Highly enantioselective addition of phenylethynylzinc to aldehydes using aziridine-functionalized tridentate sulfinyl ligands

Article abstract of DOI:10.1016/j.tetasy.2010.10.013

Diastereomerically pure tridentate heteroorganic ligands containing hydroxyl, sulfinyl and aziridine moieties as nucleophilic centers, capable of binding to various organometallic reagents, have been proven to be highly efficient catalysts in the enantioselective addition of phenylethynylzinc to aldehydes to give the desired products in very high yields (up to 95%) and with ee's up to 90%. The influence of the stereogenic centers located on the sulfinyl sulfur atom and in the aziridine moiety on the stereochemical course of the reaction is also discussed.

Full text of DOI:10.1016/j.tetasy.2010.10.013

Tetrahedron: Asymmetry 21 (2010) 2687–2689
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective addition of phenylethynylzinc to aldehydes using
aziridine-functionalized tridentate sulfinyl ligands
Michał Rachwalski a, , Stanisław Lesniak , Piotr Kiełbasinski
⇑
a
b
´
´
a
´
´
Department of Organic and Applied Chemistry, University of Łódz, Tamka 12, 91-403 Łódz, Poland
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112, 90-363 Łódz, Poland
b
´
a r t i c l e i n f o
a b s t r a c t
Article history:
Diastereomerically pure tridentate heteroorganic ligands containing hydroxyl, sulfinyl and aziridine moi-
eties as nucleophilic centers, capable of binding to various organometallic reagents, have been proven to
be highly efficient catalysts in the enantioselective addition of phenylethynylzinc to aldehydes to give the
desired products in very high yields (up to 95%) and with ee’s up to 90%. The influence of the stereogenic
centers located on the sulfinyl sulfur atom and in the aziridine moiety on the stereochemical course of the
reaction is also discussed.
Received 22 September 2010
Accepted 6 October 2010
Available online 20 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
are important building blocks in the synthesis of various biologi-
cally active and natural products.4
Enantioselective carbon–carbon bond formation using organo-
zinc reagents is commonly and widely used in the synthesis of chi-
ral non-racemic compounds and is one of the most successful areas
of asymmetric synthesis in recent years.1,2 The enantioselective
alkynylzinc addition to carbonyl compounds3 is very useful in
the preparation of chiral non-racemic propargyl alcohols, which
We have recently reported the synthesis of chiral tridentate li-
gands, bearing hydroxyl, sulfinyl, and amino moieties, with two ste-
reogenic centers located on the sulfinyl sulfur atom and on the
carbon atom in the amine moiety.5 These ligands have proven to
be very efficient catalysts for various stereoselective reactions of
asymmetric synthesis, namely for nitroaldol (Henry) reactions
(those bearing chiral acyclic amine moieties),6 for enantioselective
diethylzinc additions to aldehydes;7 and enantioselective conjugate
Michael additions of diethylzinc to enones2 (those bearing chiral
aziridinyl substituents). Each enantiomer of the product may be ob-
tained using readily available enantiopure diastereomeric ligands.
Taking into account the aforementioned results, we have
decided to extend the activity of our tridentate ligands by using
them as catalysts for the enantioselective addition of phenylethy-
nylzinc reagents to aldehydes.
R1
N
HO
O
R2
S
1
2. Results and discussion
Aziridines
Pri
2.1. Screening of the ligands
Me
Me
H
Me
H
Pri
H
Four chiral tridentate ligands containing aziridine moieties
were considered, because the best results during the diethylzinc
addition to aldehydes and enones were obtained using these chiral
catalysts (Scheme 1).
N
H
N
H
N
H
N
H
a
b
c
d
To check the ability of the ligands for catalyzing the enantiose-
lective addition of alkynylzinc reagents to aldehydes, we chose the
addition of phenylacetylene and diethylzinc to benzaldehyde as a
reference transformation. The reactions were performed under
standard conditions (Scheme 2) and the results are shown in
Table 1.
Scheme 1. Ligands for the asymmetric addition of phenylethynylzinc to aldehydes.
⇑
Corresponding author.
E-mail address: mrach14@wp.pl (M. Rachwalski).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.013

2688
M. Rachwalski et al. / Tetrahedron: Asymmetry 21 (2010) 2687–2689
Table 2
OH
Ligand, Et2Zn
THF
Addition of phenylethynylzinc to aldehydes in the presence of 1b
Ph
Ph
PhCHO
+
Ph
Entry
R
Product 2
a
Symbol Yield (%)
[
a
]
D
eeb (%) Absolute
2a
configurationc
Scheme 2. Screening of ligands 1.
1
2
3
4
5
6
7
Ph
a
b
c
d
e
f
96
93
96
94
87
95
80
À5.05 98
(S)
(R)
(R)
(R)
(R)
(S)
(R)
2-MeC6H4
2-MeOC6H4
2-ClC6H4
4-BrC6H4
n-Pr
À11.5
À8.0
92
97
95
Table 1
Screening of ligands 1
À12.5
+4.05 94
À3.3
94
Entry Ligand (absolute
configuration)
Product 2a
E-PhCH@CH
g
À0.95 91
Yield
(%)
[a
]
D
eeb
(%)
Absolute
a
a
b
c
configurationc
In chloroform, c 1.
Determined using chiral HPLC.
1
2
3
4
1a (RS)
62
96
94
91
À2.9
57
(S)
(S)
(R)
(S)
Taken from the literature.8–10
1b (RS,SC)
1c (RS,RC)
1d (RS,SC)
À5.05 98
+4.9
À4.7
95
92
a
b
c
carbon atom in the aziridine moiety, were found to be very effi-
cient catalysts for the enantioselective addition of phenylacety-
lenezinc to aldehydes. The stereogenic centers located in the
amine moieties exerted a decisive influence on the stereochemistry
of the reaction and the absolute configuration of the products. Each
enantiomer of the product may be obtained by using easily avail-
able diastereomeric ligands.
In chloroform, c 1.
Determined using chiral HPLC.
Taken from the literature.8
Inspection of Table 1 reveals that the formation of enantiomeri-
cally enriched product 2 in the presence of catalyst 1a, bearing an
achiral aziridine moiety, indicates that the stereogenic sulfinyl
group exerts a moderate asymmetric induction. Moreover, the
reactions promoted by two diastereomeric catalysts 1b and 1c,
possessing opposite enantiomers of 2-isopropylaziridine, led to
the formation of the opposite enantiomers of product 2. This
means that the stereogenic center located in the aziridine moiety
exerts a decisive influence on the stereochemistry of the reaction
and hence on the absolute configuration of the addition product.
The small differences in the ee values of the product may be ex-
plained in terms of ‘match’ and ‘mismatch’ interactions with the
stereogenic sulfinyl center.
4. Experimental
4.1. General
Unless otherwise specified, all reagents were purchased from
commercial suppliers and used without further purification. Tetra-
hydrofuran was distilled from sodium benzophenone ketyl radical.
NMRspectra were recorded on a Brukerinstrumentat 600 MHzwith
CDCl3 as solvent and relative to TMS as the internal standard. Data
are reported as s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, b = broad. Optical rotations were measured on a Per-
kin–Elmer 241 MC polarimeter with a sodium lamp at room temper-
ature (c 1). Column chromatography was carried out using Merck 60
silica gel. TLC was performed on Merck 60 F254 silica gel plates. Visu-
alization was accomplished with UV light or permanganate stain,
followed by heating. The enantiomeric excess (ee) values were
determined by chiral HPLC (Knauer, Chiralcel OD). Chiral tridentate
ligands were obtained using the procedure previously described.5
2.2. Addition of phenylethynylzinc to various aldehydes in the
presence of catalyst 1b
Having obtained the best results with ligands 1b and 1c, we
then decided to check the scope of the reaction. The title reaction
was performed using a series of aldehydes in the presence of ligand
1b as a catalyst (Scheme 3). The results are collected in Table 2.
OH
R
Ligand 1b, Et2Zn
Ph
Ph
RCHO
4.2. General procedure for the asymmetric addition of
phenylethynylzinc to aldehydes
+
THF
2
To a solution of ligand 1 (0.2 mmol) in THF (5 mL), was added a
solutionofEt2Zn(1.4 mL, 1.4 mmol, 1.0 Minhexane)atroomtemper-
ature under an argon atmosphere. After the mixture was stirred at
ambient temperature for 30 min., phenylacetylene (0.154 mL,
1.4 mmol) was added, and stirring continued for another 30 min.
The solution was cooled to 0 °C and treated with an aldehyde
(1 mmol) and then the resultant mixture stirred for 2 h at 0 °C and
overnight at room temperature. After completion of the reaction
(TLC), it was quenched by 5% aqueous HCl. The mixture was extracted
withether, andthecombinedorganicphaseswerewashedwithbrine,
dried over MgSO4, and concentrated under vacuum. The residue was
purified by column chromatography (silica gel, hexane, and ethyl ace-
tate in gradient) to give the product. The yields, specific rotations, and
enantiomeric excess values are shown in Tables 1 and 2.
Scheme 3. The addition of phenylethynylzinc to various aldehydes in the presence
of ligand 1b.
The results clearly indicate that the selected ligand 1b very effi-
ciently catalyzes the title reaction to give the appropriate propar-
gylic alcohols in high yields with high enantiomeric excesses.
Both aryl and alkyl aldehydes are suitable for the reaction. Interest-
ingly, no product of conjugate addition is formed in the case of cin-
namaldehyde (Table 2, entry 7). Since both diastereomers of this
ligand, 1b and 1c, are available, and each of them leads to the for-
mation of the opposite enantiomer of the product (Table 1, entries
2 and 3), this approach constitutes an easy access to the desired
sterically defined propargylic alcohols.
4.2.1. (S)-1,3-Diphenyl-prop-2-yn-1-ol 2a
3. Conclusions
Yellow liquid; 1H NMR (CDCl3): d = 2.39 (br s, 1H), 5.67 (s, 1H),
7.33–7.62 (m, 10H). Other spectroscopic data of compound 2a are
in agreement with those reported in the literature.8
Chiral tridentate ligands, which contain two stereogenic cen-
ters, one located on the sulfinyl sulfur atom, and the other on the

M. Rachwalski et al. / Tetrahedron: Asymmetry 21 (2010) 2687–2689
2689
4.2.2. (R)-1-(2-Methylphenyl)-3-phenyl-prop-2-yn-1-ol 2b
Yellowish oil; 1H NMR (CDCl3): d = 2.27 (br s, 1H), 2.54 (s, 3H),
5.87 (s, 1H), 7.22–7.38 (m, 6H), 7.48–7.52 (m, 2H), 7.75–7.78 (m,
1H). Other spectroscopic data of compound 2b are in agreement
with those reported in the literature.8
1H), 7.29–7.32 (m, 3H), 7.42–7.44 (m, 3H). Other spectroscopic
data of compound 2f are in agreement with those reported in the
literature.9
4.2.7. (R)-1,5-Diphenyl-pent-1-en-4-yn-3-ol 2g
Yellow solid; 1H NMR (CDCl3): d = 2.20 (br s, 1H), 5.29 (d,
J = 6.0 Hz, 1H), 6.40 (dd, J = 6.0 Hz, J = 15.6 Hz, 1H), 6.85 (d,
J = 15.6 Hz, 1H), 7.26–7.50 (m, 10H). Other spectroscopic data of
compound 2g are in agreement with those reported in the
literature.9
4.2.3. (R)-1-(2-Methoxyphenyl)-3-phenyl-prop-2-yn-1-ol 2c
Colorless oil; 1H NMR (CDCl3): d = 3.12 (br s, 1H), 3.96 (s, 3H),
5.97 (s, 1H), 6.97–7.04 (m, 2H), 7.28–7.39 (m, 4H), 7.50–7.52 (m,
2H), 7.67–7.69 (dd, J = 7.4 Hz, 1H). Other spectroscopic data of
compound 2c are in agreement with those reported in the
literature.8
References
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4.2.4. (R)-1-(2-Chlorophenyl)-3-phenyl-prop-2-yn-1-ol 2d
Colorless oil; 1H NMR (CDCl3): d = 2.41 (br s, 1H), 6.08 (s, 1H),
7.31–7.53 (m, 8H), 7.86–7.88 (m, 1H). Other spectroscopic data
of compound 2d are in agreement with those reported in the
literature.8
´
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2. Rachwalski, M.; Lesniak, S.; Kiełbasinski, P. Tetrahedron: Asymmetry 2010, 21,
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4.2.5. (R)-1-(4-Bromophenyl)-3-phenyl-prop-2-yn-1-ol 2e
Yellowish oil; 1H NMR (CDCl3): d = 2.42 (br s, 1H), 5.68 (s, 1H),
7.29–7.31 (m, 2H), 7.34–7.39 (m, 3H), 7.49–7.57 (m, 4H). Other
spectroscopic data of compound 2e are in agreement with those
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4.2.6. (S)-1-Phenyl-hex-1-yn-3-ol 2f
Yellowish oil; 1H NMR (CDCl3): d = 0.98 (t, J = 7.2 Hz, 3H), 1.52–
1.59 (m, 2H), 1.74–1.81 (m, 2H), 2.01 (br s, 1H), 4.61 (t, J = 6.6 Hz,