Complete stereocontrol in organocatalytic additions of β- ketosulfoxides to conjugated aldehydes

Article abstract of DOI:10.1002/chem.201003267

The use of β-ketosulfoxides as nucleophiles in reactions with α,β-unsaturated aldehydes catalyzed by proline derivatives allows complete control of configuration at the two chiral centers that are created during 1,4-addition reactions. The sulfinyl group can be used to create additional chiral centers in the resulting compounds and then removed while preserving the chirality of the carbon joined to the sulfur. The catalyst and the sulfinyl group are mainly responsible for the configurational control of the carbon atoms acting as electrophile and nucleophile, respectively, which allows the preparation of the four possible diastereoisomers in optically pure form. Theoretical calculations of the possible chiral nucleophilic species bearing diastereotopic faces allow us to postulate, for the first time, that enolates, instead of enols, are the active reagents in these reactions.

Full text of DOI:10.1002/chem.201003267

DOI: 10.1002/chem.201003267
Complete Stereocontrol in Organocatalytic Additions of b-Ketosulfoxides to
Conjugated Aldehydes
Josꢀ Luis Garcꢁa Ruano,*[a] Cuauhtꢀmoc Alvarado,[a] Sergio Dꢁaz-Tendero,[b] and
Josꢀ Alemꢂn*[a]
Abstract: The use of b-ketosulfoxides
as nucleophiles in reactions with a,b-
unsaturated aldehydes catalyzed by
proline derivatives allows complete
control of configuration at the two
chiral centers that are created during
1,4-addition reactions. The sulfinyl
group can be used to create additional
chiral centers in the resulting com-
pounds and then removed while pre-
serving the chirality of the carbon
joined to the sulfur. The catalyst and
the sulfinyl group are mainly responsi-
ble for the configurational control of
the carbon atoms acting as electrophile
and nucleophile, respectively, which
allows the preparation of the four pos-
sible diastereoisomers in optically pure
form. Theoretical calculations of the
possible chiral nucleophilic species
bearing diastereotopic faces allow us to
postulate, for the first time, that eno-
lates, instead of enols, are the active re-
agents in these reactions.
Keywords: chiral auxiliaries · enan-
tioselectivity · Michael addition ·
organocatalysis · sulfoxides
Introduction
Nucleophilic additions to a,b-unsaturated aldehydes cata-
lyzed by pyrrolidines have become one of the most popular
reactions in organocatalysis.[1] Despite this, these reactions
suffer some limitations that seriously restrict their useful-
ness. The main challenge concerns the use of prochiral nu-
cleophilic carbon atoms for the simultaneous creation of
two connected chiral tertiary carbons, due to the usually low
stereoselective control exerted by the catalyst on the carbon
atom acting as the nucleophile in the reaction. The first ami-
nocatalytic example of the use of prochiral nucleophiles was
the addition of b-ketoesters to a,b-unsaturated aldehydes,[2]
which was reported by Ley and Jørgensen and co-work-
ers.[2a,b] Later, Jørgensen reported the addition of b-ketoest-
ers to different iminum intermediates.[2c] In most of these
cases, reactions result in the formation of almost unselective
mixtures of epimers at the g-position (the nucleophilic
center), but with almost complete stereoselective control at
the b-position (the electrophilic center) of the aldehyde
(Scheme 1). This problem is usually solved by elimination of
the ester function (in many cases by applying harsh acidic
and basic conditions), which results in the disappearance of
Scheme 1. Problems of using prochiral nucleophilic carbon atoms.
chirality at the g-carbon atom. Thus, stereoselective forma-
tion of two tertiary-vicinal chiral centers in the same syn-
thetic step remains elusive in these reactions. Another strat-
egy[3] involves the formation of cyclic compounds that easily
epimerize (due to the high acidity of the proton at the
carbon acting as nucleophile) into the most stable isomer,
which is obtained in high diastereomeric ratio (d.r.). Howev-
er, this indirect method has also serious restrictions because
it is limited to cyclic compounds.
At this point, we reasoned that the use of reagents bear-
ing chiral auxiliaries able to control the configuration at the
nucleophilic center could provide an appropriate solution
for the preparation of acyclic compounds with two connect-
ed chiral carbons. Reactions of these nucleophiles with a,b-
unsaturated aldehydes catalyzed by pyrrolidines could be
considered to be examples of double asymmetric induction
applied to the organocatalysis (with the catalyst and the
auxiliary acting as chiral elements), which has rarely been
explored.[4] In the best of the cases, each one of the chiral el-
ements in the starting products could be responsible for the
control at one of the two created chiral centers, thus allow-
ing the preparation of any of the four possible diastereoiso-
mers in high optical purity by choosing the configuration of
[a] Prof. Dr. J. L. Garcꢀa Ruano, Dr. C. Alvarado, Dr. J. Alemꢁn
Departamento de Quꢀmica Orgꢁnica (Modulo-1)
Universidad Autꢂnoma de Madrid (Spain)
Fax : (+34)91497466
E-mail: joseluis.garcia.ruano@uam.es
jose.aleman@uam.es
[b] Dr. S. Dꢀaz-Tendero
Departamento de Quꢀmica (Modulo 13)
Universidad Autꢂnoma de Madrid (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003267.
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FULL PAPER
the catalyst and the auxiliary. An additional advantage of
this method is that the presence of the auxiliary in the re-
sulting products allows the creation of new chiral centers
before its removal. Furthermore, the use of chiral nucleo-
philes would allow the course of the reactions of b-ketoest-
ers and derivatives to be studied in more detail and would
clarify the nature of the species acting as nucleophiles (enols
or enolates).[1h] The correlation between the relative stability
of the species acting as nucleophiles (determined by density
functional theory calculations), which bear diastereotopic
faces that are sterically differentiated, and the obtained ste-
reochemical results, could provide valuable information con-
cerning the nature of the active species.
Results and Discussion
We started our study with the reactions of (E)-2-pentenal
(1a) with enantiomerically pure (R)-2-p-tolylsulfinylmethyl
phenyl ketone[5] [(R)-2A] catalyzed by silylprolinol ether
(S)-3a (Table 1). After 18 h at room temperature in CH2Cl2,
Table 1. Screening the reaction of 1a with 2A.[a]
To minimize the inherent limitations in the use of enantio-
pure compounds as starting materials, the substrates must
be easily synthesized from commercially available com-
pounds, or through trivial procedures. Moreover, the remov-
al of the auxiliary must be possible without affecting the
previously created chirality. b-Ketosulfoxides fulfill all these
requirements. They are prepared in high yields by direct re-
action of commercially available (R)- or (S)-p-tolylmethyl
sulfoxide and the corresponding esters in the presence of
lithium diisopropylamide (LDA).[5] Additionally, the sulfinyl
group can be removed in multiple ways, some of them in-
volving stereoselective reactions that preserve the configura-
tional integrity of the carbon joined to the sulfur atom.[6]
Moreover, the sulfinyl group has been shown to be efficient
at controlling the configuration at its a-carbon in reactions
of a-sulfinylcarbanions with electrophiles.[6] Concerning Mi-
chael additions, reactions of simple a-sulfinylcarbanions[7]
have provided good stereochemical results,[7b,c] whereas acti-
vated sulfinylmethylenes reacted with unsaturated esters in
very low stereoselectivity (although this could be improved
with cyclopentenone substrates).[7d] Thus, we decided to ex-
plore the behavior of b-ketosulfoxides in reactions with a,b-
unsaturated aldehydes, catalyzed by pyrrolidine derivatives.
This reaction, and the subsequent asymmetric transforma-
tions of the resulting compounds, which allowed the number
of chiral centers to be increased before removing the sulfi-
nyl group, are reported here (Scheme 2).
Entry
Solvent
CH2Cl2
Cat
Time [h]
Conversion [%]
d.r.[b]
1
2
3
4
5
6
7
8
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(R)-3a
(S)-3b
(S)-3b
(R)-3b
(R)-3b
(R)-3b
(R)-3b
3c
18
18
18
18
18
18
18
18
9[h]
18
40
20[h]
24
24
24
40
17
>98:2
>98:2
>98:2
–
[c]
CH2Cl2
CH2Cl2
[d]
37
CH3CN
hexane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
toluene
toluene
n.r.[e]
69
92
90
72:28
90:10
72:28
>98:2
>98:2
94:6
94:6
95:5
95:5
–
>99 (86)[g]
>99 (75)[g]
80
9
10
11
12
13
14
15
>98 (68)[g]
>99 (76)[g]
55
[f]
–
–
n.r.[e]
–
[a] All reactions were performed on a 0.2 mmol scale in 0.4 mL of sol-
vent. [b] Determined by 1H NMR analysis of the crude reaction mixture
by integration of well-defined signals. [c] 20 mol% PhCO2H was added
as an additive. [d] 20 mol% LiOAc was added as an additive. [e] No reac-
tion. [f] A complex mixture was formed. [g] Yield of isolated product.
[h] Reaction performed at 408C.
40% conversion was observed and only one diastereoisomer
could be identified in the crude reaction mixture (Table 1,
entry 1). The use of additives (benzoic acid and lithium ace-
tate) did not improve the conversion and only poor yields of
4Aa were obtained (Table 1, entries 2 and 3). No reaction
was observed in CH3CN (Table 1, entry 4), whereas in
hexane a mixture of diastereoisomers was obtained (Table 1,
entry 5). The best conversion was obtained in toluene, but
the stereoselectivity was slightly lower, giving a 90:10 mix-
ture of isomers after 18 h (Table 1, entry 6). Use of the
enantiomer (R)-3a as catalyst in toluene, afforded a 72:28
mixture of two diastereoisomers (Table 1, entry 7). These re-
sults were improved by using a bulkier catalyst. Thus, when
(S)-3b was used in toluene, full conversion into only one
diastereomer (4Aa) was obtained after 18 h (Table 1,
entry 8). Almost complete control of the stereoselectivity
was also observed by using (R)-3b as the catalyst (Table 1,
entries 10–13), making it possible to obtain epi-4Aa in high
yields. These reactions were slightly slower and, after 18 h
Scheme 2. Results reported in this work.
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J. L. Garcꢀa Ruano, J. Alemꢁn et al.
(time required for (S)-3b), the conversion was 80% in tolu-
ene (Table 1, entry 10; d.r.=94:6) and 55% in CH2Cl2
(Table 1, entry 13; d.r.=95:5); thus it was necessary to in-
crease the reaction time to 40 h to obtain full conversion in
toluene (Table 1, entry 11). Finally, we also studied the reac-
tion of 1a and (R)-2A catalyzed by pyrrolidine (3c), but
low conversion and the formation of a complex mixture was
obtained (Table 1, entry 14). At this point, the influence of
the temperature on the reaction course was studied. When
reactions of 1a with 2A catalyzed by both (S)-3b and (R)-
3b, were performed at 408C in toluene, the required reac-
tion times for completion were reduced by half (compare
Table 1, entries 8 with 9 and 11 with 12). Fortunately, the in-
crease in temperature did not affect the stereoselectivity,
which remained unaltered. The use of higher temperatures
provoked desulfinylation, thus affording complex mixtures.
The reaction did not proceed in the absence of catalyst and
the starting material was recovered (Table 1, entry 15),
which suggested that the reaction required the LUMO
energy of the aldehyde to be lowered by its association to
the catalyst.
(80% yield and d.r.=98:2), indicating that the reaction is
not significantly affected by the amount of starting materials
(Table 2, entry 3). Enals with aromatic residues also reacted
with complete control of the stereoselectivity (Table 2, en-
tries 6–10) regardless the electronic effect of the substitu-
ents, although these substituents did exert a clear influence
on the reaction rate, which decreased with a p-MeO substi-
tuted group (Table 2, entry 7) but was not affected by a o-
MeO substituted moiety (Table 2, entry 8), presumably due
to the lost of planarity.
Electron-withdrawing groups led to incomplete conver-
sions, even with extended reaction times (Table 2, entries 9
and 10). The behavior of b-ketosulfoxides bearing alkyl
chains instead of aryl groups (2B–D) was also studied
(Table 2, entries 11–13). Compounds 2B (R2 =Me), 2C
(R2 =nPr), and 2D (R2 =iPr) reacted with 1e, yielding 4Be,
4Ce, and 4De, respectively, in a completely stereoselectivity
manner (Table 2, entries 11–13). The reactivity decreased
when the size of R2 was increased, but full conversion was
not observed in any case, even when the reaction times were
extended.
As the conditions given in Table 1, entry 8 seemed to be
optimal for reactions catalyzed by (S)-3b avoiding desulfiny-
lation, we first explored the scope of the reaction by study-
ing the reaction of aldehydes 1a–i with a range of b-keto-
sulfoxides 2A–D in toluene (Table 2). Enals 1a–d, bearing
aliphatic chains, reacted with 2A to exclusively yield the re-
spective diastereoisomers 4Aa–Ad in good yields (Table 2,
entries 1–5). All reactions were performed on a 0.2 mmol
scale in 0.2 mL of toluene. The reaction of 1b with 2A was
also performed on a 2.0 mmol scale, with similar results
We then studied the Michael reactions of (R)-2A with
enals 1a, 1b, and 1e by using (R)-3b as the catalyst and tol-
uene as solvent at 408C (Scheme 3). These reactions evolved
Scheme 3. Synthesis of some epimers of 4A by using (R)-3b as the cata-
lyst.
Table 2. Scope of the reaction of aldehydes 1a–i with b-sulfinylketones
(R)-2A–D catalyzed by (S)-3b.[a]
in a highly (but not completely) stereoselective manner, af-
fording compounds epi-4A (only differing from 4A in the
configuration at the b-carbon with respect to the carbonyl
group) as the major isomers, which were obtained in high
yields (Scheme 3) after straightforward chromatographic pu-
rification. The formation of these compounds indicates that
the catalyst controls the configuration at the electrophilic
center, whereas the configuration at the nucleophilic center
is mainly controlled by the sulfoxide. This means that the
preparation of all possible diastereoisomers in optically pure
form can be accomplished by judicious choice of the catalyst
and of the sulfinyl configuration at the starting ketosulfox-
ide.[8]
Because we were unable to obtain suitable crystals of
compounds 4, unequivocal configurational assignment was
performed with the corresponding diols 5, which were ste-
reoselectively obtained by reduction (Table 3). The most ste-
reoselective reduction was observed by using two equiva-
lents of lithium aluminum hydride (LiAlH4) in THF at 08C
(other reagents or conditions gave inferior results). This
Entry
Enal (R1)
2A–D (R2)
Time
[h]
Product
AHCTUNGTRENNG(UN yield [%])
d.r.[b]
1
2
3
4
5
6
7
8
1a (Et)
1b (Me)
1b (Me)
1c (nBu)
1d (n-Hexyl)
1e (Ph)
1 f (p-MeOPh)
1g (o-MeOPh)
1h (p-BrPh)
1i (p-NO2Ph)
1e (Ph)
2A (Ph)
2A (Ph)
2A (Ph)
2A (Ph)
2A (Ph)
2A (Ph)
2A (Ph)
2A (Ph)
2A (Ph)
2A (Ph)
2B (Me)
2C (n-Pr)
2D (iPr)
18
18
18
40
40
30
48
18
48
48
24
30
60
4Aa (86)
4Ab (88)
4Ab (80)[c]
4Ac (73)
4Ad (80)
4Ae (72)
4Af (84)[e]
4Ag (71)
4Ah (40)[d]
4Ai (31)[d,e]
4Be (58)[d]
4Ce (51)[d]
4De (35)[d]
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
9
10
11
12
13
1e (Ph)
1e (Ph)
[a] All reactions were performed on a 0.2 mmol scale in 0.4 mL of tolu-
ene and stopped after full conversion. [b] Determined by H NMR analy-
sis of the crude reaction mixture. [c] Reaction carried out on a 2.0 mmol
scale. [d] Full conversion not reached at the indicated time. [e] This prod-
uct was reduced to the alcohol 5 for isolation, see Table 4. [f] Reaction
performed at 408C.
1
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Stereocontrolled Michael Addition
FULL PAPER
Table 3. Reduction of ketosulfoxides with LiAlH4.
Configurational assignment of compound epi-4Ab was
performed by chemical correlation with its diastereoisomer
4Ab. As sulfones 7Ab and epi-7Ab, obtained by oxidation
of both compounds, have different NMR parameters, we
can conclude that they differ in only one chiral center,
which must be the nucleophilic center (C-g), because the
electrophilic center (C-b) was clearly controlled by the cata-
lyst, 3b or ent-3b (Scheme 4).
Entry Starting
material
R2
Ph
R1
Product Yield [%] d.r.[b]
1
2
3
4
5
6
4Ab
4Ce
4Ac
4Af
4Ai
4Ae
Me
5Ab
78
55
82
95:5
95:5
95:5
95:5
95:5
nPr Ph
5Ce
5Ac
Ph
Ph
Ph
Ph
nBu
p-MeO-C6H4 5Af
p-NO2-C6H4
Ph
84[a]
31[a]
65
5Ai
5Ae
>98:2
[a] These reactions were performed in a one-pot process from the corre-
sponding b-ketosulfoxide, applying the conditions described in Tables 2
and 3 (see the Supporting Information). [b] Determined by 1H NMR
analysis of the crude reaction mixture.
transformation illustrates the possibility of creating addition-
al chiral centers controlled by the chiral auxiliary.
A range of aromatic and alkyl substituted substrates 4
were assayed, and good diastereomeric ratios and yields
ranging from moderated to good were obtained in all cases
(Table 3). We could obtain suitable crystals for X-ray analy-
sis only in the case of compound 5Ce[9] (Figure 1, R2 =nPr),
Scheme 4. Correlation and determination of the configuration from ent-
4Aa.
Finally, removal of the chiral auxiliary under conditions
that preserved the stereochemical integrity of compounds 5,
containing three chiral carbons, was studied. Conversion of
5Ce into epoxide 6Ce (Scheme 5) was performed by pro-
Scheme 5. Removal of the sulfinyl group while preserving the configura-
tional integrity of the substrate.
Figure 1. X-ray ORTEP representation of 5Ce.
which allowed unequivocal assignment of its absolute con-
figuration as (RS,3S,4S,5R), which, in turn, means that the
configuration of its precursor 4Ce is (RS,3S,4S). This config-
uration was also assigned to the rest of the compounds 4 (all
of which exhibited similar NMR parameters). It is notewor-
thy that the S configuration assigned to C-3 in compounds 4
is expected for reactions of nucleophiles with conjugated al-
dehydes catalyzed by (S)-3b.[10]
Scheme 6. Mechanistic proposal for the formation of 6Ce.
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J. L. Garcꢀa Ruano, J. Alemꢁn et al.
tecting the primary alcohol with triisopropylsilyl chloride
(ClTIPS; not isolated), reducing the sulfinyl into sulfenyl
group with trifluoroacetic anhydride (TFAA)/NaI (not iso-
lated), and finally treating the thioether with the Me3OSbCl5
salt and then with NaHCO3 (typical method for obtaining
epoxides[11]).
thesis shown in Scheme 5 can be explained by assuming that
the methylation with Me3OSbCl5 salt took place on the
OTIPS moiety instead of the STol group (Scheme 6). This
oxonium intermediate evolved in an intramolecular manner
by attack of the sulfur into the five-membered cyclic sulfoni-
um salt, which was finally opened by the free hydroxyl
group, affording the epoxithioether 6Ce.
The unexpected formation of epoxithioether 6Ce instead
of the protected hydroxyepoxide in the last step of the syn-
Table 4. Absolute energies (in hartrees) obtained at the B3LYP/6-311++GACTHNUTRGENUGN(3df,2p)//B3LYP/6-31G(d) level, zero-point energy (in hartrees) at the
B3LYP/6-31G(d) level, relative energies (kcalmolÀ1) including the ZPE correction and structure of the most stable conformations of (Z) and (E)-b-sulfi-
nyl enols (the starting geometry point shows the “initial guess” for the geometry and the final structure the optimized geometry).
Enol
Starting geometry
Final structure
E [a.u.]
ZPE
[a.u.]
DE
N
[kcalmolÀ1
]
A
À1089.57950
0.22514
0.00
B
À1089.57137
0.22495
4.98
C
À1089.56718
0.22487
7.56
D
À1089.56109
0.22498
11.45
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Stereocontrolled Michael Addition
FULL PAPER
Table 5. Absolute energies (in hartrees) obtained at the B3LYP/6-311++GACTHNUTRGENUGN(3df,2p)//B3LYP/6-31G(d) level, zero-point energy (in hartrees) at the
B3LYP/6-31G(d) level, relative energies (kcalmolÀ1) including the ZPE correction and structure of the four possible stereoisomers of the b-sulfinyl
anion (the starting geometry point shows the “initial guess” for the geometry and the final structure the optimized geometry).[a]
Enolate
Starting geometry
Final structure
E [a.u.]
ZPE
[a.u.]
DE
N
[kcalmolÀ1
]
E
À1089.03122
0.21090
2.46
F
À1089.03496
0.21072
0.00
G
À1089.03386
0.21126
1.03
H
À1089.02974
0.21150
3.76
DFT Calculations
um of the ketosulfoxide into its enolic form, two possible
species, enol and enolate, could act as nucleophile. Despite
the fact that this dual possibility exists for any -CO-CH2-
EWG grouping, to the best of our knowledge, no proposal,
supported by theoretical or experimental data, has been re-
ported in the literature concerning the nature of the species
To understand the observed enantio- and diastereoselectiv-
ity in these reactions, the unequivocal identification of the
species acting as nucleophile was necessary. As the pKa of
the catalyst is not sufficient to completely shift the equilibri-
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J. L. Garcꢀa Ruano, J. Alemꢁn et al.
acting as nucleophile in these reactions.[15] This could be be-
cause the low selectivity observed would be expected for
both enols and enolates with diastereotopic faces scarcely
differentiated on steric or electronic grounds. In our case,
the presence of the chiral auxiliary at the nucleophile must
produce a clear differentiation of the faces, which should be
correlated with the stereochemical results. To investigate
this question, density functional theory calculations[12] on the
À
conformational stability around the C S bond for the (Z)
and (E) b-sulfinylenols derived from (R)-2A were per-
formed (Table 4). A similar study was made for the corre-
sponding enolates (Table 5). Four structures were obtained
in each case (enols and enolates, Tables 4 and 5, respective-
ly). Results obtained for the enols (Table 4) indicate that
conformation A of the (Z) isomer, is clearly favored over
conformation B of the same enol (by 4.98 kcalmolÀ1) and
even more with respect to conformations C and D of the
(E) isomer (by 7.56 and 11.45 kcalmolÀ1 respectively). Hy-
drogen bonding could explain these differences. Conforma-
tion A is strongly stabilized by association of the sulfinyl
oxygen with the hydroxyl group, whereas the hydrogen
bond formed between the sulfur and the hydroxyl group
present in the B rotamer must be less strong. For conform-
ers C and D, the most stable conformations for the (E)-enol,
are clearly less stable, presumably due to the lack of these
bonds. The stability differences are so large that we can
assume that enol molecules will adopt the A conformation.
The situation is not so clear for enolates (Table 5). Con-
formation F of the (Z) isomer is more stable than conforma-
tion G of the (E) enolate, but only by 1.02 kcalmolÀ1. The
lower steric repulsion and the possible formation of hydro-
gen bonds between the enolic oxygen and the sulfinyl
oxygen[13] with the ortho-protons of the aromatic ring joined
to sulfur, could be partially responsible of the stability of
conformation F. Moreover, conformations E and H are de-
stabilized with respect to conformation F by 2.46 and
3.76 kcalmolÀ1, respectively. These differences are too small
to predict a negligible population of any of the conforma-
tions. However, as shown in Table 5, the approach of the
electrophile to the lower face of the most stable F confor-
mation is clear of significant steric interactions, whereas in
the other three conformations shown in Table 5, both faces
of the enolate are hindered to some degree by the sulfinyl
oxygen and the phenyl group, and therefore must exhibit a
lower reactivity. This analysis suggests that the stereochemi-
cal behavior of the enolates can be predicted on the basis of
the F conformation. These theoretical calculations have also
been performed by taking into account the solvent used in
the reactions (toluene); the results obtained were, however,
almost identical in all cases.[14]
Figure 2. Favored approaches of the electrophiles to the most stable and/
or reactive conformations of enols (A) and enolates (F) of (R)-2A.
tacked by the electrophile on their pro-R-face, whereas the
preferred attack on the enolates must take place on their
pro-S-face (Figure 2). As products 4 obtained from (R)-2
(Table 2) have the S configuration at the carbon joined to
the sulfur, we can conclude that enolates are the species
acting as nucleophiles in these reactions.
Conclusion
The use of enantiomerically pure b-ketosulfoxides as nucle-
ophiles in 1,4-additions to a,b-unsaturated aldehydes cata-
lyzed by proline derivatives allows complete control of the
two chiral centers to be simultaneously created in the reac-
tion. Because the catalyst and the sulfinyl group mainly con-
trol the configuration of the carbon atoms acting at the elec-
trophile and nucleophile, respectively, the method allows
the preparation of all four possible diastereoisomers in opti-
cally pure form. Advantage can be taken of the presence of
the sulfinyl group in the resulting compounds for further ste-
reoselective transformations before its removal, which can
be made while preserving the configurational integrity. The-
oretical calculations concerning the relative stability of the
most stable conformations for enols and enolates derived
from b-ketosulfoxides, strongly supports the proposed inter-
mediacy of enolates as the only species able to explain the
observed stereochemical results.
Acknowledgements
Financial support from the Spanish Government (CTQ-2009-12168) and
CAM (programa AVANCAT CS2009/PPQ-1634) is gratefully acknowl-
edged. J. A. and S. D. T thank MICINN for “Ramon y Cajal” contracts
and C. A. thanks the Consejo Nacional de Ciencia y Tecnologꢀa de
Mꢄxico for a postdoctoral fellowship. We gratefully acknowledge compu-
tational time provided by the Centro de Computaciꢂn Cientꢀfica at the
Universidad Autꢂnoma de Madrid CCC-UAM.
In Figure 2 we have depicted the expected evolution of
the most stable and reactive conformations of enols (A con-
formation) and enolates (F conformation), in which the
structure of the iminium ion[15] is represented as E+. By as-
suming steric control of the approach (the favored attack of
the electrophile takes place on the opposite face to that oc-
cupied by the p-tolyl group), enols will be preferentially at-
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ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 4030 – 4037

Stereocontrolled Michael Addition
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[8] We have obtained the four possible diastereoisomers of 4Ae (two
pairs of enantiomers) by reactions of (R) and (S)-2A with 1e in the
presence of (R) and (S)-3a. We could check by chiral HPLC that
the ee of the alcohols resulting from their LiAlH4-mediated reduc-
tion (the aldehydes decompose during HPLC analysis) are higher
than 99% (see the Supporting Information for more details).
[15] Attack of the nucleophile on the iminium ion takes place from the
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Received: November 13, 2010
Published online: February 25, 2011
Chem. Eur. J. 2011, 17, 4030 – 4037
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4037