Enzyme-promoted desymmetrization of bis(2-hydroxymethylphenyl) sulfoxide as a route to tridentate chiral catalysts

Article abstract of DOI:10.1016/j.tetasy.2008.08.017

The desymmetrization of prochiral bis(2-hydroxymethylphenyl) sulfoxide 3 was efficiently performed via acetylation promoted by commonly available lipases. Two lipases, namely, CAL-B and LPL proved particularly efficient to give 2-acetoxymethylphenyl 2-hydroxymethylphenyl sulfoxide 4 in up to 98% yield and with up to 98% ee. On the basis of an X-ray analysis, the absolute configuration of 4 was determined as (+)-(R). The enantiomerically pure product 4 was then transformed into a series of enantiomerically pure diastereomeric 2-aminomethylphenyl 2-hydroxymethylphenyl sulfoxides 8 in which the amino groups originated from enantiomerically pure amines having additional C-stereogenic centres. Compounds 8 were examined as possible tridentate chiral catalysts in a reference reaction of diethylzinc with benzaldehyde to give the expected product, 1-phenylpropan-1-ol, in moderate yields and with ee's of up to 50%.

Full text of DOI:10.1016/j.tetasy.2008.08.017

Tetrahedron: Asymmetry 19 (2008) 2096–2101
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enzyme-promoted desymmetrization of bis(2-hydroxymethylphenyl)
sulfoxide as a route to tridentate chiral catalysts
Michał Rachwalski a, Małgorzata Kwiatkowska a, Józef Drabowicz a, Marcin Kłos a, Wanda M. Wieczorek b,
c
b
a,
*
´
´
Małgorzata Szyrej , Lesław Sieron , Piotr Kiełbasinski
a
´
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Łódz, Poland
b
_
´
´
Institute of General and Ecological Chemistry, Technical University of Łódz, Zeromskiego 116, 90-924 Łódz, Poland
c Jan Długosz Academy, Institute of Chemistry and Environmental Protection, Armii, Krajowej 13/15, 42-201 Cze˛stochowa, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 August 2008
Accepted 19 August 2008
The desymmetrization of prochiral bis(2-hydroxymethylphenyl) sulfoxide 3 was efficiently performed
via acetylation promoted by commonly available lipases. Two lipases, namely, CAL-B and LPL proved par-
ticularly efficient to give 2-acetoxymethylphenyl 2-hydroxymethylphenyl sulfoxide 4 in up to 98% yield
and with up to 98% ee. On the basis of an X-ray analysis, the absolute configuration of 4 was determined
as (+)-(R). The enantiomerically pure product 4 was then transformed into a series of enantiomerically
pure diastereomeric 2-aminomethylphenyl 2-hydroxymethylphenyl sulfoxides 8 in which the amino
groups originated from enantiomerically pure amines having additional C-stereogenic centres. Com-
pounds 8 were examined as possible tridentate chiral catalysts in a reference reaction of diethylzinc with
benzaldehyde to give the expected product, 1-phenylpropan-1-ol, in moderate yields and with ee’s of up
to 50%.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
products which will have in the molecule those three functional
groups: sulfinyl, hydroxy and amino, accompanied by an additional
Enzyme-promoted desymmetrization of prochiral substrates is
commonly and widely used in the synthesis of chiral non-racemic
compounds.1 This methodology has also been successfully applied
in our Laboratory in the preparation of selected chiral heteroorgan-
ic compounds, taking advantage of the fact that a number of com-
mercially available hydrolytic enzymes proved capable of
recognizing and stereoselectively binding heteroatom stereogenic
centres.2 In this way, properly functionalized optically active sulf-
oxides,3,4 phosphine oxides5,6 and phosphine P-boranes7 have been
obtained in good yields and with good enantiomeric excess.
In the course of our studies we have become interested in
developing a new strategy for the synthesis of chiral polydentate
catalysts/ligands having a stereogenic sulfinyl group as one of the
possible coordinating nucleophilic centres capable of binding orga-
nometallic reagents. In this search, it should be mentioned that our
previous attempt, in which chiral hydroxy sulfoxides were investi-
gated as possible catalysts for the stereoselective addition of dieth-
ylzinc to benzaldehyde, was unsuccessful, most probably due to
the insufficient binding properties of the catalysts.8 Since it is
known that the best catalysts for the above reaction are chiral ami-
noalcohols9 and that chiral sulfinamides also show some interest-
ing properties,10 we have decided to develop a synthesis of the
stereogenic centre on a carbon atom. To this end, we have decided
to use an enzymatic approach and to perform desymmetrization of
the prochiral sulfoxide 3 and to use the product as the basic sub-
strate for further transformations.
2. Results and discussion
2.1. Synthesis of bis(2-hydroxymethylphenyl) sulfoxide 3
The synthesis of prochiral sulfoxide 1 comprises three steps.
Bis(2-carboxyphenyl) sulfide 1 was prepared in quantitative yield
using the methodology which was described by Martin et al.11 To
reduce the carboxylic moieties, compound 1 was boiled with an
excess of a complex of dimethyl sulfide and borane in THF for
2 h, and the corresponding diol 2 was obtained in 98% yield. The
crude diol 2 was oxidized without purification with sodium
metaperiodate in a 1:1 mixture of water and ethanol to form the
desired sulfoxide 3 in 85% yield after purification via column chro-
matography (Scheme 1).
2.2. Enzymatic desymmetrization of bis(2-hydroxy-
methylphenyl) sulfoxide 3
The prochiral sulfoxide 3 was subjected to acetylation with an
excess of vinyl acetate in chloroform at 30 °C using various lipases
* Corresponding author. Tel.: +48 42 680 32 34; fax: +48 42 6847126.
E-mail address: piokiel@bilbo.cbmm.lodz.pl (P. Kiełbasin´ ski).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.017

M. Rachwalski et al. / Tetrahedron: Asymmetry 19 (2008) 2096–2101
2097
COOH
SH
COOH
I
COOH
S
COOH
KOH, copper bronze
+
H2O, Δ
1
BH3 Me2S
THF, Δ
HO
OH
HO
OH
O
S
S
NaIO4
EtOH/H2O 1:1, rt
2
3
Scheme 1. Synthesis of prochiral sulfoxide 3.
AcO
OAc
HO
OH
HO
OAc
O
S
O
S
O
S
, lipase
CHCl3
AcO
+
5
3
4
Scheme 2. Enzymatic desymmetrization of prochiral sulfoxide 3.
(Scheme 2). The reactions were monitored by TLC and after
completion, the enzymes were filtered off, the solvent and excess
of vinyl acetate were evaporated and the residue was separated
via column chromatography. The results are collected in Table 1.
The best results were obtained using two lipases: lipase from
Candida antarctica (CAL-B) and Lipoprotein lipase (LPL). In the first
case monoacetate 4 was formed in up to 98% chemical yield and
with an enantiomeric excess of up to 98%. In the second case—
98% yield and 92% ee, respectively. However, it should be stressed
that the reaction had to be carefully controlled, since too long a
reaction time led to the formation of diacetate 5 with a concomi-
tant decrease of the enantiomeric purity of the monoacetate 4
(vide infra). The monoacetate 4 of the highest ee value was crystal-
lized from benzene, and an enantiomerically pure crystalline sam-
ple thus obtained ([a]D = +60) was subjected to X-ray analysis. On
the basis of the molecular structure (Fig. 1) the absolute configura-
tion of the monoacetate 4 was determined as (+)-(R).
Reactions catalyzed by lipases AMANO AH, AK and PS gave
worse results. In the case of lipase AMANO AH almost 80% of the
unreacted substrate was recovered. Interestingly, in the cases of li-
Figure 1. Molecular structure of monoacetate (+)-(R)-4.
Table 1
pases AK and PS relatively large quantities of the prochiral diace-
tate 5 were formed. Since it was obvious that the diacetate must
have arisen from the monoacetate 4 as a result of its subsequent
acetylation, it was quite reasonable to assume that this reaction
proceeded under kinetic resolution conditions and, in this way,
could influence the final enantiomeric excess. To check this
assumption, an independent experiment was carried out. The opti-
cally active monoacetate 4 was further acetylated under the same
reaction conditions in the presence of CAL-B to form diacetate 5
(Scheme 3).
Enzymatic desymmetrization of prochiral sulfoxide 3
Entry Reaction Lipase
time (h)
Monoacetate 4
Diacetate 5
a
Yield (%)
20
[
a
]
D
ee (%) Absolute
Yield (%)
configuration
1
2
3
4
5
144
72
72
144
144
AK
À2
4
98b
92b
9
S
Rc
R
S
R
60
—
—
35
—
CAL-B 98
+53
+50
À5
LPL
PS
AH
98
44
22d
+10
19
a
b
c
In chloroform (c 1).
Determined by chiral HPLC.
Determined by X-ray analysis.
After separation from the reaction mixture, the isolated mono-
acetate 4 exhibited substantially lower enantiomeric excess than
the starting monoacetate. Hence, a conclusion can be drawn that
d
Unreacted substrate was recovered.

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M. Rachwalski et al. / Tetrahedron: Asymmetry 19 (2008) 2096–2101
AcO
OAc
HO
OAc
HO
OAc
O
O
O
S
S
S
CAL-B
CHCl3
AcO
+
(+)-(R)-4 ee = 70%
(+)-(R)-4 ee = 30%
5
cy = 53%
Scheme 3. Further acetylation of optically active monoacetate 4.
AcO
OAc
HO
OAc
O
S
O
S
lipase
buffer/solvent
4
5
Scheme 4. Enzymatic hydrolysis of diacetate 5.
indeed a kinetic resolution process took place, but, unexpectedly,
the prevailing enantiomer was preferentially consumed. This may
explain both the low enantiomeric excess of the monoacetate
shown in entries 1 and 4 (Table 1) and the observed decrease of
the enantiomeric excess of 4 after a prolonged reaction time using
lipases CAL-B and LPL.
In an attempt to take advantage of a general feature of enzymes,
which exhibit the same sense of stereoselectivity irrespective of
the direction of the reversible reaction they catalyze (e.g., ester for-
mation vs hydrolysis), enzymatic hydrolysis of diacetate 5 was
investigated in the hope of obtaining the opposite enantiomer of
the monoacetate 4 (Scheme 4). Such an approach was successfully
applied by us in the desymmetrization of prochiral bis-(hydroxy-
methyl)phenylphosphine oxide.5 The reactions, catalyzed by
lipases CAL-B and LPL, were carried out in a mixture of potassium
phosphate buffer (pH 7.2) and an organic solvent at 30 °C within
144 h. The results are collected in Table 2.
The experiment, in which acetone was used as solvent in the acet-
ylation of 3 showed that indeed the yield and enantiomeric excess
of the resulting 4 were lower than those obtained in chloroform
(75% and 30% vs 98% and 98%, respectively; cf. Table 1 entry 2),
although its absolute configuration remained the same, (+)-(R).
This must lead to the conclusion that acetone decreased the
enantioselectivity of the lipases in this process, but in fact does
not allow us to ultimately explain the unusual stereochemistry
observed.
2.3. Synthesis of tridentate catalysts from monoacetate 4
The synthesis of tridentate catalysts 8a–f comprises three steps
(Scheme 5). First, enantiomerically pure monoacetate 4 was mesy-
lated with methanesulfonic anhydride in dichloromethane in the
presence of triethylamine to form the mesyl derivative 6 in quan-
titative yield. Mesylate 6 was then reacted with a series of enantio-
merically pure amines in chloroform in the presence of
triethylamine leading to the products 7a–f in chemical yields
87–99%. Finally, compounds 7a–f were subjected to deacetylation
with sodium methoxide in methanol to give products 8a–f in
yields 77–99%. The results are collected in Table 3.
Table 2
Enzymatic hydrolysis of 5
Entry
Lipase
Solvents
Monoacetate 4
Yielda (%)
[
a
]
D
eec (%)
b
1
2
3
4
CAL-B
LPL
CAL-B
LPL
Acetone + buffer
Acetone + buffer
Diisopropyl ether + buffer
Diisopropyl ether + buffer
12
5.5
4
+31
À19
+41
+39
57
35
76
72
2.4. The use of catalysts 8 in the asymmetric addition
of diethylzinc to benzaldehyde
5
Optically active compounds 8a–f constitute enantiomerically
pure diastereomeric tridentate ligands/catalysts, as their three
coordinating nucleophilic centres can bind various organometallic
reagents. Moreover, compound 8c has an additional coordinating
centre on the pyridine nitrogen atom. Therefore, we decided to test
their catalytic activity using the asymmetric addition of diethylzinc
to benzaldehyde as a reference reaction (Scheme 6). The results are
collected in Table 4.
Inspection of Table 4 shows that the yields of the product 9
were moderate and so were the enantiomeric excess values. The
relatively low yields of 9 were the result of the formation of benzyl
alcohol produced in a side reaction—reduction of benzaldehyde by
diethylzinc. The fact that the resulting alcohol 9 had the same
absolute configuration in each case may be taken as proof for the
strong impact of the absolute configuration at the sulfinyl sulfur
atom [which was always (R)] on the stereoselectivity. The
influence of the additional stereogenic centres, present in the
amine part of the molecule, could be considered as a ‘match’ or a
a
Unreacted diacetate 5 was recovered.
In chloroform (c 1).
Determined by comparison of [a] values.
D
b
c
Much to our surprise, in all cases the chemical yields of mono-
acetate 4 were very low (4–12%), the rest being the unreacted sub-
strate. Moreover, only in the case shown in entry 2 did the
experiment meet our expectations to produce the opposite enan-
tiomer (À)-(S)-4. In all other cases the same (+)-(R)-4 enantiomer
was obtained as from the enzymatic acetylation of 3 (cf. Table 1).
Thus, the latter outcome was incompatible with the rule men-
tioned above. However, similar precedents could also be found in
the chemical literature.12 Although there is no clear explanation
for such a result, it seems reasonable to assume that this is the
effect of an influence of solvent on the enantioselectivity of the
enzyme.13 The presence of a buffer, either in a homogeneous solu-
tion with acetone or in a two-phase system with diisopropyl ether
could substantially change the catalytic properties of the lipases.

M. Rachwalski et al. / Tetrahedron: Asymmetry 19 (2008) 2096–2101
2099
AcO
OH
AcO
OSO2Me
O
S
O
S
(MeSO2)2O
Et3N, CH2Cl2, rt
(
-4
6
(+)-(S)-
+)-(R)
Et3N, CHCl3, rt
R NH2
H
N
H
N
HO
AcO
R
R
O
O
S
S
MeONa/MeOH
rt
8a-f
7a-f
Amines, RNH2
H
C
NH2
H3C
CH3
H
H
H3C
N
Ph CH NH2
NH2
CH3
CH3
NH2
c
d
e,f
a,b
a) (-)-(S)-1-phenylethylamine
b) (+)-(R)-1-phenylethylamine
c) (-)-(S)-1-(2'-pyridyl)ethylamine
d) (-)-cis-myrtanylamine
e) (-)-(S)-1-(1'-naphthyl)ethylamine
f) (+)-(R)-1-(1'-naphthyl)ethylamine
Scheme 5. Synthesis of tridentate ligands/catalysts 8a–f.
Table 3
Table 4
Tridentate ligands/catalysts 8a–f
Asymmetric addition of diethylzinc to benzaldehyde in the presence of 8
Entry
Amine
Products 7a–f
Products 8a–f
Entry
Catalyst
Alcohol 9
a
a,b
a
Yield (%)
[a
]
D
Yield (%)
[
a
]
D
Abs. conf.
Yield (%)
[
a]
D
Enantiomeric
excessb (%)
Absolute
configuration
1
2
3
4
5
6
a
b
c
d
e
f
99
99
87
96
99
92
À36.2
+17.3
À38.1
À19.0
À12.0
À4.1
86
99
77
79
97
94
À15.9
À15.6
À17.4
À8.8
RSSC
RSRC
RSSC
RSSC1SC2SC5
RSSC
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
52
50
51
55
50
50
+14.3
+7.3
+8.6
+22.2
+8.6
+0.5
32
16
20
50
20
1.2
(R)
(R)
(R)
(R)
(R)
(R)
+13.2
À30.7
RSRC
a
In chloroform (c 1).
ee = 100% as determined by chiral HPLC.
b
a
In chloroform (c 1).
Determined by chiral HPLC.
b
H
it was the ‘match’ or ‘mismatch’ effect, since the opposite enantio-
mer of cis-myrtanylamine is not available. The works on other
transformations of 6, using bulkier enantiomerically pure amines,
are in progress.
O
OH
Et
catalyst
benzene
Ph
C
Ph
+
Et2Zn
H
9
3. Conclusions
Scheme 6. Asymmetric addition of diethylzinc to benzaldehyde.
Enzymatic desymmetrization of prochiral bis(2-hydroxymeth-
ylphenyl) sulfoxide was performed. The corresponding mono-
acetate 4 was obtained in excellent chemical yield (98%) and
with very good enantiomeric excess (98%). On the basis of X-ray
analysis its absolute configuration was determined as (+)-(R).
‘mismatch’ (entry 1 vs entry 2 and entry 5 vs entry 6). The best re-
sult was achieved for the catalyst 8d, containing the myrtanyl moi-
ety, which means that ligands possessing a higher number of
stereogenic centres exert a stronger influence on the stereoselec-
tivity. However, in this case it was not possible to decide whether
Enantiomerically pure monoacetate
4 was converted into

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M. Rachwalski et al. / Tetrahedron: Asymmetry 19 (2008) 2096–2101
enantiomerically pure diastereomeric tridentate ligands/
catalysts 8 containing chiral amine moieties. Their activity was
tested in a reference reaction, that is, the asymmetric addition of
diethylzinc to benzaldehyde. The resulting chiral alcohol was
obtained in moderate yields and exhibited enantiomeric excesses
of up to 50%.
Diacetate 5—colourless oil. 1H NMR (CDCl3): d 1.93 (s, 6H), 5.22
(s, 4H), 7.48–7.74 (m, 8H). MS (CI): m/z 347 (M+H). HRMS (CI) calcd
for C18H19O5S: 347.3975. Found 347.3972.
4.4. Synthesis of tridentate ligands 8a–f—general procedure
Monoacetate 4 ([a]D = +60, ee >99%, 1 g, 3.29 mmol) was dis-
solved in dichloromethane (20 mL) and triethylamine (0.4 g,
3.95 mmol) and mesyl anhydride (0.69 g, 3.95 mol) were added.
The mixture was stirred at room temperature for 2 h. After this
time water was added and the layers were separated. The aqueous
layer was extracted with dichloromethane (3Â). The combined
organic layers were dried over anhydrous MgSO4, the solvent
was evaporated to give the mesyl derivative 6 (1.257 g, 100%,
4. Experimental
4.1. General
The enzymes were purchased from AMANO or FLUKA. NMR
spectra were recorded on a Bruker instrument at 200 MHz with
CDCl3 and CD3OD as solvents. Optical rotations were measured
on a Perkin–Elmer 241 MC polarimeter (c 1). Column chromatogra-
phy was carried out using Merck 60 silica gel. TLC was performed
on Merck 60 F254 silica gel plates. The enantiomeric excess (ee)
values were determined by chiral HPLC (Varian Pro Star 210,
Chiralpak AS).
[a]
D = +12.4). 1H NMR (CDCl3): d 1.93 (s, 3H), 2.92 (s, 3H), 5.33
(AB, 2H), 5.47 (s, 2H), 7.59–7.86 (m, 8H). MS (CI): m/z 383
(M+H). HRMS (CI) calcd for C17H19O6S2: 383.4512. Found 383.4587.
Mesylate 6 (0.5 mmol) was dissolved in chloroform (10 mL) and
triethylamine (0.5 mmol) and corresponding enantiomerically
pure amine (0.5 mmol) were added. The mixture was stirred at
room temperature for 72 h. After this time chloroform was evapo-
rated and the residue was purified via preparative TLC (chloro-
form/methanol 20:1) to give derivatives 7a–f.
4.2. Synthesis of prochiral sulfoxide 3
Bis(2-carboxyphenyl) sulfide 1 was prepared in quantitative
yield using a methodology described by Martin et al.11 Sulfide 1
(5 g, 0.018 mol) was dissolved in THF (40 mL) and a complex of
BH3ÁMe2S (2.0 M solution in THF, 36 mL, 0.072 mol) was added.
The mixture was stirred and refluxed for 2 h. After this time THF
was evaporated, 5% aqueous solution of NaHCO3 was added and
the mixture was extracted with dichloromethane (3Â). After dry-
ing over anhydrous MgSO4 and evaporation of the solvent, diol 2
was obtained (4.40 g, 98%) and used in the ensuing reaction with-
out purification.
4.4.1. Compound 7a
1H NMR (CDCl3): d 1.32 (d, J = 6.6 Hz, 3H), 1.93 (s, 3H), 3.58–
3.76 (m, 3H), 5.21 (s, 2H), 7.20–7.73 (m, 13H). MS (CI): m/z 408
(M+H). HRMS (CI) calcd for
408.1662.
C24H26NO3S: 408.1638. Found
4.4.2. Compound 7b
1H NMR (CDCl3): d 1.25 (d, J = 6.6 Hz, 3H), 1.91 (s, 3H), 3.63–
3.84 (m, 3H), 5.14 (AB,2H), 7.23–7.87 (m, 13H).
1H NMR (CDCl3): d 2.10 (br s, 2H), 4.76 (s, 4H), 7.23–7.48 (m,
8H).
4.4.3. Compound 7c
1H NMR (CDCl3): d 1.34 (d, J = 6.7 Hz, 3H), 1.96 (s, 3H), 3.68 (m,
2H), 3.77 (q, J = 6.7 Hz, 1H), 5.24 (AB, 2H), 7.12–8.62 (m, 12H). MS
(CI): m/z 409 (M+H). HRMS (CI) calcd for C23H25N2O3S: 409.1583.
Found 409.1590.
Diol 2 (3.8 g, 0.015 mol) was dissolved in ethanol (50 mL) and
the solution of sodium metaperiodate (6.42 g, 0.03 mol) in water
(50 mL) was added. The mixture was stirred at room temperature
for 4 h. After this time the resulting inorganic salt was filtered off,
solvents were evaporated and column chromatography (chloro-
form/methanol in gradient from 100:1 to 1:1) was performed to
yield the desired prochiral sulfoxide 3 (3.44 g, 85%).
4.4.4. Compound 7d
1H NMR (CDCl3): d 0.90 (s, 3H), 1.14 (s, 3H), 1.30–2.40 (m, 9H),
1.97 (s, 3H), 2.49 (d, J = 8.0 Hz, 2H), 3.84 (AB, 2H), 4.78 (br s, 1H),
5.29 (AB, 2H), 7.37–7.96 (m, 8H). MS (CI): m/z 440 (M+H). HRMS
(CI) calcd for C26H34NO3S: 440.2247. Found 440.2201.
White powder, mp 125–127 °C; 1H NMR (CD3OD): d 4.71 (s, 4H),
4.86 (s, 2H), 7.49–7.69 (m, 8H). 13C NMR (CD3OD): d 62.02, 127.14,
129.62, 129.74, 132.92, 141.80, 141.89.
MS (CI): m/z 263 (M+H). Anal. Calcd for C14H14O3S: C, 64.12; H,
5.34; S, 12.21. Found: C, 63.99; H, 5.28; S, 12.19.
4.4.5. Compound 7e
1H NMR (CDCl3): d 1.44 (d, J = 6.6 Hz, 3H), 1.88 (s, 3H), 3.81 (AB,
2H), 4.57 (q, J = 6.6 Hz, 1H), 5.17 (s, 2H), 7.33–8.08 (m, 15H). MS
(CI): m/z 458 (M+H). HRMS (CI) calcd for C28H28NO3S: 458.1768.
Found 458.1733.
4.3. Enzymatic desymmetrization of prochiral sulfoxide
3—general procedure
Prochiral sulfoxide 3 (0.2 g, 0.76 mmol) was dissolved in chloro-
form (10 mL) and then enzyme (80 mg) and vinyl acetate (4 mL)
were added. The mixture was stirred at 30 °C and the reaction
was monitored by TLC (chloroform/methanol 10:1). After comple-
tion the enzyme was filtered off, chloroform and an excess of vinyl
acetate were evaporated. The residue was separated by column
chromatography using chloroform/methanol in gradient as elu-
ents, or by preparative TLC (chloroform/methanol 10:1).
Monoacetate 4—colourless crystals, mp. 117 °C; 1H NMR
(CDCl3): d 1.89 (s, 3H), 3.61 (br s, 1H), 4.74 (s, 2H), 5.17 (s, 2H),
7.42–7.88 (m, 8H). 13C NMR (CDCl3): d 20.55, 62.06, 62.52,
126.55, 127.08, 128.59, 129.68, 129.88, 131.61, 131.89, 134.32,
140.84, 141.48, 141.61, 170.2; MS (CI): m/z 305 (M+H). Anal. Calcd
for C16H16O4S: C, 63.16, H, 5.26; S, 10.53. Found: C, 63.07; H, 5.31;
S, 10.47.
4.4.6. Compound 7f
1H NMR (CDCl3): d 1.41 (d, J = 6.6 Hz, 3H), 1.85 (s, 3H), 3.85 (AB,
2H), 4.63 (q, J = 6.6 Hz, 1H), 5.10 (AB, 2H), 7.31–8.16 (m, 15H).
Compound 7 (0.15 mmol) was dissolved in methanol (2 mL) and
sodium (0.15 mmol) was slowly added. The mixture was stirred at
room temperature for 0.5 h. After this time methanol was evapo-
rated and the residue was separated by preparative TLC (chloro-
form/methanol 10:1) to obtain chiral tridentate catalyst 8.
4.4.7. Compound 8a
1H NMR (CDCl3): d 1.44 (d, J = 6.6 Hz, 3H), 3.89 (q, J = 6.6 Hz,
1H), 4.07 (AB, 2H), 4.22 (AB, 2H), 7.17–8.14 (m, 13H). MS (CI):
m/z 366 (M+H). HRMS (CI) calcd for C22H24NO2S: 366.1529. Found
366.1534.

M. Rachwalski et al. / Tetrahedron: Asymmetry 19 (2008) 2096–2101
2101
4.4.8. Compound 8b
were washed with brine (10 mL) and dried over MgSO4. The sol-
vents were evaporated to give the crude alcohol 9, which was puri-
fied by preparative TLC (ethyl acetate/hexane 1:7).
1H NMR (CDCl3): d 1.35 (d, J = 6.6 Hz, 3H), 3.85 (AB, 2H), 3.86 (q,
J = 6.6 Hz, 1H), 4.42 (AB, 2H), 7.28–8.06 (m, 13H).
1H NMR (CDCl3): d 0.94 (t, J = 7.4 Hz, 3H), 1.69–2.06 (m, 2H), 2.0
(br s, 1H), 4.59 (t, J = 6.59 Hz, 1H), 7.25–7.45 (m, 5H).
Crystallographic data for (+)-(R)-4 have been deposited with the
Cambridge Crystallographic Data Center, as Supplementary Publi-
cation No. CCDC 696032 and can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: (internat.) +44–1223/336-033; e-mail: deposit@ccdc.cam.
ac.uk].
4.4.9. Compound 8c
1H NMR (CDCl3): d 1.43 (d, J = 6.7 Hz, 3H), 3.90 (AB, 2H), 3.98 (q,
J = 6.7 Hz, 1H), 4.31 (AB, 2H), 7.20–8.64 (m, 12H). MS (CI): m/z 367
(M+H). HRMS (CI) calcd for
367.1464.
C21H23N2O2S: 367.1476. Found
4.4.10. Compound 8d
1H NMR (CDCl3): d 0.96 (s, 3H), 1.17 (s, 3H), 1.47–2.40 (m, 9H),
2.80 (d, J = 8.0 Hz, 2H), 4.08 (AB, 2H), 4.31 (AB, 2H), 7.28–8.14 (m,
8H). MS (CI): m/z 398 (M+H). HRMS (CI) calcd for C24H32NO2S:
398.2149. Found 398.2170.
Acknowledgement
Financial support by the Polish Ministry of Science and Higher
Education, Grant No. PBZ 126 T09 03, is gratefully acknowledged.
4.4.11. Compound 8e
1H NMR (CDCl3): d 1.58 (d, J = 6.6 Hz, 3H), 4.05 (AB, 2H), 4.39
(AB, 2H), 4.78 (q, J = 6.6 Hz, 1H)), 7.22–8.13 (m, 15H). MS (CI):
m/z 416 (M+H). HRMS (CI) calcd for C26H26NO2S: 416.1677. Found
416.1693.
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_
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