First synthesis of the chiral mixed O/S ligands, 1,2-sulfinyl thiols: Application as chiral proton sources in enantioselective protonations of enolates

Article abstract of DOI:10.1016/S0957-4166(00)00330-X

A suitable method for the preparation of the chiral mixed O/S ligands 1,2-sulfinyl thiols is described. These compounds have then been used as a chiral proton source in the enantioselective protonation of 2-methyl tetralone enolate and the results are com

Full text of DOI:10.1016/S0957-4166(00)00330-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3481–3493
First synthesis of the chiral mixed O/S ligands,
1,2-sulfinyl thiols: application as chiral proton sources
in enantioselective protonations of enolates
Gregorio Asensio,* Pablo Gavin˜a, Ana Cuenca, M. Carmen Ram´ırez de Arellano,
Luis R. Domingo and Mercedes Medio-Simo´n
Departamento de Qu´ımica Orga´nica, Universidad de Valencia, 46100 Burjassot, Spain
Received 31 May 2000; accepted 21 August 2000
Abstract
A suitable method for the preparation of the chiral mixed O/S ligands 1,2-sulfinyl thiols is described.
These compounds have then been used as a chiral proton source in the enantioselective protonation of
2-methyl tetralone enolate and the results are compared with those obtained from the analogous alcohols.
A theoretical model is proposed to explain the different behaviors exhibited in the protonation reaction
for each of these proton sources. Configurational assignments for the new chiral thiols have been carried
out by means of X-ray analysis. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
In the course of our research on the enantioselective protonation of enolates1 we have
undertaken the preparation of 1,2-sulfinyl thiols (S,Rs)-1. This topic constitutes a new aspect of
the field of enantioselective protonation of enolates since, while chiral alcohols have been widely
used as proton sources,2 there are no precedents for the utilization of chiral thiols. In addition
to their application as chiral proton sources, these compounds and their related derivatives, such
as the corresponding thioethers, have structural features which make them attractive for use as
chiral catalysts; they are chiral ligands with a heteroatom pair containing a strong sulfur donor
and a weak oxygen donor. This type of chiral mixed O/S ligands have gained increasing
attention because, as is the case with C2 symmetry ligands, they exhibit powerful stereochemical
restrictions that are the consequence of electronic effects.3 An additional class of thiol deriva-
tives with interesting potential applications are thioesters, which can be used as mild acylating
reagents of amines and alcohols.4,5 The asymmetric version of these reactions should result from
the use of the S-acyl derivatives of 1,2-sulfinyl thiols and can most likely be applied to alcohol
and amine resolution or desymmetrization.
* Corresponding author. Fax: +34-963864939; e-mail: gregorio.asensio@uv.es
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00330-X

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Due to the interesting nature of chiral 1,2-sulfinyl thiols and the lack of references in the
literature as to their preparation, we considered it of interest to develop a suitable method to
synthesize these compounds. In addition, we have also undertaken the testing of these com-
pounds as chiral proton sources in the enantioselective protonation of 2-methyl tetralone enolate
in order to compare the results with those obtained from the analogous 1,2-sulfinyl alcohols that
we have previously described.1
2. Results and discussion
2.1. Synthesis of 1,2-sulfinyl thiols
Since the 1,2-sulfinyl thiols have two stereogenic atoms, two diastereomers (S,Rs)-1 and
(R,Rs)-2 can, in principle, be considered as proton sources. However, since among the
analogous compounds 1,2-sulfinyl alcohols (S,Rs)-3 and (R,Rs)-4, sulfinyl alcohols 3 with the
(S,Rs) configuration have been shown to be more effective as protonating reagents than the
corresponding diastereomers (R,Rs)-4,6 our objective was the preparation of compounds 1
having the configuration (S,Rs) (Scheme 1).
Scheme 1. Preparation of 1,2-sulfinyl alcohols
The preparation of compounds (S,Rs)-1 following a procedure similar to that described by
Solladie´ for 1,2-sulfinyl alcohols (S,Rs)-37 was not feasible due to the high tendency of
thioketones to undergo enolization and oligomerization.8 Thus, since alcohols are among the
most usual precursors of thiols,9 we devised the preparation of 1,2-sulfinyl thiols 1 from the
corresponding sulfinyl alcohols. In order to prepare compounds 1 with the (S,Rs) configuration
and taking into consideration that the methods of conversion of alcohols into other derivatives
such as amines10 (or, in our case, thiols) involve configuration inversion at the stereogenic
carbon, sulfinyl alcohols (R,Rs)-4 were chosen as precursors. The interconversion was originally
assayed in the case of 4b by means of a modified Mitsunobu procedure,11 but the purification
of the products was difficult due to contamination from by-products derived from azodicarboxyl-
ate. We thus performed an alternative pathway based on a previously described procedure for
the synthesis of analogous compounds.12 The method involves the conversion of alcohol
(R,Rs)-4 into mesylate (R,Rs)-5, the displacement of mesylate anion with cesium thioacetate to

G. Asensio et al. / Tetrahedron: Asymmetry 11 (2000) 3481–3493
3483
afford thioester (S,Rs)-6 and the subsequent hydrolysis of (S,Rs)-6 to afford the corresponding
thiol (S,Rs)-1 (Scheme 2).
Scheme 2. Synthesis of 1,2-sulfinyl thiols 1 from 1,2-sulfinyl alcohols 4
1,2-Sulfinyl alcohols (R,Rs)-4a–d were converted into mesylates (R,Rs)-5a–d with high yields
(80–85%). Mesylates (R,Rs)-5a–c reacted with cesium acetate in DMF affording the thioacetates
(S,Rs)-6a–c with acceptably good yields (65–85%); however, with the branched mesylate
(R,Rs)-5d, only a 25% yield of the substitution product (S,Rs)–6d was obtained as elimination
was an important side reaction in this case. The substitution reaction took place as expected
with complete inversion of the configuration, which was unequivocally assigned by X-ray
diffraction (see below). Hydrolysis of thioacetates (S,Rs)-6 was accomplished in ammonia and
lead to thiols (S,Rs)-1 and sulfides 7 as by-products. In the case of thioacetate (S,Rs)-6a, the
disulfide 7a was the only product. We observed that thiols (S,Rs)-1b–d yielded the correspond-
ing disulfides 7 even under an inert atmosphere. In view of the lack of stability of thiols (S,Rs)-1,
no further assays were carried out. The conversion of thioacetates into thiols in aprotic media
was not undertaken since disulfides can be produced during the work-up.
Although the conversions of thiols into disulfides are, in the context of our work, undesirable
reactions, it is worth noting that chiral disulfides can also be useful catalysts in asymmetric
reactions.13
2.2. Enantioselective protonation with 1,2-sulfinyl thiols as chiral proton sources
There are no precedents in the literature about the application of thiols as chiral proton
sources in the enantioselective protonation of enolates.2 This fact can be related in part to the
lack of commercially available chiral thiols, but also to their greater acidity if compared with
alcohols, which may result in a difficult kinetic control in the proton transfer step. However,
thiols have an acidity similar to that of succinimides,14 the chiral derivatives of which have been
shown by Yamamoto et al. to be efficient protonating reagents.15 We were thus interested in
testing the 1,2-sulfinyl thiols (S,Rs)-1b–c as chiral proton transfer reagents.
Enantioselective protonation runs were performed under the same conditions used previously
for protonations with 1,2-sulfinyl alcohols (S,Rs)-3.1 2-Methyl tetralone enolate 8 was generated
upon treatment of the corresponding enol acetate precursor 716 with 2.2 equiv. of methyl lithium

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complexed with lithium bromide and submitted to protonation with sulfinyl thiols (S,Rs)-1 in
dichloromethane. Runs were carried out at two different temperatures (−78 and −100°C).
Interestingly, compounds (S,Rs)-1 lead to a higher ee at the lower temperature (entries 1–4, Table
1). Upon comparison with the series of related alcohols (S,Rs)-3, we observed the same behavior
for the alcohol (S,Rs)-3e,17 the most acidic member of the series (entries 11 and 12, Table 1). With
the less acidic alcohols (S,Rs)-3a–d, the stereoselection obtained was similar regardless of whether
the reactions were performed at −78 (entries 5–7, Table 1) or −100°C (8–10, Table 1).
Table 1
Enantioselective protonations with 1,2-sulfinyl thiols 1 and 1,2-sulfinyl alcohols 3
Entry
Proton source
Temperature (°C)
(R)-9 ee
1
2
3
4
5
6
7
8
9
(S,Rs)-1b
(S,Rs)-1c
(S,Rs)-1b
(S,Rs)-1c
(S,Rs)-3b
(S,Rs)-3c
(S,Rs)-3b
(S,Rs)-3c
(S,Rs)-3e
(S,Rs)-3e
−78
−78
−100
−100
−78
45
44
61
55
80a
84
85
83
67
92b
−78
−100
−100
−78
10
−100
a Ref. 17.
b Ref. 1.
These results show the dependence of the enantioselectivity on the acidity of the proton source
and the reaction temperature. This trend fits well with the fact that the enantioselective protonation
is a kinetically controlled reaction. It would be interesting to see whether the stereoselection could
be improved by using temperatures below −100°C, but the freezing of the solvent prevents any
further investigation. 1,2-Sulfinyl thiols (S,Rs)-1 prove to be less effective as chiral proton sources
compared with alcohols (S,Rs)-3. While alcohols (S,Rs)-3 lead to the corresponding ketone (R)-9
with high enantiomeric excess (entries 5–7, Table 1), the stereoselection achieved with 1,2-sulfinyl
thiols (S,Rs)-1 was only moderate (entries 1–4, Table 1). This fact may be related to both structural
factors and reaction conditions. First, structural features of compounds (S,Rs)-1 might negatively
influence the stereoselection since CꢀS and SꢀH bonds are longer than CꢀO and OꢀH bonds,
respectively, and as a consequence, the proton will be delivered from a position farther from the
stereogenic center in the case of compounds 1 than in that of compounds 3. The impossibility
of any practical work below −100°C does not allow for the determination of the optimal reaction
temperature for effective kinetic control in the proton transfer with compounds 1.

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2.3. Theoretical model
In order to clarify the influence of the structural factors in the stereoselection achieved with
thiols (S,Rs)-1, we have performed quantum mechanical calculations at the PM3 semiempirical
level (see Section 4 for details). Calculations have been carried out with the aid of our theoretical
model for alcohols (S,Rs)-3.1 This model is based on the existence of a lithium enolate and
lithium bromide mixed dimer defined as a four-membered ring, in which the bromide anion and
the oxygen atom are connected by two lithium cations. These bridging cations are in a nearly
tetrahedral environment provided by coordination with the oxygen and sulfur atoms of thiol
(S,Rs)-1b and two molecules of dimethyl ether. The corresponding transition structures TS1-R
and TS1-S that account for the two possible enolate protonation pathways can be described as
six-membered rings in which the proton transfer takes place via a favorable intramolecular
pathway (Fig. 1). The PM3 calculations indicate that TS1-R is 1.47 kcal/mol more favorable
than TS1-S. Consequently, the theoretical calculations based on our model are in good
agreement with the experimental results and predict the enantioselective formation of ketone
(R)-9. The calculated length of the breaking SꢀHt bond and the forming CꢀHt bond in TS1-R
,
,
are 1.758 and 1.301 A, respectively, whereas in TS1-S they are 1.745 and 1.314 A, respectively
(Fig. 1). The distance between the donor and acceptor proton centers in TS1-R and TS1-S are
,
3.036 and 3.028 A, respectively.
Figure 1. PM3 selected geometrical parameters (in angstroms) for the transition structures TS1-R and TS1-S. Data
in parenthesis correspond to TS2-R and TS2-S, respectively
The energy difference for thiol (S,Rs)-1b between TS1-R and TS1-S (1.47 kcal/mol) is lower
than that previously determined for alcohol (S,Rs)-3e between the transition structures TS2-R
and TS2-S (3.9 kcal/mol). These transition structures arise from the linkage of lithium enolate

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8, lithium bromide, the corresponding chiral thiol or alcohol and two molecules of dimethyl
ether (Fig. 1). The TS energy differences calculated on the basis of our model are also in good
agreement with the lower stereoselection found experimentally with the chiral thiol (S,Rs)-1b
relative to the alcohol (S,Rs)-3e. Inspection of TS1-S and TS2-S allows us to deduce that the
,
distance between the S-donor and the C-acceptor in TS1-S (3.028 A) is longer than that existing
,
between the O-donor and the C-acceptor in TS2-S (2.646 A) (Fig. 1). Consequently, TS1-S is
less crowded than TS2-S because the unfavorable steric interactions between thiol (S,Rs)-1b and
enolate 8 are weaker than those in the case of alcohol (S,Rs)-3e. Thus, TS1-S becomes closer in
energy to TS1-R and the kinetically controlled stereoselection of the proton transfer process
decreases. According to our model, the structural differences observed in the calculated
transition structures account for the different behavior of 1,2-sulfinyl thiols (S,Rs)-1 and
1,2-sulfinyl alcohols (S,Rs)-3 as chiral proton transfer reagents.
2.4. X-ray crystal structures of compounds (S,Rs)-1b, (S,Rs)-1d and (S,Rs)-6c
Both configurational assignment and conformational analysis for the thiols (S,Rs)-1b and
(S,Rs)-1d (Fig. 2) and the thioacetate (S,Rs)-6c (Fig. 3) were carried out after X-ray crystal
structure determination. The absolute configuration was determined as (S,Rs) for compounds
(S,Rs)-1b, (S,Rs)-1d and (S,Rs)-6c [absolute structure parameters 0.04(7), 0.0(3) and 0.03(8),
Figure 2. Ellipsoid plot (50% probability level) of compounds 1b and 1d with the labeling scheme

G. Asensio et al. / Tetrahedron: Asymmetry 11 (2000) 3481–3493
3487
respectively].18 The conformational analysis of compound (S,Rs)-1b based on the corresponding
vicinal coupling constant values of the methyne proton H1 with the methylene protons H2 and
3
H3 (3J1,2=9.9 and J1,3=4.4 Hz) led us to propose structure C1b as the prevalent conformer in
solution (Fig. 2). The analogous conformer C1d (Fig. 2) can account for the coupling constants
3
(3J1,2=11.5 and J1,3=3.2 Hz) found for thiol (S,Rs)-1d in solution. The deduced major
conformations in solution C1b and C1d corresponding to thiols (S,Rs)-1b and (S,Rs)-1d,
respectively, correspond to the conformations adopted in the solid state having torsion angles
O-S1···C2ꢀS2 100.8(1)° and 123.7(4)° (Fig. 2). In addition, the structures of the major conform-
ers C1b and C1d are in good agreement with the most stable conformations determined by
molecular mechanics force field analysis for related 1,2 sulfinyl alcohols.19 Conformational
analysis of compound (S,Rs)-6c, also based on the coupling constant values of methyne H1 and
methylene H2 and H3, reveals the prevalence in solution of a different conformer C6c since in
this case the coupling constant values are similar (3J=8.1 and 6.4 Hz). The same conformation
was found for compound (S,Rs)-6c in solution and in the solid state corresponding to the
gauche conformation for the ethyl and sulfinyl groups with respect to the C1ꢀC2 bond [torsion
angles S1ꢀC1ꢀC2ꢀC3 51.7(2)°, S1ꢀC1ꢀC2ꢀS2 74.5(2)°], as determined by X-ray analysis (Fig. 3).
Figure 3. Ellipsoid plot (50% probability level) of compound 6c with the labeling scheme
For both thiols (S,Rs)-1b and (S,Rs)-1c an intermolecular SꢀH···O hydrogen bond producing
infinite chains is present in the crystals [(S,Rs)-1b: H(2)···Oc (c: x+1/2, −y−1/2, −z−1) 2.14,
S(2)···Oc 3.426(1), S(2)ꢀH(2)...Oc 157.3; (S,Rs)-1d: H(2)...Oc (c: x−1, y, z) 2.63, S(2)···Oc
3.751(6), S(2)ꢀH(2)···Oc 139.0] (see Fig. 4).
3. Conclusions
A convenient synthesis of the chiral mixed O/S ligands 1,2-sulfinyl thiols (S,Rs)-1 is described
for the first time. These compounds are readily accessible in three steps from the corresponding
sulfinyl alcohols (R,Rs)-4. The absolute configuration of these new chiral thiols (S,Rs)-1 has
been established by X-ray analysis. Compounds (S,Rs)-1 are moderately good proton sources
when the enantioselective protonation of enolates is carried out at very low temperatures, a fact
which reflects their high acidity, but they are less effective than the related 1,2-sulfinyl alcohols

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G. Asensio et al. / Tetrahedron: Asymmetry 11 (2000) 3481–3493
Figure 4. Infinite chains formed in compounds 1b and 1c through SH···O hydrogen bonds
(S,Rs)-3 with the same configuration at the stereogenic centers. The differences found between
the protonating reagents (S,Rs)-1 and (S,Rs)-3 can be explained with the aid of the proposed
theoretical model on the basis of their different structural parameters.
4. Experimental
4.1. General methods
1H NMR and 13C NMR spectra were recorded on a Bruker AC-250 with tetramethylsilane as
an internal reference in CDCl3. 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.

G. Asensio et al. / Tetrahedron: Asymmetry 11 (2000) 3481–3493
3489
4.2. Materials
Methyllithium 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 from calcium hydride.
4.3. Computational details
The computational study was carried out using the PM3 semiempirical method20 implemented
in the MOPAC program.21 The molecular geometries of the transition structures (TS) were
optimized with the optimization routine TS.22 Stationary points on the potential energy surface
,
(PES) were located by minimizing the gradients of energy to 0.1 kcal/mol/A-radian. Examina-
tion of the TSs was achieved by the evaluation of the Hessian matrix; the nature of these
stationary points was established by analytical calculations and diagonalization of the matrix of
energy second derivatives in order to determine the unique imaginary frequency.
4.3.1. (S,Rs)-1-(4-Methylphenylsulfinyl)-2-propanethiol (S,Rs)-1b
White solid; isolated yield: 78%; mp (hexane/ethyl acetate): 62–64°C; [h]2D0=+257 (c=1.0,
1
CHCl3); H NMR (CDCl3, 250 MHz): l 7.53 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H),
3.51–3.43 (m, 1H), 3.05 (dd, J=13.1 and 4.4 Hz, 1H), 2.77 (dd, J=13.1 and 9.9 Hz, 1H), 2.41
(s, 3H), 2.05 (d, J=6.7 Hz, 1H) and 1.45 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz)
(DEPT): l 141.7 (C), 140.6 (C), 130.0 (CH), 123.9 (CH), 69.3 (CH2), 30.1, 25.1 and 21.4 (CH3);
EIMS: m/z (rel. int.%) 214 (M+, 88), 198 ([M−O]+, 5), 165 ([M−SH−O]+, 21), 151 (96), 137 (50),
123 (72), 93 (100) and 77 ([M−137], 80); CIMS: m/z (rel. int.%) 215 (MH+, 29), 198 (M−O, 25),
181 (MH+−H2S, 34), 165 (M−SH−O, 72), 153 (M−C2H5S, 54), 139 (M−C3H7S, 56), 125 (100)
+
and 91 (C7H7 , 68); HRMS (FAB): m/z 215.0558; calcd for C10H15OS2: 215.0564.
4.3.2. (S,Rs)-1-(4-Methylphenylsulfinyl)-2-butanethiol (S,Rs)-1c
1
White solid; isolated yield: 51%; mp (hexane): 51–52.5°C; [h]2D0=+280 (c=1.0, CHCl3); H
NMR (CDCl3, 250 MHz): l 7.54 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 3.36–3.22 (m,
1H), 3.07 (dd, J=13.1 and 3.8 Hz, 1H), 2.73 (dd, J=13.1 and 10.7 Hz, 1H), 2.41 (s, 3H), 1.87
(d, J=7.3 Hz, 1H), 1.82–1.54 (m, 2H) and 1.03 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 62.5
MHz): l 141.6, 140.7, 130.0, 123.9, 67.8, 36.7, 31.5, 21.4 and 11.2; HRMS (EI): m/z 228.0642;
calcd for C11H16OS2: 228.0643.
4.3.3. (S,Rs)-3-Methyl-1-(4-methylphenylsulfinyl)-2-butanethiol (S,Rs)-1d
White solid; isolated yield: 67%; mp: 49–51°C; [h]2D0=+272.2 (c=1.0, CHCl3); H NMR
1
(CDCl3, 250 MHz): l 7.55 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 3.43–3.32 (m, 1H), 3.00
(dd, J=13.0 and 3.2 Hz, 1H), 2.72 (dd, J=13.0 and 11.5 Hz, 1H), 2.42 (s, 3H), 2.01–1.88 (m,
1H), 1.69 (d, J=8.0 Hz, 1H), 1.02 (d, J=6.7 Hz, 3H) and 0.92 (d, J=6.7 Hz, 3H); 13C NMR
(CDCl3, 62.5 MHz): l 141.6, 140.8, 130.0, 123.8, 66.3, 41.3, 33.8, 21.4, 20.0 and 17.3; HRMS
(EI): m/z 242.0792; calcd for C12H18OS2: 242.0799.
4.3.4. (R,Rs)-2-(4-Methylphenylsulfinyl)-1-ethanol (R,Rs)-4a
Mp: 95–98°C; [h]2D0=+322 (c=1.0, CHCl3); H NMR (CDCl3, 250 MHz), l 7.54 (d, J=8.2
1
Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 4.25–4.10 (m, 1H), 4.10–3.95, (m, 1H), 3.54 (br. s, 1H), 3.16

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G. Asensio et al. / Tetrahedron: Asymmetry 11 (2000) 3481–3493
(ddd, J=13.5, 8.6 and 3.9 Hz, 1H), 2.86 (ddd, J=13.5, 5.5 and 3.1 Hz, 1H) and 2.43 (s, 3H).13C
NMR (CDCl3, 62.5 MHz): l 141.8, 139.6, 130.1, 124.0, 58.0, 57.2 and 21.4.
4.3.5. (R,Rs)-1-(4-Methylphenylsulfinyl)-2-propanol (R,Rs)-4b
Colorless oil; [h]2D0=+273 (c=1.1, CHCl3) (de]90%; by H NMR); H NMR (CDCl3, 250
MHz): l 7.54 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.48–4.38 (m, 1H), 3.93 (br. s, 1H),
2.98 (dd, J=13.1 and 8.9 Hz, 1H), 2.74 (dd, J=13.1 and 2.8 Hz, 1H), 2.41 (s, 3H) and 1.30 (d,
J=6.3 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz): l 141.9, 140.4, 130.1, 123.9, 64.9, 63.8, 23.2 and
21.4.
1
1
4.3.6. (R,Rs)-1-(4-Methylphenylsulfinyl)-2-butanol (R,Rs)-4c
White solid; [h]2D0=+258 (c=1.0, CHCl3); H NMR (CDCl3, 250 MHz): l 7.56 (d, J=8.1 Hz,
1
2H), 7.35 (d, J=8.1 Hz, 2H), 4.29–4.21 (m, 1H), 3.85 (br. s, 1H), 2.94 (dd, J=13.1 and 9.3 Hz,
1H), 2.78 (dd, J=13.1 and 2.3 Hz, 1H), 2.43 (s, 3H), 1.66–1.53 (m, 2H) and 0.96 (t, J=7.4 Hz,
3H); 13C NMR (CDCl3, 62.5 MHz): l 142.0, 140.5, 130.1, 123.9, 70.1, 62.0, 30.1, 21.4 and 9.4.
4.3.7. (R,Rs)-3-Methyl-1-(4-methylphenylsulfinyl)-2-butanol (R,Rs)-4d
1
White solid; mp: 65–66.5°C (hexane); [h]2D0=+232 (c=1.0, CHCl3); H NMR (CDCl3, 250
MHz): l 7.56 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 4.13–4.05 (m, 1H), 3.86 (d, J=2.1
Hz, 1H), 2.91 (dd, J=13.1 and 9.7 Hz, 1H), 2.77 (dd, J=13.1 and 1.9 Hz, 1H), 2.43 (s, 3H),
1.86–1.74 (m, 1H), 0.93 (d, J=6.8 Hz, 3H) and 0.92 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 62.5
MHz): l 142.4, 141.1, 130.5, 124.6, 73.6, 60.5, 34.3, 21.8, 18.3 and 17.7.
4.3.8. (R,Rs)-2-(4-Methylphenylsulfinyl)ethyl methane sulfonate (R,Rs)-5a
White solid; isolated yield: 84%; mp: 79–80°C; [h]2D0=+182 (c=1.1, CHCl3); 1H NMR (CDCl3,
250 MHz): l 7.53 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 4.70–4.60 (m, 1H), 4.54–4.46 (m,
1H), 3.26–3.15 (m, 1H), 3.06 (s, 3H), 3.10–3.01 (m, 1H) and 2.43 (s, 3H); 13C NMR (CDCl3, 62.5
MHz): l 142.1, 139.4, 130.2, 123.8, 62.2, 56.0, 37.4 and 21.4.
4.3.9. (R,Rs)-1-Methyl-2-(4-methylphenylsulfinyl)ethyl methane sulfonate (R,Rs)-5b
White solid; isolated yield: 88%; mp: 71–74°C; [h]2D0=+154 (c=1.0, CHCl3); 1H NMR (CDCl3,
250 MHz): l 7.57 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H), 5.07 (sextet, J=6.1 Hz, 1H), 3.26
(dd, J=13.6 and 5.8 Hz, 1H), 3.03 (s, 3H), 2.99 (dd, J=13.6 and 6.2 Hz, 1H), 2.42 (s, 3H) and
1.64 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) (DEPT): l 142.1 (C), 139.8 (C), 130.2
(CH), 124.1 (CH), 73.6 (CH), 63.1 (CH2), 38.7 (CH3) and 21.4 (2×CH3).
4.3.10. (R,Rs)-1-(4-Methylphenylsulfinyl)propyl methane sulfonate (R,Rs)-5c
1
Colorless oil; isolated yield: 84%; H NMR (CDCl3, 250 MHz): l 7.57 (d, J=8.3 Hz, 2H),
7.35 (d, J=8.3 Hz, 2H), 4.95–4.86 (m, 1H), 3.26 (dd, J=13.7 and 5.6 Hz, 1H), 3.05 (s, 3H), 3.04
(dd, J=13.7 and 5.8 Hz, 1H), 2.42 (s, 3H), 2.04–1.88 (m, 2H) and 1.02 (t, J=7.4 Hz, 3H); 13C
NMR (CDCl3, 62.5 MHz): l 142.1, 139.9, 130.2, 124.1, 78.4, 61.6, 38.6, 27.8, 21.4 and 9.2.
4.3.11. (R,Rs)-2-Methyl-1-(4-methylphenylsulfinyl)propyl methane sulfonate (R,Rs)-5d
White solid; isolated yield: 87%; mp: 82–84°C; [h]2D0=+111.1 (c=1.0, CHCl3); H NMR
1
(CDCl3, 250 MHz): l 7.59 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 4.80–4.73 (m, 1H), 3.27
(dd, J=13.9 and 6.9 Hz, 1H), 3.09 (s, 3H), 3.00 (dd, J=13.9 and 4.7 Hz, 1H), 2.42 (s, 3H),

G. Asensio et al. / Tetrahedron: Asymmetry 11 (2000) 3481–3493
3491
2.28–2.18 (m, 1H), 1.01 (d, J=6.8 Hz, 3H) and 0.93 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3, 62.5
MHz): l 142.2, 140.0, 130.2, 124.2, 81.2, 59.6, 38.8, 32.0, 21.4, 17.8 and 17.0.
4.3.12. (S,Rs)-2-(4-methylphenylsulfinyl)ethyl ethanethioate (S,Rs)-6a
1
Pale yellow oil; isolated yield: 83%; H NMR (CDCl3, 250 MHz): l 7.52 (d, J=8.2 Hz, 2H),
7.34 (d, J=8.2 Hz, 2H), 3.23–2.97 (m, 4H), 2.42 (s, 3H) and 2.33 (s, 3H); 13C NMR (CDCl3,
62.5 MHz): l 195.1, 141.7, 139.4, 130.0, 124.0, 56.0, 30.5, 21.9 and 21.4.
4.3.13. (S,Rs)-1-Methyl-2-(4-methylphenylsulfinyl)ethyl ethanethioate (S,Rs)-6b
1
Colorless oil; isolated yield: 66%; H NMR (CDCl3, 250 MHz): l 7.53 (d, J=8.3 Hz, 2H),
7.33 (d, J=8.3 Hz, 2H), 3.90 (sextet, J=7.1 Hz, 1H), 3.00 (d, J=7.2 Hz, 2H), 2.41 (s, 3H), 2.31
(s, 3H) and 1.49 (d, J=7.1 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz): l 194.7, 141.7, 140.6, 130.0,
124.0, 64.5, 35.3, 30.6, 21.4 and 20.8.
4.3.14. (S,Rs)-1-(4-Methylphenylsulfinylmethyl)propyl ethanethioate (S,Rs)-6c
1
Pale yellow solid; isolated yield: 75%; mp: 48–50°C; [h]2D0=+113.7° (c=1.0 CHCl3); H NMR
(CDCl3, 250 MHz): l 7.54 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 3.83 (m, 1H), 3.08 (dd,
J=13.3 and 6.4 Hz, 1H), 2.97 (dd, J=13.3 and 8.1 Hz, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 1.97–1.71
(m, 2H) and 0.99 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz): l 194.8, 141.7, 140.8, 130.0,
124.0, 63.2, 41.7, 30.8, 27.4, 21.4 and 11.2.
4.3.15. (S,Rs)-2-Methyl-1-(4-methylphenylsulfinylmethyl)propyl ethanethioate (S,Rs)-6d
1
Colorless oil; isolated yield: 25%; [h]2D0=+111.9 (c=1.1, CHCl3); H MNR (CDCl3, 250
MHz): l 7.55 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 3.98 (ddd, J=9.4, 5.6 and 3.9 Hz,
1H), 3.07 (dd, J=13.3 and 5.6 Hz, 1H), 2.85 (dd, J=13.3 and 9.4 Hz, 1H), 2.42 (s, 3H), 2.37
(s, 3H), 2.23–2.11 (m, 1H), 0.96 (d, J=6.7 Hz, 3H) and 0.94 (d, J=6.7 Hz, 3H); 13C NMR
(CDCl3, 62.5 MHz): l 194.1, 141.7, 140.9, 130.0, 124.0, 62.3, 46.0, 32.0, 30.8, 21.4, 20.0 and
18.4.; HRMS (EI): m/z 285.0974; calcd for C14H21O2S2: 285.0983.
4.3.16. (S,S,Rs,Rs)-Di[2-(4-methylphenylsulfinyl)ethyl] disulfide (S,Rs,S,Rs)-7a
1
Wax; isolated yield: 81%; [h]2D0=+284 (c=1.0, CHCl3); H NMR (CDCl3, 250 MHz): l 7.49
(d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 3.24–3.11 (m, 1H), 3.05–2.91 (m, 2H), 2.76–2.64 (m,
1H) and 2.42 (s, 3H); 13C NMR (CDCl3, 62.5 MHz): l 141.7, 139.4, 130.0, 123.9, 55.4, 29.4 and
21.4; EIMS: m/z (rel. int.%) 259 (M−S(O)p-tol), 199 (35) and 139 ([S(O)p-tol]+, 98]; HRMS
(FAB): m/z 399.0578; calcd for C18H23O2S4: 399.0581.
4.3.17. (S,S,Rs,Rs)-Di[1-methyl-2-(4-methylphenylsulfinyl)ethyl] disulfide (S,Rs,S,Rs)-7b
Wax; [h]2D0=+152 (c=1.1, CHCl3); H NMR (CDCl3, 250 MHz): l 7.54 (d, J=8.1 Hz, 2H),
1
7.33 (d, J=8.1 Hz, 2H), 3.35–3.22 (m, 1H), 3.07 (dd, J=13.2 and 7.6 Hz, 1H), 2.94 (dd, J=13.2
and 6.7 Hz, 1H), 2.41 (s, 3H) and 1.43 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz)
(DEPT): l 141.8 (C), 140.6 (C), 130.1 (CH), 123.9 (CH), 64.1 (CH2), 40.8, 21.4 (CH3) and 21.0;
EIMS: m/z (rel int.%) 427 (MH+, 2), 287 (M−S(O)p-tol, 93), 245 (59), 215 (78), 149 (MH+−2×
S(O)p-tol, 54) and 124 (215-C7H7, 100); CIMS: m/z (rel. int.%) 213(1.5), 181 (4), 165 (213-SO,
35), 153 (19), 139 (69) and 125 (100).

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G. Asensio et al. / Tetrahedron: Asymmetry 11 (2000) 3481–3493
4.3.18. (S,S,Rs,Rs)-Di[1-(4-methylphenylsulfinylmethyl)propyl] disulfide (S,Rs,S,Rs)-7c
Colorless oil; isolated yield, ca. 23%; [h]2D0=+204 (c=1.9, CHCl3); H NMR (CDCl3, 250
1
MHz): l 7.54 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 3.19–3.05 (m, 1H), 3.04–2.98 (m, 2H),
2.40 (s, 3H), 1.90–1.65 (m, 2H) and 1.01 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz): l
141.7, 140.7, 130.1, 123.9, 62.7, 47.8, 27.4, 21.4 and 11.1; HRMS (FAB): m/z 455.1213; calcd for
C22H31O2S4: 455.1207.
4.3.19. (S,S,Rs,Rs)-Di[2-methyl-1-(4-methylphenylsulfinylmethyl)propyl] disulfide (S,Rs,S,Rs)-7d
Colorless oil; isolated yield ca. 15%; [h]2D0=+189 (c=1.0, CHCl3); H NMR (CDCl3, 250
1
MHz): l 7.56 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 3.22–3.14 (m, 1H), 3.06 (dd, J=13.3
and 4.6 Hz, 1H), 2.92 (dd, J=13.3 and 10.1 Hz, 1H), 2.40 (s, 3H), 2.27–2.14 (m, 1H), 1.01 (d,
J=6.6 Hz, 3H) and 1.00 (d, J=6.6 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz): l 141.6, 141.0,
130.0, 123.9, 61.0, 53.5, 31.6, 21.4, 19.2 and 19.1; HRMS (FAB): m/z 483.1526; calcd for
C24H35O2S4: 483.1520.
4.3.20. X-Ray structure analysis of (S,Rs)-1b
Colorless lath of 0.73×0.42×0.14 mm size, orthorhombic, space group P212121, a=9.2243(5),
3
b=9.7841(5), c=12.3344(6) A, V=1113.2(1) A , Z=4, zcalcd=1.279 g/cm3, 2qmax=61°, diffrac-
,
,
,
tometer Smart CCD, Mo Ka (u=0.71073 A), ꢀ-scan, T=173 K, 9284 reflections collected of
which 3390 (Rint=0.0351) were independent, absorption correction with SADABS, max. and min.
transmission 0.9412 and 0.7402, direct primary solution and refinement on F2 using the
SHELX-97 program,23 120 refined parameters, rigid methyl [C(3)] and thiol group hydrogen,
others riding, R1[I>2|(I)]=0.0329, wR2 (all data)=0.0750, residual electron density 0.218
−3
,
(−0.294) A , absolute structure parameter 0.04(7).
4.3.21. X-Ray structure analysis of (S,Rs)-1d
Colorless lath of 0.72×0.20×0.04 mm size, orthorhombic, space group P212121, a=5.6209(12),
3
b=10.4745(12), c=23.1229(19) A, V=1361.4(3) A , Z=4, zcalcd=1.183 g/cm3, 2qmax=50°,
,
,
,
diffractometer Nonius CAD4, Mo Ka (u=0.71073 A), ꢀ-scan, T=293 K, 4880 reflections
collected of which 2391 (Rint=0.0984) were independent, direct primary solution and refinement
on F2 using the SHELX-97 program, 142 refined parameters, rigid thiol group hydrogen, others
riding, a methyl group [C(5)] is disordered over two sites, R1[I>2|(I)]=0.0857, wR2 (all
−3
,
data)=0.1519, residual electron density 0.177 (−0.224) A , absolute structure parameter 0.0(3).
4.3.22. X-Ray structure analysis of (S,Rs)-6c
Colorless plate of 0.17×0.11×0.02 mm size, monoclinic, space group P21, a=5.5457(6),
3
b=7.5279(9), c=16.6643(19) A, i=94.400(2)°, V=693.6(1) A , Z=2, zcalcd=1.295 g/cm3,
,
,
,
2qmax=61°, diffractometer Smart CCD, Mo Ka (u=0.71073 A), ꢀ-scan, T=173 K, 5856
reflections collected of which 3145 (Rint=0.0243) were independent, absorption correction with
SADABS, max. and min. transmission 0.9926 and 0.9395, direct primary solution and refinement
on F2 using the SHELX-97 program, 157 refined parameters, rigid methyl and thiol group
hydrogens, others riding, R1[I>2|(I)]=0.0372, wR2 (all data)=0.0861, residual electron density
−3
,
0.489 (−0.229) A , absolute structure parameter 0.03(8).
Crystallographic data (excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre and can be obtained on request from CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK.

G. Asensio et al. / Tetrahedron: Asymmetry 11 (2000) 3481–3493
3493
Acknowledgements
We thank the Direccio´n General de Ensen˜anza Superior (PB96-0757) and the Generalitat
Valenciana (GVDOC99-22-2) for financial support. Additional thanks go to the Generalitat
Valenciana for a grant (A.C.).
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