Radical halogenation-mediated latent-active glycosylations of allyl glycosides

Article abstract of DOI:10.1039/c7cc07332a

Radical halogenation-mediated glycosylation using allyl glycosides as donors and as acceptors emerges to be an efficient and hither-to unknown glycosylation method, adhering to the concept of the latent-active methodology. Several di- and trisaccharides that possess the allyl moiety at their reducing end are prepared through this new glycosylation methodology.

Full text of DOI:10.1039/c7cc07332a

Volume 54 Number 6 18 January 2018 Pages 573–696
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Chemical Communications
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COMMUNICATION
Narayanaswamy Jayaraman et al.
Radical halogenation-mediated latent–active glycosylations of allyl
glycosides

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Radical halogenation-mediated latent–active
glycosylations of allyl glycosides†
Cite this: Chem. Commun., 2018,
54, 588
Rita Pal, Anupama Das and Narayanaswamy Jayaraman
*
Received 19th September 2017,
Accepted 27th November 2017
DOI: 10.1039/c7cc07332a
rsc.li/chemcomm
Radical halogenation-mediated glycosylation using allyl glycosides
as donors and as acceptors emerges to be an efficient and hither-to
unknown glycosylation method, adhering to the concept of the
latent–active methodology. Several di- and trisaccharides that
possess the allyl moiety at their reducing end are prepared through
this new glycosylation methodology.
Fig. 1 Allylic halogenation mediated glycosylation using O-allyl glycosyl
donors and acceptors.
Chemical glycosylations bear a crucial importance in efforts to
secure diverse, complex oligosaccharides and glycoconjugates
of functional importance.1 A plethora of glycosylation methods,
including enzymatic routes, permit preparation of complex formation of a glycoside product. This new methodology is
oligosaccharides under solution and solid phase conditions.2,3 fine-tuned further such that an allyl glycoside forms a donor
The allyl moiety is used commonly as a protecting group and is and an acceptor under the latent–active glycosylation metho-
deprotected under mild conditions, prominently through a dology (Fig. 1). In this strategy, allyl glycoside donor I is
metal-mediated isomerization to vinyl ether, followed by an acid subjected to (i) a free radical induced allylic halogenation,
treatment.4,5 The sugar vinyl ether is also used beneficially to which forms an ‘active’ glycosyl donor moiety (II); and (ii)
conduct a glycosylation reaction with an acceptor alcohol.6 Such treatment of the glycosyl allylic halide intermediate II with an
a vinyl glycoside intermediate is established as a glycosyl donor acid promoter, followed by reaction with a ‘latent’ allyl glyco-
under the ‘latent–active’ glycosylation methodology,6b,7 wherein side acceptor (III), which leads to the formation of glycoside IV.
an allyl glycoside is activated as a reactive vinyl glycoside donor, Reiteration of the above steps leads to higher glycoside product
whose reaction with an acceptor alcohol moiety leads to a VI. The sequence of converting the allyl glycoside to a product
glycoside product. The newly formed glycoside possesses the oligosaccharide allyl glycoside is accomplished in one pot.
allyl moiety at the reducing end, which is useful to reiterate the
The reaction of allyl tetra-O-acetyl-D-glucopyranoside (1) was
reaction sequence, leading to the formation of a newer glycoside. carried out initially, in which 1 when reacted with N-bromo-
An advantage is that it does not require installation of an succinimide (NBS) and azo-bis-isobutyronitrile (AIBN) in CCl4
alternate anomeric leaving group, such that the glycosyl donor under refluxing conditions led to allyl bromide intermediate
and acceptor can be prepared from a common building block formation. Allylic bromination using NBS under irradiation is
and the sequential glycosylation can be performed via a single known earlier as a deprotection method, wherein the newly
glycosylation method.
formed allyl bromide intermediate is hydrolysed to the corres-
We herein report a new, hither-to unknown glycosylation ponding sugar lactol.8 Radical halogenations at the ring positions
method that combines a free radical induced halogenation of of carbohydrates are known.9 The reaction of the allylic bromide
an allyl glycoside, which in the presence of an acid promoter intermediate with methanol in the presence of AgClO4 or Ag2CO3
reacts with a glycosyl or aglycosyl acceptor, leading to the (1.2 molar equiv. relative to the donor) at 0 1C to room tempera-
ture led the reaction to only the methoxy substitution product 2
(Scheme 1). A similar substitution product was also obtained in
the reaction of allyl tetra-O-acetyl-D-mannopyranoside with
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012,
India. E-mail: jayaraman@iisc.ac.in; Fax: +91-80-2360-0529; Tel: +91-80-2293-2578
methanol. A change in solvent and optimizing reaction condi-
tions were found to overcome the formation of a substitution
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c7cc07332a
588 | Chem. Commun., 2018, 54, 588--590
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Table 1 List of glycosides formed by allylic halogenation and subsequent
acid-catalyzed glycosylation between allyl glycoside donors and acceptorsa
Scheme 1 Radical halogenation mediated reactions of allyl glycosides.
product and to promote the formation of an oxocarbenium ion
required for a successful glycosylation. Radical bromination in
CCl4 followed by reaction with n-pentanol in the presence of
AgOTf in CH2Cl2 at À40 1C afforded glycoside 3 as the b-anomer,
in 37% yield, along with hemiacetal in 60% yield (Scheme 1). The
unreacted aglycosyl acceptor also remained in the reaction. Similar
results were observed with the acetate protected fucosyl donor and
its reaction with n-pentanol (ESI†). The yield of the desired
glycosylation product increased when the benzoyl protected allyl
glycoside donor and AgOTf promoter were used. Thus, the reaction
of O-benzoyl protected allyl glycoside 4 with acceptor 5 afforded
disaccharide 6, in 63% yield as the b-anomer (Scheme 1).
Modification of the promoter to a Brønsted acid in place of a
halophilic reagent promoted the glycosylation even better.
Glycosylation experiments were conducted using a catalytic
amount of TfOH10 as promoter in place of silver salts and, in
this instance, the formation of glycoside 6 occurred, with an
isolated yield of 90%, resulting from the reaction of allyl
glycoside 4 with methyl glycoside acceptor 5. We premise
that protonation of the glycosidic oxygen by TfOH facilitates
a
Isolated yields based on the acceptor glycoside molar equivalent and
b
anomeric linkage as determined using the NMR spectra. O-Deacylated
product was also observed. Disaccharide with a 1,6-glycosidic linkage
was also isolated in 20% yield.
c
the generation of the oxocarbenium ion intermediate, along crude reaction mixture was purified (SiO2, hexanes/EtOAc) to
with the bromohydrin of acrolein as the by-product.11 A series afford glycoside products, which were characterized by physical
of reactions showed the following: (i) conducting the reaction at techniques (ESI†). The outcomes of the glycosylation thus
–78 1C or at room temperature led to either no reaction or the performed using varied types of allyl glycoside donors and
formation of a complex mixture, respectively; (ii) increasing the acceptors are given in Table 1. As listed in the table, a number
reaction duration to 24 h did not aid in the formation of of allylic glycoside donors and acceptors (Fig. 2) were tested in
the desired product in a quantitative yield; (iii) change of order to verify the efficacy of the new glycosylation method
solvent for glycosylation to CH3CN and CH3NO2 led to poor developed herein. The isolated yields are good to excellent in
yields of the desired product and (iv) reaction between the all cases and the anomeric configurations were essentially
glycosyl donor and acceptor did not occur in the absence of 1,2-trans at the newly formed glycosidic bond, which suggests
NBS/AIBN reagents in the first step and in the presence of TfOH that the glycosylation reaction occurs via the oxocarbenium ion
alone. From these reactions, the following reaction conditions intermediate, stabilized by a neighboring group participation.
are optimized for the glycosylation reactions: (i) treatment of a Further, the b-anomer of the allyl glycoside donor is also
mixture of the allyl glycoside donor (1 molar equiv.) and powdered suitable as the glycosyl donor during glycosylation. Exclusion
molecular sieves (4 Å) (B200 mg) with NBS (0.9 molar equiv.) in of moisture was necessary to avoid the lactol formation. Lower
CCl4 (20 mL for 100–150 mg of donor); (ii) degassing the reaction yields in the case of acetate and silyl protecting groups on the
mixture under an Ar atmosphere for B5 min; (iii) addition of donors were observed, wherein these moieties were partially
AIBN (cat.), again degassing for B5 min and refluxing the reaction deprotected in the product glycosides, leading to decreasing the
mixture for B30 min; (iv) removal of solvents in vacuo, yields of fully protected products. In this instance, donors
re-dissolving the reaction mixture in CH2Cl2 (5 mL) under an with benzoate protecting groups afforded glycoside products with
Ar atmosphere, and cooling to À40 1C and (v) adding TfOH considerably increased yields.12 Benzyl and benzylidene protecting
(10 mol%), stirring for B10 min, then adding acceptor alcohol groups are well tolerated in the glycosyl acceptor component,
(0.7 molar equiv.) and work-up of the reaction after B2 h. The although competitive to the allyl moiety in the donor component.
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catalyst poisoning and reduction of the allyl moiety to the
n-propyl moiety. Further, allyl glycosides are prepared directly
from bench-top free sugars and the glycosylations conducted in
one pot add advantage to the methodology developed herein.
We thank the Department of Science and Technology (DST)
and the Council of Scientific and Industrial Research, New Delhi,
for financial support. DST is gratefully acknowledged for support
under the Women Scientists Scheme to RP. The University
Grants Commission, New Delhi, is acknowledged for a research
fellowship to AD.
Fig. 2 List of (a) allyl glycoside donors and (b) methyl and allyl glycoside
acceptors used to synthesize di- and trisaccharides as given in Table 1.
Conflicts of interest
There are no conflicts to declare.
The importance of the reaction is that the presence of the
allyl protecting moiety at the anomeric carbon of the glycosyl
acceptor does not interfere in the reaction with the allyl glyco-
side donor and the desired glycoside products formed in good
yields in all cases, adhering to the ‘latent–active’ glycosylation
methodology. Further double glycosylation of an allyl glycoside
having primary and secondary hydroxyl group acceptor sites
(18) with an allyl glycoside donor (9) led to the desired product
38, in a moderate yield. The glycosylation was conducted in a
gram scale quantity in the case of the formation of 31 and the
product was obtained in 80% yield.
Having established the successful glycosylation of allyl
glycoside donors with glycosyl and aglycosyl acceptors through
radical halogenation activation, leading to di- and trisaccharides, the
feasibility of subjecting the newly formed allyl glycosides as glycosyl
donors to further glycosylations was tested. Performing allylic activa-
tion through radical halogenation of glycosyl allyl halides 31 and 32
as active donors, followed by continuing the reactions with appro-
priate latent allyl glycoside acceptor 14, in the presence of TfOH and
molecular sieves in CH2Cl2, afforded trisaccharides 39 and 40
(Table 1), in good yields, as a-anomers. These reactions illustrate
that the newly formed disaccharides are available for activation and
further glycosylation reaction with allyl glycoside acceptors.
In conclusion, a new glycosylation methodology is developed,
by utilizing an allyl glycoside as the common substrate, acting as
a donor and an acceptor. Key reactions involved are the allyl
glycoside activation through radical halogenation and the sub-
sequent reaction with a glycosyl or aglycosyl acceptor in the
presence of triflic acid. A range of allyl glycosides as donors and
acceptors is utilized in a ‘latent–active’ manner, leading to the
corresponding product glycosides, with the allylic moiety at
the reducing end, in good to excellent yields. The presence of
the allyl moiety at the reducing end of the newly formed glyco-
side facilitates further glycosylation. Thus product allyl glyco-
sides are extended to the preparation of trisaccharides that
possess the allyl moiety at the reducing end. In a plethora of
chemical glycosylations,1–3 the novelty and advantages of the
method developed herein are as follows: (i) the reactions are
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´
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590 | Chem. Commun., 2018, 54, 588--590
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