Convenient Access to 2-β-d-Glucopyranosylpyridines by Using Bohlmann–Rahtz Heteroannulation

Article abstract of DOI:10.1002/ejoc.201800789

Convenient synthesis of 2-β-d-Glucopyranosylpyridines has been achieved by using Bohlmann–Rahtz heteroannulation reaction between a sugar alkynone and ethyl β-aminocrotonate. The synthesized compounds are analogues of Dapagaliflozin, an approved drug for

Full text of DOI:10.1002/ejoc.201800789

A Journal of
Accepted Article
Title: Convenient Access to 2-b-D-Glucopyranosylpyridines Using
Bohlmann-Rahtz Hetero Annulation
Authors: Mannem Rajeswara Reddy and Indrapal Singh Aidhen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800789
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800789
Supported by

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
Convenient Access to 2--D-Glucopyranosylpyridines Using
Bohlmann–Rahtz Hetero-Annulation
Mannem Rajeswara Reddy, Indrapal Singh Aidhen*
Dedication ((optional))
Abstract: Convenient synthesis of 2--D-Glucopyranosylpyridines
has been achieved using Bohlmann–Rahtz hetero-annulation
reaction between the sugar alkynone and ethyl β-aminocrotonate.
The synthesized compounds were envisaged as potential analogues
of Dapagaliflozin, an approved drug for lowering of blood glucose
levels through inhibition of sodium-glucose transporters in the kidney.
Introduction
Diabetes mellitus is a widespread disease that is characterized by
hyperglycemia, either because the pancreas does not produce
enough insulin (type 1 diabetes)[1] or the tissue cells poorly
respond to the insulin that is produced (type 2 diabetes)[2] It is
estimated that the patient population had reached 422 million in
2014 and is expected to increase to 480 million by 2030.[3] In the
recent times, to address hyperglycemia and prevent deleterious
consequences of hyperglycemic condition, a new class of drugs
has emerged for glycemic control through blocking of glucose
reabsorption in kidneys and enabling release of excess glucose
through urine. These drugs are inhibitors of renal sodium–glucose
cotransporters (SGLT) and to date, Dapagliflozin[4] (1),
Canagliflozin[5] (2) and Empagliflozin[6] (3) have been approved by
Figure 1. Prominent SGLT 2 Inhibitors and our target for synthesis
the FDA for the treatment of type 2 diabetes. Another two drugs,
Ipragliflozin[7] (4) and Ertugliflozin[8] (5), bearing a unique dioxa-
bicycle in place of the glucose residue of Dapagliflozin, has been
approved by the FDA in December 2017 (Figure 1). After the
discovery of Dapagliflozin, for further understanding of structure
activity relationship, the main focus of modification has been
centered on the diarylmethylene aglycone part and not on the
glucose residue. The proximal and distal aryl rings in the
diarylmethylene aglycone have been replaced by heterocyclic
rings. The proximal aryl ring in particular has been replaced with
heterocyclic rings such as thiophene,[9] pyrrole,[7] pyridine,[7]
pyridine ring and the anomeric carbon of the D-glucosyl unit
resulting in the formation of 2--D-Glucopyranosylpyridines has
been achieved through nucleophilic addition reaction on protected
carbohydrate derived lactones. Among the several methods
available for de novo synthesis of the substituted pyridine ring,[14]
we were attracted to use Bohlmann-Rahtz reaction[15] for the
construction of the pyridine ring due to the simplicity of the
reaction conditions and the required starting substrates, alkynone
8 and -amino unsaturated ester 9 (Figure 2). The results of these
synthetic efforts are described herein.
pyrazine,[7] pyridazine,[10] thiazole[10]
and
benzo-fused
heterocycles[11] too. Given the growing significance of sodium-
glucose transporters (SGLT) as a target for therapeutic agents,
beyond the realm of diabetes, such as cerebral ischemia[12] and
cancer[13], we undertook exploring a new synthetic route for
convenient acesss to 2--D-Glucopyranosylpyridines 6 through
annulation of a pyridine ring at the anomeric position. In an
isolated report[7] the direct C-C bond formation between the
[*]
Department of Chemistry, Indian Institute of Technology Madras,
Chennai 600036, India.
Figure 2. Proposed retrosynthetic scheme for the target compound 6.
E-mail: isingh@iitm.ac.in
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
concomittant elimination of benzyl alcohol explains the formation
of glycal 18 (Scheme 2). In the context of poor isolated yield of 17,
despite optimization efforts, coupled with its failure to furnish 8,
compelled us to look for an alternative synthetic scheme for 8.
The TMS substituted alkynone 17 has been synthesized in the
literature,[16] starting with readily available lactone[17] 10.
Assuming TMS substituted alkynone 17 should enable ready
access to 8, we ventured into using this method for our need of
alkynone 8. The reported procedure[16] uses the ability of
benzothiazole (BT) unit to function as masked carbonyl equivalent
for the access to 17. Although the 2-lithio derivative of
benzothiazole (BT) formed from the reaction between BT and n-
BuLi, successfully adds onto protected D-gluconolactone 10
leading to installation of BT at the anomeric position, the reaction,
in our hands also yielded 11 along with 12, as separable products.
To circumvent this difficulty, the C2-H in BT was deprotanated
with isopropylmagnesium bromide and the addition of the
corresponding benzothiazol-2-ylmagnesium bromide (2-BTMgBr)
was explored onto the lactone 10. To our satisfaction, the addition
product 11 was obtained in 79% yield, as a single product. This
minor change enabled access to gram-scale quantities of 11 for
the envisaged synthetic route. The subsequent three-step
protocol for deoxygenation at C-1 position was trouble free and
furnished the C-1 deoxygenated product 14 (Scheme 1).
Scheme 2. Synthetic efforts towards the synthesis of alkynone 8.
The new scheme envisaged the use of aldehyde 19 for
nucleophilic addition of TMS-ethynylmagnesium bromide. An
efficient synthetic route entailing use of lactone 10 as starting
material and reported by Frederic Labeguere was used for the
[18]
synthesis of aldehyde 19.
Successful addition of TMS-
ethynylmagnesium bromide, generated from trimethylsilyl-
acetylene and ethylmagnesium bromide, onto the aldehyde 19
afforded a diastereomeric mixture of expected propargylic
alcohols 20a and 20b (3:2) in 67% yield. The addition reaction,
always accompanied recovery of 5-10% of starting aldehyde 19.
These alcohols 20a and 20b were easily seperable using column
chromatography over silica-gel and were found to be bench stable.
The diastereo selectivity of this reaction, although of no
consequence to our objective, has been described by Genêt and
Scheme 1. Modified synthetic route for the synthesis of precursor 14.
For synthesis of the TMS-substituted alkynone 17, a one-pot
reaction sequence was performed on the precursor 14. This
involved N-methylation of 14 with methyl triflate (MeOTf) followed
by addition of the trimethylsilylethynylmagnesium bromide onto
the crude benzothiazolium salt 15 and finally mercuric chloride
assisted hydrolysis of the C-2- disubstituted benzothiazoline 16.
Although the sequence furnished the desired alkynone 17, the
isolated yield of the purified material was merely 20%. Simple
desilylation reaction on 17, using tetrabutyl ammonium fluoride
leads to decomposition of the starting material, while use of
potassium carbonate in methanol afforded 18 as the only product
in 79% yield. Presumably the anticipated desilylated product 8
underwent Michael addition with two molecules of methanol and
Scheme 3. Synthesis of intermediate alkynone 8 from aldehyde 19.
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
acetate in the presence of AcOH in toluene at reflux condition.
These conditions apparently simple, however, did not afford any
product nor recovery of starting alkynone 8. Pyridine ring
annulation reaction was now performed by the reaction between
8 and preformed ethyl -aminocrotonate[21] 9 in toluene and acetic
acid mixture (5:1) at 70 °C. The reaction was completed in 6 h,
affording the anticipated tri-substituted pyridine 7 in good yields
(90%). Reduction of the ester functionality in 7 with DIBAL-H gave
a mixture of the desired aldehyde 23 and over reduced product,
alcohol 22. A two-step protocol involving complete reduction with
LiAlH4 and subsequent oxidation of the resultant alcohol 22 with
IBX was followed. This afforded the building block 23 as colorless
solid in good yield (95%) (Scheme 4). The single crystal X-ray
analysis of 23 confirmed the structural features, therein (Figure 4).
With the availability of building block 23 in gram scale, the stage
was now set for the synthesis of the target compound 6. The
addition of various arylmagnesium bromides on 23, resulted in the
formation of the corresponding compounds 24a-i as
diastereomeric mixtures (Scheme 5). Direct hydrogenation in
24a-f using Pd/C or Pd(OH)2 in THF: acetic acid mixture (1:1)
furnished the 2--D-Glucopyranosylpyridines 6a-f as colorless
solids in a period ranging from 30-72 h (Table 1).
Figure 3. Single crystal X-ray analysis of the building block 21a.
co-workers.[19] The removal of the TMS group in 20a and 20b was
readily achieved using K2CO3 in methanol. The reaction afforded
the corresponding propargylic alcohols 21a and 21b respectively
in quantitative yields. The alcohol 21a could be crystallized
enabling single crystal X-ray analysis (Figure 3). Having
seperated, the propargylic alcohols, 21a and 21b were
independently oxidized with IBX in DMSO at room temperature.
Clean reaction ensued in 3 h furnishing the desired alkynone 8 in
excellent yield (94%). Subsequent requirement of multi-gram
quantity of the alkynone 8 was met by direct oxidation of mixture
of 20a and 20b, circumventing need of column chromatography
(Scheme 3).
For annulating the pyridine, using Bolhmann-Rahtz reaction, we
first explored reaction conditions involving simply heating of three
components,[20] alkynone 8, ethyl acetoacetate and ammonium
Scheme 5. Addition of various arylmagnesium bromides on building block 23,
synthesis of targeted molecules 6a-f.
Table 1. Reduction followed by benzyl ether deprotection in compounds
24a-f in a single step.
Entry
R (24)
Yield[a]
R (6)
Yield[b]
1
2
3
4
5
6
Me (24a)
Et (24b)
OMe (24c)
OEt (24d)
F (24e)
90%
83%
80%
72%
84%
77%
Me (6a)
Et (6b)
73%
60%
90%
60%
45%
85%
Scheme 4. Synthesis of building block 24 by using Bolhmann-Rahtz reaction.
OMe (6c)
OEt (6d)
F (6e)
Cl (24f)
H (6f)
[a] Isolated yields for the mixture of diastereomers. [b] Isolated yield.
The hydrogenolysis reaction works well for the substrates 24a-e
as expected, whereas the compound 24f (R = Cl) under the same
reaction conditions yielded the dechlorinated product 6f. It has
been observed that aromatic dechlorination during hydrogenation
Figure 4. Single crystal X-ray analysis of the building block 23.
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
condition can be circumvented by addition of 1,2-dichlorobenzene
as additive. [22] However even with the addition of 20 equivalents
of 1,2-dichlorobenzene, the dechlorination in substrate 24f could
not be arrested. With substrates, 24g-i, no benzylic
deoxygenation and debenzylation was observed under the same
reaction conditions. With these substrates, we adopted two-step
reaction sequence involving Barton-McCombie deoxygenation
method[23] and Lewis acid mediated debenzylation.[24] The alcohol
24f was converted into the thiocarbonyl derivative using 1,1-
thiocarbonyldiimadazole, followed by treatment with n-Bu3SnH in
the presence of cat. amount of AIBN. The reaction yielded the
desired target compound 25 in 76% yield. We extended this
protocol with three other substrates 24g-i and obtained the
corresponding deoxygenated compounds 26-28 respectively
(Scheme 6). The final removal of the benzyl ether protection in
compounds 25-28 was achieved with the use of BBr3 in
dichloromethane. The corresponding glucosylated pyridine target
compounds 29-32 respectively were obtained in good yields.
Scheme 6. Synthesis of selected pyridinyl C-glycosides 29-32, using Barton-McCombie deoxygenation followed by BBr3 promoted ether deprotection.
were determined for compounds 21a, 23 was recrystallized from EtOAc:
Conclusions
hexanes, remaining compounds were purified by silica gel column
1
chromatography (100-200 mesh) by using respective solvent system. H
In conclusion, we have developed a new synthetic route for
convenient access to pyridinyl C-glucosides via Bohlmann–Rahtz
hetero-annulation reaction. The requisite alkynone for the
synthetic route is now available in multi gram scale, paving way
for the D-glucosylated pyridine 23 as a key building block.The
building block is a self stable, crystalline solid. The synthesized
target molecules, as novel Dapagliflozin analogues, await SGLT2
inhibitory activity studies.
(400 MHz and 500 MHz) and 13C (100 MHz and 125 MHz) high resolution
NMR experiments were recorded on BRUKER AV 400 and 500 FT NMR
spectrometer using tetramethylsilane (TMS) as an internal standard. 1H
NMR spectra were referenced to CDCl3 ( =7.26 ppm), MeOH [D4] (  =
3.34 ppm) and central line of DMSO [D6] ( =2.5 ppm), whereas 13C NMR
spectra were referenced to the central line of CDCl3 ( =77.16 ppm), MeOH
[D4] ( = 49.15 ppm) and DMSO [D6] ( =39.5 ppm). Multiplicities are given
as, s = singlet, d = doublet, t = triplet, dd = doublet of doublet, m = multiple,
and br. s = broad singlet. IR spectra was recorded with a JASCO-FT/IR-
4100 Spectrometer with a NaCl cell. Elemental analyses were determined
with Perkin–Elmer Instruments series II CHNS/O analyzer. HRMS were
recorded with a MICRO-QTOF mass spectrometer by using the ESI
technique at 10 eV.
Experimental Section
All reactions were carried out in oven dried glassware. Solvents used for
column chromatography were laboratory reagent grade. Solvents were
distilled from CaH2 (CH2Cl2, DMF), Na/Benzophenone for THF, Mg/I2
(MeOH). Reactions were performed under nitrogen atmosphere. NMR
spectra were recorded at 293 K, unless stated otherwise. Thin layer
chromatography was performed on aluminum plates coated with silica gel
60. Visualization was observed by U.V. light or by dipping into a solution
of cerium(IV) sulfate (2.5 g) and ammonium molybdate (6.25 g) in 10 %
sulfuric acid (250 mL) followed by charring on a hot plate. Melting points
The additions of benzothiazol-2-ylmagnesium bromide (2-BTMgBr)
on lactone 10 (synthesis of compound 11): A dried two necked round
bottom flask was charged with magnesium turnings (0.401 g, 16.7 mmol)
and a catalytic amount of I2 was added. The flask was pre-heated under
vacuum to activate the magnesium and anhydrous THF (25 mL) was
added. At stirring isopropylbromide (1.26 mL, 16.7 mmol) was added
slowly, after 5 min the mixture was strongly self heated. As the magnesium
turnings were finished, benzo[d]thiazole (1.26 mL, 11.57 mmol) was added
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
to the reaction mixture at 0 oC slowly and stirring was continued for 30-45
min at the same temperature. To the resulting yellow color precipitation
was added lactone 10 (3.0 g, 5.67 mmol) in anhydrous THF for 15 min at
0 oC, and the solution was warmed to rt, allowed to stir overnight at same
temperature. The solution was diluted with cold aq. NH4Cl solution,
aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined
organic layer was washed with brine solution, dried over Na2SO4, and
concentrated under reduced pressure. The crude product was purified by
column chromatography on silica gel (EtOAc/hexanes, 1:3) affording the
lactol 11 (2.97 g, 79.2%) as the -anomer exclusively. All spectroscopic
data for our synthetic molecule (1H, 13C, HRMS) were well in agreement
with those reported for the same. [16]
pressure, the residue was extracted with EtOAc, the organic phase was
washed with water, dried over Na2SO4, and concentrated under reduced
pressure. The crude product was purified by column chromatography on
silica gel (EtOAc/hexanes, 1:3) affording the deprotected alkyne 21.
1-(3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran-6-
yl)-3,3-dimethoxypropan-1-one (18): Compound 17 (0.06 g, 0.092
mmol), K2CO3 in MeOH (1 mL) were treated according to the general
procedure A for 3 h, to give the title compound 18, after column
chromatography on silica gel (EtOAc/hexanes, 1:4) as yellow color gum
(0.039 g, 79.5%); Rf = 0.5 (EtOAc/hexanes, 1:3); []23 = 63.5 (c 1.0,
D
CHCl3); 1H NMR (400 MHz, CDCl3):2.91(d, J = 5.6 Hz, 2H), 3.27 (s,
6H), 3.70-3.76 (m, 1H), 3.78-3.84 (m, 1H), 4.05-4.09 (m, 1H), 4.21 (dd, 1J
= 6.4, 2J = 3.2, 1H), 4.49-4.54 (m, 4H), 4.57-4.62 (m, 2H), 4.74 (d, J = 11.2
Hz, 1H), 4.84 (d, J = 5.6 Hz, 1H), 5.90 (d, J = 2.8 Hz, 1H), 7.16-7.21 (m,
15H). 13C NMR (100 MHz, CDCl3): = 42.2 (CH2), 53.7 (CH3), 68.1 (CH2),
71.0 (CH2), 73.0 (CH2), 73.7 (CH2), 75.6 (CH), 77.6 (CH), 101.2 (CH),
105.7 (CH), 127.6 (CH), 127.7 (CH), 127.9 (CH), 128.4 (CH), 128.5 (CH),
128.6 (CH), 137.8 (C), 137.9 (2xC), 150 1 (C), 193.0 (C). IR (CHCl3): 1260,
1437, 1520, 1697, 2933, 3102 cm-1. HRMS: calcd for C32H36O7Na (M+Na)+
555.2461 found. 555.2353.
The additions of ((trimethylsilyl)ethynyl) magnesium bromide on
aldehyde 19: A dried two necked flask was charged with magnesium
turnings (0.436 g, 18.11 mmol) and catalytic amount of I2 was added. The
flask was pre-heated under vacuum to activate the magnesium and
anhydrous THF (25 mL) was added. At stirring ethylbromide (1.38 mL,
18.11 mmol) was added slowly, after 5 min the mixture got self heated
strongly. As the magnesium turnings finished, trimethylsilyl acetylene (1.49
mL, 10.86 mmol) was added to the reaction mixture at 0 oC slowly and
stirring was continued for 2 h at the same temperature. The sugar
aldehyde 19 (2.0 g, 3.62 mmol) in anhydrous THF was added for 15 min
at 0 oC, and the solution was allowed to stir overnight at same temperature.
The solution was diluted with cold aq. NH4Cl solution, aqueous phase was
extracted with EtOAc (3 x 100 mL) and the combined organic layer was
washed with brine solution, dried over Na2SO4, and concentrated under
reduced pressure. The resulting yellow color residue was purified by
column chromatography on silica gel (EtOAc/hexanes, 85:15 then 1:4)
affording two diastereomers (20a:20b; 60:40) 67.47%.
(1S)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco--C-pyranosyl)-prop-2-yne
(21a): Compound 20a (1.5 g, 2.4 mmol), K2CO3 in MeOH (20 mL) were
treated according to the general procedure A for 6 h, to give the title
compound 21a, after column chromatography on silica gel
(EtOAc/hexanes, 1:4) as colorless solid (1.35 g, 97.12%); Rf = 0.3
o
(EtOAc/hexanes, 1:4); m.p = 98-100 C; []23 = 78.3 (c 0.5, CHCl3); 1H
D
NMR (400 MHz, CDCl3):  = 2.16s, 1H), 2.44 (s,1H), 3.41 (d, J = 8.0 Hz,
1H), 3.53 (d, J = 9.2 Hz, 1H), 3.62 (t, J = 8.0 Hz, 1H), 3.72-3.80 (m, 4H),
4.53-4.62 (m, 4H), 4.72 (d, J = 11.2 Hz, 1H), 4.82 (d, J = 10.8 Hz, 1H),
4.91 (m, 3H), 7.19-7.32 (m, 20H).13C NMR (100 MHz, CDCl3): = 61.4
(CH), 68.7 (CH2), 73.2 (C), 73.4 (CH2), 75.1 (CH2), 75.3 (CH2), 75.5 (CH2),
78.0 (CH), 78.1 (CH), 79.1 (CH), 80.1 (CH), 82.9 (C), 86.9 (CH), 127.6
(CH), 127.7 (CH), 127.8 (CH), 127.8 (CH), 127.9 (CH), 127.9 (CH), 128.0
(CH), 128.4 (CH), 128.4 (CH), 128.4 (CH), 128.5 (CH), 137.8 (C), 138.0
(C), 138.0 (C), 138.4 (C).IR (CHCl3): 1569, 2220, 2957, 3297, 3420 cm-1.
Elemental analysis calcd (%) for C37H38O6 (650.89): C 76.79, H 6.62;
found: C 77.20, H 6.64.
(1S)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-3-
trimethylsilylprop- 2-yne (20a): Colorless solid, Rf = 0.6 (EtOAc/hexanes,
o
1:4); m.p = 98-100 C; []23 = 64.9 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3):  = 0.002 (s, 9H), 3.27 (dd, 1J = 9.2 Hz, 2J = 2.0 Hz, 1H), 3.3-3.39
(m, 1H), 3.476 (t, J = 10.8 Hz, 1H), 3.57-3.61 (m, 4H), 4.37-4.47 (m, 5H),
4.57 (d, J = 10.8 Hz, 1H), 4.67 (d, J = 10.8 Hz, 1H), 4.7-4.78 (m, 3H), 7.02-
7.18 (m, 20H). 13C NMR (100 MHz, CDCl3):  = 0.044 (TMS), 62.47 (CH),
68.81 (CH2), 73.47 (CH2), 75.17 (CH2), 75.45 (CH2), 75.69 (CH2), 78.36
(CH), 78.63 (CH), 79.38 (CH), 80.22 (CH), 86.98 (CH), 90.20 (C), 104.71
(C), 127.72 (CH), 127.75 (CH), 127.79 (CH), 127.84 (CH), 127.88 (CH),
127.95 (CH), 128.04 (CH), 128.100 (CH), 128.46 (CH), 128.52 (CH),
128.52 (CH), 128.57 (CH), 128.64 (CH), 137.92 (C), 138.15 (C), 138.22
(C), 138.47 (C). IR (CHCl3): 1422, 1569, 2150, 2913, 3050, 3370 cm-1.
Elemental analysis calcd (%) for C40H46O6Si (650.89): C 73.81, H 7.12;
found: C 73.87, H 7.32.
(1R)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco--C-pyranosyl)-prop-2-yne
(21b): Compound 20b (1.8 g, 2.89 mmol), K2CO3 in MeOH (25 mL) were
treated according to the general procedure A for 6 h, to give the title
compound 21b, after column chromatography on silica gel
(EtOAc/hexanes, 2:3) as colorless solid (1.47 g, 88.0%); Rf = 0.3
(EtOAc/hexanes, 1:3); m.p = 74-76 oC; []23 = 22.5 (c 1.0, CHCl3); 1H
D
NMR (400 MHz, CDCl3):2.48(d, J = 2.4 Hz, 1H), 3.0 (d, J = 10.4 Hz,
1H), 3.47-3.52 (m, 2H), 3.63-3.68 (m, 1H), 3.71-3.75 (m, 4H), 4.56 (d, J =
12.0, 1H), 4.61-4.65 (m, 2H), 4.70 (d, J = 10.8 Hz, 2H), 4.83 (d, J = 10.8
Hz, 1H), 4.87-4.91 (m, 3H), 7.18-7.35 (m, 20H). 13C NMR (100 MHz,
CDCl3): = 62.7 (CH), 68.9 (CH2), 73.4 (C), 74.7 (CH2), 75.1 (CH2), 75.3
(CH2), 75.6 (CH2), 78.4 (CH), 79.2 (CH), 79.5 (CH), 80.4 (CH), 81.2 (C),
86.9 (CH), 127.7 (CH), 127.8 (CH), 127.8 (CH), 127.9 (CH), 128.1 (CH),
128.4 (CH), 128.5 (CH), 128.6 (CH), 137.9 (C), 138.0 (C), 138.2 (C), 138.4
(C).IR (CHCl3): 1520, 2257, 2933, 3321, 3431 cm-1. Elemental analysis
calcd (%) for C37H38O6 (650.89): C 76.79, H 6.62; found: C 77.33, H 6.72.
(1R)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-3-
trimethylsilylprop- 2-yne (20b): Colorless gum; Rf = 0.4 (EtOAc/hexanes,
1:4); []23D = 37.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3):  = 0.002 (s,
9H), 2.79 (d, J = 10.4 Hz, 1H), 3.29-3.33 (m, 2H), 3.49-3.64 (m, 5H), 4.39-
4.57 (m, 5H), 4.69-4.74 (m, 4H), 7.05-7.19 (m, 20H). 13C NMR (100 MHz,
CDCl3):  = 0.053 (-TMS), 63.1 (CH), 68.5 (CH2), 73.3 (CH2), 75.2 (CH2),
75.5 (CH2), 75.9 (CH2), 78.4 (CH), 79.4 (CH), 80.1 (CH), 80.5 (CH), 86.9
(CH), 91.7 (C), 103.0 (C), 127.7 (CH), 127.8 (CH), 127.9 (CH), 127.9 (CH),
128.0 (CH), 128.4 (CH), 128.6 (CH), 138.1 (C), 138.2 (C), 138.3 (C), 138.4
(C). IR (CHCl3): 1533, 2227, 2813, 3107, 3327 cm-1. HRMS: calcd for
C40H46O6SiNa (M+Na)+ 673.2961 found. 673.2961.
1-(2,3,4,6-Tetra-O-benzyl-D-gluco--C-pyranosyl)-prop-2-yne-1-one
(8): To a solution of alcohol 21a (3.1 g, 3.97 mmol) in DMSO (35 mL) was
added IBX (2.25 g, 5.90 mmol) at room temperature, and the reaction
mixture was stirred at the same temperature for 3 h. After completion, the
reaction mixture was diluted with H2O, and filtered by using a pad of celite.
The filtrate was extracted with EtOAc, the organic layer was washed with
brine, dried over Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/hexanes, 85:15)
General procedure A for deprotection of the TMS group in compound
17, 20a, 20b: To the TMS protected compound (1 mmol) in a round bottom
flask was added 0.5 M solution of K2CO3 in MeOH (8 ml) at room
temperature. Stirring was continued until complete consumption of the
starting material, confirmed by TLC and aq. NH4Cl solution was added to
the reaction mixture. The solution was concentrated under reduced
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
affording compound 8 as a colorless solid (2.9 g, 94.15 %); Rf = 0.6
(EtOAc/hexanes, 1:4); m.p= 60-62 oC; []22D = 134 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3):  = 3.27 (s, 1H), 3.53 (dt, 1J = 9.6 Hz, 2J = 1.6 Hz, 1H),
3.67 (t, J = 9.6 Hz, 1H), 3.73-3.77 (m, 2H), 3.83 (t, J = 9.2 Hz, 1H), 3.94
(d, J = 9.2 Hz, 1H), 4.56-4.66 (m, 5H), 4.77 (d, J = 10.4 Hz, 1H), 4.82 (d, J
= 10.8Hz, 1H), 4.9 (m, 2H), 7.16-7.34 (m, 20H). 13C NMR (100 MHz,
CDCl3):  = 68.57 (CH273.4 (CH2), 75.1 (CH2), 75.3 (CH2), 75.7 (CH2),
77.7 (CH), 78.9 (CH), 79.5 (CH), 80.3 (C), 81.7 (C), 83.3 (CH), 86.9 (CH),
127.6 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH), 127.9 (CH), 128.2 (CH),
128.3 (CH), 128.4 (CH), 128.5 (CH), 128.5 (CH), 137.4 (C), 137.8 (C),
138.2 (C), 138.3 (C). 182.6 (C). IR (CHCl3): 1533, 1710, 2190, 2918, 3018,
3412 cm-1. HRMS: calcd for C37H36O6Na (M+Na)+ 599.2410 found.
599.2400.
DMSO (20 mL) was added IBX (1.23 g, 4.41 mmol) at room temperature,
the reaction mixture was stirried at 70 C for 3 h. After completion of the
o
reaction, it was cooled to room temperature, diluted with H2O and filtered
through a pad of celite. The filtrate was extracted with EtOAc, the organic
layer was washed with brine, dried over Na2SO4, concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(hexanes: EtOAc, 7:3) to give the title compound 23 as a colorless solid
(1.8 g, 95.23 %); Rf = 0.3 (EtOAc/hexanes, 3:7); m.p= 64-66 oC; []23D =-
73.9 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3): = 2.8 (s, 3H), 3.62-3.66
(m, 1H), 3.73-3.78 (m, 2H), 3.80-3.88 (m, 3H), 4.03 (d, J = 11.2 Hz, 1H),
4.43 (d, J = 9.2 Hz, 1H). 4.51-4.62 (m, 4H), 4.8-4.93 (m, 3H), 6.86 (dd, 1J
= 7.6 Hz, 2J = 2.0 Hz, 2H). 7.11-7.19 (m, 5H), 7.26-7.40 (m, 14H), 7.4 (d,
J = 8.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H).13C NMR (100 MHz, CDCl3): =
22.2 (CH3), 68.9 (CH2), 73.5 (CH2), 74.7 (CH2), 75.2 (CH2), 75.6 (CH2),
78.0 (CH), 79.4 (CH), (CH), 82.1 (CH), 82.2 (CH), 86.9 (CH, 120.9 (CH),
127.5 (CH), 127.6 (CH), 127.7 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH),
128.0 (CH), 128.1 (CH), 128.2 (CH), 128.5 (CH), 137.4 (C), 138.2 (2xC),
138.3 (C),138.7(CH), 159.6 (C), 162.0 (C), 191.1 (CHO). IR (CHCl3): 1216,
1730, 2918, 3018 cm-1. HRMS: calcd for C41H41NO6Na (M+Na)+ 666.2832
found. 666.2850.
(1S)-1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1-(5-ethoxycabonyl-6-
methylpyridin-2-yl)-D-glucitol (7): To a solution of alkynone 8 (1.4 g,
2.43 mmol) in toluene (15 mL) was added ethyl - aminocrotonate 9 (0.490
g, 3.64 mmol) and acetic acid (3 mL) at rt. The reaction mixture was stirred
at 70 oC for 6 h, then cooled and concentrated, the residue obtained was
extracted with EtOAc, the organic layer was washed with saturated aq.
NaHCO3 solution, dried over Na2SO4 and then concentrated under
reduced pressure. The resulting residue was purified by column
chromatography on silica gel (EtOAc/hexanes, 1:4) to give the title
General procedure B for the preparation of ArMgBr: An oven dried two
necked flask was charged with magnesium turnings (4 equiv.), and a
catalytic amount of molecular iodine was added. The flask was pre-heated
under vacuum to activate the magnesium. At stirring under nitrogen
atmosphere, aryl bromide (4 equiv.) in THF was added dropwise. As
magnesium turnings was consumed, the aldehyde 23 (1 equiv.) was added
at 0 oC. The reaction mixture was stirred at the same temperature for 3 h
and diluted with cold NH4Cl solution. The resulting solution was extracted
with EtOAc, the organic layer was washed with brine solution, dried over
Na2SO4, and then concentrated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel
(EtOAc/hexanes) to give the alcohols as a mixture of diastereomers.
compound 7 as a light yellow color solid (1.5 g, 89.87%); Rf = 0.6
(EtOAc/hexanes, 1:4); m.p = 50-52 C; []22 = -12.4 (c 1.0, CHCl3); 1H
o
D
NMR (400 MHz, CDCl3):  = 1.41 (t, J = 7.2 Hz, 3H), 2.8 (s, 3H), 3.53
2
3
dddJ = 6.8 Hz, J = 4.0 Hz, J = 2.4 Hz, 1H), 3.74-3.80 (m, 2H), 3.82-
3.85 (m, 1H), 3.86-3.89 (m, 2H), 3.91 (d, J = 10.8 Hz, 1H), 4.01 (d, J = 10.8
Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.42- 4.53 (m, 2H), 4.58-4.62 (m, 1H),
4.73 (d, J = 10.8 Hz, 1H), 4.84-4.94 (m, 3H), 6.84-6.86 (m, 2H), 7.13-7.25
(m, 4H), 7.28-7.34 (m, 15H), 8.15 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3):  = 14.3 (CH3), 24.7 (CH3), 61.3 (CH2), 68.9 (CH2), 73.5 (CH2),
74.8 (CH2), 75.2 (CH2), 75.6 (CH2), 78.0 (CH), 79.4 (CH), 82.2 (CH), 82.5
(CH), 86.8 (CH), 120.1 (CH), 125.1 (C), 127.6 (CH), 127.7 (2xCH), 127.8
(CH), 127.9 (CH), 128.0 (CH), 128.2 (CH), 128.4 (CH), 128.5 (CH), 137.6
(C), 138.0 (2xC), 138.2 (C), 139.0 (CH), 159.2 (C), 160.2 (C), 166.5 (CO).
IR (CHCl3): 1520, 2257, 2933, 3321, 3431 cm-1. Elemental analysis calcd
(%) for C43H45NO7 (687.83): C 75.09, H 6.59, N 2.04; found: C 75.17, H
6.2, N 2.34.
(1S)-1,
5-Anhydro-1-[5-(4-methylbenzyl)-6-methylpyridin-2-yl]-D-
glucitol (6a): Building block 23 (0.28 g, 0.435 mmol), magnesium turnings
(0.041 g, 1.74 mmol) and 4-bromotoluene (0.214 mL, 1.74 mmol) were
treated as described in the general procedure B for 3 h, to give the alcohol
24a, after column chromatography on silica gel (EtOAc/hexanes, 2:3) as a
white foam (0.29 g, 90.3%).
(1S)-1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1-(5-hydroxymethyl-6-
methylpyridin-2-yl)-D-glucitol (22): To a solution of 7 (2.9 g, 4.22 mmol)
in anhydrous THF (30 mL) was added LiAlH4 (0.240 g, 6.33 mmol) at 0 oC
under nitrogen atmosphere. The reaction mixture was stirred at the same
temperature for 2 h. After completion, the reaction mixture was diluted with
slow addition of H2O and filtered. The filtrate was extracted with EtOAc,
the organic layer was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The resulting residue was purified
by column chromatography on silica gel (EtOAc/hexanes, 2:3) to give the
title compound 22 as light yellow color gum (2.43 g, 89.33%); Rf = 0.3
To obtained alcohol 24a (0.22 g, 0.3 mmol) in THF (5 mL) and AcOH (1
mL) mixture was added Pd/C (0.03 g, 10 mol%) at rt. The reaction mixture
was stirred under H2 atmosphere (balloon pressure) for 36 h. The solution
was filtered through a pad of celite, and the filtrate was concentrated under
reduced pressure. The residue was purified by column chromatography on
silica gel (MeOH/CH2Cl2, 1:9) to give the title compound 6a as a colorless
solid (0.093 g, 72.65%); Rf = 0.5 (MeOH/CH2Cl2, 1:9); []23D = 81.4 (c 0.5,
MeOH); 1H NMR (400 MHz, CD3OD): = 2.28 (s, 3H), 2.44 (s, 3H), 3.45-
3.49 (m, 1H), 3.52 (t, J = 8.4 Hz, 1H), 3.57 (t, J = 9.2 Hz, 1H), 3.65 (t, J =
6.4 Hz, 1H), 3.72 (dd, J = 12.0 Hz, 2J = 4.8 Hz, 1H), 3.87 (dd, J = 12.0
Hz, 2J = 2.0 Hz, 1H), 3.97 (s, 2H), 4.24 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 8.0
Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6
Hz, 1H). 13C NMR (100 MHz, CD3OD):  = 19.6 (C20.6 (CH3), 37.5
(CH2), 61.5 (CH2), 69.9 (CH), 74.0(CH), 78.2 (CH), 80.7 (CH), 81.0 (CH),
120.5 (CH), 128.2 (CH), 128.8 (CH), 134.6 (C), 135.6 (C), 136.0 (C), 138.2
(CH), 155.5 (C), 156.1 (C). IR (KBr): 1561, 2818,3120, 3297, 3418 cm-1.
HRMS: calcd for C20H25O5Na (M+Na)+ 382.1630 found. 382.1647.
(EtOAc/hexanes, 2:3); []22 = -67.4 (c 1.0, CHCl3); 1H NMR (400 MHz,
1
1
D
CDCl3): = 2.5 (s, 3H), 3.63-3.65 (m, 1H), 3.72-3.80 (m, 2H), 3.82-3.86
(m, 2H), 3.88-3.92 (m, 1H), 3.95 (d, J = 10.8 Hz, 1H), 4.36 (d, J = 9.2 Hz,
1H), 4.45 (d, J = 10.8 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.56-4.63 (m, 2H),
1
2
4.70 (s, 2H), 4.84-4.91 (m, 3H), 6.86 (dd, J = 8.0 Hz, J = 2.4 Hz, 2H),
7.13-7.17 (m, 5H), 7.24-7.34 (m, 15H), 8.66 (d, J = 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3):  = 21.4 CH3), 62.0 (CH2), 68.9 (CH2), 73.5 (CH2), 74.6
(CH2), 75.1 (CH2), 75.5 (CH2), 78.0 (CH), 79.0 (CH), (CH), 82.2 (CH), 82.5
(CH), 86.8 (CH, 120.9 (CH), 127.4 (CH), 127.5 (CH), 127.6 (CH), 127.7
(CH), 127.8 (CH), 127.9 (CH), 128.0 (CH), 128.1 (CH), 128.4 (CH), 128.5
(CH), 133.8 (C), 135.4 (CH), 137.4 (2xC), 138.2 (C), 138.3 (C), 155.6 (C),
155.7 (C). IR (CHCl3): 1160, 1270, 2813, 2918, 3018, 3463 cm-1. HRMS:
calcd for C41H44NO6 (M+H)+ 646.3169 found. 646.3159.
(1S)-1,5-Anhydro-1-[5-(4-ethylbenzyl)-6-methylpyridin-2-yl]-D-
glucitol (6b): Building block 23 (0.3 g, 0.466 mmol), 1-bromo-4-
ethylbenzene (0.19 mL, 1.4 mmol) and magnesium turnings (0.034 g, 1.4
mmol), were treated as described in the general procedure B for 3 h, to
give alcohol 24b, after column chromatography on silica gel
(EtOAc/hexanes, 2:3) as a white foam (0.29 g, 83.1%).
(1S)-1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1-(5-formyl-6-methylpyridin-
2-yl)-D-glucitol (23): To a solution of alcohol 22 (1.9 g, 2.24 mmol) in
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
The obtained alcohol 24b (0.27 g, 0.36 mmol) and Pd/C (0.03 g, 10 mol%)
were treated as described for the preparation of 6a for 36 h, to give the 2-
-D-Glucopyranosylpyridine 6b, after column chromatography on silica gel
(MeOH/CH2Cl2, 1:9) as a colorless solid (0.08 g, 60%); Rf = 0.5
(1S)-1,5-Anhydro-1-[5-(4-fluorobenzyl)-6-methylpyridin-2-yl]-D-
glucitol (6e): Building block 23 (0.3 g, 0.466 mmol), 1-bromo-4-
fluorobenzene (0.25 mL, 2.33 mmol) and magnesium turnings (0.056 g,
2.33 mmol) were treated as described in the general procedure B for 3 h,
to give the alcohol 24e, after column chromatography on silica gel
(EtOAc/hexanes, 2:3) as a white foam (0.29 g, 84.05%).
(MeOH/CH2Cl2, 1:9); m.p = 166-168 C; []23 = 75.4 (c 0.4, MeOH); H
o
1
D
NMR (400 MHz, CD3OD):  = 1.19 (t, J = 7.5 Hz, 3H), 2.45 (s, 3H), 2.6 (q,
J = 7.5 Hz, 2H), 3.40-3.43 (m, 1H), 3.48 (t, J = 9.0 Hz, 1H), 3.52 (t, J = 9.0
Hz, 1H), 3.57 (t, J = 9.0 Hz, 1H), 3.72 (dd, 1J = 12.0 Hz, 2J = 5.0 Hz, 1H),
The obtained alcohol 24e (0.28 g, 0.37 mmol) and Pd/C (0.06 g, 10 mol%)
were treated as described for the preparation of 6a for 72 h, to give the
tetral compound 6e, after column chromatography on silica gel
(MeOH/CH2Cl2, 1:9) as a color less solid (0.06 g,45%); Rf = 0.6
2
3.87 (dd, 1J = 12.0 Hz, J = 2.0 Hz, 1H), 3.9 (s, 2H), 4.24 (d, J = 9.0 Hz,
1H), 7.03 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz,
1H), 7.5 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CD3OD): = 14.8, (CH2),
20.6 (CH2), 28.0 (CH2), 37.5 (CH2), 61.5 (CH2), 69.9 (CH), 74.0(CH), 78.2
(CH), 80.7 (CH), 81.0 (CH), 120.5 (CH), 127.6 (CH), 128.3 (CH), 134.6 (C),
136.3 (C), 138.2 (CH), 142.2 (C), 155.5 (C), 156.1 (C). IR (KBr): 1581,
2823, 2967, 3183, 3408, 3586 cm-1. HRMS: calcd for C21H28NO5 (M+H)+
374.1967 found. 374.1946.
(MeOH/CH2Cl2, 1:9); []23 = 95.4 (c 0.4, MeOH); 1H NMR (400 MHz,
D
CD3OD): =2.44 (s, 3H), 3.41-3.44 (m, 1H), 3.46-3.60 (m, 3H), 3.72 (dd,
1J = 12.0 Hz, 2J = 5.0 Hz, 1H), 3.87 (dd, 1J = 12.0 Hz, 2J = 2.0 Hz, 1H), 4.0
(s, 2H), 4.24 (d, J = 9.2 Hz, 1H), 7.00 (t, J = 8.8 Hz, 2H), 7.13 (dd, 1J = 8.8
Hz, 2J = 5.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H). 13
C
NMR (100 MHz, CD3OD):  = 20.5 (CH3), 37.0 (CH2), 61.4 (CH2), 69.4
(CH), 73.9 (CH), 78.1 (CH), 80.6 (CH), 80.9 (CH), 114.8 (d, 2J = 21.4 Hz,
CH), 120.5 (CH), 130.0 (d, 3J = 7.9 Hz, CH), 134.2 (C), 135.1 (d, J 4 = 3.3
Hz, C), 138.1 (CH), 155.7 (C), 156.0 (C). 161.5 (d, J = 241.8 Hz, C). IR
(KBr): 1027, 1610, 2823, 3271, 3397, 3517 cm-1. HRMS: calcd for
C19H22NO5FNa (M+Na)+ 386.1380 found. 386.1351.
(1S)-1,5-Anhydro-1-[5-(4-methoxybenzyl)-6-methylpyridin-2-yl]-D-
glucitol (6c): Building block 23 (0.3 g, 0.466 mmol), 4-bromoanisole
(0.234 mL, 1.86 mmol) and magnesium turnings (0.044 g, 1.86 mmol) were
treated as described in the general procedure B for 3 h, to give the alcohol
24c, after column chromatography on silica gel (EtOAc/hexanes, 2:3) as a
white foam (0.28 g, 80%).
1
(1S)-1,5-Anhydro-1-(6-methyl-5-phenylpyridin-2-yl)-D-glucitol
(6f):
The obtained alcohol 24c (0.24 g, 0.32 mmol) and Pd(OH)2 (0.09 g, 20
wt%) were treated as described for the preparation of 6a for 72 h, to give
the 2--D-Glucopyranosylpyridine 6c, after column chromatography on
silica gel (MeOH/CH2Cl2, 1:9) as a colorless solid (0.11 g, 90%); Rf = 0.4
(MeOH/CH2Cl2, 1:9); m.p 70-72 oC; []23D = 101.4 (c 0.4, MeOH); 1H NMR
(400 MHz, CD3OD):  = 2.45 (s, 3H), 3.40-3.4 (m, 1H), 3.45-3.50 (m, 1H),
3.52 (t, J = 8.0 Hz, 1H), 3.57 (t, J = 9.2 Hz, 1H), 3.70-3.733 (m, 1H),3.74
(s, 3H), 3.87 (dd, J = 12.0 Hz, J = 2.4 Hz, 1H), 3.9 (s, 2H), 4.24 (d, J =
9.2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.32 (d, J =
7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CD3OD):  =
20.6 (CH2), 37.5 (CH2), 54.26 (CH3), 61.5 (CH2), 69.9 (CH), 74.0(CH), 78.2
(CH), 80.7 (CH), 81.0 (CH), 113.6 (CH), 120.5 (CH), 129.3 (CH), 131.0 (C),
138.3 (CH), 155.5 (C), 156.1 (C). 158.3 (C). IR (KBr): 1267, 1587, 2823,
2967, 3175, 3408, 3517 cm-1. HRMS: calcd for C20H26NO6 (M+H)+
376.1760 found. 376.1776.
Building block 23 (0.31 g, 0.482 mmol), 1-bromo-4-chlorobenzene (0.461
g, 2.4 mmol) and magnesium turnings (0.057 g, 2.4 mmol) were treated as
described in the general procedure B for 3 h, to give the alcohol 24f, after
column chromatography on silica gel (EtOAc/hexanes, 2:3) as a white
foam (0.28 g, 77%).
The obtained alcohol 24f (0.28 g, 0.38 mmol) and Pd/C (0.040 g, 10 mol%),
1,2-dichlorobenzene (0.80 mL, 7.4 mmol) were treated as described for
the preparation of 6a for 36 h, to give the 2--D-Glucopyranosylpyridine 6f,
after column chromatography on silica gel (MeOH/CH2Cl2, 1:9) as a color
less solid (0.11 g, 84.6%); Rf = 0.5 (MeOH/CH2Cl2, 1:9); []23D = 26.4 (c
0.4, MeOH); 1H NMR (400 MHz, CD3OD): = 2.45 (s, 3H), 3.23-3.25 (m,
1H), 3.30-3.40 (m, 3H), 3.52 (d, J = 11.6 Hz, 1H), 3.67 (d, J = 12.0 Hz,
1H), 3.94 (s, 2H), 4.04 (d, J = 9.0 Hz, 1H), 6.91(d, J = 7.2 Hz, 2H),6.82 (t,
J = 7.2 Hz, 1H ) 7.06 (t, J = 7.2 Hz, 2H), 7.12 (d, J = 7.6 Hz, 1H), 7.33 (d,
J = 7.6 Hz, 1H). 13C NMR (125 MHz, CD3OD):  = 20.6 (CH3), 37.0 (CH2),
62.9 (CH2), 71.3 (CH), 75.4 (CH), 79.6 (CH), 82.1 (CH), 82.3 (CH), 121.9
(CH), 127.4 (CH), 129.6 (CH), 129.7 (CH), 13.8 (C), 139.7 (CH), 140.6 (C),
157.0 (C). 157.6 (C). IR (KBr): 1530, 1610, 2823, 3097, 3339, 3479 cm-1.
HRMS: calcd for C19H23NO5Na (M+Na)+ 368.1474 found. 368.1497.
1
2
(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-6-methylpyridin-2-yl]-D-
glucitol (6d): Building block 23 (0.43 g, 0.68 mmol), 1-bromo-4-
ethoxybenzene (0.537 g, 2.67 mmol) and magnesium turnings (0.064 g,
2.67 mmol) were treated as described in the general procedure B for 3 h,
to give the alcohol 24d, after column chromatography on silica gel
(EtOAc/hexanes, 2:3) as a white foam (0.37 g, 72.3%).
General procedure C for the reduction of alcohol: To a solution of
alcohol
(1equiv.)
in
1,2-dichloroethane
was
added
1,1’-
To obtained alcohol 24d (0.34 g, 0.45 mmol) and Pd(OH)2 (0.19 g, 20 wt%)
were treated as described for the preparation of 6a for 72 h, to give the 2-
-D-Glucopyranosylpyridine 6d, after column chromatography on silica gel
(MeOH/CH2Cl2, 1:9) as a colorless solid (0.1 g, 60.36%); Rf = 0.4
(MeOH/CH2Cl2, 1:9); m.p 73-75oC; []23D = 188.4 (c 0.4, MeOH); 1H NMR
(500 MHz, CDCl3):  = 1.35 (t, J = 7.0 Hz, 3H), 2.45 (s, 3H), 3.40-3.43 (m,
1H), 3.48 (t, J = 8.5 Hz, 1H), 3.52 (t, J = 8.5 Hz, 1H), 3.57 (t, J = 9.0 Hz,
1H), 3.72 (dd, 1J = 12.0 Hz, 2J = 5.0 Hz, 1H), 3.87 (dd, 1J = 12.0 Hz, 2J =
2.0 Hz, 1H), 3.94 (s, 2H), 3.82 (q, J = 6.5 Hz, 2H), 4.24 (d, J = 9.0 Hz, 1H),
6.81(d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H),
7.5 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3):  = 13.7 (CH2), 20.6
(CH3), 37.0 (CH2), 61.5 (CH2), 63.0 (CH2), 69.9 (CH), 74.0(CH), 78.2 (CH),
80.7 (CH), 81.0 (CH), 114.2 (CH), 120.5 (CH), 129.3 (CH), 130.9 (C),
134.9 (C), 138.2 (CH), 155.5 (C), 156.1 (C). 157.6 (C). IR (KBr): 1118,
1420, 1563, 2871, 2967, 3167, 3337, 3498 cm-1HRMS: calcd for
C21H28NO6 (M+H)+ 390.1917 found. 390.1893.
thiocabonyldiimidazole (TCDI; 1.5 equiv.) at rt. The resulting solution was
stirred at 80 oC for 3-6 h. The reaction mixture was cooled to rt,
concentrated under reduced pressure, and the resulting residue was used
for next step without further purification.
To a solution of above residue in anhydrous toluene was added n-Bu3SnH
(1.5 equiv.), cat. amount of ’-azoisobutyronitrile (AIBN) at rt. The
o
reaction mixture was stirred at 80 C for 6 h, then cooled down to rt and
concentrated in vacuo. The resulting residue was partitioned between
hexane and hot acetonitrile. The acetonitrile layer was washed with
hexane (2 x 50 mL), dried over Na2SO4 and concentrated. The crude
residue was purified by column chromatography on silica gel
(EtOAc/hexanes as eluent).
(1S)-1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(4-chlorobenzyl)-6-
methylpyridin-2-yl]-D-glucitol (25): Building block 23 (0.7 g, 1.08 mmol),
magnesium turnings (0.130 g, 5.44 mmol), and 1-bromo-4-chlorobenzene
(1.042 g, 5.44 mmol) were treated as described in the general procedure
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
B, to give the alcohol 24f, after column chromatography on silica gel
alcohol 24h, after column chromatography on silica gel (EtOAc/hexanes,
(EtOAc/hexanes, 2:3) as a white foam (0.630 g, 75%).
1:1) as a yellow color foam (0.29 g, 48%).
The alcohol 24f (0.530 g, 0.718 mmol), TCDI (0.191 mL, 1.07 mmol), and
n-Bu3SnH (0.5 mL, 1.85 mmol) were treated as described in the general
procedure C, to give the title compound 25, after column chromatography
The alcohol 24h (0.4 g, 0.51 mmol), TCDI (0.137 mL, 0.77 mmol) and n-
Bu3SnH (0.321 mL, 1.19 mmol) were treated as described in the general
procedure C to give the title compound 27, after column chromatography
on silica gel (EtOAc/hexanes, 2:3) as a black colored gum (0.26 g, 66%);
Rf = 0.5 (EtOAc/hexanes, 2:3); []23D = -212.8 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3):  = 2.50 (s, 3H), 3.54-3.56 (m, 1H), 3.65-3.73 (m, 3H), 3.76-
3.82 (m, 3H), 3.94 (d, J = 10.0 Hz, 1H), 4.31 (d, J = 8.5 Hz, 1H), 4.36 (d, J
= 1.5 Hz, 2H), 4.40 (d, J = 8.5 Hz, 1H), 4.43 (d, J = 10.5 Hz, 1H), 4.49 (d,
J = 11.0 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 11.5 Hz, 1H), 4.82
(d, J = 11.5 Hz, 1H), 4.88 (d, J = 11.0 Hz, 1H), 6.79-6.80 (m, 2H), 7.00-
7.08 (m, 4H), 7.17-7.27 (m, 16H), 7.36-7.39 (m, 1H), 7.51 (d, J = 8.0 Hz,
1H), 7.65-7.67 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3):  = 22.4 (CH3), 37.6 (CH2), 68.8 (CH2),73.5 (CH2), 74.7 (CH2), 75.1
(CH2), 75.6 (CH2), 77.9 (CH), 79.2 (CH), 82.2 (CH), 82.4 (CH), 86.8 (CH),
121.3 (CH), 121.6 (CH), 122.9 (CH), 125.1 (CH), 126.2 (CH), 127.5 (CH),
127.6 (CH), 127.7 (2xCH), 127.8 (CH), 128.0 (CH), 128.1 (2xCH), 128.4
(CH), 130.8 (C), 135.4 (C), 137.8 (C), 137.9 (C), 138.1 (C), 138.2 (CH),
138.7 (C), 153.2 (C), 156.2 (C), 157.0 (C), 169.5 (C). IR (CHCl3): 1557,
1617, 2897, 2947, 3019 cm-1. HRMS: calcd for C48H47N2O5S (M+H)+
763.3206 found. 763.3177.
on silica gel (EtOAc/hexanes, 1:4) as a colorless gum (0.42 g, 76.36%); Rf
1
= 0.6 (EtOAc/hexanes, 1:4); []23 = 116.4 (c 1.0, CHCl3); H NMR (400
D
MHz, CDCl3):  = 2.46 (s, 3H), 3.61-3.64 (m, 1H), 3.75-3.80 (m, 2H), 3.83-
3.85 (m, 2H), 3.87-3.93 (m, 4H), 4.36 (d, J = 9.2 Hz, 1H), 4.46 (d, J = 10.8
Hz, 1H), 4.50 (d, J = 12.4 Hz, 1H), 4.56 (d, J = 10.8 Hz, 1H), 4.62 (d, J =
12.0 Hz, 1H), 4.85 (d, J = 10.4 Hz, 1H), 4.89 (d, J = 10.4 Hz, 1H), 4.94 (d,
J = 10.4 Hz, 1H), 6.83 (d, J = 6.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 7.10-
7.16 (m, 5H), 7.18-7.13 (m, 2H), 7.27-7.35 (m, 15H). 13C NMR (100 MHz,
CDCl3):  = 22.4 (CH3), 38.0 (CH2), 68.9 (CH2), 73.5 (CH2), 74.7 (CH2),
75.1 (CH2), 75.6 (CH2), 78.0 (CH), 79.3 (CH), 82.3 (CH), 82.6 (CH), 86.8
(CH), 121.9.1 (CH), 127.5 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 127.9
(CH), 128.0 (CH), 128.1 (CH), 128.4 (2xCH), 128.7 (CH), 130.0 (CH),
132.2 (C), 133.4 (C), 137.5 (C), 137.8 (CH), 137.9 (C), 138.0 (C), 138.1
(C), 138.2 (C), 138.8 (C), 155.2 (C), 156.8 (C). IR (CHCl3): 917, 1579, 1610,
2823, 2997 cm-1. HRMS: calcd for C47H47NO5Cl (M+H)+ 740.3143 found.
740.3146.
(1S)-1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1-[5-{(1,1’-biphenyl-4yl)
methyl}-6-methylpyridin-2-yl]-D-glucitol (26): An oven dried two necked
flack was charged with magnesium turnings (0.104 g, 4.35 mmol), and
catalytic amount of molecular iodine was added. The flask was pre-heated
under vacuum to activate the magnesium. At stirring under nitrogen
atmosphere, 4-bromobiphenyl (1.05 g, 4.35 mmol) in anhydrous THF was
added dropwise. Stirring was continued at 50 oC until the magnesium
turnings were consumed and aldehyde 23 (0.7 g, 1.08 mmol) was added
at 0 oC. The reaction mixture was stirred at the same temperature for 3 h
and diluted with cold NH4Cl solution. The resulting solution was extracted
with EtOAc, the organic layer was washed with brine, dried over Na2SO4,
and then concentrated under reduced pressure. The resulting residue was
purified by column chromatography on silica gel (EtOAc/hexanes, 2:3) to
give the alcohol 24g as a white foam (0.73 g, 84%).
(1S)-1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1-[5-{(napthalen-2-yl)
methyl}-6-methylpyridin-2-yl]-D-glucitol (28): Building block 23 (0.5 g,
0.78 mmol), 2-bromonaphthalene (0.80 g, 3.9 mmol) and magnesium
turnings (0.093 g, 3.9 mmol) were treated as described in the general
procedure B, to give the alcohol 24i, after column chromatography on silica
gel (EtOAc/hexanes, 2:3) as a white foam (0.39 g, 66%).
The alcohol 24i (0.8 g, 1.03 mmol), TCDI (0.275 mL, 1.03 mmol) and n-
Bu3SnH (0.68 mL, 2.54 mmol) were treated as described in the general
procedure C, to give the title compound 28, after column chromatography
on silica gel (EtOAc/hexanes, 1:4) as a yellow colored gum (0.39 g, 48%);
Rf = 0.6 (EtOAc/hexanes, 1:4); []23D = 51.4 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3):  = 2.52 (s, 3H), 3.63-3.64 (m, 1H), 3.74-3.81 (m, 2H), 3.83-
3.87 (m, 2H), 3.89-3.91 (m, 1H), 3.93-3.95 (m, 1H), 4.13 (s, 2H), 4.38 (d,
J = 9.2 Hz, 1H), 4.45-4.52 (m, 2H), 4.55-4.64 (m, 2H), 4.86 (d, J = 10.4 Hz,
1H), 4.89 (d, J = 11.2 Hz, 1H), 4.95 (d, J = 11.2 Hz, 1H), 6.87 (d, J = 6.8
Hz, 2H), 7.06-7.16 (m, 5H), 7.22-7.35 (m, 16H), 7.39-7.42 (m, 2H),7.47 (s,
1H), 7.61-7.63 (m, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.77-7.80 (m, 1H). 13C
NMR (125 MHz, CDCl3):  = 22.5 ( CH3), 38.8 (CH2), 68.9 (CH2), 73.5
(CH2), 74.7 (CH2), 75.1 (CH2), 75.6 (CH2), 78.1 (CH), 79.3 (CH), 82.4 (CH),
82.6 (CH), 86.8 (CH), 121.0 (CH), 125.6 (CH), 126.2 (CH), 127.1 (CH),
127.2 (CH), 127.5 (CH), 127.6 (CH), 127.7 (2xCH), 127.8 (CH), 128.0 (CH),
128.1 (2xCH), 128.3 (CH), 128.4 (CH), 132.1 (C), 133.5 (C), 133.8 (C),
136.6 (C), 137.9 (C), 138.0 (CH), 138.2 (C), 138.8 (C), 155.1 (C), 157.0
(C). IR (CHCl3): 1488, 1557, 1610, 2896, 2915, 3019 cm-1. HRMS: calcd
for C51H50NO5 (M+H)+ 756.3689 found. 756.3661.
The alcohol 24g (0.85 g, 1.1 mmol), TCDI (0.284 mL, 1.03 mmol) and n-
Bu3SnH (1.33 mL, 4.9 mmol) were treated as described in the general
procedure
C to give, after column chromatography on silica gel
(EtOAc/hexanes, 1:4), 26 as a colorless gum (0.62 g, 74.69%); Rf = 0.7
(EtOAc/hexanes, 2:3); []23 = 37.4 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3):  = 2.51 (s, 3H), 3.62-3.64 (m, 1H), 3.73-3.80 (m, 2H), 3.83-3.85
(m, 2H), 3.87-3.91 (m, 1H), 3.94 (d, J = 10.8 Hz, 1H), 4.02 (s, 2H), 4.37 (d,
J = 9.2 Hz, 1H), 4.47 (d, J = 10.8 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.57
(d, J = 10.4 Hz, 1H), 4.62 (d, J = 12.4 Hz, 1H), 4.85 (d, J = 10.4 Hz, 1H),
4.89 (d, J = 11.2 Hz, 1H), 4.95 (d, J = 10.8 Hz, 1H), 6.84-6.86 (m, 2H),
7.10-7.17 (m, 6H), 7.24-7.35 (m, 16H), 7.40-7.44 (m, 3H), 7.48 (d, J = 8.4
Hz, 2H), 7.54-7.57 (m, 2H). 13C NMR (100 MHz, CDCl3):  = 22.5 (CH3),
38.2 (CH2), 68.9 (CH2), 73.4 (CH2), 74.7 (CH2), 75.1 (CH2), 75.5 (CH2),
78.1 (CH), 79.3 (CH), 82.4 (CH), 82.6 (CH), 86.8 (CH), 120.9 (CH), 127.0
(CH), 127.2 (CH), 127.3 (CH), 127.4 (CH), 127.5 (CH), 127.6 (CH), 127.7
(CH), 127.8 (CH), 127.9 (2xCH), 128.0 (CH), 128.1 (CH), 128.4 (CH),
128.7 (CH), 129.1(CH), 133.8 (C), 137.9 (CH), 138.0 (C), 138.1 (C), 138.2
(2xC), 138.8 (C), 139.4 (C), 140.8 (C), 155.1 (C), 156.8 (C). IR (CHCl3):
1426, 1518, 1607, 2818, 2961, 3097 cm-1. HRMS: calcd for C53H51NO5Na
(M+Na)+ 804.3665 found. 804.3680.
General procedure D for benzyl ether deprotection by using BBr3: To
a cold (-60 o C) solution of benzyl ether protected compound (1 equiv.) in
anhydrous CH2Cl2 was added BBr3 (1M solution in heptane, 12 equiv.) and
o
the reaction was stirred at -60 C for 4-6 h. The progress of the reaction
was monitored by TLC. The reaction mixture was diluted by adding MeOH
at -60 oC then allowed to stir for further 1 h. The resulting mixture was
concentrated in vacuo and the residue was purified by column
chromatography on silica gel (MeOH:CH2Cl2, 1:9).
(1S)-1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1-[5-{(1,3-benzothiazol-2yl)
methyl}-6-methylpyridin-2-yl]-D-glucitol (27): Aldehyde 23 (0.5 g, 0.78
mmol), magnesium turnings (0.075 g, 3.12 mmol), isopropylbromide
(0.292 mL,3.12 mmol) and benzo[d]thiazole (0.296 mL, 2.72 mmol) were
treated as described for the preparation of compound 11, to give the
(1S)-1,5-Anhydro-1-[5-(4-chlorobenzyl)-6-methylpyridin-2-yl]-D-
glucitol (29): Compound 25 (0.38 g, 0.54 mmol) and BBr3 (1M solution in
heptane, 6.17 mL, 6.17 mmol) were treated as described in the general
procedure D for 4 h, to give the title compound 29, after column
chromatography on silica gel (MeOH/CH2Cl2, 1:9) as a colorless solid
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
(0.128 g, 65.64%); Rf = 0.6 (MeOH/CH2Cl2, 1:9); []23 = 26.4 (c 0.4,
Crystal data for compound 21a and 23: Formula: C37H38O6; unit cell
parameters: a = 14.934 (7), b = 4.963 (2), c = 21.548 (8), space group P21;
CCDC 1831567 for 21a and Formula: C41H41N1O6; unit cell parameters: a
= 26.565 (4), b = 8.7123 (10), c = 16.662 (2), space group C2; CCDC
1831568 for 23 respectively. These data can be obtained free of charge
D
MeOH); 1H NMR (400 MHz, CD3OD):  = 2.60 (s, 3H), 3.31-3.34 (m, 1H),
3.41-3.46 (m, 2H), 3.74 (dd, 1J = 9.6 Hz, J = 3.2 Hz, 1H), 3.80 (dd, J =
9.2 Hz, 2J = 1.6 Hz, 1H), 4.0 (dd, 1J = 11.2 Hz, 2J = 5.6 Hz, 1H), 4.1 (s, 2H),
4.22 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 6.8 Hz, 2H), 7.24 (d, J = 6.8 Hz, 2H),
7.77 (d, J = 6.4 Hz, 1H), 8.00 (d, J = 6.4 Hz, 1H). 13C NMR (100 MHz,
CD3OD):  = 16.5 (CH3), 36.0 (CH2), 60.4 (CH2), 69.4 (CH), 73.6 (CH),
77.4 (CH), 77.6 (CH), 80.7 (CH), 123.7 (d, CH), 128.7 (CH), 130.5 (CH),
132.6 (C), 135.8 (C), 139.1 (C), 146.2 (CH), 150.4 (C). 153.1 (C). IR (KBr):
896, 1590, 2896, 2997, 3297, 3425 cm-1. HRMS: calcd for C19H23NO5Cl
(M+H)+ 380.1265 found. 380.1277.
2
1
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif by using CCDC number.
Acknowledgements
We thank the Department of Science and Technology (DST) New
Delhi for funding towards the 400 MHz NMR spectrometer to the
Department of Chemistry, IIT-Madras under the IRPHA Scheme
and the ESI-MS facility under the FIST program. The Council of
(1S)-1,5-Anhydro-1-[5-{(1,1’-biphenyl-4-yl) methyl}-6-methylpyridin-
2-yl]-D-glucitol (30): Compound 26 (0.6 g, 0.76 mmol) and BBr3 (1M
solution in heptane, 9.26 mL, 9.26 mmol) were treated as described in the
general procedure D for 6 h, to give the title compound 30, after column
chromatography on silica gel (MeOH/CH2Cl2, 1:9) as a colorless solid
(0.26 g, 80.74%); Rf = 0.3 (MeOH/CH2Cl2, 1:9); m.p = 160-162 oC. 1H NMR
(400 MHz, DMSO-d6):  = 2.4 (s, 3H), 3.13-3.17 (m, 1H), 3.22-3.26 (m,
1H), 3.27-3.31 (m, 1H), 3.33-3.45 (m, 1H), 3.51-3.57 (m, 1H), 3.69 (dd, 1J
= 10.0 Hz, 2J = 2.0 Hz, 1H), 4.02 (s, 2H), 4.08 (d, J = 9.6 Hz, 1H), 4.49 (t,
J = 5.6 Hz, 1H), 4.98 (d, J = 5.2 Hz, 1H), 3.96 (dd, 1J = 4.8 Hz, 2J = 2.4 Hz,
2H), 7.24-7.26 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H),
7.56 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz,
2H).13C NMR (125 MHz, DMSO-d6):  = 22.7 ( CH3), 37.6 (CH2), 61.9 (CH2),
70.8 (CH), 73.7 (CH), 78.7 (CH), 81.9 (CH), 82.3 (CH), 121.0 (CH), 127.2
(CH), 127.7 (CH), 129.3 (CH), 129.6 (CH), 133.8 (C), 138.0 (CH), 138.5
(C), 139.3 (C), 140.3 (C), 155.7 (C), 156.5 (C). IR (KBr): 1493, 1537, 1616,
2887, 2927, 3116, 3237, 3469 cm-1. HRMS: calcd for C25H28NO5 (M+H)+
422.1967 found. 422.1932.
Scientific
&
Industrial Research (CSIR) New Delhi is
acknowledged for funding of the project in 2015. M. R. Reddy Is
thankful to IIT-Madras for a Senior Research Fellowship (SRF).
Keywords:C-glycosides•2-D-Glucopyranosylpyridines
•SGLT2 Inhibitors•Bohlmann–Rahtz hetero-annulation
[1]
S. Del Prato, M. Matsuda, D. C. Simonson, L. C. Groop, P. Sheehan, F.
Leonetti, R. C. Bonadonna, R. A. DeFronzo, Diabetologia. 1997, 40,
687–697.
[2]
[3]
R. C. Bonadonna, Rev. Endocr. Metab. Disord. 2004, 5, 89–97.
P.Norman, Diabetes Pipeline: Intense Activity to Meet Unmet Need, 2010,
pp.1-166.
[4]
W. Meng, B. Ellsworth, A. Nirschl, P. McCann, M. Patel, R. Girotra, G.
Wu, P. Sher, E. Morrison, S. Biller, R. Zahler, PP. Deshpande, A.
Pullockaran, DL. Hangan, N. Morgan, J.R. Taylor, M.T. Obermeier, W.G.
Humphreys, A. Khanna, L. Discenza, J.G. Robertson, A. Wang, S. Han,
J.R. Wetterau, E.B. Janovitz, O.P. Flint, JM. Whaley, W.N. Washburn, J.
Med. Chem. 2008, 51, 1145–1149.
(1S)-1,5-Anhydro-1-[5-{(1,3-benzothiazol-2-yl)methyl}-6-
methylpyridin-2-yl]-D-glucitol (31): Compound 27 (0.26 g, 0.34 mmol)
and BBr3 (1M solution in heptane, 4.1 mL, 4.1 mmol) were treated as
described in the general procedure D for 6 h, to give the title compound
31, after column chromatography on silica gel (MeOH/CH2Cl2, 1:9) as a
light black colored gum (0.095 g, 69.85%); Rf = 0.4 (MeOH/CH2Cl2, 1:9);
[]23D = 19.4 (c 0.3, MeOH); 1H NMR (400 MHz, CD3OD):  = 2.4 (s, 3H),
3.38-3.41 (m, 2H), 3.42-3.46 (m, 2H), 3.71 (dd, 1J = 12.0 Hz, 2J = 4.4 Hz,
1H), 3.80 (dd, 1J = 11.6 Hz, 2J = 2.0 Hz, 1H), 4.0 (d, J = 9.6 Hz, 1H), 4.56
(s, 2H), 7.31 (td, 1J = 11.6 Hz, 2J = 2.0 Hz, 1H), 7.37-7.41 (m, 1H), 7.60 (d,
J = 8.4 Hz, 1H), 7.79 (d, J = 6.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 8.12 (d,
J = 8.0 Hz, 1H). 13C NMR (100 MHz, CD3OD):  = 20.4 ( CH3), 36.0 ( CH2),
60.7 (CH2), 69.1 (CH), 73.4 (CH), 77.4 (CH), 79.8 (CH), 89.9 (CH), 120.1
(CH), 120.9 (CH), 121.3 (CH), 124.5 (CH), 125.5 (CH), 130.1 (C), 134.3
(C), 138.1 (CH), 151.9 (C), 155.7 (C), 156.3 (C), 169.8 (C). IR (KBr): 1417,
1590, 2896, 2968, 3397, 3517 cm-1. HRMS: calcd for C20H23N2O5S (M+H)+
403.1328 found. 403.1322.
[5]
S. Nomura, S. Sakamaki, M. Hongu, E. Kawanishi, Y. Koga, T. Sakamoto,
Y. Yamamoto, K. Ueta, H. Kimata, K. Nakayama, M. Tsuda-Tsukimoto,
J. Med. Chem. 2010, 53, 6355–6360.
[6]
[7]
X. Wang, L. Zhang, D. Byrne, L. Nummy, D. Weber, D. Krishnamurthy,
N. Yee, C. H. Senanayake, Org. Lett. 2014, 16, 4090–4093.
M. Imamura, K. Nakanishi, T. Suzuki, K. Ikegai, R. Shiraki, T. Ogiyama,
T. Murakami, E. Kurosaki, A. Noda, Y. Kobayashi, et al., Bioorg. Med.
Chem. 2012, 20, 3263–3279.
[8]
a) V. Mascitti, B. A. Thuma, A. C. Smith, R. P. Robinson, T. Brandt, A. S.
Kalgutkar, T. S. Maurer, B. Samas, R. Sharma, Med. Chem. Commun.
2013, 4, 101–111; b) A. T. Ndefo, U.A., Anidiobi, N.O., Basheer, E.,
Eaton, Drug Forecast. 2015, 40, 364–368.
[9]
S. H. Lee, K. S. Song, J. Y. Kim, M. Kang, J. S. Lee, S. H. Cho, H. J.
Park, J. Kim, J. Lee, Bioorg. Med. Chem. 2011, 19, 5813–5832.
(1S)-1,5-Anhydro-1-[5-{(napthalen-2-yl)
methyl}-6-methylpyridin-2-
yl]-D-glucitol (32): Compound 28 (0.25 g, 0.33 mmol), BBr3 (1M solution
in heptane, 3.96 mL, 3.96 mmol) were treated as described in the general
procedure D for 6 h, to give the title compound 32, after column
chromatography on silica gel (MeOH/CH2Cl2, 1:9) as a colorless gum (0.08
g, 61.53%); Rf = 0.2 (MeOH/CH2Cl2, 1:9); []23D = 73.9 (c 0.3, MeOH);1H
NMR (400 MHz, CD3OD) : = 2.7 (s, 3H), 3.38-3.55 (m, 1H), 3.37-3.47 (m,
2H), 3.50 (d, J = 9.6 Hz, 1H), 3.75-3.82 (m, 2H), 4.3 (s, 2H), 4.53 (d, J =
9.6 Hz, 1H), 7.27 (dd, 1J = 8.4 Hz, 2J = 1.6 Hz, 1H), 7.35-7.38 (m, 2H), 7.60
(s, 1H), 7.71- 7.72 (m, 1H), 7.73-7.79 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H).
8.15 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz, DMSO-d6):  = 22.7 (CH3),
38.2 (CH2), 61.9 (CH2), 70.8 (CH), 73.7 (CH), 78.7 (CH), 81.9 (CH), 82.3
(CH), 120.9 (CH), 125.9 (CH), 126.6 (CH), 127.1 (CH), 127.8 (CH), 127.9
(C), 128.4 (CH), 132.1 (C), 133.5 (C), 133.7 (C), 137.6 (C), 138.1 (CH),
155.8 (C), 155.7 (C), 156.5 (C). IR (KBr): 1427, 1547 1610, 2819, 2967,
3271, 3397, 3517 cm-1. HRMS: calcd for C23H25NO5Na (M+Na)+ 418.1625.
found. 418.1622
[10] S. Y. Kang, K. S. Song, J. Lee, S. H. Lee, J. Lee, Bioorg. Med. Chem.
2010, 18, 6069–6079.
[11] H. Zhou, D. P. Danger, S. T. Dock, L. Hawley, S. G. Roller, C. D. Smith,
A. L. Handlon, ACS Med. Chem. Lett. 2010, 1, 19–23.
[12] Y.Yamazaki, S. Harada, S. Tokuyama, Brain Res. 2012, 1489, 113–120.
[13] C. Scafoglio, B. A. Hirayama, V. Kepe, J. Liu, C. Ghezzi, N. Satyamurthy,
N. A. Moatamed, J. Huang, H. Koepsell, J. R. Barrio, E.M. Wright, Proc.
Natl. Acad. Sci. U. S. A. 2015, 112, E4111-9. For a recent review on the
significance of SGLT as a novel emerging therapeutic target, see: Y.
Yamazaki, S. Harada, S. Tokuyama, Eur. J. Pharmacol. 2018, 822, 25–
31.
[14] M. D. Hill, Chem. Eur. J. 2010, 16, 12052–12062.
[15] a) M. C. Bagley, C. Glover, E. A. Merritt, Synlett. 2007, 2459–2482; b) F.
Bohlmann, D. Rahtz, 1957, 90, 2265.
[16] A. Dondoni, N. Catozzi, A. Marra, J. Org. Chem. 2005, 70, 9257–9268.
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
[17] H. Kuzuhara, H. G. Fletcher, J. Org. Chem. 1967, 32, 2531-2534.
[18] F. Labéguère, J. P. Lavergne, J. Martinez, Tetrahedron Lett. 2002,
43,7271–7272.
[23] S. W. McCombie, W. B. Motherwell, The Barton-M C Combie Reaction,
2012, pp.164-591.
[24] a) J. Lee, J. Y. Kim, J. Choi, S. H. Lee, J. Kim, J. Lee, Bioorg. Med. Chem.
Lett. 2010, 20, 7046–7049; b) K. Ikegai, M. Imamura, T. Suzuki, K.
Nakanishi, T. Murakami, E. Kurosaki, A. Noda, Y. Kobayashi, M. Yokota,
T. Koide, K. Kosakai, Y. Ohkura, M. Takeuchi, H. Tomiyama, M. Ohta,
Bioorg. Med. Chem. 2013, 21, 3934–3948.
[19] V. Michelet, K. Adiey, S. Tanier, G. Dujardin, J.-P. Genêt, Eur. J. Org.
Chem. 2003, 2947–2958.
[20] M. C. Bagley, J. W. Dale, J. Bower, Chem. Commun. 2002, 1682–1683.
[21] A. C. Cope, S.A. Glickman, J. Am. Chem. Soc. 1945, 67, 1017–1020.
[22] Y. H. Liu, D. L. Li, L. De Lu, Arkivoc. 2008, XV, 65–70.
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800789
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Text for Table of Contents
Key Topic*
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm;
NOTE: the final letter height should
not be less than 2 mm.))
*one or two words that highlight the emphasis of the paper or the field of the study
Layout 2:
FULL PAPER
Key Topic*
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Bohlmann–Rahtz hetero-annulation reaction between the sugar alkynone and ethyl
β-aminocrotonate open the access for novel 2--D-Glucopyranosylpyridines. We
have been prepared 10 examples, based on the importance of varying in aglycon
part of Dapagliflozin. The synthesized compounds were envisaged as potential
analogues for lowering of blood glucose levels through inhibition of sodium-glucose
transporters in the kidney.
*one or two words that highlight the emphasis of the paper or the field of the study
11
This article is protected by copyright. All rights reserved.