Facile and efficient synthesis of ido-heptulosan via a strategy derived from Mo(VI)-catalysed reactions

Article abstract of DOI:10.1055/s-2001-12773

A simple and high-yielding method for the preparation of 2,7-anhydro-β-D-ido-heptulopyranose (IDO) is described. It utilises the ability of molybdate ions to create the conditions for the skeletal rearrangement in the molecule of 2-C-branched aldose. This evidence is used in the synthesis of IDO from 2-C-(hydroxymethyl)-2,3:5,6-di-O-isopropylidene-D-gulofuranose in one step. The title compound is obtained in 95percent yield.

Full text of DOI:10.1055/s-2001-12773

PAPER
751
Facile and Efficient Synthesis of ido-Heptulosan via a Strategy Derived from
Mo(VI)-Catalysed Reactions
F
Z
acile andEffic
u
ient
S
ynthes
z
is of ido-H
e
a
ptulosan na Hricovíniová
Institute of Chemistry, Slovak Academy of Sciences, 842 38 Bratislava, Slovakia
Fax +421(7)5941–0222; E-mail: chemhric@savba.sk
Received 4 January 2001; revised 2 February 2001
Interconversion of 2-C-(hydroxymethyl) aldoses and 2-
ketoses with mutually inverted positions of hydroxyl
groups at C-2 and C-3 is a consequence of the highly ste-
Abstract: A simple and high-yielding method for the preparation of
,7-anhydro- -D-ido-heptulopyranose (IDO) is described. It utilises
the ability of molybdate ions to create the conditions for the skeletal
2
rearrangement in the molecule of 2-C-branched aldose. This evi- reospecific carbon skeleton rearrangement that is taking
dence is used in the synthesis of IDO from 2-C-(hydroxymethyl)- place during the chelation of these sugars in tetradentate
2
,3:5,6-di-O-isopropylidene-D-gulofuranose in one step. The title
dimolybdate complexes. In the present case, the 2,3:5,6-
di-O-protected derivative of D-gulose was used as the
compound is obtained in 95% yield.
Key words: ido-heptulosan,
nose, 2-C-(hydroxymethyl)-2,3:5,6-di-O-isopropylidene- -D-gulo-
furanose, 2-C-(hydroxymethyl)-D-gulose, Mo(VI) catalysis
2,7-anhydro- -D-ido-heptulopyra- starting compound for the planned synthesis. D-Gulose
was acetonated with 2,2-dimethoxypropane and toluene-
-sulfonic acid to give 2,3:5,6-di-O-isopropylidene- -D-
4
gulofuranose (1) (Scheme 1) as a colourless crystalline
solid (65% yield). The structural assignments were based
1
13
Higher saccharides, occurring in small quantities in on H and C NMR spectra. Introduction of a hydroxym-
plants, are known to activate various biochemical process- ethyl group at C-2 was provided by alkali-based addition
1,2
es. They are often obtained from natural sources by iso- of 1 to formaldehyde, yielding the fully characterised 2-C-
lation. However, substantial efforts have also been made
to prepare this type of compounds by synthetic methods
exclusively. The attention was focussed mainly on those
carbohydrates that are useful for pharmaceutical purposes
(
hydroxymethyl)-2,3:5,6-di-O-isopropylidene- -D-gulo-
furanose (2) in 75% yield. The transformations of the pro-
tected sugars were conveniently followed by TLC, since
the substrates and products have distinctive R values on
normal-phase silica plates. A part of product 2 was treated
with an ion-exchange resin (H form in H O) to give 2-C-
(
of compound 3 was confirmed by NMR spectroscopy. In-
spection of both, 1D and 2D NMR spectra revealed that
four isomers ( , , pyranose, and furanose) are present in
aqueous solution at 40 °C. As the anomeric signals of both
f
3
or biochemical studies.
+
The application of catalysed reactions is one of the most
promising techniques in organic synthesis. Recently, it
was shown that a convenient synthetic method exists
which can be used as an alternative way to obtain some
2
hydroxymethyl)-D-gulose (3) in 89% yield. The structure
4
–6
rare carbohydrates. This approach is based on molyb-
7
dic-acid-catalysed reactions that can significantly simpli-
-
forms overlap, the population of the individual isomers
fy synthetic procedures. The convenient one-pot
methodology, developed for epimerisation of aldoses ca-
talysed by molybdate ions, was shown to be applicable
also for the mutual isomerisation of 2-C-(hydroxymethyl)
aldoses and 2-ketoses. It was confirmed that equilibrium
mixtures during these transformations favoured 2-keto-
ses. Thus, 2-C-(hydroxymethyl) aldoses become ideal
precursors for the synthesis of 2-ketoses.This method was
1
3
was estimated from C NMR spectra. The signal intensi-
ties indicate that the furanose forms are more abundant
(
populated in both forms. Thus, the abundance of the indi-
vidual isomers is approximately as follows: 30% f, 30%
f, 20% p, and 20% p.
about 60%) and that - and -anomers are almost equally
In order to assess the viability of the aforementioned con-
cept, we first explored the isomerisation reaction cataly-
sed by molybdate ions during the conversion of 2-C-
4
utilised for the synthesis of D-hamamelose, sedoheptu-
5
6
lose, and D-glycero-D-ido-octulose. On the basis of pre-
vious observations on general stereospecificity trends,
(
hydroxymethyl)-D-gulose (3) to D-ido-heptulose, and
8
,9
shown by aldose/epi-aldose and 2-C-(hydroxymethyl)
then compared it with the conversion of 2-C-(hydroxym-
4
,10
aldose/2-ketose
mutual isomerisation promoted by ethyl)-2,3:5,6-di-O-isopropylidene- -D-gulofuranose (2)
Mo(VI), as well as the knowledge of structure of the under the same reaction conditions. The branched-chain
Mo(VI) carbohydrate complexes,
an efficient and direct route to 2,7-anhydro- -D-ido-hep- amount of molybdic acid in acidic aqueous solution at en-
tulopyranose (IDO).
1
1–15
we describe herein aldose 3 was subjected to treatment with a catalytic
hanced temperature. The progress of the reaction was
monitored by NMR spectroscopy. A smooth isomerisa-
tion reaction took place to give the desired product in ex-
cellent yield under the previously optimised conditions.
The transformation lead relatively fast to an equilibrium
mixture of D-ido-heptulose and the remaining starting
Synthesis 2001, No. 5, 12 04 2001. Article Identifier:
1
©
437-210X,E;2001,0,05,0751,0754,ftx,en;Z00101SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

7
52
Z. Hricovíniová
PAPER
Scheme 1
sugar. The created D-ido-heptulose was converted imme- complex involves four O-C bonds to the carbons C-1, C-
diately to 2,7-anhydro- -D-ido-heptulopyranose (IDO) 2, C-3, and C-4 in its hydrated form (A). In the transition
(
4), directly in the reaction mixture. The starting com- state of the reaction a bond formation between C-1 and C-
pound was converted to ido-heptulosan in almost quanti- 3 occurs with simultaneous cleavage of the C-2-C-3 bond
tative yield (97%) after 3 h. Thus, under these conditions (B). The dimolybdate complex C of the acyclic D-ido-
a very high yield of IDO (anhydrisation proceeds with heptulose is the product of this transformation
marked stereoselectivity) was obtained. The formation of (Scheme 2). This transformation involves an isomerisa-
IDO is strongly favoured, because all isomers of D-ido- tion of the carbon skeleton, and a prolongation of the main
heptulose are rather unstable due to substantial destabilis- chain of the sugar is observed. Thus, a higher sugar (hep-
1
6,17
ing interactions.
Apparently, it is readily dehydrated tulose) is obtained from the lower branched-chain hexose
even under mild acidic conditions. So, at 20 °C IDO by a stereospecific bond rearrangement, in which the
1
would furnish more than 91% anhydride.
former branch CH OH becomes the C-1 carbon of the re-
2
sulting 2-ketose.
The formation of the 2-ketose D-ido-heptulose is in accor-
dance with the mechanism of isomerisation reactions Alternatively, a molybdic acid-catalysed isomerisation of
4
,10
studied recently. In the present case, 2-C-(hydroxyme- 2-C-(hydroxymethyl)-2,3:5,6-di-O-isopropylidene- -D-
thyl)-D-gulose in its acyclic form is bound in a catalytical- gulofuranose (2) under similar reaction conditions
ly active dimolybdate complex. This dimolybdate reached the thermodynamic equilibrium mixture of the
Scheme 2
Synthesis 2001, No. 5, 751–754 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Facile and Efficient Synthesis of ido-Heptulosan
753
two isomeric saccharides after 6 h. In this case, the kinet- 2,3:5,6-Di-O-isopropylidene- -D-gulofuranose (1)
The reaction mixture of D-gulose (1 g, 5.55 mmol) in 1,2-dimethox-
yethane (75 mL), toluene-4-sulphonic acid monohydrate (0.1 g),
and 2,2-dimethoxypropane (5 mL, 40.7 mmol) was stirred for 6 h,
followed by addition of Drierite (1 g). Then the reaction mixture
was allowed to stand at r.t. overnight. After completion of the reac-
tion as revealed by TLC (EtOAc-light petroleum, 3:1) the reaction
ics of the conversion of 2 is different. A longer reaction
time is required owing to several subsequent reaction
steps which take place in a single array: hydrolysis of iso-
propylidene groups, skeletal rearrangement of 2-C-(hy-
droxymethyl)-D-gulose (3) to D-ido-heptulose and its
subsequent anhydrisation leading to ido-heptulosan. The mixture was neutralised (NaHCO ), the neutral mixture was filtered
3
branched-chain aldose 2 was stereospecifically converted with suction and washed with MeOH (2 × 20 mL). The filtrate was
concentrated to give a colourless syrupy residue which was purified
by flash-chromatography on silica gel (EtOAc-light petroleum,
to ido-heptulosan, as determined from its 1D and 2D
NMR spectra. This modification, involving concomitant
3
:1). The main fraction after chromatographic separation, as indi-
hydrolysis of the protective groups and simultaneous
isomerisation, makes this method more useful from a pre-
parative point of view. Investigations of the scope of the
reaction showed that both, 2-C-branched aldoses 2 and 3
react readily to give the same anhydro sugar in compara-
ble excellent yield (95–97%) (Scheme 1). The analysis of
the components, obtained by separation of the reaction
mixture, showed a very small amount (about 2%) of -
and -D-threo-furanose in addition to the product. The
formation of D-threo-furanose can be explained by a deal-
dolisation reaction. The acyclic form of D-ido-heptulose,
cated by TLC, was the major product 1, isolated as a white, crystal-
line solid.
Yield 0.94 g (65%); mp 111–113 °C; R 0.71 (EtOAc-light petro-
f
20
leum, 3:1); [ ]D –1.54° (c = 1, acetone).
1
H NMR (300.13 MHz, acetone-d ): = 5.30 (H-1), 4.82 (H-3),
6
4
.57 (H-2), 4.27 (H-5), 4.13 (H-6), 4.08 (H-4), 3.77 (H-6’).
1
3C NMR (75.45 MHz, acetone-d6): = 114.57 (2,3-CMe ), 111.41
2
(
5,6-CMe ), 103.61 (C-1), 88.46 (C-2), 84.43 (C-4), 82.75 (C-3),
2
7
8.54 (C-5), 68.28 (C-6).
2
-C-(hydroxymethyl)-2,3:5,6-Di-O-isopropylidene- -D-
created during the release from the dimolybdate complex, gulofuranose (2)
undergoes dealdolisation revealing D-threose and 1,3-di- To the solution of 1 (0.5 g, 1.7 mmol) in MeOH (6.5 mL), K
CO
3
2
(
0.36 g) and an aq solution of formaldehyde (37%, 4.3 mL, 42
hydroxyacetone. Since the acyclic form rearranges imme-
diately to the more stable cyclic form, and further to the
anhydro form, the amount of product of the dealdolisation
process (D-threose) is nearly negligible.
mmol) was added. The mixture was refluxed under Ar atmosphere
at 85 °C for 48 h. The conversion was checked with TLC (EtOAc-
light petroleum, 3:1) until the disappearance of 1. After cooling the
reaction mixture to 25 °C, it was neutralised with aq H SO (10%)
2
4
and evaporated. The residue was extracted with CHCl (3 × 35 mL)
In conclusion, this communication describes a facile syn-
thesis of D-ido-heptulosan by a simple, efficient method
and complements the series of syntheses of rare saccha-
3
and the combined layers were dried (MgSO ) overnight and concen-
4
trated. The crude product was purified by flash-chromatography on
a column of silica gel (EtOAc-light petroleum, 6:1). TLC indicated
one major syrupy product, which solidified on trituration with sol-
4
–6
rides prepared via this approach. The method encom-
passes all the advantages of traditional catalysis-high vent. Crystallisation from acetone gave 2 as a colourless solid.
stereoselectivity and ease of workup procedure. In this re-
Yield 0.42 g (75%); mp 95–96 °C; R 0.69 (EtOAc-light petroleum,
f
gard, the molybdic-acid-catalysed isomerisation proved
to be a particularly valuable approach for the preparation
of such compounds and can be successfully extended to
the preparation of other biologically interesting carbohy-
drates.
20
3
:1); [ ]D –5.57° (c = 1, acetone).
1
3C NMR (75.45 MHz, acetone-d6): = 114.21 (2,3-CMe ), 109.82
2
(
5,6-CMe ), 104.27 (C-1), 95.77 (C-2), 84.04 (C-3), 83.18 (C-4),
2
7
6.69 (C-5), 66.53 (C-6), 62.61 [CH (C-2)].
2
2
-C-(Hydroxymethyl)-D-gulose (3)
A mixture of 2 (45 mg), H O (2 mL), and Dowex 50 W X4 resin in
the H form (1 mL) was stirred at 75 °C for 5 h. The resin was re-
2
NMR spectra were recorded on a Bruker DPX 300 spectrometer
equipped with a 5 mm inverse broadband probe with a shielded z-
+
moved by filtration, washed with H O (3 × 3 mL), and the combined
2
gradient. The experiments were carried out at 40 °C (D O) or 25 °C
2
filtrate was purified with charcoal followed by evaporation to dry-
ness giving syrupy 3.
1
13
(
acetone), respectively. The H and C chemical shifts were refer-
enced to internal TSP (D O) and TMS (acetone). 5 mm QNP probe
2
Yield 29 mg (89%); [ ]D20–9.8 to –9.5° (c = 1, H O) (24 h).
1
3
was used for measurements of the 1D C NMR spectra. Two-di-
mensional techniques, COSY, HMBC, and HSQC were used to de-
termine the 1H and C chemical shifts. Melting points were
measured with a Kofler hotstage and are uncorrected. The optical
rotations were measured on a Perkin-Elmer polarimeter (Model
2
1
3
C NMR (75.45 MHz, D O): = 103.73 (C-1 f), 99.43 (C-1 f),
2
13
98.79 (C-1 p), 94.43 (C-1 p), 83.35 (C-2 f), 82.34 (C-2 f),
82.21 (C-4 f), 81.08 (C-4 f), 77.73 (C-5 p), 75.73 (C-2 p),
75.45 (C-2 p), 74.46 (C-3 f), 73.77 (C-3 f, C-5 f), 73.65 (C-3
p), 73.23 (C-4 p), 72.77 (C-5 p), 72.28 (C-3 p, C-4 p, C-5 f),
65.80 [CH (C-2) f], 65.60 (C-6 f), 65.48 [CH (C-2) p], 65.34
1
41), at 20 °C. Thin-layer chromatography (TLC) was performed
on precoated silica gel GF254 glass plates (Merck), exposed to
H SO spray followed by charring. Chromatography columns of sil-
2
2
2
4
(C-6 f), 65.20 [CH (C-2) f], 64.41 [CH (C-2) p], 63.90 (C-6 p),
2
2
ica gel were prepared with silica gel 60 (40 60 m, Merck), using
the flash technique. Column chromatography was performed on
Dowex 50W X8 (200 400 mesh) ion-exchange resin (Fluka) in
62.36 (C-6 p).
D-ido-Heptulosan (2,7-anhydro- -D-ido-heptulopyranose) (4)
A mixture of 2 (200 mg, 7 mmol) and a 0.3% (w/w) solution of
H MoO in 0.3 M HCl (10.5 mL) was stirred at 85 °C for 7 h. The
2
+
Ba cycle, using H O as eluent. Paper chromatography (PC) was
2
performed applying the descending method on Whatman No. 1 pa-
2
4
per and using EtOAc-pyridine-H O (8:2:1) as mobile phase. An al-
composition of the reaction mixture was examined by paper chro-
2
kaline silver nitrate was used to locate the spots on the
chromatograms. All evaporations were carried out under reduced
pressure at a bath temperature not exceeding 45 °C.
matography (EtOAc-pyridine-H O, 8:2:1) until the equilibrium was
2
reached. The mixture was treated batch-wise with an excess of the
–
ion-exchange resin Amberlite IRA-400 in the HCO3 form (50 mL)
Synthesis 2001, No. 5, 751–754 ISSN 0039-7881 © Thieme Stuttgart · New York

7
54
Z. Hricovíniová
PAPER
to remove the catalyst. Then the resin was filtered off and washed References
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2
(
(
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under reduced pressure to give a syrup (120 mg). The syrupy resi-
due (120 mg) was fractionated by column chromatography on
2
+
Dowex 50W X8 (200–400 mesh) in the Ba form with H O as elu-
2
(
(
(
(
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1
9
00 mL) contained 2,7-anhydro- -D-ido-heptulopyranose (114 mg,
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2
in press.
The obtained physical and spectroscopic data are in accordance
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(7) (a) Bílik, V. Chem. Zvesti. 1972, 26, 183. (b) Bílik, V.
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1
3
C NMR (75.45 MHz, D O): = 110.47 (C-2), 78.83 (C-6), 77.64
2
(
(
8) Bílik, V. Chem. Listy 1983, 77, 496.
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(
C-4), 76.75 (C-3), 73.93 (C-5), 68.77 (C-7), 62.68 (C-1).
Fraction 2 (eluting between 100 and 120 mL) showed the presence
of - and -D-threo-furanose (3 mg, 2%) in a mixture with IDO.
Fraction 3 (eluting between 140 and 170 mL) contained a small
amount of 2-C-(hydroxymethyl)-D-gulose (3, 1%).
(
10) Hricovíniová, Z.; Hricovíni, M.; Petru, L. Chem. Papers
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(
(
(
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This research was partly supported by VEGA grant No. 2/6037/99
awarded by the Slovak Academy of Sciences.
(
(
16) Angyal, S. J.; Le Fur, R. Carbohydr. Res. 1984, 126, 15.
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Synthesis 2001, No. 5, 751–754 ISSN 0039-7881 © Thieme Stuttgart · New York