Efficient conversion of D-mannitol into 1,2:5,6-diacetonide with Aquivion-H as a recyclable catalyst

Article abstract of DOI:10.1016/j.carres.2020.108229

Heterogeneous solid catalysis by the commercially available perfluorosulfonic ionomer Aquivion-H allowed 1,2:5,6-diacetonide of D-mannitol (1), immediate precursor of important unichiral C3-synthons, to be efficiently obtained from D-mannitol and 2,2-dimethoxypropane in DMF at room temperature. The 1,2-monoacetonide, whose intermediate formation is the rate-limiting step, could be almost completely converted into 1 with limited concurrent transformation of 1 into triacetonides. In line with recent literature reports, these results indicate that heterogeneous catalysis by Aquivion-H surpasses the performances of homogeneous acidic catalysis assuring, presumably for its peculiar morphology, a higher product selectivity. Easy recovery at the end of the reaction and recyclability are additional advantages of this solid acid catalyst.

Full text of DOI:10.1016/j.carres.2020.108229

Carbohydrate Research 499 (2021) 108229
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Efficient conversion of D-mannitol into 1,2:5,6-diacetonide with
Aquivion-H as a recyclable catalyst
Cristiano Bolchi*, Rebecca Appiani, Gabriella Roda, Valentina Bertolini, Sebastiano Arnoldi,
Marco Pallavicini
`
Dipartimento di Scienze Farmaceutiche, Universita Degli Studi di Milano, via Mangiagalli 25, Milano, 20133, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords:
Heterogeneous solid catalysis by the commercially available perfluorosulfonic ionomer Aquivion-H allowed
1,2:5,6-diacetonide of D-mannitol (1), immediate precursor of important unichiral C3-synthons, to be efficiently
obtained from D-mannitol and 2,2-dimethoxypropane in DMF at room temperature. The 1,2-monoacetonide,
whose intermediate formation is the rate-limiting step, could be almost completely converted into 1 with
limited concurrent transformation of 1 into triacetonides. In line with recent literature reports, these results
indicate that heterogeneous catalysis by Aquivion-H surpasses the performances of homogeneous acidic catalysis
assuring, presumably for its peculiar morphology, a higher product selectivity. Easy recovery at the end of the
reaction and recyclability are additional advantages of this solid acid catalyst.
D-mannitol
Aquivion-H
1,2:5,6-di-O-Isopropylidene-D-mannitol
2,2-Dimethoxypropane
Acetonides
1. Introduction
desired 1,2:5,6 diacetonide, after crystallization from dibutyl ether, in
42% yield. In more recent years, a significant improvement of the
Conversion into cyclic acetals and ketals is one of the most common
methods to protect 1,2-diols and, among these, one of the most studied
and applied procedure is the acetonation of the two terminal diols of the
natural hexa-alcohol D-mannitol to 1,2:5,6-di-O-isopropylidene-D-
mannitol (1). Thanks to the identical S configuration of C(2) and C(5),
oxidative cleavage of unprotected central diol of 1 affords, with 100%
method yield (82%) was reported by avoiding any heating treatment
during the reaction work up and the product purification [20,21].
In the meantime, namely in the eighties and in the nineties, the
1,2:5,6 diacetonation of D-mannitol was deeply investigated [22–24].
With the analytical support of gas chromatography and of 13C NMR
spectroscopy, the monitoring of the Baer’s method and of some newly
developed procedures highlighted the major concern of any preparation
of 1. This is to limit the formation of triacedonides and competing
diacetonides, primarily 1,2:4,6- and secondarily 1,2:3,6-di-O--
isopropylidene-D-mannitol, while maximizing consumption of
D-mannitol and of the 1,2-monoacetal, whose initial formation is the
rate-determining step because of the very poor solubility of D-mannitol
in non-aqueous solvents [22,23] (Fig. 2). Such studies, based on GC
analyses of the reaction mixtures at different times, converged on
identifying the acetone/zinc chloride procedure by Baer [19,25,26] and
the transacetonation with 2,2-dimetoxypropane (2.4 equiv) and cata-
lytic tin(II) chloride in 1,2-dimethoxyethane successively developed by
Chittenden [27–29] as the two methods capable of achieving, respec-
tively, the maximal 60 and 55% conversion of D-mannitol into 1. After
16–24 h at room temperature, the former procedure yields minimal
quantities of triacetonides and other diacetonides but leaving behind
almost 30% residual mannitol and 1,2-diacetonide. In 2–3 h at reflux,
atom
economy,
two
molecules
of
(R)-2,3-O-iso-
propylideneglyceraldehyde (2) [1] and, upon reduction, of (S)-1,
2-O-isopropylideneglycerol (3) [2,3], two of the most important
C3-synthons within the chiral pool (Fig. 1). Apart from their predictable
wide use in the synthesis of the numerous molecules including the
mono-, di- or trisubstituted glycerol framework, 2 and 3 are useful
blocks to build other chiral linear molecules [4] and chiral cyclic sys-
tems. Examples of the latter are hexahydroindenes [5] benzomorpho-
lines [6], benzodioxanes [7–11], dihydropyrroles [12], dihydrooxazines
[12], dioxanes [13,14], pyridodioxanes [15,16], 2-oxazolidinones [17],
spirobisdioxanes [18], and spirobisoxathianes [18].
The first satisfactory method of acetonation of mannitol to the
diacetonide 1 was developed in the decade between the thirties and the
forties by Baer by using acetone and more than stoichiometric zinc
chloride at room temperature [19]. The procedure, which involves a
laborious removal of the large amount of zinc chloride, affords the
* Corresponding author.
E-mail address: cristiano.bolchi@unimi.it (C. Bolchi).
https://doi.org/10.1016/j.carres.2020.108229
Received 20 November 2020; Received in revised form 23 December 2020; Accepted 24 December 2020
Available online 30 December 2020
0008-6215/© 2021 Elsevier Ltd. All rights reserved.

C. Bolchi et al.
Carbohydrate Research 499 (2021) 108229
Fig. 3. Chemical structure of Aquivion-H (R–SO3H: equivalent weight 870
g/eq).
commercially available perfluorosulfonic ionomer (Aquivion PW87S),
possessing superacid character, used to prepare polymer electrolyte
membranes [33], whose iron-salt we have recently reported as an effi-
cient recyclable catalyst of one-pot reductive aminations [34,35].
Furthermore, in the reported polyols acetonidations utilizing DMF and
p-TsOH, such as the one mentioned above of D-mannitol with 2-methox-
ypropene [22,30], or in those of pentoses with 2,2-dimethoxypropane
[36], the reaction seems more directable to mono-, di- or
three-acetonidation by adjusting reaction parameters, such as temper-
ature, time, and quantity of the acetalating agent, anyway without
leaving starting material unreacted. The same is not feasible when
working with solvents, such as acetone or dimethoxyethane, in which,
unlike in DMF, mannitol is insoluble at all [37,38]. In these solvents,
complete consumption of mannitol necessarily results in high percent-
ages of triacedonides.
Fig. 1. D-mannitol and its most important acetonide derivatives.
2. Results and discussion
Given the above considerations, we developed the here reported
procedure of conversion of D-mannitol into 1 by treatment with 2,2-
dimethoxypropane in DMF in the presence of catalytic Aquivion-H at
room temperature for 16 h (Scheme 1). The catalyst was used in 2.8%
mol of H+ relative to mannitol, namely 133 mg per gram of substrate,
since stabilized powdered Aquivion-H PW87S has, insofar as sulfonic
acid (R–SO3H), a nominal equivalent weight of 870 g/eq. The aceta-
lating agent, 2,2-dimethoxypropane, was used in 4:1 M ratio to
mannitol, namely 2.7 ml per gram of substrate, while the solvent DMF in
5:1 v/w to mannitol, namely 5 ml per gram of substrate.
Fig. 2. Main secondary products in the conversion of D-mannitol to the 1,2:5,6
diacetonide (1).
the latter achieves a similar yield converting almost all mannitol and 1,
2-diacetonide but producing more than 30% of triacetonides and other
undesired diacetonides. Furthermore, the same studies showed that a
third procedure, based on the treatment of D-mannitol with two equiv-
alents of 2-methoxypropene and catalytic p-toluenesulfonic acid in DMF
at 0 ◦C, affords 1 with 36% yield and not with 90% yield as previously
claimed [30]. However, it is to be noted that this latter procedure
interestingly differs from the two previous ones: the products mixture is
richer in diacetals (72%), represented by 1, 1,2:4,6- and 1,2:3,6-di-O--
isopropylidene-D-mannitol in 3:2:1 ratio, while triacetals are practically
absent and the quantities of monoacetonides and unreacted mannitol
are modest. The use of catalytic p-toluenesulfonic acid was proposed
also in conjunction with 2,2-dimethoxypropane (2.5 equiv) or acetone
(4.9 equiv) in DMSO claiming a 62% and 77% yield of 1 respectively
[31,32].
The reactions were initially performed on 1 g of mannitol. After 16 h
vigorous stirring, the reaction mixture was filtered to remove the cata-
lyst. The filtrate was concentrated under vacuum at 40 ◦C. The resultant
solid was triturated in cyclohexane (15 ml) and recovered by filtration to
give 1 in 76% yield. At the end of the first catalytic cycle, Aquivion-H
was washed with acetonitrile and then dried under vacuum. Aquivion-
H was then recycled for five times without appreciable variation in its
catalytic performances (Fig. 4).
The reactions were successively performed on 10 g of mannitol by
the same protocol without difficulties and yield decrease.
Based on the previously mentioned literature investigations, point-
ing out how complex mixtures of mono- and poly-acetonides can form
from mannitol, we carefully analyzed both the crude resulting from DMF
removal and final 1 obtained by trituration in cyclohexane. Besides
routinary melting point and 1H NMR determinations, we relied on 13
C
Although the efficiency of the p-toluenesulfonic acid catalyzed con-
version of D-mannitol into 1 with 2-methoxypropene or 2,2-dimethoxy-
propane in polar aprotic solvents is questionable in some respects, we
were interested in developing a procedure for the preparation of 1
preferring the catalytic use of an acid, in particular of a sulfonic acid, to
stoichiometric zinc chloride. In terms of sustainability, the catalytic
approach is superior and, in the present case, an additional attractive
feature could be a heterogeneous catalysis with the recyclable solid
NMR and on GC analyses of the acetylated derivatives. The spectro-
scopic analysis clearly distinguishes among dioxolane, 1,3-dioxane and
catalyst we intended to use. This was Aquivion-H (Fig. 3),
a
Scheme 1. Preparation of 1 from D-mannitol.
2

C. Bolchi et al.
Carbohydrate Research 499 (2021) 108229
or in DMSO, but here, the preferential formation of diacetonides over the
other acetals is more pronounced and what is more with a much larger
prevalence of the desired diacetonide 1.
We think that a key role in determining the efficiency (high con-
version into diacetonides) and the selectivity (high yield of the diac-
etonide 1) of the procedure is the combination of a polar aprotic solvent
with a heterogeneous solid catalyst such as Aquivion-H. In less polar
aprotic solvents, such as acetonitrile, glyme, ethyl acetate or acetone,
the Aquivion-H catalyzed acetonidation led to triacetals as the main
products, as indicated by the almost exclusive presence of singlets im-
putable to the geminal methyls of the 1,2:3,4:5,6 triacetonide in the
most upfield region of the 1H NMR spectra of the crudes and by the
concomitant absence, at lower field, of the diagnostic signals for 1,
namely those of the two hydroxylated methines. On the other side, DMF,
in which the solubility of mannitol at room temperature is low but not
null as in the above less polar solvents, can ensure a supply of dissolved
substrate proportioned to the turnover frequency of the catalysts, which
is, as desirable, lower than that of soluble acids such as p-TsOH or
H2SO4. In this heterogeneous catalysis, other key aspects able of
modulating the reactivity of the species involved are the more difficult
accessibility to the catalytic sites by the reactants, reasonably varying
with their acetonidation extent, and the amphiphilic nature of the
polimer Aquivion-H favouring the reactivity of a highly hydrophilic
substrate, such as mannitol, in a non-aqueous environment. The synergy
of these factors allows a fine control of the reaction and tunes the re-
action selectivity. Evaluation of the individual weigh of such factors
would imply further ad hoc investigations. However, our statements are
supported by the negative or less positive results obtained replacing
Aquivion-H with soluble acids or DMF with solvents unable to dissolve
mannitol.
Fig. 4. Recycling of Aquivion-H: 1 yield of the first cycle and of the subsequent
five recycles.
1,3-dioxepane substructures thanks to the different shifts of the dime-
thylated acetal carbon thus revealing the undesired 4,6-acetonidation
(1,3-dioxane) and 3,6-acetonidation (1,3-dioxepane) [23]. The GC
analysis elutes, in the order, the triacetonides, the diacetyl derivatives of
the diacetonides, the tetraacetyl derivatives of the monoacetonides and,
finally, the peracetylated mannitol and furthermore it can separate the
different isomers within each group. GC analyses of the crudes from
three consecutive reactions revealed that triacetonides made up less
than 10% of the crude solid resultant from removal of the catalyst and
DMF, while the 1,2-monocetonide was present in traces and mannitol
was absent. The remainder consisted of a largely preponderant product,
namely the desired diacetonide 1. Consistently, 1H NMR spectrum of the
crudes appeared like that of a unitary product (See the 1H NMR spec-
trum of crude 1 and that of pure 1 reported in Supplementary Infor-
mation). Indeed, the revealing signals, namely those for the
hydroxylated methines and for the geminal methyls, were relatively
clean. 13C NMR spectrum showed only one signal for the dimethylated
acetal carbons, positioned at 109.4 ppm and imputable to the desired
acetonidation of vicinal diols to dioxolane rings. Furthermore, it is
noteworthy that the main impurity of the crudes was represented by less
polar triacetonides and not by the highly polar 1,2-monoacetonide. This
fact allowed us to avoid the purification of 1 by the usual crystallization
from di-n-butyl or diisopropyl ether. Simple trituration of the crudes in
more acceptable solvents, such as cyclohexane or cyclohexane and
‘green ether’ (CPME, TAME, MeTHF), recently employed by us in the
esterification of amino acids [39,40], was enough to remove the mi-
nority by-products, namely the triacetonides, which were dissolved
leaving 1 as a white solid with >98% GC purity. Indeed, when we halved
the catalyst amount, the main impurity became the 1,2-monoacetonide
and, as expectable, trituration of the crude in cyclohexane did not
remove it but enriched 1 in it. Therefore, it was necessary to wash an
ethyl acetate solution of the crude with water first and only then to
triturate the solid resultant from ethyl acetate removal in cyclohexane.
These results indicate that, in a polar aprotic solvent and under the
selected conditions, the heterogeneous catalysis by Aquivion-H can
efficiently promote diacetonidation of mannitol with almost complete
consumption of the starting material and of the intermediate mono-
acetonide and minimal formation of triacetonides. Such an output is in
line with those of the reported homogeneous catalysis by p-TsOH in DMF
The present procedure of mannitol diacetonidation catalyzed by
Aquivion-H places itself beside the recently reported Aquivion catalyzed
acetalizations of sugars with fatty alcohols to give amphiphilic alkyl
glycosides [41–43], surfactants of great interest for many desirable
intrinsic properties. There, acetalization reaction was between hydro-
philic carbonyl compounds (glucose, cellulose) and a hydrophobic
alcohol (n-dodecanol). Here, on the contrary, a highly hydrophilic
alcohol (mannitol) reacts with a hydrophobic acetalating agent (2,
2-dimethoxypropane). In both cases, due to its amphiphilic nature,
Aquivion-H proves to be able to efficiently catalyze the reaction between
substrates of very different polarity while showing, because of its
structured catalytic sites, good selectivity for a single product inside a
large series of candidate products. Among a dozen of mono-, di- and
triacetonides, Aquivion-H selectively catalyzes the formation of the
desired 1,2:5,6 diacetonide although in the presence of exceeding ace-
talating agent for moderately long time at room temperature, main-
taining such a performance unaltered through several recycles.
3. Experimental
D-Mannitol (1 g, 5.49 mmol), Aquivion-H (133 mg, 0.153 mmol), 2,2
dimethoxypropane (2.7 ml, 22.0 mmol) and 5 ml of dimethylformamide
were introduced into a round bottom flask under inert atmosphere. The
reaction mixture was vigorously stirred for 16 h at room temperature.
Afterward the suspension was filtered to remove the catalyst and the
filtrate was concentrated under vacuum to obtain a white solid crude
that was triturated in cyclohexane (15 ml). 1 was recovered by filtration
25
D
as a white solid in 76% yield (1.09 g): mp = 120.3–121.6 ◦C; [
α]
=
+2.6 (c 1, EtOH). 1H NMR (CDCl3) δ 4.19 (q, J = 6.2 Hz, 2H), 4.12 (dd, J
= 8.4 Hz and 6.4 Hz, 2H), 3.97 (dd, J = 8.4 Hz and 5.6 Hz, 2H), 3.75 (t, J
= 6.6 Hz, 2H), 2.59 (d, J = 6.6 Hz, 2H), 1.42 (s, 6H), 1.36 (s, 6H). 13
C
NMR (CDCl3) δ 109.4, 76.3, 71.2, 66.7, 26.7, 25.2. GC analysis of the
diacetylated derivative showed >98% purity. The catalyst removed
from the reaction mixture was rinsed with acetonitrile, dried under
vacuum, and recycled for five times.
GC analyses were conducted on samples acetylated by treatment
3

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