Design and synthesis of N–acetylglucosamine derived 5a-carbasugar analogues as glycosidase inhibitors

Article abstract of DOI:10.1016/j.tet.2018.02.063

An efficient synthesis of new six-membered carbasugars in both L-form and D-form starting from N–acetylglucosamine is described. The key synthetic steps involved regioselective protection and deprotection, Ferrier carbocyclization, Peterson olefination, h

Full text of DOI:10.1016/j.tet.2018.02.063

Accepted Manuscript
Design and synthesis of N–acetylglucosamine derived 5a-carbasugar analogues as
glycosidase inhibitors
Chintam Narayana, Priti Kumari, Daisuke Ide, Nasako Hoshino, Atsushi Kato, Ram
Sagar
PII:
S0040-4020(18)30223-0
10.1016/j.tet.2018.02.063
TET 29334
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 October 2017
Revised Date: 16 February 2018
Accepted Date: 27 February 2018
Please cite this article as: Narayana C, Kumari P, Ide D, Hoshino N, Kato A, Sagar R, Design and
synthesis of N–acetylglucosamine derived 5a-carbasugar analogues as glycosidase inhibitors,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.02.063.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
OR
HO
HO
NHAc
OH
O
OH
OH
HO
HO
9 steps
2 steps
L
-form
NHAc
NHAc
BnO
Cl
OR
OBn
OH
HO
HO
N-Acetylglucosamine
NHAc
OH
D-form

ACCEPTED MANUSCRIPT
Design and synthesis of N–acetylglucosamine derived 5a-
carbasugar analogues as glycosidase inhibitors
Chintam Narayana,1 Priti Kumari,1 Daisuke Ide,2 Nasako Hoshino,2 Atsushi Kato2
and Ram Sagar1,3,
1Department of Chemistry, School of Natural Sciences, Shiv Nadar University (SNU), NH91, Tehsil-
Dadri, Gautam Buddha Nagar, Uttar Pradesh, 201314, India.
2 Department of Hospital Pharmacy, University of Toyama, Sugitani, Toyama 930-0194, Japan.
3Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh,
221005, India.
E-mail (Corresponding author): ram.sagar@snu.edu.in
ABSTRACT
An efficient synthesis of new six membered carbasugars in both L-form and D-form starting
from N–acetylglucosamine is described. The key synthetic steps involved regioselective
protection and deprotection, Ferrier carbocyclization, Peterson olefination, hydroboration and
stereoselective epoxidation followed by regioselective epoxide ring opening reactions. These six
member carbasugars showed moderate glycosidase inhibitory activity and one of the compounds
was found selective towards β-galactosidase inhibitory activity.
Key words: Carbasugar, Peterson olefination , Glycosidase inhibitors, Ferrier carbocyclization,
N-acetyl glucosamine.
1.
Introduction
Carbasugars are carbohydrate mimics, in which methylene group (-CH2-) replaces endocyclic
oxygen atom.1 Carbasugars are first prepared by Professor G. E. McCasland and named as
pseudosugars.2 Carbasugars exhibit several biological activities such as antitumor, antiviral,
antifungal and as inhibitors/activators of carbohydrate processing enzymes.3 There are several
reports where carbasugars have been used as precursor for synthesizing natural products.4
Carbasugars are metabolically more stable than their glycopyranoside precursors therefore, they
provide better mimics in biological systems.5 Carbasugars are attractive moieties in drug
discovery because of their stability towards endogenous degradative enzymes as well as their
interesting biological properties, mainly as antibiotics and as glycosidase inhibitors.6,7 In fact
many carbasugar based drugs have already been developed for therapeutic applications (Figure
1) and they work through inhibiting a particular glycosidase enzyme.8
1

ACCEPTED MANUSCRIPT
OH
OH
O
H
N
OH
NH2
OH
NH2
NH
HO
HO
HO
HO
EtO
OH
OH
OH
O
O
C
B
A
Oseltamivir (Tamiflu)
Validamine
Voglibose
Figure 1. Carbasugar based drug molecules: A. Tamiflu, is a currently used antiviral drug; B.
Validamine, is an antidiabetics drug; C. Voglibose, is a drug for diabetes mellitus.
Due to immense biological applications of carbasugars, various research groups devoted
significant effort towards synthesis of carbasugar analogues.1,9 Vankar and coworkers. reported
the efficient synthesis of hybrids oxa-carbasugars skelton as glycosidase inhibitors.10,11 Ramesh
and coworkers used a chiron approach for preparing diverse amino cyclitol in the form of
carbasugars.12 Sureshan and coworkers published total synthesis of seven natural carabasugars
from vinylogous ketal.13 Lopez and coworkers used a stereodivergent approach based on 6-endo
trig radical cyclization and prepared a number of carbasugars in efficient manner.14,15
Intramolecular 1,3-dipolar cycloaddition of the sugar derived nitrones were used for the
stereoselective synthesis of carbasugars.16 Pd-catalyzed cyclopropanol ring opening approach has
been reported for the synthesis of carbasugar C-1 phosphates.17 Carbasugars have also been
synthesized through Pd-catalyzed cyclitolization /postcyclitolization transformations.18 Shing
and coworkers reported concise and stereodivergent synthesis of carbasugars as SGLT2
inhibitors starting from
D
-gluconolactone.19 There are very few reports documented in the
literature for the chemical syntheses of N-acetylglucosamine based carbasugar derivatives.20-22
Quiclet-Sire and coworkers used a benzyl carbamate-protected glucosamine derivative as a
precursor to a Ferrier carbocyclization followed by a homologation to get carbasugars.20 Ogawa
and coworkers reported a synthesis of the pseudo β-anomer of carba-N-acetylglucosamine from
noncarbohydrate precursors.21 Nitz and coworkers reported syntheses of few carbocyclic
analogues with one example being N-acetylglucosamine carbasugar from methyl D
-mannoside.22
In view of above reports on the biopotential of carbasugars, we became interested to develop a
simple and efficient route for synthesis of new N–acetylglucosamine derived carbasugars in both
L
and D-form that bear a halogen atom at C-5 and different length of alkyl chain at pseudo C-1
position and to study their inhibitory profile with various glycosidase enzymes. Thus in our
moderate effort, we have designed and developed efficient synthetic route for the synthesis of
new 5a-carbasugars in both L-form and halogenated D-form starting from N–acetylglucosamine.
These carbasugars were evaluated for their glycosidase inhibitor activity. Herein we are
reporting the details of synthetic challenges and successful efficient synthesis along with
glycosidase inhibitor activity of thus prepared 5a-carbasugars.
2

ACCEPTED MANUSCRIPT
2.
Results and Discussion
Synthesis of designed carbasugars was commenced from commercially available N–acetyl-
D-
glucosamine 1 as shown in Scheme 1. N–acetyl- -glucosamine 1 was refluxed with methanol in
D
presence of Amberlite IR-120-H+ resin to produce methyl glycoside (α:β=9:1) in 90% yield,23
which upon treatment with tritylchloride in pyridine gave 6-O-trityl derivative 2 in good yield.24
Benzylation on compound 2 followed by removal of trityl group afforded compound 3 with 6-
OH as primary alcohol in 80% isolated yield.25 Tosylation followed by iodination and dehydro-
halogenation using NaH in DMF at room temperature furnished olefin compound 4 in very good
yield (Scheme 1).
O
OH
O
O
O
O
O
O
HO
HO
TrO
HO
HO
BnO
a
b
c
NHAc
NHAc
NHAc
BnO
NHAc
OH
OH
OBn
OBn
1
2
3
4
Scheme 1: a) i. Amberlite IR-120 H+, MeOH, 80 °C, 24 h, 90%; ii. Trityl chloride, pyridine, rt, 48 h, 79%; b) i.
NaH, BnBr, THF, 80 °C, rt, 1.5 h; ii. 33% HBr in acetic acid, CH2Cl2, 0 °C to rt 80%; c) i. TsCl, Et3N, CH2Cl2, rt,
94%; ii. NaI, DMF 100 °C to rt, NaH, 72%.
Compound 4 was subjected to HgSO4 catalysed Ferrier carbocyclization in 1,4-dioxane and 5
mM H2SO4 (2:1) at 50 °C, which cleanly furnish β-hydroxy cyclohexanone 5 as a pure α-isomer
with free hydroxyl group at pseudo C-1 position in 65% yield.26 The next challenging step was to
convert this β-hydroxy cyclohexanone 5 into olefin compound 5a. We attempted several
reactions, using phosphine catalysed Wittig reaction,22 titanium catalysed Petasis reaction27 and
chromium catalysed Takai reaction,28 to convert β-hydroxy cyclohexanone 5 to β-hydroxy
exocyclic olefin 5a but disappointingly all attempts were unsuccessful. The above reactions
either resulted in the formation of undesired aromatic compounds or there was no reaction at all
(Table S1, SI). Even protected (OTHP at pesudo C-1) β-hydroxy cyclohexanone failed to give
our desired β-hydroxy exocyclic olefin 5a under Wittig reaction condition. We envisioned that
preparing the exocyclic olefin 5a by dehydrative desilylation in a Peterson olefination29
condition might be a good alternative to the conventional methods for olefination. This
methodology offers many advantages over common protocols for olefination e.g. it would be
phosphine free, not involve highly toxic reagents (trimethylsilyl)diazomethane, and involves
simpler reaction conditions. Peterson olefination was carried out on β-hydroxyl cyclohexanone 5
which resulted in the formation of the desired product 5a in acceptable isolated yield (55%) over
two steps. At this juncture it was decided to perform stereoselective hydroboration using a bulky
hydroboronating reagent, therefore hydroboration reaction was carried out on 5a using 9-BBN 22
,
but surprisingly it didn’t work even at elevated temperature. We tried several reaction conditions
but none of them resulted in to expected product in good yield (Table S2, SI). At this moment we
considered using BH3·THF30 as the hydroboronating reagent and indeed it resulted in to expected
product and pure product 6a was obtained after work up and column chromatography
3

ACCEPTED MANUSCRIPT
purification. The BH3·THF mediated hydroboration was showing more than 95%
stereoselectivity towards formation of the
final step, debenzylation reaction was carried out on 6a using Pd(OH)2 and hydrogen gas, which
furnished the -form of carbasugar 7a in 75% yield (Scheme 2). We were interested to see the
L-form of carbasugar 6a in good yield (65%). In the
L
effect of alkyl substitution at pseudo C-1 in biological activity. Therefore compound 5a was
methylated using methyl iodide in THF, which furnished compound 5b in very good yield
(90%). Hydroboration on 5b using 9-BBN was again futile, only starting material was recovered;
therefore, BH3·THF was used as the hydroboration reagent which furnished methylated L-form
of carbasugar 6b in good yield. The debenzylation reaction was done using Pd(OH)2 and H2 gas,
and compound 7b was obtained in 82% yield (Scheme 2).
6
5a
OR
1
OR
5
O
OH
OR
HO
BnO
HO
HO
e
d
a
b
4
2
4
NHAc
NHAc
BnO
NHAc BnO
NHAc
3
OBn
OH
OBn
OBn
5
7a R = H
7b R = Me
5a R = H
5b R = Me
6a R = H
6b R = Me
c
Scheme 2: a) HgSO4 1,4-dioxane:5mM H2SO4 (2:1), 50 °C, 3 h, 65%; b) (chloromethyl)trimethyl silane, Mg
turnings, THF, rt, then PTSA, CH2Cl2, rt 55% in two steps; c) NaH, CH3I, THF, 0 °C to rt; d) BH3·THF, H2O2,
NaOH, THF 0 °C to rt 1.5 h, 65%; e) Pd(OH)2, H2 gas, methanol, rt, 82%.
At this juncture we were interested to prepare the
biological activity with -form analogues (7a and 7b). We planned to oxidize the primary
alcohol in 6b to get aldehyde, which may easily get recemise to the more stable -form in
presence of pyridine,22 which followed by reduction and debenzylation may furnish the desired
-form product. Therefore, the compound 6b was subjected to oxidation with freshly prepared 2-
D-form of carbasugar 9 in order to compare
L
D
D
Iodoxybenzoic acid (IBX), but this resulted in a mixture of two products along with undesired
α,β-unsaturated aldehyde (Scheme S1, SI) At this juncture, we redesigned our synthetic route
and decided to proceed towards stereoselective epoxidation, followed by regioselective epoxide
ring opening in order to get our designed final molecules like 9. Therefore, compound 5b was
subjected to epoxidation using m-CPBA in dichloromethane, which showed the formation of two
epoxides with desired one in equal ratio (Fig S1, SI). The m-CPBA mediated epoxidation
reaction on 5a, having α-pseudo C-1 free hydroxyl group, gave stereoselectively one desired
epoxide 8 in very good isolated yield (80%). Here stereoselectivity was controlled by α-pseudo
C-1 free hydroxyl group (Fig S2, SI). Boron trifluoride diethyl etherate (BF3.Et2O) mediated ring
opening of epoxide 8 was found inappropriate as it furnished multiple spots on TLC. TiCl4
mediated regioselective ring opening of epoxide on compound 8 gave the desired
D-form
1
compound 9 (C-6-β-1° OH) very quickly (5-10 min), confirmed by H NMR, which upon
debenzylation furnishes compound 9a in good yield (Scheme 3). Further stereoselective epoxide
ring opening towards the D-form was confirmed by looking at the NH- chemical shift (δ 5.52) in
1H NMR spectrum of protected derivative 11a and comparing it with similarly protected
intermediate 6b (
L
-form,C6-α-1° OH) NH proton chemical shift (δ 6.26). The downfield
4

ACCEPTED MANUSCRIPT
chemical shift (NH) in case of
(axial), which was not possible when C5-CH2OH was equatorial, as in the case of compound
11a. Its worth to mention here that -form compounds 9a has a choloro atom installed
L-form (6b) was due to hydrogen bonding with C5-CH2OH
D
stereoselectively at C-5 position. The halogenated carbacycles and sugars are known for their
better glycosidase inhibitory activity than their nonhalogenated derivatives.31 We performed
preliminary docking studies of compounds 7a, 9a and nonhalogenated derivative of 9a with
bovine liver β-galactosidase enzyme and it was found that halogenated derivative 9a has better
binding with β-galactosidase enzyme (SI). The same was noticed experimentally in enzyme
binding assays (Table 1).
Cl
Cl
6
OH
5a
OH
1
OH
OH
O
HO
HO
a
HO
BnO
b
c
5
2
BnO
NHAc
BnO
NHAc
4
NHAc
NHAc
3
OBn
OBn
8
OH
9a
OBn
5a
9
Scheme 3: a) m-CPBA, CH2Cl2, 0 °C to rt, 3 h, 80%; b) TiCl4, dry CH2Cl2, 0 °C, 10 min, 62%; c) Pd(OH)2, H2 gas,
methanol, rt, 90%.
After getting optimized stereoselective epoxidation reaction condition, it was decided to prepare
a different alkyl chain length at α-pseudo C-1 on epoxide 8 through alkylation reaction and study
the structure activity relationship in the final compounds. It is evidenced from the literature that,
hydrophobicity of the alkyl chain is essential for the cell membrane permeability and
enhancement of inhibitory activity.32 Therefore, epoxide 8 was treated with various alkyl halides
in presence of sodium hydride in DMF, which gave corresponding alkyl chain containing
derivatives of epoxides 10a-10c in good to very good yield (64-88%). Stereoselective ring
opening of epoxides using TiCl4 furnishes desired primary alcohols 11a-11c. The final
compounds 12a-12c were obtained after debenzylation reaction using Pd(OH)2 and H2 gas in
methanol at room temperature (Scheme 4).
Cl
Cl
OH
OR
OR
OR
a
b
c
HO
BnO
HO
HO
O
O
BnO
NHAc
BnO
NHAc
NHAc
NHAc
OBn
OBn
OBn
OH
11a R = methyl
11b R = butyl
11c R = hexyl
12a R = methyl
12b R = butyl
12c R = hexyl
8
10a R = methyl
10b R = butyl
10c R = hexyl
Scheme 4: a) NaH, RBr, DMF, 0 °C to rt, 64-88%; b) TiCl4, CH2Cl2, 0 °C, 10 min, 69-72%; c) Pd(OH)2, H2 gas,
methanol, rt, 77-83%.
Glycosidase inhibition activity of all the final prepared compounds were carried out using various
glycosidase enzymes and adopting standard enzyme assays protocol,33 the results are summarized
5

ACCEPTED MANUSCRIPT
in Table 1. Compound 7a, 7b and 9a did not show any significant inhibition toward all
glycosidases. In contrast, compound 12a with O-Me group in the α-pseudo C-1 position showed
selective inhibition activity against bovine liver β-galactosidase, with IC50 0.77 mM. Furthermore,
this study revealed that extension of O-alkyl group tends to increase their inhibitions. Compound
12b with O-butyl group in the α-pseudo C-1 position showed inhibition activity against β-
glucosidase, bovine liver and β-galctosidase, bovine liver with IC50 1.70 and 1.0 mM, respectively.
Compound 12c showed inhibition toward yeast α-glucosidase, bovine liver β-glucosidase, bovine
liver β-galactosidase, coffee beans α-glucosidase, bovine kidney α-L-fucosidase, and E. coli β-
glucuronidase, with IC50 0.32, 0.40, 0.25, 0.19, 0.42, and 0.17, respectively.
Table 1. Glycosidase inhibition activity
Cl
Cl
Cl
Cl
OH
OMe
compounds
OH
OMe
OBut
OHex
NHAc
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
NHAc
NHAc
NHAc
HO
NHAc
NHAc
OH
OH
OH
12b
OH
OH
12a
OH
12c
7b
7a
enzymes
9a
α-glucosidase
yeast
NIa (1.8%)b NI (11.0%)
NI (2.6%)
NI (1.8%)
NI (11.8%)
1.7
0.32c
0.40
0.25
0.19
β-glucosidase
bovine liver
β-galctosidase
bovine liver
α-galctosidase
coffee beans
α-mannosidase
jack bean
NI (16.1%) NI (22.4%) NI (19.3%) NI (27.1%)
NI (18.9%) NI (16.8%) NI (10.0%)
0.77
1.0
NI (0.0%)
NI (0.0%)
NI (0.0%)
NI (3.9%)
NI (4.5%)
NI (0.0%)
NI (0.6%)
NI (0.0%)
NI (0.0%)
NI (0.0%)
NI (0.0%)
NI (0.0%)
NI (0.0%)
NI (0.0%)
NI (0.3%)
NI (0.0%)
NI (2.5%)
NI (23.4%)
NI (20.6%)
NI (9.4%)
0.42
β-mannosidase
snail
NI (0.3%) NI (0.0%)
α-
L-fucosidase
NI (5.9%)
NI (2.9%)
NI (1.0%)
bovine kidney
β-glucuronidase
E-coli
NI (15.1%) NI (11.1%)
0.17
aNI- No inhibition (less than 50% inhibition at 1 mM concentration), b( )-actual inhibition % at 1 mM, IC50 (50%
c
inhibition, concentration in mM)
3.
In summary, we have developed an efficient synthetic protocol for the synthesis of new N–acetyl
glucosamine derived carbasugars in both - and -forms in good to very good yield. We have
Conclusions
L
D
shown that the Peterson olefination is key reaction condition for doing olefination on the β-
hydroxy ketone system, where other olefination reactions unsuccessful due to high reactivity of
this substrate towards elimination reaction and aromatization. These carbasugar molecules were
designed based on literature reports on bio-potentials of this class of molecules. Subsequently,
we have successfully demonstrated that these synthesized carbasugars possess moderate
glycosidase inhibitor activity, and one of the carbasugar is very selective towards β-galactosidase
enzymes. This selective inhibition activity opens a new door for making more derivatives of
6

ACCEPTED MANUSCRIPT
these analogues and to study the mechanism of its inhibition. The complete library realization of
this new carbasugar and their enzyme inhibition activity will be reported in due course of time.
4.
Experimental
4.1. General Experimental Methods.
All experiments were performed in an oven-dried apparatus and using anhydrous solvents. High-
resolution ESI mass spectra were recorded using Agilent 6540 Q-TOF instrument. Optical
rotations were measured on krüss polarimeter. Solvents were distilled using standard distillation
procedure and stored on 4Å molecular sieves. 1H (400 MHz), 13C (100 MHz) NMR spectra were
recorded with a Bruker AMX-400 MHz instrument. 1H and 13C chemical shifts are referenced to
1
13
the solvents residual signals (CDCl3: δ 7.26 in H NMR and δ 77.16 in C NMR; CD3OD: δ
1
13
3.31 in H NMR and δ 49.00 in C NMR) and reported in parts per million (ppm) at 25 °C.
Coupling constants are expressed in hertz (Hz). Reactions were monitored by thin-layer
chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254), Spots were
visualized by phosphomolybdic acid and 10% H2SO4 in ethanol
.
4.2.Methyl 6-O-trityl 2-deoxy-2-acetamido-α-D-glucopyranoside (2).
Amberlite IR 120 H+ resin (20 g) was added to a pre-stirred solution of N-Acetyl
D-glucosamine
(20 g, 90.41 mmol) in methanol (200 mL). Reaction mixture was stirred at 80 °C for 24 h or until
it becomes clear solution. Reaction mixture was cooled to room temperature and filtered through
sintered funnel, filtrate was concentrated and evaporated to dryness to obtain compound methyl
N-acetyl-D-glucosamine as white solid (20 g, 90%). as anomeric mixture (α:β, 9:1), which was
used in next step without any further purification. To a stirred solution of methyl N-acetyl-
D
-
glucosamine (15.2 g, 64.68 mmol) in anhydrous pyridine, Trityl chloride (21.63 g, 77.61 mmol)
and DMAP (0.7 g, 6.46 mmol) were added and the resulting mixture was stirred at room
temperature for 48 h. After completion of the reaction (TLC), the reaction mixture was diluted
with water (150 mL) and extracted with ethyl acetate (3 × 150 mL), the combined organic layer
was washed with copper sulfate solution (250 mL) followed by saturated brine solution (200
mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to get the residue. The residue was purified by column chromatography (ethyl
acetate/methanol: 95:5) to furnish compound 2 as an amorphous solid (24.5 g) in 79% isolated
yield.
7

ACCEPTED MANUSCRIPT
20
1
[α]D +28.3 (c 0.6, CHCl3); H NMR (400 MHz, CDCl3) δ 7.47-7.21 (m,15H), 5.91 (d, J = 8.4
Hz, 1H, NH), 4.70 (d, J = 4.0 Hz, 1H, H-1), 4.08 (ddd, J = 10.0 Hz, 8.8 Hz, 3.6 Hz, 1H, H-2),
3.67-3.59 (m, 2H, H-5 and H-3), 3.54 (t, J = 8.0 Hz, 1H, H-4), 3.43 (dd, J = 2.8 Hz, 6.4 Hz, 1H,
13
H-6a), 3.40 (s, 3H, OCH3), 3.34 (dd, J = 5.6 Hz, 10.0 Hz, 1H, H-6b), 2.04 (s, 3H, NHAc); C
NMR (100 MHz, CDCl3) δ 172.0 (NHCO), 143.9 (ArqC), 128.8, 128.1, 128.0, 127.2 (ArC), 98.2
(C-1), 87.0 (CPh3), 74.4 (C-3), 72.8 (C-4), 70.2 (C-5), 63.9 (C-6), 55.1 (OCH3), 53.8 (C-2), 23.4
(NHAc); HRMS (ESI) m/z: calcd for C28H31NO6 [M+Na]+ 500.2044, found 500.2063.
4.3. Methyl 3,4-di-O-benzyl-2-deoxy-2-acetamido-α-D-glucopyranoside (3).
To a stirred solution of compound 2 (14 g, 29.32 mmol) in anhydrous THF, sodium hydride (3.5
g, 87.96 mmol, 3.0 equiv) was added at 0 °C. After 20 min, benzyl bromide (10.4 mL, 87.96
mmol, 3.0 equiv) was added drop wise and the resulting mixture was heated at 80 °C with
stirring for 1.5 h. After completion of the reaction (TLC), the reaction mixture was allowed to
cool down to room temperature and then it was quenched by adding methanol (10 mL). The
reaction mixture was dissolved in ethyl acetate (500 mL) and washed with water (3 × 200 mL)
followed by saturated brine solution (2 × 250 mL). The organic layer was dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure to get a yellow residue. The
residue was washed with pentane to furnish corresponding benzylated derivative of compound 2
as a brown sticky solid (15 g, 78%), which was used in the next step without further purification.
To a solution of benzylated derivative of compound 2 (10 g, 15.28 mmol) in anhydrous CH2Cl2,
a 33% solution of HBr in acetic acid (6.6 mL) was added at 0 °C drop wise. The reaction mixture
was stirred for 10 min at same temperature. Completion of the reaction was confirmed by TLC,
after the reaction mixture was quenched with ice cold water (50 mL) and extracted with CH2Cl2
(400 mL) the combined organic layer washed with water (100 mL), saturated sodium bicarbonate
solution (250 mL) and saturated brine solution (100 mL). The organic layer was dried over
anhydrous sodium sulfate, filtered and evaporated under reduced pressure which gave a residue.
The residue was purified by flash column chromatography (ethylacetate/hexane 80: 20) which
gave compound 3 as white gelatinous solid, which after re-crystallization with CH2Cl2 furnished
20
the title compound 3 as a white solid (5 g) in 80% isolated yield. [α]D +42.5 (c 0.2, MeOH);1H
NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 8.0 Hz, 1H, N-H), 7.35–7.23 (m, 10H, ArH), 4.77 (t,
J = 6.4 Hz, 1H, O-H), 4.73-4.60 (m, 4H, 2 × CH2Ph), 4.54 (d, J = 3.6 Hz, 1H, H-1), 3.96 (ddd, J
8

ACCEPTED MANUSCRIPT
= 12.8 Hz, 10.4 Hz, 3.2 Hz, 1H, H-2), 3.71 (dd, J = 8.4 Hz, 4.0 Hz, 1H, H-3), 3.66 (dd, J = 4.0
Hz, 11.6 Hz, 1H, H-6a), 3.59-3.56 (m, 1H, H-6b), 3.51-3.47 (m, 2H, H-4, H-5), 3.30 (s, 3H,
13
OCH3), 1.85 (s, 3H, NHAc); C NMR (100 MHz, DMSO-d6) δ 169.3 (NHCO), 138.7, 138.4
(ArqC), 128.2, 128.1, 127.6, 127.5, 127.4, 127.3 (ArC), 98.2 (C-1), 79.9, 78.0 (C-3, C-4), 74.0,
73.9 (CH2Ph), 71.69 (C-5), 60.1 (C-6), 54.3 (OCH3), 52.6 (C-2), 22.5 (NHAc); HRMS (ESI) m/z:
calcd for C23H29NO6 [M+Na]+ 438.1887, found 438.1910.
4.4. Methyl 3,4 -di-O-benzyl-2,6-di-deoxy-2-acetamido-α-D-xylohex-5-enoside (4).
To a stirred solution of compound 3 (7.0 g, 16.86 mmol) in anhydrous CH2Cl2, was added
DMAP (0.206 g, 1.686 mmol) and triethyl amine (23 mL, 168.6 mmol). The reaction mixture
was cooled to 0 °C and tosyl chloride (3.5 g, 18.54 mmol) was added portion wise over 30 min
and resulting mixture was stirred for 1 h at 0 °C. The reaction mixture was allowed to warm to rt
and stirred for another 12 h. After completion of the reaction (TLC), the reaction mixture was
quenched with saturated ammonium chloride solution (100 mL) and extracted with CH2Cl2 (5 ×
50 mL), the combined organic layer was washed with brine solution (100 mL) dried over
Na2SO4, filtered and evaporated to get sticky residue. The residue was purified by column
chromatography over silica gel (hexane/ethyl acetate 30:70) to furnish corresponding tosylated
derivative of 3 (9.0 g) in 94% isolated yield.
To a stirred solution of tosylated derivative of 3 (8.0 g, 14.05 mmol) in anhydrous DMF, Sodium
iodide (21.06 g, 140.54 mmol, 10 equiv) was added. The reaction mixture was stirred at 80 °C
for 3 h. After completion of reaction (TLC), reaction mixture was cooled to room temperature
and sodium hydride (1.12 g, 28.1 mmol) was added portion wise to this mixture. The resulting
mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction
mixture was quenched with ammonium chloride solution (100 mL) and extracted with ethyl
acetate (3 × 150 mL) the combined organic layer was washed with brine solution, dried over
Na2SO4, filtered and evaporated to dryness to obtain crude residue. The residue was purified by
flash column chromatography (ethylacetate/ hexane 1:1 to pure ethyl acetate), to furnish
20
compound 4 as a white color solid (4.0 g) in 72% isolated yield. [α]D +57.5 (c 0.2, MeOH): 1H
NMR (400 MHz, CDCl3) δ 7.39-7.28 (m, ArH, 10H), 5.42 (d, J = 9.2 Hz, 1H, NH), 4.83 (d, J =
11.6 Hz, 2H, CH2Ph), 4.79-4.69 (m, 4H), 4.32 (dt, J = 3.2 Hz and 9.2 Hz ,1H, H-2), 4.01 (d, J =
13
8.0 Hz, 1H, H-4), 3.63 (t, J = 9.2 Hz, 1H, H-3), 3.39 (s, 3H, OCH3), 1.84 (s, 3H, NHAc); C
9

ACCEPTED MANUSCRIPT
NMR (100 MHz, CDCl3) δ 169.9 (NHCO), 153.8, 138.4, 137.8 (ArqC), 128.62, 128.6, 128.3,
128.0, 127.9 (ArC), 99.6 (C-1), 97.7 (C-6), 79.7 (C-2), 78.6 (C-3), 74.5, 73.9 (2 × CH2Ph), 55.7
(OCH3), 51.8 (C-4), 23.5 (NHAc); HRMS (ESI) m/z: calcd for C23H27NO5 [M+H]+ 398.1962,
found 398.1991.
4.5. Synthesis of compound (5).
To a solution of compound 4 (4.0 g, 10.07 mmol) in 1,4-dioxane and 5mM H2SO4 (2:1, 120 mL)
was added HgSO4 (0.746 g, 2.51 mmol). The reaction mixture was stirred at 50 °C for 3 h. After
completion of reaction (TLC), the reaction mixture was diluted with water and extracted with
CH2Cl2. The combined organic layer was washed with brine solution, dried over sodium
sulphate, filtered and evaporated to give a crude compound. The residue was washed with diethyl
20
ether, to furnish corresponding ketone compound 5 as a white color powder (2.5 g, 65%). [α]D
1
+12.5 (c 0.2, MeOH): H NMR (400 MHz, DMSO-d6): δ 8.03 (d, J = 9 Hz, 1H. NH), 7.38-7.22
(m, 10H), 5.41 (d, J = 3.6 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H, CH2Ph), 4.71 (d, J = 11.0 Hz, 1H,
CH2Ph), 4.61 (d, J = 11.0 Hz, 1H, CH2Ph), 4.45 (d, J = 11.6 Hz, 1H, CH2Ph), 4.35 (d, J = 9.4
Hz, 1H, H-4), 4.30 (td, J = 2.0 Hz and J = 10.8 Hz, 1H, H-2), 3.93 (quint, J = 2.8 Hz, 1H, H-3),
3.74 (t, J = 9.6 Hz, 1H, H-3), 2.89 (dd, J = 14.0 Hz and 2.4 Hz, 1H, H-5a), 2.30 (dd, J = 13.6 Hz
13
and 3.2 Hz, H-5a'), 1.84 (s, 3H, NHAc); C NMR (100 MHz, DMSO-d6) δ 205.5 (C=O), 169.1
(NHC=O), 138.9, 138.5 (ArqC), 128.1, 128.0, 127.6, 127.5, 127.4, 127.2 (ArC), 86.1 (C-4), 80.0
(C-3), 73.7, 72.3 (2 × CH2Ph), 67.1 (C-1), 53.6 (C-2), 45.7 (C-5a), 22.7 (NHAc); HRMS (ESI)
m/z: calcd for C22H25NO5 [M+H]+ 384.1805, found 384.1826.
4.6. 2-Acetamido-3,4-di-O-benzyl-6-deoxy -5a -Carba-α-D-xylo-hex-5-enopyranose (5a).
To a round bottom flask Magnesium turnings (1.5 g, 65.25 mmol) and Iodine (catalytic) were
added under argon atmosphere. The flask was heated (50-60 °C) with hot gun for 5 min then
cooled to rt. Anhydrous THF (5 ml) was added followed by addition of (chloromethyl)
trimethylsilane (2 mL). The reaction mixture was again heated with hot gun in order to initiate
reaction followed by addition of remaining (chloromethyl) trimethylsilane (6.4 g, 52.2 mmol)
and THF (35 mL) at rt. The resulting mixture was stirred at room temperature for 1 h. Compound
5 (1.0 g, 2.61 mmol) in anhydrous THF (15 mL) was added to this mixture and stirring was
continued for another 1 h. After completion of reaction (confirmed by TLC) the reaction mixture
was quenched with methanol (10 mL), diluted with saturated NH4Cl solution (50 mL) and
10

ACCEPTED MANUSCRIPT
extracted with dichloromethane (3 × 100 mL). The combined organic layer was washed with
brine solution (100 mL), dried over sodium sulphate, filtered and evaporated to get silylated
Grignard product derivative, which was forwarded next step without further purification. To a
stirred solution of Grignard product derivative (1.2 g, 5.21mmol) in anhydrous CH2Cl2 was
added p-toluenesulfonic acid monohydrate (0.44g, 2.60 mmol) portion wise. The reaction
mixture was stirred at room temperature for 24 h. After completion of the reaction (TLC), the
reaction mixture was quenched with triethyl amine evaporated under reduced pressure. The
residue was diluted with water (50 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined
organic layer was washed with brine solution (100 mL), dried over sodium sulphate, filtered and
evaporated to dryness obtained a crude product residue. The crude product residue was purified
by column chromatography (Ethyl acetate: hexane, 8:2) to furnished compound 5a as an off-
20
white solid (0.54 g) in 55% isolated yield over two steps: [α]D +46.0 (c 0.5, MeOH); 1H NMR
(400 MHz, CDCl3) δ 7.36-7.26 (m, 10H), 6.78 (brs, NH), 5.23 (s, 1H, =CH), 5.17 (s, 1H, =CH),
4.63 (s, 2H), 4.59 (d, J = 11.2 Hz, 1H, CH2Ph), 4.44 (quin, J = 4.0 Hz, 1H, H-2), 4.34 (d, J =
10.0 Hz, 1H, CH2Ph), 4.09 (quin, J = 4.5 Hz, 1H, H-1), 3.95 (d, J = 5.0 Hz, 1H, H-4), 3.65 (t, J =
5.0 Hz, 1H, H-3), 2.98 (brs, 1H), 2.41 (dd, J = 8.0 Hz, 4.9 Hz, 2H, H-5a and H-5a'), 1.84 (s, 3H,
NHAc); 13CNMR (100 MHz, CDCl3) δ 172.0 (NHCO), 140.4, 137.9, 137.7 (ArqC), 128.7, 128.6,
128.2, 128.0, 127.9, 127.8 (ArC), 117.1 (=CH2), 81.2 (C-3), 78.3 (C-4), 72.4, 70.8 (2 × CH2Ph),
69.5 (C-1), 52.6 (C-2), 35.0 (C-5a), 23.4 (NHAc); HRMS (ESI) m/z: calcd for C23H27NO4
[M+H]+ 382.2013, found 382.2042.
4.7. Methyl 2-acetamido-3,4-di-O-benzyl-6-deoxy -5a -Carba-α-D-xylo-hex-5-enopyranoside
(5b).
To a stirred solution of sodium hydride (0.3 g, 0.789 mmol) in anhydrous THF (3 mL) at 0 °C
was added a solution of compound 5a (0.047 g, 1.18 mmol) in anhydrous THF (2 mL) dropwise
and resulting reaction mixture was stirred at 0 °C for 10 min. Methyl iodide (0.24 mL, 3.945
mmol) was added dropwise to this reaction mixture and stirring was continued at room
temperature for 3 h. After completion (TLC) of reaction, the reaction mixture was quenched by
addition of saturated aqueous NH4Cl solution (25 mL) and extracted with ethyl acetate (2 × 25
mL). The organic phase was separated; aqueous layer was extracted with ethyl acetate (2 × 25
mL). The combined organic phases were washed with saturated brine solution, dried over
anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by
11

ACCEPTED MANUSCRIPT
column chromatography (Ethyl acetate/hexane 6:4) to furnish compound 5b as a colourless solid
20
(0.280 g) in 90% isolated yield. [α]D +42 (c 0.2, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.37-
7.26 (m, 10H, ArH), 6.14 (bs, 1H), 5.19 (s, 1H, =C-H), 5.11 (s, 1H, =C-H), 4.73 (d, J = 9.6 Hz,
1H, CH2Ph), 4.59 (d, J = 10.0 Hz, 2H, CH2Ph), 4.50-4.44 (m, 2H), 3.95 (d, J = 5.0 Hz, 1H, H-2),
3.62 (t, J = 5.0 Hz, 1H, H-3), 3.54-3.51 (m, 1H, H-1), 3.32 (s, 3H, OMe), 2.50 (dd, J = 6.4 Hz
and 11.2 Hz, 1H, H-5a), 2.26 (dd, J = 2.4 Hz and 11.2 Hz, H-5b), 1.82 (s, 3H, COCH3); 13CNMR
(125 MHz, CDCl3) δ 169.7 (NHCO), 140.5, 138.2, 137.9 (ArqC), 128.4, 128.3, 127.9, 127.8,
127.6 (ArC), 114.2(=C), 82.2 (C-3), 79.7 (C-4), 77.08 (C-1), 73.3, 71.6 (2 × CH2Ph), 56.3
(OCH3) , 50.1 (C-2), 32.7 (C-5a), 23.5 (NHAc); HRMS (ESI) m/z: calcd for C24H29NO4 [M+H]+
396.2169, found 396.2137.
4.8.General Procedure for the preparation of carbasugars 6a-b and 7a-b
4.8.1. 2-Acetamido-2-deoxy-3,4-di-O-benzyl-5a-carba-α-L-Iodopyranose (6a). To a stirred
solution of compound 5a (0.4 g, 1.05 mmol) in anhydrous THF under nitrogen atmosphere was
added BH3·THF (3.1 mL, 3.14 mmol, 1M in THF) dropwise at 0 °C. The resulting solution was
stirred at room temperature (rt) till disappearance (TLC) of the starting material (1.5 h). 3M
NaOH (1 mL) solution and 30% H2O2 solution (1.5 mL) was added to the reaction mixture at 0
°C and resulting mixture was stirred for 1h at rt. The reaction mixture was quenched with 0.5 N
Na2S2O3 solution and extracted with CH2Cl2 (2 × 50 mL). The combined organic layer was
washed with brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue
was purified by column chromatography (Ethyl acetate) to furnish the desired carbasugar
20
1
derivative 6a as colorless oil (0.27 g, 65%). [α]D +15.2 (c 0.2, CHCl3); H NMR (400 MHz,
CDCl3) δ δ 7.38-7.27 (m, 10H, ArH), 6.83 (brs, 1H, NH), 4.67 (d, J = 9.6 Hz, 1H, CH2Ph), 4.57-
4.47 (m, 4H, CH2Ph and H-2), 4.12 (dt, J = 3.6 and 9.2 Hz, 1H, H-1), 3.81 (m, 1H, H-4), 3.74 (t,
J = 2.8 Hz, 1H, H-3), 3.68-3.66 (m, 2H, H-6), 2.12-2.10 (m, 1H, H-5), 1.78 (s, 3H, NHAc), 1.64
(td, J = 3.6 Hz and 10.4 HZ, 1H, H-5a), 1.50 (dd, J = 9.6Hz and 19.2 Hz 1H, H-5a'); 13C NMR
(100 MHz, CDCl3) δ 172.0 (NHCO), 137.7, 137.4 (ArqC), 128.8, 128.5, 128.5, 128.1, 128.0,
127.7 (ArC), 76.8 (C-4), 75.2 (C-3), 73.4(CH2Ph), 72.1 (CH2Ph), 68.0 (C-1), 63.5 (C-6), 51.6
(C-2), 37.9 (C-5), 25.6 (C-5a), 23.3 (NHAc); HRMS (ESI) m/z: calcd for C23H29NO5 [M+H]+
400.2118, found 400.2125.
12

ACCEPTED MANUSCRIPT
4.8.2. Methyl 2-acetamido-2-deoxy-3,4-di-O-benzyl-5a-carba-α-L-Iodopyranoside (6b). To a
stirred solution of compound 5b (0.209 g, 0.50 mmol) in anhydrous THF was added BH3·THF
(1.01 ml, 1M in THF, 1.01 mmol), dropwise at 0 °C. The resulting solution was stirred at room
temperature for 2.5 h. TLC (Ethyl acetate) showed that the starting material was consumed
completely. 3N NaOH aqueous solution (1.0 mL, 3.03 mmol) and 30% H2O2 solution (1 mL)
was added at 0 °C and reaction mixture was stirred for another 2 h at room temperature. The
reaction mixture was quenched with 0.5 N Na2S2O3 solution and extracted with CH2Cl2. The
combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, filtered
and evaporated to dryness. The residue was purified by column chromatography (Ethyl
20
acetate/hexane 8:2) to give compound 6b as a colourless oil. (0.132 g), 61% isolated yield. [α]D
+17.5 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38-7.29 (m, 8H, ArH), 7.26-7.23 (m, 2H,
ArH), 6.27 (d, J = 9.2 Hz, 1H, NH), 4.74 (dd, J = 4.4 Hz, 1H, H-2), 4.69 (d, J = 11.9 Hz, 1H,
CH2Ph), 4.57 (d, J = 12.0 Hz, 1H, CH2Ph), 4.49 (dd, J = 11.2 Hz, 2H, CH2Ph), 3.87 (t, J = 8.0
and 10.4 Hz, 1H, H-3), 3.77 (t, J = 2.4 Hz, 1H, H-4), 3.71 (brd, J = 7.6 Hz, 1H, H-6a), 3.64 (dd,
J = 4.8 Hz, 10.4 Hz, 1H, H-6b), 3.58 (dt, J = 4.4 and 11.6 Hz, 1H, H-1), 3.32 (s, 3H, OCH3),
2.16-2.12 (m, 1H, H-5a), 1.78 (s, 3H, NHAc), 1.65 (dt, J = 4.4 and 13.2 Hz, H-5), 1.53 (brd, J =
13
12.4 Hz, H-5a'); C NMR (100 MHz, CDCl3) δ 169.9 (NHCO), 138.0, 137.4 (ArqC), 128.8,
128.6, 128.4, 128.1, 127.9, 127.8 (ArC), 75.6, 74.9, 72.7, 72.4, 64.2, 56.6 (OCH3), 38.1, 25.0 (C-
5a), 23.5 (NHAc); HRMS (ESI) m/z: calcd for C24H31NO5 [M+H]+ 414.2275, found 414.2263.
4.9. Synthesis of compound 7a and 7b. To a solution of compound 6a (0.12 g, 3.03 mmol) in
methanol was added Pd(OH)2/C (20 mg, 20 wt % on carbon, wet) at room temperature. The
reaction mixture was stirred under H2 gas (balloon) for 12 h. The reaction mixture was filtered
through celite, and the filtrate was evaporated to dryness to furnish compound 7a (49 mg, 75%)
as a colorless sticky solid. Similarly compound 7b (32 mg, 82%) was prepared starting from 6b
(70 mg, 0.16 mmol).
20
1
4.9.1. 2-Acetamido-2-deoxy-5a-carba-α-L-Iodopyranose (7a). [α]D +11.3 (c 0.2, CH3OH); H
NMR (400 MHz, D2O): δ 4.08-4.05 (m, 2H), 3.93-3.88 (m, 2H), 3.76-3.74 (m, 2H), 2.21-2.17
13
(m, 1H, H-5a), 2.06 (s, 3H, NHAc), 1.77 (m, 2H, H-5a', H-5); C NMR (100 MHz, D2O): δ
174.1 (NHCO), 71.2, 70.3, 66.8, 62.1 (C-1, C-3, C-4, and C-7) 54.4 (C-2), 38.4 (C-5), 29.8 (C-
6), 22.2 (NHAc); HRMS (ESI) m/z: calcd for C9H17NO5 [M+Na]+ 220.1179, found 220.1172.
13

ACCEPTED MANUSCRIPT
20
4.9.2. Methyl 2-acetamido-2-deoxy-5a-carba-α-L-Iodopyranoside (7b). [α]D +12.6 (c 0.5,
CH3OH); 1H NMR (400 MHz, D2O) δ 4.22 (brs, 1H), 3.89 (s, 2H), 3.78 (dd, J = 7.2 and 11.2 Hz,
1H), 3.71-3.64 (m, 2H), 3.36 (s, 3H, OCH3), 2.18 (m, 1H, H-5a), 2.04 (s, 3H, NHAc), 1.72-1.68
13
(m, 2H, H-5a' & H-5); CNMR (100 MHz, D2O) δ 173.9 (NHCO), 76.5 (C-3), 70.5 (C-4), 62.2
(C-6), 56.2 (OCH3), 51.6 (C-1), 48.8 (C-2), 38.3 (C-5), 23.9 (C-5a), 22.2 (NHAc); HRMS (ESI)
m/z: calcd for C10H19NO5 [M+Na]+ 256.1155, found 256.1172.
4.10. Synthesis of compound (8).
To a solution of compound 5a (0.250 g, 0.45 mmol) in anhydrous CH2Cl2 was added m-CPBA
(0.22 g, 1.31 mmol) and suspension was stirred at rt for 3 h. After completion (TLC) of reaction,
the reaction mixture was quenched with sodium bicarbonate solution (10 mL) and extracted with
CH2Cl2 (2 × 50 mL). The combined organic layer was washed with brine solution (50 mL) dried
over Na2SO4 filtered and evaporated to dryness to obtain a crude compound. The residue was
purified by flash chromatography (Ethyl acetate), to furnished compound 8 as a white color solid
1
(0.208 g, 80%). [α]D20 +19.3 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 7.38-7.29 (m, 10H,
ArH), 6.88 (brs, 1H), 4.87 (d, J = 11.2 Hz, 1H, CH2Ph), 4.63 (d, J = 11.2 Hz, 1H, CH2Ph), 4.54
(d, J = 12.4 Hz, 3H, CH2Ph), 4.24 (dt, J = 4.0 Hz and J = 10.4 Hz, 1H, H-2), 3.75 (t, J = 4.0 Hz,
1H, H-3), 3.35 (d, J = 3.2 Hz, 1H, H-4), 2.68 (s, 2H, H-6), 2.26 (t, J = 11.6 Hz, 1H, H-5a), 1.84
(s, 3H, NHAc), 1.54 (d, J = 10.8 Hz, 1H, H-5a'); 13C NMR (100 MHz, CDCl3) δ 172.2 (NHCO),
137.6, 137.5 (ArqC), 128.8, 128.7, 128.4, 128.3, 128.1, 128.0, 127.6 (ArC), 80.2, 77.8, 77.3,
73.2, 72.7, 69.0, 57.3, 51.7, 50.5, 32.8, 23.3 (NHAc); HRMS (ESI) m/z: calcd for C23H27NO5
[M+Na]+ 420.1781, found 420.1829.
4.11. 2-Acetamido-2-deoxy-3,4-di-O-benzyl-5-chloro 5a-carba-α-D-glucopyranose (9).
To a stirred solution of compound 8 (0.03 g, 0.07 mmol) in anhydrous CH2Cl2 at 0 °C, TiCl4
(0.18 ml, 1M in CH2Cl2, 0.15 mmol) was added dropwise. The resulting mixture was stirred at 0
°C for 10 minutes. TLC (Ethylacetate : hexane, 9:1) showed that starting material was consumed.
The reaction was quenched with sodium chloride solution (5 mL) and extracted with CH2Cl2 (2 ×
20 mL), The combined organic layer was washed with brine solution dried over anhydrous
Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography
14

ACCEPTED MANUSCRIPT
(Ethyl acetate/hexane,7:3), to furnish compound 9 as a colorless oil (0.020 g, 62%): [α]D20 +21.6
1
(c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 10H, ArH), 5.89 (d, J = 8.0 Hz,
1H, NH), 4.98 (d, J = 10.4 Hz, 1H, CH2Ph), 4.83 (d, J = 11.2 Hz, 1H, CH2Ph), 4.69 (d, J = 10.8
Hz, 2H, CH2Ph), 4.09 (t, J = 8.0 Hz, 1H, H-2), 3.95-3.82 (m, 4H), 3.53 (d, J = 10.8 Hz, 1H, H-
6a), 3.34 (d, J = 10.8 Hz, 1H, H-6b), 3.24 (s, 1H), 2.03 (brs, 2H, H-5a), 1.84 (s, 3H, NHAc); 13C
NMR (100 MHz, CDCl3) δ 170.2 (NHCO), 138.1, 137.6 (ArqC), 128.75, 128.7, 128.4, 128.3,
128.0 (ArC), 80.9 (C-3), 79.2 (C-4), 77.8 (C-5), 76.0 (CH2Ph), 75.6 (CH2Ph), 69.8 (C-1), 54.7
(C-2), 47.5 (C-6), 34.6 (C-5a), 23.6 (NHAc); HRMS (ESI) m/z: calcd for C23H28ClNO5 [M+H]+
434.1729, found 434.1735.
4.12. 2-Acetamido-2-deoxy-5-chloro 5a-carba-α-D- glucopyranose (9a).
To a stirred solution of compound 9 (0.018 g, 0.16 mmol) in methanol was added Palladium
hydroxide (0.020 g, 20% weight on carbon, wet) at room temperature. The reaction mixture
stirred under H2 balloon pressure for 12 h. After completion of reaction, the reaction mixture
was filtered through Celite, and the filtrate was evaporated to dryness to furnish compound 9a as
1
a colourless sticky solid (0.009 g, 90%): [α]D20 +36.0 (c 0.2, CH3OH); H NMR (400 MHz,
CD3OD); δ 4.02 (dd, J = 2.7 Hz and 5.7 Hz, 1H), 3.82 (dd, J = 2.7 Hz and J = 10.6 Hz, 1H), 3.75
(dd, J = 10.5 Hz and 1.6 Hz, 1H), 3.65 (d, J = 10.9 Hz, 1H, H-6a), 3.51 (d, J = 8.8 Hz, 1H, H-4),
3.47 (d, J = 10.9 Hz, 1H, H-6b), 2.04 (m, 4H, H-5a and NHAc), 1.90 (dd, J = 2.8 Hz, 15.2 Hz,
13
1H, H-5a'); C NMR (100 MHz, CD3OD) δ 173.6, 77.1, 75.7, 71.1, 70.1 (C-3, C-4, C-5, C-1),
57.5 (C-6), 49.3 (C-2), 36.1 (C-5a), 22.7 (NHAc); HRMS (ESI) m/z: calcd for C9H16ClNO5
[M+H]+ 254.0795, found 254.0820.
4.13. General Procedure for the preparation of α-pseudo C-1 alkyl epoxides 10a-10c
To a stirred solution of sodium hydride (0.027 g, 1.13 mmol) in anhydrous DMF (2 mL) at 0 °C
was added a solution of compound 8 (0.18 g, 0.45 mmol) in anhydrous DMF dropwise, after the
addition the reaction mixture was stirred at same temperature for 10 min. Methyl iodide (0.07
mL, 1.13 mmol) was added dropwise to this reaction mixture and the reaction mixture was
stirred at room temperature for 3 h. After completion (TLC) of reaction, the reaction mixture was
quenched by addition of saturated NH4Cl aqueous solution (25 mL) and extracted with ethyl
acetate (3 × 20 mL), and combined organic layer was washed with brine solution, dried over
15

ACCEPTED MANUSCRIPT
anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by
column chromatography (Ethyl acetate/ hexane, 7:3) to furnished compound 10a as a colorless
solid (0.16 g) in 88% isolated yield. Similar reaction protocol was adopted for the preparation of
compounds 10b and 10c.
4.13.1. Compound (10a). [α]D20 – 17.5 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37-7.26
(m, 10H, ArH), 6.46 (d, J = 8.4 Hz, 1H, NH), 4.82 (d, J = 11.2 Hz, 1H, CH2Ph), 4.76-4.73 (m,
1H, H-2), 4.66 (d, J = 12.0 Hz, 1H, CH2Ph), 4.54 (d, J = 11.6 Hz, 2H, CH2Ph), 3.81 (t, J = 3.9
Hz, 1H, H-3), 3.69 (dt, J = 3.9 Hz and J = 10.8 Hz, 1H, H-1), 3.35 (s, 4H, OCH3 and H-4), 2.67
(dd, J = 5.2, and 6.4 Hz, 2H, H-6), 2.25 (t, J = 12.0 Hz, 1H, H-5a), 1.81 (s, 3H, NHAc), 1.48 (dd,
13
J = 4.0 and 12.8 Hz, 1H, H-5a'); C NMR (400 MHz, CDCl3) δ 169.9 (NHCO), 137.86, 137.8
(ArqC), 128.7, 128.6, 128.1, 128.0, 127.8, 127.6 (ArC), 80.3, 78.1, 77.3, 75.8 (C-5), 73.1, 72.8,
75.3, 57.2, 57.0 (OCH3 and, C-6), 50.6, 30.8 (C-5a), 23.6 (NHAc); HRMS (ESI) m/z: calcd for
C24H29NO5 [M+H]+ 411.2046, found 411.2051.
4.13.2. Compound (10b)
Compound 10b was prepared starting from 8 (150 mg, 0.39 mmol) using DMF (5mL) and butyl
bromide (0.07 mL, 1.17 mmol, 3.0 equiv) at elevated temperature (50 °C, 3 h) and pure product
1
was isolated (Ethyl acetate/hexane 1:1) in 65% yield (112 mg). [α]D20 – 14.3 (c 0.2, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 10H, ArH), 6.39 (d, J = 8.0 Hz, 1H, NH), 4.81 (d, J =
11.2 Hz, 1H, CH2Ph), 4.71 (m, 1H, H-2), 4.67 (d, J = 12.0 Hz, 1H, CH2Ph), 4.54 (d, J = 11.6 Hz,
2H, CH2Ph), 3.82 (t, J = 4.0 Hz, 1H, H-3), 3.74 (dt, J = 3.9 Hz and 10.8 Hz, 1H, H-1), 3.58 (dd,
J = 6.4 Hz and 14.8 Hz, 1H, H-4 ), 3.35-3.30 (m, 2H, O-butyl), 2.69 (q, J = 4.0 Hz, 2H, H-6),
2.26 (t, J = 12.0 Hz, 1H, H-5a), 1.80 (s, 3H, NHAc), 1.49-1.44 (m, 3H, CH2 of butyl and H-5a'),
13
1.34-1.25 (m, 2H), 0.88 (t, J = 7.6 Hz, 3H, CH3 of butyl); C NMR (100 MHz, CDCl3) δ 169.8
(NHCO), 137.9, 137.8 (ArqC), 128.6, 128.0, 127.8, 127.7 (ArC), 80.3 (C-4), 78.1 (C-3), 77.3 (C-
5), 74.1 (C-1), 73.0 (CH2Ph), 72.9 (CH2Ph), 69.0 (C-6), 57.3 (C-2), 32.0 (C-5a), 31.3, 23.6
(NHAc), 19.4, 14.0 (CH3 of butyl); HRMS (ESI) m/z: calcd for C27H35NO5 [M+H]+ 454.2588,
found 454.2623.
16

ACCEPTED MANUSCRIPT
4.13.3. Compound (10c)
Compound 10c was prepared starting from 8 (80 mg, 0.20 mmol) using DMF (5mL) and hexyl
bromide (0.06 mL, 0.40 mmol, 3.0 equiv) at elevated temperature (50 °C, 3 h) and pure product
20
was isolated after flash chromatography (Ethyl acetate/hexane 7:3) in 64% yield (62 mg). [α]D
1
– 11.7 (c 0.2, CHCl3); H NMR (400 MHz,CDCl3) δ 7.36-7.28 (m, 10H, ArH), 6.39 (d, J = 8.0
Hz, 1H, NH), 4.81 (d, J = 11.2 Hz, 1H, CH2Ph), 4.72-4.70 (m, H-2), 4.66 (d, J = 12.0 Hz, 1H,
CH2Ph), 4.55 (t, J = 11.6 Hz, 2H, CH2Ph), 3.82 (t, J = 4.0 Hz, 1H, H-3), 3.74 (dt, J = 3.9, 10.8
Hz, 1H, H-1), 3.57 (dd, J = 6.4, 14.8 Hz, 1H, H-4), 3.35-3.29 (m, 2H, hexyl), 2.66 (q, J = 4.0 Hz,
2H, H-6), 2.26 (t, J = 12.0 Hz, 1H, H-5a), 1.80 (s, 3H, NHAc), 1.49-1.45 (m, 4H), 1.25 (m, 8H),
13
0.87 (t, J = 7.6 Hz, 3H, CH3 of hexyl); C NMR (100 MHz, CDCl3) δ 169.8 (NHCO), 137.9,
137.8 (ArqC), 128.6, 128.1, 128.0, 127.8, 127.7 (ArC), 80.3 (C-4), 78.1 (C-3), 77.3 (C-5), 74.1
(C-1), 73.0 (CH2Ph),72.8 (CH2Ph), 69.3 (C-6), 57.3 (C-2), 31.8 (C-5a), 31.3, 29.9, 29.8, 25.8,
23.6 (NHAc), 22.7, 14.1; HRMS (ESI) m/z: calcd for C29H39NO5 [M+H]+ 482.2901, found
[M+H]+ 482.2941.
4.14. General Procedure for the preparation of α-pseudo C-1 alkyl carbasugars 11a-11c.
4.14.1. Methyl 2-Acetamido-2-deoxy-3,4-di-O-benzyl-5-chloro 5a-carba-α-D- glucopyranoside
(11a).
To a stirred solution of compound 10a (0.08 g, 0.38 mmol) in anhydrous CH2Cl2 was added
TiCl4 (0.32 ml, 1M in CH2Cl2, 2.01 mmol) dropwise at 0 °C. The reaction mixture was stirred at
0 °C for 10 minutes. After completion (TLC) of reaction, the reaction mixture was quenched
with sodium chloride solution (5 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined
organic layer was washed with brine solution, dried over Na2SO4, filtered and evaporated to
dryness. The residue was purified by flash chromatography (Ethyl acetate / hexane 7:3) and
compound 11a was obtained as sticky oil (0.06 g) in 69% isolated yield: [α]D20 + 28.0 (c 0.5,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 10H, ArH), 5.54 (d, J = 8.8 Hz, 1H, NH),
4.94 (d, J = 11.2 Hz, 1H, CH2Ph), 4.86 (d, J = 11.6 Hz, 1H, CH2Ph), 4.72 (d, J = 11.2 Hz, 1H,
CH2Ph), 4.64 (d , J = 11.2 Hz, 1H, CH2Ph), 4.13 (td, J = 3.2 Hz and J = 10 Hz, 1H, H-2), 3.86 (t,
J = 9.6 Hz, 1H, H-3), 3.75 (d, J = 9.6 Hz, 1H, H-4), 3.67 (m, 1H, H-1), 3.60 (d, J = 11.2 Hz, 1H,
H-6a), 3.37 (s, 3H, OCH3), 3.37-3.35 (m, 1H, H-6b), 2.08 (dd, J = 3.2 Hz, 15.0 Hz, 1H, H-5a),
17

ACCEPTED MANUSCRIPT
13
1.83 (s, 3H, NHAc), 1.81-1.80 (m, 1H, H-5a'); C NMR (100 MHz, CDCl3) δ 169.9 (NHCO),
138.4, 138.0 (ArqC), 128.7, 128.6, 128.38, 128.3, 128.2, 128.0 (ArC), 81.5, 79.0, 78.6 (C-3, C-4,
C-1), 76.2 (C-5), 75.7, 75.3 (CH2Ph), 58.2 (OCH3), 53.6 (C-2), 48.0 (C-6), 31.4 (C-5a), 23.5
(NHAc);. HRMS (ESI) m/z: calcd for C24H30ClNO5 [M+Na]+ 448.1885, found 448.1896.
4.14.2. Butyl 2-Acetamido-2-deoxy-3,4-di-O-benzyl-5-chloro 5a-carba-α-
D-glucopyranoside
(11b).
Compound 11b was prepared starting from 10b (0.1 g, 0.22 mmol) and pure product was isolated
(Ethyl acetate/hexane 7:3) in 70% yield (76 mg) after purification. [α]D20 + 23.0 (c 0.5, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 10H, ArH), 5.27 (d, J = 10.8 Hz, 1H, NH), 4.96 (d,
J = 11.7 Hz, 1H, CH2Ph), 4.87 (d, J = 8 Hz, 1H, CH2Ph), 4.74 (d, J = 12 Hz, 1H, CH2Ph), 4.65
(d, J = 12 Hz ,1H, CH2Ph), 4.21 (s, 1H, OH), 4.02 (td, J = 2.8, 10.8 Hz, 1H, H-2), 3.88 (t, J = 9.6
Hz, 1H, H-3), 3.80 (dd, J = 3.2 and 6.0 Hz, 1H), 3.73 (d, J = 11.5 Hz, 1H, H-6a), 3.65-3.60 (m,
2H, OCH2 of Butyl) 3.35 (d, J = 10.4 Hz, 1H, H-6b), 3.26 (dt, J = 6.4 Hz and 9.2 Hz, H-1), 2.00
(dd , J = 3.2 Hz and 15.2 Hz, 1H, H-5a), 1.83 (dd, J = 2.4 Hz and 15.2 Hz, 1H, H-5a'), 1.78 (s,
3H, NHAc), 1.53-1.45 (m, 2H, CH2 of butyl), 1.35-1.25 (m, 2H, CH2 of butyl), 0.89 (t, J = 7.6
13
Hz, 3H, CH3 of butyl); C NMR (100 MHz, CDCl3) δ 169.8 (NHCO), 138.4, 138.1 (ArqC),
128.78, 128.7, 128.5, 128.4, 128.1, 127.9 (ArC), 81.8 (C-4), 78.0 (C-3), 77.6 (C-5), 77.4, 76.4
(C-1), 75.8 (CH2Ph),75.2 (CH2Ph), 70.8 (C-6), 54.0 (C-2), 47.8, 32.3 (C-5a), 31.8, 23.4 (NHAc),
19.3 (CH2 of Butyl), 13.8 (CH3 of Butyl); HRMS (ESI) m/z: calcd for C27H36ClNO5 [M+Na]+
512.2174, found 512.2217.
4.14.3. Hexyl 2-acetamido-2-deoxy-3,4-di-O-benzyl-5-chloro 5a-carba-α-D- glucopyranoside
(11c).
Compound 11c was prepared starting from 10c (0.04 g, 0.08 mmol) and pure product was
20
isolated (Ethyl acetate/hexane 7:3) in 72% yield (31 mg). [α]D + 21.5 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.37-7.25 (m, 10H, ArH), 5.28 (d, J = 9.2 Hz, 1H, NH), 4.96 (d, J = 11.6
Hz, 1H, CH2Ph ), 4.87 (d, J = 11.6 Hz, 1H, CH2Ph), 4.74 (d, J = 10.8 Hz, 1H, CH2Ph), 4.66 (d , J
= 12.0 Hz , 1H, CH2Ph), 4.21 (s, 1H, OH), 4.03 (td, J = 3.2 Hz, J = 10.7 Hz, 1H, H-2), 3.88 (t, J
= 9.2 Hz, 1H, H-3), 3.80 (dd, J = 3.2 Hz, 1H), 3.74 (d, J = 9.2 Hz, 1H), 3.65-3.61 (m, 2H, OCH2
of hexyl), 3.35 (d, J = 12 Hz, 1H, H-6a) 3.26 (dt, J = 7.2 Hz, J = 15.1 Hz, 1H, H-1), 1.99 (dd , J
18

ACCEPTED MANUSCRIPT
= 3.2, 15.2, 1H, H-5a), 1.86 (dd, J = 2.3, 15.0 Hz, 1H, H-5a'), 1.78 (s, 3H, NHAc), 1.50-1.48 (m,
13
2H), 1.29-1.25 (m, 7H), 0.88 (t, J = 7.6 Hz, 3H, CH3 of hexyl); C NMR (100 MHz, CDCl3) δ
169.8 (NHCO), 138.4, 138.1 (ArqC), 128.78, 128.7, 128.6, 128.5, 128.4 128.1, 128.0 (ArC),
81.7, 78.2 (C-3, C-4), 76.4 (C-5), 75.8, 75.2 (CH2Ph), 71.1, 54.0, 47.8 (C-2, C-6), 32.3, 31.6 (C-
5a), 29.8, 25.8, 23.5 (NHAc), 22.7, 14.1 (CH3 of hexyl); HRMS (ESI) m/z: calcd for
C29H40ClNO5 [M+H]+ 518.2668, found 518.2718.
4.15. General Procedure for the preparation of α-pseudo C-1 alkyl carbasugars 12a-12c.
4.15.1. Methyl 2-acetamido-2-deoxy-5-chloro 5a-carba-α-D- glucopyranoside (12a).
To a stirred solution of compound 11a (0.05 g, 0.11 mmol) in methanol was added Palladium
hydroxide (0.020 g, 20% weight on carbon, wet) in methanol (5 mL) at room temperature. The
reaction mixture was stirred under H2 gas balloon pressure for 12 h. The reaction mixture was
filtered through celite, and the filtrate was evaporated to dryness to furnish compound 12a as a
20
colorless sticky solid (0.025 g, 83%): [α]D + 37.0 (c 0.2, CH3OH); 1H NMR (400 MHz, D2O) δ
3.92-3.82 (m, 2H), 3.74 (s, 1H), 3.66 (brs, 2H), 3.62 (d, J = 11.2 Hz, 1H, H-6b), 3.42 (s, 3H,
OCH3), 2.40 (dd, J = 3.6 Hz and 16.0 Hz, 1H, H-5a), 2.09 (s, 3H, NHAc), 1.80 (d, J = 12.0 Hz,
1H, H-5a'); 13C NMR (125 MHz, D2O) δ 176.7 (NHCO), 80.7 (C-3), 77.8 (C-4), 76.5 (C-5), 72.0
(C-1), 60.5 (C-2), 57.3 (OCH3), 51.5 (C-6), 33.3 (C-5a), 24.5 (NHAc); HRMS (ESI) m/z: calcd
for C10H18ClNO5 [M+Na]+ 290.0766, found 290.0770.
4.15.2. Butyl 2-acetamido-2-deoxy-5-chloro 5a-carba-α-D- glucopyranoside (12b).
Compound 12b was prepared starting from 11b (60 mg, 0.122 mmol) and pure product was
1
obtained in 78% yield (35 mg). [α]D20 +34.0 (c 0.2, CH3OH); H NMR (400 MHz, CD3OD) δ
3.85-3.84 (m, 1H), 3.79-3.77 (m, 2H), 3.67-3.61 (m, 2H), 3.48-3.41 (m, 3H), 2.18 (dd, J = 2.8,
15.6 Hz, 1H, H-5a), 2.15 (s, 3H, NHAc), 1.69 (dd, J = 2.8 Hz and 15.6 Hz, 1H, H-5a'), 1.58-1.52
(m, 2H), 1.42-1.29 (m, 2H), 0.93 (q, J = 7.6 Hz, 3H, CH3 of hexyl); 13C NMR (100 MHz,
CD3OD) δ 173.4 (NHCO), 78.5, 76.5, 75.8, 72.0, 71.0, 56.7, 32.9, 32.8, 22.5 (NHAc), 20.1 14.1;
HRMS (ESI) m/z: calcd for C13H24ClNO5 [M+H]+ 310.1415, found 310.1445.
4.15.3. Hexyl 2-acetamido-2-deoxy-5-chloro 5a-carba-α-D- glucopyranoside (12c).
19

ACCEPTED MANUSCRIPT
Compound 12c was prepared starting from 11c (30 mg, 0.057 mmol) and pure product was
1
obtained in 77% yield (15 mg). [α]D20 + 30.5 (c 0.2, CH3OH); H NMR (400 MHz, CD3OD) δ
3.85 (dd, J = 2.0 Hz, 1H), 3.79-3.77 (m, 2H), 3.67-3.61 (m, 2H), 3.49-3.46 (m, 2H), 3.43 (dt, J =
6.4 Hz, J = 9.6 Hz, 1H), 2.16 (dd, J = 3.2 Hz and J = 15.6 Hz, 1H, H-5a), 2.00 (s, 3H, NHAc),
1.80 (dd, J = 2.8 Hz, 15.6 Hz, 1H, H-5a'), 1.59-1.56 (m, 2H), 1.38-1.28 (m, 6H), 0.91 (t, J = 6.4
Hz, 3H, CH3 of hexyl); 13C NMR (100 MHz, CD3OD) δ 78.5, 76.5, 75.8, 72.3, 71.0, 56.7, 33.0,
32.7, 30.7, 26.7, 23.6 (NHAc), 22.6, 14.3; HRMS (ESI) m/z: calcd for C15H28ClNO5 [M+H]+
338.1729, found 338.1756.
Appendix A. Supplementary data
Supplementary data related to this article can be found at DOI: XXXX.
These data includes 1 H, 13 C NMR spectra for all new compounds and for previously reported
1
1
compounds. The data also includes H-1H COSY and H-13C HSQC spectra of selected new
compounds. Reaction optimization for synthesis of 5a, 6a, IBX mediated oxidation of 6b and
transition states of stereoselecetive epoxidation on 5a. (PDF)
Author Information
Corresponding Author
*E-mail: ram.sagar@snu.edu.in
Acknowledgements
Authors are thankful to the Shiv Nadar University (SNU) for providing required lab facilities.
CN and PK are thankful to Council of Scientific and Industrial Research (CSIR), India for junior
research fellowships. Authors are also thankful to the Department of Science and technology
(DST) India for financial support (DST-EMR/2014/000320). This work was supported by Grant-
in-Aid for Scientific Research (C) (No: JP17K08362) (AK) from the Japanese Society for the
Promotion of Science (JSPS).
20

ACCEPTED MANUSCRIPT
References
1. Arjona, O.; Gómez, A. M.; López, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919–2036.
2. McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org. Chem. 1966, 31, 1516–1521.
3. Witte, M.; Kallemeijn, W. W.; Aten, J.; Li, K.-Y.; Strijland, A.; Donker-Koopman, W. E.;
Van Den Nieuwendijk, A. M. C. H.; Bleijlevens, B.; Kramer, G.; Florea, B. I.; Hooibrink, B.;
Hollak, C. E. M.; Ottenhoff, R.; Boot, R. G.; Van Der Marel, G. A.; Overkleeft, H. S.; Aerts,
J. M. F. G. Nat. Chem. Biol. 2010, 6, 907–913.
4. Ghavre, M.; Froese, J.; Pour, M.; Hudlicky, T. Angew. Chem. Int. Ed. 2016, 55, 5642−5691.
5. Leclerc, E.; Pannecoucke, X.; Ethève-Quelquejeu, M.; Sollogoub, M. Chem. Soc. Rev. 2013,
42, 4270–4283.
6. Lünse, C. E.; Schmidt, M. S.; Wittmann, V.; Mayer, G. ACS Chem. Biol. 2011, 6, 675–678.
7. Dwek, R. A.; Butters, T. D.; Platt, F.; Zitzmann, N. Nat. Rev. Drug Discov. 2002, 1, 65−75.
8. Collins, P.J.; Haire, L. F.; Lin, Y. P.; Liu, J.; Russell, R. J.; Walker, P.A.; Skehel, J.
J.; Martin, S. R.; Hay, A. J.; Gamblin, S. J. Nature 2008, 453, 1258–1261.
9. Lahiri, R.; Ansari, A. A.; Vankar, Y. D. Chem. Soc. Rev. 2013, 42, 5102–5118.
10. Jayakanthan, K.; Vankar, Y. D. Org. Lett. 2005, 7, 5441–5444.
11. Ansari, A. A.; Rajasekaran, P.; Khan, M. M.; Vankar, Y. D. J. Org. Chem. 2014, 79,
1690−1699.
12. Harit, V. K.; Ramesh, N. G. J. Org. Chem. 2016, 81, 11574–11586.
13. Mondal, S.; Sureshan, K. M. J. Org. Chem. 2016, 81, 11635–11645.
14. Gómez, A. M.; Uriel, C.; Company, M. D.; and López, J. C. Eur. J. Org. Chem. 2011, 7116–
7132.
15. Gómez, A. M.; Moreno, E.; Valverde, S.; and López, J. C. Eur. J. Org. Chem. 2004, 1830–
1840.
16. Lalk, M.; Reinke, H.; and Peseke, K. Eur. J. Org. Chem. 2001, 759–765.
17. Shan, M.; O'Doherty, G. A. Org. Lett. 2008, 10, 3381–3384.
18. Shan, M.; O'Doherty, G. A. Org. Lett. 2010, 12, 2986–2989.
19. Ng, W-L.; Li, H-C.; Lau, K-M.; Chan, A. K. N.; Lau, C. B-K.; Shing, T. K. M. Sci. Rep.
2017, 7, 5581 and references cited therein.
21

ACCEPTED MANUSCRIPT
20. (a) Barton, D. H. R.; Géro, S. D.; Augy-Dorey, S.; Quiclet-Sire, B. J. Chem. Soc., Chem.
Commun. 1986, 1399–1401. (b) Barton, D. H. R.; Augy-Dorey, S.; Camara, J.; Dalko, P.;
Delaumény, J. M.; Géro, S. D.; Quiclet-Sire, B.; Stütz, P. Tetrahedron 1990, 46, 215−230.
21. (a) Ogawa, S.; Iwasawa, Y.; Nose, T.; Suami, T.; Ohba, S.; Ito, M.; Saito, Y. J. Chem. Soc.,
Perkin Trans. 1 1985, 903−906. (b) Ogawa, S.; Aoyama, H.; Sato, T. Carbohydr. Res. 2002,
337, 1979−1992. (c) Ogawa, S.; Funayama, S.; Okazaki, K.; Ishizuka, F.; Sakata, Y.; Doi, F.
Bioorg. Med. Chem. Lett. 2004, 14, 5183−5188.
22. Sun, Y.; Nitz, M. J. Org. Chem. 2012, 77, 7401−7410.
23. Goyal, N.; Mangunuru, H. P. R.; Parikh, B.; Shrestha S. and Wang, G. Beilstein J. Org.
Chem. 2014, 10, 3111–3121.
24. Roy, A.; Ray, A. K.; Mukherjee, A.; Roy, N. Indian J. of Chem., Sec B: 1987, 26B, 1165-
1167.
25. Falcone-Hindley, M.L. and Davis, J. T. J. Org. Chem. 1998, 63, 5555–5561.
26. Scaffidi, A.; Stubbs, K. A.; Vocadlo, D. J.; Stick, R. V. Carbohydr Res. 2008, 343, 2744–
2753.
27. Petasis, N. A.; Bzowej, E. I.. J. Am. Chem. Soc. 1990, 112, 6392–6394.
28. Takai, K.; Tadahiro, K.;Yasutaka, K. J. Org. Chem., 1994, 59, 2668–2670.
29. Hamlin, T. A.; Kelly, C. B.; Cywar, R. M.; Leadbeater, N. E. J. Org. Chem. 2014, 79, 1145–
1155.
30. Sollogoub, M.; Pearce, A. J.; Hérault, A. and Sinaÿ, P. Tetrahedron: Asymmetry 2000, 11,
283–294.
31. (a). Williams, S. J.; Withers, S. G. Carbohydr Res. 2000, 327, 27–46. (b) Skelton, B. W.;
Stick, R. V.; Stubbs, K. A.; Watts, A. G; White, A. H. Aust. J. Chem. 2004, 57, 345-353.
32. Kuno, S.; Higaki, K.; Takahashi, A.; Eiji Nanbab, E. and Ogawa, S. Med. Chem. Commun.
2015, 6, 306–310.
33. Bouquet, J.; King, D. T.; Vadlamani, G.; Benzie, G. R.; Iorga, B.; Ide, D.; Adachi, I.; Kato,
A.; Vocadlo, D. J.; Mark, B. L.; Blériot, Y. and Désiré, J. Org Biomol Chem. 2017, 15,
4609–4619.
22