60 diastereomeric ratio.
Compound 12m constitutes a highly useful chiral intermedi-
ate for the synthesis of natural products due to its citronellal
scaffold improved by the introduction of a versatile gem-sul-
fonyl group.[29]
Entry Aldehyde/Product R1
R2
Yield[a] [%] ee[b] [%]
1
2
3
4
6g/10g
6h/10h
6k/10l
6l/10l
Et
Ph
Me 75
Me 78
12
47
91
64
1-naphthyl Me 76
cHex Me 71
[a] Isolated yields after purification by column chromatography on Flori-
sil. [b] eeꢀs were determined by chiral SFC.
spite the presence of a very labile proton at the a-position
of the carbonyl (entry 2). Replacement of phenyl group with
the bulkier 1-naphthyl group resulted in a higher enantiose-
lectivity of 91% ee (entry 3). By grafting cyclohexylmethyl
appendages, chiral quaternary carbon center was formed in
good yield and with 64% ee (entry 4). Thus, we have dem-
onstrated that our methodology is also suitable for chiral
quaternary carbon center formation, reaching to good enan-
tioselectivity.
Consistently, higher yields and ee values were achieved
with (S)-diphenylprolinol silyl ether 18k in comparison to
(S,S)-iPBP 18a The most obvious cases were represented by
propionaldehyde 8e and 2-phenylpropionaldehyde 8h for
which (S,S)-iPBP 18a could induce any stereoinduction
whereas catalyst 18k generated moderate to good enantiose-
lectivities (Table 5, entry 5 vs Table 7, entry 5 and Table 5,
entry 8 vs Table 8, entry 2).
ACA of aldehydes to vinyl phosphonates—Reactivity: to
broaden the scope of our methodology and to confirm our
hypothesis on the requirement of bis-activated Michael ac-
ceptors, vinyl phosphonates were selected as electrophilic
olefins. We initially evaluated the reactivity of vinyl phos-
phonates 6–7 in the conjugate addition of isovaleraldehyde
8a using pyrrolidine as catalyst (Scheme 4). As previously
emphasized for vinyl sulfones, we found that the Michael re-
action was only effected with vinyl bis(phosphonate) 7
(Scheme 4). No reaction occurred with vinyl mono-phospho-
nate 6 whereas full conversion was achieved in 1 h with
vinyl bis(phosphonate) 7 (Scheme 4). Consequently, we
assume that the Michael acceptor, with the exception of ni-
troolefins[7] and methyl vinyl ketone„[7f,9] should bear gemi-
nal bis-electron withdrawing groups in order to enable the
aminocatalytic ACA of carbonyl donors.
Citronellal 8m was then selected as donor partner in
order to examine the plausibility of kinetic resolution
(Scheme 3). Racemic (Æ)-citronellal 8m underwent reaction
with vinyl bisACHTUNGTRENNUNG(sulfone) 4 with excellent enantioselectivity
with respect to the diastereomers but without significant se-
lectivity in the kinetic resolution [dr syn/anti 40:60,
Scheme 3, Equation (1)]. By performing the reaction with
ACA of aldehydes to vinyl phosphonates—Optimisation of
reaction conditions: The stereochemical outcome of the
ACA of isovaleraldehyde 8a to vinyl bis(phosphonate) 7
was next explored with a short
array of pyrrolidine-core orga-
nocatalysts (Table 9). Despite
its excellent catalytic activity,
iPBP 18a led to moderate
yield and low enantioselectivi-
ty no matter the temperature
(entries 1–2). It is notable that
vinyl bisACTHNUGRTENUNG(sulfone) 4 is more re-
active than vinyl bis(phospho-
nate) 7 which is underlined by
the lack of reactivity at À308C
of the latter Michael acceptor
(Table 5, entry 1 vs Table 9,
entry 3). The reaction rate and
the enantioselectivity were di-
Scheme 3. ACA of citronellal 8m to vinyl bisACHTUNTRGNEUNG(sulfone) 4 catalyzed by (S)-diphenylprolinol silyl ether 18k.
Chem. Eur. J. 2009, 15, 3204 – 3220
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3209

A. Alexakis et al.
minished when the isopropyl substituent in catalyst 18a was
exchanged by a methyl group in 18d (entry 4). Although di-
amine 18h catalyzed the reaction as fast as diamine 18a, it
was revealed to be unselective (entry 5). Neither l-proline
nor (S)-diphenylprolinol 18j generated the Michael adduct
20a after 48 h (entries 6–7).
Delightfully, (S)-diphenylprolinol silyl ether 18k was
found to induce particularly high stereocontrol for the ACA
of isovaleraldehyde 6a to vinyl bis(phosphonate) 7. The re-
action was complete within 12 h at room temperature in the
presence of 20 mol% of catalyst 18k in CHCl3 and fur-
nished Michael adduct 20a in good yield (80%) and with
excellent enantioselectivity (90% ee; entry 8). A decrease in
the enantiomeric excess (from 90 to 80% ee) was observed
upon decreasing the temperature (entry 8 vs 9). Heating the
reaction did not improve the enantiocontrol and decreased
the yield (entry 10). Changing CHCl3 to a mixture of H2O/
EtOH (95:5) gave lower yield and selectivity (entry 8 vs 11).
The catalyst loading could be reduced to 10 mol% while re-
taining a high level of enantioselectivity (entry 12).
Scheme 4. Pyrrolidine-catalyzed conjugate addition of isovaleraldehyde
8a to vinyl phosphonates 6–7. Comparison of reactivity.
Table 9. ACA of isovaleraldehyde 8a to vinyl bis(phosphonate) 7. Opti-
mization of reaction conditions.
ACA of aldehydes to vinyl phosphonates—Scope of alde-
hyde: With the optimized conditions in hand (Table 9,
entry 8), the generality of the reaction for various aldehydes
was demonstrated, with the results summarized in Table 10.
Good to high enantioselectivities were obtained with
regard to the aldehyde substituent, ranging from 75–97% ee
(entry 1–5). Interestingly, phenetylaldehyde 8n afforded
equally good ee value (entry 4). Unfortunately, pent-4-enal
8i, bearing a terminal double bond, gave the Michael
adduct 20i in moderate yield and with low enantiomeric
excess (entry 6). The challenging formation of quaternary
carbon center was achieved in good yield using isobutyralde-
Entry Catalyst[a]
1
Reaction conditions Conv.[b]
[%]
Yield[c]
[%]
ee[d]
[%]
CHCl3, RT, 1 h
100
100
0
71
75
–
31
33
2
3
4
CHCl3, 08C, 5 h
CHCl3, À308C, 48 h
CHCl3, 08C, 24 h
(+)[e]
–
84
55
29
Table 10. ACA of aldehydes 8a, c-f, h, i, n to vinyl bis(phosphonate) 7
catalyzed by (S)-diphenylprolinol silyl ether 18k.
5
6
CHCl3, 08C, 5 h
100
0
70
–
15
CHCl3, RT, 48 h
–
–
7
8
CHCl3, RT, 48 h
CHCl3, RT, 12 h
0
–
Entry
Aldehyde/Product
R1
R2
Yield[a] [%]
ee[b] [%]
1
2
3
4
5
6
8a/20a
8c/20c
8d/20d
8n/20n
8e/20e
8i/20i
iPr
H
H
H
H
H
H
Me
Me
80
85
75
81
75
65
80
–
90 (S) (+)[c]
100
80
90
tBu
nPr
Bn
Me
allyl
Me
Ph
97
86
85[d]
75
46
–
(+)[e]
80
91
9
10
11
CHCl3, 08C, 18 h
CHCl3, 608C, 12 h
H2O/EtOH (95:5),
RT, 12 h
100
100
100
82
71
49
83
7[e]
8[f]
8 f/20 f
8h/20h
12
CHCl3, RT, 15 h
100
81
85
–
[a] Entries 1–11: 20 mol%, entry 12: 10 mol%. [b] Determined by
1H NMR of the crude material. [c] Isolated yields after purification by
column chromatography on silica gel. [d] eeꢀs were determined by
1H NMR on the corresponding imidazolidines 21a–22a derived from Mi-
chael adduct 20a and N,N-dimethyl-1,2-diphenyl ethylene diamine (23),
see Scheme 5. [e] Sign of the optical rotation.
[a] Isolated yields after purification by column chromatography on silica
gel. [b] eeꢀs were determined by 1H NMR on the corresponding imidazo-
lidines 21–22 derived from Michael adduct 20 and 23, see Scheme 5.
[c] Sign of the optical rotation. [d] ee was confirmed by chiral SFC.
[e] Performed with 20 mol% of pyrrolidine. [f] No conversion was ob-
served after 48 h at RT.
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Enantioselective Organocatalysis
FULL PAPER
1
hyde 8 f as nucleophile and pyrrolidine as organocatalyst
(entry 7). However, phenylpropionaldehyde 8h was not re-
active enough to undergo the conjugate addition (entry 8).
21a–22a, the H NMR spectrum of diastereomeric imidazo-
lidines 24a–25a shows a major deshielded signal and a
minor shielded one for the same benzylic proton. Conse-
quently, we ascribed the (S) absolute configuration to the
(+)-Michael adduct 20a and the same spatial arrangement
was assumed for the other products 20.
Determination of the ee of g-gem-phosphonate aldehydes:
In view of the high molecular weight and non-UV active
groups in Michael adducts 20, the optical purity could not
be attributed by usual chiral separative techniques. Conse-
quently, the enantiomeric excess of g-gem-phosphonate al-
dehydes 20 was determined by 1H NMR analysis through
the formation of diastereomeric imidazolidine 21–22 with
(R,R)-diamine 23 (Scheme 5).[30,31]
Synthetic utility of g-gem-sulfonyl aldehydes and determina-
tion of their absolute configuration: the applicability of g-
gem-sulfonyl aldehydes as highly tunable synthons was illus-
trated by a variety of synthetic transformations involving
the aldehyde as well as the sulfonyl groups. The large scale
synthesis of the chiral Michael
adduct 12a was carried out
with only 1 mol% of (S)-di-
phenylprolinol silyl ether 18k
with still high level of enantio-
selectivity (85% ee). We first
chose to selectively manipulate
the aldehyde functionality. The
Michael adduct (S)-12a with
Scheme 5. Determination of the ee of g-gem-phosphonate aldehydes 20.
85% ee was easily oxidized
into carboxylic acid 26a in
The use of (R,R)-diamine 23 for the derivatization of
95% yield after a brief KMnO4 exposure with no loss of
enantioselectivity. Further transformation into methyl ester
27a was achieved in high yield by the addition of
TMSCHN2 to confirm the optical purity of 84% ee
(Scheme 7).[33]
1
chiral aldehydes 20 provides H and 31P NMR spectra with
different signals for each diastereomeric imidazolidine 21
and 22.[32] Very mild conditions are required for this trans-
formation (Et2O, molecular sieves, room temperature) and
an excess of (R,R)-diamine 23
was used to avoid kinetic reso-
lution.
The
enantiomeric
excess was determined on the
crude diasteromeric imidazoli-
dine mixture 21–22 to prevent
the selective enrichment of
one diastereoisomer. In one in-
Scheme 7. Methyl ester derivatization of optically active of g-gem-sulfonyl aldehyde 12a.
stance, the enantiomeric excess
of the Michael adduct 20n
with a phenyl moiety could be confirmed by supercritical
fluid chromatography (SFC), proving the efficiency of the
NMR spectroscopy for determination of the enantiomeric
excess.
Conversely, Baeyer–Villiger oxidation of the (S)-adduct
12a followed by saponification of formyl ester compound
28a furnished secondary alcohol 29a in high yield with per-
fect retention of configuration (Scheme 8).[34]
We also managed to perform methylenation of aldehyde
(S)-12a with freshly prepared Petasis reagent[35] giving the
vinyl derivative 30a with conservation of the ee (Scheme 9).
It is pertinent to note that the corresponding Wittig reagent
as well as Horner–Wadsworth–Emmons reagent induced
only epimerisation of aldehyde (S)-12a, probably due to
their basic propertities.
Determination of the absolute configuration g-gem-phos-
phonate aldehydes: The absolute configuration of the
adduct 20a was established by analogy with known Michael
adduct 12a, (S)-bis(phenylsulfonyl)ethyl)-3-methylbutanal
(85% ee) (Scheme 6). As for diastereomeric imidazolidines
Besides the obvious synthet-
ic utility of the aldehyde
moiety, we also considered the
transformation of the sulfonyl
groups.[36] After suitable reduc-
tion and protection of the pri-
mary alcohol 31a as its
TBDMS ether 32a with reten-
Scheme 6. Determination of the absolute configuration of g-gem-phosphonate aldehydes 20a (Scheme 5, R=
iPr) by analogy with known g-gem-sulfonyl aldehyde 12a.
Chem. Eur. J. 2009, 15, 3204 – 3220
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3211

A. Alexakis et al.
samarium Barbier reaction
gave the desired cyclobutanol
36a in good yield as a single
diastereomer although a small
degree of racemisation was ob-
served (Scheme 12).
Scheme 8. Secondary alcohol derivatization of optically active of g-gem-sulfonyl aldehyde 12a.
Scheme 12. Synthesis of cyclobutanol 36a.
Scheme 9. Methylenation of optically active of g-gem-sulfonyl aldehyde
12a.
Finally, we were interested in effecting bis-desulfonyla-
tion[11h,k–l] by exchanging the sulfonyl groups of primary alco-
hol 31a with hydrogens (Scheme 13). Reduction with Raney
Nickel[43] even with ultrasound activation led to the recovery
of starting material 31a. Only one sulfonyl group was reduc-
tively cleaved with aluminium amalgam (Al/Hg)[44] in 75%
conversion after 5 d. Seemingly, these reducing reagents
were not suitable for totally removing non-activated geminal
tion of the optical purity, freshly prepared samarium diio-
dide,[37,38] efficiently mediated reductive monodesulfonyla-
tion of g-gem sulfonyl protected alcohol 32a to give a poten-
tially nucleophilic reagent 33a in good yield and with 82%
ee (Scheme 10).[39] It is worth noting that the exact sequence
of reagent addition is critical for the reaction. Indeed, addi-
tion of gem-sulfonyl compound 32a to a solution of SmI2 in
THF gave only partial conversion (40%) whereas the re-
verse addition led to full conversion.
bisACHTNUTRGNEUNG(sulfones). Fortunately, the bis-desulfonylation can be
performed using activated magnesium turnings in MeOH.[45]
Hence, alcohol 37a was ob-
tained in 45% yield with no
loss of enantioselectivity (74%
ee). Usefully, the S absolute
configuration of the Michael
adduct 12a was determined by
comparison of the optical rota-
tion of the resulting alcohol
Scheme 10. Reduction–protection and subsequent monodesulfonylation of optically active of g-gem-sulfonyl al-
dehyde 12a.
37a with literature.[46] It was
Next, a-deprotonation of compound 33a with KHMDS
and subsequent addition of ethyl chloroformate afforded the
acylated product 34a in 74% yield as a mixture of diaste-
reomers (3:2) with 84% ee (Scheme 11).[40] Chiral synthon
34a could easily access enantioenriched valerolactone 35a
Scheme 13. Bis-desulfonylation of alcohol 31a; determination of the ab-
solute configuration of g-gem-sulfonyl aldehydes 12a.
which is a ubiquitous structural intermediate in natural
product synthesis.[41]
We also investigated the intramolecular reductive cycliza-
tion of g-geminal bis
(sulfone) aldehyde 12a in order to
assumed that the spatial arrangement of the other Michael
adducts 12 was the same.
The absolute configuration of Michael adducts 12 was
confirmed by X-ray analysis of carboxylic acid 26c derived
from g-gem-sulfonyl aldehyde 12c (Figure 2).
obtain cyclobutanol 36a which could be an interesting chiral
building block for total synthesis.[37b,42] The intramolecular
Many other synthetic transformations of Michael adducts
12 could be envisaged for the remaining aldehyde and sulfo-
nyl groups. For instance, naphthalene-catalyzed lithiation of
sulfones and the in situ reaction of the resulting organolithi-
um with aldehydes and halogen compounds could be investi-
gated to broaden the scope of the synthetic utility of Mi-
chael adduct 12.[38b,47] Moreover, the presence of a double
Scheme 11. Towards the synthesis of enantioenriched valerolactone 35a.
3212
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Enantioselective Organocatalysis
FULL PAPER
Scheme 14. Functionalization of g-gem-phosphonate aldehyde 20a; a new
route to enantioenriched b-substituted vinyl phosphonate 40a.
clinal transition state based on Seebachꢀs model[52] in which
there are favourable electrostatic interactions between the
nitrogen of the enamine and the electron-withdrawing group
of the Michael acceptor. As the selectivity depends on steric
hindrance, the very bulky diphenyl silyl ether moiety in-
duced better enantioselectivity than the N-iPr-pyrrolidine
moiety (93% ee vs 75% ee, see Table 6, entry 1 vs Table 5
entry 1). It is worth noting that (S,S)-iPBP 18a and (S)-di-
phenylprolinol silyl ether 18k afforded the same major en-
antiomer (+)-(S)-12a which involves the same face selectivi-
ty due to steric shielding. The bulky group on the catalyst
framework would promote the selective formation of the
anti enamine and selective shielding of the Re approach.
Consequently, the less hindered Si transition state is well fa-
vored compared to the Re and leads to the (S)-12a adduct
(R=iPr) (Scheme 15).
Figure 2. X-ray crystal structure of (S)-carboxylic acid 26c derived from
g-gem-sulfonyl aldehyde 12c. CCDC 662357 (26c) contains the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif
À
carbon carbon bond on Michael adducts 12i,j,m supplies
new opportunities such as ozonolysis, cross-metathesis, radi-
cal cyclization[48] after appropriate transformations.
Synthetic application of g-gem sulfonyl phosphonates: To il-
lustrate the synthetic utility of this methodology, the enan-
tioenriched g-gem-phosphonate aldehyde 20a was easily
converted into b-substituted
vinyl phosphonate 40a with no
loss
of
enantioselectivity
(Scheme 14). Reduction of
compound 20a with NaBH4
and subsequent protection of
the primary alcohol 38a with a
TBDMS group affords the cor-
responding g-gem-phosphonate
protected alcohol 39a in high
overall yield. The HWE reac-
tion with aqueous formalde-
hyde using 50% aqueous
NaOH solution[49] provides the
Scheme 15. Proposed transition state for the organocatalytic ACA of aldehydes to vinyl bis
bis(phosphonates) according to steric shielding.
ACHTUNGTREN(NUNG sulfones) and vinyl
enantioenriched b-substituted vinyl phosphonate 40a in high
yield (81%) with retention of the enantiomeric excess (90%
ee).[50] This new versatile building block could be involved in
a variety of synthetic transformations such as ozonolysis, cy-
cloaddition, conjugate addition or methyl ketone forma-
tion.[16,51]
The origin of the selectivity in the organocatalytic ACA
of aldehydes to vinyl sulfones has also been investigated for
N-iPr-2S,2’S-bipyrrolidine (iPBP) catalyst by density func-
tional theory (DFT) using the PBE1PBE/6-31G* method[53]
within the Gaussian03 package.[54]
Transition-state modeling by DFT calculations: In the fol-
lowing preliminary account of computational modeling we
focus mainly on the structure of the transition states of the
enamine, derived from (S,S)-iPBP 18a and 3,3-dimethyl bu-
tyraldehyde 8c, and vinyl sulfone 4, since their properties
can provide the best indications (leads) for understanding of
Proposed transition-state model: The determination of the
absolute configuration allowed us to postulate a Michael ac-
ceptor attack from the Si face of the (E)-enamine according
to steric shielding (Scheme 15).[6c,25a] The selectivity of the
organocatalytic ACA could be explained by an acyclic syn-
Chem. Eur. J. 2009, 15, 3204 – 3220
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3213

A. Alexakis et al.
and 3.491 ꢃ, respectively). The
charge build-up on oxygen
atoms in the II-TS, together
with relatively short distances
between the involved atoms,
allow for improved electrostat-
ic interactions.
Scheme 16. Studied case for the transition state modeling by DFT calculations.
During the Re approach
(Figure 4), when compared to
the observed selectivity (Scheme 16) (Computational meth-
ods, see Supporting Information).
the reactant, the negative charge on the two crucial oxygen
atoms decrease in the transition state V-TS with computed
charges for atoms O3 and O4 of À0.417 and À0.461, respec-
tively (Figure 4). In addition, the latter oxygen is further
apart from the enamine nitrogen (4.072 ꢃ). Such charge de-
pletion and elongation of oxygen–nitrogen distance is in
contrast with what was observed for the attack of the Si
face. The optimized geometry parameters of V-TS are clear-
ly less favorable for the electrostatic interactions between
the enamine and sulfone moieties. At the origin of this
structural perturbation is the steric hindrance between the
bulky substituent and the O4. Particularly, one of the hydro-
gens (attached to C10, see Figure 4) comes into close con-
tact with this oxygen atom. This type of unfavorable interac-
tion is absent in the II-TS structure (Figure 3), setting there-
by the stage for the improved electrostatic interactions and
providing further stabilization of the transition state for the
Si approach. Indeed, in the II-TS transition state, the bulky
Indeed, on the reactant side the potential energy surface
for enamines is quite complex, nevertheless the conforma-
tional search provided five low energy minima within a 4
[kcalmolÀ1] range. All five minima belong to (E)-enamines
and the lowest energy conformer corresponds to anti enam-
ine. Although, the selective steric shielding of the Re face is
apparent, at least to a certain degree, from the optimized
structure of this reactant, it could not provide a full ration-
ale for the observed selectivity.
One of the key factors that can enhance the selectivity of
the Michael-acceptor attack of the (E)-enamine is the ability
of this system to develop the stabilizing electrostatic interac-
tions at the transition state between the nitrogen of the en-
amine and sulfone oxygen atoms. For the reaction pathway
leading to the Si-face adduct (Figure 3), our modeling re-
vealed a progressive increase of the negative charge on the
oxygen atoms. When comparing the charges between the re-
actant and transition state II-TS it increased, respectively,
from À0.397 to À0.425 for O1 and from À0.409 to À0.438
for O2 (Figure 3). These two oxygen atoms are quite close
and equidistant with respect to the enamine nitrogen (3.428
À
substituent is extending its C10 C12 moiety away form the
incoming sulfone (Figure 3).
Figure 3. Schematic energy profile for ACA to the Si face of the (E)-en-
Figure 4. Schematic energy profile for ACA to the Re face of the (E)-en-
amine, together with the optimized structure (top) of the transition state.
amine, together with the optimized structure (top) of the transition state.
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Enantioselective Organocatalysis
FULL PAPER
The present modeling can
also be used to evaluate
whether the tert-butyl substitu-
ent on the enamine can addi-
tionally be involved in the face
selectivity of the vinyl sulfone
addition. Indeed, for the vinyl
sulfone approach to the Re
face, one of the vinyl hydro-
gens develop two close con-
tacts with the tert-butyl sub-
stituent. In the V-TS geometry
(Figure 4), this steric hindrance
translates into H····H distances
of 1.966 and 2.258 ꢃ. Again
the analogous steric interfer-
ence is less severe in the II-TS
transition state of the Si face
attack (Figure 3).
~
.
&
Figure 5. ee Values ( ) as a function of time, conversion:
The favorable and unfavora-
ble
interactions
described
&
above are reflected in clearly different energy barriers for
the two modes of addition. Expressed in terms of relative
energies, the barrier for the vinyl sulfone 4 addition to the
Si face amounts to 2.4 kcalmolÀ1, while the barrier for the
Re approach is 5.3 kcalmolÀ1 higher. The incorporation of
the ZPE correction only marginally changes the energy pro-
file. Since all stationary points of the potential energy sur-
face were characterized by the vibrational analysis, we were
able to apply the thermal corrections and compute the free
energy (right column in Table 11). When comparing the free
energies, the energy difference DDG between the two transi-
tion states further increased to 6.8 kcalmolÀ1. These prelimi-
nary DFT results not only correlate well with the reported
experimental results, but they also provide the rationale for
the origin of the observed selectivity. The modelling of the
solvent effects is currently in progress.
time gave a near straight line ( ) which indicates there is no
epimerisation during the reaction.
The absence of racemisation was also previously deter-
mined by observing that the ee of aldehyde 12a was almost
similar to the one of the corresponding primary alcohol 31a
(see Scheme 10). In accordance with Jørgensenꢀs explanatio-
n,[25a] the stability of the chiral center during the reaction
could arise from the steric hindrance of the aminocatalyst
(S,S)-iPBP 18a and especially (S)-diphenylprolinol silyl
ether 18k.[25a] This undesired pathway is generally prevented
because the formation of the bulky disubstituted enamine
species VIII is disfavored in comparison to the iminium VII
hydrolysis leading to enantioenriched Michael adduct 12
(Scheme 17). This phenomenon is also in agreement with ki-
netic control.
To obtain further information on the influence of kinetic
control in our reaction, Michael adduct 12a (75% ee) was
subjected to standard conditions [Scheme 18, Eq. (1)]. Nei-
ther variation of enantiomeric excess nor formation of vinyl
Table 11. Relative energies and relative free energies [kcalmolÀ1] for
ACA to (E)-enamines at the PBE1PBE level of theory.
bisACHTNUTRGNEUNG(sulfone) 4, that is, retro-addition, were observed which
corroborates our kinetic control hypothesis. This trend was
Face
Species
DE[a]
DE
(ZPE)[b]
DG[c]
Si
I
0.0
0.0
0.0
II-TS
III
IV
2.4
3.3
6.2
À14.1
À11.1
À7.8
Re
0.0
0.0
0.0
V-TS
VI
7.7
À7.6
8.6
À4.5
13.0
À0.3
[a] Relative energies. [b] ZPE corrected relative energies. [c] Relative
free energies at 258C.
Mechanistic insights: In order to establish the role of (S,S)-
iPBP in ACA, we investigated advanced mechanistic studies
on this catalytic system. The stability of the chiral center in
the product is as important as its enantioselective formation.
Consequently, we first conducted an epimerisation study by
monitoring the enantiomeric excess as a function of time
(Figure 5). Plotting the ee of the Michael adduct 12a versus
Scheme 17. Proposed transition state for the organocatalytic ACA of al-
dehydes to vinyl bis
steric shielding.
ACHTUNGTREN(NGNU sulfones) and vinyl bis(phosphonates) according to
Chem. Eur. J. 2009, 15, 3204 – 3220
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3215

A. Alexakis et al.
uct 17. Indeed, the introduction of (S,S)-iPBP 18a last to the
reaction mixture at À608C prevented the formation of tetra-
sulfone 17 (Figures 6 and 8). This result was experimentally
confirmed and led to an increase of the chemical yield from
71 to 82%. Unfortunately, no improvement of enantioselec-
tivity was observed showing that the structure of the catalyst
or more precisely its steric hindrance mainly governs the
stereoinduction. Unfortunately, neither iminium 42 nor en-
amine 43 intermediates (Figure 9) were detected by these
1H NMR experiments (Figure 6). However, the formation of
the enamine intermediate 43 derived from isovaleraldehyde
Scheme 18. Evaluation of kinetic control.
confirmed by reacting a less
hindered aldehyde such as va-
leraldehyde 6d and compound
12a which led only to the re-
covery of Michael adduct 12a
with no loss of enantioselectiv-
ity [Scheme 18, Eq. (2)].
NMR spectroscopy was also
investigated to gain insight
into the intermediates of the
catalytic cycle. Preliminary re-
sults indicated the formation
Figure 8. 1H NMR study: addition of (S,S)-iPBP 18a to a mixture of isovaleraldehyde 8a and vinyl bis
ACTHNUGRTENUNG(sulfone) 4.
of by-product 17 in large amounts (Hb) and the addition of
(S,S)-iPBP 18a to vinyl bis(sulfone) 4 which trapped the cat-
AHCTUNGTRENNUNG
alyst as product 41 (Ha) (Figures 6 and 7). The reaction
evolved into a 1:4 ratio of Michael adduct 12a to by-product
17, suggesting a slow transformation of trapped catalyst 41
into the desired 1,4-adduct 12a.
It is clear that the temperature as well as the sequence of
reagent addition could influence the proportion of by-prod-
Figure 9. Iminium 42 and enamine 43 derived from isovaleraldehyde 8a
and and (S,S)-iPBP 18a.
6a and (S,S)-iPBP 18a during the reaction was confirmed by
ESI-MS method (see Supporting Information).
Finally, we studied linear/non-linear effects in ACA of iso-
valeraldehyde 8a to vinyl bisACTHNUTRGENUGN(sulfone) 4 catalyzed by (R,R)-
iPBP 18a (Figure 10). Plotting the ee value of catalyst 18a
versus that of the Michael adduct 12a gave a slight negative
non-linear relationship. Diastereomeric active species are
not in accordance with our transition sate model based on
steric shielding in which there is probably no H-bonding or
aggregation in solution. No solid phase was observed ex-
cluding an explanation by physical phase behavior.[55] Appa-
Figure 6. Identified compounds by NMR spectroscopy.
Figure 7. 1H NMR study: Addition of isovaleraldehyde 8a to a mixture
Figure 10. Slight non-linear effect in the ACA of isovaleraldehyde 6a to
of vinyl bis
G
vinyl bisACTHNGUTERNNU(G sulfone) 4 catalyzed by (R,R)-iPBP 18a.
3216
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Enantioselective Organocatalysis
FULL PAPER
(0.0162 mmol, 10 mol%). The evolution of the reaction was controlled by
TLC until completion. The solution was hydrolysed with sat. aq. NH4Cl
(2 mL). The layers were separated and the aqueous phase was extracted
with CH2Cl2 (3ꢄ3 mL). The combined organic layers were dried over
Na2SO4, filtered, concentrated and purified by flash column chromatogra-
phy on Florisil using a mixture of cyclohexane (c-Hex) and ethyl acetate
(AcOEt).
rently, there is neither epimerisation nor influence of the ad-
dition of the enantioenriched Michael adduct 12a in the re-
action conditions suggesting that there is no interaction be-
tween the chiral catalyst and the chiral product (see Figure 5
and Scheme 17). However, reversible trapping of the cata-
lyst as compound 41 (Figure 6) could decrease the amount
of available catalyst and consequently this phenomenon of
reservoir effect would explain the observed negative non-
linear effect.
(2S)-Bis(phenylsulfonyl)ethyl)-3-methylbutanal (12a): From isovaleralde-
hyde (8a; 1.62 mmol, 10 equiv, 0.18 mL), 1,1-bis(benzenesulfonyl)ethy-
lene (4; 0.162 mmol, 1 equiv, 50 mg) and 18k (0.0162 mmol, 10 mol%,
5.3 mg) according to GP 1 (2 h, À608C) to give a yellow oil as crude
product which is purified by column chromatography on Florisil (c-Hex/
AcOEt 2:1) to obtain a pale yellow oil (57.5 mg, 90%). The enantiomeric
excess was determined by chiral SFC (chiralcel OJ column, 2 mLminÀ1
,
Conclusion
200 bar, MeOH 10%-2–1–25%, 308C, tR = 4.14 (R), 5.80 min (S)); [a]D20
= +44.5 (c=1.45 in CHCl3, 92% ee); 1H NMR (400 MHz, CDCl3): d=
9.59 (s, 1H), 7.96–7.88 (dd, J = 24.1, 7.4 Hz, 4H), 7.73–7.67 (m, 2H),
7.60–7.53 (m, 4H), 4.71–4.68 (dd, J = 9.1, 3.1 Hz, 1H), 2.94–2.90 (m,
1H), 2.54–2.47 (m, 1H), 2.17–2.11 (m, 2H), 0.99 (d, J = 7.1 Hz, 3H),
0.94 ppm (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=203.99
(1CHO), 137.89 (1Cquat.), 137.74 (1Cquat.), 134.75 (1CH), 134.57 (1CH),
129.78 (1CH), 129.37 (1CH), 129.186 (1CH), 129.14 (1CH), 80.55
(1CH), 54.67 (CH), 28.62 (1CH), 21.51 (1CH2), 19.84 (1CH3), 19.04 ppm
(1CH3); MS (EI mode): m/z (%): 396 (1), 225 (28), 169 (12), 145 (14),
143 (25), 141 (11), 134 (13), 125 (49), 97 (15), 91 (17), 83 (19), 81 (10), 79
(12), 78 (25), 77 (100), 69 (13), 67 (10), 55 (35), 51 (35); IR (CHCl3): n˜ =
3065w, 3020w, 2964w, 2928w, 2873w, 1724s, 1585m, 1448m, 1331s, 1311m,
1157s, 1079scmÀ1. HRMS (ESI): m/z: calcd for C19H22O5S2 417.08046,
found 417.08063 [M+Na]+.
We are in the “golden age of organocatalysis”, and organo-
catalytic reactions are recognized as a powerful tool for the
preparation of optically active compounds. The use of chiral
amines such as pyrrolidine analogues for the enantioselec-
tive Michael reaction via enamine activation represents an
important breakthrough in modern asymmetric synthesis.
We have demonstrated the high potential of the organocata-
lytic ACA via enamine activation by expanding the scope of
Michael acceptors. Hence, we disclosed the first intermolec-
ular enantioselective organocatalytic conjugate addition of
aldehydes to vinyl sulfones and vinyl phosphonates with
high enantioselectivity. The principle of double activation
through the presence of geminal electron-withdrawing
groups on the olefin was demonstrated for inducing reactivi-
ty. Although 2,2’-bipyrrolidine derivatives 18a–e proved to
be interesting organocatalysts for these reactions (up to
80% ee), a catalytic system with diphenylprolinol silyl ether
18k is more flexible allowing the reaction to proceed with-
out the formation of by-products in various solvents and
with excellent enantioselectivity regardless of temperature,
catalyst loading, the quantity of aldehyde, or nature of alde-
hyde (up to 99% ee). We were also gratified to see that our
methodology proceeded efficiently towards the formation of
chiral quaternary carbon centers (up to 91% ee). The deter-
mination of the absolute configuration as well as DFT calcu-
lations allowed us to postulate a Si transition state via an
acyclic synclinal Seebachꢀs model. Hence, the asymmetric in-
duction depends on highly steric shielding involving an en-
amine intermediate. This novel enantioselective organocata-
lytic ACA led to optically active g-gem-sulfonyl aldehydes
and g-gem-phosphonate aldehydes as useful tunable chiral
synthons as exemplified by various functionalizations with
conservation of the optical purity.
For the other Michael adducts 12 and their derivatives, see Supporting
Information.
ACA of aldehydes to vinyl phosphonates (General procedure 2): To a so-
lution of tetraethyl ethylidenebis(phosphonate) (7; 100 mg, 0.33 mmol,
1 equiv) in CHCl3 (3 mL) was successively added aldehyde 8 (3.33 mmol,
10 equiv) and then pyrrolidine (0.066 mmol, 20 mol%) or 18k
(0.066 mmol, 20 mol%) at RT. The reaction was monitored by TLC until
complete conversion. The reaction mixture was hydrolyzed with aq. sat.
NH4Cl (2 mL). The layers were separated and the aqueous phase was ex-
tracted with CH2Cl2 (2ꢄ3 mL). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
crude material was purified by flash column chromatography on silica gel
(CH2Cl2/EtOH 9:1) to afford 1,4-adduct 20. The enantiomeric excess
1
were determined by H and 31P NMR on imidazolidine 21–22 which were
prepared by adding successively molecular sieves and N,N-dimethyl-
1R,2R-diphenyl ethylene diamine (23; 25 mg, 0.103 mmol, 4 equiv) to a
solution of compound 20 (10 mg, 0.025 mmol, 1 equiv) in diethyl ether
(3 mL) at room temperature. After stirring overnight at room tempera-
ture, the reaction mixture was filtered over Celite, washed with diethyl
ether (2ꢄ5 mL) and concentrated in vacuo to give the diastereomeric
mixture of imidazolidine 21–22 (quant.).
(S)-2-Isopropyl-4,4’-ethylphosphonate-butanal (20a): Compound 20a was
prepared from 7 and isovaleraldehyde 8a according to GP 2. After purifi-
cation, compound 20a was obtained as a pale yellow oil (102 mg, 80%).
The enantiomeric excess was determined by 1H and 31P NMR on imida-
zolidines 21a–22a derived from compound 20a and (R,R)-diamine 23:
1H NMR (400 MHz, C6D6):
d = 4.57–4.55 (R,R,S), 4.51–4.48 ppm
(R,R,R); 31P NMR (162 MHz, C6D6): d = 25.75 (R,R,S), 25.41–25.21 ppm
(R,R,R). The absolute configuration of compound 20a was established by
analogy with imidazolidines 269b–270b derived from known Michael
adduct (S)-bis(phenylsulfonyl)ethyl)-3-methylbutanal (12a; 85% ee) and
imidazolidines 24a–25a. [a]2D0 =+21.5 (c=1.05 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=9.67 (d, J = 1.52 Hz, 1H), 4.21–4.14 (m, 8H),
2.82–2.77 (m, 1H), 2.51–2.21 (m, 2H), 2.19–2.05 (m, 1H), 1.99–1.87 (m,
1H), 1.36–1.02 (m, 12H), 1.00 (d, J = 10.1 Hz, 3H), 0.98 ppm (d, J =
6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=204.92 (1CHO), 63.12–
62.72 (m, 4CH2), 56.16–56.02 (m, 1CH), 34.61 (t, 1CH), 28.88 (1CH),
21.62 (1CH2), 20.10 (1CH3), 19.53 (1CH3), 16.61–16.55 ppm (m, 4CH3);
31P NMR (162 MHz, CDCl3): d=23.41–23.12 ppm; MS (EI mode) m/z
Experimental Section
For experimental procedures, characterizations, chiral separations, crys-
tallographic information files (CIF) and DFT calculations, see Supporting
Information.
ACA of aldehydes to vinyl sulfones (General procedure 1): To a solution
of 1,1-bis(benzenesulfonyl)ethylene (4; 50 mg, 0.162 mmol, 1 equiv) in
dry chloroform filtered on basic alumina (1.5 mL) was added aldehyde 8
(1.62 mmol, 10 equiv) at the appropriate temperature, and then pyrroli-
dine (0.08 mmol, 50 mol%) or diphenylprolinol silyl ether 18k
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A. Alexakis et al.
(%): 386 (2), 357 (11), 289 (119, 288 (100), 261 (32), 249 (20), 242 (15),
233 (14), 215 (17), 177 (12), 165 (10), 159 (13), 152 (51), 109 (11), 41 (12),
29 (17); HRMS (EI): m/z: calcd for C15H32O7P2: 386.162331 and found
386.161380 [M]+.
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For the other Michael adducts 20 and their derivatives, see Supporting
Information.
Acknowledgement
The authors thank Richard Frantz, Sꢁbastien Belot, Matthieu Tissot, and
Sandrine Perrothon for experimental help.
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Enantioselective Organocatalysis
FULL PAPER
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Received: September 15, 2008
Published online: February 9, 2009
3220
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3204 – 3220