Highly stereoselective aldol reactions of lithium ester enolates with (Rs)-2-(p-tolylsulfinyl)cyclohexanones

Article abstract of DOI:10.1021/jo961643t

Aldol reactions lithium alkyl acetates (LiCRR″CO₂R′) with (R_S)-2-(p-tolylsulfinyl)cyclohexanone (1) (as an epimeric mixture at C-2) take place with very efficient control of the configuration at the tertiary hydroxylic carbon (C-1). Stereoselectivity becomes complete if R and/or R″ are not hydrogen. Only carbinols derived from (S₂,R_S)-1 epimer were obtained, the major ones being those exhibiting S configuration (opposite to that of the sulfur) at the hydroxylic carbon. When LiCHRCO₂R′ is used, mixtures of the two epimers at the new stereogenic center C-1′ are obtained (～10-82% de), their proportion being dependent on the size of R. The use of lactone enolates avoids the formation of epimeric mixtures, affording only one diastereoisomer with an (R_3′-,S₁,S₂,R_S) configuration at the four adjacent chiral centers. Tricoordinated lithium species, which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates, are invoked to explain the stereoselectivity observed in these aldol reactions with sulfinyl ketones as electrophiles.

Full text of DOI:10.1021/jo961643t

9462
J . Org. Chem. 1996, 61, 9462-9470
High ly Ster eoselective Ald ol Rea ction s of Lith iu m Ester En ola tes
w ith (RS)-2-(p-Tolylsu lfin yl)cycloh exa n on es
J ose´ L. Garc´ıa Ruano,*,† David Barros,† M. Carmen Maestro,*,† Ramiro Araya-Maturana,‡ and
J ean Fischer§
Departamento de Quı´mica Orga´nica, Universidad Auto´noma, Cantoblanco 28049-Madrid, Spain,
Departamento de Quı´mica, Facultad de Ciencias, Universidad de Chile, casilla 653, Santiago, Chile, and
Laboratoire de Cristallochimie, UA 424, Universite´ Louis Pasteur, 67070-Strasbourg, France
Received August 26, 1996X
Aldol reactions lithium alkyl acetates (LiCRR′′CO2R′) with (RS)-2-(p-tolylsulfinyl)cyclohexanone
(1) (as an epimeric mixture at C-2) take place with very efficient control of the configuration at the
tertiary hydroxylic carbon (C-1). Stereoselectivity becomes complete if R and/or R′′ are not hydrogen.
Only carbinols derived from (S2,RS)-1 epimer were obtained, the major ones being those exhibiting
S configuration (opposite to that of the sulfur) at the hydroxylic carbon. When LiCHRCO2R′ is
used, mixtures of the two epimers at the new stereogenic center C-1′ are obtained (∼10-82% de),
their proportion being dependent on the size of R. The use of lactone enolates avoids the formation
of epimeric mixtures, affording only one diastereoisomer with an (R3′,S1,S2,RS) configuration at
the four adjacent chiral centers. Tricoordinated lithium species, which involve the enolate and
the sulfinyl and carbonyl oxygens of the substrates, are invoked to explain the stereoselectivity
observed in these aldol reactions with sulfinyl ketones as electrophiles.
Asymmetric aldol reactions are among the most pow-
has been extended to N,N-dimethylacetamide derivatives
with good results8 (only in the case of aldehydes), whereas
reaction of magnesium enolates of R-sulfinyl ketones with
several aldehydes proceeds with modest stereoselectiv-
ity.9 Our experience in the field of asymmetric synthesis
mediated by sulfoxides10 has allowed us to show the high
efficiency of the sulfinyl group in the stereochemical con-
trol of the reduction,11 alkylation,11a,12 and hydrocyana-
tion11a,13 processes of R-sulfinyl ketones. Additionally,
other authors have been able to perform reactions of eno-
lates with N-sulfinylimines with high selectivity.14 De-
spite this efficiency, no studies concerning the use of
R-sulfinyl ketones as chiral electrophiles in aldolic reac-
tions have been reported as far as we know. This has
prompted us to investigate the behavior of optically pure
â-keto sulfoxides with enolates. In this paper we report
the results obtained in the aldol reactions of 2-(p-
tolylsulfinyl)cyclohexanone (1) with the lithium enolates
derived from different esters and lactones. Our results
reveal that the sulfinyl group on the electrophilic moiety
is also a very effective chiral auxiliary that produces
highly stereoselective aldol reactions.
erful methods for the stereochemical control in natural
products synthesis. Absolute and relative stereochem-
istries of these reactions can be controlled by the use of
chiral enolates, substrates, or catalysts, with hundreds
of papers and some excellent comprehensive reviews1
covering this topic. Most of these reports are related to
the aldehydes, the number of papers concerning the use
of ketones being significantly lower. In these cases, chiral
ketones have been mainly used as a source of enolate,
whereas very few stereoselective reactions have been
reported with ketones acting as electrophiles. In this
sense, the results attained in reactions of chiral enolates
with ketones2 or achiral enolates with chiral ketones3
usually show moderate stereoselectivity.
The sulfinyl group has been used as a chiral auxiliary
in asymmetric aldol reactions. Thus, it has been reported
by Solladie´ et al. that reactions of magnesium enolates
derived from R-sulfinyl acetates (lithium enolates do not
react) with aldehydes and some ketones take place with
very high diastereofacial selectivity.4 Several synthetic
applications of these chiral enolates have been devel-
oped.5 Nevertheless, attempts to extend the methodology
to R-sulfinyl6 and â-sulfinyl7 derivatives of other esters
have achieved only moderate success. Solladie´’s method
Resu lts a n d Discu ssion
The synthesis of the starting sulfinylcyclohexanone 1
was performed by sulfinylation of cyclohexanone N-
† Universidad Auto´noma de Madrid.
‡ Universidad de Chile.
(6) Solladie´, G.; Matloubi-Moghadam, F.; Luttmann, C.; Mioskowski,
C. Helv. Chim. Acta 1982, 65, 1602.
§ Universite´ Louis Pasteur.
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) (a) Evans, D. A.; Nelson, J . V.; Taber, T. R. Top. Stereochem.
1982, 13, 1. (b) Heathcock, C. H. In Asymmetric Synthesis; Morrison,
J . D., Ed.; Academic Press: New York, 1984; Vol. 3, p 111. (c)
Heathcock, C. H.; Moon Kim, B.; Williams, S. F.; Masamune, S.;
Paterson I.; Gennari, C. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol 2. (d)
Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1995, 317.
(2) (a) Bartroli, J .; Turmo, E.; Belloc, J .; Forn, J . J . Org. Chem. 1995,
60, 3000 and references cited therein. (b) Pausler, G. M.; Rutledge, P.
S. Tetrahedron Lett. 1994, 35, 3345
(3) (a) Akiyama, T.; Ishikawa, K.; Ozaki, S. Synlett 1994, 275. (b)
Guanti, G.; Riva, R. Tetrahedron Lett. 1995, 36, 3933.
(4) (a) Mioskowski, C.; Solladie´, G. Tetrahedron 1980, 36, 227. (b)
Solladie´, G. Synthesis 1981, 185. (c) Solladie´, G. Chimia 1984, 38, 233.
(5) (a) Corey, E. J .; Weigel, L. O.; Chamberlin, A. R.; Cho, H.; Hua,
D. H. J . Am. Chem. Soc. 1980, 102, 6613. (b) Solladie´, G.; Matloubi-
Moghadam, F. J . Org. Chem. 1982, 47, 91.
(7) Albinati, A.; Bravo, P.; Ganazzoli, F.; Resnati, G.; Viani, F. J .
Chem. Soc., Perkin Trans. 1 1986, 1405.
(8) Annunziata, R.; Cinquini, M.; Cozzi, F.; Montanari, F.; Restelli,
A. J . Chem. Soc., Chem. Commun. 1983, 1138; Tetrahedron 1984, 40,
3815.
(9) Schneider, F.; Simon R. Synthesis 1986, 582.
(10) Carren˜o M. C. Chem. Rev. 1995, 1717.
(11) (a) Garc´ıa Ruano, J . L. Phosphorus, Sulfur Silicon 1993, 74,
233 and references cited therein. (b) Bueno, A. B.; Carren˜o, M. C.;
Garc´ıa Ruano, J . L.; Pen˜a, B.; Rubio, A.; Hoyos, M. A. Tetrahedron
1994, 50, 9355.
(12) Bueno, A. B.; Carren˜o, M. C.; Garc´ıa Ruano, J . L. An. Quı´m.
1992, 90, 442.
(13) (a) Garc´ıa Ruano, J . L.; Mart´ın Castro, A. M.; Rodriguez, J . H.
J . Org. Chem. 1992, 57, 7235. (b) Escribano, A.; Garc´ıa Ruano, J . L.;
Mart´ın Castro, A. M.; Rodriguez, J . H. Tetrahedron 1994, 50, 7567.
(14) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y. J . Org.
Chem. 1996, 61, 440 and references cited therein.
S0022-3263(96)01643-X CCC: $12.00 © 1996 American Chemical Society

Aldol Reactions of Lithium Ester Enolates
J . Org. Chem., Vol. 61, No. 26, 1996 9463
Sch em e 1
Ta ble 1. Ad d ition of R2CHCO2R′ Lith iu m En ola tes to 1
entry
compd
R
R′
a:b
yield (%)
1
2
3
4
3
2
4
8
H
H
H
Me
Me
Et
t-Bu
Et
91:9
93:7
96:4
88
92
81
90
100:0
phenylimine, according to the previously reported
method,15 to yield a 75:25 mixture of the two epimers at
C-2. The above mixture was used, without previous
separation, in all the reactions with enolates reported
herein. The results obtained in reactions of 1 with
lithium enolates from alkyl acetates and ethyl 2-meth-
ylpropanoate are shown in Scheme 1 and Table 1.
The addition of keto sulfoxide 1 (as a 75:25 epimeric
mixture at C-2) over a THF solution of 2 equiv of ethyl
acetate lithium enolate16 affords a 93:7 mixture of the
two diastereoisomeric hydroxy esters 2a and 2b. The use
of methyl or tert-butyl acetates as the source of the
corresponding enolates slightly modifies the stereoselec-
tivity of the reaction (Table 1, entries 1-3). The major
diastereoisomer of each mixture can be obtained in
optically pure form by a single crystallization (de > 97%
F igu r e 1. Significant conformations around the C-S bond
for diastereomers of compounds 2-4.
Sch em e 2
1
by H NMR). Chromatographic separation of the 96:4
mixture of the hydroxy esters 4a and 4b, obtained from
tert-butyl acetate, allowed the isolation and characteriza-
tion of the minor component 4b.17
The configurational assignment of the diastereoisomers
1
a and b was ascertained from their H NMR parameters,
assuming that the sulfur configuration remains unaltered
under the reaction conditions. The equatorial arrange-
ment of the sulfinyl group in the favored conformation
of both isomers could be deduced from the axial orienta-
tion of their C-2 protons [3J vic(CDCl3) ≈ 12.5 and 3.8 Hz].
The hydroxy group signal [δ (CDCl3) ∼4.25 ppm] of the
major isomers 2a -4a appears as a doublet due to the
In order to know the configuration of the minor isomers
2b-4b, we have effected the following transformations
(Scheme 2). A 75:25 mixture of 2a + 2b19 was oxidized
with m-CPBA, yielding a mixture of diastereomeric
sulfones 5a + 5b, in the same proportion as the starting
1
sulfoxides. Since both sulfones have different H NMR
long-range coupling with the axial C-6 proton (4J OH,6
≈
spectra, they must be epimers in only one of their chiral
centers, either C-1 or C-2. The same must be true for
their precursor sulfoxides. The reduction of the 2a + 2b
mixture with TFAA/NaI, yielding the corresponding
diastereoisomeric sulfides 6a + 6b, confirms the above
statement. The pyrolytic sulfinyl elimination from the
same mixture of 2a + 2b yielded compound 7 as a
mixture of enantiomers, in the same proportion as the
starting sulfoxides.20 This fact demonstrates that sul-
foxides 2a and 2b have the opposite configuration at C-1
and, therefore, identical configurations at C-2 and sulfur.
Thus, the (R1,S2,RS) configuration must be assigned to
the minor diastereoisomer 2b and, accordingly, to the
minor components of the mixtures obtained from methyl
and tert-butyl acetates 3b and 4b, respectively. It is
remarkable that only the hydroxy sulfoxides derived from
diastereoisomer (S2,RS)-1 were obtained in these reac-
1.4). These data indicate a relative W planar arrange-
ment and suggest a strong intramolecular hydrogen bond
between the hydroxy and sulfinyl groups.18 In Figure 1,
we have depicted the presumably most stable conforma-
tions around the C-S bond in the four possible diastere-
oisomers of compounds 2-4, assuming unaltered sulfur
configuration. From this figure, it can be deduced that
the above mentioned hydrogen bonding can be exclusively
formed for the (S1,S2,RS) isomers, because the conforma-
tion required for such an association in the (R1,R2,RS)
isomers, would be strongly destabilized by the steric
interaction between the p-tolyl and -CH2CO2R′ groups
in a 1,3-parallel arrangement. Therefore the (S1,S2,RS)
configuration must be assigned to the major diastereo-
isomers 2a -4a obtained in these reactions.
1
(15) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Pedregal, C.; Rubio, A. J .
Chem. Soc. Perkin Trans. 1 1989, 1335.
(16) When the reaction was carried out on direct addition mode
(ester enolate was added over the keto sulfoxide), the yield diminished
drastically.
(17) Starting from 2a + 2b or 3a + 3b diastereoisomeric mixtures,
only the the major component can be isolated by chromatography.
(18) J ochins, J . G.; Taigel, G.; Seeliger, A.; Lutz, P.; Driesen, H. E.
Tetrahedron Lett. 1967, 4363.
tions. The H NMR spectrum of compound 4b strongly
supports the stereochemical assignment depicted in
(19) This mixture, enriched in the minor diastereoisomer 2b, was
prepared from the original mixture by repeated crystallizations of the
major one 2a .
(20) This was established from the 1H NMR spectrum of a sample
containing 7 and Eu(tfc)3 as chiral shift reagent.

9464 J . Org. Chem., Vol. 61, No. 26, 1996
Garc´ıa Ruano et al.
Figure 1. The most significant datum is the long-range
coupling constant (4J CH2,H6 ) 1.5) between the H-6 axial
and one proton of the methylene group next to the ester
group. This coupling evidences a W planar arrangement
of both protons, which can be maintained due to the
hydrogen bond between the hydroxy and the ester group.
Starting from R,R-dimethyl-substituted acetate, the
stereoselectivity of the reaction became complete at the
carbonyl center. Thus, the epimeric mixture of keto
sulfoxides 1 yields exclusively the (S1,S2,RS)-8a isomer
(similar spectroscopic parameters than those of 2a -4a ),
indicating again that only the (S2,RS)-1 epimer evolves
under these conditions, and in a completely stereoselec-
tive manner (Scheme 1).
In order to propose a mechanistic model to explain the
obtained results, it is important to point out the essential
role of the lithium, acting as a template for these aldol
reactions. In fact, they do not work with sodium or
potassium enolates. The same is true for lithium eno-
lates in the presence of HMPA, which acts by removing
the metal. On the other hand, the reactivity and ste-
reoselectivity of these reactions decreased in the presence
of ZnBr2 (which had proved to be an efficient catalyst in
many other nucleophilic additions to â-keto sulfoxides),
presumably due to the strong association of the metal
with the carbonyl and sulfinyl oxygens, making the
chelating effect of the lithium atom more difficult.
On the basis of steric grounds, the equatorial approach
of the enolates on the carbonyl group of the sulfinylcy-
clohexanones 1 was expected to be favored. Thus, the
formation of 2a -4a and 8a as major or exclusive products
was not unexpected. The alternative axial approach on
the presumably favored conformation of the substrate
(the sulfinyl group in equatorial arrangement21 ) must
be unstabilized by the interaction of the nucleophile with
the syn-diaxial protons at C-3 and C-5. This would justify
the high stereoselectivity obtained in the reactions with
different alkyl acetates (∼95:5 ratio of epimers), which
become complete with R-alkyl-substituted esters (higher
size of the nucleophilic carbon). Nevertheless, it has been
reported that the attack of ethyl acetate lithium enolates
on 2-methyl-5-isopropenylcyclohexanone (with the methyl
group equatorially arranged) mainly yields the equatorial
tertiary alcohol (axial attack).22 The fact that our
substrates 1 exhibit an inverted stereoselectivity in their
reactions with ester enolates suggests the important role
of the sulfinyl group in the stereochemical course of these
reactions. From a steric and stereoelectronic point of
view, the axial arrangement of the sulfinyl oxygen in the
presumably most populated conformation around the
C-S bond23 (Figure 2) must contribute to make even
more difficult the axial approach of the electrophilic
enolate. Otherwise, the much higher reactivity of the
(S2,RS)-1 epimer, with respect to that of the (R2,RS)-1 one
(carbinols derived from the first one are exclusively
formed in these reactions), can be explained by assuming
F igu r e 2. Favored approach of acyclic ester enolates in aldol
reactions of 2-(p-tolylsulfinyl)cyclohexanone.
Sch em e 3
Ta ble 2. Ad d ition of RCH2CO2R′ Lith iu m En ola tes to 1
entry
compd
R
R′
Et
t-Bu
Et
Et
Et
A:B
yield (%)
1
2
3
4
5
9
13
10
11
12
Me
Me
Et
i-Pr
t-Bu
55:45
60:40
66:34
74:26
91:9
88
92
92
88
75
a lithium chelate additionally stabilized by the sulfinyl
oxygen, forming a tricoordinated species. This is not
possible from the (R2,RS) epimer because the spatial
arrangement of the tolyl group strongly destabilizes such
a tricoordination (Figure 2).
According to all the above data, we can conclude that
the addition of lithium enolates derived from esters to
the carbonyl group of the 2-(p-tolylsulfinyl)cyclohexanone
(1) is highly or completely stereoselective, yielding the
â-hydroxy esters that result of the enolate equatorial
approach, in high diastereoisomeric excess.
Additionally, reactions of ethyl R-alkylacetate lithium
enolates present a supplementary interest because of the
formation of a second stereogenic center in the aldolic
process. Thus, reactions of RCH2CO2Et (propanoate,
butanoate, 3-methylbutanoate, and 3,3-dimethylbu-
tanoate) enolates with keto sulfoxide 1 (as an epimeric
mixture in C-2) afforded mixtures of two diastereoiso-
mers, the stereoselectivity being higher as the size of R
becames larger (R ) Me, 55:45 of 9A and 9B; R ) Et,
66:34 of 10A and 10B; R ) i-Pr, 74:26 of 11A and 11B;
and R ) t-Bu, 91:9 of 12A and 12B) (Scheme 3). As in
the case of unsubstituted enolates, the reaction with tert-
butyl propanoate enolate illustrates that a bulkier group
in the ester moiety produces only a slight increase in the
stereoselectivity (R ) Me, R′ ) t-Bu 60:40 of 13A and
13B).
(21) The axial approach on the cyclohexanone ring must be favored
when the attack of the reagent takes place on the presumably minor
conformations of these cyclohexanones (those arranging the sulfinyl
group in axial position), because the steric interactions with the
substituent must be more severe than those with the syn-diaxial
protons. Nevertheless, the diastereoisomer formed from this attack
would be the same as that obtained by the equatorial approach on the
major conformation of the substrates.
(22) Maestro, M. A.; Castedo, L.; Mourin˜o, A. J . Org. Chem. 1992.
57, 5208.
(23) Carren˜o, M. C.; Garc´ıa Ruano, J . L.; Mart´ın , A. M.; Pedregal,
C; Rodriguez, J . H.; Rubio, A; Sa´nchez, J .; Solladie´, G. J . Org. Chem.
1990, 55, 2120.
The components of the above mixtures are epimers at
C-1′, as could be deduced from the following facts: (a)
Reduction of the hydroxy sulfoxides 9A + 9B yielded a
mixture of two nonenantiomeric thioethers 14A and 14B
1
with different H NMR spectra. Treatment of 14A + 14B
with NiB2 produces the reductive cleavage of C-S bond,24
affording a mixture of the two enantiomers at C-1′ of the

Aldol Reactions of Lithium Ester Enolates
J . Org. Chem., Vol. 61, No. 26, 1996 9465
Sch em e 4a
Sch em e 5
Sch em e 6
a
(a) TFAA/NaI, -60 °C; (b) Ni2B; (c) NaHCO3, 145 °C.
desulfenylated compound 1525 (identical 1H NMR spectra,
which became different in the presence of a chiral shift
reagent). The ee of compound 15 was identical to the de
of the starting hydroxy sulfoxides. This demonstrates
that 9A and 9B exhibit opposite configurations at C-1′.
(b) Pyrolytic elimination of the sulfinyl group from the
initial mixture of 9A + 9B yielded a diastereoisomeric
mixture of 16A and 16B (they show different 1H NMR
spectra). Thus, 16A and 16B must exhibit a different
relative configuration and therefore are epimers at
C-1′. As a consequence, we can conclude that hydroxy
sulfoxides 9A and 9B have the same configuration at C-1,
C-2, and sulfur, but differ in configuration at C-1′
(Scheme 4).
Once this point is clarified, we are sure that the
stereoselectivity of the aldol reaction of R-CH2-CO2R′ with
1 is complete on the electrophilic center (keto sulfoxide)
but only moderated on the nucleophilic one (lithium ester
enolates). This behavior could be explained by assuming
a totally stereoselective attack of each one of the two
isomeric enolates (E and Z)26 on the less hindered face
of the carbonyl group (equatorial approach). Since the
highly favored formation of the E-enolates27 was expected
under our experimental conditions, the hydroxy sulfox-
ides ratios, which in some cases was not very much
different (Table 2), suggested to us that equilibration
between E and Z enolates must take place in the reaction
conditions. This is not surprising if the strong acidic
character of the â-keto sulfoxide protons is taken into
account. Therefore, diastereoisomeric ratio of the ob-
tained â-hydroxy esters would depend on both the
reactivity of each enolate and their relative proportion
in the equilibrium.
and the same configuration was assigned to 18 by com-
parison of the H NMR spectra of both hydroxy lactones.
The complete stereocontrol observed in the later cases,
strongly supports a highly stereoselective attack of the
enolates.
1
Two different bicyclic structures can be postulated for
the tricoordinated lithium species, depending on the
chairlike (TSc) or boatlike (TSb) transition states adopted
by the six-membered ring containing the lactone enolate
fragment (Scheme 6). The results obtained in their
reactions with the keto sulfoxide 1 (exclusive formation
of diastereoisomer with R configuration at C-3′) suggest
that TSb must be much more stable than TSc. The
electronic repulsion between the lone electron pairs at
sulfur and alkoxy oxygen could account for the strong
destabilization of TSc (presumably favored from a steric
point of view), which would explain that only TSb was
the operative transition state in all these reactions. The
spatial restrictions imposed by the cyclic structure of the
lactone are determinant of the strong stereoelectronic
destabilization, because this interaction can be easily
diminished by opening of the lactone ring, as can be seen
from proper molecular models (see later).
From the spectroscopic data of hydroxy esters 9-12,
obtained from acyclic enolates (Table 3), we can establish
that the relative configuration of diastereoisomers A,
obtained as the major isomers in all cases, must be
identical. The same is true for the minor B ones, which
must be epimers at C-1′ of the hydroxy esters A.
Nevertheless, these spectroscopic parameters cannot be
used to carry out their unambiguous configurational
assignment. Unfortunately, neither was conclusive the
comparison of the spectroscopic parameters of these A
and B epimers with those of compounds of known
absolute configuration 17 and 18, obtained from lactones,
because the cyclic and acyclic structures of the ester
In order to confirm this assumption, we have made the
reaction of the keto sulfoxides 1 with the lithium enolates
derived from γ-butyrolactone and δ-valerolactone, the
cyclic structure of which precludes the mentioned equili-
bration. Only one diastereoisomer was obtained in both
cases (17 and 18, respectively, Scheme 5), indicating that
these reactions are completely stereoselective either in
the electrophilic carbonyl or in the nucleophilic center.
The absolute configuration of 17 was unequivocally
established as (R3′,S1,S2,RS) by X-ray diffraction studies28
(24) Back, T. G.; Baron, D. L.; Yang K. J . Org. Chem. 1993, 58, 2407.
(25) Direct reduction of the sulfoxides 9A + 9B into 15 failed with
NiB2 or Raney nickel.
(26) We refer to the stereoisomeric enolates as Z or E, assigning to
the “OLi” a higher priority than “OR” group.
(27) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J . Am. Chem.
Soc. 1976, 98, 2868. (b) Oare, D. A.; Heathcock, C. H. J . Org. Chem.
1990, 55, 157.
(28) The crystal structure of compound 17 reinforces the previous
configurational assignment, based on 1H NMR parameters. The author
has deposited atomic coordinates for this structure with the Cambridge
Crystallographic Data Centre. The coordinates can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK.

9466 J . Org. Chem., Vol. 61, No. 26, 1996
Ta ble 3. Sign ifica n t 1H NMR P a r a m eter s of Com p ou n d s 9-12 a n d 19 (A a n d B Ep im er s)
1H NMR
Garc´ıa Ruano et al.
13C NMR
J 2,3 (CDCl3) J OH (CDCl3) δ H-2 (C6D6) δ H-1′ (C6D6) δ OH (C6D6) ∆δ AA′BB′ (C6D6) δ CArb (CDCl3)
a
compd
R
9A
9B
Me
Me
Et
12.4, 3.7
11.2, 3.9
12.5, 3.8
11.6, 4.0
12.6, 3.6
10.0, 3.9
12.0, 3.6
9.1, 4.3
2
3.13
2.36
2.68
2.27
2.86
2.62
2.71
2.71
2.80
2.47
3.81
3.72
3.67
3.57
3.60
3.53
3.85
3.80
3.85
3.87
4.68
4.77
4.85
4.78
4.76
4.93
4.80
5.05
4.79
4.84
0.63
0.41
0.65
0.40
0.54
0.51
0.53
0.50
0.62
0.47
136.8
138.8
136.9
137.8
136.8
138.8
137.2
139.4
136.8
137.4
10A
10B
11A
11B
12A
12B
19A
19B
1.7
2.2
Et
i-Pr
i-Pr
t-Bu
t-Bu
(CH2)3OEt
(CH2)3OEt
1.3
12.5, 3.8
11.6, 3.8
2.0
1.9
a
b
Observed chemical shift differences between p-tolyl protons. Chemical shift of upper field quaternary aromatic carbon.
Sch em e 7
reagents through the first one and, therefore, the forma-
tion of a higher proportion of isomer B than expected
from the low ratio of Z-enolate generated in the experi-
mental conditions used.
Con clu sion s
In summary, we have described the aldol reactions of
R-sulfinylcyclohexanones with different esters. They
evolve with a complete control of the stereoselectivity in
both the carbonyl and enolate prochiral centers. The
equilibration of the enolates determines the formation
of mixtures of two diastereoisomers, epimers at C-1′, the
proportion of which is related with the nature of the
starting ester. The use of lactones as reagents, which
are unable to equilibrate, yields only one isomer. The
key of the stereoselectivity is the formation of a tricoor-
dinated lithium species with the sulfinyl oxygen of the
chiral auxiliary. Studies related to the use of other cyclic
and acyclic ketones as well as other compounds as sources
of nucleophiles (nitriles, amides, acids, sulfones, sulfox-
ides, etc.) are been investigated in our laboratory, and
the results obtained will be reported in due course.
moieties induce important differences in the considered
parameters. Therefore, we have carried out the chemical
correlation depicted in Scheme 7. The reaction of the
ethyl 5-ethoxypentanoate lithium enolate with keto sul-
foxide 1 yielded a 60:40 mixture of compounds 19A and
19B. As we can see, the relative proportion of the
epimers is almost identical to that obtained from ethyl
butanoate (Table 2), as it can be expected by assuming a
scarce influence of the ethoxy group on the stereochem-
ical course of the reaction and a similar size of the
involved R groups (ethyl and 4-ethoxypropyl). Otherwise,
the ethanolysis of the lactone 18, followed by the O-
alkylation of the resulting carbinol,29 yielded a single
δ-alkoxyester, which could be spectroscopically identified
as 19B, the minor diastereoisomer of the above men-
tioned aldol reaction. This correlation allowed us to
assign the absolute configuration (R3′,S1,S2,RS) exhibited
by the compounds attained from lactones to the minor
adducts obtained from acyclic esters lithium enolates.
In order to explain the stereochemical results obtained
from acyclic esters, we must consider the evolution of the
two stereoisomeric enolates. None of the two possible
transition states derived from the Z-enolates [TSb-(Z) and
[TSc-(Z)] is affected by important stereoelectronic interac-
tions; therefore, the steric effects are the main factors
controlling their relative stability, which must be higher
for the chairlike [TSc-(Z)], thus explaining the formation
of the R configuration at C-1′ (Scheme 8). A similar
situation takes place in the attack of the E-enolate. The
chairlike transition state [TSc-(E)] must be favored with
respect to the boatlike one [TSb-(E)] (the stereoelectronic
repulsion unstabilizing the first one is much less restric-
tive than in lactones), and the formation of the S
configuration at C-1′ results from this approach. The
steric interactions in [TSc-(Z)] are lower than those for
[TSc-(E)], which would explain the faster evolution of the
Exp er im en ta l Section
Diastereoisomeric aldols ratios were established by integra-
tion of well-separated signals of the diastereoisomers in the
crude reaction mixtures and are listed in Tables 1 and 2. Mass
spectra were obtained in the electron impact (EI) mode at 70
eV unless stated otherwise. All reactions were monitored by
TLC, which was performed on precoated sheets of silica gel
60 (F254), and flash chromatography was effected with silica
gel 60 (230-400 mesh). The apparatuses for inert atmosphere
experiments were dried by flaming in a stream of dry argon.
THF was distilled from sodium/benzophenone under argon and
CH2Cl2 over P2O5. Diisopropylamine and diisopropylethy-
lamine were distilled from potassium hydroxide.
A. Con d en sa t ion of Lit h iu m E st er E n ola t es a n d
â-Keto Su lfoxid es. Gen er a l P r oced u r e. A solution of
butyllithium (5.9 mL of a 2.5 M solution in hexanes, 14.9
mmol) was dropwise added to a cooled (-78 °C) THF solution
of diisopropylamine (2.2 mL, 15.7mmol in 60 mL of THF). After
20 min of stirring, a solution of the corresponding ester (14.9
mmol) in 5 mL of THF at -78 °C was added via cannula. The
mixture was maintained 30 min at the same temperature, and
a solution of 2-(p-tolylsulfinyl)cyclohexanone (1, 1.75 g, 7.4
mmol) in 25 mL of THF was added via cannula. After 20 min
at -78 °C, the reaction was quenched with a NH4Cl saturated
solution (40 mL) and the mixture extracted with ethyl acetate
(2 × 40 mL). The organic extracts were washed with brine (2
× 20 mL) and dried (MgSO4). The solvent was removed under
vacuum and the crude product purified by flash chromatog-
raphy to afford the corresponding hydroxy ester.
1-[(E t h oxyca r b on yl)m et h yl]-2-(p -t olylsu lfin yl)cyclo-
h exa n ol (2) was obtained following the general procedure
from ethyl acetate (1.31ml, 14.9 mmol) as a 93:7 mixture of
diastereomers 2a :2b (global yield 92%). Column chromatog-
(29) In the reported conditions for lactone simultaneous cleavage
and O-alkylation (King, S. A. J . Org. Chem. 1994, 59, 2253), compound
18 afforded exclusively cleavage.

Aldol Reactions of Lithium Ester Enolates
J . Org. Chem., Vol. 61, No. 26, 1996 9467
Sch em e 8
raphy on silica gel (hexane-ethyl acetate, 3:1) and recrystal-
lization (benzene) afford pure 2a (82%) as a white solid.
MS m/z 296(1) M+, 279 (18), 213 (10), 157 (72), 140 (100), 123
(19), 97 (60); HRMS calcd for C19H28SO4 352.17083, found
352.17081. Anal. Calcd for C19H28SO4: C, 64.74; H, 8.01; S,
9.08. Found: C, 63.20; H, 7.81; S, 8.15.
Isolation of diastereomer 2b has not been accomplished:
1
[1S,2S,(S)R]-2a : mp 95-96 °C; [R]25 +156 (c 1, CHCl3); H
D
NMR δ 7.42 and 7.33 (4H, AA′BB′ system), 4.25 (1H, d, J )
1.8 Hz), 4.20 (2H, q, J ) 7.1 Hz), 3,31 and 2.94 (2H, AB system,
J ) 15.3 Hz), 2.95 (1H, dd, J ) 12.5 and 3.8 Hz), 2.42 (3H, s),
2.20-1.10 (8H, bm), 1.32 (3H, t, J ) 7.1 Hz); 13C NMR δ 171.1,
141.0, 137.3, 129.8, 124.2, 72.9, 64.9, 60.6, 45.9, 37.6, 24.6, 21.2,
20.4, 16.4, 14.1; IR (CHCl3) 3390, 1705, 1170, 1020, 1010, 800.
Anal. Calcd for C17H24SO4: C, 62.94; H, 7.46; S, 9.86.
Found: C, 62.98; H, 7.30; S, 9.82.
[1S,2S,(S)R]-1-[2′-(Eth oxycar bon yl)pr op-2′-yl]-2-(p-tolyl-
su lfin yl)cycloh exa n ol (8A) was obtained as the sole dias-
tereomer (ed >97%) following the general procedure from ethyl
2-methylpropanoate (1.99 mL, 14.9 mmol). Column chroma-
tography (hexane-ethyl acetate, 3:1) affords pure 8A as a
white solid: yield 90%; mp 84-86 °C; [R]25D +101 (c 1, CHCl3);
1H NMR δ 7.42 and 7.33 (4H, AA′BB′ system), 4.83 (1H, d, J
) 2 Hz), 4.27 (2H, q, J ) 7.2 Hz), 2.60 (1H, dd, J ) 12.5 and
3.7 Hz), 2.43 (3H, s), 2.08 (1H, m), 1.9-1.1 (7H, bm), 1.36 and
1.35 (3H, t), 1.25 (3H, t, J ) 7.2 Hz); 13C NMR δ 178.3, 140.6,
138.9, 129.6, 123.9, 76.8, 66.6, 61.5, 49.1, 33.6, 24.9, 23.1, 21.5,
21.2, 20.6, 16.6, 13.7; IR (CHCl3) 3510, 3410, 1690, 1240, 1150,
1040. Anal. Calcd for C19H28SO4: C, 64.74; H, 8.01; S, 9.08.
Found: C, 64.93; H, 8.02; S, 9.11.
1-[(Meth oxyca r bon yl)m eth yl]-2-(p-tolylsu lfin yl)cyclo-
h exa n ol (3) was obtained following the general procedure
from methyl acetate (1.18 mL, 14.9 mmol) as a 91:9 mixture
of diastereomers 3a :3b (global yield 88%). Column chroma-
tography on silica gel (hexane-ethyl acetate, 3:1) and subse-
quent recrystallization (benzene) afford pure 3a (74%) as a
white solid. Isolation of diastereomer 3b has not been ac-
complished.
1-[1′-(E t h oxyca r b on yl)et h yl]-2-(p -t olylsu lfin yl)cyclo-
h exa n ol (9) was obtained from ethyl propanoate (1.70 mL,
14.9 mmol) as a 55:45 mixture of C-1′ epimers 9A:9B (yield
88%). Separation of both epimers was effected by column
chromatography (hexane-acetone, 4:1).
[1S,2S,(S)R)-3a : mp 156-157 °C; [R]25 +176 (c 1, CHCl3);
D
1H NMR δ 7.42 and 7.33 (4H, AA′BB′ system), 4.27 (1H, d, J
) 1.4 Hz), 3.75 (3H, s), 3.34 and 2.96 (2H, AB system, J )
16.4 Hz), 2.95 (1H, dd, J ) 12.5 and 3.8 Hz), 2.42 (3H, s), 2.20-
1.10 (8H, bm), 1.32 (3H, t, J ) 7.1 Hz); 13C NMR δ 171.6, 141.1,
137.1, 129.8, 124.3, 73.1, 64.6, 51.7, 45.8, 37.7, 24.7, 21.4, 20.4,
16.4; IR (CHCl3) 1720, 1180, 1040, 1030, 810. Anal. Calcd
for C16H22SO4: C, 61.91; H, 7.15; S, 10.31. Found: C, 61.75;
H, 6.98; S, 10.04.
[1′S,1S,2R,(S)R]-9A: mp 102-103 °C; [R]25 +111 (c 1,
D
1
CHCl3); H NMR δ 7.41 and 7.33 (4H, AA′BB′ system), 4.23
(2H, q, J ) 7.1 Hz), 4.09 (1H, d, J ) 2 Hz), 3.69 (1H, q, J )
7.2 Hz), 2.89 (1H, dd, J ) 12.4 and 3.7 Hz,), 2.42 (3H, s), 2.20-
1.10 (8H, bm), 1.38 (3H, d, J ) 7.1 Hz)., 1.33 (3H, t, J ) 7.2
Hz); 13C NMR δ 173.5, 140.5, 136.8, 129.4, 123.8, 74.3, 64.5,
60.1, 47.6, 31.7, 24.3, 20.9, 19.9, 16.2, 13.9, 10.6; IR (CHCl3)
1-[ter t-Bu t oxyca r b on yl)m et h yl]-2-(p -t olylsu lfin yl)cy-
cloh exa n ol (4) was obtained following the general procedure
from tert-butyl acetate (2.0 mL, 14.9 mmol) as a 96:4 mixture
of diastereomers 4a :4b (global yield 81%). Both diastereomers
were separated by column chromatography on silica gel
(hexane-ethyl acetate, 3:1).
3390, 1705, 1140, 1040, 1010, 870. Anal. Calcd for C18H26
-
SO4: C, 63.88; H, 7.77; S, 9.45. Found: C, 63.94; H, 7.64; S,
9.32.
[1′R,1S,2R,(S)R]-9B: mp 140-142 °C; [R]25 +104 (c 1,
D
1
CHCl3); H NMR δ 7.48 and 7.30 (4H, AA′BB′ system), 4.20
[1S,2S,(S)R]-4a : mp 143-145 °C; [R]25 +140 (c 1, CHCl3);
(2H, q, J ) 7.2 Hz), 4.07 (1H, bs), 3.53 (1H, q, J ) 7.2 Hz),
2.56 (1H, dd, J ) 11.2 and 3.9 Hz), 2.42 (3H, s), 2.20-1.10
(8H, bm), 1.29 (3H, d, CH3CH, J ) 7.1 Hz), 1.27 (3H, t, J )
7.2 Hz); 13C NMR δ 174.4, 141.0, 138.8, 129.7, 124.1, 75.1, 65.0,
60.6, 47.2, 32.5, 24.3, 21.2, 20.2, 17.1, 14.0, 12.6; IR (CHCl3)
D
1H NMR δ 7.39 and 7.28 (4H, AA′BB′ system), 4.22 (1H, d, J
) 1.3 Hz), 3,13 and 2,86 (2H, AB system, J AB ) 15.2 Hz), 2.87
(1H, dd, J ) 12.1 and 2.1 Hz), 2.39 (3H, S), 2.20-1.10 (8H,
bm), 1.47 (9H, s); 13C NMR δ 170.5, 140.9, 137.7, 129.7, 124.2,
81.3, 72.9, 65.4, 46.9, 37.5, 28.1, 24.7, 21.3, 20.5, 16.5; IR
(CHCl3) 3400, 1705, 1150, 1020, 1010, 840; MS m/z 296(2) M+,
279 (14), 213 (4), 157 (80), 140 (100), 123 (17), 97 (73); HRMS
calcd for C19H28SO4 352.17083, found 352.17136. Anal. Calcd
for C19H28SO4: C, 64.74; H, 8.01; S, 9.08. Found: C, 64.17;
H, 7.87; S, 8.84.
3400, 1710, 1175, 1040, 1010, 850. Anal. Calcd for C18H26
-
SO4: C, 63.88; H, 7.77; S, 9.45. Found: C, 63.99; H, 7.70; S,
9.33.
1-[1′-(Eth oxyca r bon yl)p r op yl]-2-(p-tolylsu lfin yl)cyclo-
h exa n ol (10) was obtained from ethyl butanoate (1.97 mL,
14.9 mmol) following the general procedure as 66:34 mixture
of C-1′ epimers 10A:10B (yield 92%). Purification and separa-
tion of both epimers was effected by column chromatography
on silica gel (hexane-acetone, 4:1). The isomer 10A, obtained
as solid, was crystallized (CH2Cl2-hexane) to white plates,
whereas the isomer 10B was obtained as a colorless oil.
[1S,2R,(S)R]-4b: mp 136-137 °C; [R]25D +101 (c 0.6, CHCl3);
1H NMR δ 7.46 and 7.30 (4H, AA′BB′ system), 4.96 (1H, s),
3.08 (1H, part A of and ABX system, J ) 1.4, J ) 16.2 Hz)
and 2.79 (1H, part B of an ABX system), 2.40 (1H, m), 2.39
(3H, s), 2.20-1.10 (8H, bm), 1.49 (9H, s); 13C NMR δ 172.6,
140.5, 140.0, 129.7, 124.3, 82.2, 76.4, 72.6, 39.4, 38.5, 28.1, 24.6,
23.0, 21.3, 17.7; IR (CHCl3) 3340, 1690, 1150, 1020, 1010, 830;
[1′S,1S,2R,(S)R]-10A: mp 115-116 °C; [R]25 +138 (c 0.7,
D
CHCl3); 1H NMR δ 7.37-7.31 (4H, m), 4.24 (2H, m), 4.08 (1H,

9468 J . Org. Chem., Vol. 61, No. 26, 1996
Garc´ıa Ruano et al.
d, J ) 1.7 Hz), 3,41 (1H, dd, J ) 3.0 and 11.3 Hz), 2.54 (1H,
dd, J ) 12.5 and 3.8 Hz), 2.41 (3H, s), 2.20-0.9 (8H, bm), 1.33
(3H, t, J ) 7.1 Hz), 0.98 (3H, d, CH3CH, J ) 7.3 Hz); 13C NMR
δ 173.8, 141.1, 136.9, 129.8, 124.3, 75.1, 64.9, 60.5, 57.4, 32.8,
24.7, 21.4, 20.3, 19.2, 16.7, 14.4, 12.9; IR (CHCl3) 3390, 1710,
1150, 1020.
366.18648, found 366.18701. Anal. Calcd for C20H30SO4: C,
65.54; H, 8.26; S, 8.73. Found: C, 65.27; H, 8.07; S, 8.86.
[1′R,1S,2R,(S)R]-13B: mp 141-142 °C; [R]25 +105 (c 1,
D
CHCl3); 1H NMR δ 7.43 and 7.33 (4H, AA′BB′ system), 4.0 (1H,
s), 3.34 (1H, q, J ) 7.1 Hz), 2.59 (1H, dd, J ) 10.2 and 4.1
Hz), 2.40 (3H, s), 2.30-0.80 (8H, bm), 1.45 (9H, s), 1.23 (3H,
d, CH3CH, J ) 7.2 Hz); 13C NMR δ 174.1, 141.0, 129.8, 128.3,
124.5, 81.7, 74.9, 66.8, 47.4, 32.5, 28.1, 24.1, 21.4, 20.6, 17.8,
12.5; IR (CHCl3) 3420, 1710, 1370, 1150, 1040, 1010, 840; MS
m/z (35 eV) 366 (0.4) M+, 293 (14), 237 (29), 171 (80), 140 (84),
123 (18), 97 (100). Anal. Calcd for C20H30SO4: C, 65.54; H,
8.26; S, 8.73. Found: C, 64.97; H, 8.14; S, 8.99.
[1′R,1S,2R,(S)R]-10B: [R]25 +105 (c 0.6, CHCl3); 1H NMR
D
δ 7.39 and 7.33 (4H, AA′BB′system), 4.20 (2H, m), 4.08 (1H,
d, J ) 2.2 Hz), 3.35 (1H, dd, J ) 3.0 and 8.9 Hz), 2.57 (1H, dd,
J ) 11.6 and 4.0 Hz), 2.41 (3H, s), 2.30-0.8 (8H, bm), 1.29
(3H, t, J ) 7.0 Hz), 0.98 (3H, d, CH3CH, J ) 7.3 Hz); 13C NMR
δ 173.9, 141.2, 137.8, 129.8, 124.4, 75.4, 64.8, 60.5, 56.4, 33.4,
24.6, 21.4, 21.3, 20.3, 19.2, 17.6, 14.3, 12.8; IR (CHCl3) 34000,
1700, 1150, 1090.
[3′R,1S,2S,(S)R]-1-(2′-Oxot et r a h yd r ofu r a n -3′-yl)-2-(p -
tolylsu lfin yl)cycloh exa n ol (17) was obtained as a sole
diastereomer (ed >97%) following the general procedure from
γ-butyrolactone (1.14 mL, 14.9 mmol). Purification by column
chromatography (hexane-ethyl acetate, 3:1) afforded com-
pound 17 as a white solid: yield 88%; mp 170 °C (benzene);
[R]25D +108 (c 1, CHCl3); 1H NMR δ 7.41 and 7.32 (4H, AA′BB′
1-[1′-(Eth oxyca r bon yl)-2′-m eth ylp r op yl]-2-(p-tolylsu lfi-
n yl)cycloh exa n ol (11) was obtained from ethyl 3-methylbu-
tanoate (2.28 mL, 14.9 mmol) following the general procedure
as a 74:26 mixture of the epimers in C-1′, 11A:11B (yield 88%).
Purification and separation of both epimers were effected by
column chromatography (hexane-ethyl acetate, 7:2).
system), 4.52 and 4.36 (2H, AB from an ABX2 system, J AB
)
[1′S,1S,2R,(S)R]-11A: mp 79-81 °C; [R]25 +106 (c 1,
9.5, J AX ) 2.5, and J BX ) 7.0 Hz), 4.14 (1H, d, J ) 1.3 Hz), 3.6
(1H, dd, J ) 11.6 and 9.6 Hz), 2.57-2.34 (4H, m), 2.42 (3H,
s), 2.0-1.0 (8H, m); 13C NMR δ 178.2, 141.2, 138.7, 129.9,
124.1, 74.1, 66.8, 66.2, 47.9, 34.3, 25.3, 24.4, 21.3, 20.4, 16.4;
IR (CHCl3) 3480, 1740, 1360, 1170, 1040, 1010. Anal. Calcd
for C17H22SO4: C, 63.33; H, 6.88; S, 9.93. Found: C, 63.10;
H, 6.64; S, 9.71.
D
1
CHCl3); H NMR δ 7.27 (4H, m), 4.20 (2H, m), 3.99 (1H, s),
3.24 (1H, d, J ) 6.8 Hz), 2.59 (1H, dd, J ) 12.6 and 3.6 Hz),
2.37 (3H, S), 2.34 (1H, m), 2.50-1.1 (8H, bm), 1.30 (3H, t, J )
6.8 Hz), 1.18 and 0.92 (3H, d, J ) 6.8 Hz); 13C NMR δ 173.5,
141.0, 136.8, 129.8, 124.1, 75.8, 65.1, 60.7, 60.1, 32.5, 26.5, 24.5,
23.9, 21.2, 20.4, 16.8, 14.4; IR (CHCl3) 3480, 1700, 1170, 1100,
1010, 820. Anal. Calcd for C19H28SO4: C, 65.54; H, 8.26; S,
8.73. Found: C, 65.43; H, 8.24; S, 8.93.
[3′R,1S,2S,(S)R ]-1-(2′-Oxot et r a h yd r op yr a n -3′-yl)-2-(p -
tolylsu lfin yl)cycloh exa n ol (18) was obtained as a sole
diastereomer (ed >97%) from δ-valerolactone (1.38 mL, 14.9
mmol), yield 88%. Column chromatography of the crude
[1′R,1S,2R,(S)R]-11B: mp 72-74 °C; [R]25 +86 (c 1,
D
1
CHCl3); H NMR δ 7.38 and 7.29 (4H, AA′BB′ system), 4.12
(1H, bs), 3.27 (1H, d, J ) 7.2 Hz), 2.66 (1H, dd, J ) 10.0 and
3.9 Hz), 2.38 (3H, s), 2.17 (1H, m), 2.50-1.1 (8H, bm), 1.24
(3H, t, J ) 7.2 Hz), 1.13 and 1.0(3H, d, J ) 6.8 and 6.7 Hz,
respectively); 13C NMR δ 173.4, 141.0, 138.8, 129.7, 124.4, 75.5,
67.1, 60.2, 58.3, 32.9, 27.2, 24.0, 23.4, 21.3, 20.9, 20.6, 18.3,
14.2; IR (CHCl3) 3420, 1710, 1160, 1070, 1030, 810. Anal.
Calcd for C19H28SO4: C, 65.54; H, 8.26; S, 8.73. Found: C,
65.44; H, 8.21; S, 8.92.
1-[1′-(Eth oxyca r bon yl)-2′,2′-d im eth ylp r op yl]-2-(p-tolyl-
su lfin yl)cycloh exa n ol (12) was obtained from ethyl 3,3-
dimethylbutanoate (2.14 g, 14.9 mmol) following the general
procedure as a 91:9 mixture of the epimers in C-1′ 12A:12B
(yield 75%). Purification and separation of both epimers was
effected by column chromatography (hexane-acetone, 4:1).
[1′S,1S,2R,(S)R]-12A: [R]25D +115 (c 1.5, CHCl3); 1H NMR
δ 7.34 (4H, s) 4.23 (2H, m), 4.05 (1H, d, J ) 1.6 Hz), 3.54 (1H,
s), 2.55 (1H, dd, J ) 12.0 and 3.6 Hz), 2.41 (3H, s), 2.35-0.8
(8H, bm), 1.34 (3H, t, J ) 7.1 Hz), 1.23 (9H, s); 13C NMR δ
173.6, 141.0, 137.2, 129.8, 124.2, 77.5, 66.1, 62.3, 60.1, 35.1
product (hexane-ethyl acetate, 3:1) affords compound 18 as
1
a white solid: mp 152-153 °C; [R]25 +129 (c 1, CHCl3); H
D
NMR δ 7.46 and 7.35 (4H, AA′BB′ system), 4.71 (1H, d, J )
0.7 Hz), 4.60-4.42 (2H, m, OCH2CO), 3.49 (1H, dd, J ) 11.5
and 7.8 Hz), 2.64 (1H, ddd, J ) 0.7 Hz, 4.3, 11.6 Hz), 2.41
(3H, s), 2.4-0.7 (12H, m); 13C NMR δ 173.2, 141.0, 137.6, 129.8,
124.3, 92.3, 69.2, 65.7, 48.6, 34.5, 24.6, 22.7, 22.2, 21.3, 20.5,
16.4; IR (CHCl3) 340, 1700, 1165, 1080, 1040. Anal. Calcd
for C18H24SO4: C, 64.26; H, 7.20; S, 9.51. Found: C, 64.26;
H, 6.93; S, 9.9.59.
1-[1′-(Eth oxyca r bon yl)-4′-eth oxybu tyl]-2-(p-tolylsu lfi-
n yl)cycloh exa n ol (19) was obtained from ethyl 5-ethoxy-
pentanoate27 (2.59 g, 14.9 mmol) as a 60:40 mixture of C-1′
epimers 19A:19B (yield 85%). Purification and separation of
both epimers was effected by column chromatography on silica
gel (CH2Cl2-ethyl acetate-acetone, 9:0.5:0.5).
[1′S,1S,2R,(S)R]-19A: [R]25 +121 (c 0.5, CHCl3); 1H NMR
D
δ 7.28 (4H, m), 4.12 (2H, m), 4.06 (1H, J ) 2 Hz), 3.42 (5H,
m), 2.34 (3H, s), 2.1-0.8 (12 H, m), 1.26 (3H, t, J ) 7.1 Hz),
1.13 (3H, t, J ) 7.0 Hz);13C NMR δ 173.7, 141.1, 136.8, 129.8,
124.3, 75.1, 70.4, 66.0, 64.8, 60.6, 55.2, 32.8, 28.6, 24.7, 22.8,
(2C), 30.7, 24.4, 21.3, 20.6, 16.9, 14.3; HRMS calcd for C21H32
-
SO4 380.20213, found 380.20236; MS m/z 322 (0.3) M+, 363
(3), 241 (32), 237 (24) 185 (100), 139 (82), 97 (65).
21.3, 20.3, 16.7, 15.2, 14.3; IR (CHCl3) 3400, 1720, 1100, 1000.
[1′R,1S,2R,(S)R]-12B: [R]25 +91 (c 1, CHCl3); H NMR δ
[1′R,1S,2R,(S)R]-19B: [R]25 +99 (c 1.5, CHCl3); H NMR
1
1
D
D
7.44 and 7.31 (4H, AA'BB' system), 4.30 (1H, s), 4.03 (2H, q,
J ) 7.0 Hz), 3.46 (1H, s), 2.85 (1H, dd, J ) 9.1 and 4.3 Hz),
2.41 (3H, s),2.50-1.1 (8H, bm), 1.23 (3H, t, J ) 6.8 Hz), 1.26
(9H, s); 13C NMR δ 173.4, 141.2, 139.4, 129.8, 124.5, 77.0, 68.2,
60.1 (2C), 34.3, 34.2,, 30.5, 23.8, 21.4, 21.1, 19.6, 14.2; MS m/z
322 (0.4) M+, 363 (4), 241 (15), 237 (33) 185 (100), 139 (63), 97
(69).
δ 7.41 and 7.32 (4H, AA′BB′ system), 4.19 (2H, q, J ) 7.1 Hz),
3.94 (1H, J ) 1.9 Hz), 3.51 (5H, m), 2.41 (3H,s), 2.1-0.8 (12
H, m), 1.27 (3H, t, J ) 7.1 Hz), 1.18 (3H, t, J ) 7.0 Hz); 13C
NMR: δ 173.4, 140.8, 137.4, 129.8, 124.3, 76.4, 69.1, 65.8, 64.4,
60.3, 53.7, 32.9, 27.9, 24.2, 22.6, 21.3, 20.3, 17.0, 15.0, 14.1;
IR (CHCl3) 3370, 1700, 1100, 1060.
Diastereoisomer 19B was also obtained as a sole diastereo-
isomer, in two steps, from lactone 18 following the next
procedure.
[1′R,1S,2S,(S)R]-1-[1′-(Eth oxyca r bon yl)-4′-h yd r oxybu -
tyl]-2-(p-tolylsu lfin yl)cycloh exa n ol (20). To a stirred solu-
tion of hydroxylactone 18 (300 mg, 0.89 mmol) and trimethyl
orthoformate (296 µL, 1.78 mmol) in dried ethanol (4 mL) was
added H2SO4 (0.06 equiv). The reaction mixture was heated
at 50 °C for 6 h. The solvent was carefully removed and the
residue partitioned between ethyl acetate and saturated
NaHCO3 solution. The aqueous layer was twice extracted with
ethyl acetate (20 mL), the combined organic layers were
washed with brine and dried (Na2SO4), and the solvent was
removed under reduced pressure. The residue was purified
by column chromatography on silica gel (acetone-hexane,
1:2.5) to obtain pure 20 as a white solid: yield 78%; mp 119-
1-[1′-(ter t-bu toxyca r bon yl)eth yl]-2-(p-tolylsu lfin yl)cy-
cloh exa n ol (13) was obtained from tert-butyl propanoate (2.24
mL, 14.9 mmol) following the general procedure as 60:40
mixture of C-1′ epimers 13A:13B (yield 92%). Purification and
separation of both epimers was effected by column chroma-
tography on silica gel (hexane-acetone, 4:1).
[1′S,1S,2R,(S)R]-13A: mp 121-123 °C; [R]25 +143 (c 1,
D
1
CHCl3); H NMR δ 7.39 and 7.32 (4H, AA′BB′ system), 4.05
(1H, d, J ) 2.1 Hz), 3,54 (1H, q, J ) 7.2 Hz), 2.91 (1H, dd, J
) 12.4 and 3.8 Hz), 2.41 (3H, s), 2.20-0.9 (8H, bm), 1.50 (9H,
s), 1.18 (3H, d, CH3CH, J ) 7.2 Hz); 13C NMR δ 173.7, 141.0,
136.9, 129.8, 124.3, 80.8, 75.0, 64.3, 49.0, 32.1, 28.1, 24.9, 21.4,
20.4, 17.1, 11.4; IR (CHCl3) 3400, 1710, 1370, 1150, 1030, 1010,
840; MS m/z (35 eV): 366 (0.2) M+, 293 (11), 237 (16), 171
(75), 140 (76), 123 (15), 97 (100); HRMS calcd for C20H30SO4

Aldol Reactions of Lithium Ester Enolates
J . Org. Chem., Vol. 61, No. 26, 1996 9469
1
121 °C; [R]25 +112 (c 0.4, CHCl3); H NMR δ 7.41 and 7.32
1710, 1180, 1030, 960; MS m/z 322 (76) M+, 304 (4), 221 (22),
181 (55), 153 (37), 124 (100), 97 (62), 91(50); HRMS calcd for
C18H26SO3 322.16026, found 322.15973
D
(4H, AA′BB′system), 4.21 (2H, q, J ) 7.1 Hz), 4.01 (1H, d, J )
2 Hz), 3.82- 3.51 (2H, m), 3.50 (1H, dd, J ) 2.4 and 11.9 Hz),
2.59 (1H, dd, J ) 11.8 and 3.7 Hz), 2.42 (3H, s), 2.30-0.8 (8H,
bm), 1.30 (3H, t, J ) 7.1 Hz); 13C NMR δ 173.8, 141.2, 137.3,
129.9, 124.4, 64.4, 61.8, 60.7, 54.0, 33.3, 31.0, 24.7, 24.0, 21.4,
20.3, 17.4, 14.3.
[1′R,1S,2R,(S)R]-1-[1′-(Eth oxycar bon yl)-4′-eth oxybu tyl]-
2-(p-tolylsu lfin yl)cycloh exa n ol (19B). Into a flame-dried
flask was placed diisopropylethylamine (0.94 mmol, 158 µL),
and a solution of 0.3 g of hydroxy ester 20 (0.76 mmol) in 5
mL of CH2Cl2 and 1 mmol of triethyloxonium tetrafluorborate
(1 M solution in CH2Cl2 from Aldrich) were added via syringe.
The resulting solution was stirred at room temperature for 3
h before it was quenched with ice water and extracted with
ethyl acetate (2 × 20 mL). The organic extracts were washed
twice with 5% aqueous NaHCO3 and once with water and dried
over Na2SO4. The solvent was removed and the crude product
purified by flash chromatography (acetone-hexane, 1:2.5) to
afford pure 19B (0.22 g, 68%).
B. Su lfin yl Gr ou p Oxid a tion . (1S,2S)-1-[(Eth oxyca r -
bon yl)m eth yl]-2-(p-tolylsu lfon yl)cycloh exa n ol (5a ). To a
solution of hydroxy sulfoxide 2a (200 mg, 0.62 mmol) in
dichloromethane (15 mL) was dropwise added a solution of
m-CPBA (50-60% in water, 282 mg, 0.75 mmol) in chloro-
form (15 mL). After 30 min, a saturated solution of NaHCO3
(5 mL) was added and stirring was maintained during 30 min.
The layers were separated and the organic one was washed
with saturated NaHCO3 solution (2 × 30 mL) and dried
(MgSO4). Removal of the solvent afford pure 5a as a colorless
(1′R,1S,2S)-1-[1′-(Eth oxycar bon yl)eth yl]-2-(p-tolylsu lfe-
n yl)cycloh exa n -1-ol (14B) was obtained from 9B following
the general procedure. The crude was chromatographed
(hexane-acetone, 7:1) to afford pure 14B (457 mg, 83%) as a
pale yellow oil: [R]25 +10 (c 1.2, CHCl3); 1H NMR δ 7.34 and
D
7.10 (4H, AA′BB′ system), 4.19 (2H, q, J ) 7.1 Hz), 3.62 (1H,
d, J ) 1), 3,38 (1H, q, J ) 7.3 Hz), 3.01 (1H, dd, J ) 10 and
5.7 Hz), 2.32 (3H, s), 2.0-1.0 (8H, bm), 1.28 (3H, t, J ) 7.1
Hz), 1.20 (3H, d, J ) 7.1 Hz); 13C NMR δ 175.5, 137.0, 132.5,
131.7, 129.6, 75.0, 60.8, 55.2, 46.7, 32.1, 30.2, 25.9, 21.0, 20.8,
14.1, 11.8; IR (CHCl3) 3480, 1710, 1180, 1030, 960; MS m/z
322(85) M+, 304 (10), 221 (22), 181 (55), 153 (41), 124 (100),
97 (65), 91 (52); HRMS calcd for C18H26SO3 322.16026, found
322.16016
D. Su lfin yl Gr ou p R ed u ct ive E lim in a t ion . 1-[1′-
(Eth oxyca r bon yl)eth yl]cycloh exa n ol (15). NaBH4 (516
mg, 13.5 mmol) was added in small portions to a cooled (0 °C)
and vigorously stirred suspension of NiCl2‚6H2O (1.16 g, 4.86
mmol) in a THF-MeOH (1:3) solution containing a 60:40
mixture of diastereomers 14A:14B (198 mg, 0.63 mmol).
A
black precipitate appeared with H2 evolution. Stirring was
continued during 30 min, and the reaction was monitored by
TLC (hexane-ethyl acetate, 5:1). The crude was filtered
through Celite and washed with the solvent mixture. The
organic extracts were concentrated in vacuo, and the residue
was diluted with CH2Cl2-H2O (1:1). The two layers were
separated, and the aqueous one was extracted with CH2Cl2 (2
× 60 mL), washed with brine, and dried (MgSO4). The
solvents were evaporated under reduced pressure, and the
crude was purified by chromatography (hexane-CH2Cl2, 3:1)
to afford 1530 as a mixture of enantiomers: yield 71%; 1H NMR
δ 4.15 (2H, q, J ) 7.1 Hz), 3.0 (1H, d, J ) 1.8 Hz), 2.40 (1H,
c, J ) 7.2 Hz), 1.75-1.35 (10H, m), 1.20 (3H, t, J ) 7.1 Hz),
1.11 (3H, d, J ) 7.1 Hz); 13C NMR δ 176.8, 71.1, 60.3, 47.8,
36.8, 25.6, 21.8, 21.5, 14.0, 11.3. Starting from pure 14A,
enantiomerically pure (S)-15 was obtained as an oil, [R]25D +20
(c 0.5, CHCl3).
solid which was recrystallized from acetone-hexane: yield
90%; mp 90-92 °C; [R]25 -11 (c 1, CHCl3); H NMR δ 7.74
1
D
and 7.34 (4H, AA′BB′ system), 4.12 (2H, q, J ) 7.1 Hz), 3.64
(1H, dd, J ) 12.6 and 3.6 Hz), 3.25 and 3.02 (2H, AB system,
J ) 17.2 Hz), 2.45 (3H, s), 2.20-1.10 (8H, bm), 1.27 (3H, t, J
) 7.1 Hz); 13C NMR δ 171.5, 144.7, 135.7, 129.6, 128.8, 71.3,
66.3 ,60.4, 45.4, 38.1,24.8, 23.8, 21.6, 20.2, 14.1; IR (CHCl3)
3500, 1705, 1280, 1270, 1160, 1110, 1060, 1010. Anal. Calcd
for C17H24SO5: C, 59.98; H, 7.11; S, 9.40. Found: C, 60.14;
H, 6.82; S, 9.32.
E. Su lfin yl Gr ou p P yr olysis. Gen er a l P r oced u r e. To
a flame-dried flask equipped with a reflux condenser contain-
ing sodium bicarbonate (3.5 g, 40.6 mmol) was added via
cannula a solution of the corresponding hydroxy sulfoxide (1.06
mmol) in o-xylene (10 mL) . The mixture was vigorously
stirred and heated in an oil bath at the tempeature indicated
in each case. The reaction progress was monitored by TLC
(ethyl acetate-hexane, 1:4). The mixture was cooled to room
temperature, and the crude product was filtered over Celite
and washed with a saturated NH4Cl solution (20 mL). The
organic layer was separated, and the aqueous one was
extracted with ethyl acetate (2 × 20 mL). The combined
organic extracts were finally washed with brine and dried
(MgSO4). To prevent any reaction product evaporation, ethyl
acetate was eliminated under reduced pressure without heat-
ing. Cycloalkenol isolation was effected by flash chromatog-
raphy using successively hexane (to remove remaining o-xy-
lene) and the eluent indicated in each case.
C. Su lfin yl Gr ou p Red u ction . Gen er a l P r oced u r e. A
cooled (-40 °C) solution of TFAA (0.97 mL, 6.85 mmol) in
acetone (5 mL) was dropwise added via cannula to a stirred
suspension of the corresponding hydroxy sulfoxide (1.71 mmol)
and sodium iodide (778 mg, 5.14 mmol) in acetone (25 mL) at
the same temperature. The solution turned to dark red, and
after 15 min of stirring, a saturated sodium carbonate solution
and a 5% sodium thiosulfate solution were sequentially added.
The reaction mixture was allowed to reach room temperature,
and the organic solvent was evaporated, The residue was
extracted with ethyl acetate (2 × 40 mL), washed with brine
(2 × 20 mL), and dried (MgSO4). The extracts were evaporated
in vacuo to yield the crude product.
(1S,2S)-1-[(Eth oxyca r bon yl)m eth yl]-2-(p-tolylsu lfen yl-
)cycloh exa n -1-ol (6a ) was obtained from 2a following the
general procedure. The crude product was chromatographed
(hexane-acetone, 6:1) to afford pure 6a (474 mg, 90%) as a
pale yellow oil: [R]25 +2 (c 2, CHCl3); 1H NMR δ 7.31 and
D
(1S)-1-[(Eth oxyca r bon yl)m eth yl]cycloh ex-2-en -1-ol (7)
was obtained from 2a by heating during 3 h at 150 °C.
Chromatographic purification (ethyl acetate-hexane, 1:5)
7.05 (4H, AA′BB′ system), 4.10 (2H, q, J ) 7.1 Hz), 3.53 (1H,
s), 3.17 and 2.48 (2H, AB system, J ) 15.3 Hz), 3.02 (1H, t, J
) 8.0 Hz), 2.28 (3H, s), 2.0-1.40 (8H, bm), 1.22 (3H, t, J ) 7.1
Hz); 13C NMR δ 172.4, 135.5, 132.0, 129.4, 130.3, 72.1, 60.3,-
57.6, 44.3, 36.9, 30.1, 23.7, 20.7 (two peaks), 13.8; MS m/z 308
(62) M+, 290 (15), 221 (19), 167 (77), 1398 (44), 124 (100), 97
(59), 91 (55); HRMS calcd for C17H24SO3 308.14462, found
322.14422.
affords compound (1S)-7 (132 mg, 68%) as an oil: [R]25 +13
D
(c 0.3 CHCl3); 1H NMR δ 5.71(1H, dt, J ) 10.0 and 3.7 Hz)
5.57 (1H, bd, 10) 4.09 (2H, q, CH3CH2, J ) 7.2 Hz), 3.64 (1H,
s), 2.46 (2H, s), 2.40-1.40 (6H, bm), 1.32 (3H, t, J ) 7.2 Hz);
13C NMR δ 172.3, 130.7, 130.0, 67.9, 60.4, 45.3, 35.5, 24.8, 18.7,
14.0; IR(CHCl3) 3500, 1700, 1180, 1030, 1000; MS m/z 184(1)
(1′S,1S,2S)-1-[1′-(Eth oxyca r bon yl)eth yl]-2-(p-tolylsu lfe-
n yl)cycloh exa n -1-ol (14A) was obtained from 9A following
the general procedure. Column chromatography on silica gel
(hexane-acetone, 6:1) afforded pure 14A (473 mg, 86%) as a
M+, 166 (14), 156 (17), 121 (11), 83 (37); HRMS calcd for C10H16
SO3 184.10995, found 184.11017.
-
(1′R,1R)-1-[1′-(Eth oxyca r bon yl)eth yl]cycloh ex-2-en -1-
ol (16A) was obtained from 9B by heating during 3 h at 145
°C. Chromatographic purification (CH2Cl2-hexane, 2:1) af-
fords 16B (143 mg, 82%) as an oil: [R]25D +68 (c 1, CHCl3); 1H
pale yellow oil: [R]25 +1.5 (c 1.15, CHCl3); 1H NMR δ 7.35
D
and 7.08 (4H, AA′BB′ system), 4.08 (2H, m), 3.45 (1H, t, J )
8.0 Hz,), 3,14 (1H, q, J ) 7.3 Hz), 2.73 (1H, s), 2.32 (3H, s),
1.90-1.20 (8H, bm), 1.23 (3H, d, J ) 7.3 Hz), 1.20 (3H, t, J )
7.1 Hz); 13C NMR δ 174.8, 137.0, 132.8, 131.4, 129.5, 74.2, 60.3,
55.6, 45.9, 32.7, 30.2, 24.8, 21.1, 13.9, 11.4; IR (CHCl3) 3480,
(30) Diem, M. J .; Burow, D. F.; Fry, J . L. J . Org. Chem. 1977, 42,
1801.

9470 J . Org. Chem., Vol. 61, No. 26, 1996
Garc´ıa Ruano et al.
NMR δ 5.88 (1H, ddd, J ) 10.2, 3.9, and 2.6 Hz) 5.57 (1H, d,
J ) 10.2 Hz), 4.16 (2H, q, J ) 6.9 Hz), 3.02 (1H, s), 2.57 (1H,
c), 2.20-1.10 (6H, bm), 1.27 (3H, t, J ) 6.9 Hz), 1.22 (3H, t, J
) 7.2 Hz); 13C NMR δ 176.1, 131.4, 129.0, 70.1, 60.5, 48.2, 34.7,
25.0, 18.7, 14.2, 12.1; IR(CHCl3) 3480, 1750, 1150, 960; IR
(CHCl3) 3460, 1710, 1190, 960; HRMS calcd for C10H16SO3
184.10995, found 184.11017.
Ack n ow led gm en t. We thank Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (PB-93-0257) and
Comunidad Auto´noma de Madrid (AE-00144/94) for
financial support. D. Barros and R. Araya-Maturana
are grateful to CAM and Ministerio de Educacio´n y
Ciencia of Spain, respectively, for their fellowships.
(1′S,1R)-1-[1′-(Eth oxyca r bon yl)eth yl]cycloh ex-2-en -1-
ol (16B) was obtained from 9A by heating during 5 h at 125
°C. Chromatographic purification (CH2Cl2-hexane, 2:1) af-
fords 16A (157 mg, 75%) as an oil: [R]25D +40 (c 2, CHCl3); 1H
NMR δ 5.7 (1H, m), 5.47 (1H, d, J ) 9.8 Hz), 4.12 (2H, q, J )
6.9 Hz), 3.38 (1H, s), 2.50 (1H, q, J ) 7.1 Hz), 2.20-1.40 (6H,
bm), 1.22 (3H, t, J ) 7.1 Hz), 1.11 (3H, t, J ) 7.2 Hz); 13C
NMR δ 176.1, 131.0, 130.8, 70.1, 60.6, 48.1, 31.6, 25.0, 18.4,
14.1, 12.1.
Su p p or tin g In for m a tion Ava ila ble: X-ray experimental
data of compound 17. 1H NMR spectral data of compounds
9A-12A and 9B-12B recorded in benzene-d6 solution (3
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, can be ordered from ACS; see any current masthead
pages for ordering instructions.
J O961643T