Synthesis of Carbon-Branched Sugars Involving an Unprecedented 1,5- or 1,6-Alkyl Transposition Reaction

Article abstract of DOI:10.1002/ejoc.201900752

An unusual 1,5- or 1,6-alkyl transposition along with acetalization of 3-deoxy glycals is reported. TMSOTf was used as the Lewis acid for carrying out the transformation. A plausible mechanism is proposed. The novel method provided access to 2-C-branched bicyclic acetals of various deoxy-sugar derivatives as well as 2-C-branched levoglycosan derivatives.

Full text of DOI:10.1002/ejoc.201900752

A Journal of
Accepted Article
Title: Synthesis of Carbon-branched Sugars Involving an
Unprecedented 1,5- or 1,6-Alkyl Transposition Reaction
Authors: Perali Ramu Sridhar, Boddu Umamaheswara Rao, and Gadi
Madhusudhan Reddy
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900752
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10.1002/ejoc.201900752
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of Carbon-branched Sugars Involving an
Unprecedented 1,5- or 1,6-Alkyl Transposition Reaction
Perali Ramu Sridhar,* Boddu Umamaheswara Rao and Gadi Madhusudhan Reddy
Dedicated to Professor S. Chandrasekaran on the occasion of his 75th birthday
Abstract: An unusual 1,5- or 1,6-alkyl transposition along with
acetalization of 3-deoxy glycals is reported. TMSOTf was used as the
Lewis acid for carrying out the transformation. A plausible mechanism
is proposed. The novel method provided an access to the synthesis
of 2-C-branched bicyclic acetals of various deoxy-sugar derivatives
as well as 2-C-branched levoglycosan derivatives.
Introduction
The structural reorganizational “shifts” in carbocation
Scheme 1. Lewis acid catalysed 1,7-hydrogen shift and glycal dimerization
intermediates has received immense importance in the
development of novel methodologies and innovative protocols for
the total synthesis of several natural products.1 The study of such
intermediates form the basis of fundamental and practical
chemistry.2 A couple of named reactions have evolved based on
the skeletal reorganization of this reactive species.3 In this context,
the oxocarbenium ion rearrangement reactions in carbohydrate
derivatives have been immensely studied for a long time.4 By
virtue of the presence of the endocyclic oxygen in these
substrates stabilize the carbocation at the anomeric position by
forming the oxocarbenium ion.5 Glycals, the 1,2-unsaturated
cyclic sugar derivatives, have been one of the primary sources for
the generation of oxocarbenium ion, in the presence of an acid
catalyst, to study various glycosylation reactions.6 Appropriately
functionalized glycals undergo rearrangement reactions in the
presence of a Lewis acid catalyst.7 Apart from the Ferrier type
rearrangement of glycals, dimerization of glycals8 and Gin’s9
hypervalent iodine mediated oxidative ring contraction of 6-deoxy-
gulal are noteworthy. Steel et al. showed that 3,4,6-tri-O-benzyl
D-glucal 1 in the presence of catalytic amount of acetyl
perchlorate converts into a bicyclic acetal 3 through an unusual
1,7-hydrogen shift.10 While carrying out this transformation using
reactions.
Results and Discussion
To study the influence of the protecting groups in the C-
disaccharide formation using 3-deoxy glycals, we have attempted
to carry out the dimerization reaction of 3-deoxy 4,6-di-O-(p-
methoxybenzyl) glucal 5. However, to our surprise, glycal 5 upon
treatment with TMSOTf (0.1 eq) at -78 oC in dichloromethane did
not provide the expected dimer 7. Instead, the major product was
found to be the 1,6-anhydro 2-C-branched levoglucosan
derivatives 6a and 6b. The structure and stereochemistry of the
products were fully established by H, 13C, COSY and NOESY
1
NMR experiments (Scheme 2). In the proton NMR spectra of 6a,
the axial hydrogen at C2 position appeared as a multiplet at
δ2.19-2.27 whereas in compound 6b the equatorial hydrogen at
C2 appeared at δ1.90. The difference in chemical shift value is
apparent due to the 1,3-diaxial interactions between the axial
oxygen at C4 which deshields the C2 axial hydrogen to a lower δ
value in 6a. Similarly, the protons on the benzyl carbon at C2 in
compound 6a appeared δ 2.39 and δ 2.57 whereas in 6b they
appear at δ 2.87 and δ 2.94. These chemical shift values again
provide an ample evidence for the assigned stereochemistry at
the C2 position for compound 6a and 6b (Scheme 2).
3-deoxy 4,6-di-O-benzyl glycal
2
we have observed
a
stereoselective dimerization reaction which led to the formation of
2-(β-C-glycosyl)-glycal 411 (Scheme 1). This typical reactivity of 3-
deoxy glycals under Lewis acid conditions prompted us to
investigate further on the fate of oxocarbenium ion generated
using these scaffolds. Thus, herein, we report an unusual 1,6 or
1,5 alkyl transposition reaction of 3-deoxy glycals providing
carbon branched 1,6-anhydrosugar derivatives.
[a]
Prof. P. R. Sridhar, B. U. Rao, Dr. G. M. Reddy
School of Chemistry
University of Hyderabad
Gachi Bowli, Hyderabad – 500 046
E-mail: p_ramu_sridhar@uohyd.ac.in
http://chemistry.uohyd.ac.in/prs.htm
Scheme 2. An unprecedented 1,6-alkyl shift in 3-deoxy glucal derivative.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900752
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COMMUNICATION
diastereomers and no isolable amount of the corresponding 2-(β-
C-glycosyl)-glycal derivative was observed. Application of the
similar method on 3-deoxygalactal derivative 15, synthesized
from 14, provided the corresponding 1,6-anhydro 2-(p-
methoxybenzyl) 3-deoxy galactose derivative 16 as a single
diastereomer in moderate yield (Table 1, entry 2). Interestingly,
6-O-(p-methoxybenzyl)-3,4-dideoxy glucal 18,16 obtained by the
p-methoxybenzylation of 17,17 upon treating with TMSOTf
However, in view of obtaining the crystal structure, various
methods to crystalize either compound 6a or 6b were
unsuccessful. Then, we planned to synthesize derivatives of the
compounds 6a or 6b expecting to get a crystal. Towards this,
compound 6b was subjected to the hydrogenolysis to get alcohol
8 which was esterified with 4-bromobenzoyl chloride and 4-
nitrobenzoyl chloride to give the benzoate derivatives 9 and 10,
respectively (Scheme 3). To our fortune, compound 9 was found
to be a solid and we were able to crystalize this using ethyl acetate
and hexane. The ORTEP diagram of ester 9 is provided in the
figure 1.12
provided
a
1:1 diastereomeric mixture of
2-C-branched
levoglucosan derivatives 19a and 19b via an unprecedented 1,6-
migration of the p-methoxybenzyl (PMB) group.
Table 1. Synthesis of 2-C-branched levoglycosan derivatives by
1,6-alkyl transposition.
Scheme 3. Synthesis of the derivatives of compound 6b.
Figure 1. The ORTEP diagram of compound 9.12
The unprecedented formation of the C2-branched bicyclic acetals
6a and 6b and the importance of levoglucosan (1,6-
anhydrosugar) derivatives in the total synthesis of natural
products13 made us curious to study the generality of various
orthogonally protected 3-deoxy glycal derivatives. Thus, 3-deoxy
4-O-benzyl 6-O-(p-methoxybenzyl) glucal 1214 was synthesized
from 3-deoxy 4-O-benzyl glucal 1115 and subjected to TMSOTf
(0.1 eq) at -78 oC. Interestingly, this reaction also provided the 2-
C-branched levoglucosans 13a and 13b, as 1:1 mixture of
[a] Yield refers to pure and isolated products. [b] The major byproduct was found
to be the corresponding 2-(4-alkyloxy)6,8-dioxabicyclo[3.2.1]octane derivative.
[c] The diastereomeric ratio was calculated based on the 1H NMR spectra of
crude product. [d] The stereochemistry at the anomeric position was assigned
based on 1H-1H NOESY experiment.
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We assumed that the possible reason for the migration of the
PMB group from C6-oxygen to the C2 might be due to its higher
carbocation stabilization than the unsubstituted benzyl group.
Keeping this in mind, we further investigated the alkyl groups
which could stabilize the carbocation. In this process, we have
chosen to use the prenyl group in place of PMB. Thus, prenylation
of glucal 11 provided the 3-deoxy 6-O-prenyl glucal derivative 20,
and it was subjected to the acid catalyzed 1,6-migration reaction.
To our delight, under the similar reaction conditions, prenyl group
underwent the 1,6-migration and provided the 2-C-prenyl
levoglucosan derivatives 21a and 21b in 50% yield. To evaluate
the feasibility of dimethoxy substituted benzyl migration the C-6
position of the glycal 11 was alkylated with 3,4-dimethoxy benzyl
bromide to give compound 22 and subjected to catalytic TMSOTf
at -78 oC. However, this reaction did not yield the expected 2-C-
branched glycal. Instead, the reaction provided only the 2,3-
dideoxy levoglucosan derivative 23. Later, a C-6 geranylated
glycal 24 was synthesized and subjected to the migration reaction
conditions. Surprisingly, it was found that the geranyl group was
very stable under the reaction conditions and no reaction was
observed at -78 oC. When the reaction mixture was warm to 0 oC,
hydration of the glycal was observed and the product 25 was
isolated in 52% yield. These results suggest that only some typical
carbocation stabilizing groups could be allowed to this novel
unprecedented migration reaction. Further, to investigate the
migratory aptitude of the p-methoxybenzoyl group, 3-deoxy 4-O-
benzyl 6-O-benzoyl glucal 26 was synthesized by p-
methoxybenzoylation of 11, and subjected to TMSOTf. However,
the reaction provided the 2-(β-C-glycosyl)-glycal derivative 27 as
the only isolable product in 51% yield (Table 1, entry 7).
Participation of the lone pair of electrons present on the C6-
oxygen which further will have the extended resonance structures
5d18 and 5e. Finally, regeneration of the catalyst, TMSOTf, by
reaction of the triflate anion on to the trimethylsilyl group which
could help in the formation of a new C-C bond between C2 and
the p-methoxybenzyl carbon will lead to the formation of the 1,6-
migrated products 6a and 6b (Figure 2).
Having synthesized, a series of 2-C-branched levoglycosan
derivatives involving 1,6-transposition reaction, we focused our
attention on incorporating the p-methoxy benzyl or prenyl group
on another oxygen atom, apart from the C6 position. Thus, p-
methoxy benzyl protected 3-deoxy 3-C-branched glycal 29 was
synthesized from glycal 2819 and subjected to TMSOTf mediated
1,6-transposition reaction. Interestingly, this reaction also
proceeded smoothly and gave the expected 2,3-dideoxy carbon-
branched bicyclic acetal 30 as a 1:1 mixture of diastereomers in
60% yield (Table 2, entry 1). Extending the methodology to other
PMB protected 3-C-branched galactal derivative 32, synthesized
Table 2. Synthesis of 2,3-dideoxy 2- and 3-C-branched bicyclic
acetal derivatives by 1,5-alkyl transposition reaction.
Based on the product formation, a possible mechanism is
proposed for the formation of the 2-C-branched levoglucosan
derivative. Accordingly, glycal 5 upon reaction with TMSOTf might
form the corresponding oxo-carbenium ion intermediate 5a. This
oxocarbenium ion can further undergo deprotonation to give the
2-trimethylsilyl glycal derivative 5b and triflic acid. On the other
hand, intermediate 5a can have the resonance structure 5c by the
[a] Yield refers to pure and isolated products. [b] The diastereomeric ratio was
calculated based on the 1H NMR spectra of crude product. [c] The major
byproduct was found to be the corresponding 4-(benzyloxy)-3-
((benzyloxy)methyl)-2,8-dioxabicyclo[3.3.1]nonane
derivative.
[d]
The
stereochemistry at the anomeric position was assigned based on 1H-1H NOESY
experiment.
from 31, also led to the formation of the 1,5-alkyl migrated carbon-
branched bicyclic acetal 33 (table 2, entry 2). Further, we
proceeded to investigate the generality of this 1,5- alkyl
transposition reaction using prenyl protected 3-C-branched
glycals. Thus, the hydroxyl group in 3-C-branched glycals 28 and
31 were treated with prenyl bromide in the presence of NaH in
THF to obtain prenyl ether containing 3-C-branched glycals 34
Figure 2. Proposed mechanism for the 1,6-alkyl transposition reaction;
Synthesis of 2-C-branched levoglycosan derivatives.
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o
and 36. Subjecting these glycals to TMSOTf at -78 C provided
the 2-C-prenyl substituted 3-C-branched bicyclic acetals 35 and
37, respectively, as a 1:1 mixture of diastereomers. However, 1,5-
alkyl transposition of the p-methoxybenzoyl group in glycal
derivative 38 was again unsuccessful. Instead, this reaction
provided the C-disaccharide 39 as a single diastereomer (table 2,
entry 5).
The authors thank DST-SERB grant (File No. EMR/20l6/007816)
for financial support. B.U.R thank UGC-India for Senior Research
Fellowship.
Keywords: Carbohydrates • Deoxy-Glycals • Carbocation •
Rearrangement • Carbon-branched sugars
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Conclusion
In conclusion, we have reported an unprecedented 1,5- and 1,6-
alkyl transposition reaction of 3-deoxy glycals. The methodology
provides access to the synthesis of various 2-C-branched
levoglycosan
derivatives
as
well
as
2,8-
dioxabicyclo[3.3.1]nonane systems. To the best of knowledge,
this is the first of its kind in the literature. The application of the
developed methodology in total synthesis of natural products20
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Experimental Section
General method for the 1,6-alkyl migration (exemplified for
compounds 5a and 5b): A stirred solution of compound 4 (700 mg, 1.9
mmol) in dry dichloromethane (20 mL) under inert atmosphere was added
4 Å MS and the suspension was cooled to -78 oC. TMSOTf (34 µL, 0.19
mmol) was added dropwise and continued stirring at the same temperature.
After 15 min the reaction was quenched by the addition of Et3N (~60 µL)
and allowed it to come to room temperature. The reaction mixture was
filtered through a small pad of Celite and the filter cake was washed with
dichloromethane (20 mL). Evaporation of the solvent under reduced
pressure followed by column chromatography of the obtained crude
product provided the mixture of 2-C-branced levoglucosan derivatives 5a
and 5b (1:1) (666 mg) as a colourless gum in 95% yield. Rf: 0.75 (20%
EtOAc/hexanes). 5a: IR (neat): 2934, 2892, 2835, 1610, 1509 cm-1. 1H
NMR (400 MHz, CDCl3): δ 7.27 (d, 2H, J = 8.4 Hz), 7.08 (d, 2H, J = 8.8
Hz), 6.88 (d, 2H, J = 8.8 Hz), 6.83 (d, 2H, J = 8.4 Hz), 5.26 (s, 1H), 4.56-
4.58 (m, 1H), 4.50-4.54 (m, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.77-3.79 (m,
1H), 3.71-3.73 (m, 1H), 3.35-3.36 (m, 1H), 2.57 (dd, 1H, J = 8.0 Hz, J =
13.6 Hz), 2.39 (dd, 1H, J = 6.8 Hz, J = 13.6 Hz), 2.19-2.27 (m, 1H), 1.74-
1.79 (m, 1H), 1.44-1.49 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 159.19,
157.90, 131.07, 130.23, 129.90, 129.22, 113.79, 113.75, 103.36, 74.58,
72.58, 70.07, 66.41, 55.25, 55.21, 39.12, 37.30, 27.64. HRMS (ESI) calcd
[12] Crystal data for compound 8 (C21H21O5Br), M.Wt = 433.29,
orthorhombic, space group P212121
a = 6.3899 Å, b =
16.3327 Å, c = 19.0663 Å, V = 1989.84(15) Å3, Z = 4, MoKα
radiation (λ = 0.71073), T = 297.68 K; R1 = 0.0349, wR2 =
0.0780 [I >=2σ (I)]; R1 = 0.0490, wR2 = 0.0841 (all data). The
CIF file for the crystal data of compound 8 is available from the
[ ]25
-50.4 (c 0.63,
D
for C22H26O5+Na+ 393.1672, found 393.1672. 5b:
훼
CHCl3); IR (neat): 2956, 2920, 2853, 1608, 1510 cm-1. 1H NMR (400 MHz,
CDCl3): δ 7.33 (d, 2H, J = 8.8 Hz), 7.14 (d, 2H, J = 8.8 Hz), 6.91 (d, 2H, J
= 8.8 Hz), 6.84 (d, 2H, J = 8.8 Hz), 5.37 (s, 1H), 4.61-4.64 (m, 2H), 4.54
(d, 1H, J = 12.0 Hz), 3.83 (s, 3H), 3.80 (s, 3H), 3.75-3.79 (m, 2H), 3.32-
3.33 (m, 1H), 2.94 (dd, 1H, J = 7.2 Hz, J = 13.6 Hz), 2.87 (dd, 1H, J = 9.2
Hz, J = 14.0 Hz), 1.90 (dd, 1H, J = 7.6 Hz, J = 15.6 Hz), 1.78-1.84 (m, 1H),
1.67 (d, 1H, J = 14.8 Hz). 13C NMR (100 MHz, CDCl3): δ 159.18, 157.84,
132.76, 130.46, 130.16, 129.05, 113.83, 113.74, 104.09, 75.33, 73.17,
70.12, 66.03, 55.28, 55.24, 40.48, 36.40, 23.17. HRMS (ESI) calcd for
C22H26O5+Na+ 393.1672, found 393.1671.
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif under CCDC ref
no.1887125.
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Acknowledgements
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(b) A. A. Ansari, Y. D. Vankar, J. Org. Chem. 2013, 78, 9383–
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Carbohydrates
COMMUNICATION
An unprecedented 1,5- or 1,6-alkyl
transposition reaction of 3-deoxy
glycals led to the formation of various
carbon branched bicyclic
Perali Ramu Sridhar,* Boddu
Umamaheswara Rao and Gadi
Madhusudhan Reddy
Page No. – Page No.
frameworks.
Synthesis of Carbon-branched
Sugars Involving an Unprecedented
1,5- or 1,6-Alkyl Transposition
Reaction
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