Tropolonyl ethers of saccharides and cyclitol derivatives

Article abstract of DOI:10.1016/S0040-4039(02)02286-4

Mitsunobu coupling between tropolones and saccharide or cyclitol derivatives featuring primary or secondary alcohol functions provides for the first time an easy, general and efficient access to the corresponding tropolonyl ethers. Selective deprotection of the carbohydrate or cyclitol units demonstrates that naked saccharides and cyclitols bearing a tropolonyl ether moiety may be prepared by this route.

Full text of DOI:10.1016/S0040-4039(02)02286-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9217–9220
Tropolonyl ethers of saccharides and cyclitol derivatives
Henri Houte, Jean-Yves Valnot and Serge R. Piettre*
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes, UMR 6014 CNRS, Universite´ de Rouen, rue Tesnie`re,
F-76821 Mont Saint Aignan, France
Received 19 September 2002; accepted 3 October 2002
Abstract—Mitsunobu coupling between tropolones and saccharide or cyclitol derivatives featuring primary or secondary alcohol
functions provides for the first time an easy, general and efficient access to the corresponding tropolonyl ethers. Selective
deprotection of the carbohydrate or cyclitol units demonstrates that naked saccharides and cyclitols bearing a tropolonyl ether
moiety may be prepared by this route. © 2002 Elsevier Science Ltd. All rights reserved.
The early suggestion by Dewar that natural products
such as colchicine 1 and derivatives of puberulonic acid
2, for instance, encompass the troponoid ring has gen-
erated a massive amount of work aiming at understand-
More recently, 3,7-dihydroxytropolone (4) has been
reported to be a potent inhibitor of dimetallic enzymes
via a novel mode of action linked to its ability to
chelate metal ions.4 Modeling studies have shown that
in the case of inositol monophosphatase (IMPase), for
example, 4 acts as a competitive inhibitor of the enzyme
by efficiently replacing the phosphate group of the
substrate in the chelation of the two magnesium ions
present in the active site.5 This suggests that the tro-
polone moiety (or its hydroxylated derivatives) might
be used as an organic analogue of the phosphate group in
the design of bioactive molecules.
ing
and
exploiting
the
chemistry
of
the
cyclohepta-2,4,6-trienone cycle (tropone) (Fig. 1).1 The
belief that the tropone ring might be at least partly
aromatic induced additional interest; this has however
been largely refuted since then.2
Over a hundred natural compounds featuring the tro-
pone moiety or its 2-hydroxyl derivative (3, tropolone)
have been isolated in the past sixty years and shown to
possess various bioactivities.3
Thus, developing a regiocontrolled access to ethers of
the type 5 requires (i) an efficient method of synthesis
of tropolonyl ethers, and (ii) a regiocontrolled protec-
tion of two of the three hydroxyl groups of dihydroxy-
tropolone 4. We herein report our results concerning
the first part of this task.
Ethers of tropolones have traditionally been prepared
(i) by alkylation of tropolones under basic conditions,
(ii) by substitution reactions between halotropolones
and alcoholates and (iii) through condensation reaction
between alcohols and tropolones in the presence of
dicyclohexylcarbodiimide (DCC) and catalytic amounts
of cuprous chloride at 80°C.6–8 Several drawbacks and
limitations are associated with the two first methods; in
particular, good yields were obtained only with simple
or activated alcohols or halides. Takeshita reported the
third method as being more general, albeit results are
often erratic. For example, cyclopentanol furnished the
expected ether in 90% yield, while cyclohexanol and
cycloheptanol gave the desired products in only 15 and
8% yields, respectively. In this context and in view of
the central roles played by inositol phosphates as well
Figure 1. Troponoids 1–5.
Keywords: tropolone; Mitsunobu; ether; saccharide; cyclitol.
* Corresponding author. Fax: +33 (0)235 52 29 71; e-mail:
serge.piettre@univ-rouen.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02286-4

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H. Houte et al. / Tetrahedron Letters 43 (2002) 9217–9220
Table 1. Ethers 10a–i from coupling reactions between 3
or 6 and alcohols (9a–i), including protected saccharide
derivatives
as phosphorylated saccharides, we have induced a search
to develop an efficient and general synthetic route to
compounds encompassing both a tropolonyl unit and
either a saccharide or a cyclitol, linked by an ether
function.
One of the most powerful methods available to date for
the preparation of aryl ethers involves the interaction of
two alcohols, a phosphine and a dialkyl azodicarboxyl-
ate.9 The so-called Mitsunobu reaction has thus been
largely exploited in organic chemistry. Surprisingly,
however, and despite the acidic properties of tropolones,
it has never been applied to the synthesis of tropolonyl
ethers. When a mixture of tropolone 3, triphenylphos-
phine (PPh3 1.5 equiv.) and methanol (9a) (1.5 equiv.) in
diethyl ether was treated at room temperature with
diisopropylazodicarboxylate (DIAD) (1.5 equiv.), a
rapid reaction ensued to produce 2-methoxytropone
(10a), isolated in 72% yield (Scheme 1; Table 1, entry 1).
Isopropyl alcohol reacted similarly, leading to a clean
conversion of 3 into 2-isopropyloxytropone (10b) (60%
isolated yield, entry 2). 2-Methoxyethanol furnished the
first case of a more functionalized substrate, yielding the
corresponding ether 10c in 75% yield (entry 3).
A variety of protected furanosyl and pyranosyl carbohy-
drates were next tested. 3,7-Dibromotropolone 6 was
chosen due to its ability to further undergo substitution,
acetolysis and transition metal-catalyzed coupling reac-
tions.10 Saccharides featuring a primary alcohol cleanly
produced the desired ethers 10e–h in good to high yields
(entries 4–8). Even the secondary alcohol function of
diacetone allose (9i) furnished the expected ether under
heating, albeit in lower yield (entry 9). Analysis of the
1H NMR spectrum of 10i indicated complete inversion
of configuration at C3.
The extensive studies of the past decades aiming at
understanding and controlling the inositol cycle are due
to its crucial importance in the metabolism of the cell.
Thus, for instance, inositol-1,4,5-trisphosphate is a sec-
ond messenger directing the release of intracellular
stocks of calcium and it has been suggested that inhibi-
tion of inositol monophosphatase might lead to a treat-
ment for bipolar disorders.11 In this context, the
hereabove described methodology may find application
in the preparation of useful inositol phosphate ana-
logues. Thus, both cyclohex-2-enol 9j and cyclohex-3-
enol 9k reacted satisfactorily with tropolone 6 at room
temperature to yield ethers 10j and 10k in 72 and 77%
isolated yield, respectively (Table 2, entries 1–2).12 Here
again, the reaction proved to be somewhat sensitive to
steric hindrance: interaction of cis or trans monopro-
tected cyclohexan-1,2-diols (9l or 9m, respectively) with
6 required heating at 65°C to give the desired ethers 10l
and 10m (Table 2, entries 3 and 4).13 On the other
hand, 4,5-protected cyclohex-2-en-1,4,5-triol 9n and
Scheme 1. Coupling reaction between tropolones and alcohols
9a–p.

H. Houte et al. / Tetrahedron Letters 43 (2002) 9217–9220
9219
Table 2. Ethers 10j–o from coupling reactions between 6
and protected carbosaccharide derivatives (9j–o)
Figure 2. Additional tropolonyl ethers.
phate and -inositol-3-phosphate, respectively. Com-
D
petitive inhibitors of inositol-3-phosphate synthase and
inositol monophosphatase may help modulate the inos-
itol cycle. Deprotection of the products can easily be
achieved by using standard procedures. For example,
ethers 10d and 10e are quantitatively converted into
compounds 11 and 12 by simply heating an aqueous
acetic acid solution (60% v/v; 10d: 45°C, 45 minutes;
10e: 90°C, 4 hours) while sequentially subjecting cycli-
tol derivative 10o to tetra-n-butylammonium fluoride
(25°C, 18 hours) and aqueous acetic acid (60% v/v,
25°C, 2 hours) produces 13 (Fig. 2).
The possibility for (poly)hydroxytropolones to undergo
multiple alkylations under the hereabove-described con-
ditions was also investigated. Thus, reaction between
7-hydroxytropolone (8) and two equivalents of allyl
alcohol quantitatively furnished a mixture of both iso-
meric 2,3- and 2,7-bis(allyloxy)tropones 14 and 15
(75:25 ratio).15
The methodology described in this communication
efficiently leads to tropolonyl ethers of saccharides and
cyclitols under mild conditions.16 The procedure is sim-
ple to implement and may find direct applications in
combinatorial chemistry and in the production of
libraries of bioactive tropolonyl ethers as isosters of
biological phosphates.
4,5-protected-1,3,4,5-cyclohexantetraol
9o
(both
obtained from quinic acid) furnished ether 10n and 10o
at room temperature in very good isolated yields (Table
2, entries 5 and 6).
The procedure may also be applied to other substrates.
Combining 3,7-dichlorotropolone (7) with o-iodobenzyl
alcohol (9p) liberates compound 10p (83% isolated
yield) featuring different halogen atoms (Fig. 2); the
possibility of conducting two different, sequential palla-
dium-catalyzed cross-coupling reactions paves the way
for the synthesis of various analogues and makes of
ethers such as 10p valuable scaffolds for the generation
of libraries by parallel synthesis.
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synthesis of tropolonyl analogues of glucose-6-phos-

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H. Houte et al. / Tetrahedron Letters 43 (2002) 9217–9220
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verted into a 1:1 mixture of tropolonyl ethers 10o.
15. Bis-O-alkylated (di)hydroxytropolones might thus also
constitue useful analogues of diesterified phosphates.
16. Representative procedure for ether 10h: pure diisopropyl
azodicarboxylate (303 mg, 1.5 mmol) was added at room
temperature to a stirring solution of tropolone 6a (140
mg, 0.5 mmol), triphenylphosphine (393 mg, 1.5 mmol)
and alcohol 9h (697 mg, 1.5 mmol) in diethyl ether (10
mL). Stirring was continued for 1 h, after which period of
time the mixture was diluted with dichloromethane (10
mL). The organic phase is washed with aqueous HCl (10
mL of a 1 M solution), dried over magnesium sulfate and
filtered. Evaporation of the volatiles under reduced pres-
sure leaves a residue which is purified by chromatography
over silica and eluted with a mixture of ethyl acetate/
heptane (30:70) to deliver the desired product 10h as a
yellowish solid (272 mg, 75%). Mp=106–107°C. [h]D=
+47.6 (CH2Cl2, c=2.1, 21°C). IR (KBr) w 3455, 1608,
1590, 1559, 1554, 1450, 1358, 1330, 1294, 816 cm−1 1H
.
NMR (300 MHz, CDCl3) l=7.86 (dd, 1H, J=0.8, 9.4
Hz), 7.41 (dd, 1H, J=0.8, 11.7 Hz), 7.29–7.18 (m, 15H),
6.33 (dd, 1H, J=9.4, 11.7 Hz), 4.91 (d, 1H, J=10.5 Hz),
4.84 (d, 1H, J=10.5 Hz), 4.76 (d, 1H, J=10.5 Hz), 4.72
(d, 1H, J=11.8 Hz), 4.61 (d, 1H, J=10.5 Hz), 4.57 (d,
1H, J=11.8 Hz), 4.56 (dd, 1H, J=3.8, 12.0 Hz), 4.47 (d,
1H, J=3.4 Hz), 4.40 (dd, 1H, J=1.9, 12.0 Hz), 3.94 (dd,
1H, J=8.7, 9.6 Hz), 3.77 (ddd, 1H, J=1.9, 3.8, 9.8 Hz),
3.68 (dd, 1H, J=8.7, 9.8 Hz), 3.27 (s, 3H) ppm. 13C
NMR (75 MHz, CDCl3) l=173.8, 159.4, 139.0, 138.6,
138.5, 138.4, 138.3, 138.1, 129.8, 128.8, 128.6, 128.5,
128.4, 128.3, 128.2, 128.1, 125.9, 125.0, 98.5, 82.3, 80.2,
78.0, 70.8, 76.3, 75.6, 73.9, 71.3, 55.8 ppm. Anal. calcd
for: C35H34Br2O7: C, 57.87; H, 4.72. Found C, 57.95; H,
4.68.