First synthesis of a carbohydrate-derived pyridyl bis(thiazoline) ligand

Article abstract of DOI:10.1016/j.tetlet.2007.08.101

The first synthesis of a carbohydrate-based pyridyl bis(thiazoline) ligand starting from d-glucosamine and its application in asymmetric cyclopropanation reactions are reported.

Full text of DOI:10.1016/j.tetlet.2007.08.101

Tetrahedron Letters 48 (2007) 7890–7893
First synthesis of a carbohydrate-derived pyridyl
bis(thiazoline) ligand
Mustafa Irmak, Tobias Lehnert and Mike M. K. Boysen*
Institute of Organic Chemistry, Leibniz University of Hannover, Schneiderberg 1 B, Hannover D-30167, Germany
Received 13 June 2007; revised 21 August 2007; accepted 29 August 2007
Available online 31 August 2007
Abstract—The first synthesis of a carbohydrate-based pyridyl bis(thiazoline) ligand starting from D-glucosamine and its application
in asymmetric cyclopropanation reactions are reported.
Ó 2007 Elsevier Ltd. All rights reserved.
As asymmetric metal catalysed reactions have become
an invaluable tool in organic synthesis, the development
of new chiral ligands is an important scientific task.
Bis(oxazolines)1 represent one important ligand family
that has witnessed a rapid evolution. They are nowadays
employed in reactions as different as cyclopropanations,
pericyclic and Michael reactions as well as aldol type
additions. Thiazolines, the sulfur congeners of oxazo-
lines have been rarely used for this purpose, even though
the first application of a chiral bis(thiazoline) ligand was
reported in one of the first publications on bis(oxazo-
lines) by Helmchen2 in 1991.
ysed Diels–Alder reactions were described by the group
of Kunieda,6 followed shortly afterwards by a report
from Nishio and co-workers,7 using a ligand with an
ethylene bridge for the same reaction. Both ligand types
led to quite promising results. These reports show that
bis(thiazolines) have certainly potential as a new class
of ligands in enantioselective synthesis. In this Letter,
we report the first preparation of a carbohydrate-
derived pyridyl bis(thiazoline) ligand from glucosamine
hydrochloride.
With the aim to develop new synthetic tools based on
carbohydrates as inexpensive and versatile starting
materials from the chiral pool8 we recently prepared a
new bis(oxazoline) ligand (glucoBox)9 starting from
D-glucosamine. After this bis(oxazoline) had led to good
enantioselectivities in copper catalysed cyclopropana-
tions, we became interested in the corresponding thiazo-
line derivative.
Recently bis(thiazolines) have received renewed atten-
tion after Masson and Gulea prepared several methylene
bridged bis(thiazolines) and pyridyl bis(thiazolines).3a
Both types were tested in the Tsuji–Trost reaction,3a,b
the former led to good selectivities while the pyridyl
bis(thiazoline) provided only low stereoinduction in this
reaction. This ligand was also tried out in ruthenium
catalysed cyclopropanations,3c and yielded products
with moderate to good selectivity. Further examples of
methylene bridged bis(thiazolines) prepared by Du and
N-Acetyl glucosamine can be easily converted into the
corresponding thiazoline by treating the peracetylated
compound with Lawesson’s reagent10 following a proce-
dure reported by Withers et al.11 Therefore we decided
to prepare our target molecules via peracetylated bis-
(amide) precursors. This approach appeared particularly
attractive, for a bis(amide) of glucosamine and dimethyl
malonic acid is an intermediate in the synthesis of the
new bis(oxazoline) ligand.9
co-workers4 led to moderate selectivities in the Tsuji–
5
´
Trost reaction. Molina and Tarraga prepared ferrocene
bridged bis(thiazolines) albeit without reporting on their
application. Recently a number of sterically congested
bis(thiazolines) and their testing results in copper catal-
For the preparation of the desired acetyl-protected bis-
(amide), amino sugar 1 was per-O-TMS protected and
the resulting derivative 2 was subsequently coupled with
dimethylmalonyl dichloride to yield bis(amide) 3a,
Keywords: Thiazoline; Carbohydrates; Stereoselective synthesis;
Asymmetric catalysis; Chiral ligands.
*
Corresponding author. Tel.: +49 511 762 4643; fax: +49 511 762
3011; e-mail: mike.boysen@oci.uni-hannover.de
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.101

M. Irmak et al. / Tetrahedron Letters 48 (2007) 7890–7893
7891
Scheme 1. Synthesis of bis(thiazolines). Reagents and conditions: (a) TMSCl, HMDS, pyridine, rt; (b) Et3N, CH2Cl2, 0 °C to rt; (c) TFA/MeOH 1:9,
rt; (d) Ac2O, pyridine, rt; (e) toluene, reflux.
which was then deprotected. Acetylation of deprotected
compound 4a under standard conditions with acetic
anhydride in pyridine gave 5a, the precursor for the
cyclisation reaction. Treatment of 5a with Lawesson’s
reagent in refluxing toluene according to the literature
procedure11 led to selective formation of bis(thioamide)
6a12 but no cyclisation occurred. Longer reaction time
and variation of the reaction conditions as changing
the number of equivalents for Lawesson’s reagent,
microwave conditions or addition of Lewis acids as
e.g. TMSOTf did not effect the desired double cyclisa-
tion either. Instead mono(thiazoline) 7 was identified
as the major product of this reaction (Scheme 1).
unchanged. The desired double cyclisation could finally
be effected with Lawesson’s reagent by prolonging the
reaction time. After flash chromatography on silica gel
with petroleum ether/ethyl acetate 1:3 only 18% of the
target compound were obtained, but after eluting the
column residue with pure ethyl acetate, we were pleased
to find that this last fraction contained another batch of
the product. Thus target compound 8 was obtained in
an overall yield of 44% directly from starting material
After this first unsuccessful attempt we tried the reaction
with Lawesson’s reagent on bis(amide) derived from
dipicolinic acid (Scheme 1). This was prepared analo-
gously to malonyl bis(amide). First O-TMS-protected
2 was reacted with dipicolinic acid chloride to yield com-
pound 3b,13 which was de-silylated and subsequently
acetylated to give bis(amide) 5b. All these steps pro-
ceeded smoothly and in good to excellent yields. The
reaction with Lawesson’s reagent in refluxing toluene
under the conditions described in the literature11 gave
bis(thioamide) 6b.14 Belleau’s reagent15 and phosphorus
pentasulfide16 were also tried as thionation agents, but
from these tests the starting material was recovered
Scheme 2. Cyclopropanation experiments with ligand 8.

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M. Irmak et al. / Tetrahedron Letters 48 (2007) 7890–7893
Table 1. Cyclopropanation reactions of styrene with ligand 8
Entry
Alkene
Metal salt
Conditionsa
Yieldb (%)
trans:cisc
ee trans (%)
ee cisc (%)
1
2
3
4
5
6
7
8
9
Styrene (9a)
Styrene (9a)
Styrene (9a)
Styrene (9a)
Styrene (9a)
Styrene (9a)
4-Methoxy styrene (9b)
1,1-Diphenyl ethylene (12)
1,1-Diphenyl ethylene (12)
[RuCl2(p-cymene)]2
Cu(OTf)Æ0.5PhÆH
Cu(OTf)Æ0.5PhÆH
Cu(OTf)Æ0.5PhÆH
Cu(OTf)Æ0.5PhÆH
Cu(OTf)Æ0.5PhÆH
Cu(OTf)Æ0.5PhÆH
[RuCl2(p-cymene)]2
Cu(OTf)Æ0.5PhÆH
CH2Cl2, 0 °C
CH2Cl2, 0 °C
CH2Cl2, ꢀ20 °C
CH2Cl2, 35 °C
Toluene, 0 °C
Et2O, 0 °C
CH2Cl2, 0 °C
CH2Cl2, 0 °C
CH2Cl2, 0 °C
44
65
55:45
58:42
—
63:37
54:46
61:39
70:30
—
Racemicd
28d
—
22d
22d
18d
24e
18d
—
No reaction
70
64
44
19
5
20d
24d
16d
10e
Racemice
Racemice
6
—
a Ligand 8 (1.1 mol %), metal salt (1 mol %).
b Isolated yields after chromatography.
c Determined after separation of isomers.
d Determined by GC on a chiral stationary phase.
e Determined by 1H NMR with Rh2[R-(+)-MTPA]4 as chiral complexing reagent (dirhodium method).21
5b.17 The different behaviour of bis(amides) 5a and 5b in
the double cyclisation reaction may be explained by
invoking steric aspects. While in bis(amide) 5b the gluco-
samine moieties are connected via a planar pyridyl
bridge, those in 5a are connected by a dimethyl methy-
lene spacer. This bridge is a bulky unit as well as a lot
shorter than the pyridyl spacer. While the first part of
the cyclisation reaction with Lawesson’s reagent, forma-
tion of bis(thioamides) 6a and 6b works for both com-
pounds, the double cyclisation is only observed for 6b
with the longer, flat bridging unit, while 6a only gives
monocyclisation product 7. Therefore it seems likely
that steric congestion prevents a second cyclisation step
in compound 7. For this reaction the sulfur atom of the
remaining thioamide has to attack the anomeric centre
as a nucleophile, which in this case is formidably bulky.
but switching the solvent from dichloromethane to
toluene or diethyl ether (entries 5 and 6) lowered the
enantioselectivities compared to those achieved in
dichloromethane under the same conditions (entry 2).
Finally two other alkenes, 4-methoxy styrene (9b) and
1,1-diphenyl ethylene (12) were tried in the reaction
(Scheme 2). These gave the corresponding products only
in severely decreased yield and with low or no selectivity.
All results of the cyclopropanation experiments are sum-
marised in Table 1.
In conclusion we have prepared a new carbohydrate-
derived pyridyl bis(thiazoline) ligand in five simple steps
and employed it in asymmetric cyclopropanation as a
trial reaction. Although the first trials did not lead to
high enantioselectivities, we think that the new ligand
structure may be of more value in other metal catalysed
transformations. Investigations to this end are currently
underway.
With pyridyl bis(thiazoline) 8 in hand we tried the new
ligand in the metal catalysed cyclopropanation of
styrene (9a) with ethyl diazoacetate (10), which is often
used as a benchmark reaction for new ligand structures
(Scheme 2, Table 1). The first experiments were per-
formed with ruthenium(II) as the metal centre according
to the protocol reported by Nishiyama18 and also
employed by Masson.3c Bicyclic ligand 8 gave only race-
mic products in rather poor yield, while the monocyclic
bis(thiazoline) ligands reported by Masson et al. led to
enantiomeric excesses above 85%. Therefore bicyclic
ligand 8 appears as not well suited for the ruthenium
catalysed reaction. While copper(I) catalysed cyclopro-
panations with bis(oxazoline) ligands yield products
with good to excellent enantioselectivities,19 pyridyl
bis(oxazolines) have rarely been used as ligands in this
reaction and optical yields of cyclopropanes are low.20
Using ligand 8 and copper(I) triflate at 0 °C in dichloro-
methane as the solvent, cyclopropanation products 11a
trans and 11a cis were obtained in improved yields
and with improved but still low enantioselectivities.
Next we performed several cyclopropanation experi-
ments under varying conditions to increase the enanti-
oselectivity (cf. Table 1). Running the reaction at
lower temperature (entry 3) did not give any product,
while elevated temperatures led to a small increase in
product yield but predictably to slightly lower enantio-
selectivities (entry 4). Keeping the temperature at 0 °C
Acknowledgements
We thank Deutsche Forschungsgemeinschaft, VW
Stiftung and Fonds der Chemischen Industrie for
financial support.
References and notes
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M. Irmak et al. / Tetrahedron Letters 48 (2007) 7890–7893
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spectroscopic data proved it to be another batch of pyridyl
bis(thiazoline) 8, which was isolated in an overall yield of
44% (0.41 g, 0.55 mmol) as a brown foam. Analytical data
for compound 8: 1H NMR (400 MHz; CDCl3, rt): 8.19
(2H, d, J = 7.2 Hz, pyridine H), 7.92 (1H, t, J = 7.9 Hz,
pyridine H), 6.32 (2H, d, J = 7.5 Hz, H-1), 5.68 (2H, dd,
J = 2.1, 3.1 Hz, H-3), 5.03 (2H, dd ꢁ d, J = 8.9 Hz, H-4),
4.82 (2H, m, H-2), 4.18–4.05 (4H, m, H-6, H-60), 3.62 (2H,
ddd ꢁ t, J = 4.8 Hz, H-5), 2.19, 2.06, 2.04 (each s, each
6H, OAc) ppm; 13C NMR (100 MHz; MeOD, rt): 174.9,
174.8, 173.9 (C, C@O, Ac), 173.7 (C, S–C@N), 153.8 (C,
pyridine), 142.2 (CH, pyridine) 127.3 (CH, pyridine), 89.9
(CH, C-1), 81.3 (CH, C-2), 74.3 (CH, C-3), 73.5 (CH, C-
4), 72.4 (CH, C-5), 67.2 (CH2, C-6), 23.4, 23.4, 23.2 (CH3,
Ac–CH3) ppm; HR ESI MS (positive): [M+Na]+ found
m/z 760.0986, C31H35O14N3S2 requires m/z 760.1560; [a]
+81.3 (c 0.8, CHCl3).
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J = 9.4 Hz, H-1), 5.39 (2H, dd ꢁ t, J = 9.5 Hz, H-3), 5.20
(2H, dd ꢁ t, J = 9.5 Hz, H-4), 5.21 (2H, ddd, J = 3.8, 8.5,
10.9 Hz, H-2), 4.26 (2H, dd, J = 4.8, 12.9 Hz, H-6), 4.07–
3.99 (4H, m, H-60, H-5), 2.17, 2.07, 2.03, 2.01 (each s, each
6H, OAc) ppm; HR ESI MS (positive): [M+Na]+ found
m/z 845.1854, C33H46O18N2S2 requires m/z 845.2085.
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CDCl3, rt): 8.43 (1H, d, J = 7.8 Hz, pyridine H), 8.05 (2H,
t, J = 7.9 Hz, pyridine H), 7.38 (2H, d, J = 10.4 Hz, NH),
5.19 (2H, d, J = 3.8 Hz, H-1), 4.41 (2H, m, H-2), 3.65–3.90
(10H, m, H-3, H-4, H-5, H-6, H-60), 0.25, 0.22, 0.19, 0.10
(each 18H, each s, TMS) ppm; 13C NMR (100 MHz,
CDCl3, rt): 163.9 (C, C@O), 149.5 (C, pyridine), 139.5
(CH, pyridine), 128.1 (CH, pyridine), 92.4 (CH, C-1), 74.2,
72.3, 72.2 (CH, C-3, C-4, C-5), 61.9 (CH2, C-6), 55.0 (CH,
C-2), 1.4, 0.8, 0.5, 0.2 (CH3, TMS) ppm; HR ESI MS
(positive): [M+Na]+ found m/z 1088.4624, C43H91O12-
N3Si8 requires m/z 1088.4758; [a]D +247.4 (c 1.8, CHCl3).
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J = 7.8, pyridine H), 7.93 (1H, t, J = 7.8 Hz, pyridine H),
6.18 (2H, d, J = 8.5 Hz, H-1), 5.74 (2H, dd ꢁ t,
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(2H, dd, J = 4.8, 12.6 Hz, H-6), 4.15 (2H, dd, J = 2.4,
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