Synthesis of carbohydrate-based chiral crown ethers as ligands in asymmetric hydrogenation

Article abstract of DOI:10.1055/s-2001-12357

Starting from phenyl 2,3-di-O-allyl-4,6-O-benzylidene-β-D-glucopyranoside (1) the chiral crown ethers 6 and 7, containing a 1,4-bridged α-D-glucopyranoside moiety, were synthesized in four steps via phenyl 2,3-O-allyl-6-O-benzyl-β-D-glucopyranoside (2). To build up the corresponding polyethylene glycol side chain at 4-position, compound 2 was subsequently alkoxylated with bis(2-chloroethyl)ether and diethylene glycol or triethylene glycol yielding via 3 the polyethylene glycol derivatives 4 and 5, respectively. On a similar way phenyl 2,3-di-O-allyl-6-O-benzyl-4-O-{2-[ω-hydroxypenta(oxyethylene)ethyl]} -β-D-galactopyranoside (15) was prepared from phenyl 4,6-O-benzylidene-β-D-galactopyranoside (10) via the intermediates 11, 12 and 13. The chiral crowns 6, 7, and 16 were obtained in yields of 26-38% by intramolecular transglycosylation of 4, 5, and 15, respectively. Whereas a high α-stereoselectivity was found for the cyclization of the 1,4-bridged D-glucose crowns 6 and 7, galactose derivative 15 gave the β-glycosidic linked crown 16. In order to obtain the rhodium chelates 18 and 20 as pre-catalysts for asymmetric hydrogenations, the gluco-crown ethers 6 and 7 were deallylated to 8 and 9 and phosphorylated under anaerobic conditions giving the bis(phosphinic esters) 17 and 19. The latter were used as ligands for 18 and 20. Finally, asymmetric hydrogenations of amino acid precursors 21a-d were investigated in the presence of the rhodium chelates 18 and 20. Under hydrogen, they show as catalysts in different solvents a diminished range of enantioselectivity in comparison with an analogous complex without such a crown ether ring. This can be explained by a stiffening effect of the anellated ring on the chelate ring conformation which is confirmed by the unusually uniform CD-spectra of 20 in solvents of different polarity.

Full text of DOI:10.1055/s-2001-12357

638
PAPER
Synthesis of Carbohydrate-based Chiral Crown Ethers as Ligands in
Asymmetric Hydrogenation
Franziska Faltin,a Volker Fehring,b Renat Kadyrov,b Antonio Arrieta,a Thomas Schareina,b Rüdiger Selke,*b Ralf
Miethchen*a
a Universität Rostock, Lehrstuhl Organische Chemie II, Buchbinderstrasse 9, 18051 Rostock, Germany
Fax +49(381)4981819; E-mail: ralf.miethchen@chemie.uni-rostock.de
b Institut für Organische Katalyseforschung an der Universität Rostock e.V., Buchbinderstrasse 5 6, 18055 Rostock, Germany.
Received 18 October 2000; revised 29 November 2000
Dedicated to Prof. Dr. Peter Köll on the occasion of his 60th birthday
and the formation of cryptate species with alkali ions
Abstract: Starting from phenyl 2,3-di-O-allyl-4,6-O-benzylidene-
strongly influence the conformation of crown ethers,13 we
-D-glucopyranoside (1) the chiral crown ethers 6 and 7, containing
wanted to investigate whether the tuning of these effects
would increase the enantioselectivity of these new cata-
a 1,4-bridged -D-glucopyranoside moiety, were synthesized in
four steps via phenyl 2,3-O-allyl-6-O-benzyl- -D-glucopyranoside
(2). To build up the corresponding polyethylene glycol side chain at lysts. More detailed background information on asymmet-
4-position, compound 2 was subsequently alkoxylated with bis(2-
chloroethyl)ether and diethylene glycol or triethylene glycol yield-
ing via 3 the polyethylene glycol derivatives 4 and 5, respectively.
On a similar way phenyl 2,3-di-O-allyl-6-O-benzyl-4-O- 2- -hy-
ric hydrogenation can be found in the latest review by
Brown.14
Based on a strategy reported before,8 the 17-membered
and 20-membered macrocyclic compounds 6 and 7, were
synthesized in four steps according to Scheme 1. At first,
the benzylidene acetal of phenyl 2,3-di-O-allyl-4,6-O-
benzylidene- -D-glucopyranoside (1) was reductively
cleaved using a method by Garegg et al.15 The major prod-
uct, phenyl 2,3-di-O-allyl-6-O-benzyl- -D-glucopyrano-
side (2),16 was separated by column chromatography and
droxypenta(oxyethylene)ethyl }- -D-galactopyranoside (15) was
prepared from phenyl 4,6-O-benzylidene- -D-galactopyranoside
(10) via the intermediates 11, 12 and 13. The chiral crowns 6, 7, and
16 were obtained in yields of 26 38% by intramolecular transglyc-
osylation of 4, 5, and 15, respectively. Whereas a high -stereose-
lectivity was found for the cyclization of the 1,4-bridged D-glucose
crowns 6 and 7, galactose derivative 15 gave the -glycosidic linked
crown 16. In order to obtain the rhodium chelates 18 and 20 as pre-
catalysts for asymmetric hydrogenations, the gluco-crown ethers 6 etherified with bis(2-chloroethyl)ether under phase trans-
and 7 were deallylated to 8 and 9 and phosphorylated under anaer-
fer conditions (catalyst: tetrabutylammonium hydrogen
obic conditions giving the bis(phosphinic esters) 17 and 19. The lat-
sulfate) giving the diethylene glycol derivative 3 in mod-
ter were used as ligands for 18 and 20. Finally, asymmetric
erate yield. Compound 3 was the starting material for the
hydrogenations of amino acid precursors 21a d were investigated
synthesis of tetraethylene glycol derivative 4 and penta-
in the presence of the rhodium chelates 18 and 20. Under hydrogen,
ethylene glycol derivative 5 by alkoxylation with diethyl-
ene glycol and triethylene glycol, respectively, in the
presence of potassium hydroxide. This synthetic step re-
quires exact compliance with the given reaction condi-
tions, because HCl-elimination competes more or less
efficiently depending on the base and the solvent used.
The best yields of 4 (72%) and 5 (32%) were obtained by
adding 3 to a solution of KOH in the corresponding glycol
(excess) at 80 90 °C under vigorous stirring. Finally, an
intramolecular transglucosylation of 4 forming crown
ether 6 was carried out in acetonitrile with Fe(III) chloride
for the activation of the glycoside and KBF4 as template
reagent. Exclusively the -anomer (C-1: = 97.1; doublet
of 1-H: = 4.86, J1,2 = 3.2 Hz) was formed and isolated in
a yield of 38% (Scheme 1). Cyclizations of longer-chain
ethylene glycol derivatives were more effective when tri-
methylsilyl triflate (TMSOTf) was used instead of Fe(III)
chloride. Thus, pentaethylene glycol 5 gave in the pres-
ence of TMSOTf exclusively the -anomeric crown 7 (C-
1: = 97.7; doublet of 1-H: = 4.84, J1,2 = 3.4 Hz) in 30%
yield. Deallylation of the -D-gluco-crowns 6 and 7 was
carried out according to literature17 by heating in aqueous
methanolic solution with palladium-on-charcoal and cata-
lytic amounts of p-toluenesulfonic acid (Scheme 1).
they show as catalysts in different solvents a diminished range of
enantioselectivity in comparison with an analogous complex with-
out such a crown ether ring. This can be explained by a stiffening
effect of the anellated ring on the chelate ring conformation which
is confirmed by the unusually uniform CD-spectra of 20 in solvents
of different polarity.
Key words: crown compounds, chiral auxiliaries, homogeneous ca-
talysis, hydrogenations, ligands, rhodium, carbohydrates
Carbohydrate-based chiral crown ethers find increasing
10
interest in asymmetric organic synthesis.1 Therefore,
these compounds should be useful tools for the separation
of enantiomers, chiral recognition in enzymatic reactions,
and for the control of asymmetric syntheses. However,
only a few of them proved to be effective in enantioselec-
tive reactions.2b,3b,4,5,7c
Rhodium(I) chelates of D-hexopyranoside-2,3-O-bisphos-
phinites are extremely useful in the asymmetric hydroge-
nation of amino acid precursors11 and have even found ap-
plication in the industrial production of L-DOPA.12 Our
aim was to synthesize analogous catalysts containing an
anellated crown ether-like ring in the 1,4-position of the
carbohydrate. Since it is well known that solvent polarity
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbohydrate-based Chiral Crown Ethers
639
Scheme 1 Synthesis of the -glycosidic linked gluco-crown ethers
In order to synthesize -glycosidic linked crown ethers, 11 to the benzyl derivative 12 required a longer reaction
ethylene glycol substituted D-galactose moieties were time (48 h) than the benzylidene acetal opening of the glu-
synthesized as starting materials (Scheme 2) using the cose derivative 1. Furthermore, it is accompanied by a rel-
same synthetic strategy as described in Scheme 1 for atively unfavourable product ratio of 6-O-benzyl
chiral crowns with D-gluco-configuration. Scheme 2 regioisomer 12 to phenyl 2,3-di-O-allyl-4-O-benzyl- -D-
shows the reaction steps starting with phenyl 4,6-O-ben- galactopyranoside (about 1:1). However, this mixture
zylidene- -D-galactopyranoside (10).
could be separated by column chromatography; the pure
6-O-benzyl isomer 12 was isolated in 56% yield. Stepwise
etherification of 12 via 13 (85%) gave the hexaethylene
glycol derivative 15 (73%) in moderate yield (Scheme 2).
The intramolecular transacetalation of 15 to 16 was car-
ried out in the presence of TMSOTf. However, a maxi-
The allylation procedure generating the 2,3-di-O-allyl de-
rivative 11 from phenyl 4,6-O-benzylidene- -D-galacto-
pyranoside (10)11 is similar to those reported in the
literature.18,19 The reductive benzylidene acetal opening of
Reagents and conditions: i) CH2=CHCH2Br/NaH/DMF; ii) NaBH3CN/HCl/THF; iii) O(CH2CH2Cl)2/50% KOH/THF/PTC; iv) KOH/
HOCH2(CH2OCH2)nCH2OH; v) TMSOTf/Cl(CH2)2Cl/KBF4/NaBF4
Scheme 2 Synthesis of the -glycosidic linked galacto-crown ethers
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York

640
F. Faltin et al.
PAPER
mum yield of 26% was achieved only if the reaction 19 in yields of 95%. The NMR spectra of the non-crystal-
conditions given in the experimental part were exactly line product 17 showed impurities. Because bis(phosphin-
kept. At this time the starting material was still not com- ic esters) are very sensitive to oxidation and hydrolysis,
pletely converted. As expected, the -glycosidic bridged chelate 18 was directly generated from this product 17 by
macrocycle 16 (C-1: = 103.8; doublet of 1-H: = 4.23, treatment with Rh(COD)acac/HBF4 (Scheme 3). Upon re-
J
1,2 = 7.3 Hz) was formed due to the orientation of the gly- action with Rh(COD)acac/HBF4 the 20-membered ligand
col chain at the 4-position which allows only a -attack. 19 isolated as a pure solid gave the chelate 20 in much bet-
In contrast to the long-chain ethylidene glycol galactoside ter quality.
15, cyclisation of phenyl 2,3-di-O-allyl-6-O-benzyl-4-O-
2- -hydroxytri(oxyethylene)ethyl }- -D-galactopyran-
The chelates 18 and 20 were used as precatalysts for the
hydrogenation of the 2-N-acyl-2-dehydroamino acid de-
oside (14) was not successful. The shorter ethylene glycol
rivatives 21a d (Scheme 4). The microanalysis of com-
chain is not long enough to close a ring free of tension.
pound 18 deviated from the theoretical values. 31P NMR
analysis and mass spectrum confirmed that the desired tar-
get chelate is the major component contaminated by a
complex of one monophosphinite of 8. Because purifica-
tion of such chelates by recrystallization were not success-
ful, this crude product was used for preliminary
hydrogenation experiments (Table 1). The complex was
highly active and the selectivity outcome comparable with
the results of the hydrogenations using the pure chelate 20
(Table 2). This indicates, that the desired complex 18
should be the main catalytic active component in the mix-
ture and that the influence of the impurities seems to be
negligible.
Scheme 4 Hydrogenation of the 2-N-acyl-2-dehydroamino acid de-
rivatives 21a d
The aim of these hydrogenation experiments was to exam-
ine whether catalysts modified by an anellated crown
ether ring change their enantioselectivity under the influ-
ence of alkali ions. Earlier, we found that the enantiose-
Scheme 3 Synthesis of the chelates 18 and 20 (precatalysts for hy-
lectivity of rhodium(I) chelates – particularly of the
drogenations)
methyl 4,6-O-benzylidene-2,3-O-bis(diphenylphosphi-
no)- -D-glucopyranoside (Me- -glup) – in asymmetric
The -D-gluco-crown ethers 8 and 9 gave in reaction with hydrogenations of 2-N-acyldehydroamino acid esters
chloro-diphenylphosphine the non-crystalline bis(phos- showed a considerable solvent dependence, which in the
phinic ester) 17 and the crystalline bis(phosphinic ester) extreme case of benzene as solvent even led to a change
Table 1 Hydrogenation of 2-N-Acyl-2-dehydroamino Acid Derivatives Using Precatalyst 18a
S u b s t r a t e
R
R ’
MeOH
% ee (S)-22
C6H6
% ee (S)-22
H2O
% ee (S)-22
t/2 min
t/2 min
t/2 min
21a
21b
21c
21d
H
Me
H
H
H
Ph
Ph
1
1
5
5
59
400
1
41
3
48
455
73
14
34 (22)
75 (73)
55 (72)
57 (72)
41 (4 R)
58 (70 S)
43 (6 R)
Me
a Reference values published for [Rh(Me- -glup)(COD)]BF4 (23)11,31 are given in parenthesis. Conditions for hydrogenation: 1 mmol substrate,
0.01 mmol precatalyst 18, 15 mL solvent, 25°C, 0.1 MPa.
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbohydrate-based Chiral Crown Ethers
641
of the preferred product enantiomer.11,20 We attribute this only in benzene with the substrate acids 21a and 21c (71
large range of enantioselectivity to the changes in the con- and 80% ee).
formation of the seven-membered chelates, which may re-
sult in a nearly enantiomorphic arrangement of the P-aryl
The hydrogenations in water were completed by measure-
ments in the presence of Triton X100 as a solubility pro-
groups in the intermediate catalyst-substrate complexes.
moter. The well known promoting effect of such
According to a hypothesis of Knowles,21 modified by See-
26
amphiphiles on the activity and enantioselectivity11,24
bach,22 the spatial orientation of such P-aryl groups deter-
also occurred with the catalyst released from 20
(44 69% ee, Table 3). Again we could not find a distinct
mines the enantioselectivity and we succeeded in
calculating for some catalysts the energy barriers for the
effect of alkali ions on the selectivity. Only in benzene as
preferred conformations.23 Some of them which show ap-
the solvent the hydrogenation of acetamidocinnamic acid
(21c) was influenced by lithium tetrafluoroborate
(80 64% ee). We assume that this effect is not caused by
proximately enantiomorphic aryl orientation are found by
NMR in solution or estimated by X-ray structure analysis.
It is well known that crown ethers suffer considerable
the formation of a lithium cryptate, deviating the confor-
conformational change under the influence of different
mation of the catalyst, but mainly by generation of ion
solvents13 or by complexation of alkali ions. Consequent-
pairs between lithium and the substrate acid which there-
ly, it seemed reasonable to look for similar effects on cat-
by changes the type of substrate coordination to the cata-
alysts with ligands analogous to Me- -glup carrying an
lyst. This could explain the absence of this effect both in
anellated crown ether ring and to expect an influence on
polar solvents and with the substrate ester 21d in benzene.
Such ion pair formation in benzene should be prevented
the enantioselectivities as consequence.
The results indicate a reduced solvent influence on the for the other, less soluble alkali salts.
new complex 18 compared to the parent complex
From these results we conclude that for the catalysts gen-
[Rh(Me- -glup)(COD)]BF4 (23) (Table 1). Particularly,
erated from 18 as well as from 20 the conformation of the
the absence of the selectivity inversion for the esters 21b
seven-membered chelate ring is stiffened by the crown
ether-like anellation. The enantioselectivity remains rela-
tively constant under varying conditions in contrast to the
and 21d going from methanol to benzene as solvent shall
be mentioned here. Furthermore, we noted that the addi-
tion of alkali ions has no influence on the enantioselectiv-
behaviour of the original parent precatalyst [Rh(Me- -
ity. For the hydrogenation of ester 21b in the presence of
glup)(COD)]BF4 (23).27 A conformational change result-
0.1 mmol Li-, Na-, K-, Rb- or Cs-tetrafluoroborate the de-
ing in a more or less enantiomorphic orientation of the P-
aryl groups seems to be not noticable for the precatalyst
20 because its CD-spectra are similar in methanol and
benzene (Figure). The reverse is the case for the precata-
lyst 23 which in benzene hydrogenates the substrate esters
as 21b and 21d under increase of the unexpected (R)-
enantiomer part and which CD-spectra in both solvents
viation from the control remained below % ee = 3 in all
three solvents. The same is valid for the hydrogenation of
acid 21a in methanol. These results indicate that anella-
tion with the crown ether ring may cause a restriction of
the conformational lability of the seven-membered che-
late ring, thus limiting the range of enantioselectivity.
The distinctly higher enantioselectivity for the ester 21b show nearly enantiomorphic shape of its curves (Figure).
compared to the corresponding acid 21a and the ester 21d
is surprising. The low solubility of the substrate 21a in
benzene and water causes the time for half hydrogenation
(t/2) in these solvents to be very large.
CD spectra can only hint at tendencies for conformational
change in different solvents. It is important to state that it
is not possible to predict the direction of enantioselectivity
from the CD spectra of precatalysts because this depends
Precatalyst 20, with one additional oxyethylene unit, from the preequilibria between diastereomeric (Re)- and
shows nearly the same gradation in dependence of the ap- (Si)-catalyst-substrate complexes as well as their different
plied substrates and solvents and in most cases somewhat hydrogenation kinetics,28 30 and is strongly influenced by
lower enantioselectivities than precatalyst 18 (Table 2). the nature of the substrate.
Significantly higher enantiomeric excesses were found
Table 2 Hydrogenation of 2-N-Acyl-2-dehydroamino Acid Derivatives Using Precatalyst 20 (For Conditions of Hydrogenation, see Table 1)
Substrate
R
R’
MeOH
C6H6
H2O
H2O + Triton
(0.1 mmol)a
H2O + Triton
(0.5 mmol)a
t/2
% ee
t/2
% ee
t/2
% ee
t/2
% ee
t/2
% ee
min
(S)-22
min
(S)-22
min
(S)-22
min
(S)-22
min
(S)-22
21a
21b
21c
21d
H
Me
H
H
H
Ph
Ph
1
1
3
3
56
71
52
53
485
1
31
2
71
36
80
41
6
4
42
69
3
3
42
70
20
44
Me
a Triton X100, amphiphile as solubility promoter.
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York

642
F. Faltin et al.
PAPER
Table 3 Hydrogenation with Precatalyst 20 in the Presence of Alkali Salts (For Conditions of Hydrogenation, see Table 1)
Alkali Salt (MBF4)
M
21b
H2O
21b
21d
21c
C6H6
H2O + Triton (0.1 mmol) C6H6
t/2
% ee
t/2
% ee
t/2
% ee
t/2
% ee
min
(S)-22b
min
(S)-22b
min
(S)-22d
min
(S)-22c
20
31
33
32
37
37
44
43
40
42
42
41
4
7
6
6
9
8
69
68
68
68
68
68
2
2
1
1
2
2
41
45
41
41
41
41
31
30
18
27
20
28
80
64
83
82
82
83
Li
Na
K
Rb
Cs
a In the presence of 0.1 mmol MBF4 in 15 mL of the reaction mixture.
Column chromatography: Silica gel 60 (63 200 m, Merck); TLC:
Silica gel foils 60 F254 (Merck). NMR spectra: Bruker AC 250 and
glucopyranoside was purified by column chromatography; Rf 0.46
(toluene/EtOAc, 5:1 v/v) (Table 4).
1
ARX 400 equipment, H NMR and 13C{1H} NMR referenced to
Anal. calcd for C26H32O6 (440.5): C, 70.89; H, 7.32. Found: C,
70.86; H, 7.53.
TMS, IR spectra: Nicolet FTIR Protegé 460 (pellets, KBr). Melting
points: Polarizing microscope Leitz (Laborlux 12 Pol) equipped
with a hot stage (Mettler FP 90). The hydrogenations and gaschro-
matography of the products were conducted as described in refer-
ence 11. Acidic hydrogenation products were esterified before GC
analysis. Chemicals: Pd/charcoal (Fluka), chlorodiphenylphosphine
(Fluka), [Rh(COD)(acac)].31 CD spectra: Jasco J710. Measure-
ments were performed in anhydrous and degassed solvents at a con-
centration of 2 10-4 molL 1 and a cell length of 1 cm. The solutions
were handled under argon and the cuvettes were equipped so as to
exclude air and moisture during filling and measurement.
Phenyl 2,3-Di-O-allyl-4-[2-(2-chloroethoxy)ethyl]-6-O-benzyl-
-D-glucopyranoside (3)
A vigorously stirred solution of 2 (8.38 g, 19.5 mmol) in THF (24
ml) was added dropwise to a mixture of 50% aq KOH (40 mL),
bis(2-chloroethyl)ether (40 mL, 0.34 mol) and catalytic amounts of
tetrabutylammonium hydrogen sulfate. The mixture was stirred for
4 5 h at 50 °C (TLC control) and then allowed to stand overnight
at r.t. After neutralization with 50% aq AcOH and addition of H2O
(50 mL), the product was extracted with CHCl3 (3 × 100 mL). The
combined organic layers were dried (Na2SO4) and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography (Table 4).
1H NMR (400 MHz, CDCl3): = 7.54 7.24 (m, 10 H, 2 C6H5),
6.26 6.13 (m, 2 H, 2 CH2CH=CH2), 5.55 5.38 (m, 4 H, 2
CH2CH=CH2), 5.1 (d, 1 H, J1,2 = 7.6 Hz, 1-H), 4.84, 4.77 (2 d, 2 H,
J = 12.1 Hz, PhCH2), 4.7 4.49 (m, 4 H, 2 CH2CH=CH2), 4.19 (ddd,
1 H, J4,5 = 10.5, J5,6 = 5.3, J5,6‘ = 3.7 Hz, 5-H), 4.07 3.63 (m, 13 H,
2-H, 3-H, 4-H, 6-H, 6’-H, 4 CH2).
Phenyl 2,3-Di-O-allyl-6-O-benzyl- -D-glucopyranoside (2)
To a stirred solution of 119 (5.0 g, 13.8 mmol) in anhyd THF (85
mL) were added NaBH3CN (4.40 g, 70.0 mmol), solid Methylor-
ange (100 mg) and activated molecular sieve 3Å (2.0 g). After cool-
ing the mixture to 0 °C, Et2O (freshly saturated with HCl) was
added dropwise taking care that the temperature did not exceed
10 °C. HCl addition was stopped when the solution took on a pink
colour, and the mixture was stirred at r.t. for 16 h (TLC control) and
was followed by addition of H2O (150 mL) and repeated extractions
with Et2O (total 150 mL). Subsequently, the combined organic lay-
ers were neutralized with sat. aq NaHCO3 solution (20 mL), washed
with H2O (20 mL), dried (Na2SO4), and concentrated in vacuo. The
residue, a mixture of 2 and phenyl 2,3-di-O-allyl-4-O-benzyl- -D-
13C NMR (100 MHz, CDCl3): = 135.7, 135.4 (2 CH2CH=CH2),
138.7 117.5 (2 C6H5), 117.4, 117.2 (2 CH2CH=CH2), 102.0 (C-1),
84.4 (C-2), 81.9, 78.6, 75.5, 74.9 (C-3, C-4, C-5), 74.9, 74.2, 73.8,
72.5, 71.6, 71.2, 69.2 (C-6, 6 CH2), 43.1 (CH2Cl).
Figure CD-spectra of the precatalysts 20 and 23 in methanol or benzene (c = 2 10 4 molL 1).
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbohydrate-based Chiral Crown Ethers
643
Table 4 Data of the gluco-Precursors 2–5, galacto-Precursors 11–15, gluco-Crowns 6–9, galacto-crown 16, gluco-Precatalysts 18, 20
Prod- Pre-
Yield
(%)
Mp (°C)
(solvent)
Formula (molar mass)
[ ]2D4 CHCl3 (c)
Rf (eluents v/v)
uct
cursor
a
2
1
2
3
3
4
5
75
84
72
32
38
37
colorless syrup
colorless syrup
colorless syrup
brownish syrup
colorless syrup
colorless syrup
C26H32O6 (440.5)
C29H37ClO7 (533.1)
C33H46O10 (602.7)
C35H50O11 (646.8)
C27H40O9 (508.6)
C29H44O10 (552.7)
0.46 (toluene/ EtOAc, 5:1)
0.28 (toluene/ EtOAc, 5:1)
0.30 (CH2Cl2/MeOH, 50:1)
0.48 (EtOAc/acetone, 5:1)
0.40 (hexane/EtOAc, 1:2)
3
–15.0 (1.45)
a
4
5
21.4 (1.3)
a
6
7
+63.8.0 (1.5)
0.27 (toluene/EtOAc/MeOH,
7.5:1:0.5)
a
8
9
6
7
72
64
65
56
85
73
73
26
90
99
colorless syrup
colorless syrup
175 (EtOH)
114 115
C21H32O9 (428.5)
0.24 (CHCl3/MeOH, 10:1)
0.34 (CHCl3/MeOH, 10:1)
C23H36O10•H2O (490.6)
C25H28O6 (424.4)
+68.3 (1.36)
13.4 (1.04)
14.7 (1.02)
18.2 (1.00)
13.4 (1.03)
16.6 (0.99)
11.9 (0.37)
11
12
13
14
15
16
18
20
10
11
12
13
13
15
8
C25H30O6 (426.4)
0.14 (toluene/ EtOAc, 15:1)
0.29 (heptane/EtOAc, 3.5:1)
0.23 (EtOAc)
55 57
C29H37O7 (533.0)
colorless syrup
colorless syrup
colorless syrup
crystalline b)
crystalline b)
C33H46O10 (602.5)
C37H54O12 (690.8)
0.40 (EtOAc/acetone, 5:1)
0.14 (EtOAc)
C31H48O11 (596.7)
C53H62BF4O9P2Rh (1094.7)c
C55H66BF4O10P2Rh (1138.8)d
19
a [ ]D was not determined.
b Mp was not determined because of the high sensitiveness of the compound.
c MS-FAB pos., matrix NBA [M BF4]+ 1007; [M BF4 COD]+ 899; impurity 823; 715.
d MS-FAB pos., matrix NBA [M BF4]+ 1051; [M BF4 COD]+ 943.
Anal. Calcd for C29H37ClO7 (533.1): C, 65.34; H, 7.00; Cl, 6.65.
Found: C, 65.10; H, 7.24; Cl, 7.00.
Phenyl 2,3-Di-O-allyl-6-O-benzyl-4-O-{2[ -hydroxytetra(oxy-
ethylene)ethyl]}- -D-glucopyranoside (5)
The 2-chloroethoxyethyl derivative 3 (9.62 g, 18 mmol) was treated
with a solution of KOH (28.0 g, 0.5 mol) in triethylene glycol (96
mL) and the mixture was worked up (Rf 0,48, EtOAc/acetone, 5:1
v/v) as described for compound 4. The pure product 5 was isolated
as brownish syrup (Table 4).
Phenyl 2,3-Di-O-allyl-6-O-benzyl-4-O-{2[ -hydroxytri(oxyeth-
ylene)ethyl]}- -D-glucopyranoside (4)
Powdered KOH (6.0 g, 106.9 mmol) was dissolved in diethylene
glycol (20 mL) under stirring and moderate heating. The solution
was poured onto 3 (2.8 g, 5.2 mmol) under vigorous stirring and
heated for about 5 h at 80 90 °C. After complete conversion (TLC
control), the mixture was diluted with H2O (30 mL), neutralized
with dil aq HCl, and extracted with CH2Cl2 (3 × 50 mL). The com-
bined organic phases were dried (Na2SO4), concentrated under re-
duced pressure and compound 4 was separated from the residue by
column chromatography (Table 4).
1H NMR (400 MHz, CDCl3): = 7.55 7.24 (m, 10 H, 2 C6H5),
6.27 6.13 (m, 2 H, 2 CH2CH=CH2), 5.55-5.38 (m, 4 H, 2
CH2CH=CH2), 5.11 (d, 1 H, J1,2 = 7.6 Hz, 1-H), 4.84, 4.77 (2 d, 2 H,
J = 11.9 Hz, PhCH2), 4.7 4.49 (m, 4 H, 2 CH2CH=CH2), 4.19 (ddd,
1 H, J4,5 = 10.8, J5,6 = 5.4, J5,6‘ = 3.9 Hz, 5-H), 4.07 3.62 (m, 21 H,
2-H, 3-H, 4-H, 6-H, 6’-H, 8 CH2).
1
IR (KBr): = 886 cm
( C-Haxial).
1H NMR (400 MHz, CDCl3): = 7.33 7.23 (m, 5 H, C6H5), 5.99
5.83 (m, 2 H, 2 CH2CH=CH2), 5.28 5.09 (m, 4 H, 2 CH2CH=CH2),
4.74 (d, 1 H, J1,2 = 3.4 Hz, 1-H), 4.61, 4.51 (2 d, 2 H, J = 12.1 Hz,
PhCH2), 4.35 4.08 (m, 4 H, 2 CH2CH=CH2), 3.9 (ddd, 1 H, J4,5
=
10.6, J5,6 = 3.8, J5,6‘ = 5.5 Hz, 5-H), 3.74 3.34 (m, 25 H, 2-H, 3-H,
4-H, 6-H, 6’-H, 10 CH2), 3.36 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): = 135.9, 135.3 (2 CH2CH=CH2),
128.7, 128.2, 128.0 (C6H5), 117.6, 116.5 (2 CH2CH=CH2), 98.2 (C-
1), 81.2 (C-2), 79.4, 78.2 (C-3, C-4), 77.8-70.8 (12 CH2), 70.7 (C-
5), 70.4 (C-6), 62.1 (CH2OH), 55.4 (OCH3).
Anal. Calcd for C35H50O11 (646.8): C, 65.00; H, 7.79. Found: C,
65.46; H, 7.96.
13C NMR (100 MHz, CDCl3): = 138.7 117.4 (2 C6H5), 135.7,
135.4 (2 CH2CH=CH2), 117.3, 117.2 (2 CH2CH=CH2), 101.9 (C-
1), 84.4 (C-2), 81.8, 78.7, 75.4 (C-3, C-4, C-5), 74.9, 74.1, 73.8,
72.9, 72.5, 71.2, 71.1, 71.0, 70.9, 70.7, 69.3, 62.1 (C-6, 11 CH2).
2,3-Di-O-allyl-6-O-benzyl-1,4-O-(3,6,9-trioxaundecan-1,11-
diyl)- -D-glucopyranose (6)
To a stirred solution of 4 (3.33 g, 5.5 mmol), KBF4 (1.33 g, 10.6
mmol) in anhyd MeCN (130 mL) was added FeCl3 (1.05 g, 6.47
mmol) at r.t. After stirring for 6 8 h the conversion was complete
Anal. Calcd for C33H46O10 (602.7): C, 65.76; H, 7.69. Found: C,
65.30; H, 7.80.
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York

644
F. Faltin et al.
PAPER
(TLC control). H2O (50 mL) was added, the mixture was extracted
with CHCl3 (3 × 50 mL), and the dried organic phases (Na2SO4)
were concentrated under reduced pressure giving a syrupy residue.
Pure crown ether 6 was isolated by column chromatography (Table
4).
1H NMR (400 MHz, CDCl3): = 7.38 7.23 (m, 5 H, C6H5), 6.03
5.86 (m, 2 H, 2 CH2CH=CH2), 5.31 5.11 (m, 4 H, 2 CH2CH=CH2),
4.86 (d, 1 H, J1,2 = 3.2 Hz, 1-H), 4.66, 4.52 (2 d, 2 H, J = 12.1 Hz,
PhCH2), 4.38 3.44 (m, 25 H, 3-H, 4-H, 5-H, 6-H, 6’-H, 10 CH2),
3.4 (dd, 1 H, J2,3 = 9.6 Hz, 2-H).
13C NMR (100 MHz, CDCl3): = 138.7 127.8 (C6H5), 136.2,
135.5 (2 CH2CH=CH2), 118.0, 116.5 (2 CH2CH=CH2), 97.1 (C-1),
81.0 (C-2), 79.6, 77.6 (C-3, C-4), 74.6, 73.5, 73.1, 72.2, 71.2, 71.1,
71.0, 71.0, 70.9, 69.9, 69.3, 66.8 (C-6, 11 CH2), 69.7 (C-5).
6-O-Benzyl-1,4-O-(3,6,9,12-tetraoxatetradecan-1,14-diyl)- -D-
glucopyranose (9)
A vigorously stirred suspension of 7 (1.77 g, 3.2 mmol), p-toluene-
sulfonic acid (0.81 g) and Pd/C (0.80 g) in MeOH/H2O (160 mL, 5:1
v/v) was refluxed for 2 3 h (argon atmosphere, TLC control) and
then allowed to cool on r.t. After the addition of aq satd NaHCO3
solution (2–3 mL), the mixture was filtered (kieselguhr) and the fil-
trate was concentrated under reduced pressure. The residue was pu-
rified by column chromatography (Table 4).
Anal. Calcd for C23H36O10•H2O (490.6): C, 56.32; H, 7.81. Found:
C, 56.38; H, 7.79.
Phenyl 2,3-Di-O-allyl-4,6-O-benzylidene- -D-galactopyrano-
side (11)
To a stirred solution of 1011 (5.0 g, 14.5 mmol) in anhyd DMF (57
mL) was added NaH (4.05 g, 102 mmol) in portions under cooling.
Then, allyl bromide (3.7 mL, 43.5 mmol) was added dropwise to the
solution at 0 °C while stirring, the mixture was allowed to warm up
to r.t. and to react for about 20 h (TLC control). Subsequently, the
excess of NaH was carefully decomposed (stirring, cooling) with
MeOH/H2O (40 mL, 1:1 v/v), the mixture diluted with H2O (100
mL) and the product 11 was extracted with CHCl3 (2 × 50 mL). The
combined organic phases were washed with aq NaHCO3 solution
(2 × 70 mL) and H2O (2 × 70 mL), dried (Na2SO4) and concentrated
under reduced pressure. The crystalline product 11 was recrystal-
lized from EtOH (Table 4).
Anal. Calcd for C27H40O9 (508.6): C, 63.76; H, 7.93. Found: C,
63.93; H, 7.84.
2,3-Di-O-allyl-6-O-benzyl-1,4-O-(3,6,9,12-tetraoxatetradecan-
1,14-diyl)- -D-glucopyranose (7)
To a stirred solution of 5 (0.74 g, 1.45 mmol), KBF4 (0.37 g, 2.94
mmol) in anhyd MeCN (40 mL) was added TMSOTf (0.39 ml, 2.2
mmol) under cooling (argon atmosphere). Stirring was continued at
r.t. up to the conversion was complete (TLC control). Satd aq
NaHCO3 solution (20 mL) was added and the mixture was extracted
with Et2O (3 × 40 mL). The dried organic phases (Na2SO4) were
concentrated under reduced pressure to give a syrupy residue. Pure
crown ether 7 was isolated as colourless syrup by column chroma-
tography (Table 4).
1H NMR (250 MHz,CDCl3): = 7.57 6.97 (m, 10 H, C6H5), 6.03
5.86 (m, 2 H, 2 CH2CH=CH2), 5.55 (s, 1 H, acetal-H), 5.37 5.08
(m, 4 H, 2 CH2CH=CH2), 4.94 (d, 1 H, J1,2 = 7.8 Hz, 1-H), 4.47
4.20 (m, 6 H, 2 CH2CH=CH2, 4-H, 6’-H), 4.07 (dd, 1 H, J6,5 = 1.8,
1
IR (KBr): = 849 cm
(
Hequatorial).
C
1H NMR (400 MHz, CDCl3): = 7.37 7.23 (m, 5 H, C6H5), 6.02
5.84 (m, 2 H, 2 CH2CH=CH2), 5.3 5.1 (m, 4 H, 2 CH2CH=CH2),
4.84 (d, 1 H, J1,2 = 3.4 Hz, 1-H), 4.67, 4.53 (2 d, 2 H, J = 12.1 Hz,
PhCH2), 4.37 3.37 (m, 30 H, 2-H, 3-H, 4-H, 5-H, 6-H, 6’-H, 12
CH2).
13C NMR (100 MHz, CDCl3): = 136.0, 135.4 (2 CH2CH=CH2),
128.6, 128.3, 127.8 (C6H5), 118.0, 116.7 (2 CH2CH=CH2), 97.7 (C-
1), 82.0 (C-2), 79.7, 78.2 (C-3, C-4), 74.6-68.8 (13 CH2), 70.2 (C-
5), 67.9 (C-6).
J
6,6‘ = 12.4 Hz, 6-H), 3.93 (dd, 1 H, J2,3 = 9.6 Hz, 2-H), 3.54 (dd, 1
H, J3,4 = 3.5 Hz, 3-H), 3.48 (m, 1 H, 5-H).
13C NMR (62 MHz, CDCl3): = 157.6, 137.7, 129.3, 128.9, 128.1,
126.5, 122.6, 117.3 (C6H5), 135.1, 135.0 (2 CH2CH=CH2), 117.4,
116.7 (2 CH2CH=CH2), 102.0, 101.7 (acetal-C, C-1), 78.7, 77.6,
74.1 (C-2, C-3, C-4), 74.0, 71.6, 69.1 (2 CH2CH=CH2, C-6), 66.5
(C-5).
Anal. Calcd for C25H28O6 (424.4): C, 70.72; H, 6.65. Found: C,
70.75; H, 6.62.
MS (70 eV): m/z = 511 (M All).
Phenyl 2,3-Di-O-allyl-6-O-benzyl- -D-galactopyranoside (12)
A solution of benzylidene acetal 11 (1.0 g, 2.34 mmol) in anhyd
THF (18 mL) was treated with NaBH3CN (0.884 g, 14.1 mmol) and
solid methylorange as described for compound 2. However, the re-
action was only complete after 3 4 d (TLC control). The reaction
mixture was worked up as described for 2 and the product purified
by column chromatography; colourless crystals (Table 4).
1H NMR (250 MHz, CDCl3): = 7.38 6.99 (m, 10 H, C6H5), 6.05
5.87 (m, 2 H, 2 CH2CH=CH2), 5.38 5.13 (m, 4 H, 2 CH2CH=CH2),
4.90 (d, 1 H, J1,2 = 7.9 Hz, 1-H), 4.61, 4.55 (2 d, 2 H, J = 13.1 Hz,
Anal. Calcd for C29H44O10 (552.7): C, 63.03; H, 8.02. Found: C,
62.82; H, 8.11.
6-O-Benzyl-1,4-O-(3,6,9-trioxaundecan-1,11-diyl)- -D-glucopy-
ranose (8)
A vigorously stirred suspension of 6 (1.19 g, 2.3 mmol), p-toluene-
sulfonic acid (0.3 g) and Pd/C (0.59 g) in MeOH/H2O (160 mL, 5:1
v/v) was refluxed for 2 3 h (argon atmosphere, TLC control) and
then allowed to cool to r.t. After addition of Et3N (1 mL), the mix-
ture was filtered (kieselguhr) and the filtrate was concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (Table 4).
1H NMR (400 MHz, CDCl3): = 7.37 7.24 (m, 5 H, C6H5), 4.93 (d,
1 H, J1,2 = 3.2 Hz, 1-H), 4.66, 4.53 (2 d, 2 H, J = 12.2 Hz, PhCH2),
4.17 3.45 (m, 22 H, 2-H, 3-H, 4-H, 5-H, 6-H, 6’-H, 8 CH2).
13C NMR (100 MHz, CDCl3): = 138.8, 128,6, 128.2, 127.9
(C6H5), 98.8 (C-1), 78.3 (C-2), 74.0, 73.3 (C-3, C-4), 70.7 (C-5),
73.6, 72.0, 71.5, 71.1, 71.0, 70.8, 70.8, 69.6, 69.4, 67.4 (C-6, 9
CH2).
PhCH2), 4.49 4.20 (m, 4 H, 2 CH2CH=CH2), 4.06 (dd, 1 H, J4,5
=
0.6, J3,4 = 3.4 Hz, 4-H), 3.88 3.68 (m, 4 H, 2-H, 5-H, 6-H, 6`-H),
3.46 (dd, 1 H, J2,3 = 9.4 Hz, 3-H), 2.35 (br, 1 H, OH).
13C NMR (62 MHz, CDCl3): = 157.4, 137.9, 129.3, 128.4, 127.7,
122.5 (C6H5), 135.0, 134.5 (2 CH2CH=CH2), 117.4, 117.0 (2
CH2CH=CH2), 101.7 (C-1), 80.2 (C-2), 78.1 (C-3), 73.9, 73.7 (2
CH2), 73.6, 66.9 (C-4, C-5), 71.6 (CH2Ph), 69.2 (C-6).
Anal. Calcd for C25H30O6 (426.4): C, 70.40; H, 7.09. Found: C,
70.46; H, 6.97.
Anal. Calcd for C21H32O9 (428.5): C, 58.87; H, 7.53. Found: C,
58.38; H, 7.57.
Phenyl 2,3-Di-O-allyl-6-O-benzyl-4-O- (2-chloroethoxy)ethyl -
-D-galactopyranoside (13)
To a vigorously stirred solution of 12 (426 mg, 1.0 mmol) in THF
(1 mL) was dropwise added a mixture of 50% aq KOH (2 mL),
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbohydrate-based Chiral Crown Ethers
645
bis(2-chloroethyl)ether (2 mL) and tetrabutylammonium hydrogen
sulfate (20 mg) at r.t. The reaction was complete after about 4-5
days (TLC control). After neutralisation with 10% aq AcOH, the
product was extracted with CHCl3 (3 × 10 mL). The combined or-
ganic phases were dried (Na2SO4) and concentrated under reduced
pressure in a rotary evaporator. The residue was purified by column
chromatography (Table 4).32
1H NMR (300 MHz, CDCl3): = 7.4 6.98 (m, 10 H, C6H5), 6.06
5.88 (m, 2 H, 2 CH2CH=CH2), 5.39 5.12 (m, 4 H, 2 CH2CH=CH2),
4.88 (d, 1 H, J1,2 = 7.9 Hz, 1-H), 4.57, 4.53 (2 d, 2 H, J = 11.9 Hz,
CH2Ph), 4.49 4.22 (m, 4 H, 2 CH2CH=CH2), 4.08 (m, 1 H, 5-H),
3.89 3.57 (m, 12 H, 2-H, 4-H, 6-H, 6‘-H, 4 CH2), 3.43 (dd, 1 H, J3,4
= 3.1, J2,3 = 9.7 Hz, 3-H).
Anal. Calcd for C37H54O12 (690.8): C, 64.30; H, 7.88. Found: C,
64.16; H, 7.93.
2,3-Di-O-allyl-6-O-benzyl-1,4-O-(3,6,9,12,15-pentaoxaheptade-
can-1,17-diyl)- -D-galactopyranose (16)
Under argon phenyl galactoside 15 (500 mg, 0.724 mmol) was dis-
solved in anhyd dichloroethane (20 mL) in the presence of molecu-
lar sieve (4 Å). After cooling the mixture to 10 °C, a solution of
TMSOTf (130 L, 0.724 mmol) in anhyd CH2Cl2 (5 mL) was added
while stirring within 15 min. (argon atmosphere). Stirring was con-
tinued at 10 °C for 1 h. Subsequently, the mixture was allowed to
warm up to r.t. within 2 h. Then the reaction was terminated by the
addition of CHCl3 (15 mL), H2O (5 mL) and satd aq NaHCO3 solu-
tion (10 mL) while stirring vigorously (5 min.). The organic phase
was separated, washed with H2O, dried (Na2SO4), filtered and con-
centrated under reduced pressure. After column chromatographic
purification 16 was isolated as a syrupy product (Table 4).
1H NMR (250 MHz, CDCl3): = 7.30 7.25 (m, 5 H, C6H5), 6.02
5.79 (m, 2 H, 2 CH2CH=CH2), 5.30 5.07 (m, 4 H, 2 CH2CH=CH2),
4.57, 4.53 (2 d, 2 H, J = 11.9 Hz, CH2Ph), 4.39 4.09 (m, 4 H, 2
CH2CH=CH2), 4.23 (d, 1 H, J1,2 = 7.3 Hz, 1-H), 4.09 3.44 (m, 29
H, 2-H, 4-H, 5-H, 6-H, 6’-H, 12 CH2), 3.28 (dd, 1 H, J2,3 = 9.7, J3,4
= 3.1 Hz, 3-H).
13C NMR (62 MHz, CDCl3): = 157.5, 138.8, 129.3, 128.4, 127.8,
127.7, 122.4 (C6H5), 135.4, 134.9 (2 CH2CH=CH2), 116.7, 116.6 (2
CH2CH=CH2), 101.9 (C-1), 81.4 (C-3), 78.7, 75.2 (C-2, C-5), 73.8
(C-4), 74.0, 73.6, 72.6, 72.0, 71.2, 70.9, 68.7, (C-6, 6 CH2), 42.9
(CH2Cl).
Anal. Calcd for C29H37O7 (533.0): C, 65.34; H, 7.00. Found: C,
65.37; H, 6.99.
Phenyl 2,3-Di-O-allyl-6-O-benzyl-4-O- 2- -hydroxytri(oxyeth-
ylene)ethyl }- -D-galactopyranoside (14)
13C NMR (62 MHz, CDCl3): = 138.1, 128.4, 127.9, 127.7 (C6H5),
135.5, 135.1 (2 CH2CH=CH2), 116.4, 116.2 (2 CH2CH=CH2),
103.8 (C-1), 81.5 (C-3), 79.1, 74.8, 72.9 (C-2, C-4, C-5), 74.2, 73.9,
73.8, 72.1, 71.5, 71.4, 71.2, 71.2, 71.2, 71.1, 71.1, 71.0, 70.9, 70.8,
(14 CH2), 69.4, 68.3 (CH2, C-6).
A solution of KOH (112 mg, 2.0 mmol) in diethylene glycol (6 mL)
was poured into 13 (533 mg, 1.0 mmol) under vigorous stirring and
the mixture was heated for about 5 h at 70 °C (TLC control). After
cooling to r.t., the mixture was diluted with H2O (10 mL), neutra-
lised with 10% aq HCl, and extracted with CH2Cl2 (2 × 10 mL). The
combined organic phases were dried (Na2SO4), concentrated under
reduced pressure and compound 14 was separated from the residue
by column chromatography (Table 4).
Anal. Calcd for C31H48O11 (596.7): C, 62.38; H, 8.11. Found: C,
62.62; H, 8.11.
1H NMR (250 MHz, CDCl3): = 7.38 6.98 (m, 10 H, C6H5), 6.06
5.87 (m, 2 H, 2 CH2CH=CH2), 5.39 5.12 (m, 4 H, 2 CH2CH=CH2),
4.88 (d, 1 H, J1,2 = 7.94 Hz, 1-H), 4.57 (dd, 2 H, J = 11.91 Hz,
CH2Ph), 4.49 4.21 (m, 4 H, 2 CH2CH=CH2), 4.08 (m, 1 H, 5-H),
3.91 3.47 (m, 20 H, 2-H, 4-H, 6-H, 6’-H, 8 CH2), 3.43 (dd, 1 H, J2,3
= 9.76, J3,4 = 3.05 Hz, H-3).
13C NMR (62 MHz, CDCl3): = 157.5, 138.1, 129.3, 128.4, 127.8,
127.7, 122.4 (C6H5), 135.4, 134.9 (2 CH2CH=CH2), 116.7, 116.6 (2
CH2CH=CH2), 101.8 (C-1), 81.4 (C-3), 78.7, 75.2 (C-2, C-5), 73.9
(C-4), 73.9, 73.6, 72.5, 71.9, 70.8, 70.6, 70.5, 70.3 (10 CH2), 68.8
(C-6), 61.7 (CH2OH).
6-O-Benzyl-2,3-O-bis(diphenylphosphino)-1,4-O-(3,6,9-triox-
aundecan-1,11-diyl)- -D-glucopyranoside]Rh(COD)}BF4 (18)
To a stirred solution of 8 (0.91 g, 2.1 mmol) and pyridine (0.51 mL,
6.3 mmol) in THF (10 mL) was added dropwise chlorodiphe-
nylphosphine (0.96 g, 4.3 mmol) at 0 °C and the mixture was al-
lowed to warm up to r.t. (inert gas atmosphere). After filtration
(removal of pyridine hydrochloride), the filtrate was concentrated in
vacuum and the residue dissolved in Et2O (5 mL). The Et2O solution
was diluted with pentane (4 mL), then filtered, and concentrated.
The 6-O-benzyl-2,3-O-bis(diphenylphosphino)-1,4-O-(3,6,9-triox-
aundecan-1,11-diyl)- -D-glucopyranoside (17) obtained did not
crystallize. This was used as such in the next step. Under anaerobic
conditions a solution of 17 in THF (5 mL) was added dropwise to a
stirred solution of [Rh(COD)(acac)] (620 g, 3.0 mmol) in THF (3
mL). Subsequently, 40% aq tetrafluoroboric acid (0.25 mL) was
added to the homogenous solution and complex 18 was precipitated
with Et2O, isolated by filtration, and dried in vacuum (Table 4).
Anal. Calcd for C33H46O10 (602.5): C, 65.76; H, 7.69. Found: C,
65.58; H, 7.73.
Phenyl 2,3-Di-O-allyl-6-O-benzyl-4-O- 2- -hydroxypenta(oxy-
ethylene)ethyl }- -D-galactopyranoside (15)
31P{1H} NMR (CDCl3): = 134.5 (dd, J = 180, 25 Hz) and 138.3
(dd, J = 182, 25 Hz).
A solution of KOH (112 mg, 2.0 mmol) in tetraethylene glycol (6
mL) was poured onto 13 (533 mg, 1.0 mmol) under vigorous stir-
ring and the mixture was heated for about 5 h at 70 °C (TLC con-
trol). The mixture was worked up as described for compound 14
yielding the syrupy product 15 after column chromatographic puri-
fication (Table 4).
1H NMR (250 MHz, CDCl3): = 7.34 6.94 (m, 10 H, C6H5), 6.02
5.83 (m, 2 H, 2 CH2CH=CH2), 5.35 5.08 (m, 4 H, 2 CH2CH=CH2),
4.85 (d, 1 H, J1,2 = 7.6 Hz, 1-H), 4.57, 4.53 (2 d, 2 H, J = 11.9 Hz,
CH2Ph), 4.45 4.16 (m, 4 H, 2 CH2CH=CH2), 4.04 (m, 1 H, 5-H),
3.86 3.54 (m, 28 H, 2-H, 4-H, 6-H, 6’-H, 12 CH2), 3.39 (dd, 1 H,
Anal. Calcd for C53H62BF4O9P2Rh (1094.7): C, 58.15; H, 5.71; P,
5.66; Rh 9.40. Found: C, 54.22; H, 5.61; P, 4.80; Rh, 8.99.
6-O-Benzyl-2,3-O-bis-diphenylphosphino-1,4-O-(3,6,9,12-tet-
raoxatetradecan-1,14-diyl)- -D -glucopyranoside (19)
To a solution of 9 (1.53 g, 3.24 mmol) and pyridine (0.72 mL, 8.9
mmol) in THF (5 mL) was added dropwise a solution of chlo-
rodiphenylphosphine (1.43 g, 6.48 mmol) in THF (10 mL) at 0 °C
while stirring (inert gas atmosphere) and the mixture was allowed
to warm up to r.t. After filtration (removal of pyridine hydrochlo-
ride), the filtrate was concentrated in vacuum, the residue was treat-
ed with toluene (5 mL), filtered, and concentrated (95 % yield of
crystalline 19).
J2,3 = 9.7, J3,4 = 3.1 Hz, 3-H).
13C NMR (62 MHz, CDCl3): = 157.5, 138.1, 129.3, 128.4, 127.8,
127.7, 122.4, 116.9 (C6H5), 135.4, 134.9 (2 CH2CH=CH2), 116.6,
116.5 (2 CH2CH=CH2), 101.9 (C-1), 81.5 (C-3), 78.7, 75.2 (C-2, C-
5), 73.9 (C-4), 73.9, 73.6, 72.5, 72.4, 71.9, 70.8, 70.6, 70.5, 70.3 (10
CH2), 68.8 (C-6), 61.7 (CH2OH).
31P{1H} NMR (161.9 MHz, C6D6): = 110.9 (s) and 117.4 (s).
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York

646
F. Faltin et al.
PAPER
(c) Kanakamma, P. P.; Mani, N. S.; Maitra, U.; Nair, V. J.
Chem. Soc., Perkin Trans.1 1995, 2339.
(8) Miethchen, R.; Fehring, V. Synthesis 1998, 94.
(9) Sharma, G. V. M.; Reddy, V. G.; Krishna, P. R. Tetrahedron:
Asymmetry 1999, 10, 3777.
(10) (a) Stoddart, J. F. Chem. Soc. Rev. 1979, 8, 85.
(b) Stoddart, J. F. Topics Stereochem. 1987, 17, 207.
(11) Selke, R.; Ohff, M.; Riepe, A. Tetrahedron 1996, 52, 15079.
(12) Vocke, W.; Hänel, R.; Flöther, F.-U. Chem. Tech. (Leipzig)
1987, 39, 123.
1H NMR (400 MHz, C6D6): = 3.04 4.10 (m, 22 H), 4.49 4.56
(m, 2 H), 4.66 (ddd, J = 2.0, 2.9, 10.0 Hz), 4.80 (AB, J = 12.0 Hz),
4.86 (AB, J = 12.0 Hz), 5.15 (dd, J = 1.0, 3.8 Hz), 5.21 (ddd, J = 0.8,
9.2, 18.5 Hz), 7.09 7.85 (m, 25 H).
13C NMR (100 MHz, C6D6): = 67.97, 68.05, 69.66, 70.58, 70.64,
71.18, 71.21, 71.28, 71.32, 71.78, 71.89, 72.09, 73.74, 78.44 (d, J =
1.9 Hz), 80.72 (dd, J = 1.9, 16.2 Hz), 83.94 (d, J = 6.7, 19.1 Hz),
98.34 (d, J = 8.6 Hz), 127 133 (arom), 139.88, 142.49 (d, J = 13.4
Hz), 143.84 (d, J = 12.4 Hz), 144.42 (d, J = 21.9 Hz), 145.05 (d, J
= 22.9 Hz).
(13) Vögtle, F. Supramolekulare Chemie; Teubner Studienbücher
Chemie: Stuttgart, 1992, p 58.
(14) Brown, J. M. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:
Berlin, 1999, pp 121 182.
[6-O-Benzyl-2,3-O-bis(diphenylphosphino)-1,4-O-(3,6,9,12-
tetraoxatetradecan-1,14-diyl)- -D-glucopyrano-
side]Rh(COD)}BF4 (20)
To a stirred solution of [Rh(COD)(acac)] (0.92 g 3.0 mmol) in THF
(1.5 mL) was added dropwise a solution of the ligand 19 (2.52 g, 3.0
mmol) in THF (3 mL) (inert gas atmosphere). Subsequently, 40%
aq tetrafluoroboric acid (0.42 mL) was added, the complex 20 was
precipitated with Et2O, separated, and dried in vacuum (Table 4).
31P{1H} NMR (161.9 MHz, CDCl3): = 137.29 (dd, J = 180.3, 25.0
Hz) and 139.77 (dd, J = 181.7, 25.0 Hz),
1H NMR (400 MHz, CDCl3): = 2.36 2.54 (br m, 4 H), 2.68 2.82
(br m, 4 H), 3.30 (ABMX, JAB = 11.0, J = 8.7, J = 2.0 Hz), 3.39 (AB-
MX, JAB = 11.0, J = 3.6, J = 2.1 Hz), 3.52 (ddd, J = 10.4, 3.5, 2.2
Hz, 1 H), 3.56 3.92 (m, 20 H), 3.98 (t, J = 2.1 Hz, 1 H), 4.09 (dd, J
= 10.9, 2.6 Hz, 1 H), 4.39 (q, J = 9.6 Hz, 1H), 4.55 (br dd, J = 14.4,
7.8 Hz), 4.63 (br dd, J = 15.5, 7.3 Hz), 4.69 (AB, J = 11.9 Hz), 4.70
(d, J = 4.0 Hz, 1 H), 4.80 (AB, J = 11.9), 4.91 (br s, 1 H), 5.07 (br
s, 1 H), 7.49 8.40 (m, 25 H).
13C NMR (100 MHz, CDCl3): = 28.92, 31.65, 31.92, 68.03, 68.77,
69.59, 70.04, 70.22, 70.47, 70.99, 71.10, 71.17, 71.38, 71.50, 72.31,
73.86, 77.15 (d, J = 13.4 Hz), 77.19, 80.78 (d, J = 11.4 Hz), 97.76
(d, J = 3.8 Hz), 101.68, 101.95, 108.39, 109.34, 128.14 138.23
(arom).
(15) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982,
108, 97.
(16) The ratio of the two regioisomers, 6-O-benzyl and 4-O-benzyl
derivative, was about 8 9:1. The compounds showed very
similar retention times (TLC). The pure product 3 was
isolated in 35% yield besides a mixed fraction of both.
(17) Jain, R. K.; Matta, K. L. Carbohydr. Res. 1990, 208, 280.
(18) Brimacombe, J. S.; Jones, B. D.; Stacey, M.; Willard, J. J.
Carbohydr. Res. 1966, 2, 167.
(19) Liptak, A.; Pekar, F.; Janossy, L.; Jodal, I.; Fügedi, P.;
Harangi, J.; Nanasi, P.; Szejtli, J. Acta Chim. Acad. Sci. Hung.
1979, 99, 201.
(20) Berens, U.; Fischer, C.; Selke, R. Tetrahedron: Asymmetry
1995, 6, 1105.
(21) (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106.
(b) Knowles, W. S.; Vineyard, B. D.; Sabacky, M. J.; Stults,
B. R. In Fundam. Res. Homogeneous Catal.,Tsutsui, M. Ed.,
1978, 3, 537.
(c) Koenig, K. E.; Sabacky, M. J.; Bachman, G. L.;
Christopfel, W. C.; Barnstorff, H. D.; Friedman, R. B.;
Knowles, W. S.; Stults, B. R.; Vineyard, B. D.; Weinkauff, D.
J. Ann. N. Y. Acad. Sci. 1980, 333, 16.
Anal. Calcd for C55H66BF4O10P2Rh (1138.8): C, 58.01; H, 5.84; P,
5.44; Rh 9.04. Found: C, 57.07; H, 5.86; P, 5.94; Rh, 8.61.
(22) (a) Seebach, D.; Plattner, D. A.; Beck, A. K.; Wang, J. M.;
Hunzicker, D. Helv. Chim. Acta 1992, 75, 2171.
(b) Seebach, D.; Devaquet, E.; Ernst, A.; Hayakawa, M.;
Kühnle, F. N. M.; Schweizer, W. B.; Weber, B. Helv. Chim.
Acta 1995, 78, 1636.
(23) Kadyrov, R.; Börner, A.; Selke, R. Eur. J. Inorg. Chem. 1999,
705.
(24) Oehme, G.; Paetzold, E.; Selke, R. J. Mol. Catal. 1992, 71, L1.
(25) Grassert, I.; Paetzold, E.; Oehme, G. Tetrahedron 1993, 49,
6605.
(26) Kumar, A.; Oehme, G.; Roque, J. P.; Schwarze, M.; Selke, R.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2197.
(27) Me- -glup = methyl 4,6-O-benzylidene-2,3-O-
bis(diphenylphosphino)- -D-glucopyranoside: Selke, R. J.
Prakt. Chem. 1987, 329, 717.
(28) Halpern, J. Pure Appl. Chem. 1983, 55, 99.
(29) Heller, D.; Buschmann, H. Topics of Catalysis 1998, 5, 159.
(30) Landis, C. R.; Hilfenhaus, P.; Feldgus, S. J. Am. Chem. Soc.
1999, 121, 8741.
(31) Selke, R. J. Organomet. Chem. 1989, 370, 241.
(32) Excess of bis(2-chloroethyl)ether should be removed by
distillation before column chromatographic purification if the
batch is scaled up to > 6 g of the starting material.
References
(1) (a) Stoddart, J. F.; Szarek, W. A.; Jones, J. K. N. Can. J. Chem.
1969, 47, 3213.
(b) Curtis, W. D.; Laidler, D. A.; Stoddart, J. F. J. Chem. Soc.,
Perkin Trans. 1 1977, 1756.
(c) Andrews, D. G.; Ashton, P. R.; Laidler, D. A.; Stoddart, J.
F.; Wolstenholme, J. B. Tetrahedron Lett. 1979, 28, 2629.
(2) (a) Bakó, P.; Fenichel, L.; Töke, L.; Czugler, M. Liebigs Ann.
Chem. 1981, 1163.
(b) Töke, L.; Bakó, P.; Keserü, Gy. M.; Albert, M.; Fenichel,
L. Tetrahedron 1998, 54, 213, and references therein.
(3) (a) Alonso-Lopez, M.; Martin-Lomas, M.; Penades, S.
Tetrahedron Lett. 1986, 27, 3551.
(b) Alonso-Lopez, M.; Jimenez-Barbero, J.; Martin-Lomas,
M.; Penades, S. Tetrahedron 1988, 44, 1535.
(c) Vicent, C.; Martin-Lomas, M.; Penades, S. Tetrahedron
1989, 45, 3605.
(4) van Maarschalkerwaart, D. A. H.; Willard, N. P.; Pandit, U. K.
Tetrahedron 1992, 48, 8825.
(5) Aoki, S.; Sasaki, S.; Koga, K. Heterocycles 1992, 33, 493.
(6) Miethchen, R.; Gabriel, T. Chem. Ber. 1993, 126, 2309.
(7) (a) Mani, N. S.; Kanakamma, P. P. Tetrahedron Lett. 1994,
35, 3629.
Article Identifier:
1437-210X,E;2001,0,04,0638,0649,ftx,en;T03600SS.pdf
(b) Kanakamma, P. P.; Mani, N. S.; Nair, V. Synth. Commun.
1995, 25, 3777.
Synthesis 2001, No. 4, 638–646 ISSN 0039-7881 © Thieme Stuttgart · New York