One-pot synthesis of orthogonally protected sugars through sequential base-promoted/acid-catalyzed steps: A solvent-free approach with self-generation of a catalytic species

Article abstract of DOI:10.1016/j.tetlet.2019.05.066

A varied set of solvent-free, one-pot synthetic sequences were developed to carry out the orthogonal protection of saccharide polyols. These sequences are composed of an initial regioselective benzylation, silylation or iodination (under mildly basic cond

Full text of DOI:10.1016/j.tetlet.2019.05.066

Accepted Manuscript
One-pot synthesis of orthogonally protected sugars through sequential base-
promoted/acid-catalyzed steps: a solvent-free approach with self-generation of
a catalytic species
Serena Traboni, Emiliano Bedini, Maddalena Giordano, Alfonso Iadonisi
PII:
S0040-4039(19)30527-1
https://doi.org/10.1016/j.tetlet.2019.05.066
TETL 50838
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Reference:
Tetrahedron Letters
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25 May 2019
30 May 2019
Please cite this article as: Traboni, S., Bedini, E., Giordano, M., Iadonisi, A., One-pot synthesis of orthogonally
protected sugars through sequential base-promoted/acid-catalyzed steps: a solvent-free approach with self-
generation of a catalytic species, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.066
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One-pot synthesis of orthogonally protected sugars
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Serena Traboni, Emiliano Bedini, Maddalena Giordano, and Alfonso Iadonisi

1
Tetrahedron Letters
One-pot synthesis of orthogonally protected sugars through sequential base-
promoted/acid-catalyzed steps: a solvent-free approach with self-generation of a
catalytic species
Serena Traboni,a Emiliano Bedini,a Maddalena Giordano,a and Alfonso Iadonisia
a Department of Chemical Sciences, University of Naples Federico II, Via Cinthia 4, I-80126 Naples (Italy)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A varied set of solvent-free, one-pot synthetic sequences were developed to carry out the
orthogonal protection of saccharide polyols. These sequences are composed of an initial
regioselective benzylation, silylation or iodination (under mildly basic conditions), followed by
an acid catalyzed protection of two further hydroxyl sites via the generation of a cyclic acetal.
These processes allow recycling of the ammonium or pyridinium side products generated in the
former step as effective catalytic species for the latter step.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Protecting groups
Carbohydrates
One-pot synthesis
Solvent-free reaction
The search for practical and more streamlined approaches to
the large scale preparation of saccharide building-blocks with a
properly differentiated profile of protecting or functional groups
represents a fundamental issue in organic synthesis, whose
implications are not only restricted to oligosaccharide targets.
Because of their low cost and abundance, carbohydrates are
routinely employed as advantageous precursors in the synthesis
of complex chiral targets with a broad range of applications.1
for over 30 years.10 Besides applications in protecting group
chemistry, the solvent free strategy also proved useful in the
anomeric chlorination of sugar hemiacetals11 and the selective
conversion of primary alcohols into the corresponding iodides,
with the possible in situ elaboration of these latter
intermediates.12 Remarkably, all of the above mentioned methods
were often successfully applied to highly polar substrates, in spite
of their poor solubility in the reaction medium.
The introduction of one-pot sequences for the synthesis of
sugars with varied protection profiles represents an important
advance in this area.2-4 These strategies are mostly based on
sequential acid catalyzed processes such as acetalation, reductive
etherification, and reductive benzylidene opening. These are
moisture sensitive processes, and careful experimental control is
needed. In addition, these strategies frequently require per-O-
silylation of the saccharide precursors prior to execution of the
actual one-pot sequence;2 consequently, a de-O-silylation step
needs to be added in the sequence to restore the free alcohol
positions in the final product.
Herein, we describe an unprecedented and versatile strategy to
achieve the one-pot synthesis of a range of orthogonally
protected carbohydrates; this approach takes advantage of
sequential solvent-free reactions entailing an initial base-
promoted alkylation (or iodination) step followed by acid
catalyzed acetalation, exclusively promoted by the ammonium
(or pyridinium) species generated in the former step. In designing
this general scheme, we started by considering that previously
described conditions for the tin-catalyzed regioselective
benzylation of sugars afforded
a mixture containing an
approximately equimolar amount of DIPEA and the
corresponding ammonium cation (2.5 equiv. DIPEA is initially
introduced and 1.0 equiv. is protonated upon the alkylation of 1.0
equiv. alcohol).6 This type of buffered system could potentially
serve as an acid catalyst, in view of the highly concentrated
conditions of a process performed in the absence of solvents.
Very recently, our laboratory has devoted a broad effort
towards the development of experimentally simple solvent-free
procedures under air for the regioselective installation of
protecting functional groups such as benzyl-,5-6 allyl- silyl- and
6-8
trityl ethers, and acetals.9 The potential impact of the solvent-
free conditions was especially evidenced by the first reported
examples of the tin-catalyzed regioselective benzylation of
polyols,6 after that the traditional approach, based on
—stoi—chi—ometric stannylene acetal intermediates, had been applied
To test the viability of this hypothesis, the previously
described6 3-O-benzylation of methyl mannoside 1 at 70 °C
(Table 1) was used as the model alkylation step, and the resulting
crude mixture was directly submitted to the solvent-free
 Corresponding author. e-mail address: iadonisi@unina.it (A. Iadonisi)

2
Tetrahedron Letters
acetalation conditions.9 In order to assess the catalytic activity
benzylidenation yield. As shown in entries 4-7, improved results
for the synthesis of were achieved using the
of the amine/ammonium system, the acetalation step was
attempted by adding the requisite benzylidenation agent (either a
dimethyl acetal or a benzaldehyde/orthoester combination)9 and
no further acidic species (Table 1).
3
aldehyde/orthoester combination at 70 °C; however the yields
were dependent on the use of stoichiometric amounts of both
reagents. An excess of benzaldehyde over triethyl orthoformate
was necessary for producing the desired product 3 (Entries 4, 5,
and 7), whereas an equimolar amount mainly afforded 4,6-
orthoester 5 (diastereomeric mixture) (Entry 6). A periodic
analysis of the reaction mixture under the optimized
stoichiometric conditions (Table 1, entry 7) revealed that
orthoester 5 was indeed an intermediate that preceded the
generation of benzylidene 3. The specific nature of the orthoester
reagents also affected the yields, with ethyl orthoformate being
better performing than the corresponding methyl counterpart
(data not shown). It should be noted that under the optimized
conditions (Table 1, entry 7) the benzylation/benzylidenation
sequence afforded a similar yield (65%) to that of the benzylation
step alone (64%),6 thus evidencing that the ammonium/amine
mixture is capable of promoting the 4,6-O-benzylidenation in
quantitative yield.
Table 1. Optimization studies for the one-pot, solvent-free
benzylation/benzylidenation sequence.
Entry
Second step conditions (eq.)
PhCH(OMe)2 (2), 100 °C, 2 h
Products and yields a
3 28%
1
2
The scope of this one-pot strategy was examined by
evaluating the effect of several structural variables in both the
saccharide precursor and the acetalation reagent (Table 2). The
tin-catalyzed regioselective 3-O-benzylation of manno- and
galacto- precursors provided intermediates which were further
derivatized in situ using a range of broadly used diol protecting
groups such as benzylidene (Entries 4, 8), anisylidene (Entries 1,
5, 9), isopropylidene (Entry 3), and 2-naphthylidene (Entry 2).
The general benzylation/acetalation procedure was also possible
starting from tin-free regioselective benzylation at the primary
position5 of galactoside precursor 9 (Entries 6 and 7) and
subsequent 3,4-O-benzylidenation of the cis-diol moiety.
Although moderate, the obtained yield of 14 (ca. 35%) is
synthetically useful compared with that of the lengthy multi-step
routes described to obtain the same product.13 Also interesting in
this synthesis is the higher reactivity of benzaldehyde dimethyl
acetal as the acetalation agent in the second step (compare the
reaction times in entries 5 and 6). As also shown below, this
reagent was better performing when five-membered benzylidenes
were generated from vicinal diols.
PhCH(OMe)2 (2), 70 °C to 100
°C, 2 h
3 32%
3
p-MeO-ArCH(OMe)2 (2.5), 80
°C to 90 °C, 2 h
4 41%
3 42%
4
5
6
PhCHO (3), HC(OMe)3 (2),
90 °C, 2 h
PhCHO (3), HC(OEt)3 (2),
70 °C, 3 h
3 45%
PhCHO (3), HC(OEt)3 (3),
70 °C, 3 h
5 57%
3 65%
7
PhCHO (4), HC(OEt)3 (3),
70 °C, 3 h
It is worth noting that the benzylation/benzylidenation
sequence also proved viable from mannose in its free hemiacetal
form (Table 2, entries 8 and 9), taking advantage of an efficient
tin-catalyzed initial step yielding a -configured 1,3-di-O-
benzylated mannopyranoside intermediate.6 Interestingly, the
final products 15 and 16 were obtained mainly as -anomers,
indicating the occurrence of rapid anomerization during the
acetalation step. This process was not unexpected as recent
studies evidenced that pyranosides contained in bicyclic systems
are especially amenable to acid-promoted isomerization via an
endocyclic cleavage mechanism.14
aIsolated yield
These experiments evidenced that the crude mixture from the
preliminary tin-catalyzed 3-O-benzylation step was capable of
catalyzing the acetalation processes. Application of benzaldehyde
dimethyl acetal as the benzylidenation reagent at high
temperature (up to 100 °C) provided moderate yields of
orthogonally-protected product 3 (Entries 1-2) along with several
side products (Fig. 1) arising from either mono- and
dibenzylidenation of unreacted starting mannoside 1 (products 6
and 7, respectively), or competitive 6-O-benzylation
of
In order to increase the synthetic scope of this one-pot
strategy, we examined sequential selective protection of the
primary positions followed by a benzylidenation step to protect
the vicinal cis-diol.
intermediate 2 (product 8).5
In this regard, we searched for a higher yielding sequence than
the benzylation/benzylidenation consecutive steps examined in
Table 2 (Entries 5 and 6). An effective solvent-free silylation of
primary alcohols in the presence of a reduced amount of pyridine
Figure 1. Main side products from the reactions in Table 1.
was available,7 prompting us to investigate
a
6-O-
6-O-
silylation/benzylidenation
sequence.
The
A slightly improved result was observed under similar
conditions for the installation of an anisylidene acetal (4, entry
3), presumably due to the higher reactivity of the corresponding
acetalation agent.
TBDPS/benzylidenation modification proved effective with a
variety of model substrates (Scheme 1).
In order to minimize the competitive generation of undesired
product 8, favoured at high temperatures via a tin-uncatalyzed
route,5 lower temperatures were examined for increasing the

3
Table 2. Scope of the one-pot benzylation/acetalation procedure.
Entry
1
Substrate
Benzylation step
conditions (eq)
Acetalation step conditions (eq)
Products and yieldsa
1
1
1
Bu2SnO (0.1), DIPEA
(2.5), BnBr (4), TBAB
(0.3);
p-MeO-ArCHO (4), HC(OEt)3 (3);
80 °C, 3 h
70 °C, 3.5 h
4 60%
2
3
As per entry 1
2-NapthCHO (4), HC(OEt)3 (3);
100 °C, 3 h
10 53%
Me
As per entry 1
2,2-dimethoxypropane (4);
80 °C, 2 h
OH
O
O
Me
O
BnO
OMe
11 54%
4
5
6
Bu2SnO (0.1), DIPEA
(2.5), BnBr (4), TBAB
(0.3);
PhCHO (4),
HC(OEt)3 (3),
70 °C, 2.5 h
70 °C, 2 h
9
9
12 60%
13 62%
As per entry 3
p-MeO-ArCHO (4),
HC(OEt)3 (3),
80 °C, 2.5 h
9
DIPEA (4), BnBr (4),
TBAI (0.3);
PhCHO (4), HC(OEt)3 (3);
90°C, 6 h
90 °C, 5 h
14 36%
14 35%
7
8
9
As per entry 5
As per entry 1
PhCH(OMe)2 (2); 90 °C, 2 h
PhCHO (4), HC(OEt)3 (3);
70 °C, 2 h
D-mannose
15 58%
16 46%
9
D-mannose
As per entry 1
p-MeO-ArCHO (4),
HC(OEt)3 (3);
80 °C, 2.5 h
aIsolated yield
The success of this reaction sequence was dependent on the
benzylidenation agent, with benzaldehyde dimethyl acetal
performing better than the benzaldehyde/ethyl orthoformate
system; the latter reagent combination led to preferential
orthoesterification of the cis-diols without subsequent conversion
into the corresponding benzylidenes which was observed with
4,6-diols (Table 1 and 2). Interestingly, when digititol 18 was
submitted to the silylation/benzylidenation sequence, product 22
with a six-membered benzylidene ring was predominantly
formed (68% yield) over the possible isomers with five-
membered acetals. Overall, the whole sequence took a few hours,
and the benzylidenation step required only the addition of
benzaldehyde dimethyl acetal and adjustment of the temperature
(90 °C). The possible installation of an isopropylidene protecting
group in the second step was also demonstrated with the
Scheme 1. One-pot, solvent-free silylation/benzylidenation
sequences.

4
Tetrahedron
conversion of 1 into 20. The obtained results indicate that
References and notes
pyridinium/pyridine mixtures can be as effective as
ammonium/amine mixtures from DIPEA to promote in situ acetal
functionalization.
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12
followed by an acetalistion step (Scheme 2). Benzylidenation
or isopropylidenation reactions could be performed in the second
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Scheme 2. One-pot, solvent-free iodination/acetalation
sequence.
Conclusion
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In this paper we have highlighted the synthetic usefulness of
solvent-free, one-pot reaction sequences based on base- and acid
promoted reactions where ammonium (or pyridinium) species
formed as side-products in the former step are recycled as
catalysts in the latter step. The broad scope of this general
strategy was demonstrated by the number of useful saccharide
building-blocks with orthogonal protection obtained using simple
protocols working under air and with short reaction times. In
most cases, unprecedented combinations of functional groups,
not accessible with previously described one-pot methodologies,
were assembled. We believe that the scope of the general strategy
underpinning this work might be further extended in organic
synthesis, with the development of new one-pot synthetic
strategies for the multiple elaboration of highly functionalized
substrates.
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Supplementary Material
Acknowledgments
Supplementary Information (ESI) available: experimental
details, NMR data and spectra of all products.
Financial
support
from
Ministero
dell’Istruzione,
dell’Univesita` e della Ricerca (MIUR) (Progetto PON_00117:
“Antigeni ed adiuvanti per vaccini ed immunoterapie”).
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One-pot synthesis of orthogonally functionalized
sugars under solvent-free conditions
One-pot sequential steps with self-generation of the
catalyst
Experimentally simple procedures working under
air