Highly efficient chiral polydentate sulfinyl ligands/catalysts containing prolinol moiety

Article abstract of DOI:10.1016/j.tet.2015.05.103

New polydentate chiral ligands, containing the hydroxyl group, stereogenic sulfinyl group and enantiomeric prolinol moieties were synthesized and proved very efficient catalysts in the asymmetric diethylzinc addition to benzaldehyde, the asymmetric aldol

Full text of DOI:10.1016/j.tet.2015.05.103

Tetrahedron xxx (2015) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly efficient chiral polydentate sulfinyl ligands/catalysts
containing prolinol moiety
a
b
b
b
ꢀ
Jacek Chrzanowski , Micha1 Rachwalski , Adam M. Pieczonka , Stanis1aw Lesniak ,
a
a,
*
ꢀ
ꢀ
Jozef Drabowicz , Piotr Kie1basinski
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112 90-363 Łodz,
a
ꢀ ꢀ
Poland
b
ꢀ ꢀ
ꢀ ꢀ
Department of Organic and Applied Chemistry, University of Łodz, Tamka 12 91-403 Łodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New polydentate chiral ligands, containing the hydroxyl group, stereogenic sulfinyl group and enan-
tiomeric prolinol moieties were synthesized and proved very efficient catalysts in the asymmetric di-
ethylzinc addition to benzaldehyde, the asymmetric aldol condensation and the asymmetric Mannich
reaction. Replacement of the central hydroxyl group with the second prolinol moiety of the same ab-
solute configuration gave new ligands in which the sulfinyl group was not a stereogenic centre anymore,
but which proved almost equally efficient as catalysts for the reactions investigated. The absolute con-
figuration of the proline moiety exerted a decisive impact on the stereochemical outcome of these re-
actions, deciding about the absolute configuration of the products formed.
Received 25 March 2015
Received in revised form 21 May 2015
Accepted 27 May 2015
Available online xxx
Keywords:
Chiral sulfinyl ligands
Asymmetric synthesis
Prolinol
Ó 2015 Elsevier Ltd. All rights reserved.
Diethylzinc addition to aldehydes
Asymmetric aldol condensation
Asymmetric Mannich reaction
1. Introduction
Thus, the ligands bearing enantiomeric primary amine moieties
(4aef) proved particularly efficient catalysts in aldol,2 nitroaldol
A search for new organocatalysts for the stereoselective for-
mation of optically active compounds is one of the most important
and challenging tasks of contemporary asymmetric synthesis. The
main advantage of using organocatalysts in asymmetric synthesis is
the ability to avoid toxic and expensive metals complexes.
(Henry),3,4 aza-Henry5 and Mannich6 reactions, while those bear-
ing enantiomeric aziridine moieties (4hej)din the reactions in-
volving organozinc reagents, i.e., in the asymmetric organozinc
additions to aldehydes,7,8 the Michael diethylzinc additions to
enones9 and the Simmons e Smith cyclopropanation of allyl alco-
hols.10 In all cases the products were obtained in the yields up to
98% and with ee’s up to 98%. It was found by us that the absolute
configuration of the amine substituent exerted a decisive impact on
the stereochemical outcome of the reactions and, hence, on the
Our recent works have been focused on the preparation of
enantiopure heteroatom-containing compounds that could be used
as chiral ligands or catalysts in the asymmetric CeC bond forma-
tion. We have succeeded in the chemoenzymatic synthesis of
a variety of ligands 4, containing a stereogenic sulfinyl moiety, an
enantiomeric amine fragment and the hydroxyl group (Scheme 1).1
The crucial step was the Candida antarctica lipase (CAL-B)-pro-
moted desymmetrization of prochiral bis(2-hydroxymethylphenyl)
sulfoxide 1, which allowed us to obtain the desired pre-
cursordmonoacetate 2 in one step in a high yield (98%) and in an
almost enantiomerically pure form. Simple ensuing chemical
transformations, consisting of mesylation of the hydroxyl group to
give 3, followed by the reaction with a relevant amine and removal
of the acetyl group, led to ligands 4, which proved to be excellent
catalysts in various reactions of asymmetric synthesis.
absolute configuration of the products, with only
a small
‘matchemismatch’ effect caused by the chirality of the sulfinyl
group. Nevertheless, the presence of all the coordinating centers,
i.e., the hydroxyl, sulfinyl groups and the amine nitrogen atom, was
proven to be essential for the efficiency of the catalysts and allowed
us to conclude that the ligands 4 demonstrated a tridentate char-
acter.4,6 Particularly, the presence of the stereogenic sulfinyl group
proved crucial for the outcome of all the reactions since its re-
placement with the corresponding sulfide or sulfone moiety
resulted in a substantial decrease of both the yield and enantio-
meric excess of the products. Interestingly, the hydroxyl group in 4
could be replaced by the identical enantiomeric amine moiety, but
in order to achieve high catalytic activity of the newly formed
ꢀ
* Corresponding author. E-mail address: piokiel@cbmm.lodz.pl (P. Kie1basinski).
http://dx.doi.org/10.1016/j.tet.2015.05.103
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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J. Chrzanowski et al. / Tetrahedron xxx (2015) 1e7
HO
OH
AcO
OH
O
S
O
AcO
CAL-B
S
(MeSO2)2O
Et3N, CH2Cl2, rt
CHCl3
(+)-(R)-2
ee = 98%
1
R1
N
AcO
OSO2Me
HO
R
O
O
S
1. RR1NH, Et3N,
CHCl3, rt
S
2. MeONa/MeOH
(+)-(S)-3
4
Primary amines:
Me
NH2
Me
NH2
H
H
NH2
Me
N
Me
NH2
Me
f
a, b each enantiomer
e
c, d each enantiomer
Aziridines:
i-Pr
Me
Me
H
i-Pr
Me
H
H
N
H
g
N
H
h
N
H
i
N
H
j
Scheme 1. Synthesis of sulfinyl ligands 4.
ligand 5 (Fig. 1) and stereoselectivity of the reactions in which it
was used as catalyst, it was necessary to retain in its molecule the
sulfinyl moiety, even if the latter lost in this case its stereogenic
character.4,6
having four or five potential coordination centers, respectively
(Scheme 3).
2. Results and discussion
2.1. Synthesis of ligands
We attempted to synthesize the basic substrate, namely bis(2-
hydroxymethylphenyl) sulfoxide 1, in a different way than that
originally described.1 We started from o-bromobenzyl alcohol 6, in
which the hydroxyl group was protected with dihydropyran (DHP),
according to the literature procedure,16 to give 7 in 98% yield. In the
next step the protected alcohol was transformed into a Grignard
reagent and treated with dimethyl sulfite to yield 8 (83.7%), fol-
lowed by the removal of the tetrahydropyranyl group (THP) with
pyridinium p-toluenesulfonate (PPTS) to give the desired com-
pound 1 (86.5%) (Scheme 2). The overall yield of 1 achieved using
the present method was higher than using the one previously
described.1
Synthesis of ligands/catalysts 9a and 9b, with a stereogenic
sulfur atom, was carried out according to the procedure previously
described (Scheme 1),1 by enzymatic desymmetrization of the
sulfoxide 1, mesylation of the hydroxyl group, reaction with (S)-
prolinol or (R)-prolinol, respectively, and removal of the acetyl
group with sodium methoxide. In turn, the ligands/catalysts 10a
Fig. 1. The diamino analog of ligand 4d.
Looking for other chiral amine-type substituents that could be
useful in the designing of new ligands we focused our attention on
prolinol, which seemed particularly interesting due to the presence
of the hydroxyl group, capable of acting as an additional co-
ordinating centre. In this context it should be mentioned that
proline and its analogs are widely used as chiral organocatalysts.11
Particularly, prolinol and its various derivatives are commonly ap-
plied in asymmetric synthesis.12 They proved to be valuable
auxiliaries13 and catalysts in the asymmetric formation of carbon-
ecarbon14 and carbon-heteroatom bonds.15 Therefore, we decided
to replace the amino groups in our original sulfinyl ligands 4 and 5
with one or two prolinol moieties, to obtain new ligands 9 and 10,
Scheme 2. Synthesis of prochiral bis(2-hydroxymethylphenyl) sulfoxide 1.
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J. Chrzanowski et al. / Tetrahedron xxx (2015) 1e7
3
Scheme 3. Synthesis of chiral polydentate ligands 9 and 10.
and 10b were prepared by mesylation of both hydroxyl groups in
sulfoxide 1 followed by the reaction with each enantiomer of
prolinol (Scheme 3).
may be explained in terms of evident ‘matched’ and ‘mismatched’
interactions with the sulfinyl stereogenic center. Following our
previous results on the effect of replacement of the hydroxy group
with the next identical amino moiety,4,6 we decided to check the
influence of a similar change in our new ligand and used the analog
10a, in which the sulfinyl group is not a stereogenic centre anymore
(due to the presence of two identical substituents at the sulfur
atom). Table 1, entry 3 clearly indicates that the enantiomeric ex-
cess of the product was in this case only slightly lower than that
obtained with ligand 9a, which can be considered to result from the
lack of the stereogenic centre at sulfur.
2.2. Screening of ligands 9 and 10
The ligands were tested as catalysts in several asymmetric re-
actions: diethylzinc addition to benzaldehyde (Table 1), aldol con-
densation (Table 2) and Mannich reaction (Table 3).
Table 1
Addition of diethylzinc to benzaldehyde in the presence of ligands 9a, 9b, 10a
The same stereochemical outcome was observed for the aldol
reaction (Table 2). Again the absolute configuration of the product
depended on the absolute configuration of the prolinol moiety,
with only a small match/mismatch effect (entries 1 and 2). Such an
effect was the same as in the case of the aldol condensation per-
formed in the presence of the catalysts 4aed, previously reported
by us,2 in spite of the fact that in the present experiments the re-
action conditions were entirely different. Obviously, the catalysts
10a and 10b which, due to the lack of stereogenicity of the sulfinyl
group, may be considered as enantiomers, led to the opposite en-
antiomers of the product (entries 3 and 4).
The identical relationship was noted while investigating the
asymmetric Mannich reaction. Also in this case the absolute con-
figuration of the major diastereomeric product depended on the
enantiomer of prolinol used (Table 3) and the efficiency of the
catalysts was very high, resembling the results obtained by us
earlier.6 Moreover, the product was obtained with very high dia-
stereoselectivity and each enantiomer of the product was available
using easily accessible enantiopure catalysts.
Since the catalysts 10 exhibited the highest efficiency in terms of
chemical yield and enantiomeric excess of the chiral Mannich
product, we decided to determine the scope of the activity of cat-
alyst 10a. It was therefore applied in the asymmetric three-
component Mannich reactions involving acetone (R]H) or
hydroxyacetone (R]OH) as a ketone, p-anisidine and a number of
various aldehydes as starting materials under identical reaction
conditions as in the experiments shown above. The results of these
Mannich transformations are shown in Table 4.
Entry
Catalyst
Product
ee [%]b
Abs. Conf.c
a
Yield [%]
[a]
D
1
2
3
9a
9b
10a
88
83
74
ꢀ38.6
þ33.7
ꢀ35.9
86
75
80
(S)
(R)
(S)
a
In chloroform (c¼1).
b
c
Determined by chiral HPLC.
Based on literature data.7
Interestingly, in case of diethylzinc addition to benzaldehyde
(Table 1), the ligands containing prolinol moieties exerted a similar
asymmetric induction as those containing the aziridine moieties7
and much higher than those bearing open-chain amines.1 Thus,
the prolinol moiety must coordinate diethylzinc as efficiently as
aziridines. The use of both diastereomeric ligands 9a and 9b, con-
taining opposite enantiomers of prolinol, led to the formation of
chiral products with opposite absolute configurations. Thus, the
stereogenic centers located in the prolinol moieties exerted a de-
cisive effect on the absolute configuration of the products. The
observed differences in their ee values (Table 1, entries 1 and 2)
Inspection of Table 4 makes it clear that catalyst 10a efficiently
catalyzes the title reaction leading to the appropriate Mannich
adducts. Only in the case of entry 4, where an aliphatic aldehyde
was applied, the corresponding optically active product was
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4
J. Chrzanowski et al. / Tetrahedron xxx (2015) 1e7
Table 2
Aldol condensation in the presence of ligands 9a, 9b, 10a, 10b
Entry
Catalyst
Product
ee [%]b
Abs. conf.c
a
Yield [%]
[a
]
D
1
2
3
4
9a
9b
10a
10b
43
41
40
44
þ57.6
ꢀ53.6
þ55.6
ꢀ53.5
87
81
84
80
(R)
(S)
(R)
(S)
a
In chloroform (c¼1).
b
c
Determined by chiral HPLC.
Based on literature data.2
obtained in lower chemical yield and with lower enantioselectivity
(62 and 73%, respectively). In the reaction of hydroxyacetone and p-
methoxybenzaldehyde (entry 9), the product was formed in good
chemical yield, but unexpectedly with a lower ee value. In the other
entries, the enantiopure Mannich adducts were formed in high
chemical yields (80e94%), excellent enantioselectivities (87e96%
ee) and in some cases high diastereoselectivities.
anisidinedtakes place. The chiral catalyst, whose tertiary amine
moiety acts as a Brønsted base and hydroxy groups as hydrogen
bond donors,17 induce a stereoselective attack of the ketone enolate
on the imine formed.
3. Conclusions
Although the detailed mechanism of the above reaction cannot
be presented at this stage, it seems reasonable to assume, that
initial formation of an imine from the substratesdaldehydes and p-
The newly synthesized polydentate ligands, containing the hy-
droxyl group, stereogenic sulfinyl group and enantiomerically pure
prolinol moieties with a free hydroxyl group proved very efficient
Table 3
Mannich reaction in the presence of catalysts 9a, 9b, 10a, 10b
Entry
Catalyst
Product
ee [%]b
drc
a
Yield [%]
[a
]
D
1
2
3
4
9a
9b
10a
10b
91
90
94
95
þ3.3
ꢀ3.2
þ3.4
ꢀ3.5
90
89
94
96
18:1
18:1
20:1
20:1
a
In chloroform (c¼1).
b
c
Determined by chiral HPLC for the major diastereoisomer.
Based on 1H NMR data of the crude product.
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J. Chrzanowski et al. / Tetrahedron xxx (2015) 1e7
5
Table 4
Screening of aldehydes and ketones in the Mannich reaction using catalyst 10a
Entry
R
R1
Mannich product
Yield [%]
[a]
D
Ee [%]b
d.r.c
a
1
2
3
4
5
6
7
8
9
OH
OH
OH
H
o-MeOC6H4
m-Tol
90
92
94
62
80
89
94
84
91
ꢀ2.1
ꢀ8.2
þ3.4
ꢀ7.1
87
91
94
73
92
96
96
94
65
4:1
6:1
20:1
d
p-O2NC6H4
CH2CH2CH]CH
CH2CH2Ph
CH2CH2Ph
p-BrC6H4
Ph
H
ꢀ10.8
þ13.1
ꢀ1.0
d
OH
OH
OH
OH
12:1
15:1
9:1
3:1
ꢀ52.6
þ1.4
p-MeOC6H4
a
In chloroform (c¼1).
b
c
Determined by chiral HPLC for the major diastereoisomer.
Based on 1H NMR data of the crude product.
catalysts in some reactions of the asymmetric CeC bond formation,
i.e., the diethylzinc addition to aldehydes, the aldol condensation
and the three-component Mannich reaction. Replacement of the
central hydroxyl group in these ligands with the second prolinol
moiety of the same absolute configuration gave new ligands in
which the sulfinyl group was not a stereogenic centre anymore.
Nevertheless, these ligands proved almost equally efficient as cat-
alysts for the reactions investigated. The absolute configuration of
the proline moiety exerted a decisive impact on the stereochem-
istry of these reactions, hence, decided about the absolute config-
uration of the products formed.
for 24 h at room temperature. A solution of 10% HCl (40 ml) was
added, the layers were separated and the aqueous layer was
extracted with Et2O (3ꢂ50 ml). The combined organic layers were
dried over anhydrous MgSO4, the solvent was evaporated and the
residue was purified by column chromatography (CHCl3:MeOH
100:1) to give 8 as a colorless oil (7.1451 g, 83.7%). 1H NMR (CDCl3)
d
1.45e1.79 (m, 12H), 3.47e3.53 (m, 2H), 3.76e3.90 (m, 2H),
4.58e4.63 (m, 2H), 4.65e4.92 (m, 4H), 7.40e7.55 (m, 6H), 7.69e7.72
(m, 2H).
4.2.2. Bis(2-hydroxymethylphenyl) sulfoxide (1). Sulfoxide
8
(7.145 g, 16.6 mmol) was dissolved in ethanol (100 ml) and PPTS
(10%-mol) was added. The reaction mixture was heated under
reflux for 3 h and reaction was monitored by TLC (CHCl3:MeOH
20:1). After completion of the reaction the solvent was evaporated.
The residue was dissolved in CH2Cl2 (100 ml) and washed with
water (100 ml). Aqueous layer was extracted with CH2Cl2
(3ꢂ50 ml). The combined organic layers were dried over anhydrous
MgSO4, the solvent was evaporated and the residue was purified by
column chromatography (CHCl3:MeOH 20:1) to give 1 as white
4. Experimental
4.1. General information
Unless otherwise specified, all the reagents were purchased
from commercial suppliers and used as received. Reactions were
followed using thin layer chromatography (TLC) on silica gel-coated
plates (Merck 60 F254) with the indicated solvent mixture. De-
tection was performed with UV-light. Optical rotations were mea-
sured on a PerkineElmer 241 MC polarimeter (c 1). Column
chromatography was carried out using Merck 60 silica gel. 1H NMR
spectra were recorded at 200 or 500 MHz and 13C NMR spectra at
101 or 126 MHz in CDCl3 and CD3OD as solvents. Chemical shifts are
given in ppm with respect to tetramethylsilane (TMS) as an internal
standard. Coupling constants are reported as J values in Hz. Mass
spectra (MS) were recorded using chemical ionization technique on
Finningan MAT 95 spectrometer. The enantiomeric excess (ee)
crystals (4.239 g, 86.5%). 1H NMR (CD3OD)
d
4.69 (s, 4H), 4.88 (s,
2H), 7.43e7.69 (m, 8H).1
Enzymatic desymmetrization of prochiral sulfoxide
1
and
mesylation of 2 were performed according to the literature
procedure.1
4.3. Synthesis of hydroxymethylphenyl N-prolinylmethyl-
phenyl sulfoxides 9a and 9b
values were determined by chiral HPLC Column: Lux 5
1 (Phenomenex).
m Cellulose e
4.3.1. Acetoxymethylphenyl N-prolinylmethylphenyl sulfoxides. To
acetoxymethyl-phenyl mesyloxymethylphenyl sulfoxide 31
(0.311 g, 0.81 mmol), dissolved in CHCl3 (20 ml), triethylamine
4.2. Synthesis of prochiral bis(2-hydroxymethylphenyl) sulf-
oxide 1
(0.11 ml, 0.81 mmol) and (S)-prolinol (80 ml, 0.81 mmol) were
added. The mixture was stirred at room temperature for 72 h, and
the reaction progress was controlled by TLC (AcOEt:MeOH 20:1).
After completion of the reaction the solvent was evaporated and
the crude product was purified by column chromatography to give
acetoxymethylphenyl N-prolinylmethylphenyl sulfoxide as a white
4.2.1. Bis(2-tetrahydropyranyloxymethylphenyl)
sulfoxide
(8). Magnesium (0.504 g, 21.0 mmol) was placed in a three-necked
flask and a solution of 7 (0.1143 g, 0.45 mmol) in THF (4 ml) was
added. The mixture was refluxed for 1 h and the remaining sub-
strate 7 (5.194 g, 20.37 mmol) in THF (30 ml) was added. The re-
action mixture was slowly cooled to 0 ꢁC and the solution of
dimethyl sulfite in THF was added dropwise. Stirring was continued
solid (0.288 g, 91.4%, [
dimensional NMR spectra were recorded (COSY, HSQC, HMBC). 1H
NMR (CDCl3) 1.70e1.78 (m, 2H), 1.82 (s, 3H), 1.93e1.96 (m, 2H),
2.20e2.24 (m, 1H), 2.82 (m, 1H), 2.90 (m, 1H), 3.51 (dd, 1H, J¼2.2,
a
]D¼ꢀ25.3, c 1). To confirm its structure, two-
d
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6
J. Chrzanowski et al. / Tetrahedron xxx (2015) 1e7
9.0 Hz), 3.53 (d, 1H, J¼12.5 Hz), 3.95 (dd, 1H, J¼2.2, 9.0 Hz), 4.64 (d,
1H, J¼12.5 Hz), 4.92e5.03 (AB, 2H, J¼13.0 Hz), 7.24e7.66 (m, 7H),
reaction chloroform was evaporated and the crude product was
purified by column chromatography (ethyl acetate: MeOH in gra-
dient, 100:0e10:1) to give 0.6241 g (76.4%) of 10a as a yellow oil;
8.17 (d, 1H, J¼8.0 Hz). 13C NMR (CDCl3)
d 20.50; 24.01; 27.72; 54.28;
56.48; 62.25; 62.82; 65.35; 126.11; 128.77; 129.51; 130.18; 130.34;
131.14; 131.4; 131.81; 133.12; 140.54; 141.67; 142.32; 170.31. MS (CI)
m/z 388.2 (MþH) C21H25O4SN.
[a
]D¼ꢀ63.0 (c 1, CHCl3). 1H NMR (CDCl3)
d 1.57e1.64 (m, 4H)
1.67e1.73 (m, 3H), 1.70e1.79 (m, 2H), 1.82e1.88 (m, 2H), 1.98 (bs,
1H), 2.32 (q, 1H, J¼9.0 Hz), 2.57e2.62 (m, 1H), 2.70e2.78 (m, 2H),
2.95 (t, 1H, J¼7.0 Hz), 3.18 (dd, 1H, J¼3.0, 11.5 Hz), 3.27 (dd, 1H,
J¼3.0, 11.5 Hz), 3.38 (dd, 1H, J¼3.0, 11.5 Hz), 3.42 (br s, 1H), 3.63 (dd,
1H, J¼3.0, 11.5 Hz), 3.73 (d, 1H, J¼13.5 Hz), 3.83 (d, 1H, J¼13.5 Hz),
4.22e4.29 (m, 1H), 7.31e7.34 (m, 1H), 7.35e7.44 (m, 5H), 7.46 (bs,
1H), 7.49 (d, 1H, J¼7.5 Hz), 7.60 (d, 1H, J¼7.5 Hz). 13C NMR (CDCl3)
The same reaction was performed using (R)-prolinol. Yield
0.290 g (91.7%), [
a
]D¼þ34.6, c 1. 1H NMR (CDCl3)
d 1.77 (s, 3H),
1.77e1.99 (m, 3H), 2.46e2.58 (m, 1H), 2.74e2.83 (m, 1H), 3.14e3.24
(m, 3H), 4.09 (AB, 2H, J¼13.32 Hz), 4.24 (bs, 1 H), 5.01 (AB, 2H,
J¼12.81 Hz), 7.07 (d, 1H, J¼7.69 Hz), 7.20e7.68 (m, 6H), 8.16 (d, 1H,
J¼7.69 Hz).
d
23.40 (CH2), 23.50 (CH2), 27.39 (CH2), 27.68 (CH2), 54,23 (CH2),
55.27 (CH2), 55.43 (CH), 57.06 (CH), 62.51 (CH2N), 62.84 (CH2N),
65.28 (CH2O), 65.67 (CH2O), 126.84 (CAr), 126.93 (CAr), 126.99 (CAr),
128.29 (CAr), 128.38 (CAr), 129.42 (CAr), 130.01 (CAr), 131.14 (CAr),
131.19 (CAr), 139.28 (qC), 141.21 (qC), 141.77 (qC), MS (CI) m/z 429.3
(MþH) C24H32O3SN2. HRMS: m/z calculated for C24H32O3SN2:
428.2134; found 428.21336.
4.3.2. Hydroxymethylphenyl N-(S)-prolinylmethylphenyl sulfoxide
(9). Acetoxymethylphenyl
N-prolinylmethylphenyl
sulfoxide
(0.274 g, 0.71 mmol) was dissolved in methanol (6 ml) and sodium
(0.016 g, 0.71 mmol) was slowly added. The mixture was stirred at
room temperature for 30 min. After this time the solvent was
evaporated and the residue was purified by column chromatogra-
phy (AcOEt:MeOH 10:1) to give the desired product-s 9 as white
crystals;
4.4.3. Bis[N-(R)-prolinylmethylphenyl] sulfoxide 10b. Bis[N-(R)-
prolinylmethylphenyl] sulfoxide 10b was obtained in the same way
as 10a, starting from bis(mesyloxymethylphenyl) sulfoxide and (R)
9a: (0.213 g, 87.5%); [
a
]D¼ꢀ72.0. 1H NMR (CDCl3)
d 1.63e1.75 (m,
2H), 1.78e1.85 (m, 1H), 1.87e1.94 (m, 1H), 2.26e2.31 (m, 1H)
2.84e2.89 (m, 2H), 3.39 (dd, 1H, J¼3.2 Hz, 11.1 Hz), 3.62 (dd, 1H,
J¼3.2 Hz, 11.1 Hz), 3.70 (d, 1H, J¼13.0 Hz), 4.30 (d, 1H, J¼13.0 Hz),
4.49 (s, 2H), 7.31e7.35 (m, 1H), 7.37e7.46 (m, 6H), 7.78e7.81 (m,
prolinol. 0.5996 (73.4%); [
a
]D¼þ62.8 (c 1, CHCl3).
4.5. The reactions of asymmetric synthesis
1H). 13C NMR (CDCl3)
d 23.63 (CH2), 27.51 (CH2), 54.52 (CH2), 56.57
The reactions of asymmetric synthesis were performed
according to the literature procedures: the diethylzinc addition to
benzaldehyde,7 the aldol condensation18 and the Mannich re-
action.6 The detailed descriptions are given in the Supplementary
data.
(CH), 61.79 (CH2N), 62.85 (CH2O), 65.46 (CH2O-prolinol), 125.81
(CAr), 127.74 (CAr), 128.30 (CAr), 128.90 (CAr), 129.09 (CAr), 130.42
(CAr), 131.14 (CAr), 131.58 (CAr), 139.06 (qC), 139.81 (q C), 140.78 (qC),
142.03 (qC). MS (CI) m/z 346.3 (MþH) C19H23O3SN. HRMS: m/z calcd
for C19H23O3NS: 345.1399; found: 345.13987.
9b: (0.1346, 55.3%); [
1.63e1.65 (m, 1H), 1.71e1.78 (m, 1H), 1.81e1.88 (m, 1H), 1.89e1.96
a
]D¼þ38.1 (c 1, CHCl3); 1H NMR (CDCl3)
Acknowledgements
d
(m, 1H), 2.39 (q, 1H, J¼9.9 Hz), 2.76 (bs, 1H), 2.94 (t, 1H, J¼2.9 Hz),
3.52 (dd, 1H, J¼3.3 Hz, J¼12.1 Hz), 3.57 (d, 1H, J¼12.7 Hz), 3.68 (dd,
1H, J¼2.8 Hz, 12.1 Hz), 4.23 (d, 1H, J¼13.4 Hz), 4.45 (d, 1H,
J¼13.4 Hz), 4.64 (d, 1H, J¼12.8 Hz), 7.23 (d, 1H, J¼7.9 Hz), 7.28e7.32
(m, 2H), 7.36e7.42 (m, 2H), 7.44 (t, 1H, J¼7.5 Hz), 7.51 (t, 1H,
J¼7.5 Hz), 8.01 (d, 1H, J¼7.7 Hz). 13C NMR (CDCl3): 23.23; 26.80;
54.92; 57.18; 62.43; 62.62; 66.77; 126.22; 128.14; 128.98; 129.65;
130.88; 130.91; 131.70; 138.70; 139.81; 141.52; 143.32.
The part of experimental works, which was carried out in the
CMMS laboratory was financially supported by the National Science
Center fund awarded based on the decision UMO-2012/06/A/ST5/
00227.
Supplementary data
Supplementary data (NMR spectra of 9 and 10; general methods
of the asymmetric syntheses and selected HPLC analyses of their
products) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2015.05.103.
4.4. Synthesis of bis(N-prolinylmethylphenyl) sulfoxides 10a
and 10b
4.4.1. Bis(mesyloxymethylphenyl) sulfoxide. Sulfoxide 1 (0.518 g,
2 mmol) was dissolved in methylene chloride (100 ml) and trie-
thylamine was added (0.63 ml, 4.54 mmol). To this solution mesyl
anhydride (0.791 g, 4.54 mmol) was dropped. The reaction mixture
was stirred at room temperature for 45 min (TLC monitoring ethyl
acetate:methanol 20:1). After completion of the reaction 50 ml of
water was added, the layers were separated, and the aqueous layer
was extracted with methylene chloride (3ꢂ20 ml). The combined
organic layer was drying over anhydrous MgSO4 and the solvent
was evaporated. The residue was purified by column chromatog-
raphy (ethyl acetate) to give 0.801 g of a colorless oil (96.9%). 1H
References and notes
1. Rachwalski, M.; Kwiatkowska, M.; Drabowicz, J.; K1os, M.; Wieczorek, W. M.;
ꢀ
ꢀ
Szyrej, M.; Sieron, L.; Kie1basinski, P. Tetrahedron: Asymmetry 2008, 19,
2096e2101.
ꢀ
ꢀ
2. Rachwalski, M.; Lesniak, S.; Kie1basinski, P. Tetrahedron: Asymmetry 2011, 22,
1325e1327.
ꢀ
ꢀ
3. Rachwalski, M.; Lesniak, S.; Sznajder, E.; Kie1basinski, P. Tetrahedron: Asymmetry
2009, 20, 1547e1549.
ꢀ
ꢀ
4. Kie1basinski, P.; Rachwalski, M.; Kaczmarczyk, S.; Lesniak, S. Tetrahedron:
Asymmetry 2013, 24, 1417e1420.
ꢀ
ꢀ
5. Rachwalski, M.; Lesniak, S.; Kie1basinski, P. Tetrahedron: Asymmetry 2011, 22,
1087e1089.
ꢀ
ꢀ
6. Rachwalski, M.; Leenders, T.; Kaczmarczyk, S.; Kie1basinski, P.; Lesniak, S.;
Rutjes, F. P. J. T. Org. Biomol. Chem. 2013, 11, 4207e4213.
NMR (CDCl3)
8H).
d
2.93 (s, 6H), 5.38 (AB, 4H, J¼7.0 Hz), 7.58e7.78 (m,
ꢀ
ꢀ
7. Lesniak, S.; Rachwalski, M.; Sznajder, E.; Kie1basinski, P. Tetrahedron: Asymmetry
2009, 20, 2311e2314.
ꢀ
ꢀ
8. Rachwalski, M.; Lesniak, S.; Kie1basinski, P. Tetrahedron: Asymmetry 2010, 21,
2687e2689.
4.4.2. Bis[N-(S)-prolinylmethylphenyl] sulfoxide 10a. In
a round
bottom flask bis(mesyloxymethylphenyl) sulfoxide (0.856 g,
2.22 mmol) and triethylamine (0.62 ml, 4.44 mmol) were dissolved
in 40 ml of chloroform. (S)-prolinol (0.43 ml, 4.44 mmol) was added
dropwise. The reaction mixture was stirred for 24 h (TLC moni-
toring ethyl acetate: methanol 5: 1). After completion of the
ꢀ
ꢀ
9. Rachwalski, M.; Lesniak, S.; Kie1basinski, P. Tetrahedron: Asymmetry 2010, 21,
1890e1892.
ꢀ
ꢀ
10. Rachwalski, M.; Kaczmarczyk, S.; Lesniak, S.; Kie1basinski, P. ChemCatChem
2014, 6, 873e875.
11. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395e2396;
(b) Uyanik, A.; Bayrakci, M.; Eymur, S.; Yilmaz, M. Tetrahedron 2014, 70,
Please cite this article in press as: Chrzanowski, J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.103

J. Chrzanowski et al. / Tetrahedron xxx (2015) 1e7
7
9307e9313; (c) Petakamsetty, R.; Das, R. P.; Ramapanicker, R. Tetrahedron 2014,
70, 9554e9563.
12. For a review see: Larson, G. L. Spec. Chem. Mag. 2009, 29, 20e22.
13. Krawczyk, K. K.; Madej, D.; Maurin, J. K.; Czarnocki, Z. Tetrahedron: Asymmetry
2011, 22, 1103e1107.
14. (a) Xu, L.-W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010, 352, 243e279; (b) Hayashi,
Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212e4215;
(c) Hu, F.; Guo, C.-S.; Xie, J.; Zhu, H.-L.; Huang, Z.-Z. Chem. Lett. 2010, 39,
412e414; (d) Chua, P. J.; Tan, B.; Zeng, X.; Zhong, G. Bioorg. Med. Chem. Lett.
2009, 19, 3915e3918; (e) Barbayianni, E.; Bouzi, P.; Constantinou-Kokotou, V.;
Ragoussis, V.; Kokotos, G. Heterocycles 2009, 78, 1243e1252; (f) Hayashi, Y.;
Samanta, S.; Itoh, T.; Ishikawa, H. Org. Lett. 2008, 10, 5581e5583.
15. (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem. Int.
Ed. 2005, 44, 794e797; (b) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard,
A.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 3703e3706.
ꢀ
16. Kaczmarczyk, S.; Kwiatkowska, M.; Madalinska, L.; Barbachowska, A.; Rach-
ꢀ
ꢀ
walski, M.; B1aszczyk, J.; Sieron, L.; Kie1basinski, P. Adv. Synth. Catal. 2011, 353,
2446e2454.
17. (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. J. Am. Chem. Soc. 2005, 127,
11256e11257; (b) Ting, A.; Lou, S.; Schaus, S. Org. Lett. 2006, 8, 2003e2006; (c)
For a review see Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.;
Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29e41.
18. (a) M1ynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502e1511; (b) Piec-
ꢀ
zonka, A. M.; Lesniak, S.; Rachwalski, M. Tetrahedron Lett. 2014, 55, 2373e2375.
Please cite this article in press as: Chrzanowski, J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.103