A general metal-free approach for the stereoselective synthesis of C-glycals from unactivated alkynes

Article abstract of DOI:10.3762/bjoc.10.277

A novel metal-free strategy for a rapid and α-selctive C-alkynylation of glycals was developed. The reaction utilizes TMSOTf as a promoter to generate in situ trimethylsilylacetylene for C-alkynylation. Thanks to this methodology, we can access C-glycosid

Full text of DOI:10.3762/bjoc.10.277

A general metal-free approach for the stereoselective
synthesis of C-glycals from unactivated alkynes
Shekaraiah Devari1, Manjeet Kumar1, Ramesh Deshidi1, Masood Rizvi*2
and Bhahwal Ali Shah*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2649–2653.
1Academy of Scientific and Innovative Research (AcSIR); Natural
Product Microbes, CSIR-Indian Institute of Integrative Medicine,
Canal Road, Jammu -Tawi, 180001, India and 2Department of
Chemistry, University of Kashmir, 190006, India
doi:10.3762/bjoc.10.277
Received: 01 September 2014
Accepted: 01 November 2014
Published: 12 November 2014
Email:
Masood Rizvi* - masoodku2@gmail.com; Bhahwal Ali Shah* -
bashah@iiim.ac.in
Associate Editor: T. P. Yoon
© 2014 Devari et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
α-selective; C-alkynylation; glycal; metal free; TMSOTf
Abstract
A novel metal-free strategy for a rapid and α-selctive C-alkynylation of glycals was developed. The reaction utilizes TMSOTf as a
promoter to generate in situ trimethylsilylacetylene for C-alkynylation. Thanks to this methodology, we can access C-glycosides in
a single step from a variety of acetylenes , i.e., arylacetylenes and most importantly aliphatic alkynes.
Introduction
C-Glycosides represent an important class of carbohydrate followed by a Ferrier type rearrangement [31-34] (Scheme 1). A
mimics, owing to their presence in a large number of bio- consequence of the prior activation of alkynes is the involve-
logically active natural products, such as palytoxin, spongis- ment of multiple steps and thus loss of yields. Recently,
tatin, vitexin, orientin, bergenin and halichondrin [1-5]. Over Mukherjee and co-workers [35] have reported a one-step
the years myriad methods have appeared for their efficient and C-alkynylation of glycals by using metal in combination with a
stereoselective synthesis [6-12]. Among these methods, co-oxidant, i.e., Cu(OTf)2 with ascorbic acid. However, a draw-
C-alkynylation [13-16] is of particular interest as it is amenable back of the method is its limited applicability to arylacetylenes
to further modifications into chiral molecules, carbohydrate only and its restricted selectivity to reactions performed in the
analogues, and natural products, such as tautomycin [17,18] and solvent acetonitrile (Scheme 1).
ciguatoxin [19-21]. In recent past, significant efforts have been
directed toward the C-alkynylation of glycals [9,22,23]. It is obvious from the preceding discussion that the stereoselec-
However, all these methods use priorly activated terminal tive addition of alkynes to the anomeric carbon of sugar nuclei
alkynes, e.g., silylacetylene, activated with various Lewis acids in a single step still represents an interesting challenge. We
such as SnCl4, BF3·OEt2, TiCl4, I2, InBr3, and ZrCl4 [24-30], reasoned that the development of a strategy which in situ acti-
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Beilstein J. Org. Chem. 2014, 10, 2649–2653.
Scheme 1: C-alkynylation of glycals.
vates the terminal alkyne and further catalyzes the reaction Results and Discussion
without the aid of other Lewis acids might be a solution to this Initial investigations involved the use of 3,4,6-tri-O-acetyl-D-
problem. Thus, in continuation of our efforts [36-38], we glucal (1) and phenylacetylene (2) as model substrates with
describe a highly stereoselective TMSOTf catalyzed rapid TMSOTf as a promoter within DCM at −20 °C. To our delight
C-alkynylation of glycals with a wide variety of unactivated TLC showed full consumption of the starting materials in 2 min
alkynes, i.e., arylacetylenes and aliphatic alkynes. The method and yielded the desired product 3a in 80% yield (Table 1, entry
circumvents the use of metal catalysts/co-oxidants and exhibits 1). The structure and stereochemistry were elucidated by a com-
short reaction times, i.e., 2 min. This method may find use in a parison of the chemical shifts to that of reported values [35].
large number of reactions, which are characterized by a require- Also, the stereochemistry of the resulting product 3a was unam-
ment of pre-formed trimethylsilylacetylene.
biguously established as α by NOESY spectra, indicating cross
Table 1: Alkynylation reaction of 3,4,6-tri-O-acetyl-D-glucal with phenylacetylenea.
entry
Lewis acid
equiv
T (°C)
time
yieldb
(α/β)c
1
TMSOTf
In(OTf)3
Cu(OTf)2
Sc(OTf)3
BF3·OEt2
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
0.5
0.5
0.5
0.5
0.5
0.2
0.3
0.4
0.8
0.5
0.5
0.5
0.5
−20
−20
−20
−20
−20
−20
−20
−20
−20
−40
−10
0
2 min
5 h
80
–
99:1
–
2
3
5 h
–
–
4
5 h
–
–
5
5 h
–
–
6
1 h
–
–
7
1 h
<10
57
82
63
77
59
37
ND
ND
ND
ND
ND
ND
ND
8
15 min
2 min
5 min
2 min
2 min
2 min
9
10
11
12
13
rt
aIn all cases 1 equiv of 1 and 1.2 equiv of 2 were used; bisolated yields; cdetermined by 1H, 13C NMR and NOESY spectra; ND = not determined.
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Beilstein J. Org. Chem. 2014, 10, 2649–2653.
peaks between H-1, H-6 and H-4. To further establish the role further increase in catalyst loading had no significant impact on
of the catalyst we repeated the reaction with other Lewis acid the overall reaction yield and time (Table 1, entry 9). We also
catalysts, such as In(OTf)3, Cu(OTf)2, Sc(OTf)3 and BF3·OEt2, examined the effect of temperature on the reaction, and
but no product could be obtained (Table 1, entries 2–5). Next, observed that both an increase (up to rt) and a decrease (to
we focused our attention on optimizing the suitable amount of −40 °C) resulted in the loss of yield (Table 1, entries 10–13).
the catalyst loading. We observed that a decrease of the catalyst
loading below 30 mol % led to no product formation even after The scope of the present method was further expanded to a
1 h (Table 1, entries 6 and 7). However, an increase to variety of alkynes and glycals (Scheme 2). It was established
40 mol % with longer reaction time resulted in a loss of yield that the system was tolerant to a wide variety of electron-
due to the degradation of the product (Table 1, entry 8). A donating as well as electron-withdrawing terminal alkynes to
Scheme 2: Substrate scope of the reaction process under optimized reaction conditions.
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Beilstein J. Org. Chem. 2014, 10, 2649–2653.
give the corresponding products 3a–e in excellent yields and any alkyne, that is, aliphatic and aromatic. To the best of our
selectivity. It is noteworthy that the earlier reported [35] single- knowledge, this is the first report which descibres the in situ
step strategy failed to yield a product with aliphatic alkynes, so generation of trimethylsilylacetylene and its subsequent usage
that we applied the method to aliphatic alkynes. The reaction for C-alkynylation without the co-addition of a Lewis acid. The
with cyclopropylacetylene, hept-1-yne and oct-1-yne main- protocol may find application in a large number of reactions
tained a high selectivity and gave the corresponding products catalyzed by Lewis acid wherein pre-formed silylated terminal
3f–h in 54, 42 and 39% yield, respectively. To further broaden alkynes are required. Further studies are underway to broaden
the scope of the reaction, tri-O-benzyl-D-glucal was subjected the scope of the present reaction.
to the reaction with phenylacetylene, p-methylphenylacetylene,
p-(tert-butyl)phenylacetylene and p-pentylphenylacetylene
Supporting Information
giving the corresponding products 3i–l in 82, 86, 90, and 87%
yield, respectively, with >99% selectivity. Also, the reaction
Supporting Information File 1
with other glycals, i.e., 3,4,6-tri-O-acetyl-D-galactal and 2,4-di-
O-acetyl-L-rhamnal with phenylacetylene gave the corres-
ponding products 3m and 3n in 82 and 80% yield, respectively,
and with a high selectivity.
Experimental procedures, characterization data, and 1H and
13C NMR spectra of relevant compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-277-S1.pdf]
The present results indicate the activation of terminal alkynes
by TMSOTf forming trimethylsilylacetylenes [39]. In order to
confirm the formation of trimethylsilylacetylenes, we attempted
a control experiment involving the addition of molecular iodine
instead of glucal. As expected [40,41], the reaction on heating
at 70 °C for 3 h gave the iodinated phenylacetylene (Scheme 3,
reaction 1 & Figure S1, Supporting Information File 1). Thus,
the triflic acid generated in situ consequent to the formation of
trimethylsilylacetylene activates the tri-O-acetyl-D-glucal
forming an oxonium ion intermediate, which is attacked by
trimethylsilylacetylene to give the corresponding product
(Scheme 3, reaction 2). The stereochemistry of the reaction
products is possibly determined by the coordination between
two π-electron orbitals of the oxocarbonium ion and the acety-
lene groups, while the stereoelectronic control allows the
α-pseudo-axial orbital to form the bond [35].
Acknowledgements
We thank DST (SB/S1/OC-07/2013), New Delhi for financial
assistance. S.D, M.K. and R.D. thank CSIR and UGC, New
Delhi for the award of a Senior Research Fellowship. We thank
Dr. Deepika Singh for analytical support. IIIM communication
No: IIIM/1685/2014.
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