Carbohydrate-based spiro bis(isoxazolines): synthesis and evaluation in asymmetric catalysis

Article abstract of DOI:10.1016/j.tetlet.2009.11.028

Two carbohydrate-based spiro bis(isoxazolines) were synthesized via 1,3-dipolar cycloaddition from peracetylated methylene exo-glucal and the corresponding bis(arylnitrile oxide). The bis(cycloadducts) were then evaluated as ligands for enantioselective catalytic reactions. The Pd-catalyzed Tsuji-Trost reaction between a malonate and an allylic acetate did not provide good results. The poor conversion observed can be attributed to the rearrangement of the ligand in the reaction mixture to afford the corresponding ring-opened isoxazole which has been characterized. Both ligands were also evaluated in Cu(I)-catalyzed asymmetric imine alkynylation and afforded the product in good yield and modest enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2009.11.028

Tetrahedron Letters 51 (2010) 374–377
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carbohydrate-based spiro bis(isoxazolines): synthesis and evaluation
in asymmetric catalysis
a,b,c,d
, Susanne M. Telligmann , Catherine Goux-Henry b,c,d,f, Mike M. K. Boysen e,
e
David Goyard
Eric Framery
a
b,c,d,f
a,b,c,d
a,b,c,d,
*
, David Gueyrard
, Sébastien Vidal
Université de Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires Associé au CNRS, UMR 5246, Laboratoire de Chimie Organique 2, Glycochimie,
Bâtiment Curien, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
Université Lyon 1, F-69622 Villeurbanne, France
CNRS, UMR 5246, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Bâtiment Curien, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
CPE-Lyon, F-69616 Villeurbanne, France
b
c
d
e
Institute of Organic Chemistry, Leibniz University of Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
Université de Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires Associé au CNRS, UMR 5246, Laboratoire de Catalyse Synthèse et Environnement (CASYEN),
f
Bâtiment Curien, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Two carbohydrate-based spiro bis(isoxazolines) were synthesized via 1,3-dipolar cycloaddition from per-
acetylated methylene exo-glucal and the corresponding bis(arylnitrile oxide). The bis(cycloadducts) were
then evaluated as ligands for enantioselective catalytic reactions. The Pd-catalyzed Tsuji–Trost reaction
between a malonate and an allylic acetate did not provide good results. The poor conversion observed
can be attributed to the rearrangement of the ligand in the reaction mixture to afford the corresponding
ring-opened isoxazole which has been characterized. Both ligands were also evaluated in Cu(I)-catalyzed
asymmetric imine alkynylation and afforded the product in good yield and modest enantioselectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 September 2009
Revised 2 November 2009
Accepted 9 November 2009
Available online 12 November 2009
Asymmetric synthesis is an important area of synthetic chemis-
try, which has many industrial applications, including the produc-
tion of pharmaceuticals, agrochemicals, or polymers. One of the
most direct ways for accessing enantiomerically pure compounds
is through the exploitation of either chiral reagents or catalysts
prepared from metal salts and chiral ligands. Over the last decades,
O
O
O
O
O
O
N
N
N
N
N
N
N
R
R
1
R
2
R
R
3
R
oxazolines have emerged as a very successful class of chiral ligands
Figure 1. Typical bis(isoxazoline) ligands.
for asymmetric catalysis.1 Especially the C
–4
2
-symmetric chiral
bis(oxazolines) 1–3 (Fig. 1) have found wide application in various
asymmetric reactions.
O
OPiv
O
Ph
O
In the context of stereoselective synthesis, carbohydrates repre-
sent excellent starting materials for the preparation of chiral aux-
O
O
O
Ph
O
PivO
O
O
O
R2
O
R1
N
5
–10
5–10
5
5,6,11–14
iliaries,
Carbohydrate-based ligands have been mainly prepared from sac-
charides such as -xylose, -glucose, -galactose, -mannitol, and
trehalose backbones. During the last decade, ligands derived
from -glucosamine have become more and more popular. Some
reagents,
organocatalysts , and ligands.
P
O
PivO
N
2
Ar PO
N
R
O
D
D
D
D
R3
R2
Ph
2
P
5
,7,10
5
4
D
OAc
OAc
R3
prominent examples are shown in Figure 2, among them many
6
are oxazoline ligands (4–6).1
5–23
O
O
AcO
AcO
OR
NH
Recently, the Boysen group prepared glucosamine-based
AcO
AcO
OR
bis(oxazoline) and pyridyl bis(oxazoline) ligands 9a and 9b as well
N
as bis(thiazoline) 10 (Fig. 3).2
4–27
These ligands have been used in
PPh
2
PPh2
O
7
8
*
Corresponding author. Tel.: +33 4 72 44 83 49; fax: +33 4 78 89 89 14.
E-mail address: sebastien.vidal@univ-lyon1.fr (S. Vidal).
Figure 2. Examples of D-glucosamine-based ligands.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.028

D. Goyard et al. / Tetrahedron Letters 51 (2010) 374–377
375
O
O
S
S
O
O
AcO
O
O
N
N
N
N
AcO
=
OAc
OAc
AcO
OAc
AcO
OAc
AcO
OAc
AcO
OAc
9
10
N
a
b
Figure 3. Structure of bis(oxazoline) or bis(thiazoline) ligands.
H
H
H
[Pd] 2-4 mol%
20a or 20b
-8 mol%
H
H
H
MeO
2
C
CO
Ph
2
Me
R
R
R
R
OAc
4
MeO
2
C
2
CO Me
N
N
N
N
+
O
O
O
O
Ph
Ph
Ph
H
H
base / CH Cl
2 2
1
1
12
Scheme 2. Tsuji–Trost allylic alkylation.
Figure 4. Spiro bis(isoxazolines) ligands developed by Sasai et al.
AcO
AcO
OAc
OAc
the preparation of copper(I) complexes for asymmetric cycloprop-
anation (9a and 10) and imine alkynylation (9b). The yields are
generally good with medium to excellent regio- and
enantioselectivities.
O
O
N
N
N
O
O
AcO
OAc
OAc
AcO
Pd(OAc)
CDCl
24- 36h
2
0b
2
Isoxazolines are rigid five-membered ring systems with two
heteroatoms acting as Lewis bases. Spiro bis(isoxazolines) have
been previously developed as chiral ligands by Sasai and co-work-
3
2
8
ers (Fig. 4) promoting Pd-catalyzed asymmetric Wacker-type
28
AcO
OAc
cyclization of alkenyl alcohols, intramolecular amino-carbonyl-
AcO
N
OAc
29
ation of alkenyl amines and tosylamides, intramolecular cycliza-
N
N
O
3
0
31
O
tion of 2-alkynoates , and glyoxylate-ene reaction. Nevertheless,
the synthesis of this type of spiro bis(isoxazolines) requires several
steps including a Trost asymmetric allylic alkylation to introduce
chirality, which is a disadvantage for a broader application of these
ligands.
OAc
AcO
AcO
21
OAc
OH
HO
2
Scheme 3. Ring-opening of ligand 20b upon treatment with Pd(OAc) .
We present herein the preparation of two carbohydrate-based
bis spiro(isoxazoline) ligands prepared via 1,3-dipolar cycloaddi-
Ph
H
Ph
2
0b 8 mol%
N
Ph
HN
CuOTf 0.5 C 5 mol%
6 5
H
3
2,33
tion of a bis(nitrile oxide) and methylene exo-glucal.
The
+
Ph
Ph
2 2
CH Cl
resulting bis(cycloadducts) were then evaluated in two enantiose-
22
23
Ph
3
4
52%
17%ee
lective reactions: the Pd-catalyzed Tsuji–Trost allylic alkylation
S-(+)-24
and the Cu-catalyzed imine alkynylation.35,36
A convenient approach for the preparation of exo-glycals
Scheme 4. Cu(I)-catalyzed addition of phenylacetylene 23 to imine 22.
through a modified Julia olefination from the corresponding lac-
tones has recently been reported by Gueyrard et al.3
7,38
The silylat-
the corresponding (bis)oximes 18a–b and chlorination by NCS in
ed methylene exo-glucal 14 was therefore prepared from the
lactone 13 and then converted into the corresponding acetylated
glucal 15 (Scheme 1). 2,6-Pyridinedimethanol 16 was converted
to the (bis)aldehyde 17b by a Swern oxidation.39 The benzene-
and pyridine-based dialdehydes 17a–b were then converted to
the presence of a catalytic amount of HCl gas afforded the bis(car-
4
0
boximidoyl) chlorides 19a–b. The 1,3-dipolar cycloaddition was
then carried out by generating the bis(nitrile oxides) in situ from
19a–b and in the presence of dipolarophile 15 to afford the desired
spiro bis(isoxazolines) 20a–b.
OTES
O
OTES
O
OAc
O
a
b,c
TESO
TESO
TESO
TESO
AcO
AcO
7
4%
87%
O
CH
OTES
2
CH
2
AcO
AcO
OAc
OAc
OTES
OAc
1
3
14
15
O
O
g
X
N
N
O
O
AcO
OAc
OAc
20a X = CH 73%
0b X = N 71%
AcO
d
e
f
H
H
Cl
Cl
N
OHC
X
CHO
X
X
2
OH
OH
N
N
N
N
1
7a X = CH
HO
OH
HO
OH
1
6
17b X = N 52%
18a X = CH 37%
8b X = N 97%
19a X = CH 52%
19b X = N 82%
1
Scheme 1. Synthesis of the glucose-based bis(spiroisoxazoline) ligands. Reagents and conditions: (a) MeSO
THF, rt, 4h. (c) Ac O, pyridine, rt, 16h; (d) (COCl) , DMSO, Et N, CH Cl OHÁHCl, EtOH/H
, À78 °C, 2 h; (e) NH
2
Btz, LiHMDS, THF, À78 °C, 30 min then DBU, THF, rt, 1 h; (b) TBAF,
O, 3 h; (f) NCS, DMF, HCl(g) cat., rt, 1 h; (g) Et N, CH Cl , rt, 16 h.
2
2
3
2
2
2
2
3
2
2

3
76
D. Goyard et al. / Tetrahedron Letters 51 (2010) 374–377
Figure 5. 1H NMR stability study for ligand 20b in the presence of Cu(I) (400 MHz, 298 K, CDCl
). (a) Without metal salt and with 1 equiv of CuOTfÁ0.5C
3
6 6
H after (b) 25 min,
(
c) 1 h, (d) 2 h, (e) 4 h, (f) 6 h, (g) 12 h, (h) 24 h, (i) 48 h, (j) 72 h, (k) 96 h, (l) 144 h.
The Tsuji–Trost allylic alkylation was performed using a stan-
trum a) displays sharp multiplets for both the pyranose ring and
the pyridine system. Upon addition of 1 equiv of CuOTfÁ0.5C
1
6,17
dard protocol
using racemic (E)-1,3-diphenyl-2-propenyl ace-
6 6
H ,
tate and dimethyl malonate in CH
conditions (Scheme 2).
2
Cl
2
under two experimental
-allyl
these signals become significantly broader due to the presence of
Cu(I) species and their interactions with the ligand in solution
(Fig. 5, spectrum b). The peak resolution for the pyranose peaks im-
proves significantly after 24 h (Fig. 5, spectrum h) and after almost
4 days the pyridine signals were also well resolved again (Fig. 5,
spectrum k). We can therefore assume that ligand 20b is stable un-
der the conditions required for the imine alkynylation reaction.
In conclusion, we have designed a short synthetic route to car-
bohydrate-based spiro bis(isoxazoline) ligands using a 1,3-dipolar
cycloaddition of a methylene exo-glucal as the key step. These li-
gands were then evaluated in the Tsuji–Trost allylic alkylation pro-
viding only modest conversion. Ring-opening of the carbohydrate
The reaction was performed with either 4 mol % of a
p
complex of Pd(II) or 2 mol % of a tetrakis phosphine Pd(0) deriva-
tive. Even though we could observe a modest conversion of the
substrate to the desired product, the amount of material obtained
was too small to determine reliable enantiomeric excess values.
When pyridine-based ligand 20b was placed in solution with
equiv of Pd(OAc) in CDCl , we observed by NMR the formation
2 3
of a new product after only a few minutes. Its proportion kept
slowly increasing and the reaction reached to completion within
1
2
4–36 h. The structure of the product was assigned to the ring-
opened derivative 21 in which the aromatic isoxazole ring is
formed as a driving force for the reaction (Scheme 3). We therefore
assume that the poor conversion observed under Tsuji–Trost allylic
alkylation conditions is mostly due to the gradual decomposition
of the ligand in the presence of the Pd catalyst.
2
isoxazoline moieties upon addition of Pd(OAc) could explain the
lack of conversion observed. Nevertheless, in Cu(I)-catalyzed imine
alkynylation the pyridine-bridged ligand 20b provided better re-
sults in terms of reactivity. This finding is encouraging us in pursu-
ing this research program toward more rigid carbohydrate
scaffolds but also furanose derivatives, involving a 2,6-disubsti-
tuted pyridine motif as the central core unit for the selective for-
mation of tridentate complexes with Cu(I).
Next, the Cu(I)-catalyzed addition of imine alkynylation was
2
4
investigated using conditions employed previously (Scheme 4).
While the catalyst formed with benzene-based ligand 20a did
not promote the conversion of imine 22 and alkyne 23 even after
prolonged reaction time, pyridine-based ligand 20b afforded the
desired addition product 24 in good yield albeit with modest
enantioselectivity. This shows that new pyridine-based ligand
Acknowledgments
The authors wish to thank CNRS and Université Lyon 1 (S.V.),
the DFG, and VolkswagenFoundation (M.M.K.B) for financial
support.
2
0b is capable of forming a catalytically active N,N,N-tridentate
complex with the metal. On the other hand, benzene-based ligand
0a, possibly because of the lack of the pyridine’s nitrogen atom, is
2
not suitable for the formation of an efficient copper catalyst,
affording poor results in the alkynylation. These results were favor-
ably compared with the data obtained for the Tsuji–Trost reaction,
even though the enantioselectivity has to be improved.
Supplementary data
Supplementary data (experimental details for all new com-
pounds and enantioselective reaction procedures) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.11.028.
The stability of pyridine-based ligand 20b under the conditions
1
required for the imine alkynylation protocol was verified in a
H
NMR study (Fig. 5). The initial NMR spectrum of 20b (Fig. 5, spec-

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