A General and efficient route to 3-O-Modified carbohydrate bis(oxazoline) ligands

Article abstract of DOI:10.1055/S-2008-1078419

An efficient route to derivatives of carbohydrate-based bis(oxazoline) ligands with 3-O substituents of varying steric demand is described. The synthesis of the new ligands proceeds via a thioglucoside key intermediate, the double cyclisation reaction to

Full text of DOI:10.1055/S-2008-1078419

LETTER
1483
A General and Efficient Route to 3-O-Modified Carbohydrate
Bis(oxazoline) Ligands
Efficient
Prepar
o
ation of 3-O
b
-Modified glu
i
coBox
a
Ligands s Minuth, Mike M. K. Boysen*
Institute of Organic Chemistry, Leibniz University of Hannover, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: mike.boysen@oci.uni-hannover.de
Received 20 March 2008
stereoselectivity of reactions involving substrates bound
to the metal centres. We therefore set out to prepare a se-
ries of ligands with 3-O substituents of varying steric de-
mand, choosing 3-O-Me as a small, 3-O-Bn as a medium-
Abstract: An efficient route to derivatives of carbohydrate-based
bis(oxazoline) ligands with 3-O substituents of varying steric de-
mand is described. The synthesis of the new ligands proceeds via a
thioglucoside key intermediate, the double cyclisation reaction to
the desired bis(oxazolines) is initiated with N-iodo succinimide un- sized and 3-O-TES as a large residue (Figure 1). To selec-
der mild conditions. Employing this strategy, four new 3-O-modi-
fied bis(oxazoline) ligands were obtained in good yields.
tively access the 3-O position, we planned to employ ben-
zylidene acetals to block the 4- and 6-hydroxyls. Our
Key words: carbohydrates, ligand design, oxazolines, asymmetric
synthesis
studies towards these target structures were done on the
glucoBox scaffold.
O
O
Asymmetric metal-catalysed transformations are one of
the most efficient methods for preparation of chiral com-
pounds. To achieve high levels of asymmetric induction,
optimisation of the chiral ligands employed is often nec-
essary. Therefore the design of new ligand structures is a
very active field of research today.
1
3
O
O
6
2
5
N
N
4
M
O
O
O
O
O
O
3-O substituents of
varying steric demand
Carbohydrates, although far less frequently employed
than other compounds from the chiral pool, are versatile
starting materials for the preparation of novel and unusual
chiral complex ligands.1 In the course of our work we be-
came interested in chiral bis(oxazoline) ligands, which are
successfully applied in many asymmetric reactions.2 Re-
cently we introduced two new carbohydrate-based
ligands, glucoBox and glucoPybox, which were prepared
via bis(amides) of D-glucosamine using a one-pot double
cyclisation reaction.3,4 The glucoBox ligand was em-
ployed in cyclopropanations affording enantioselectivi-
ties up to 82% ee,3 while the glucoPybox ligand yielded
up to 99% ee in the alkynylation of imines.4 To further in-
crease the enantioselectivity for the cyclopropanation
with the carbohydrate box and to extend the substrate
scope for the carbohydrate pybox ligand, we decided to
perform systematic modifications on the ligand scaffold
to obtain optimised ligands through structural variation.
3-O-substituents
R =
small
Me
medium
Bn
large
TES
Me Me
=
N
Figure 1 General structure of carbohydrate bis(oxazoline) ligands
and points for the attachment of substituents with varying steric de-
mand
Initial attempts to introduce benzylidene acetal groups
into the preformed glucoBox ligand were unsuccessful.
Cyclising a benzylidene-protected bis(amide) using the
one-pot reaction employed for the preparation of
glucoBox3 led to decomposition because of the acidic
conditions of the first step. Therefore a new strategy to-
wards the desired target compounds had to be developed,
utilising a cyclisation reaction compatible with acid-sen-
sitive substrates.
The backbone of the new carbohydrate ligands offers
many options for structural modifications, as a wide range
of residues with varying steric and electronic properties
can be attached to the hydroxy groups of the pyranose
subunits. Especially the 3-O substituents located next to
the oxazoline nitrogen atoms can be expected to have con-
siderable impact on steric shielding coordinated of metal
centres (Figure 1). This in turn will directly influence the
For the new synthetic route thioglycosides were selected
as key intermediates, as they are easy to prepare, stable
against all reaction conditions necessary for ligand syn-
thesis, and can finally be activated for the cyclisation re-
action under specific and mild conditions. The synthesis
started from D-glucosamine hydrochloride (1) which was
transformed into peracetylated phthalimido derivative 2.5
Subsequently, this was treated with ethane thiol and
SYNLETT 2008, No. 10, pp 1483–1486
x
x
.x
x
.2
0
0
8
Advanced online publication: 19.05.2008
DOI: 10.1055/s-2008-1078419; Art ID: G10108ST
© Georg Thieme Verlag Stuttgart · New York

1484
T. Minuth, M. M. K. Boysen
LETTER
BF3·OEt2 as Lewis acid to afford thioglucoside 3,6 which temperatures, conditions that have previously been de-
was deacetylated7 and 4,6-O-benzylidene protected.8 scribed for the synthesis of monomeric oxazolines from
Deprotection of the amino function with ethylenediamine thioglycosides.11 With this protocol 3-O-acetylated
in ethanol9 gave amine intermediate 6. Next amine 6 was bis(oxazoline) 9 was obtained from bis(amide) 8 in one
coupled with dimethylmalonyl dichloride under condi- step in an excellent yield of 92% (Scheme 2).
tions described previously.3 This reaction yielded
7
bis(amide) 7 carrying thioglucoside residues, which was
a
97%
used as a key intermediate for the preparation of 3-O-
modified glucoBox ligands. All reactions of this sequence
proceeded with good to excellent yields (Scheme 1).
O
SEt
EtS
O
O
O
O
O
Ph
O
N
H
N
H
O
Ph
OH
OAc
O
a
Me Me
OAc
OAc
O
HO
HO
AcO
AcO
8
98%
OAc
NPhth
OH
Cl NH3
1
b
92%
2
b
72%
Me
Me
N
O
O
O
O
OAc
O
OH
O
c
N
AcO
AcO
HO
HO
SEt
SEt
O
O
94%
O
OAc
AcO
O
NPhth
NPhth
9
3
4
Ph
Ph
d
87%
Scheme 2 Reagents and conditions: a) Ac2O, pyridine, r.t., 16 h; b)
NIS, cat. TfOH, MS 4 Å, CH2Cl2, –30 °C, 1 h.
e
O
O
Ph
Ph
O
O
O
88%
O
SEt
NPhth
SEt
HO
Starting from key intermediate 7 we then prepared
bis(amide) precursors with the small, medium and large 3-
O substituents as proposed earlier. Methylation under
standard conditions with sodium hydride and
iodomethane12 gave compound 10a in 94% yield, the 3-O-
Bn-protected bis(amide) 10b was obtained by treating 7
with benzylbromide, sodium hydride, and catalytic
amounts of tetrabutylammonium iodide9 in a yield of
84%. Silylation with TESOTf and triethylamine13 yielded
83% of the 3-O-TES-modified compound 10c.
HO
NH2
5
6
f
quant.
O
SEt
EtS
O
O
O
O
O
Ph
O
N
N
O
Ph
H
H
Me Me
OH
OH
7
Scheme 1 Reagents and conditions: a) NaOH, NaHCO3, MeOH,
H2O, acetone, r.t., 16 h; then Ac2O, pyridine, r.t., 16 h; b) HSEt,
BF3·OEt2, CH2Cl2, 0 °C to r.t., 16 h; c) NaOMe, MeOH, r.t., 4 h; d)
neat benzaldehyde, anhyd ZnCl2, r.t., 16 h; e) ethylene diamine, abs.
EtOH, reflux, 4 h; f) dimethylmalonyl dichloride, Et3N, CH2Cl2, 0 °C
to r.t., 2 h.
The three bis(amides) 10a, 10b, and 10c were then sub-
jected to the NIS-mediated activation protocol. In each
case the double cyclisation reaction was successful irre-
spective of the 3-O substituent giving 3-O-methylated
11a, 3-O-benzylated 11b, and 3-O-silylated 11c in very
good yields14 (Scheme 3).
In order to obtain a ligand with the same 3-O substituent
as the original glucoBox, bis(amide) 7 was 3-O-acetyl
protected under standard conditions with acetic anhydride
in pyridine. For the double cyclisation reaction to the cor-
responding bis(oxazoline) elemental bromine was added
to acetylated bis(amide) 8 to exchange the anomeric thio-
ethyl groups to bromides.10 Subsequently, the intermedi-
ate bromide was treated with sodium hydrogen carbonate
and tetrabutylammonium chloride as previously described
for the synthesis of glucoBox.3 Via this sequence target 3-
O-acetylated bis(oxazoline) 9 was obtained in pure form
but only in 20% yield over two steps from 8. This rather
disappointing yield and the two-step procedure involving
elemental bromine made us look for alternative activation
protocols for the thioglycosyl groups.
The 3-O-modified bis(oxazolines) 9 and 11a–c are cur-
rently under investigation in asymmetric cyclopropana-
tion reactions, the results of these experiments will be
reported in due course. Further we intend to prepare a
wide spectrum of box ligands with 3-O substituents vary-
ing in steric and electronic properties as well as the corre-
sponding pybox ligands.
In conclusion, we have developed a simple and efficient
pathway to structural variants of glucosamine-based
bis(oxazoline) ligands via a bis(amide) carrying thiogly-
coside moieties. This approach allows us to selectively di-
versify the 3-O position in carbohydrate bis(oxazoline)
ligands. The mild cyclisation protocol using N-iodo suc-
cinimide leads to bis(oxazoline) formation in good yields
irrespective of the 3-O substituent.
We then tried treating 8 with N-iodosuccinimide and a
catalytic amount of trifluoromethanesulfonic acid at low
Synlett 2008, No. 10, 1483–1486 © Thieme Stuttgart · New York

LETTER
Efficient Preparation of 3-O-Modified glucoBox Ligands
1485
(7) Zemplén, G.; Pacsu, E. Ber. Dtsch. Chem. Ges. 1929, 62,
1613.
O
SEt
EtS
O
O
O
O
O
(8) Roth, W.; Pigman, W. J. Am. Chem. Soc. 1960, 82, 4608.
(9) Huang, L.; Wang, Z.; Li, X.; Ye, X.; Huang, X. Carbohydr.
Res. 2006, 341, 1669.
(10) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
(11) Sherman, A. A.; Yudina, O. N.; Mironov, Y. V.; Sukhova,
E. V.; Shashkov, A. S.; Menshov, V. M.; Nifantiev, N. E.
Carbohydr. Res. 2001, 336, 13.
Ph
O
N
N
H
O
Ph
H
Me Me
OH
OH
7
a (to 10a)
b (to 10b)
c (to 10c)
(12) Bourgeaux, E.; Combret, J.-C. Tetrahedron: Asymmetry
2000, 11, 4189.
(13) Abrous, L.; Jokiel, P. A.; Friedrich, S. R.; Hynes, J. Jr.;
Smith, A. B. III.; Hirschmann, R. J. Org. Chem. 2004, 69,
280.
(14) General Procedure for the Double Cyclisation of
Bis(amides) with Thioglycoside Moieties
O
SEt
O
EtS
O
O
O
O
Ph
O
N
H
N
O
Ph
H
Me Me
OR
OR
10a R = Me
10b
10c
94%
84%
R = TES 83%
R = Bn
A mixture of the 3-O-protected thioglycoside (280 mg, 0.38
mmol) and MS 4 Å (300 mg) in anhyd CH2Cl2 (5 mL) was
stirred for 1 h under N2 atmosphere in a flame-dried flask. To
this NIS (210 mg, 91 mmol) was added and the mixture was
cooled to –30 °C. Then, TfOH (5 mL, 50 mmol) was added
and the mixture was stirred for 1 h at –30 °C. The reaction
was quenched with Et3N (0.1 mL), and the mixture was
filtered through Celite, diluted with CH2Cl2, washed with
sat. aq NaHCO3, aq Na2S2O3 (3 M), and dried over Na2SO4.
The solvent was removed under reduced pressure, and the
residue was purified by flash chromatography on SiO2
(eluants given for the respective compound) to yield the
desired product.
d
Me
Me
O
O
O
O
N
N
O
O
O
O
O
O
Ph
Ph
R
R
11a R = Me
90%
79%
R = Bn
R = TES 85%
Analytical Data for 3-O-Acetylated Compound 9
Eluant: EtOAc. 1H NMR (400 MHz, CDCl3): d = 1.52 [6 H,
s, (CH3)2C], 2.10 (6 H, s, CH3CO), 3.61 (2 H, dd ≈ t,
11b
11c
Scheme 3 Reagents and conditions: a) NaH, MeI, THF, reflux, 4 h;
b) NaH, BnBr, TBAI, DMF, 0 °C to r.t.,16 h; c) TESOTf, Et3N,
CH2Cl2, –78 °C to r.t., 16 h; d) NIS, cat. TfOH, MS 4 Å, CH2Cl2,
–30 °C, 1 h.
J5,6¢ = J6,6¢ = 9.9 Hz, H-6¢), 3.75 (2 H, ddd ≈ td, J4,5 = 9.9 Hz,
J5,6 = 5.1 Hz, J5,6¢ = 9.9 Hz, H-5), 3.81 (2 H, dd, J3,4 = 7.5 Hz,
J4,5 = 9.9 Hz, H-4), 4.14 (2 H, dd, J1,2 = 7.1 Hz, J2,3 = 2.7 Hz,
H-2), 4.39 (2 H, dd, J5,6 = 5.1 Hz, J6,6¢ = 10.2 Hz, H-6), 5.28
(2 H, dd, J2,3 = 2.7 Hz, J3,4 = 7.5 Hz, H-3), 5.51 (2 H, s,
CHPh), 5.98 (2 H, d, J1,2 = 7.1 Hz, H-1), 7.32–7.37 (6 H, m,
Ph), 7.44–7.46 (4 H, m, Ph) ppm. 13C NMR (100 MHz,
CDCl3): d = 21.1 (CH3, OAc), 23.4 [CH3, (CH3)2C], 38.9 (C,
[CH3)2C], 62.9 (CH, C-5), 67.8 (CH2, C-6), 68.2 (CH, C-2),
73.5 (CH, C-3), 78.4 (CH, C-4), 101.4 (CH, PhCH), 101.4
(CH, C-1), 126.1 (2 CH, Ph), 128.2 (2 CH, Ph), 129.0 (CH,
Ph), 136.8 (C, Ph), 169.6 (C, O–C=N), 169.8 (C, C=O, Ac)
ppm. ESI-HRMS (+): m/z calcd for C35H39N2O12 [M + H]+:
679.2503; found: 679.2511. [a]D20 +106 (c 1.0, CHCl3).
Analytical Data for 3-O-Methylated Compound 11a
Eluant: PE–EtOAc (1:2). 1H NMR (400 MHz, CDCl3):
d = 1.53 [6 H, s, (CH3)2C], 3.54 (6 H, s, OCH3), 3.60–3.71 (8
H, m, H-3, H-4, H-5, H-6¢), 4.11 (2 H, dd, J1,2 = 7.5 Hz,
J2,3 = 2.4 Hz, H-2), 4.33–4.41 (2 H, m, H-6), 5.56 (2 H, s,
CHPh), 5.97 (2 H, d, J1,2 = 7.5 Hz, H-1), 7.32–7.37 (6 H, m,
Ph), 7.44–7.47 (4 H, m, Ph) ppm. 13C NMR (100 MHz,
CDCl3): d = 23.4 [CH3, (CH3)2C], 39.0 [C, (CH3)2C], 58.5
(CH3, OCH3), 62.6 (CH, C-5), 67.8 (CH, C-2), 68.2 (CH2, C-
6), 80.1 (CH, C-3), 81.7 (CH, C-4), 101.3 (CH, PhCH),
102.2 (CH, C-1), 126.1 (2 CH, Ph), 128.2 (2 CH, Ph), 129.0
(CH, Ph), 137.1 (C, Ph), 168.8 (C, O–C=N) ppm. ESI-
HRMS (+): m/z calcd for C33H38N2O10 [M + H]+: 662.2526;
found: 662.2534. [a]D20 +124 (c 1.0, CHCl3).
Acknowledgment
We thank Deutsche Forschungsgemeinschaft, VW Stiftung, and
Fonds der Chemischen Industrie for financial support.
References and Notes
(1) For reviews on carbohydrate-based complex ligands, see:
(a) Diéguez, M.; Pàmies, O.; Claver, C. Chem. Rev. 2004,
104, 3189. (b) Diéguez, M.; Pàmies, O.; Ruiz, A.; Díaz, Y.;
Castillón, S.; Claver, C. Coord. Chem. Rev. 2004, 248,
2165. (c) Boysen, M. M. K. Chem. Eur. J. 2007, 13, 8648.
(d) Diéguez, M.; Claver, C.; Pàmies, O. Eur J. Org. Chem.
2007, 4621.
(2) For reviews on bis(oxazolines), see: (a) Desimoni, G.;
Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561.
(b) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104,
4151. (c) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev.
2003, 103, 3119. (d) Ghosh, A. K.; Mathivanan, P.;
Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1.
(3) Irmak, M.; Groschner, A.; Boysen, M. M. K. Chem.
Commun. 2007, 177.
Analytical Data for 3-O-Benzylated Compound 11b
Eluant: PE–EtOAc (1:1). 1H NMR (400 MHz, CDCl3):
d = 1.51 [6 H, s, (CH3)2C], 3.63 (2 H, dd ≈ t, J5,6¢ = J6,6¢ = 9.6
Hz, H-6¢), 3.68 (2 H, ddd ≈ td, J4,5 = J5,6¢ = 9.6 Hz, J5,6 = 4.1
Hz, H-5), 3.78 (2 H, dd, J3,4 = 7.5 Hz, J4,5 = 9.6 Hz, H-4),
3.93 (2 H, dd, J2,3 = 3.0 Hz, J3,4 = 7.5 Hz, H-3), 4.23 (2 H,
dd, J1,2 = 7.5 Hz, J2,3 = 3.0 Hz, H-2), 4.38 (2 H, dd, J5,6 = 4.1
(4) Irmak, M.; Boysen, M. M. K. Adv. Synth. Catal. 2007, 350,
403.
(5) Kotchetkov, N. K.; Byramova, N. E.; Tsvetkov, Y. E.;
Backinowsky, L. V. Tetrahedron 1985, 41, 3363.
(6) (a) Ellervik, U.; Magnusson, G. Carbohydr. Res. 1996, 280,
251. (b) Sun, D.-Q.; Busson, R.; Herdewijn, P. Eur. J. Org.
Chem. 2006, 5158.
Synlett 2008, No. 10, 1483–1486 © Thieme Stuttgart · New York

1486
T. Minuth, M. M. K. Boysen
LETTER
Hz, J6,6¢ = 9.6 Hz, H-6), 4.77 (2 H, d, J = 12.0 Hz, CH2Ph),
4.82 (2 H, d, J = 12.0 Hz, CH2Ph), 5.57 (2 H, s, CHPh), 5.98
(2 H, d, J1,2 = 7.5 Hz, H-1), 7.25–7.46 (20 H, m, Ph) ppm.
13C NMR (100 MHz, CDCl3): d = 23.4 [CH3, (CH3)2C], 38.9
[C, (CH3)2C], 62.8 (CH, C-5), 68.4 (CH, C-2), 68.6 (CH2, C-
6), 72.4 (CH2, PhCH2) 79.7 (CH, C-3), 80.1 (CH, C-4), 101.1
(CH, PhCH), 102.2 (CH, C-1), 126.0 (2 CH, Ph), 127.6 (CH,
Ph), 127.8 (2 CH, Ph), 128.1 (2 CH, Ph), 128.2 (2 CH, Ph),
128.9 (CH, Ph), 137.1 (C, Ph), 137.9 (C, Ph), 168.8 (C, O–
C=N) ppm. ESI-HRMS (+): m/z calcd for C45H47N2O10 [M +
H]+: 775.3231; found: 775.3234. [a]D20 +82 (c 1.0, CHCl3).
Analytical Data for 3-O-Silylated Compound 11c
J = 7.8 Hz, SiCH2CH3), 1.50 [6 H, s, (CH3)2C], 3.55–3.66 (6
H, m, H-4, H-5, H-6¢), 3.93 (2 H, dd, J2,3 = 3.8 Hz, J3,4 = 7.2
Hz, H-3), 3.98 (2 H, dd, J1,2 = 7.2 hz, J2,3 = 3.8 Hz, H-2),
4.36 (2 H, dd, J5,6 = 3.1 Hz, J6,6¢ = 8.9 Hz, H-6), 5.53 (2 H, s,
CHPh), 5.95 (2 H, d, J1,2 = 7.2 Hz, H-1), 7.32–7.37 (6 H, m,
Ph), 7.45–7.49 (4 H, m, Ph) ppm. 13C NMR (100 MHz,
CDCl3): d = 4.73 [CH3, (CH3CH2)3Si], 6.71 [CH2,
(CH3CH2)3Si], 23.4 [CH3, (CH3)2C], 39.0 [C, (CH3)2C], 63.2
(CH, C-5), 68.6 (CH2, C-6), 70.8 (CH, C-2), 74.4 (CH, C-3),
81.1 (CH, C-4), 101.4 (CH, PhCH), 102.7 (CH, C-1), 126.0
(2 CH, Ph), 128.0 (2 CH, Ph), 128.8 (CH, Ph), 137.3 (C, Ph),
168.5 (C, O–C=N) ppm. ESI-HRMS (+): m/z calcd for
C43H63N2O10Si2 [M + H]+: 823.4021; found: 823.4003.
[a]D20 +106 (c 0.9, CHCl3).
Eluant: PE–EtOAc (1:1). 1H NMR (400 MHz, CDCl3):
d = 0.65 (12 H, t, J = 7.8 Hz, SiCH2CH3), 0.93 (18 H, t,
Synlett 2008, No. 10, 1483–1486 © Thieme Stuttgart · New York

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