Stereoselective synthesis of C-2-methylene and C-2-methyl-C-glycosides by Claisen rearrangement of 2-vinyloxymethyl glycals

Article abstract of DOI:10.1039/c2ra21505e

An efficient protocol for the stereoselective synthesis of C-2-methylene-α- and -β-C-glycosides by a Claisen rearrangement of 2-vinyloxymethyl glycal derivatives is reported. A plausible mechanism for the formation of α-selective-C-glycoside was proposed. The methodology was further extended to the high diastereoselective synthesis of C-2-methyl-C-glycosides.

Full text of DOI:10.1039/c2ra21505e

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COMMUNICATION
Stereoselective synthesis of C-2-methylene and C-2-methyl-C-glycosides
by Claisen rearrangement of 2-vinyloxymethyl glycals{
Perali Ramu Sridhar* and Chalapala Sudharani
Received 19th July 2012, Accepted 29th July 2012
DOI: 10.1039/c2ra21505e
further provides an efficient route for the diastereoselective
preparation of C-2-methyl-C-glycosides.
An efficient protocol for the stereoselective synthesis of C-2-
methylene-a- and -b-C-glycosides by a Claisen rearrangement of
2-vinyloxymethyl glycal derivatives is reported. A plausible
mechanism for the formation of a-selective-C-glycoside was
proposed. The methodology was further extended to the high
diastereoselective synthesis of C-2-methyl-C-glycosides.
Thus, mercuric acetate-catalyzed trans vinylation of alcohol 1 with
ethylvinyl ether provided the required 2-vinyloxymethyl-3,4,6-tri-
O-benzyl-D-glucal 2 in 65% yield. When compound 2 was heated in
a sealed tube at 180 uC for 6 h in toluene the reaction produced the
expected C-2-methylene-C-glycosides 3a and 3b in 84 : 16 ratio,
respectively.11,12 Interestingly, the a-anomer 3a was found to be very
unstable and converted to the b-anomer 3b13 in the purification
process using silicagel column chromatography, probably via ring
opening to form a,b-unsaturated aldehyde 4 followed by intramo-
lecular oxa-Michael addition reaction. Whereas, direct reduction
of the crude aldehyde mixture (3a and 3b) with NaBH4/EtOH at
210 uC produced the corresponding alcohols 5a and 5b in a 84 : 16
ratio respectively (Scheme 1).
Carbon branched sugars, in which the hydroxyl groups on pyranose/
furanose ring is replaced with carbon are widely present in a number
of natural products. Notably, C-2-methyl analogues of nucleosides
have shown potential inhibitory activity against hepatitis C viral
RNA replication.1 On the other hand, C-2-methylene- and C-2-
methyl-C-glycoside derivatives exist ubiquitously in nature as
subunits of several highly bioactive natural products such as
spliceostatins, spongistatins, phorboxazoles, brevenal, brevetoxin,
gambieric acids and halichondrins etc..2 One of the widely used
approaches for stereoselective construction of C-glycosides is a
Claisen or Ireland-Claisen rearrangement3 of glucal derived allylvinyl
ethers that has been discussed extensively in the literature.4,5 Due to
the intriguing features of the Claisen-[3,3]-sigmatropic rearrangement
reaction, it has been utilized to provide key intermediates for the total
synthesis of a number of natural products possessing C-2,6 C-3,7 C-48
and C-59 carbon branched carbohydrate frameworks.
The formation of the major a-C-glycoside can be explained by
considering the following facts. (a) Due to the vinylogous anomeric
effect,14 an oxocarbenium ion formation can be visualized during the
course of the rearrangement. (b) The electrostatic stabilization of
oxocarbenium ion by C-3 and C-4 alkoxy groups assume pseudo
axial positions in their half chair conformation.15 (c) The nucleophilic
attack on the six membered ring oxocarbenium ion occur through a
chair like transition state preferably along the axial trajectory.16
5
4
Thus, for both the possible conformations, H4 2a and H5 2b, the
Surprisingly, all the reported Claisen rearrangement (CR)
reactions involving carbohydrate moieties with endo-cyclic allyl
alcohols include at least one chiral center in the rearrangement
sequence, which directs the stereochemical course of the newly
generated stereocenters. In our interest towards the stereoselective
synthesis of C-branched sugars,10 we envisaged that CR of glycal
derived allylvinyl moieties might provide a straightforward access to
the formation of C-2-methylene-C-glycosides and intern offer access
to the preparation of 2-C-branched-C-glycosides. Even though, no
chiral center is involved in the rearrangement sequence, we
anticipated the reaction to proceed in a stereoselective fashion due
to the concerted nature, highly organized transition state in CR
reactions and the influence of additional stereocenters in the
molecule. Chemoselective hydrogenation of the C-2-methylene group
CR will have an early transition state with bond breaking well in
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India.
E-mail: prssc@uohyd.ernet.in; Fax: +91 4023012460;
Tel: +91 4066794823
{ Electronic Supplementary Information (ESI) available: See DOI: 10.1039/
c2ra21505e
Scheme 1 Claisen-rearrangement of 2-vinyloxymethyl glucal derivative.
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advance with respect to bond making that may lead to the formation
of ionic resonance structures 6a and 6b. For transition state 6a the
approach of nucleophilic carbon on to the oxocarbenium ion along
the stereochemically preferred axial trajectory ensures syn-pentane
interaction17 that builds up between the nucleophile and substituent
on C-5 as well as smaller syn-butanol18 interaction with the
substituent on C-3. Due to these interactions, the transition state
6a via 5H4 is destabilized compared to the transition state 6b via 4H5
in the reaction coordinate. As a result, the formation of C-2-
methylene-a-C-glycoside 3a is major through the lowest-energy
4
transition sate, namely via H5.
However, compound 3a suffers with 1,3-diaxial interactions, that
drives the formation of a,b-unsaturated aldehyde derivative 4 which
might further undergo intramolecular oxa-Michael addition reaction
to give stable C-2-methylene-b-C-glycoside 3b during the purification
process (Fig. 1). On the other hand, the direct reduction of the crude
aldehyde mixture provides the corresponding C-2-methylene-C-
glycosides 5a and 5b in 84 : 16 ratio respectively, reflecting the ratio
in the crude aldehyde mixture.
Scheme 2 Claisen-rearrangement of 2-vinyloxymethyl galactal derivative.
Interestingly, galactose derived vinyl ether 7 upon CR provided a
mixture of aldehyde 8a as a single diastereomer along with
unexpected aldehyde 9 in a ratio of 76 : 24 respectively. However,
column chromatography of this mixture over silicagel provided only
the ring opened a,b-unsaturated aldehyde derivative 10.19 A one-pot
CR followed by reduction of the crude aldehyde provided alcohols
11 and 12. Due to the difficulty in separation of this alcoholic
mixture the crude product was acetylated to provide galactose
derived C-2-methylene-C-glycoside 13 as a single diastereomer and
C-2 alkylated galactal derivative 14 (Scheme 2).
Fig. 2 Proposed mechanism for the unexpected formation of C-2-alkyl
galactal derivative 9 under Claisen rearrangement reaction conditions.
ratio, respectively in good yield (Table 1, entry 1). Again, a similar
kind of anomerization mentioned in the case of 3a above was
observed while carrying out the purification over silicagel leading to
the formation of 17b as a single diastereomer.
The observation of unexpected aldehyde 9 supports the formation
of fully separated ionic resonance structures in the proposed
5
mechanism. As can be expected, the transition state 7a with H4
conformation will lead to the ionic resonance structure 15a. The
nucleophilic attack at the anomeric position (path a) via 15a suffers
with higher steric strain that prohibits the formation of C-2-
methylene-b-C-glycoside 8b. On the other hand, nucleophilic attack
at the less hindered site through a (1,3)-sigmatropic rearrangement
(path b) leads to the formation of aldehyde 9 (Fig. 2).
Table 1 Synthesis of C-2-methylene-C-glycosides
Entry Vinyl ether
C-2 Methylene C-glycoside (%)a a : b Ratio
b
1
87 : 13
b
Encouraged with the above results we further applied this
methodology to various 2-vinyloxymethyl-glycal derivatives. Thus,
rhamnal derived allylvinyl ether 16 upon CR provided the
corresponding C-2-methylene-C-glycosides 17a and 17b in 87 : 13
c
2
3
16
87 : 13
c
50 : 50
4
50 : 50
5
50 : 50
a
b
Yield represents pure and isolated products. The mixture upon
column chromatography provided only 17b as a single diastereomer.
The vinyl ether was subjected to CR and the obtained crude product
was directly reduced with NaBH4/EtOH.
c
Fig. 1 Proposed mechanism for the Claisen rearrangement of 2-vinylox-
ymethyl glucal derivative.
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Note added after first publication
This article replaces the version published on 16th August 2012,
which contained errors in Table 1.
Scheme 3 Synthesis of glucose derived C-2-methyl-b-C-glycoside.
Table 2 Synthesis of C-2-methyl-C-glycosides
References
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C-glycoside
C-2 Methyl
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2 Please see the supporting information.
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a
Yield represents pure and isolated products.
Nevertheless, direct reduction of the crude aldehyde mixture, 17a
and 17b, provided C-2-methylene-C-glycosides 18a and 18b in
87 : 13 ratio respectively in 85% yield (Table 1, entry 2). However,
pentose derived allylvinyl ethers 19, 21 and 23 upon thermal CR
provided a 50 : 50 mixture of 20a : 20b, 22a : 22b and 24a : 24b
respectively in good yield (Table 1, entries 3, 4 and 5). These
observations clearly indicate the significance of the C-5-substituent in
directing the stereochemical outcome of the rearrangement reaction.
The importance of the methodology was further enhanced by
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C-2-methylene-b-C-glycoside 5b was hydrogenated with 10% Pd/C,
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20
H2 in MeOH in the presence of Na2CO3 to provide C-2-methyl-
b-C-glycoside 25 as a single diastereomer in excellent yield, 93%
(Scheme 3).
Further, application of the selective hydrogenation protocol to
other C-2-methylene-C-glycosides 5b, 18a, 22a and 24a also
provided C-2-methyl-C-glycosides 26–29 in excellent yields with very
high diastereoselectivity (Table 2).
In conclusion, an efficient methodology for the stereoselective
synthesis of C-2-methylene-C-glycosides as well as C-2-methyl-C-
glycosides was developed. Importantly, the method is applicable to
synthesize a- as well as b-C-glycosides in a stereoselective fashion.
This novel method may provide an easy access to the synthesis of
natural products possessing carbon branched sugar subunits.
We thank University Grant Commission (UGC), New Delhi,
Grant number 40-56/2011 (SR).
8598 | RSC Adv., 2012, 2, 8596–8598
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