Efficient asymmetric protonation of enolates with readily accessible chiral α-sulfinyl alcohols

Article abstract of DOI:10.1016/S0957-4166(98)00426-1

The efficient asymmetric protonation of lithium enolates of 2- alkylcycloalkanones (87-96% ee) with readily accessible chiral α-sulfinyl alcohols is described. Optimal stereoselection is achieved for each lithium enolate at a different reaction temperature in the range -40 to -100°C.

Full text of DOI:10.1016/S0957-4166(98)00426-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4073–4078
Efficient asymmetric protonation of enolates with readily
accessible chiral α-sulfinyl alcohols
Gregorio Asensio,∗ Pedro Alemán, Ana Cuenca, Jesús Gil and Mercedes Medio-Simón
Departamento de Quimica Organica, Campus de Burjassot, Avda. V. Andres Estelles s/n, 46100 Burjassot, Spain
Received 7 October 1998; accepted 20 October 1998
Abstract
The efficient asymmetric protonation of lithium enolates of 2-alkylcycloalkanones (87–96% ee) with readily
accessible chiral α-sulfinyl alcohols is described. Optimal stereoselection is achieved for each lithium enolate at a
different reaction temperature in the range −40 to −100°C. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Over the past few years, enantioselective protonation of enolates or silyl enol ethers has been
recognized as an efficient approach to chiral α-carbonyl compounds.1 Although some efficient chiral
proton sources have been described by others1–4 and by us,5 it is generally difficult to obtain these
compounds. It seems reasonable that when a chiral proton source requires a complex synthesis, organic
chemists are reticent to apply enantioselective protonation to a given sequence, and this is even more
so when the outcome of this type of reaction is not yet predictable and a difficult synthesis might be
followed by low stereoselective asymmetric protonation. Thus, highly effective and readily accessible
chiral protonating reagents are needed.
We report here our results in the asymmetric protonation of enolates of 2-alkylcycloalkanones using
α-sulfinyl alcohol (S,Rs)-1a, which has been shown to be an efficient proton donor under the conditions
that are commonly used in this type of reaction. In addition, the α-sulfinyl alcohol (S,Rs)-1a can be
obtained in a homochiral form with good yield in two steps from the commercially available (R)-p-
tolylmethylsulfoxide by following procedures described in the literature.6,7
∗
Corresponding author. Fax: 34-963864939; e-mail: gregorio.asensio@uv.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00426-1

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2. Results and discussion
In previous work,5 we reported that α-sulfinyl alcohols (S,Rs)-1c and (S,Rs)-1d, bearing a trifluoro-
methyl and a difluoromethyl group, respectively, attached to the carbinol moiety, gave high ee values in
the enantioselective protonation of the lithium enolate 3a in reactions at −100°C (92% ee) and −78°C
(93% ee), respectively, in the presence of lithium bromide. The final stereochemical outcome of the
asymmetric protonation depends on both the reaction temperature and steric hindrance resulting from the
presence of the R group in the environment of the proton to be transferred (Scheme 1).
Scheme 1. Generation of enolates 3 and enantioselective protonation with 1
From the steric perspective, the trifluoromethyl group is considered to be as bulky as an isopropyl
group and similar to the tert-butyl group in terms of its enantiocontrolling capacity.8 Therefore, to assay
the enantioselective protonation of enolates, we chose the α-sulfinyl alcohols (S,Rs)-1a and (S,Rs)-1b,
which have, with the exception of their lower acidity, characteristics similar to those of (S,Rs)-1c, and
offer the advantage of being easy to prepare. While α-sulfinyl alcohols (S,Rs)-1a and (S,Rs)-1b can be
easily obtained with high diastereoselection by reduction with DIBALH6 of the corresponding ketones,7
difluoro and trifluoro α-sulfinyl ketones exist mainly as hydrates which are unreactive towards DIBALH.9
Initially, we assayed the enantioselective protonation of lithium 2-methyl-1-tetralone enolate 3a
generated from enol acetate 2a. The protonation with (S,Rs)-1a was first carried out under the same
optimal reaction conditions which we had found previously;5,10 i.e. in dichloromethane solution and
in the presence of lithium bromide in the reaction medium. Lithium bromide was incorporated in the
reaction by using a solution of commercially available MeLi–LiBr (2.1 equiv.) to generate the enolate
3a from the enol acetate 2a. At −78°C, ketone (R)-4a was obtained with 85% ee (Table 1, entry 2). The
enantioselectivity was not improved by lowering the protonation temperature to −100°C (Table 1, entry
1). In contrast, an optimal ee value (90%) was found by raising the reaction temperature to −50°C,
(Table 1, entry 4). Small changes in temperature around this optimal point negatively affected the
stereoselection (Table 1, entries 3 and 5).
To ascertain the influence of lithium bromide on the stereochemical outcome of the protonation of 3a
with (S,Rs)-1a, the reaction was repeated at the optimal temperature (−50°C) but in the absence of the
lithium salt. Under these conditions, ketone (R)-4 was obtained with only 54% ee (Table 1, entry 6).
Since lithium bromide has a positive influence on the asymmetric induction, we tested whether
the presence of chiral lithium alkoxide (S,Rs)-1a–Li in the medium would eventually lead to better
enantioselectivity. Since the effects of lithium salts may be related to the enolate structure,11,12 they
must be present in the reaction medium prior to enolate generation.13 Indeed, we prepared a solution
containing alkoxide (S,Rs)-1a–Li and enolate 3a by mixing 1 equivalent of alcohol (S,Rs)-1a with 3
equivalents of MeLi and then adding the enolate precursor 2a. Disappointingly, the ketone (R)-4 was
obtained in only moderate ee (55%) (Table 1, entry 7). Conversely, when the same experiment was
performed using MeLi–LiBr instead of MeLi, the ketone (R)-4 was isolated with 87% ee (Table 1,

G. Asensio et al. / Tetrahedron: Asymmetry 9 (1998) 4073–4078
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Table 1
Asymmetric protonation of lithium enolates of 2-cycloalkanones with α-sulfinyl alcohols (S,Rs)-1
entry 8), showing that the presence of lithium alkoxide does not affect the enantioselectivity, whereas
lithium bromide has a clear positive effect. Consequently, enolates were generated using MeLi–LiBr in
the following experiments.
The asymmetric protonation of enolate 3a in the temperature range −50 to −100°C showed that
alcohol (S,Rs)-1b was less efficient than (S,Rs)-1a. In the latter case, the best enantioselection was
achieved at lower temperatures (−78 or −100°C) (Table 1, entries 9–12).
The good results obtained in the enantioselective protonation of enolate 3a with (S,Rs)-1a prompted us
to explore the use of this chiral proton source with other ketone enolates such as 3b, 6 and 9 (Scheme 2).
With enolate 3b, lower temperatures (−78 or −100°C) again did not produce the best stereoselection
(76% ee) (Table 1, entries 13 and 14). When the reaction was performed at −40°C, the ee increased to
87% (Table 1, entry 16), but no further increase in the degree of asymmetric induction was attained by
minor changes around this temperature (Table 1, entries 15 and 16). A sharp decrease in enantioselectivity
was observed at −25°C (Table 1, entry 17).
In another series of runs, the lithium enolates 6 and 9 were subjected to protonation with alcohol
(S,Rs)-1a. With 6, the effect of temperature on the stereochemical outcome of the reaction was unusual,

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Scheme 2. Generation of enolates 6 and 9 and enantioselective protonation with 1
since optimal stereoselection was achieved at both −65 and −100°C (Table 1, entries 18 and 20), while
the ee values decreased at −50 and −78°C (Table 1, entries 19 and 21). Conversely, enolate 9 showed
normal behavior, with the greatest enantioselection at lower temperatures (−100 and −78°C) (Table 1,
entries 22–25).
3. Conclusions
We can conclude that α-sulfinyl alcohol (S,Rs)-1a is an efficient chiral proton source for the enan-
tioselective protonation of lithium enolates of 2-alkylcycloalkanones. In the case of tetralone enolates
3a and 3b, the use of low temperatures (−78 or −100°C) has a negative effect on the induction.
This peculiar trend is difficult to explain with a reaction in which proton transfer occurs under kinetic
control. However, the temperature not only affects proton transfer, but may also produce variations in
the enolate structure and probably modifies the rate of assembly (which has been postulated to be the
preceding step in the protonation of enolates by weak proton sources) of the α-sulfinyl alcohol to each
type of enolate present in the reaction medium. Thus, enantioselection depends on the temperature in
a complex way which makes it difficult to draw general conclusions about the optimal conditions to
effect a given asymmetric protonation. Until now, −78 and −100°C have been standard temperatures for
enantioselective protonation reactions with proton sources in solution. Although low (−78°C) or very low
temperatures (−100°C) may often be the best choice for such reactions, in some cases moderately low
temperatures (−40 or −50°C) provide the best enantioselection. In these latter cases, the ability to avoid
very low temperatures offers several practical advantages. In conclusion, temperature is an important
parameter to be considered in enantioselective protonation reactions, and this type of reaction should be
carefully examined over a range of temperatures to determine the optimal stereoselection in each case.
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were recorded on a Bruker AC-250 with tetramethylsilane as an
internal reference and CDCl3 as a solvent. Melting points were determined with a Cambridge Instruments
apparatus and are uncorrected. Optical rotation measurements were determined on a Perkin–Elmer 241
polarimeter at room temperature. High resolution mass spectra (HRMS) were recorded on a Fisons VG
Autospec instrument. Analytical gas chromatography was performed on a Fisons Series 9000 instrument
equipped with a flame ionization detector and a capillary column of BPX5 (0.22×30000 mm) (df 0.25
µm).

G. Asensio et al. / Tetrahedron: Asymmetry 9 (1998) 4073–4078
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4.2. Materials
Methyllithium (1.6 M solution in diethyl ether, d=0.701; 0.09 M in LiCl; 1.5 M solution in diethyl
ether, d=0.852; 1.0 M in LiBr) was purchased from Aldrich. All solvents were dried before use. Diethyl
ether was distilled under argon from sodium benzophenone and dichloromethane was distilled from
calcium hydride. Enol acetates 2a, 2b, 5 and 8 were prepared from the corresponding racemic ketones
as described previously.14 The thermodynamic enol acetates 5 and 8 were obtained as (95:5) and (92:8)
inseparable mixtures, respectively, with the corresponding less-substituted regioisomers. The mixture
composition was analyzed by GC. The ee values for chiral ketones 4a,15 4b,16 717 and 1015 were assigned
by comparison with the literature.
4.3. (R)-(+)-3-Methyl-1-(4-methylphenylsulfinyl)-2-butanone
1
This was obtained according to a literature procedure;7 m.p. and [α]D agreed with the literature; H-
NMR δ 1.02 (d, 3H, J=7.5 Hz), 1.09 (d, 3H, J=7.5 Hz), 2.42 (s, 3H), 2.53–2.64 (m, 1H), 3.81 (d, 1H,
J=12.5), 4.01 (d, 1H, J=12.5 Hz), 7.34 (d, 2H, J=7.5 Hz), 7.56 (d, 2H, J=7.5 Hz); 13C-NMR δ 17.2 (c),
17.4 (c), 21.4 (c), 42.2 (d), 66.9 (t), 124.1 (d), 130.0 (d), 140.0 (s), 142.1 (s), 205.5 (s).
4.4. (R)-(+)-3,3-Dimethyl-1-(4-methylphenylsulfinyl)-2-butanone
1
This was obtained according to a literature procedure;6 m.p, [α]D and H-NMR agreed with the
literature; 13C-NMR δ 21.2 (c), 25.4 (c), 44.4 (s), 65.2 (t), 124.2 (d), 129.8 (d), 140.4 (s), 141.9 (s),
207.2 (s).
4.5. (S,Rs)-(+)-3-Methyl-1-(4-methylphenylsulfinyl)-2-butanol (1a)
This was prepared from the corresponding ketone following the general procedure described in the
1
literature;6 yield 90%; m.p.: 83–84°C (from hexane); [α]D +304.0 (c=2, CHCl3); H-NMR δ 0.91 (d,
6H, J=7.5 Hz), 1.70–1.78 (m, 1H), 2.42 (s, 3H), 2.73 (dd, 1H, J1=15 Hz, J2=1.8 Hz), 2.95 (dd, 1H, J1=15
Hz, J2=10 Hz), 3.88–4.06 (m, 1H), 4.39 (d, 1H, J=5 Hz), 7.34 (d, 2H, J=7.5 Hz), 7.54 (d, 2H, J=7.5 Hz);
13C-NMR δ 17.3 (c), 18.2 (c), 21.3 (c), 33.6 (d), 60.6 (t), 70.3 (d), 123.9 (d), 129.9 (d), 139.8 (s), 141.3
(s); HRMS calculated for C12H18O2S: 226.1027, found 226.1105.
4.6. (S,Rs)-(+)-3,3-Dimethyl-1-(4-methylphenylsulfinyl)-2-butanol (1b)
This was prepared according to a literature procedure;6 m.p. and 1H-NMR agreed with the literature;
[α]D +297.5 (c=2, CHCl3); 13C-NMR δ 21.4 (c), 25.4 (c), 34.8 (s), 58.0 (t), 73.5 (d), 124.0 (d), 130.0
(d), 139.7 (s), 141.3 (s).
4.7. General procedure for generation of enolates
To a stirred solution of the corresponding enol acetate (1.0 mmol) in diethyl ether (9 ml) at 0°C was
added an ether solution of methyllithium as a complex with lithium bromide 1.5 M or methyllithium 1.6
M (2.1 mmol). The mixture was stirred at room temperature for 30 min.

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4.8. General procedure for protonation
The appropriate lithium enolate solution (10 ml) at −75°C was slowly added over 7 min to a solution
of α-sulfinyl alcohol (3.0 mmol) in dichloromethane (30 ml) at the temperature specified in each case
(see Table 1). The mixture was stirred (1.5 h) at the same temperature and then gradually warmed up to
0°C (temperature increase approximately 1.2°C/min). The reaction mixture was treated with phosphate
buffer (pH: 7.2) and extracted with hexane. The residue was purified by column chromatography to give
the corresponding ketone (90–94% yield).
Acknowledgements
We thank Dirección General de Enseñanza Superior (PB96-0757) for financial support and Generalitat
Valenciana for grants (P.A. and A.C.)
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