Enantioselective addition of phenylacetylene to aldehydes catalyzed by a d-glucosamine-derived sulfonamide-titanium complex

Article abstract of DOI:10.1016/j.tetlet.2011.07.051

We present the synthesis of β-hydroxy sulfonamides derived from d-glucosamine and their application as ligands in titanium tetraisopropoxide promoted enantioselective addition of phenylacetylene to benzaldehyde and selected aromatic and aliphatic aldehydes. The N-3,5-bis(trifluoromethyl) benzenesulfonamido-d-glucosamine derivative was chosen as the most efficient ligand for this addition. The reaction is highly enantioselective for several aromatic aldehydes and enantiomeric excesses up to 92% were obtained.

Full text of DOI:10.1016/j.tetlet.2011.07.051

Tetrahedron Letters 52 (2011) 4882–4884
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective addition of phenylacetylene to aldehydes catalyzed by a
D-glucosamine-derived sulfonamide–titanium complex
Tomasz Bauer a, , Sławomir Smolinski , Przemysław Gaweł , Janusz Jurczak
⇑
a
a
a,b
´
a Department of Chemistry, Warsaw University, Pasteura 1, PL-02-093 Warsaw, Poland
b Institute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
We present the synthesis of b-hydroxy sulfonamides derived from D-glucosamine and their application as
Received 1 June 2011
Revised 22 June 2011
Accepted 11 July 2011
Available online 22 July 2011
ligands in titanium tetraisopropoxide promoted enantioselective addition of phenylacetylene to benzal-
dehyde and selected aromatic and aliphatic aldehydes. The N-3,5-bis(trifluoromethyl)benzenesulfon-
amido-D-glucosamine derivative was chosen as the most efficient ligand for this addition. The reaction
is highly enantioselective for several aromatic aldehydes and enantiomeric excesses up to 92% were
obtained.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
D-Glucosamine
Aldehydes
Phenylacetylene
Enantioselective
The enantioselective organometallic addition to aldehydes is an
important method for the synthesis of optically active secondary
alcohols. We have previously reported the successful use of the
previously published procedures,1,5 and used them for alkynyla-
tion reactions (Scheme 1).
In the literature there are two general methods for the prepara-
tion of chiral ligand–alkynylzinc–Ti complexes; Pu’s method devel-
oped for BINOLs requires a separate step for the preparation of the
alkynylzinc reagent in refluxing toluene for 5 h,6 and Chan’s meth-
od, also developed for BINOLs7 and later modified by Wang for use
with sulfonamides.8 We started our investigation with the readily
available tosylamide 1 and performed the reaction at room temper-
ature according to Wang’s procedure. Unfortunately, the ratio of
alkynylation:ethylation was unacceptable (Table 1, entry 1). Obvi-
D
-glucosamine derived ligand I in titanium-mediated diethylzinc
addition to aromatic and aliphatic aldehydes.1 The obvious advan-
tage of this type of ligand is its modular synthesis. Three sites
(indicated by arrows in Fig. 1) on the ligand can be easily altered
during the synthesis, thus leading to various ligands having the
same chiral precursor.
This concept was realized efficiently for diethylzinc addition to
aromatic and aliphatic aldehydes with good to excellent enantiose-
lectivity. Enantioselective addition of terminal alkynes to carbonyl
compounds is a useful approach for the preparation of chiral sec-
ondary propargylic alcohols,2,3 which are important building
blocks for the synthesis of many natural products.4 Among the cat-
alysts developed, excellent results were obtained for BINOL and its
derivatives, and for various sulfonamides, often in the presence of
titanium tetraisopropoxide. To the best of our knowledge, sulfona-
mides derived from a monosaccharide have not been used for this
type of reaction.
In this Letter, we report the first example of titanium tetra-
isopropoxide promoted, monosaccharide-derived sulfonamide-
catalyzed addition of phenylacetylene to aromatic and aliphatic
aldehydes. Starting from cheap, commercial D-GLUCOSAMINE hydro-
chloride, we synthesized ligands 1–5 (Fig. 2) according to
ously this method did not work in the case of the D-glucosamine
sulfonamide ligand 1. Thus we turned our attention to Pu’s method,
and to our delight, we obtained the alkynylation product with very
high chemoselectivity, but with very low enantioselectivity (Table
1, entry 2). Next we used different solvents and found that the best,
but still only moderate, ee was obtained in methylene chloride
O
O
Ph
OMe
O
O
S
HO
HN
R
O
I
⇑
Corresponding author. Tel.: +48 22 822 02 11x273; fax: +48 22 822 59 96.
E-mail address: tbauer@chem.uw.edu.pl (T. Bauer).
Figure 1. The three sites of modular ligand I which can be altered during synthesis.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.051

T. Bauer et al. / Tetrahedron Letters 52 (2011) 4882–4884
4883
O
O
O
O
O
O
Ph
O
Ph
O
Ph
OMe
O
OMe
OMe
O
S
O
O
S
O
S
O
HO
HN
HO
HN
HO
HN
2
O
3
N
1
N
O
O
O
O
O
Ph
O
Ph
OMe
CF3
CF3
OMe
O
O
S
O
HO
HN
S
HO
HN
CF3
O
5
4
Figure 2.
D-Glucosamine derived sulfonamides 1-5.
O
H
Ph
R2Zn, Ti(OiPr)4
Ph
+
Ph
Ph
+
L*
OH
OH
6
7
8
9
Scheme 1. Phenylacetylene addition to benzaldehyde.
Table 1
Enantioselective addition of phenylacetylene to benzaldehyde in the presence of ligands 1–5
Entry
Liganda
R2Zn (equiv)
Ti(OiPr)4:ligand ratio
Solvent
Yieldc (%)
eed,e (%)
8:9d
1
2
3
4
5
6
7
8
1
1
1
1
2
3
4
5
5
5
5
5b
5
Et2Zn (3)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Et2Zn (2)
Me2Zn (1.2)
7:1
Toluene
Toluene
THF
59
72
52
73
74
68
52
84
87
78
82
75
82
53
30
13
66
53
3
69
79
82
88
82
82
90
57:43
99:1
92:8
95:5
98:2
86:14
72:28
77:23
79:21
93:7
79:21
75:25
99:1
3.5:1
3.5:1
3.5:1
3.5:1
3.5:1
3.5:1
4:1
5:1
6:1
7:1
7:1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
12
13
6:1
a
b
c
20 mol % of ligand was used.
10 mol % of ligand was used.
Isolated yield.
d
e
Determined by HPLC on a Chiracel OD-H column.
Configuration determined as R on the basis of the elution order and literature data6.
(Table 1, entry 4). Having established a basic set of parameters, we
performed this reaction with other sulfonamides and found that the
highest ee was obtained with ligand 5.
aliphatic aldehydes in the presence of ligand 5 (Table 2). All reac-
tions were performed at ambient temperature in the presence of
0.2 equiv of chiral ligand 5 using conditions established for
benzaldehyde.9
We continued our investigations with this ligand. One of the
most important parameters of this reaction is the Ti-chiral ligand
ratio. After optimization, we found, that in terms of chemo- and
enantioselectivity, the best ratio was 6:1 (Table 1, entry 10). Thus
we reinvestigated the synthesis without the high-temperature pre-
formed ethynylzinc. We decided to use Chan’s procedure,6 which
uses dimethylzinc instead of diethylzinc, but modified it to use cat-
alytic amounts of b-hydroxy sulfonamide 5 instead of BINOL. We
found, that this combination worked very well for our ligand and
we achieved excellent chemoselectivity and slightly better enanti-
oselectivity (Table 1, entry 13 vs 10).
The enantioselectivity of the reaction was highly dependent on
the nature of the aldehyde and substitution on the phenyl ring. The
best result was obtained for 2-fluorobenzaldehyde (Table 2, entry
4), while the reactions of 3- and 4-fluorobenzaldehydes proceeded
with very low enantioselectivity (Table 2, entries 5 and 6). Moder-
ate enantioselectivity was obtained for 4-methoxybenzaldehyde
(Table 2, entry 3), and again, 2- and 3-methoxy substituted benzal-
dehydes gave low ees (Table 2, entries 1 and 2). Good enantioselec-
tivity was observed for a cycloaliphatic aldehyde, while a simple
linear aliphatic aldehyde gave lower ee (Table 2, entries 8 and 9).
A much broader spectrum of aromatic aldehydes, including other
halogen-substituted benzaldehydes, is currently being investigated
Based on the results presented in Table 1, we carried out phen-
ylacetylene additions to some other representative aromatic and

4884
T. Bauer et al. / Tetrahedron Letters 52 (2011) 4882–4884
Table 2
Enantioselective addition of phenylacetylene to various aldehydes in the presence of 20 mol % of ligand 5
Entry
Aldehyde
Time (h)
Yielda (%)
eeb,c (%)
Alkynylation:methylation ratiob
1
2
3
4
5
6
7
8
9
2-MeOC6H4CHO
3-MeOC6H4CHO
4-MeOC6H4CHO
2-FC6H4CHO
3-FC6H4CHO
4-FC6H4CHO
(E)-PhCH@CHCHO
c-C6H11CHO
C5H11CHO
6
6
8
63
63
85
68
72
59
92
75
95
28
23
73
92
12
22
23
85
49
72:28
91:9
83:17
85:15
96:4
100:0
99:1
100:0
100:0
6
15
26
10
5
5
a
b
c
Isolated yield.
Determined by HPLC on a Chiracel OD-H column.
Configuration determined as R on the basis of the elution order and literature data6.
Liang, C.; Cai, Y.; Li, Y.-M.; Hui, X.-P. Tetrahedron: Asymmetry 2009, 20, 2733–
2736.
in this reaction in order to fully establish its scope and limitations. In
conclusion, we have synthesized several sulfonamides of -glucosa-
mine and used them for the first time in the enantioselective addi-
tion of phenylacetylene to aldehydes.
D
4. (a) Trost, B.; Krische, M. J. J. Am. Chem. Soc. 1999, 121, 6131–6141; (b) Myers, A.
G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492–4493; (c) Chang, X.-W.; Zhang, D.-
W.; Chen, F.; Dong, Z.-M.; Yang, D. Synlett 2009, 3159–3162; (d) Fox, M. E.; Li, C.;
Marino, J. P., Jr.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 5467–5480.
5. All new compounds displayed correct analytical and spectral data.
6. Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855–1857.
Acknowledgment
7. Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002, 172–173.
8. (a) Xu, Z.; Wang, R.; Xu, J.; Da, C.; Yan, W.; Chen, C. Angew. Chem. Int. Ed. 2003,
42, 5747–5749; (b) Xu, Z.; Li, L.; Xu, J.; Yan, W.; Wang, R. Adv. Synth. Catal. 2006,
348, 506.
This research was financed by the European Union within the
European Regional Development Fund, Project POIG.01.01.02.-
14–102/09.
9. Typical experimental procedure: Ti(OiPr)4 (0.18 mL, 0.6 mmol) was added to a
solution of ligand 5 (108 mg, 0.2 mmol) in CH2Cl2 (1.0 ml) and stirred for 0.5 h at
room temperature. At the same time, a 1.2 M solution of dimethylzinc in toluene
(1.0 mL, 1.2 mmol) was added to another flask containing phenylacetylene
(0.143 mL, 1.3 mmol) and the mixture stirred at 0 °C for 30 min. The Ti catalyst
was then transferred to the alkynylzinc solution via syringe. The resulting
mixture was stirred at 0 °C for 90 min, benzaldehyde (0.104 mL, 1.0 mmol) was
added and the mixture was kept at 0 °C for 4 h or until TLC showed the
disappearance of benzaldehyde. The reaction was quenched with saturated
NH4F solution (ca. 2.0 ml), then extracted with CH2Cl2 (5 Â 20 ml). The
combined organic layer was dried over anhydrous MgSO4, filtered, and
evaporated. The residue was purified using flash chromatography (hexane-
EtOAc, 8:2 v/v) to afford the chiral propargylic alcohol as an oil, the
enantiomeric composition of which was established by HPLC (Chiracel OD-H,
hexane:iPrOH, 9:1, flow 0.8 mL/min).
References and notes
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