Synthesis of Benzyl C-Analogues of Dapagliflozin as Potential SGLT2 Inhibitors

Article abstract of DOI:10.1002/ejoc.202000025

Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of therapeutic agents for the treatment of type 2 diabetes based on blocking of renal reabsorption of glucose. Dapagliflozin, a C-aryl glucoside, has emerged as a successful drug in the market based on this concept. We have synthesized hitherto unreported C-benzyl glucoside analogues of Dapagliflozin carrying the same aglycon present in the drug. The synthetic strategy involves in situ generation of functionalized arylmagnesium bromide with Weinreb-amide (WA) functionality for the first time, and addition on to the 1-β-formyl-2,3,4,6-tetra-O-benzyl-D-glucopyranoside for the synthesis of a C-benzyl glucoside building block 16. The WA functionality therein enabled variation in the nature of the distal ring of biarylmethane aglycon for convenient access to other analogues. All the new compounds were screened for their sodium-glucose co-transporters (SGLT1 and SGLT2) inhibition activity using cell-based nonradioactive fluorescence glucose uptake assay. Among them, 14 with IC₅₀: 0.64 nm emerged as the most potent SGLT2 inhibitor with the best selectivity for inhibition of SGLT2 (IC₅₀:0.64 nm) over SGLT1 (IC₅₀: 500 nm) as compare to Dapagliflozin. On the other hand, compound 15a exhibited moderate selectivity for inhibition of SGLT2 (IC₅₀: 4.94 nm) over SGLT1 (IC₅₀: 68.46 nm). These results presented herein amply demonstrate the promise of C-benzyl analogues of Dapagliflozin as novel SGLT2 inhibitors for future investigations.

Full text of DOI:10.1002/ejoc.202000025

DOI: 10.1002/ejoc.202000025
Full Paper
Benzyl C-Analogues of Dapagliflozin
Synthesis of Benzyl C-Analogues of Dapagliflozin as Potential
SGLT2 Inhibitors
Ramesh Mukkamala,[a] Roshan Kumar,[b] Sanjay K. Banerjee,[b][‡] and
Indrapal Singh Aidhen*[a]
Abstract: Sodium-glucose co-transporter (SGLT) inhibitors are aglycon for convenient access to other analogues. All the new
a novel class of therapeutic agents for the treatment of type 2 compounds were screened for their sodium-glucose co-trans-
diabetes based on blocking of renal reabsorption of glucose. porters (SGLT1 and SGLT2) inhibition activity using cell-based
Dapagliflozin, a C-aryl glucoside, has emerged as a successful nonradioactive fluorescence glucose uptake assay. Among
drug in the market based on this concept. We have synthesized them, 14 with IC50: 0.64 n
hitherto unreported C-benzyl glucoside analogues of Dapagli- inhibitor with the best selectivity for inhibition of SGLT2
flozin carrying the same aglycon present in the drug. The syn- (IC50:0.64 n ) over SGLT1 (IC50: 500 n ) as compare to Dapagli-
thetic strategy involves in situ generation of functionalized aryl- flozin. On the other hand, compound 15a exhibited moderate
magnesium bromide with Weinreb-amide (WA) functionality for selectivity for inhibition of SGLT2 (IC50: 4.94 n ) over SGLT1
the first time, and addition on to the 1-ꢀ-formyl-2,3,4,6-tetra-O- (IC50: 68.46 n ). These results presented herein amply demon-
M emerged as the most potent SGLT2
M
M
M
M
benzyl-D-glucopyranoside for the synthesis of a C-benzyl gluc- strate the promise of C-benzyl analogues of Dapagliflozin as
oside building block 16. The WA functionality therein enabled novel SGLT2 inhibitors for future investigations.
variation in the nature of the distal ring of biarylmethane
Introduction
The inhibition of sodium-glucose linked transporter 2 (SGLT2)
protein present in the kidney and responsible for reabsorption
of glucose, has emerged as successful and novel strategy for
the treatment of type 2 diabetes,[1] which is insulin-independ-
ent. The SGLT2 inhibition enables urinary excretion of glucose
and thereby reduction of elevated blood glucose levels during
hyperglycemic situation. The inspiration derived from the natu-
ral product phlorizin 1,[2] as the first SGLT2 inhibitor, has come
long-way and has paid rich dividends to the medicinal chemists
community engaged in the journey of drug discovery. Follow-
ing the initial disclosure of orally active phenol-O-glucoside
SGLT2 inhibitor 2b (T-1095),[3] a large number of O-glucosides
including T1095 2b,[3] Sergliflozin (3b)[4] and Remogliflozin (4)[5]
for SGLT2 inhibition have been developed (Figure 1).
Figure 1. Examples of some O-glucoside as SGLT inhibitors.
The significance of C-glucosides as metabolically more stable
and with improved pharmacokinetic profiles, paved their way
for successfully emerging as drugs for type 2 diabetes, based
on SGLT2 inhibition. To date, under the C-glucosides class,
[a] Department of Chemistry, Indian Institute of Technology Madras,
Chennai 600036, India
E-mail: isingh@iitm.ac.in
http://chem.iitm.ac.in/faculty/indrapal/
[b] Translational Health
Dapagliflozin (5),[6] Canagliflozin[7] (6), Empagliflozin[8] (7) and
Ipragliflozin[9] (8), Ertugliflozin[10] (9) have been approved by
the FDA for the treatment of type 2 diabetes, and many other
SGLT2 inhibitors are under different phases of clinical trials.[11]
Pre- and post-discovery period of Dapagliflozin, has witnessed
several structural modifications in the glycone or aglycon part
and the efforts continue to remain unabated in the synthetic
community. Compounds resulting from the variation in the
glycone part are represented by Ertugliflozin[10] (9), Tofogli-
flozin[12] (10), and Luseogliflozin[13] (11) (Figure 2).
Science and Technology Institute (THSTI),
Faridabad, Haryana 121001, India
E-mail: skbanerjee@thsti.res.in
[‡] Present Address: National Institute of Pharmaceutical Education and
Research (NIPER), Guwahati, Assam 781101, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000025.
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Results and Discussion
To achieve this objective of synthesizing target 14 and 15, we
envisaged functionalised C-benzyl glucosides 16 with electro-
philic Weinreb-amide functionality (WA) as the key building
block. The WA-functionality would provide the necessary han-
dle for further derivatization and chemistry leading to diverse
set of new molecules for biostudies (Figure 4). Paul Knochel's
elegant contribution towards synthesis of functionalized aryl-
magnesium reagents[16] in presence of electrophilic functional
groups such as cyano, nitro, amide and ester, provided the nec-
essary confidence in proposing 16 as the key building block.
Although, Paul Knochel's work has enabled access to function-
alized arylmagnesium halides containing cyano, nitro, amide
and ester as electrophilic functional groups, synthesis of func-
tionalized arylmagnesium halides with WA functionality in par-
ticular remains unexplored. This provided additional impetus,
for undertaking synthesis of building block 16, because of our
continued interest in the use of WA functionality for synthetic
endeavours.[17] The synthetic scheme envisages addition of
functionalized Grignard reagent 18 onto aldehyde 17 for syn-
thesis of benzyl-C-glucoside building block 16. Literature re-
ports available for the synthesis of C-benzyl glycosides are rela-
tively few[18] compared to C-aryl-glycosides.
Figure 2. Important C-glucosides as SGLT2 inhibitors.
Nomura, in 2013, probably inspired by the partial success
of O-glucosides and the aglycon part present in Dapaglifozin,
synthesized and evaluated the N-glucoside 12[14] for SGLT2 inhi-
bition. Although 12 exhibited strong hSGLT2 inhibitory activity
(IC50= 3.9 n
M
) comparable to 13 (IC50= 5.1 nM) its hydrolytic
stability remained a challenge. In the recent past,[15] inspired
from the success of Dapagliflozin (5), a C-aryl-glucoside, we had
aimed at the synthesis of hitherto unreported and challenging
C-benzyl-glucoside 14 in particular and analogues 15 resulting
from the variation in the distal aryl ring of biarylmethane-
aglycon part present in Dapagliflozin.
Figure 4. Key building block 16 for synthesis of targets 14/15.
In the context, that the original lead molecule from nature,
phlorizin 1, had one atom spacer (oxygen) between glucosyl
residue and the aglycon part, the proposed targets 14/15 paral-
lels the concept by replacing the oxygen atom with an isosteric,
methylene-unit between the glucosyl residue and the biaryl-
methane-aglycon for ensuring the hydrolytic stability (Figure 3).
Before embarking upon synthesis of the building block 16
in particular, through the proposed strategy, a model reaction
between functionalized aryl-Grignard agents 20 and aldehyde
17 was undertaken (Figure 5). Multi-gram quantities of alde-
hyde 17, 1-ꢀ-formyl-2,3,4,6-tetra-O-benzyl-D-glucopyranoside
were easily accessible in three steps using 2,3,4,6-Tetra-O-
benzyl-D-glucono-1,5-lactone 21 as a starting material, by a lit-
erature known method.[19] In a model reaction, 4-iodobenzo-
nitrile 22a in anhydrous THF was treated with isopropylmagne-
sium bromide (iPrMgBr) at –15 °C for 1.5 to 2 h to affect the
magnesium iodide exchange as reported in Paul Knochel's
method.[16] The nascent magnesiated reactive intermediate
20a, so formed in the reaction vessel was trapped by addition
of the requisite aldehyde 17 as electrophile. The reaction tem-
perature was gradually increased from –15 to 0 °C. The stirring
was continued at 0 °C temperature for 8 h. To our delight clean
reaction ensued resulting in the formation of expected addition
product 23a as a single diastereoisomer[20] in 79 % yield along
with glycal 24 as a minor side product (5–10 %) (Scheme 1).
Spurred from this successful model reaction, we undertook
generalization of this scheme with the preparation of the
Figure 3. Proposed target molecules.
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Scheme 1. Synthesis of functionalized hydroxyl C-benzyl glucosides 23a-c.
organomagnesium bromides 20b-c with varying position of ment of the stereochemistry at the new chiral centre, for com-
morpholine amide functionality from corresponding functional- pleteness of the study. As an illustrative example, the stereo-
ized aryl iodides 22b-c. Successful in situ formation of organo- chemistry of the newly formed chiral centre in compound 23a
magnesium bromides 20b and 20c occurred at –0 °C and was confirmed as R-configuration, with the use of extensive
enabled addition onto aldehyde 17 resulting in the formation 2D NMR experiments including 2-D Double Quantum Filtered
of the addition products 23b and 23c respectively in good Correlation Spectroscopy (DQF-COSY), Total Correlation Spec-
yields (Scheme 1). All the addition products 23a-c were ob- troscopy (TOCSY), Nuclear Overhauser Effect Spectroscopy
tained as single isomers, accompanied with formation of the (NOESY) and Heteronuclear-Single Quantum correlation (HSQC)
glycal 24, as separable minor side product.
experiments.[20] Although our initial efforts to deoxygenate
compounds 23a-c, at the benzylic site using BF3·OEt2/Et3SiH or
TFA/Et3SiH were unsuccessful, the same could be achieved us-
ing two step protocol employing Barton–McCombie deoxygen-
ation method. The thionocarbonate derivatives 25a-c were
readily obtained at room temperature in quantitative yields,
through reaction of substrates 23a-c with phenyl chlorothiono-
carbonate (PTC–Cl)[21] in the presence of 4-dimethylaminopyr-
idine (DMAP) as base and in dry acetonitrile as solvent. These
compounds 25a-c were subjected to radical de-oxygenation
using tri-n-butyl tin hydride (nBu3SnH) and azobisisobutyro-
nitrile (AIBN) as initiator in dry toluene at 90 °C. Clean reaction
ensued in 9–10 hours affording the functionalized benzyl C-
glucosides 19a-c in good to moderate yields (Scheme 2).
Figure 5. Addition of functionalized Grignard agent 20 onto aldehyde 17.
Although the stereochemistry of the addition product was
Having successfully synthesized functionalized C-benzyl
inconsequential, as the product 23a-c awaited immediate de- glycosides 19a-c, we now focused our efforts towards the syn-
oxygenation for the synthesis of the targeted C-benzyl glucos- thesis of specific C-benzyl glucoside building block 16, envis-
ides represented by general structure 19, we delved into assign- aged for targeted compounds 14/15 stated in our objectives.
Scheme 2. Synthesis of functionalized C-benzyl glucosides 19a-c.
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The requisite starting aryl iodide 26 containing WA, needed for (dd, J = 14.5 Hz and 2.0 Hz) were most characteristics for the
the formation of corresponding Grignard reagent banked on newly formed methylene (-CH2-) unit at anomeric centre. The
the carboxylic acid 29. Although this is commercially available, clear singlet at 3.18 ppm and broad singlet at 3.50 indicates
its prohibitive cost prompted us to synthesize this from cheap the presence of -NCH3, -NOCH3 units in the molecule and their
and commercially available anthranilic acid 27 (Scheme 3). We corresponding 13C-NMR peaks were appeared at 32.5 and 61.22
have developed a two-step procedure, not reported for the respectively. Further molecular constitution was confirmed by
preparation of carboxylic acid 29, which involved iodination fol- the presence of the molecular ion peak [M + H] at 736.3041
lowed by Sandmeyer's reaction for chlorination. Iodination of in HRMS spectrum, corresponding to molecular formula
anthranilic acid 27 was achieved using literature procedure[22] C44H47O7NCl. As envisaged, the WA functionality in the building
and this furnished the iodinated anthranilic acid 28 in good block 16, afforded the much-needed diversity point for further
yields. The diazotization reaction followed by replacement of chemistry. The addition of various arylmagnesium bromides
diazonium group with chloro-group using CuCl[23] gave the de- and obtainment of benzyl C-glucosyl diaryl ketones 32a-f in
sired carboxylic acid 29 in good yield. The acid 29 was now good yields, amply demonstrated the usefulness of this build-
converted into the corresponding Weinreb-amide 26 using ing block (Scheme 5).
standard protocol (Scheme 3).
Scheme 3. Synthesis of functionalized WA-based aryl iodide 26.
The functionalized arylmagnesium bromide 18 could be
easily formed under Paul Knochel's condition from iodide 26
Scheme 4. Syntheses of key building block 16.
and was added onto the aldehyde 17. Clean reaction ensued,
Among all the synthesized compounds (32a-f) the simple
furnishing the corresponding addition product 30 as a single hydrogenation conditions [H2 (ballon)/Pd-C] for debenzylation
isomer in 68 % yield (Scheme 4). Subsequent deoxygenation was successful only on compounds 32a, 32c and 32f and the
using Barton–McCombie deoxygenation method as described reaction afforded the corresponding de-protected C-benzyl-
in earlier Scheme 2 afforded the key building block 16. The glucosyl ketones 33a, 33c and 33f in good yields. With the
formation of compound 16 was unambiguously confirmed remaining substrates (32b, 32d, 32e) the same hydrogenation
through NMR spectroscopy and molecular constitution by mass procedure for debenzylation was unsuccessful and TLC showed
spectral analysis. In the 1H-NMR of compound 16, the presence formation of multiple products. Presumably it suggested either
of signals centred at 2.73 (dd, J = 14.5 Hz and 9.0 Hz) and 3.10 partial debenzylation or possible reduction of keto functionality
Scheme 5. Synthesis of C-benzyl analogues of Dapagliflozin 14 and 15a-e.
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and further over reduction to methylene group. With this as- all the nine derivatives, compound 14 with same aglycon unit
sumption and anticipating that keto functionality can also be which is present in Dapagliflozin exhibited the SGLT2 inhibition
reduced under high pressure hydrogenation conditions, com- at very lower concentration (IC50: 0.64 nM) as compare to Dapa-
pounds 32a-f were subjected to hydrogenation under pressure gliflozin (IC50: 8.16 nM).
of 40 psi units. To our satisfaction, we could affect complete
Table 1. Evaluation of SGLT1 and SGLT2 activity.
reduction, besides the desired, debenzylation and the synthesis
of targeted C-benzyl analogues of Dapagliflozin 14 and 15a-e
was achieved in good yields (Scheme 5).
Entry
Compound
SGLT1 (IC50, nM)[a] SGLT2 (IC50, nM[a] SGLT1/SGLT2
1
2
3
4
5
6
7
8
9
10
Dapagliflozin[b] >500
8.16
0.64
4.94
64.28
24.03
118.15
149.57
49.30
87.75
>500
61.27
781.25
13.85
0.12
15.84
>4.23
>3.34
>10.14
4.61
14
500.00
68.46
7.86
15a
15b
15c
15d
15e
33a
33c
33f
Evaluation of SGLT1 and SGLT2 Activity
380.73
>500
>500
>500
404.68
40.58
The in vitro inhibitory potential of all nine newly synthesized
C-benzyl analogues of Dapagliflozin (14, 15a-e and 33a, 33c
and 33f) were screened using cell based nonradioactive fluo-
rescent glucose uptake assay[24] for functional screening of so-
dium-glucose co-transporters SGLT1 and SGLT2 determined at
excitation/emission maxima of ~465/540 nm. SGLT1and SGLT2
transfected Human Embryonic Kidney (HEK293) cells were prop-
agated at 37 °C in 5 % CO2 in Dulbecco's minimal essential
medium (DMEM) supplemented with 1.0 % of penicillin-strepto-
mycin and 10 % heat inactivated fetal bovine serum (FBS). The
cells were cultured in a 90mm dish in DMEM with 10 % FBS
until 70–80 % confluences obtained for further use for screen-
ing SGLT1and SGLT2 inhibition activity. To measure SGLT1 and
SGLT2-mediated glucose uptake,[24b–24c] transfected stable HEK
cells were plated separately at 2 × 105/well in 12-well plate; all
culture medium was removed from each well and replaced with
100 μL of culture medium with newly synthesized Dapagliflozin
analogues (14, 15a-e and 33a, 33c and 33f) at five different
<0.08
[a] All compounds were evaluated at a concentration of 10 m
flozin was the reference compound.
M. [b] Dapagli-
We next correlated selectivity index of all the compounds
14, 15a-e, 33a, 33c and 33f for SGLT2 over SGLT1 inhibitory
activities and corresponding results are presented in Table 1.
Among all the derivatives (14 and 15a-e) having a methylene
(-CH2-) linker between proximal and distal ring, the compound
14 (IC50: 0.64 n
M for SGLT2 and 500 nM for SGLT1) showed
higher selectivity towards SGLT2 over SGLT1 as compare to Da-
pagliflozin, (SGLT1/SGLT2 ratio for 14 is 781 and for Dapagli-
flozin is >61). Similarly, compound 15a (IC50: 4.94 n
M for SGLT2
and 68.46 n for SGLT1) with 4-methyl unit at distal ring
M
showed moderate selectivity (13.85) towards SGLT2 to over
SGLT1 (Table 1).
concentrations ranging from 0.1 to 500 nM.
Surprisingly selectivity comparison among 33a, 33c and 33f
with keto functionality between proximal and distal ring exhib-
ited different selectivity towards SGLT2 over SGLT1, the com-
pounds 33a (IC50: 49.30 for SGLT2 and >500 for SGLT1) with 4-
methyl and 33c (IC50: 87.75 for SGLT2 and 404.68 for SGLT1)
with 4-methoxy unit at distal ring showed better selectivity to-
wards SGLT2 over SGLT1. Whereas, compound 33f (IC50:40.58
for SGLT1 and >500 for SGLT2) with 4-ethoxy substituent at
distal ring exhibited more selectivity towards SGLT1 over SGLT2.
After half an hour, a fluorescently labelled 2-deoxyglucose
analog, 2-NBDG (2-deoxy-2- [(7-nitro-2,1,3-benzoxadiazol-4-yl)
amino]-D-glucose) was added to the plates and incubated for
30 min. After washing three times, cells were then lysed and
fluorescence of aliquots from the lysate was measured at excita-
tion/emission maxima of 465/540nm. Dapagliflozin, a FDA ap-
proved SGLT2 inhibitor was used as a reference compound in
this fluorescent based in vitro activity evaluation system. The
IC50 values (concentration to inhibit 50 % D-glucose uptake in
cells) of new C-benzyl analogues of Dapagliflozin (14, 15a-e
and 33a, 33c and 33f) were determined from the glucose up-
take inhibition curves with reference to Dapagliflozin. IC50 val-
ues obtained for synthetic compounds (14, 15a-e and 33a, 33c
and 33f) are presented in Table 1. All nine new analogues (14,
15a-e and 33a, 33c and 33f) showed SGLT1 and SGLT2 inhibi-
Cytotoxicity Assay Cell Line
A549-cells (Human Lung Adenocarcinoma Epithelial Cell Line)
and HEK293 cells (Human Embryonic Kidney Cell Line) were
used for the cytotoxicity assay. HEK293 and A549 cell lines were
maintained in Dulbecco's modified Eagle's medium (DMEM, Ge-
netix) containing 10 % heat-inactivated fetal bovine serum, 100
tion activity with IC50 ranging from 0.64 to >500 n
M (Table 1).
Among nine new analogues, the compound 15e with 3,4-meth-
ylenedioxy unit at distal ring and compound 33f with keto
functionality between proximal and distal ring exhibited SGLT2
0
U/mL penicillin, 100 U/mL streptomycin, at 37 C in a humidi-
fied atmosphere of 5 % CO2.
inhibition at higher concentrations (IC50 for 15e: 149.57 n
for 33f: >500 n ). The other analogues such as, 15c with
4-methoxy, 15d with 4-butyloxy, and 15b with 4-ethyl substitu-
M and
M
In vitro Cytotoxicity Assay and Results
ent at distal ring exhibited moderate SGLT2 inhibition as com- The cytotoxicity of all synthesized compounds was measured
pare to Dapagliflozin with IC50 values 24.03, 118.15 and by means of a colorimetric cell culture assay using MTT (3-(4,5-
64.28 n
(IC50 4.94 n
SGLT2 inhibition as compare to Dapagliflozin. Strikingly, among 10 % FBS in each well of 96-well cell culture plates and incu-
M
respectively (Table 1). However, the compound 15a dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide). 1 × 104
M
) with 4-methyl unit at distal ring showed better cells/well were plated in 100 μL DMEM, supplemented with
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methanol, hexanes as mobile phase. Thin-layer chromatography
was performed on pre-coated silica gel F254 aluminium plates with
visualization under short UV light or by staining with Hanessian,
iodine, Bayer's reagent and anisaldehyde as spray reagents. Melting
points were obtained using a melting point apparatus and are un-
corrected. Infrared spectra were recorded using KBr pellet and the
bated for 24 h at 37 °C in a CO2 incubator. The appropriate
concentrations of the compounds were made and added to the
wells with respective vehicle, DMSO. After 24 h of incubation,
20 μL MTT (2 mg/mL) was added to each well and the plates
were further incubated for 4 h. Supernatant was removed from
each well, formazan crystals that were formed during 4h incu-
bation were dissolved in 100 μL of DMSO, and the absorbance
was recorded at 540-nm wavelength using UV Visible spectro-
photometer (MULTISCAN GO, Thermo Scientific). Percentage of
1
absorptions are reported in wave numbers (cm–1). H NMR spectra
were recorded at 400; 500 MHz Spectrometer with chemical shifts
(δ) quoted in parts per million (ppm) and coupling constants (J)
recorded in Hertz (Hz). 13C NMR spectra were recorded at 100 or
cell viability was calculated as 100 % × (absorbance of the drug 125 MHz. HRMS were recorded on a MICRO – Q TOF mass spectrom-
eter by using ESI technique at 10 eV.
DMSO treated control cells – absorbance of the blank). Percent- General Procedure for Synthesis of Compounds 23a-c: Isopropyl-
treated cells – absorbance of the blank)/(absorbance of the
magnesium bromide (iPrMgBr) was generated prior to its use from
corresponding pre-cleaned magnesium matel (3.39 mmol), iodine
(one crystal) and roasted this mixture at 55 °C water bathe tempera-
ture under vacuum for 5 minutes and was allowed to room temper-
ature under nitrogen atmosphere, to this anhydrous THF (4.0 mL),
followed by 2-bromo propane (3.39 mmol) was added and keep
water bath temperature once again 55 °C until initiation of the reac-
tion, after initiation water bath under reaction flask was removed
and continued the reaction at room temperature until complete
consumption of magnesium metal. After successful generation of
isopropylmagnesium bromide, the reaction flask was shifted to
–15 °C prior addition of functionalized aryl iodides 22a, whereas
0 °C in case of functionalized aryl iodides 22b-c and to this iso-
propylmagnesium bromide at appropriate temperature was added
functionalized aryl iodides (1.358 mmol) dissolved in dry THF
(4.0 mL) then stirred the reaction mixture at same temperature for
1.5 to 2 h to effect complete metal-iodine exchange. To this func-
tionalized arylmagnesium bromides 20a-c was added aldehyde 17
(0.5 g, 0.905mmol) pre-dissolved in dry THF (5 mL). Then reaction
temperature was gradually increased from –15 °C to 0 °C in case of
functionalized arylmagnesium bromides 20a whereas retained at
0 °C in case of functionalized arylmagnesium bromides 20b-c and
stirring was continued at the same temperature for 8 to 10 h. The
reaction mixture was quenched with saturated aqueous ammonium
chloride solution (20 mL), and then extracted into ethyl acetate
(2 × 20 mL). The combined organic layers were washed with water
(20 mL), brine (20 mL) and dried with anhydrous sodium sulfate
then filtered. The filtrate was concentrated under vacuum and the
resulting crude products were purified by silica-gel column chroma-
tography.
age inhibition was calculated as (100 - % cell viability). Here,
blank means wells containing medium but lacking cell.
Our cytotoxicity assay (Table 2) showed that Doxorubicin, a
well-known anti-cancer drug, kills both HEK293 cells as well as
A549 cells. The IC50 value of Doxorubicin for both HEK293 and
A549 cells are 86.9 μM and 0.763 μM, respectively. However,
none of the compounds used for SGLT2 assays shown any cyto-
toxicity as compared to Doxorubicin.
Table 2. Cytotoxicity (IC50) assay.
Entry Compounds IC50 Values [μ
M
] HEK 293 cells IC50 Values [μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
0.763 μ
M] A549 cells
1
2
3
4
5
6
7
8
9
10
14
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
>100 μ
M
M
15a
15b
15c
15d
15e
33a
33c
33f
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
Doxorubicin[a] 86.9 μ
M
M
[a] Doxorubicin was the reference compound.
Conclusions
Preparation of functionalized arylmagnesium halides containing
electrophilic WA-amide functionality has been achieved for the
first-time using Paul Knochel's procedure. This has enabled syn-
thesis of a new building block 16 containing WA-functionality
as handle for further chemistry leading to C-benzyl-glucosides.
The building block 16 has enabled convenient synthesis of new
C-benzyl analogues of Dapaglifozin, proposed by us, carrying
the same aglycon part, that present in the successful drug, Da-
pagliflozin. The synthesized C-benzyl analogues showed equally
good SGLT2 inhibition for possibly opening new directions.
4-((R)-Hydroxy((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benz-
yloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)benzonitrile
(23a): Yield: 0.28 g (79 %); Rf = 0.3 (EtOAc/hexanes, 3:7); white solid;
[α]2D5 = +12.18 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ:7.54 (d,
J = 8.4 Hz, 2H, ortho to CN, ArH); 7.43 (d, J = 8.0 Hz, 2H,meta to
CN, ArH); 7.35–7.18 (m, 20H, 4 × ArH); 4.97 (d, J = 10.8 Hz, PhCHaHb-
1H); 4.92–4.89 (m, PhCH2, H-7, 3H); 4.82 (d, J = 10.8 Hz,PhCHaHb
1H); 4.73 (d, J = 11.2 Hz,PhCHaHb- 1H); 4.58 (d, J = 10.8 Hz,
PhCHaHb 1H); 4.43 (s, PhCH2, 2H); 3.80–3.71 (m, H-2, H-3, 2H); 3.66–
3.57 (m, H-6, H-4, 3H); 3.39 (d, J = 8.4 Hz, H-1, 1H); 3.36–3.33 (m, H-
5 1H); 3.09 (bs, 1H, OH) ppm. 13C NMR (100 MHz, CDCl3) δ:147.7 (C);
138.5 (C); 138.1 (C); 138.0 (C); 132.0 (CH); 128.7 (CH); 128.6 (CH);
128.5 (CH); 128.2 (CH); 128.0 (CH); 127.9 (CH); 127.86 (CH); 127.8
(CH); 127.7 (CH); 127.2 (CH); 119.0 (C); 111.2 (C); 87.1 (CH); 81.2 (CH);
78.9 (CH); 78.3 (CH); 78.2 (CH); 75.7 (CH2); 75.4 (CH2); 75.2 (CH2);
Experimental Section
General Materials and Methods: All reactions were carried out in
oven-dried glassware under the inert atmosphere of nitrogen, using
commercially supplied distilled solvents used as such. Tetrahydro-
furan was dried and distilled from Na–Ph2CO, whereas, dichloro-
methane and N,N-dimethylformamide were distilled from Calcium
hydride. Hexanes refer to the petroleum fraction with bp 40–60 °C.
Column chromatography was carried out by using 100–200 mesh
silica gel as stationary phase and ethyl acetate, dichloromethane,
73.4 (CH2); 71.08 (CH); 68.9 (CH2) ppm. IR (CHCl3): ν = 3020, 2925,
˜
2861, 2365, 2223, 1495, 1448, 1216, 767 cm–1. HRMS-ESI: Calcd. For
C42H42NO6 [M + H]: 656.3012, found 656.3026.
(4-((R)-Hydroxy((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benz-
yloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)-
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(Morpholino)methanone (23b): Yield: 0.4 g (60 %); Rf: 0.1 (EtOAc the de-oxygenated product obtained were purified by using silica-
1
+ Hexanes 4:6); white gummy solid; [α]2D9 = +4.41 (c 1.0, CHCl3); H gel column chromatography. The spectral and analytical data of the
NMR (400 MHz, CDCl3) δ: 7.43 (d, J = 8.0 Hz, 2H, ortho to amide,
ArH); 7.35–7.20 (m, 22H, ArH); 5.01–4.95 (m, H-7, PhCH2, PhCHaHb-,
4H); 4.88 (d, J = 10.8 Hz, PhCHaHb-, 1H); 4.80 (d, J = 10.8 Hz,
PhCHaHb- 1H); 4.60 (d, J = 11.2 Hz, PhCHaHb-, 1H); 4.54–4.44 (m,
PhCH2, 2H); 3.85–3.60 (m, 14H); 3.48 (d, J = 9.6 Hz, H-1, 1H); 3.36 (d,
J = 9.6 Hz, H-5, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ: 170.5 (amid);
144.4 (C); 138.5 (C); 138.3 (C); 138.2 (C); 138.1 (C); 138.0 (C); 134.1
(C); 128.6 (C); 128.57 (CH); 128.53 (CH); 128.5 (CH); 128.0 (CH); 127.9
(CH); 127.8 (CH); 127.84 (CH); 127.80 (CH); 127.7 (CH); 127.6 (CH);
127.4 (CH); 127.0 (CH); 126.7 (CH); 87.1 (CH); 81.4 (CH); 78.7 (CH);
78.4 (CH); 78.1 (CH); 75.6 (CH2); 75.3 (CH2); 75.1 (CH2); 73.4 (CH2);
product 19a-c are given below.
4-(((2S,3S,4R,5R,6R)-3,4,5-Tris(benzyloxy)-6-((benzyloxy)-
methyl)tetrahydro-2H-pyran-2-yl)methyl)benzonitrile (19a):
Yield: 0.114 g (78.0 %); Rf: 0.4 (EtOAc/hexanes, 2:8); white solid
(mp = 92–94 °C); [α]3D1 = –0.60 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 7.50 (d, J = 8.5 Hz, 2H, ortho to -CN, ArH); 7.37–7.26 (m,
20H, 4 × ArH); 7.21 (d, J = 6.5 Hz, 2H,meta to -CN, ArH); 4.96–4.82
(m, 4H, 2 × PhCH2); 4.65 (d, J = 11.0 Hz, 1H, PhCHaHb); 4.61 (d, J =
11.0 Hz, 1H, PhCHaHb); 4.53 (q, J = 12.0 Hz, 2H, PhCH2); 3.71 (t, J =
9.0 Hz, 1H, H-5); 3.66–3.63 (m, 3H, H-4, H-6); 3.48 (t, J = 9.0 Hz, 1H,
H-1); 3.36–3.32 (m, 2H, H-2, H-3); 3.15 (d, J = 14.0 Hz, 1H,
-CHCHaHbPh ); 2.75 (dd, J1 = 14.5 Hz, J2 = 9.0 Hz, 1H, -CHCHaHbPh)
ppm. 13C NMR (125 MHz, CDCl3) δ: 144.6 (C); 138.5 (C); 138.2 (C);
138.16 (C); 138.13 (C); 131.9 (CH); 130.5 (CH); 128.7 (CH); 128.6 (CH);
128.5 (CH); 128.50 (CH); 128.1 (CH); 128.0 (CH); 127.9 (CH); 127.8
(CH); 127.7 (CH); 119.2 (C); 110.1 (C); 87.4 (CH); 81.6 (CH); 79.4 (CH);
78.9 (CH); 78.6 (CH); 75.7 (CH2); 75.2 (CH2); 75.1 (CH2); 73.5 (CH2);
70.9 (CH); 68.8 (CH2); 66.9 (CH2) ppm. IR (CHCl3): ν = 3058, 3022,
˜
2919, 2856, 2362, 2339, 1629, 1454, 1429, 1111, 1022, 698 cm–1
.
HRMS-ESI: Calcd. For C46H50O8N [M + H]: 744.3536 found 744.3530.
(3-((R)-Hydroxy((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)-
(Morpholino)methanone (23c): Yield: 0.47g (70 %); Rf: 0.1 (EtOAc
1
+ Hexanes 5:5); white gummy solid; [α]2D5 = +8.61 (c 1.0, CHCl3); H
69.0 (CH2); 38.0 (CH2) ppm. IR (CHCl3): ν = 3065, 3020, 2923, 2858,
˜
NMR (500 MHz, CDCl3) δ: 7.45 (d, J = 8.0 Hz,1H, ArH); 7.39–7.24 (m,
20H, ArH); 7.18–7.16 (m, 3H, ArH); 4.97–4.92 (m, H-7, PhCH2,
PhCHaHb, 4H); 4.83 (d, J = 11.0 Hz,PhCHaHb- 1H); 4.77 (d, J =
11.0 Hz, PhCHaHb-, 1H); 4.57 (d, J = 11.0 Hz, PhCHaHb-, 1H); 4.43
(AB quartet, J = 15.0 Hz, PhCH2, 2H); 3.83–3.60 (m, 11H); 3.48 (d, J =
9.5 Hz, 2H); 3.35–3.33 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3) δ:
170.6 (amide); 142.9 (C); 138.6 (C); 138.2 (C); 138.1 (C); 138.0 (C);
135.1 (C); 128.66 (C); 128.6 (CH); 128.5 (CH); 128.0 (CH); 127.9 (CH);
127.88 (CH); 127.8 (CH); 126.1 (CH); 125.1 (CH); 118.3 (CH); 117.4
(CH); 114.5 (CH); 87.1 (CH); 81.4 (CH); 78.7 (CH); 78.4 (CH); 78.1 (CH);
75.7 (CH2); 75.3 (CH2); 75.1 (CH2); 73.4 (CH2); 70.9 (CH); 69.0 (CH2);
2228, 1606, 1454, 1360, 1215, 842, 669 cm–1. HRMS-ESI: Calcd. For
C42H41NO5Na [M + Na]: 662.2882, found 662.2872.
Morpholino(4-(((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benz-
yloxy)methyl)tetrahydro-2H-pyran-2 yl)methyl)phenyl)methan-
one (19b): Yield: 0.12g (72 %); Rf: 0.3 (EtOAc + Hexanes 4:6); white
solid (mp = 72–74 °C); [α]D31 = –3.58 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ: 7.40–7.18 (m, 24H); 4.96–4.80 (m, 4H, 2 × PhCH2); 4.67–
4.48 (m, 4H, 2 × PhCH2); 3.74–3.62 (m, 11H); 3.50–3.45 (m, 2H); 3.33–
3.31 (m, 2H); 3.14 (d, J = 14.4 Hz, 1H, -CHCHaHbPh); 2.74 (dd, J1 =
14.0 Hz, J2 = 8.8 Hz, 1H, -CHCHaHbPh); 13C NMR (100 MHz, CDCl3)
δ: 170.6 (amid); 141.1 (C); 138.6 (C); 138.4 (C); 138.27 (C); 138.2 (C);
133.1 (C); 129.8 (CH); 128.6 (CH); 128.5 (CH); 128.4 (CH); 127.9 (CH);
127.8 (CH); 127.79 (CH); 127.7 (CH); 127.6 (CH); 127.1 (CH); 87.4 (CH);
81.6 (CH); 79.8 (CH); 79.0 (CH); 78.7 (CH); 75.6 (CH2); 75.2 (CH2);75.0
(CH2); 73.5 (CH2); 69.0 (CH2); 67.0 (CH2); 37.7 (CH2) ppm. IR (CHCl3):
66.9 (CH2); 48.2 (CH2); 42.6 (CH2) ppm. IR (CHCl3): ν = 3019, 2922,
˜
2861, 2400, 1625, 1455, 1431, 1215, 1111, 1063, 929, 669 cm–1
.
HRMS-ESI: Calcd. For C46H50O8N [M + H]: 744.3536 found 744.3531.
(2R,3S,4R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-di-
hydro-2H-pyran-6-carbaldehyde (24): Yield: 5–10 % in each indi-
vidual case; Rf: 0.2 (EtOAc + Hexanes 4:6); gummy liquid; 1H NMR
(400 MHz, CDCl3) δ: 9.14 (s, 1H, CHO), 7.27–7.15 (m,15 H, ArH ), 5.75
(d, J = 3.2 Hz, olefinic H, 1H), 4.75–4.45 (m, 3 × PhCH2-, 6H), 4.30–
4.28 (dd, J = 10.5 Hz, 1H, CH), 4.10–4.07 (m,1H), 3.94–3.90 (m, 1H),
3.79–3.77 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ: 186.3
(C=O), 151.7 (C) 138.0, 137.9, 137.7, 128.7, 128.5, 128.1, 128.0, 127.8,
117.1(CH), 77.8, 75.8, 74.2, 73.7, 71.7, 67.8 ppm. HRMS-ESI: Calcd for
C28H28O5Na [M + Na]: 467.1834, found 467.1816.
ν = 3020, 3007, 2903, 2857, 1633, 1511, 1454, 1428, 1361, 1277,
˜
1215, 699 cm–1. HRMS-ESI: Calcd. For C46H50O7N [M + H]: 728.3587
found 728.3600.
Morpholino(3-(((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benz-
yloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)methan-
one (19c): Yield: 0.15g (71 %); Rf: 0.3 (EtOAc + Hexanes 4:6); white
gummy solid; [α]3D2 = +1.94 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ: 7.40–7.18 (m, 24H, ArH); 4.96–4.80 (m, 4H, 2 × PhCH2); 4.67–4.48
(m, 4H, 2 × PhCH2); 3.- 3.62 (m, 11H); 3.50–3.45 (m, 2H); 3.33–3.31
General Procedure for De-oxygenation of Compounds 23a-c:
(m, 2H); 3.14 (d, J = 14.4 Hz, 1H, -CHCHaHbPh); 2.74 (dd, J1 =
14.0 Hz, J2 = 8.8 Hz, 1H, -CHCHaHbPh); 13C NMR (100 MHz, CDCl3)
δ: 170.7 (amid); 139.5 (C); 138.6 (C); 138.3 (C); 138.2 (C); 135.2 (C);
131.3 (C); 128.6 (CH); 128.59 (CH); 128.5 (CH); 128.49 (CH); 128.46
(CH); 128.2 (CH); 128.0 (CH); 127.9 (CH); 127.8 (CH); 127.79 (CH);
127.7 (CH); 87.5 (CH); 81.9 (CH); 79.9 (CH); 79.0 (CH); 78.7 (CH); 75.7
(CH2); 75.3 (CH2); 75.1 (CH2); 73.5 (CH2); 69.2 (CH2); 67.0 (CH2); 37.9
Step-I: To a stirred solution of substrates 23a-c in anhydrous aceto-
nitrile (33 mL for 1.0 mmol) under nitrogen atmosphere was added
4-(Dimethylamino) pyridine (DMAP) (5.0 equiv.) and phenyl chloro-
thionocarbonate(PTC-Cl) (2.0 equiv.). The reaction mixture was
stirred at room temperature for 3 to 4h. On completion of reaction,
the reaction mixture was evaporated under reduced pressure, and
the obtained crude residues were purified by silica-gel column chro-
matography. The thiono-carbonates intermediates 25a-c were
obtained in good to excellent yields, 25a (88 %); 25b (90 %); 25c
(93 %).
(CH2) ppm. IR (CHCl3): ν = 3022, 3000, 2905, 2856, 1635, 1514, 1454,
˜
1426, 1361, 1277, 1215, 700 cm–1. HRMS-ESI: Calcd. For C46H49O7N
Na [M + Na]: 750.3407 found 750.3415.
General Procedure for Synthesis of Molecule (29):
Step-II: The above-mentioned compounds 25a-c obtained from
step –I were dissolved in dry toluene (27 mL for 1 mmol) and to
the solution was added tributyltin hydride (nBu3SnH) (2 mmol,
2 equiv.) and AIBN (0.23 equiv.). The reaction mixture was stirred
and heated at 90 °C for 9–10 hours in each individual case. The
toluene in the reaction mixture was removed under vacuum and
(i) 2-Amino-5-iodobenzoic Acid (28): To a mixture of anthranilic
acid 27 (5 g, 36.461 mmol) NaIO4 (7.89 g, 36.461 mmol) and NaCl
(4.26 g, 72.922 mmol) in Acetic acid (110 mL) + H2O (12.0 mL) was
added KI (6.05 g, 36.46 mmol) slowly portion wise over a period of
15 min at room temperature, then stirring was continued at same
temperature for additional 8 to 10 h. Reaction mixture was diluted
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with water (200 mL) followed by extracted into DCM (3 × 100 mL)
with anhydrous sodium sulfate then filtered. The filtrate was con-
then the combined organic extracts were dried with anhydrous so- centrated under vacuum and the resulting crude products were
dium sulfate and filtered, filtrate was evaporated under reduced
pressure furnished the compound 28 in 87 % (8.4 g) as black colour
solid, 1H NMR (500 MHz, [D6]DMSO) δ: 7.90 (d, J = 2.1 Hz, 1H),
7.43(dd, J1 = 8.4 Hz, J2= 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H) ppm.
13C NMR (125 MHz, [D6]DMSO) δ: 168.7 (CO), 151.9(CH), 142.5 (CH),
138.4 (C), 119.5 (CH), 112.4 (C), 74.6 (C) ppm.
purified by silica-gel column chromatography furnished titled com-
pound 30 in good yield as presented below.
2-Chloro-5-((R)-hydroxy((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-
6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl) methyl)-N-
methoxy-N-methylbenzamide (30): Yield: 0.5 g (68 %); Rf: 0.1
(EtOAc + Hexanes 3:7); colourless gummy solid; [α]3D1 = +1.51 (c 1.0,
1
(ii) 2-Chloro-5-iodobenzoic acid (29): To a solution of compound
28 (1g, 3.78 mmol) in acetic acid (AcOH) (13 mL) + concentrate HCl
(10 mL) at 0 °C was added NaNO2 (0.26 g, 3.786 mmol) in 5 mL of
H2O. then stirring was continued at 0 °C for 30 min, finally to this
CHCl3); H NMR (500 MHz, CDCl3) δ: 7.32–7.16 (m, 23H, ArH); 4.96–
4.88 (m, 4H, H-7, PhCH2-, PhCHaHb-); 4.80 (d, J = 10.5 Hz, PhCHaHb-,
1H); 4.75 (d, J = 11.0 Hz,PhCHaHb- 1H); 4.57 (d, J = 10.5 Hz,
PhCHaHb-, 1H); 4.43 (AB quartet, J = 12.0 Hz,PhCH2, 2H); 3.78 (t, J =
reaction mixture CuCl (0.75 g, 7.573 mmol) dissolved in HCl (10 mL) 8.5 Hz, 1H); 3.72 (t, J = 9.0 Hz, 1H); 3.64–3.56 (m, NOMe, H –4, 4H);
was added slowly, then reaction flask was shifted from 0 °C to room
temperature and stirring was continued there for 10 h, reaction
mixture was poured into ice cold water (30 mL) and extracted into
ethyl acetate (2 × 20 mL), then the combined organic extracts were
dried with anhydrous sodium sulfate and filtered, filtrate was con-
centrated under reduced pressure, the obtained crude compound
3.44–3.32 (m, 8H); 13C NMR (125 MHz, CDCl3) δ: 138.67 (C); 138.4
(C); 138.3 (C); 137.9 (C); 134.9 (C); 129.5 (C); 129.2 (CH); 128.6 (CH);
128.5 (CH); 128.48 (CH); 128.3 (C); 127.9 (CH); 127.8 (CH); 127.77
(CH); 127.72 (CH); 127.7 (CH); 127.6 (C); 127.5 (C); 126.0 (CH); 87.1
(CH); 81.4 (CH); 78.9 (CH); 78.4 (CH); 78.3 (CH); 75.6 (CH2); 75(CH2);
75.0 (CH2); 70.6 (CH); 69.0 (CH2); 61.2 (OCH3); 32.4 (CH3) ppm. IR
was purified by column chromatography provided the title com- (CHCl3): ν = 3020, 2925, 2869, 1715, 1448, 1366, 1277, 1215, 1096,
˜
pound 29.
1027, 768 cm–1. HRMS-ESI: Calcd. For C44H47O8N Cl [M + H]:
752.2990 found 752.3003.
Yield:1.0g (93 %); Rf: 0.2 (EtOAc + Hexanes 3:7); light white solid; 1H
NMR (500 MHz, [D6]DMSO) δ: 8.04 (d, J = 2.4 Hz, 1H), 7.84 (dd, J1 = General Procedure for Synthesis of Building Block 16:
8.4 Hz, J2= 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H) ppm. 13C NMR
(125 MHz, [D6]DMSO) δ: 169.1 (CO), 140.2(CH), 139.2 (CH), 133.9 (C),
Step-I: To a stirred solution of compound 30 (0.9 g, 1.111 mmol) in
anhydrous acetonitrile (33 mL) under nitrogen atmosphere was
132.9 (CH), 132.0 (C), 92.9 (C) ppm and this data was well consisted
added 4-(Dimethylamino) pyridine (DMAP) (0.745 g, 6.105 mmol)
with data obtained from commercially available material.
and phenyl chlorothionocarbonate(PTC-Cl) (0.3 mL, 2.442 mmol)
(iii) 2-Chloro-5-iodo-N-methoxy-N-methylbenzamide (26): To a
solution of compound 29 (2 g, 7.078 mmol) in dry DCM (20 mL) +
dry DMF (2 mL) at 0 °C under nitrogen atmosphere was added
and reaction mixture was stirred at room temperature for 3 to 4 h,
reaction mixture was evaporated under reduced pressure and ob-
tained crude residue was purified by column chromatography pro-
thionyl chloride SOCl2 (0.72 mL, 9.909 mmol) then reflux the reac- vided the corresponding intermediates 31 in 90 % yield (0.9 g) as
tion mixture in-between 45 to 50 °C for 6h. Reaction mixture was
shifted to 0 °C followed by Me(MeO)NHHCl (0.82 g, 8.493 mmol)
and Et3N (4.64 mL, 35.39 mmol) were added slowly. Stirring was
continued for additional 3 to 4 h from 0 °C to r.t., reaction mixture
was diluted with water (50 mL) and extracted into DCM (2 × 20 mL),
then the combined organic extracts were dried with anhydrous so-
dium sulfate, filtered and filtrate was evaporated under reduced
pressure, then obtained crude compound was purified by column
chromatography furnished the titled compound 26.
white fluffy solid.
Step-II: Tributyltin hydride (nBu3SnH) (0.5 mL, 1.91 mmol) and AIBN
(0.03 g) were added to a stirred solution of compound 31 (0.85 g,
0.958 mmol) in dry toluene (26 mL). Heat the reaction mixture at
90 °C for 9 to 10h, reaction mixture was evaporated under reduced
pressure and obtained crude compound was purified by using col-
umn chromatography furnished the building block 16.
2-chloro-N-methoxy-N-methyl-5-(((2S,3S,4R,5R,6R)-3,4,5-tris-
(benzyloxy)-6-((benzyloxy) methyl)tetrahydro-2H-pyran-2-yl)-
methyl)benzamide (16): Yield: 0.31 g (75 %); Rf: 0.3 (EtOAc + Hex-
anes 2:8); White solid (mp = 60–62 °C); [α]3D1 = –6.16 (c 0.5, CHCl3);
1H NMR (500 MHz, [D6]DMSO, 100 °C) δ: 7.34–7.20 (m, 23H, ArH);
4.85–4.82 (m, 3H, PhCH2, PhCHaHb); 4.73 (d, J = 11.0 Hz, 1H,
PhCHaHb); 4.67 (d, J = 11.0 Hz, 1H, PhCHaHb); 4.57 (d, J = 11.0 Hz,
1H, PhCHaHb); 4.44 (AB quartet, J = 12.5 Hz, 2H, PhCH2); 3.73 (t, J =
9.0 Hz, 1H, H-5); 3.61–3.54 (m, 3H, H-4, H-6); 3.50–3.41 (m, 4H, H-1,
-OCH3); 3.29 (t, J = 9.5 Hz, 1H, H-2); 3.18 (bs, 4H, H-3, CH3); 3.09 (dd,
J1 = 14.5 Hz, J2 = 2.5 Hz, 1H, -CHCHaHbPh); 2.71 (dd, J1 = 14.5 Hz,
J2 = 8.5 Hz, 1H, -CHCHaHbPh); 13C NMR (125 MHz, [D6]DMSO,
100 °C) δ: 138.4 (C); 138.1 (C); 138.0 (C); 131.1 (C); 129.4 (C); 128.5
(C); 128.1 (C); 128.0 (CH); 127.9 (CH); 127.44 (CH); 127.4 (CH); 127.3
(CH); 127.29 (CH); 127.26 (CH); 127.2 (CH); 127.17 (CH); 127.15 (CH);
127.10 (CH); 127.08 (CH); 127.04 (CH); 126.9 (CH); 85.7 (CH); 81.3
(CH); 78.3 (CH); 78.0 (CH); 77.9 (CH); 74.0 (CH2); 73.6 (CH2); 72.1 (CH2);
Yield: 2.2g (95 % in 82:18 rotamers); Rf: 0.3 (EtOAc + Hexanes 2:8);
light white solid (mp = 76–78 °C); 1H NMR (400 MHz, CDCl3) δ: 7.62
–7.61 (m, 2H); 7.12 (d, J = 8.8 Hz, 1H); 3.86 (s, 0.7 H, -NOCH3); 3.47
(s, 3H, -NOCH3); 3.35 (s, 3H, -NCH3); 3.11 (s, 0.7 H, -NCH3) ppm. 13C
NMR (100 MHz, CDCl3) δ: 166.6 (CO), 139.2 (CH); 137.2 (C); 136.8
(CH); 136.2 (CH); 131.2 (C); 130.7 (C); 90.8 (C); 61.6 (-NOCH3); 32.3 (-
NCH3) ppm. HRMS-ESI: Calcd. For C9H10 N O2 Cl I [M + H]: 325.9445
found 325.9427.
General Procedure for Synthesis of Compound 30:
To a stirred solution of isopropylmagnesium bromide (iPrMgBr) in
dry THF (4 mL) at –15 °C was added aryl iodide 26 (0.425g,
1.358 mmol) dissolved in dry THF (5 mL), then stirring was contin-
ued at the same temperature for 1.5 to 2 h, during this period
reaction mixture colour was changed from colourless to slight yel-
low colour and at this point the nicely azeotroped electrophile 17
(0.5 g, 0.905 mmol) in dry THF (5 mL) was added, then slowly the
reaction temperature was increased from –15° to 0 °C and stirring
was continued there for 8 h. The reaction mixture was quenched
with saturated ammonium chloride solution (25 mL) followed by
extracted with ethyl acetate (2 × 20 mL). The combined organic
layers were washed with water (20 mL), brine (20 mL) and dried
68.9 (CH2); 60.5 (OCH3); 36.4 (CH2) ppm. IR (CHCl3): ν = 3025, 2929,
˜
2870, 1715, 1447, 1368, 1287, 1215, 1096, 1037, 777 cm–1. HRMS-
ESI: Calcd. For C44H47O7N Cl [M + H]: 736.3041 found 736.3060.
General Procedure for Grignard Addition Reaction on Building
Block (16): Various substituted phenylmagnesium bromides were
prepared prior to their use by reaction of commercially available
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substituted bromobenzenes (1.360 mmol) with pre-cleaned magne-
sium metal (0.032g, 1.360 mmol) in dry THF (2 mL) under nitrogen
2H, ArH); 4.94–4.88 (m, 3H, PhCH2, PhCHaHb); 4.81 (d, J = 11.0 Hz,
1H, PhCHaHb); 4.63 (d, J = 11.0 Hz, 1H, PhCHaHb); 4.58 (d, J =
atmosphere, after generation of arylmagnesium bromides, the reac- 10.5 Hz, 1H, PhCHaHb); 4.46 (AB quartet, J = 12.0 Hz, 2H, PhCH2);
tion flask was shifted to 0 °C and to this building block 16 (0.2 g,
0.272 mmol) in dry THF (2 mL) was added, then stirring was contin-
ued at 0 °C to room temperature for 4 to 5 h. reaction mixture was
quenched by caution addition of saturated ammonium chloride so-
lution (15 mL) followed by extracted in to ethyl acetate (2 × 15 mL),
ethyl acetate layer was washed with water (15 mL), brine (15 mL)
and dried with anhydrous sodium sulfate followed by concentrated
under reduced pressure, then obtained crude residues were purified
by silica gel column chromatography provided the corresponding
keto compounds 32a-f in good to excellent yields as presented
below.
3.83 (s, 3H, -OCH3); 3.70 (t, J = 9.0 Hz, 1H, H-5); 3.65–3.59 (m, 3H, H-
4, H-6); 3.45 (t, J = 9.0 Hz, 1H, H-1); 3.42–3.30 (m, 2H, H-2, H-3); 3.10
(d, J = 14.5 Hz, 1H, -CHCHaHbPh); 2.69 (dd, J1 = 14.5 Hz, J2 = 9.0 Hz,
1H, -CHCHaHbPh) ppm. 13C NMR (125 MHz, CDCl3) δ: 194.1 (CO);
164.1 (C); 138.65 (C); 138.60 (C); 138.3 (C); 138.2 (C); 138.1 (C); 137.8
(C); 132.6 (CH); 132.2 (CH); 130.1 (CH); 129.6 (CH); 129.0 (CH); 128.6
(CH); 128.58 (CH); 128.53 (CH); 128.5 (CH); 128.4 (CH); 128.0 (CH);
127.9 (CH); 127.88 (CH); 127.8 (CH); 127.78 (CH); 127.76 (CH); 127.7
(CH); 113.9 (CH); 87.4 (CH); 81.7 (CH); 79.6 (CH); 79.0 (CH); 78.6 (CH);
75.7 (CH2); 75.2 (CH2); 75.1 (CH2); 73.5 (CH2); 69.0 (CH2); 55.6 (OCH3);
37.2 (CH2) ppm. IR (CHCl3): ν = 3019, 2933, 2854, 1658, 1598, 1511,
˜
1455, 1359, 1252, 1216, 700, 669 cm–1. HRMS-ESI: Calcd. For
(2-Chloro-5-(((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyl-
oxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)(p-tolyl)
methanone (32a): Yield: 0.125 g (86 %); Rf: 0.5 (EtOAc + Hexanes
C49H47O7ClNa [M + Na]: 805.3010 found 805.2907.
(4-Butoxyphenyl)(2-chloro-5-(((2S,3S,4R,5R,6R)-3,4,5-tris(benz-
yloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)-
phenyl)methanone (32d): Yield: 0.125 g (81 %); Rf: 0.5 (EtOAc +
Hexanes 2:8); white solid (mp = 70–72 °C); [α]3D2 = –2.845 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.74 (d, J = 9.2 Hz, 2H, ArH);
7.31–7.21 (m, 21H, ArH); 7.18–7.16 (m, 2H, ArH); 6.87 (d, J = 8.8 Hz,
2H, ArH); 4.94–4.85 (m, 3H, PhCH2, PhCHaHb); 4.80 (d, J = 10.8 Hz,
1H, PhCHaHb); 4.63 (d, J = 11.2 Hz, 1H, PhCHaHb); 4.58 (d, J =
10.8 Hz, 1H, PhCHaHb); 4.46 (AB quartet, J = 12.0 Hz, 2H, PhCH2);
3.99 (t, J = 6.4 Hz, 2H, -OCH2CH2-); 3.70 (t, J = 8.8 Hz, 1H, H-5); 3.68–
3.58 (m, 3H, H-4, H-6); 3.44 (td, J1 = 8.8 Hz, J2 = 1.6 Hz, 1H, H-1);
3.34–3.29 (m, 2H, H-2, H-3); 3.10 (dd, J1 = 14.0 Hz, J2 = 1.6 Hz, 1H,
-CHCHaHbPh); 2.68 (dd, J1 = 14.4 Hz, J2 = 9.2 Hz, 1H, -CHCHaHbPh);
1.77 (quintet, J = 7.2 Hz, 2H, -OCH2CH2CH2CH3); 1.48 (sextet,
J = 7.6 Hz, 2H, -OCH2CH2CH2CH3); 0.97 (t, J = 7.6 Hz, 3H,
-OCH2CH2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3) δ: 194.1 (CO);
163.8 (C); 138.7 (C); 138.6 (C); 138.3 (C); 138.27 (C); 138.2 (C); 137.8
(C); 132.7 (CH); 132.2 (CH); 130.1 (CH); 129.7 (CH); 129.5 (CH); 129.0
(CH); 128.65 (CH); 128.6 (CH); 128.55 (CH); 128.5 (CH); 128.48 (CH);
128.0 (CH); 127.9 (CH); 127.83 (CH); 127.8 (CH); 127.7 (CH); 114.4
(CH); 87.4 (CH); 81.7 (CH); 79.7 (CH); 79.0 (CH); 78.7 (CH); 75.7 (CH2);
75.3 (CH2); 75.1 (CH2); 73.6 (CH2); 69.0 (CH2); 68.1 (CH2); 37.2 (CH2);
1
2:8); white solid (mp = 90 –92 °C); [α]3D2 = –2.497 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ: 7.68 (d, J = 8.0 Hz, 2H, ArH); 7.32–7.16 (m,
25H, ArH); 4.94–4.86 (m, 3H, PhCH2, PhCHaHb); 4.81 (d, J = 10.8 Hz,
1H, PhCHaHb); 4.62 (d, J = 11.2 Hz, 1H, PhCHaHb); 4.57 (d, J =
10.8 Hz, 1H, PhCHaHb); 4.46 (AB quartet, J = 12.0 Hz, 2H, PhCH2);
3.70 (t, J = 8.8 Hz, 1H, H-5); 3.65–3.57 (m, 3H, H-4, H-6); 3.43 (t, J =
8.8 Hz, 1H, H-1); 3.41–3.29 (m, 2H, H-2, H-3); 3.09 (d, J = 14.4 Hz,
1H. –CHCHaHbPh); 2.68 (dd, J1 = 14.4 Hz, J2 = 9.2 Hz, 1H,
-CHCHaHbPh); 2.40 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3) δ:
195.2 (CO); 144.7 (C); 138.6 (C); 138.5 (C); 138.27 (C); 138.2 (C); 138.15
(C); 137.8 (C); 134.2 (C); 132.4 (CH); 130.4 (CH); 130.2 (CH); 129.7
(CH); 129.4 (CH); 129.0 (CH); 128.64 (CH); 128.64 (CH); 128.6 (CH);
128.55 (CH); 128.51 (CH); 128.48 (CH); 128.0 (CH); 127.9 (CH); 127.83
(CH); 127.80 (CH); 127.7 (CH); 87.4 (CH); 81.6 (CH); 79.6 (CH); 79.0
(CH); 78.6 (CH); 75.7 (CH2); 75.3 (CH2); 75.1 (CH2); 73.5 (CH2); 69.0
(CH2); 37.1 (CH2); 21.9 (CH3) ppm. IR (CHCl3): ν = 3020, 2933, 2847,
˜
1659, 1604, 1473, 1416, 1215, 928, 669 cm–1. HRMS-ESI: Calcd. For
C49H47O6ClNa [M + Na]: 789.3061 found 789.2248.
(2-Chloro-5-(((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyl-
oxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)(4-ethyl-
phenyl)methanone (32b): Yield: 0.110 g (80 %); Rf: 0.5 (EtOAc +
Hexanes 2:8); white solid (mp = 66–68 °C); [α]3D2 = +0.22 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 8.0 Hz, 2H, ArH);
7.31–7.16 (m, 25H, ArH); 4.94–4.85 (m, 3H, PhCH2, PhCHaHb); 4.80
(d, J = 10.8 Hz, 1H, PhCHaHb); 4.62 (d, J = 11.2 Hz, 1H, PhCHaHb);
4.58 (d, J = 10.8 Hz, 1H, PhCHaHb); 4.46 (AB quartet, J = 12.0 Hz,
2H, PhCH2); 3.70 (t, J = 9.2 Hz, 1H, H-5); 3.65–3.58 (m, 3H, H-4, H-6);
3.43 (t, J = 8.8 Hz, 1H, H-1); 3.34–3.30 (m, 2H, H-2, H-3); 3.10 (d, J =
14.0 Hz, 1H, -CHCHaHbPh); 2.72–2.66 (m, 3H, -CHCHaHb, -CH2CH3);
1.24 (t, J = 7.6 Hz, 3H, -CH2CH3) ppm. 13C NMR (100 MHz, CDCl3) δ:
195.16 (CO); 150.8 (C); 138.6 (C); 138.55 (C); 138.3 (C); 138.27 (C);
138.2 (C); 137.8 (C); 134.4 (C); 132.4 (C); 130.5 (CH); 130.2 (CH); 129.7
(CH); 129.1 (C); 128.63 (CH); 128.6 (CH); 128.5 (CH); 128.4 (CH); 128.2
(CH); 128.00 (CH); 127.9 (CH); 127.8 (CH); 127.77 (CH); 127.7 (CH);
87.4 (CH); 81.7 (CH); 79.7 (CH): 79.0 (CH); 78.7 (CH); 75.7 (CH2); 75.2
(CH2); 75.1 (CH2); 73.6 (CH2); 69.0 (CH2); 37.2 (CH2); 29.1 (CH2);
31.2 (CH ); 19.3 (CH ); 13.9 (CH ) ppm. IR (CHCl ): ν = 3022, 2943,
˜
2
2
3
3
2869, 1658, 1598, 1477, 1455, 1254, 1217, 1169, 699, 624 cm–1
.
HRMS-ESI: Calcd. For C52H53ClO7Na Cl [M + Na]: 847.3479 found
847.3642.
Benzo[d][1,3]dioxol-5-yl(2-chloro-5-(((2S,3S,4R,5R,6R)-3,4,5-
tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-
yl)methyl)phenyl)methanone (32e): Yield: 0.2 g (93 %); Rf: 0.5
(EtOAc + Hexanes 2:8); light white solid (mp = 78–80 °C) [α]D32
=
–1.91 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.35–7.17 (m, 25H,
ArH); 6.76 (d, J = 8.0 Hz, 1H, ArH); 6.01 (s, 2H, -OCH2O-); 4.94–4.85
(m, 3H, PhCH2, PhCHaHb); 4.81 (d, J = 10.4 Hz, 1H, PhCHaHb); 4.63
(d, J = 11.2 Hz, 1H, PhCHaHb); 4.58 (d, J = 10.8 Hz, 1H, PhCHaHb);
4.47 (AB quartet, J = 12.0 Hz, 2H, PhCH2); 3.72–3.59 (m, 4H, H-6, H-
5, H-4); 3.43 (t, J = 8.8 Hz, 1H, H-1); 3.33–3.29 (m, 2H, H-3, H-2); 3.09
(d, J = 14.0 Hz, 1H, -CHCHaHbAr); 2.68 (dd, J1 = 14.0 Hz, J2 = 8.8 Hz,
1H, -CHCHaHbAr) ppm. 13C NMR (100 MHz, CDCl3) δ: 193.7 (CO);
152.5 (C); 148.4 (C); 138.6 (C); 138.5 (C); 138.2 (C); 137.8 (C); 132.3
(CH); 131.5 (C); 130.0 (C); 129.7 (CH); 128.9 (CH); 128.64 (CH); 128.6
(CH); 128.5 (CH); 128.0 (CH); 127.9 (CH); 127.8 (CH); 127.78 (CH);
127.75 (CH); 127.7 (CH); 109.2 (CH): 108.0 (CH); 102.1 (CH2); 87.4
(CH): 81.7 (CH); 79.66 (CH); 79.0 (CH); 78.7 (CH); 75.7 (CH2); 75.2
(CH2); 75.1 (CH2); 73.5 (CH2); 69.0 (CH2); 37.2 (CH2) ppm. IR (CHCl3):
15.2 (CH3) ppm. IR (CHCl3): ν = 3020, 2967, 2925, 2867, 1667, 1604,
˜
1454, 1356, 1215, 766, 700, and 671 cm–1. HRMS-ESI: Calcd. For
C50H49O6ClNa [M + Na]: 803.3217 found 803.3116.
(2-Chloro-5-(((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyl-
oxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)(4-meth-
oxyphenyl)methanone (32c): Yield: 0.15 g (73 %); Rf: 0.5 (EtOAc +
Hexanes 2:8); white solid (mp = 98–100 °C); [α]3D2 = –1.93 (c 1.0, ν = 3020, 2917, 2861, 1652, 1605, 1442, 1359, 1293, 1258, 1215,
˜
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.76 (d, J = 9.0 Hz, 2H, ArH);
7.31–7.22 (m, 20H, ArH); 7.18–7.17 (m, 3H, ArH); 6.88 (d, J = 8.5 Hz,
1096, 623 cm–1. HRMS-ESI: Calcd. For C49H45O8ClNa [M + Na]:
819.2803 found 819.2702.
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(2-Chloro-5-(((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyl-
oxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)(4-ethoxy-
phenyl)methanone (32f): Yield: 0.13 g (80 %); Rf: 0.4 (EtOAc + Hex-
anes 2:8); white solid (mp = 94–96 °C); [α]3D2 = –2.46 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 8.8 Hz, 2H, ArH); 7.34–7.18
(m, 23H, ArH); 6.89 (d, J = 8.4 Hz, 2H, ArH); 4.96–4.90 (m, 3H, PhCH2,
PhCHaHb); 4.82 (d, J = 10.8 Hz, 1H, PhCHaHb); 4.65 (d, J = 11.2 Hz,
1H, PhCHaHb); 4.60 (d, J = 10.8 Hz, 1H, PhCHaHb); 4.48 (AB quartet,
J = 12.0 Hz, 2H, PhCH2); 4.08 (q, J = 7.2 Hz, 2H, -OCH2CH3); 3.72 (t,
J = 8.4 Hz, 1H, H-5); 3.67–3.60 (m, 3H, H-4, H-6); 3.46 (t, J = 9.2 Hz,
1H, H-1); 3.36–3.32 (m, 2H, H-2, H-3); 3.12 (d, J = 14.4 Hz, 1H,
-CHCHaHbPh); 2.70 (dd, J1 = 14.4 Hz, J2 = 9.2 Hz, 1H, -CHCHaHbPh);
1.44 (t, J = 6.8 Hz, 3H, -OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3)
δ: 194.1 (CO); 163.6 (C); 138.6 (C); 138.3 (C); 138.2 (C); 138.15 (C);
137.7 (C); 132.7 (CH); 132.2 (CH); 130.1 (CH); 129.7 (CH); 129.5 (C);
129.0 (C); 128.64 (CH); 128.6 (CH); 128.55 (CH); 128.5 (CH); 128.4
(CH); 128.0 (CH); 127.9 (CH); 127.8 (CH); 127.4 (CH); 127.7 (CH); 87.4
(CH); 81.6 (CH); 79.6 (CH); 79.0 (CH); 78.6 (CH); 75.7 (CH2); 75.2 (CH2);
75.1 (CH2); 73.5 (CH2); 68.9 (CH2); 63.9 (CH2); 37.1 (CH2); 14.7 (CH3)
Ha); 3.39–3.10 (m, 3H); 3.25 (d, J = 9.6 Hz, 1H, H-1); 3.21 (d, J =
6.0 Hz, 1H, -CHCHaHbAr); 3.16–3.10 (m, 2H); 3.05 (t, J = 9.2 Hz, H-
2); 2.78 (dd, J1 = 14.4 Hz, J2 = 8.4 Hz, 1H, -CHCHaHbAr) ppm. 13C
NMR (100 MHz, CD3OD) δ: 198.1 (CO); 168.0 (C); 141.5 (C); 135.7
(CH); 133.3 (CH); 132.6 (CH); 132.5 (CH); 131.5 (C); 117.1 (CH); 83.5
(CH); 83.1 (CH); 81.8 (CH); 76.6 (CH); 73.8 (CH); 64.9 (CH2); 58.2
(OCH3); 39.9 (CH2) ppm. IR (CHCl3): ν = 3020, 2925, 2844, 1652, 1598,
˜
1427, 1216, 1118, 1090, 1023, 929, 669 cm–1. HRMS-ESI: Calcd. For
C21H23O7 Cl [M + H]: 423.1172 found 423.1205.
(2-Chloro-5-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxy-
methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)(4-ethoxy-
phenyl)methanone (33f): Yield: 0.07 g (86 %); Rf: 0.3 (MeOH +
DCM 2:8); white solid (mp = 166–168 °C); [α]3D2 = +1.96 (c 1.0, CHCl3);
1H NMR (400 MHz, [D6]DMSO) δ: 7.67 (d, J = 7.0 Hz, 2H, ArH); 7.44
(bs, 2H, ArH); 7.28 (s, 1H, ArH); 7.03 (d, J = 7.5 Hz, 2H); 4.11 (bs, 2H,
OCH2CH3); 3.55 (d, J = 10.5 Hz, 1H, H-6, Hb); 3.34 (d, J = 8.5 Hz, 1H,
H-6, Ha); 3.25 (bs, 1H); 3.16 (bs, 1H, H-1); 3.07 (d, J = 14.1 Hz, 1H,
-CHCHaHbAr); 3.01 (bs, 2H); 2.90 (bs 1H, -CHCHaHbAr); 2.65 (dd. J1 =
11.9 Hz, J2 = 7.4 Hz, 1H, -CHCHaHbAr); 1.32 (bs, 3H, -OCH2CH3) ppm.
13C NMR (100 MHz, [D6]DMSO) δ: 193.4 (CO); 163.6 (C); 138.9 (C);
138.2 (C); 132.8 (CH); 132.6 (CH); 130.2 (CH); 129.6 (CH); 129.1 (C);
127.5 (C); 115.1 (CH); 81.0 (CH); 79.6 (CH); 78.6 (CH); 73.5 (CH); 70.9
(CH); 64.2 (CH2); 61.8 (CH2); 36.9 (CH2); 14.9 (CH3) ppm. IR (CHCl3):
ppm. IR (CHCl3): ν = 3020, 2925, 2858, 1659, 1591, 1513, 1313, 1254,
˜
1170, 1048, 846, 699 cm–1. HRMS-ESI: Calcd. For C50H49O7Na N Cl
[M + Na]: 819.3166 found 819.3057.
General Procedure for De-benzylation of Compounds 32a-f: To
a solution of above all keto compounds (32a-f) in MeOH/EtOAc
(1:1) (3 mL for 0.208 mmol) was added 10 % Pd-C (0.15 equiv.) fol-
lowed by 1,2 dichloro benzene (20 equiv.) then de-gassed the reac-
tion mixture with hydrogen gas for two times then stirring was
continued at room temperature under hydrogen balloon condition
for 24 h. This condition yielded de-benzylated keto compounds
(33a, 33c, 33f). With the use of Parr hydrogenation apparatus and
hydrogen pressure of 40-PSI, complete reduction occurred and the
products 15a-e and 14 were obtained. The reaction work-up in-
cluded filtration through celite bed and concentration of the filtrate
under reduced pressure. The obtained crude product residues were
purified by silica-gel column chromatography using 5–10 % meth-
anol in dichloromethane as mobile phase.
ν = 3345, 2928, 2855, 1655, 1600, 1435, 1217, 1119, 1050, 1023,
˜
987, 675 cm–1. HRMS-ESI: Calcd. For C22H25O7Na Cl [M + Na]:
459.1187 found 459.1172.
(2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-methylbenzyl)benzyl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (15a): Yield:
0.023 g (82 %); Rf: 0.4 (MeOH + DCM 1:9); white gummy solid;
1
[α]3D2 = –10.76 (c 1.0, CHCl3); H NMR (400 MHz, CD3OD) δ: 7.22 (d,
J = 8.0 Hz, 1H, ArH); 7.19 (bs, 1H, ArH); 7.14–7.11 (m, 1H, ArH); 7.05
(bs, 4H, ArH); 3.99 (bs, 2H, ArCH2Ar); 3.72 (dd, J1 = 12.0 Hz, J2 = 2.0,
1H, H-6, Hb); 3.58 (dd, J1 = 11.6 Hz, J2 = 5.2 Hz, 1H, H-6, Ha); 3.29–
3.20 (m, 4H); 3.10–3.01 (m, 3H); 2.64(dd, J1 = 14.4 Hz, J2 = 8.4 Hz,
1H, -CHCHaHbAr); 2.27 (s, 3H, -CH3); 13C NMR (100 MHz, CD3OD) δ:
140.4 (C); 140.2 (C); 138.9 (C); 137.5 (C); 134.5 (C); 133.6 (CH); 131.0
(CH); 130.8 (CH); 130.7 (CH); 130.6 (CH); 82.2 (CH); 80.7 (CH); 75.6
(CH); 72.7 (CH); 63.8 (CH2); 40.4 (CH2); 38.8 (CH2); 21.9 (CH3) ppm. IR
(2-Chloro-5-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxy-
methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)(p-tolyl)meth-
anone (33a): Yield: 0.04 g (81 %); Rf: 0.3 (MeOH + DCM 1:9); white
solid (mp = 152–154 °C); [α]3D2 = –8.07 (c 1.0, CHCl3); 1H NMR
(CHCl3): ν = 3380, 3020, 2922, 2851, 1512, 1476, 1421, 1215, 1088,
˜
1039, 767, 669 cm–1. HRMS-ESI: Calcd. For C21H25ClO5Na [M + Na]:
415.1390 found 415.1288.
(500 MHz, CD3OD) δ: 7.69 (d, J = 8.0 Hz, 2H, ArH); 7.49 (dd, J1
=
8.5 Hz, J2 = 2.0 Hz, 1H, ArH); 7.41 (d, J = 8.0 Hz, 1H, ArH); 7.37 (d,
J = 2.0 Hz, 1H, ArH); 7.34 (d, J = 8.0 Hz, 2H, ArH); 3.76 (dd, J1=
11.5 Hz, 1H, H-6, Hb); 3.60 (dd, J1 = 11.5 Hz, J2 = 5.0 Hz, 1H, H-6,
Ha); 3.40–3.33 (m, 4H, H-3, H-4, 2 × OH); 3.26 (t, J = 9.5 Hz, 1H, H-
1); 3.22 (dd, J1 = 14.5 Hz, J2 = 2.0 Hz, 1H, -CHCHaHbAr); 3.18–3.14
(m,1H, H-5); 3.10 (t, J = 9.0 Hz, 1H, H-2); 2.80 (dd, J1 = 14.5 Hz, J2 =
8.0 Hz, 1H, -CHCHaHbAr); 2.44 (s, 3H, -CH3) ppm. 13C NMR (125 MHz,
CD3OD) δ: 195.6 (CO); 145.0 (C); 138.2 (C); 138.0 (C); 133.9 (C); 132.4
(CH); 130.0 (CH); 129.9 (CH); 129.1 (CH); 128.2 (CH); 80.1 (CH); 79.7
(CH); 78.4 (CH); 73.2 (CH); 70.4 (CH); 61.5 (CH2); 36.5 (CH2); 20.3 (CH3)
(2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-ethylbenzyl)benzyl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (15b): Yield:
0.06 g (83 %); Rf: 0.4 (MeOH + DCM 1:9); white solid (mp = 56–
58 °C); [α]3D2 = –11.54 (c 1.0, CHCl3); 1H NMR (400 MHz, CD3OD) δ:
7.27–7.24 (m, 2H, ArH); 7.16 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H, ArH);
7.10 (bs, 4H, ArH); 4.03 (bs, 2H, ArCH2Ar); 3.74 (dd, J1 = 11.6 Hz, J2 =
2.0 Hz, 1H, H-6, Hb); 3.60 (dd, J1 = 12.0 Hz, J2 = 5.6 Hz, 1H, H-6, Ha);
3.35–3.30 (m, 4H); 3.26 (t, J = 8.8 Hz, 1H, H-1); 3.14–3.05 (m, 3H);
2.68 (dd, J1 = 14.4 Hz, J2 = 8.4 Hz, 1H, -CHCHaHbAr); 2.60 (q, J =
7.6 Hz, 2H, -CH2CH3); 1.21 (t, J = 7.6 Hz, 3H, -CH2CH3) ppm. 13C NMR
(100 MHz, CD3OD) δ: 144.0 (C); 140.4 (C); 140.2 (C); 139.2 (C); 134.6
(C); 133.6 (CH); 131.0 (CH); 130.8 (CH); 130.7 (CH); 129.7 (CH); 82.2
(CH); 80.7 (CH); 75.6 (CH); 72.7 (CH); 63.8 (CH2); 40.4 (CH2); 38.8 (CH2);
ppm. IR (CHCl3): ν = 3022, 2925, 1658, 1650, 1563, 1452, 1218, 1086,
˜
770, 671 cm–1. HRMS-ESI: Calcd. For C21H23O6ClNa [M + Na]:
429.1183 found 429.1083.
30.3 (CH3); 17.0 ppm. IR (CHCl3): ν = 3465, 3020, 1512, 1477, 1421,
˜
(2-Chloro-5-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxy-
methyl)tetrahydro-2H-pyran-2-yl)methyl)phenyl)(4-methoxy-
phenyl)methanone (33c): Yield: 0.072 g (90 %); Rf: 0.3 (MeOH +
1215, 1090, 1035, 924, 767, 669, 623 cm–1. HRMS-ESI: Calcd. For
C22H27O5Na Cl [M + Na]: 429.1445 found 429.1415.
DCM 2:8); white solid (mp = 158–160 °C); [α]3D2 = –16.66 (c 1.0, (2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-methoxybenzyl)benzyl)-6-
1
CHCl3); H NMR (400 MHz, CD3OD) δ: 7.75 (d, J = 8.4 Hz, 2H, ArH);
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (15c): Yield:
7.45 (d, J = 8.4 Hz, 1H, ArH); 7.38 (d, J = 8.4 Hz, 1H, ArH); 7.34 (s, 0.055 g (82 %); Rf: 0.4 (MeOH+ DCM 1.5:8.5); light white solid (mp =
1H, ArH); 7.01 (d, J = 8.4 Hz, 2H, ArH); 3.88 (s, 3H, -OCH3); 3.74 (d,
J = 10.8 Hz, 1H, H-6, Hb); 3.59 (dd, J1 = 12.0 J2 = 5.2 Hz, 1H, H-6,
102–104 °C), [α]3D2 = –30.93 (c 1.0, CHCl3); 1H NMR (400 MHz, CD3OD)
δ: 7.26–7.23 (m, 2H, ArH); 7.17–7.11 (m, 3H, ArH); 6.83 (d, J = 7.6 Hz,
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2H, ArH); 4.00 (bs, 2H, ArCH2Ar); 3.77–3.74 (m, 4H, -OCH3, H-6); 3.63
(dd, J1 = 10.8 Hz, J2 = 4.0 Hz, 1H, H-6); 3.34–3.25 (m, 4H, H-1, H-4,
Acknowledgments
R. M. is thankful to the Council of Scientific and Industrial re-
search (CSIR), New Delhi for a fellowship. S. K. B. is thankful to
the Translational Health Science and Technology Institute
H-5, OH); 3.14–3.06 (m, 3H, -CHCHaHbAr, H-2, H-3); 2.70 (dd, J1
=
14.0 Hz, J2 = 8.4 Hz, 1H, -CHCHaHbAr); 13C NMR (100 MHz, CD3OD)
δ: 159.5 (C); 139.7 (C); 139.3 (C); 133.6 (CH); 133.1 (C); 132.6 (C);
130.8 (CH); 130.1 (CH); 129.9 (CH); 114.8 (CH); 81.31 (CH); 79.8 (CH); (THSTI), Faridabad, India for providing THSTI core fund and facil-
74.7 (CH); 71.8 (CH); 62.9 (CH2); 55.6 (OCH3); 39.1 (CH2); 37.9 (CH2)
ity to carry out this work.
ppm. IR (CHCl3): ν = 3426, 3020, 2918, 2861, 1612, 1512, 1476, 1424,
˜
1215, 1088, 1036, 928, 669 cm–1. HRMS-ESI: Calcd. For C21H25O6ClNa
[M + Na]: 431.1339 found 431.1235.
Keywords: Dapagliflozin · Phlorizin · Type 2 diabetes ·
SGLT2 inhibitors · C-Benzyl glucosidese
(2S,3R,4R,5S,6R)-2-(3-(4-Butoxybenzyl)-4-chlorobenzyl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (15d): Yield:
0.05 g (80 %); Rf: 0.4 (MeOH + DCM 2:8); white gummy solid; [α]D32
=
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–1.48 (c 1.0, CHCl3); 1H NMR (500 MHz, CD3OD) δ: 7.25 (d, J = 8.0 Hz,
1H, ArH); 7.22 (d, J = 1.5 Hz, 1H, ArH); 7.16 (dd, J1 = 8.0 Hz, J2
=
2.0 Hz, 1H, ArH); 7.10 (d, J = 8.5 Hz, 2H, ArH); 6.82 (d, J = 8.5 Hz,
2H, ArH); 3.99 (bs, 2H, ArCH2 Ar); 3.94 (t, J = 6.5 Hz, 2H,
-OCH2(CH2)3CH3); 3.74 (dd, J1 = 12.0 Hz, J2 = 2.5 Hz, 1H, Hb, H-6);
3.61 (dd, J1 = 12.0 Hz, J2 = 5.5 Hz, 1H, H-6,Ha); 3.34–3.30 (m, 4H);
3.26 (t, J = 9.5 Hz, 1H, H-1); 3.14–3.10 (m, 2H); 3.07 (t, J =
9.0 Hz, 1H, -CHCHaHbAr); 2.68 (dd, J1 = 14.5 Hz, J2 = 8.5 Hz, 1H,
-CHCHaHbAr); 1.74 (quintet, J = 7.0 Hz, 2H, -OCH2CH2CH2CH3); 1.51
(sextet, J = 7.5 Hz, 2H, -OCH2CH2CH2CH3); 0.99 (t, J = 7.5 Hz, 3H,
-OCH2CH2CH2CH3) ppm. 13C NMR (125 MHz, CD3OD) δ: 157.6 (C);
138.4 (C); 137.9 (C); 132.2 (CH); 131.7 (C); 131.3 (C); 129.4 (CH); 128.7
(CH); 128.5 (CH); 114.0 (CH); 79.9 (CH); 78.4 (CH); 73.3 (CH); 70.4 (CH);
67.3 (CH2); 61.5 (CH2); 37.7 (CH2); 36.6 (CH2); 31.2 (CH2); 18.9 (CH2);
12.8 (CH3) ppm. IR (CHCl3): ν = 3443, 3020, 1651, 1216, 1090, 1024,
˜
770, 669 cm–1. HRMS-ESI: Calcd. For C24H31O6 Cl Na [M + Na]:
473.1809 found 473.1706.
(2S,3R,4R,5S,6R)-2-(3-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-chloro-
benzyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
(15e): Yield: 0.05 g (83 %); Rf: 0.5 (MeOH + DCM 1.5:8.5); brown
colour gummy solid; [α]D32 = –18.24 (c 1.0, CHCl3); 1H NMR (400 MHz,
CD3OD) δ: 7.25 (d, J = 8.0 Hz, 1H, ArH); 7.23 (d, J = 2.0 Hz, 1H, ArH);
7.16 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H, ArH); 6.73–6.70 (m, 1H, ArH);
6.68–6.66 (m, 2H, ArH); 5.88 (s, 2H, -OCH2O-); 3.97 (s, 2H, ArCH2Ar);
3.76 (dd, J1 = 12.0 Hz, J2 = 2.4 Hz, 1H, H-6, Hb); 3.62 (dd, J1
=
11.6 Hz, J2 = 5.2 Hz, 1H, H-6, Ha); 3.33–3.25 (m, 4H); 3.17–3.06 (m,
3H); 2.68 (dd, J1 = 14.4 Hz, J2 = 8.4 Hz, 1H, -CHCHaHbAr) ppm. 13C
NMR (100 MHz, CD3OD) δ: 149.0 (C); 147.3 (C); 139.5 (C); 139.4 (C);
135.0 (C); 133.6 (CH); 132.6 (CH); 130.3 (CH); 129.9 (CH); 122.8 (CH);
110.2 (CH); 108.9 (CH); 102.0 (CH2); 81.3 (CH); 79.8 (CH); 74.7 (CH);
71.8 (CH); 62.9 (CH ); 39.6 (CH ); 37.9 (CH ) ppm. IR (CHCl ): ν =
˜
2
2
2
3
3402, 3020, 2924, 2886, 1605, 1504, 1486, 1441, 1215, 1091, 1040,
929 cm–1. HRMS-ESI: Calcd. For C21H23O7 Cl Na [M + Na]: 445.1132
found 445.1031.
(2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-ethoxybenzyl)benzyl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (14): Yield:
0.07 g (84 %); Rf: 0.4 (MeOH + DCM 2:8); white solid (mp = 90–
92 °C); [α]3D2 = –14.36 (c 1.0, CHCl3); 1H NMR (500 MHz, CD3OD) δ:
7.25 (d, J = 8.0 Hz, 2H, ArH); 7.22 (s, 1H, ArH); 7.15 (d, J = 8.0 Hz,
1H, ArH); 7.10 (d, J = 7.5 Hz, 1H, ArH); 6.81 (d, J = 7.0 Hz, 2H); 4.00–
3.99 (m, 4H, -OCH2, ArCH2Ar); 3.75 (d, J = 11.5 Hz, 1H, -CHaHb, H-
6); 3.62 (dd, J1 = 12.0 Hz, J2 = 5.0 Hz, 1H, -CHaHb, H-6); 3.35–3.25
(m, 4H); 3.13–3.06 (m, 3H); 2.69 (dd, J1 = 14.0 Hz, J2 = 8.5 Hz, 1H,
-CHCHaHbAr); 1.37 (t, J = 7.0 Hz, 3H, -OCH2CH3); 13C NMR (125 MHz,
CD3OD) δ: 158.8 (C); 139.8 (C); 139.3 (C); 133.6 (C); 133.1 (C); 132.6
(CH); 130.8 (CH); 130.1 (CH); 129.9 (CH); 115.4 (CH); 81.3 (CH); 79.8
(CH); 74.7 (CH); 71.8 (CH); 64.4 (CH2); 62.9 (CH2); 39.1 (CH2); 37.9
(CH2); 15.2 (CH3) ppm. IR (CHCl3): ν = 3364, 3019, 1613, 1473, 1424,
˜
1213, 1081, 1042, 924, 770, 671 cm–1. HRMS-ESI: Calcd. For
C22H27O6ClNa [M + Na]: 445.1496 found 445.1395.
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[21]
[22]
See the supporting information for complete assignment of stereochem-
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Received: January 10, 2020
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Benzyl C-Analogues of
Dapagliflozin
R. Mukkamala, R. Kumar,
S. K. Banerjee, I. S. Aidhen* .......... 1–13
Synthesis of Benzyl C-Analogues of
Dapagliflozin as Potential SGLT2 In-
hibitors
A convenient synthetic strategy has promising results, particularly, com-
been developed for the synthesis of pound 14 emerged as the most potent
C-benzyl analogues of dapagliflozin. SGLT2 inhibitor with the best selectivity
The In vitro sodium-glucose co-trans- for inhibition of SGLT2 (IC50:0.64 n )
M
porters (SGLT1 and SGLT2) inhibition over SGLT1 (IC50: 500 n
M) as compare
activity of all new compounds exhibits - to Dapagliflozin.
DOI: 10.1002/ejoc.202000025
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