2,4,6-Trichloro-1,3,5-triazine (TCT) mediated one-pot sequential functionalisation of glycosides for the generation of orthogonally protected monosaccharide building blocks

Article abstract of DOI:10.1039/c2ob25452b

Orthogonally protected monosaccharide building blocks have been prepared using TCT in a one-pot multicomponent transformation. The process involves successive steps of arylidene acetalation, esterification and regioselective reductive acetal cleavage. High regioselectivity, scope for using a broad range of substrates, functional group tolerance, mild reaction conditions, easy handling process and wide application range are a few advantages of the current process.

Full text of DOI:10.1039/c2ob25452b

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2,4,6-Trichloro-1,3,5-triazine (TCT) mediated one-pot sequential
functionalisation of glycosides for the generation of orthogonally
protected monosaccharide building blocks†
Madhubabu Tatina, Syed Khalid Yousuf and Debaraj Mukherjee*
Received 1st March 2012, Accepted 6th June 2012
DOI: 10.1039/c2ob25452b
in a single reaction vessel, would make the process more advan-
Orthogonally protected monosaccharide building blocks
have been prepared using TCT in a one-pot multicomponent
transformation. The process involves successive steps of
arylidene acetalation, esterification and regioselective reduc-
tive acetal cleavage. High regioselectivity, scope for using a
broad range of substrates, functional group tolerance, mild
reaction conditions, easy handling process and wide appli-
cation range are a few advantages of the current process.
tageous, atom economic and environmentally benign.10 Protec-
tion of a pair of appropriately oriented 1,2- or 1,3-hydroxyls as
cyclic acetals is one of the most frequently used reactions in
polyhydroxy compounds like carbohydrates and cyclitols.11 The
use of 4,6-O-arylidene acetalation in combination with esterifica-
tion at C-2 and C-3 as a protecting group strategy is widely prac-
tised on carbohydrate templates as it provides a versatile
orthogonal protection that allows for regio- and stereo-control in
oligosaccharide assembly.6a,9e,12 4,6-O-Arylidene acetals can
either undergo regioselective ring opening to provide a free
OH at 4 or 6 position or make both the hydroxyl groups free, via
acetal hydrolysis or hydrogenolysis.11 Transformations of
benzylidene acetal to a benzyl or benzoyl group are useful con-
versions in the synthesis of oligosaccharides. However these
transformations (both arylidenation and arylidene deprotection)
are often associated with several shortcomings like use of harsh
acidic conditions and expensive reagents making the processes
inconvenient for large scale production, incompatibility with
other functional groups and generation of side products.13 The
use of a milder Lewis acid to catalyse these reactions is rarely
reported. Very recently Galan et al.9e reported the application of
Cu(OTf)2 for the one-pot preparation of orthogonally protected
glycosides from unprotected ones.
A renaissance in glycobiology and glycochemistry has made
carbohydrates and their derivatives integral components of
modern drug discovery programmes.1 In synthetic organic chem-
istry, monosaccharides act as the principle chiral pool for natural
product synthesis.2 However, the structural complexity and
diversity along with the polyfunctionality of carbohydrates have
always hampered their biological studies and chemical appli-
cations.3 Chemical and chemoenzymatic synthesis provide an
alternative to exploit the biological and medicinal significance of
carbohydrates.4 Chemical synthesis involves the reaction
between selectively protected monosaccharide units, one with a
strategically positioned free hydroxyl group (a nucleophilic
acceptor) and one bearing a labile group at the anomeric carbon
(a donor), in a chemo-, regio- and stereoselective fashion.5 Thus,
stereospecific glycosylation and orthogonal protection are the
two main challenges before carbohydrate chemists. Although
more advances have been made in the former,6 the synthesis of
differentially protected monosaccharide scaffolds is still waiting
for more satisfactory processes. In the last few years elegant
Lewis acid-catalysed one-pot regioselective protection strategies
have been reported by the groups of Hung,7 Beau,6,8 and
others.9 Even then, development of catalytic synthetic strategies
for the efficient generation of monosaccharide building blocks
remains a pressing requirement in carbohydrate chemistry.
In particular, development of a catalytic process, which envi-
sages two distinct transformations promoted by a single catalyst
Inexpensive and readily available catalysts that bring about
organic transformations in operationally simple ways are always
an attractive approach for an organic chemist. Careful tuning of
catalysts in a synchronized manner can lead to new synthetic
transformations possessing significant chemoselectivity in func-
tionally complex systems. To exemplify this concept, cyanuric
chloride (TCT) has emerged as a catalyst of choice in organic
transformations owing to its easy commercial availability, com-
bined with stable, non-volatile, inexpensive, and easy to handle
nature.14 For example, it reacts with alcohols and acids to furnish
the corresponding alkyl halides15 and activated cyanurate esters
respectively, which serve as useful starting materials in organic
synthesis. Its adduct with DMF is used in the Beckman
rearrangement16 and for formyl protection of the primary
hydroxyl group,17 while that with DMSO is used in the classical
Swern oxidation.18 Syntheses of some important heterocycles
such as xanthene derivatives19 and polysubstituted quinolines20
NPC-microbes, Indian Institute of Integrative Medicine (IIIM), Jammu,
India. E-mail: dmukherjee@iiim.ac.in; Fax: +91-191-2569111;
Tel: +91-191-2569000
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25452b
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are also catalyzed by TCT. Very recently Chauhan et al.14
reported a TCT catalyzed mild protocol for the synthesis of bio-
logically active dihydro/spiro quinazolinones and quinazolinone-
glycoconjugates. But in carbohydrate chemistry its use is limited
to the preparation of glycosyl chlorides.21
With our recent success in the development of a one-pot
atom-economic approach in carbohydrate chemistry,22 particu-
larly for orthogonally protected carbohydrate building blocks,
we speculated that TCT could be a catalyst of choice for the
generation of orthogonally protected building blocks from glyco-
sides while providing a mild reaction medium. In order to extract
practical evidence in favour of our hypothesis, the potential of
TCT to activate methylene arylidene acetals was evaluated.
Thus, methyl-α-D-glucopyranoside 1 was allowed to undergo
4,6-O-arylidene acetalation in the presence of TCT (0.3 equiv.)
and methylene arylidene acetal (1.2 equiv.) in CH3CN at r.t.
(Scheme 1).
Quantitative conversions to products 4,6-O-benzylidene acetal
derivative 1a and 4,6-O-p-metoxybenzylidene acetal 1b were
achieved within 5 h. As acetalation processes are generally
favoured by ultrasound,13 irradiation of the reaction mixture with
high intensity ultrasound was resorted to, which accomplished
the acetalation of glycoside 1 within 10 min in >99% yield.
Encouraged by these results, the scope and generality of the
reaction was explored by using thio-, O-, and silyl glycosides
(entries 1–13, Table 1). In all cases, the reaction proceeded
smoothly leading to the formation of the corresponding products
in quantitative yield. The reaction conditions were found compa-
tible with different protecting groups like acetyl (entry 1) or
benzoyl (entry 2) esters, benzyl ethers (entry 3), and amino pro-
tecting groups (entries 10, 11), making the process more versa-
tile. High regioselectivity was observed with the formation of
4,6-O-arylidene products only. Formation of no side product like
2,3-O-acetal in case of methylmannoside 9 (entry 8) or 3,4-O-
acetal in case of thiogalactoside 10 (entry 9) was detected. On a
larger scale (20 g substrate), the reaction proceeded in a similar
manner even with a lower catalyst loading (10 mol%), thus
making the process amenable to easy scale up.
Scheme 1 TCT-catalysed 4,6-O-arylidene acetalation.
Table 1 TCT mediated 4,6-O-arylidene acetalation
Entry Ar Substratea Productb
Yieldc (%)
999e
1
Ph
2
Ph
9323
9824
3
Ph
4
5
6
Ph
Ph
Ph
959e
9925
9926
7
8
Ph
Ph
9527
9828
9
Ph
969e
We next designed a one-pot strategy for the preparation of
orthogonally protected monosaccharide building blocks, using
TCT for a one-pot sequential acetalation/acetylation reaction.
Thus, methyl-α-D-glucopyranoside 1 was subjected to TCT
mediated acetalation using benzaldehyde dimethylacetal, and
then treated with Ac2O for acetylation under sonication
(Scheme 2). Formation of product 12a was indeed observed after
8 h. To check the feasibility of the reaction, glycosides 6–11
were allowed to react under the same conditions to obtain the
corresponding acetalated acetylated products (13a–18a, Fig. 1).
In all cases, including the amino protecting group containing
substrate 11, good to excellent yields were obtained (Fig. 1). The
labile p-methoxybenzylidene acetal (rate of hydrolysis 10 times
faster than benzylidene acetal)9e,29 survived under the reaction
conditions (Scheme 2, 12b), underlining the mildness of the
reaction conditions.
10
11
Ph
Ph
809e
7523
a In all cases 1 mmol of glycoside, 1.2 mmol of a methylene arylidene
acetals and 0.3 mmol of cyanuric chloride were used. b Characterised by
1H NMR and 13C NMR. c Isolated yield after column chromatography.
Contemporary organic synthesis demands the development of
simple one-pot multicomponent organic transformations due to
their advantages over sequential approaches.22b We, therefore
proposed the opening of 4,6-O-benzylidene using a hydride
source in the same pot keeping in view the fact that 1 mol of
TCT generates 3 moles of HCl.30 Consequently, methyl-α-D-glu-
copyranoside 1 was subjected to one-pot acetalation–acetylation
under standardised reaction conditions followed by the addition
of NaCNBH3 as a hydride source for acetal cleavage, and
5358 | Org. Biomol. Chem., 2012, 10, 5357–5360
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Scheme 2 TCT mediated one-pot acetalation–acetylation.
Fig. 2 Library of orthogonally protected monosaccharide acceptors
prepared using current MCR.
In summary, TCT has proven to be a mild, inexpensive, non-
toxic, functional group tolerant, environmentally viable catalyst
for the generation of orthogonally protected monosaccharide
units. The high regioselectivity and substrate diversity add to the
advantages of the current methodology over the already existing
ones. The process is useful for industrial purposes owing to the
easy availability and low cost of TCT.
Fig. 1 Generation of TCT promoted orthogonally protected carbo-
hydrate units.
Notes and references
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Scheme 3 TCT mediated one-pot sequential acetalation–acetylation–
reductive opening reactions.
Table 2 Suitability of different hydride donors for reductive ring
opening
Entry
Hydride donora
Time (h)
Yieldb (%)
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