The first hetero-bifunctionalization of the secondary face of β-cyclodextrin: Selective and efficient conversion of the A-ring of a 2A,2B-disulfonate to 2A,3A- epoxymannoside

Article abstract of DOI:10.1039/b502573g

The A-ring of 2^A,2^B-O,O-di(mesitylenesulfonyl)- β-cyclodextrin was converted to 2^A,3^A-epoxymannoside without affecting the other sulfonylated residue, which affords the first approach to hetero-bifunctionalizati

Full text of DOI:10.1039/b502573g

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The first hetero-bifunctionalization of the secondary face of
b-cyclodextrin: selective and efficient conversion of the A-ring of a
2A,2B-disulfonate to 2A,3A-epoxymannoside
Makoto Fukudome, Yuji Sugimoto, De-Qi Yuan and Kahee Fujita
Received (in Cambridge, UK) 22nd February 2005, Accepted 22nd April 2005
First published as an Advance Article on the web 18th May 2005
DOI: 10.1039/b502573g
to a highly regioselective SN2 reaction with imidazole on C-6B
(42% yield) compared to C-6A (4%).4 However, there has been no
report about hetero-bifunctionalization at the secondary hydroxyl
side.
The A-ring of 2A,2B-O,O-di(mesitylenesulfonyl)-b-cyclodextrin
was converted to 2A,3A-epoxymannoside without affecting the
other sulfonylated residue, which affords the first approach to
hetero-bifunctionalization at the secondary hydroxyl side of
cyclodextrins.
We report here the first hetero-bifunctionalization at the
secondary hydroxyl side of b-CD which includes selective
conversion of the 2A-O-sulfonylglucoside residue of 2A,2B-O,O-
di(mesitylenesulfonyl)-b-CD (1)5 to the 2A,3A-epoxymannoside
residue while leaving the other sulfonylated residue unaffected,
simply by stirring the disulfonate 1 in a buffer solution.
Cyclodextrin (CD) derivatives bearing two different sorts of
functionalities turn out to be interesting in developing artificial
receptors and enzyme-like catalysts.1 The hetero-bifuntional CDs
not only effect a three point recognition of asymmetric species, but
also exercise strong asymmetric induction in catalyzing chemical
transformations such as transamination reactions.2 However these
hetero-bifunctional CDs are very difficult to access. The routine
method includes stepwise substitution of 6A,6B-dideoxy-6A,6B-
diodo-b-CD with different nucleophiles.2 An alternative method
includes the sulfonylation of mono-substituted CDs.3 In either
case, the reaction is rather a random one and subject to
competition from over-substitution. In this situation, we developed
6A,6B-O,O-mesitylenedisulfonyl-capped b-CD which was subjected
Compound 1 (516 mg), which was prepared by the reaction of
b-cyclodextrin with mesitylenesulfonyl chloride in the presence of
NaH in DMF, was added to 30 mL of a phosphate buffer solution
(pH 12.0, 0.1 M) and kept at rt. The reaction progress was
monitored by TLC.{ After 1 h, the starting material 1 disappeared
completely and monoepoxides 2 were predominate in the reaction
products, while diepoxide 5 was only formed in a trace amount.
The solution was neutralized with HCl and evaporated to dryness
in vacuo. The residue was dissolved in 15% aq ethanol (400 mL),
Fig. 1 HMBC NMR spectrum of the sugar part of compound 2a in D2O solution. The inset shows the (H-1X+1)–(C-4X) correlations. Signal assignments
1
1
were made based on H–1H and H–13C COSY spectra.
3168 | Chem. Commun., 2005, 3168–3170
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membrane-filtered (cellulose acetate, 0.2 mm), and chromato-
graphed (Rp-18 Lobar column, size C) to give 2a (323 mg, 72.2%)
and 2b (25 mg, 5.6%). 2a: mp 189 uC (decomp); Rf 5 0.51;
[a]2D5 5 +109 (c 5 0.100 in H2O); 2b: mp 183 uC (decomp);
Rf 5 0.51;{ [a]2D1 5 +107 (c 5 0.100 in H2O).
Both compounds 2a and 2b gave the common pseudo parent
peak [M + Na+] at m/z 1321 in their FAB MS spectra, and
therefore
proved
to
be
the
mono-epoxy-mono-2-
O-mesitylenesulfonyl-b-CDs, indicating that only one of the
O-sulfonyl glucosides was selectively converted to the 2,3-
epoxymannoside.
Fig. 1 shows the HMBC NMR spectrum of 2a and the
assignments were made based on 1H,1H- and 1H,13C-COSY NMR
spectra. The epoxide residue of 2a showed its C-2 at d 50.2 and C-3
at d 55.2 ppm. These very low chemical shifts together with the
singlet pattern of H-1 (d 5.15) indicated that the epoxide residue of
2a is of a manno-type,6,7 whose formation is expected from the
stereochemistry of the intramolecular nucleophilic substitution
reaction of 1. The HMBC spectrum is powerful in determining the
saccharide sequence by affording long range H–C hetero-nuclei
correlations between the O-bridged positions of two adjacent sugar
residues. The NMR signals of all the C-4 carbons and H-1 protons
are far separated from those of other nuclei, and therefore the
(HX+1-1)-(CX-4) cross peaks may provide reliable information
about the (CX+1-1)-O–(CX-4) connections. As shown in Fig. 1, one
singlet at d 5.15 and one doublet at d 5.08 were observed for the
H-1 protons of the 2,3-epoxymannoside and 2A-O-sulfonyl-
glucoside residues, and they are clearly separated from other
anomeric protons. Six peaks of C-4 and four (HX+1-1)–(CX-4)
correlation islands were observed. Although not all of the C-4
signals could be definitely assigned based on the COSY spectra,
the one resonating at d 80.6 can be unambiguously assigned to an
unmodified glucoside residue and this peak makes sense in
determining the sequence of the two modified sugar units because
it is clearly correlated to H-1 of the 2,3-epoxymannoside,
suggesting the epoxymannoside-(1 A 4)-glucoside junction while
ruling out the epoxymannoside-(1 A 4)-mesitylenesulfonylgluco-
side one. However, direct evidence for the sulfonylglucoside-(1 A
4)-epoxymannoside junction was not obtained because H-1 of the
sulfonylglucoside residue did not correlate to any C-4 carbons. In
order to gather additional evidence for the structural assignment,
an enzymatic hydrolysis of 2a was carried out.
Scheme 1 Selective formation of epoxide 2a from 2A,2B-disulfonate 1
and the fragmentation pattern (m/z) observed in the EI-MS spectrum of 4
which demonstrated the pseudo parent peak [M + Na+] at m/z 1359 in its
TOF-MS spectrum.
based on the above NMR spectral analysis. The formation of the
tetraose structure during the enzymatic hydrolysis is consistent
with the degradation pattern of a-amylase clarified in our previous
study on the enzymatic hydrolysis of mono-mannoepoxy-b-CD
and 2-O-sulfonylated b-CDs which gave 20,30-mannoepoxy-
maltotetraose and 20-O-sulfonylated maltotrioses, respectively.8
The present result further builds up the database of this enzyme.
The positional alternative 2b was structurally determined by
transformation to diepoxide 5, which gave the same spectral data
as the authentic compound.7
A mixture of 2a (203 mg) and a-amylase (EC 3.2.1.1 from
Aspergillus oryzae, Sigma) (203 mg) in 0.2 M acetate buffer (pH
5.5, 20 mL) containing 0.01 M CaCl2 was allowed to stand for 2.5
days at 40 uC. After being heated for 10 min in a boiling water-
bath, the mixture was membrane-filtered (cellulose acetate, 0.8 mm),
diluted to 250 mL with water and chromatographed on a reversed-
phase Lobar column (Rp-18, size C) to afford the major product 3
(104 mg, 80%). Rf 5 0.65.{
A kinetics study indicated that, in comparison with 2-
O-mesitylenesulfonyl-b-CD, the A-ring of 1 reacted 2.7 times
Compound 3 gave the pseudo parent peak [M + Na+] at m/z 853
in the MS spectrum, indicating that it was mono-epoxy-mono-
O-mesitylenesulfony-maltotetraose. Compound 3 was reduced
with NaBH4 and subsequently acylated to give 4 which displayed
the parent peak [M + Na+] at m/z 1359 in the TOF-MS spectrum.
The EI-MS spectrum of 4 was measured and analysis of the
fragmentation patterns (Scheme 1) indicated that the sulfonylated
sugar unit is located at the non-reducing end with the epoxy-sugar
unit being next. This result confirms the structure figured out
Scheme 2 Selective conversion of epoxide 2a to olefin 6.
Chem. Commun., 2005, 3168–3170 | 3169
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Fig. 2 1H,13C-COSY NMR spectrum of olefin 6 in D2O solution. CH3CN was used as internal standard.
faster while the B-ring reacted 5.0 times slower in a phosphate
buffer solution (pH 12.0, 0.1 M) at 15 uC. The A,C- and A,D-
regioisomers of 1 did not display meaningful ring-preference, and
the corresponding intermediate epoxy-sulfonates did not accumu-
late as the major products.
in hetero-bifuctionalization at the secondary hydroxyl side of
b-CD.
Makoto Fukudome, Yuji Sugimoto, De-Qi Yuan and Kahee Fujita
Department of Molecular Medicinal Sciences, Graduate School of
Biomedical Sciences, Nagasaki University, Bunkyo-machi 1-14,
Nagasaki 852-8521, Japan. E-mail: fujita@net.nagasaki-u.ac.jp;
Fax: +81 95 8192423; Tel: +81 95 8192423
Compound 2a may serve as a versatile starting material for
further functionalization since epoxide and sulfonate have basically
different reactivities and are both susceptible to diverse chemical
transformations. As one example, compound 2a was converted to
the corresponding olefin species 6 simply by heating an aqueous
solution of 2a in the presence of thiourea (Scheme 2). A solution of
2a (200 mg) and thiourea (587 mg) in 10 mL of water was stirred at
80 uC for 22 h and then poured into 190 mL of acetone. The
formed precipitate was membrane-filtered (cellulose acetate,
0.2 mm), dissolved in 400 mL of water and chromatographed
on a reversed-phase Lobar column (Rp-18, size C) with an elution
of 20% aq ethanol (1000 mL) and then a gradient elution from
20% to 50% aq ethanol (1000 mL each) to give 6 (121 mg, 61.5%).
Compound 6 gave the pseudo parent peak [M + Na+] at m/z 1305
in the TOF MS spectrum. Fig. 2 shows the 1H–13C COSY NMR
spectrum of 6 and assignments were made based on 1H–1H,
1H–13C COSY and HMBC NMR spectra. The mesitylenesulfonyl
group is clearly demonstrated in the spectrum and the sugar unit
bearing this substituent has the same chemical shift patterns as
those of unit B of the precursor 2a (cf. also Fig. 1). However, the
chemical shift patterns (both 1H and 13C) of unit A are remarkably
different from those of the corresponding unit in 2a, with the
H-2A, H-3A, C-2A and C-3A nuclei being all shifted from the
highest field to the lowest field in the sugar region, which is
consistent with the formation of the olefin functionality.{9 The
result indicates that the 2B-sulfonate functionality is stable enough
to sustain until the completion of the conversion of the epoxide
residue to an olefin function. Thus, for the first time, we succeeded
Notes and references
{ TLC was performed on pre-coated silica gel with a mixed solvent of
n-C3H7OH–AcOEt–H2O: 7 : 7 : 5.
{ The chemical shifts of the units A and B of compound 6: d 5.17 (d, J 5
2.6 Hz; H-1A), 5.83 (dt, J 5 10.5, ca. 1.7 Hz; H-2A), 5.70 (d, J 5 10.5 Hz;
H-3A), 4.92 (d, J 5 3.7 Hz; H-1B), 4.38 (dd, J 5 9.9, 3.5 Hz; H-2A), 4.02 (t,
J 5 9.4 Hz; H-3A); d 97.3 (C-1A), 127.4 (C-2A), 131.1 (C-3A), 98.8 (C-1B),
79.3 (C-2B), and 71.0 (C-3B).
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