Organic &
Biomolecular Chemistry
COMMUNICATION
Zinc mediated activation of terminal alkynes:
stereoselective synthesis of alkynyl glycosides†‡
Cite this: Org. Biomol. Chem., 2014,
12, 7900
Madhu Babu Tatina,a,b Anil Kumar Kusunuru,a,b Syed Khalid Yousuf*c and
Received 7th July 2014,
Accepted 26th August 2014
Debaraj Mukherjee*a,b
DOI: 10.1039/c4ob01405g
Zinc mediated alkynylation reaction was studied for the prepa- compatibilities of these organo-metallic species have widened
ration of C-glycosides from unactivated alkynes. Different glycosyl their applications in synthetic organic chemistry.7 In carbo-
donors such as glycals and anomeric acetates were tested towards hydrate chemistry, however, the use of organo-zinc reagents is
an alkynyl zinc reagent obtained from alkynes using zinc dust and limited due to solubility problems, such as the use of a combi-
ethyl bromoacetate as an additive. The method provides simple, nation of solvents,8 use of strong base,9 poor anomeric selecti-
mild and stereoselective access to alkynyl glycosides both from vity,10 oxidation–reduction sequence,11 excess use of
aromatic and aliphatic acetylenes.
promoters and drastic reaction conditions.8 To the best of our
understanding, there are no reports of the applications of
organo-zinc reagents for C-alkynylation of glycals and other
glycosyl donors. In this letter, we would like to disclose our
findings regarding C-alkynylation in carbohydrates with high
stereocontrol obviating the use of strong Lewis acids or bases
and exploiting both aromatic and aliphatic alkynes.
In order to develop a reagent system for C-alkynylation of
glycals from unactivated aliphatic alkynes, 3,4,6-tri-O-acetyl-
D-glucal (1) and 1-octyne (2) were allowed to react in the pres-
ence of various Lewis acids and metals; the results are sum-
marized in Table 1. Initially we attempted to use Lewis acids,
like Zn & In halides (Table 1, entries 1–3), where we observed
the formation of alkynyl glycoside 3 and halogenated vinyl gly-
coside 3′ in equal amounts. Changing the metal halide with
iron chloride failed to give the desired product 3, instead we
obtained complex mixtures of halogenated vinyl glycoside 3′
(Table 1, entry 4).
Triflates such as Fe(OTf)3, In(OTf)3, TMSOTf (Table 1,
entries 5–7) exclusively furnished the desired product 3,
however, in poor yields (18–20%). Taking a clue from the litera-
ture reports for zinc mediated alkyne activation,12 when the
above reaction was carried out using zinc powder in the
absence of any additive, the starting material was recovered as
such (Table 1, entry 8). We observed that the choice of additive
and the nature of the solvent play a significant role in the
outcome of the reaction. After extensive investigation of addi-
tives and solvents, the formation of the desired C-alkynyl glyco-
side (3) (68%) was witnessed with zinc powder in the presence
of ethyl bromoacetate as an additive in DCM at 40 °C (Table 1,
entry 9). Other solvents like THF (Table 1, entry 10) or other
additives like methyl iodide (Table 1, entry 12) failed to give
the desired product. Replacing zinc with indium produced the
desired product in lower yield (Table 1, entry 11).
The synthesis of chiral building blocks from cheap and easily
available starting materials has always been an interest in
organic chemistry.1 In this endeavour, carbohydrates have
uninterruptedly maintained a prominent place. Though these
naturally occurring materials on their own serve to be starting
materials for chiral synthesis,2 attachment of extra carbon
chains gives rise to new chiral scaffolds of synthetic and bio-
logical importance.3 In this regard, alkynyl C-glycosides have
attracted tremendous interest due to the presence of multiple
bonds; a real asset for target oriented synthesis and creation of
diversity.4 With our continuing interest in this direction,5 we
have reported direct access to alkynyl C-glycosides from un-
activated aromatic alkynes under copper triflate/ascorbic acid cat-
alysis.5a Despite several advantages over the literature methods,6
the main demerit of our reagent system lay in its inefficiency to
activate aliphatic alkynes and glycosyl donors, except for glycals.
In order to overcome these shortcomings of our strategy, we con-
tinued our studies in developing a universal reagent for C-alkyny-
lation of glycals and other carbohydrate donors.
C–C bond formation reactions using in situ generated
organo-zinc species have thoroughly been investigated in un-
saturated systems.7 Low reactivity and broad functional group
aAcademy of Scientific and Innovative Research, CSIR-IIIM, India.
E-mail: dmukherjee@iiim.ac.in; Fax: (+)91-011-256-9111
bIndian Institute of Integrative Medicine, Jammu, 180001, India
cIndian Institute of Integrative Medicine Br., Srinagar, 190005, India.
E-mail: khalidiiim@gmail.com
†Institutional number IIIM/1695/2014.
‡Electronic supplementary information (ESI) available: Detailed experimental
procedures and compound characterization data is given. See DOI: 10.1039/
c4ob01405g
7900 | Org. Biomol. Chem., 2014, 12, 7900–7903
This journal is © The Royal Society of Chemistry 2014
Tatina, Madhu Babu
