Deleterious effect of 7-methyl group on glycosylation of 2-naphthols

Article abstract of DOI:10.1016/j.tet.2015.06.045

C-Glycosylations of several 2-naphthols with different glycosyl donors have been investigated in the pursuit of the total synthesis of mayamycin (1). While glycosylations of the parent 2-naphthol are readily achievable, those of 5-methoxy-7-methyl-2-napht

Full text of DOI:10.1016/j.tet.2015.06.045

Accepted Manuscript
Deleterious effect of 7-methyl group on glycosylation of 2-naphthols
Prithiba Mitra, Subhajit Mandal, Soumen Chakraborty, Dipakranjan Mal
PII:
S0040-4020(15)00915-1
10.1016/j.tet.2015.06.045
TET 26881
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 May 2015
Revised Date: 10 June 2015
Accepted Date: 11 June 2015
Please cite this article as: Mitra P, Mandal S, Chakraborty S, Mal D, Deleterious effect of 7-methyl group
on glycosylation of 2-naphthols, Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.045.
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ACCEPTED MANUSCRIPT
Deleterious effect of 7-methyl group on glycosylation of 2-naphthols
Prithiba Mitra, Subhajit Mandal, Soumen Chakraborty, and Dipakranjan Mal*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
Corresponding Author E-mail: dmal@chem.iitkgp.ernet.in
ABSTRACT
C-Glycosylations of several 2-naphthols with different glycosyl donors have been investigated in
the pursuit of the total synthesis of mayamycin (1). While glycosylations of the parent 2-
naphthol are readily achievable, those of 5-methoxy-7-methyl-2-naphthol (6) embodying the
target are ineffective under different Lewis acidic conditions. The inefficiency of the
glycosylation of 6 has been attributed to the steric effect exerted by C7 methyl group, which was
corroborated by glycosylation studies of different 2-naphthols.
Keywords: C-Glycosylation, 2-naphthol, Lewis acid, steric effect.
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1. Introduction
Mayamycin (1)1 was isolated in 2010 by Imhoff et al. from the culture of marine Streptomycin
sp. stain HB202. It exhibited potent cytotoxic activities against eight different human cancer cell
lines and showed activity against several bacteria including antibiotic-resistant strains with IC50
values ranging between 0.13-0.33 ꢀM.
Figure 1. Structure of mayamycin (1)
2
1
HO
3
O
4
5
O
OH
O
OH
HN
Mayamycin (1)
OH
In addition, it has antiproliferative activities toward the mouse fibroblast cell line NIH-3T3
with an IC50 value of 0.22 ꢀM, which is 100-fold more potent than the clinical drug tamoxifen.
The unusual structural architecture of 1 along with its remarkable antibacterial and antitumor
activities prompted us to undertake its total synthesis. Recently, we reported a route for the
synthesis of angucycline C5 glycoside 2 via C-glycosylation of 2-naphthols.2 Oxidative
dearomatization of C1-glycosyl-2-naphthol 3 and Hauser annulation of 4 were the key steps of
the strategy (Scheme 1).
Scheme 1. General synthesis route of angucycline C5 glycosides
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Extension of this strategy to the total synthesis of mayamycin (1) required the C-glycosyl
naphthol 5. However, its synthesis was impeded by the failure of the C-glycosylation of the
corresponding naphthol 6 with various glycosyl donors 7 (Scheme 2).
Scheme 2. Synthetic analysis of mayamycin (1)
Herein, we report synthesis of the naphthol 6 and its analogs, and their reactivity profiles
towards C-glycosylation with three glycosyl donors.
.
2. Results and discussion
The required naphthol 6 was previously synthesized in 11 steps from commercially available
3,4-dimethylanisole.3 In the present work, a short synthesis of 6 was achieved by combined
Scheme 3: Synthesis of naphthol 6
Reagents and conditions: a) Pd(OAc)2, K2HPO4, CH2Br2, 140 °C, 16 h, 80%; b) methyl crotonate, LiHMDS, THF, -
78 °C to rt, 12 h; c) aq KOH, MeOH, 80 °C, 4 h, 60% (2 steps); d) MeI, K2CO3, acetone, 98%; e) H2, Pd-C, EtOAc-
MeOH (2:1), 12 h, 90%.
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application of Yu lactonization4a and Sammes annulation4b (Scheme 3). Benzyloxybenzoic acid
8 was subjected to Yu lactonization (CH2Br2, Pd(OAc)2, K2HPO4) to furnish phthalide 95 in 80%
yield. Annulation of 9 with methyl crotonate in the presence of LDA provided naphthol 10. The
crude naphthol 10 was heated at reflux with 30% aq KOH-MeOH6 to give naphthol 11 in 60%
overall yield. O-Methylation of 113 furnished 12, which upon debenzylation with H2, Pd-C
furnished naphthol 6.3
Chart 1. Glycosyl donors used in this study
Keeping in mind the structute of mayamycin (1), we chose to experiment with three glycosyl
donors (13-15, Chart 1) for C-glycosylation of the naphthol 6. The choice of the azido acetate
137 owes to it higher reactivity8 and our success with C-glycosylation of the parent 2-naphthol.1
Strikingly, the reaction between the azido acetate 13 with the naphthol 6 in the presence of SnCl4
furnished a complex mixture of products with small amount of C-glycosyl naphthols 16a and
16b. Variations of the catalysts, reaction time, concentration and temperature were of no avail
(Table 1) to increase the yield of the reaction.
Having failed with the glycosylation with the azido acetate 13, we turned to N-monomethyl tert-
butylcarbamate 14. It 14 was prepared in 3 steps from azido acetate13. Hydrogenolysis of the
azido acetate 13 with H2/Pd-C in methanol followed by treatment of the crude amine 17 with
Boc2O (1.2 equiv) and DMAP (cat) in DCM produced carbamate 18. N-methylation of 18 using
NaH and MeI in DMF gave the N-monomethyl-tert-butylcarbamate 14 in 65% overall yield
(Scheme 4). Glycosylation of 2-naphthol (19) with the glycosyl donor 14 in presence of SnCl4 or
9
TMSOTf-AgClO4 provided an intractable mixture of products. The complexity of the reactions
was possibly due to deprotection of the carbamate group during the reactions.10
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Table 1. Glycosylation of naphthol 6 with azido acetate 13
Entry
6 : 13
1.0 : 1.6
1.0 : 1.6
Catalyst
Concentration
Temp/h
Results
of 6 (mol/L)
1
2
SnCl4/DCM
SnCl4/DCM
0.027
- 78 °C to – 35 °
C/12
Traces of 16a
and 16 b
2.66 x10-3
- 78 °C to to – 35 °
C to rt/
do
12
3
4
1.0 : 1.6
1.0 : 1.6
SnCl4/DCM
SnCl4/DCM
0.027
- 78 °C to – 20 °
C/12
do
do
2.66 x10-3
- 78 °C to rt/
12
5
6
7
8
2.0 : 1.0
1.0 : 2.0
1.0 : 4.0
1.0 : 2.0
TMSOTf-
0.06
0.018
0.032
0.03
0 °C to rt/2
IM
SM
SM
SM
AgClO4/DCM
Cp2HfCl2-
- 78 °C to rt/
12
AgClO4/DCM
Sc(OTf)3/DCE
- 30 °C to rt/
18
BF3.Et2O/
DCM
0 °C to rt/ 12
IM = Intractable mixture, SM = Starting naphthol 6 remained unreacted, while 13 decomposed.
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Next, glycosyl donor 15 was studied in the place of 14 because it was found to be a better
glycosyl donor in the case of 4-O-benzyl analogs.8 For the preparation of 15, α-D-methyl
glucopyranoside (20) was converted to alcohol 2111a in 4 steps, which was protected as its benzyl
Scheme 4. Synthesis of 14 and glycosylation studies with 2-naphthol (19)
Reagents and conditions: a) Pd-C, H2, MeOH, 50 psi b) Boc2O, DMAP (cat) , DCM, rt c) NaH, MeI, DMF, 65% (3
steps) d) 19, SnCl4, DCM, - 78 °C to - 35° C to rt, 12 h e) 19, TMSOTf, AgClO4, DCM, 0 °C to rt, 2 h
ether 22 in excellent yield. Deprotection of benzylidene acetal 22 by TFA in DCM to 2311b
followed by tosylation furnished monotosyl derivative 24. The crude tosyl sugar 24 was heated
Scheme 5. Synthesis of 3-mesyloxy carbohydrate 15
Reagents and conditions: a) BnBr, NaH, DMF, 88%; b) DCM, TFA-H2O, 90% ; c) TsCl (1.2 equiv.), DCM-Py (1:1)
d) LAH, THF, 52% (2 steps); e) Ac2O, py, quant; f) BBr3, DCM, 98%; g) MsCl, Py, 95%.
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at reflux with excess LAH in dry THF to give 6-deoxy sugar 2511c in 52% yield over two steps
(Scheme 5). The sugar 25 was converted into its acetate 2611c, and the benzyl ether in 26 was
cleaved with BBr3 in DCM to furnish 27 as an inseparable mixture of two C1 epimers. Reaction
of 27 with 1.2 equiv mesyl chloride in pyridine provided the required mesyl sugar 15 in excellent
yield. Since the glycosylation is known to proceed through the oxacarbenium intermediate, the
stereochemistry at C1 was expected to be of no consequence in the glycosylation.
Scheme 6. Glycosylation of 2-naphthol 19 and naphthol 6 with mesyloxy sugar 15
C-Glycosylation of 19 with 15, when carried out in the presence of TMSOTf-AgClO4 as catalyst,
proceeded smoothly to furnish the β-C-aryl glycoside 28 in 64% isolated yield (Scheme 6).
Surprisingly, under the same set of conditions, naphthol 6 produced 29 only in a trace amount
(Scheme 6). The above failure intrigued us as to the effect of 7-methyl or 5-methoxy group in the
C-glycosylation reaction. The marked difference of reactivity of 6 and 19 led us to examine 7-
methyl-2-naphthol (30) to probe the effect of C5 methoxy group in 6.
Naphthol 30 was synthesized from tetralone 31 in 4 steps. Reduction of the keto functionality of
tetralone 3112a with NaBH4 resulted in the alcohols 32, which were dehydrated to obtain
dihydronaphthalene 33. Aromatization of 33 to naphthol 34 followed by demethylation using
BBr3 yielded naphthol 3012b in good overall yield (Scheme 7). The reaxction of the naphthol 30
with azido acetate 13 in the presence of SnCl4 in DCM totally failed to give glycosylated
product. The naphthol 30 was recovered in good yield . There was no indication of the
formation of C-glycosides.
Next, we studied the glycosylation of 5-methoxy-2-naphthol (35). It was synthesized from
tetralone 36,13a which was converted into acetate 3713b and then aromatized with NBS. The
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resulting mixture13c was O-methylated to give methyl ether 38 in an excellent overall yield.
Finally, the deacetylation of 38 with MeONa in methanol furnished 2-naphthol 35 in quantitative
yield. C-Glycosylation of 35 with the azido acetate 13 was then performed in the presence of
Scheme 7. Synthesis of 7-methyl-2-naphthol (30) and its glycosylation with 13
Reagents and conditions: a) NaBH4, MeOH, 0 °C to rt, 6 h, 85%; b) p-TsOH, benzene, 80 °C, 4 h, 72%; c) DDQ,
benzene, rt, 5 h, 80%; d) BBr3, DCM, 90%; e) SnCl4, DCM, - 78 °C to - 35° C to rt, 12 h.
SnCl4 in DCM. Although the reaction provided a mixture of two epimeric C-glycosides, as
1
evident of its H NMR spectrum, but we were able to isolate the C3 epimeric glycoside 39 in
20% yield (Scheme 8).
Scheme 8. Glycosylation of naphthol 35 with glycosyl donor 13
Reagents and conditions: a) Ac2O, pyridine, 96%; b) NBS, CCl4; c) MeI, DBU, acetone, 75% (2 steps); d) cat.
NaOMe, MeOH, quant; e) 13, SnCl4, DCM, - 78 °C to - 35° C to rt, 12 h, 20%.
These results imply that the effect of the C7 methyl group of 6 on its C-glycosylation of 2-
naphthols is quite significant. We anticipated that peri-effect might be preventing the C-
glycosylation as proposed by Parker et al. for 1-naphthol derivatives.7 Considering the lesser
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steric bulk of fluorine than methyl, we synthesized fluoronaphthol 40. Tetralone 4114 was
reduced with NaBH4 to the corrosponding alcohol, which was acetylated to obtain acetate 42 as
mixture of isomers (Scheme 9). Treatment of the acetate 42 with p-TSA in refluxing toluene
produced a mixture of fluoronaphthalenes 43 and 44. This mixture was then treated with DDQ in
dry DCM to provide methyl ether 43 in 40% yield. Treatment of 43 with BBr3 furnished the
desired fluoronaphthol 40 in 85% yield (Scheme 9).
Scheme 9. Preparation of fluoronaphthol 40
Reagents and conditions: a) NaBH4, THF-MeOH; b) Ac2O, pyridine, 80% (2 steps); c) p-TSA, toluene, 120 °C, 2 h;
d) DDQ, DCM, rt, 40% (2 steps); e) BBr3, DCM, 0 °C to rt, 85%.
Scheme 10. Glycosylation of fluoronaphthol 40 with 13
Reaction of fluoronaphthol 40 with the azido acetate 13 in the presence of SnCl4 resulted in a
mixture of epimeric C-glycosides 45a (30%) and 45b (10%). The yield of the glycosylation was
relatively lower than with 2-naphthol (19), but distinctly better than that with methylnaphthol 30.
To further ensure the steric perturbation of 7-methyl group of 2-naphthol in the C-glycosylation
reaction, we carried out glycosylation of 6-methyl-2-naphthol (46)15 with azido acetate 13 in the
presence of SnCl4 as Lewis acid. The reaction resulted in a mixture of three C-glycosides in 70%
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combined yield. Glycoside 47a was isolated from the mixture in 35% yield, whereas 47b and
47c were inseparable (Scheme 11). The structures of 47a and 47b were in good agreemrnt with
their NMR spectra whereas that of 47c was tentatively assigned.
Scheme 11. Glycosylation of 6-methyl-2-naphthol (46) with azido acetate 13
Table 2. Summary of C-glycosylations of different 2-naphthols
Entry Glycosyl donor Glycosyl acceptor Conditions
Product
Yield
O
AcO
SnCl4,
DCM, - 78
°C to - 35°
C to rt, 12
h
> 1%
1
O
N3
OAc
O
OH
16a, 16b
N3
OAc
13
do
do
n.d.
2
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R1
R2
R1
R2
TMSOTf,
3
O
AcO
AgClO4,
DCM, 0 °C
to rt, 2 h
OMs O
OH
OMs
O
OH
19: R1 =H, R2 = H
6:R1 =OMe, R2 = Me
OAc
15
28: R1 =H, R2 = H
29:R1 =OMe, R2 = Me
R1
R1
AcO
SnCl4,
DCM, - 78
°C to - 35°
C to rt, 12
h
4
O
N3
OAc
O
OH
OH
30: R1 = Me
N3
OAc
n.d. (R1 =
Me)
40: R1 = F
13
R1 = Me
45a, 45b: R1 = F
40%
O
do
do
do
5
6
20%
OH
35
do
O
OH
N3
47a , 47b
OAc
47a 35%
47b +
47c 35%
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OH
O
N3
OAc
n.d: not detected
3. Conclusion
In summary, several 2-naphthols were synthesized and their C-glycosylation with glycosyl
donors: azido acetate 13, N-monomethyl tert-butylcarbamate sugar 14 and mesyl sugar 15 were
studied under Lewis acidic conditions. From these studies it is evident that 7-methyl group in 2-
naphthol has a deleterious effect on the C-glycosylation under the reaction conditions. This effect
is the result of the sensitivity of C-glycosylations to the steric effect of the substituents at C7
position.
4. Experimental
4.1 General
All commercial reagents were used without further purification. Melting points were determined
in open-end capillary tubes. Solvents were dried and distilled following the standard procedures.
TLC was carried out on pre-coated plates (Merck silica gel 60, GF254), and the spots were
visualized with UV, fluorescent light or by staining with 10% H2SO4 in methanol. Column
1
chromatography was performed on silica gel (60-120 or 230-400 mesh). H and 13C NMR
1
spectra for the compounds were recorded with 200, 400 and/or 600 MHz spectrometers. H and
13C chemical shifts are reported in ppm downfield of tetramethylsilane and referenced to residual
solvent peak (CHCl3; δH = 7.26 and δC = 77.23, d6-DMSO; δH = 2.50 and δC = 39.5).
Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad resonance. IR spectra were recorded on a FT-IR using KBr
pellet on a Thermo Nicolet Nexus 870 FT-IR spectrophotometer Mass spectra were taken on a
MS-TOF mass spectrometer. The phrase ‘usual work-up’ or ‘worked up in usual manner’ refers
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to washing of the organic phase with water (2 × 1/4 the volume of organic phase) and brine (1 ×
1/4 the volume of organic phase), and drying (anhydrous Na2SO4), filtration, and concentration
under reduced pressure. Yields were referred to isolated yields after purification.
6-Benzyloxy-3-methylnaphthalen-1-ol (11)3 To a solution of 9 (720 mg, 3.0 mmol) in dry THF
(20 mL) at - 78 °C under argon atmosphere was added LHMDS (11 mL, 1 M in hexane, 11
mmol) and the reaction mixture stirred for 30 min. A solution of methyl crotonate (0.66 mL, 6.0
mmol) in THF (10 mL) was then added in portion and stirred at - 78 °C for another 30 min. After
30 min, the bath was removed and stirring was continued for 12 h at rt. The reaction mixture was
cooled to 0 °C, acidified with aq 6 N HCl and extracted with EtOAc (50 × 3 mL) and worked up
in usual manner. The crude reaction mixture was dissolved in a mixture of MeOH (
) and ,
30% aq KOH (25 mL) was added and refluxed under inert atmosphere for 4 h. It was cooled to
rt, acidified with aq 6 N HCl ( ml) and extracted with EtOAc (50 × 3 mL) and worked up in
usual manner. The crude compound was subjected to column chromatography on silica gel
1
(using 20% EtOAc/hexanes as eluent) to obtain 11 (500 mg, 60%) as yellow oil. H NMR (200
MHz, CDCl3) δ 8.06 (d, J = 9.0 Hz, 1H), 7.54-7.32 (m, 5H), 7.28-7.11 (m, 3H), 6.50 (s, 1H),
5.38 (s, 1H), 5.18 (s, 2H), 2.42 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 157.6, 151.6, 137.2, 136.9,
136.5, 128.8, 128.2, 127.8, 123.5, 119.0, 118.3, 117.3, 109.2, 107.0, 70.2, 22.0.
6-Benzyloxy-1-methoxy-3-methylnaphthalene (12)3 To a solution of naphthol 11 (1.1 g, 4.17
mmol) in dry acetone (30 mL), K2CO3 (1.73 gm, 12.5 mmol) and MeI (2.4 mL, 17 mmol) were
added. The reaction mixture was stirred at rt for 16 h, filtered and acetone was evaporated under
reduced pressure. The crude reaction mixture was extracted with ethyl acetate (50 × 3 mL),
washed with dil aq sodium thiosulfate solution and worked in usual manner. Chromatography of
the residue on silica gel (using 10% EtOAc/hexanes as eluent) provided 12 (1.1 g, 96%) as an off
1
white solid. H NMR (200 MHz, CDCl3) δ 8.10 (d, J = 8.6 Hz, 1H), 7.50-7.36 (m, 5H), 7.15-
7.10 (m, 3H), 6.52 (s, 1H), 5.16 (s, 2H), 3.97 (s, 3H), 2.47 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
157.6, 155.6, 137.2, 136.8, 136.2, 128.8, 128.1, 127.8, 123.8, 119.4, 118.6, 117.1, 106.8, 104.6,
70.1, 55.6, 22.5.
5-Methoxy-7-methylnaphthalen-2-ol (6)3 To a stirred solution of 12 (1.0 g, 3.58 mmol) in 3:1
MeOH-EtOAc (80 mL), 10% Pd-C (220 mg) was added and the reaction mixture was
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hydrogenated using parr apparatus for 6 h. The reaction mixture was filtered through celite,
solvent was evaporated under reduced pressure and purified by column chromatography on silica
gel (using 5% EtOAc/hexanes as eluent) to obtain 6 (608 mg, 90%) as pale yellow oil. 1H NMR
(200 MHz, CDCl3) δ 8.14 (d, J = 9.6 Hz, 1H),7.05-7.02 (m, 3H), 6.54 (s, 1H), 3.98 (s, 3H), 2.48
(s, 3H); 13C NMR (50 MHz, CDCl3) δ 155.6, 154.2, 136.9, 136.2, 124.1, 119.3, 118.2, 115.9,
109.1, 104.4, 55.5, 22.4.
6-Acetoxy-4-(tert-butoxycarbonyl-methyl-amino)-2-methyltetrahydropyran-3-yl-acetate
(14) The azido acetate 13 (550 mg, 2.1 mmol) was hydrogenated in the presence of 10% Pd-C
(200 mg) following the procedure used for the preparation of 6 from 12. The crude amine 17 was
dissolved in DCM (20 mL) were added Boc2O (0.62 mL, 2.7 mmol) and DMAP (10 mg) and
stirred at rt for 12 h. Water (40 mL) was added, the reaction mixture was extracted with DCM
(50 × 3 mL) and worked up in usual manner to obtain the carbamate 18. To a solution of 18 in
DMF (15 mL) was added NaH (60%, 90 mg, 2 mmol) at 0 °C and stirred for 30 min. Methyl
iodide (0.2 mL, 3.2 mmol) was added and the reaction mixture was stirred at rt for 12 h. The
reaction mixture was cooled to 0 °C, water was added and extracted with ethyl acetate (50 × 3
mL). After usual work up followed by flash column chromatography (using 20% EtOAc/hexanes
1
as eluent) of the crude product provided 14 (480 mg, 65%). H NMR (200 MHz, CDCl3) δ 6.39
(s), 5.87-5.82 (m), 4.91 (br, s), 4.69 (d, J = 11.2 Hz), 4.57 (dd, d, J = 11.4 Hz,), 4.44 (ap t, J = 4.8
Hz), 2.80 (s), 2.73 (s), 2.68 (s), 2.64 (s), 1.43 (s), 1.40 (s); 13C NMR (100 MHz, CDCl3) δ 171.3,
171.0, 170.5, 170.4, 169.9, 156.3, 156.1, 155.9, 155.6, 98.4, 98.3, 98.0, 97.9, 34.7, 34.0, 33.6,
32.2, 28.8, 28.6, 28.5; HRMS (TOF MS ES+) found [M+H]+ 346.1858, C16H28O7N calcd
346.1866.
8-(benzyloxy)-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine (22) To a stirred
solution of 21 (1.8 g, 6.76 mmol) in DMF (30 ml), NaH (440 mg, 11 mmol) was added at 0 °C in
portion under inert atmosphere and stirred for 30 min. After 30 min benzyl bromide (1.3 mL, 11
mmol) was added to the reaction mixture drop wise manner and the reaction mixture was stirred
for overnight at rt. The reaction mixture was cooled to 0 °C, quenched with MeOH (2 ml) and
brain (15 mL) was added and it was extracted with ethyl acetate (50 × 3 mL). After usual work
up followed by flash column chromatography (using 20% EtOAc/hexanes as eluent) resulted 22
(2.12 g, 86%) as yellow semisolid. 1H NMR (200 MHz, CDCl3) δ 7.54-7.25 (m, 10H), 5.60 (s,
14

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1H), 4.88-4.76 (m, 3H), 4.57-4.33 (m, 2H), 4.01 (brd, 3 Hz), 3.81-3.70 (m, 2H), 3.46 (s, 3H),
2.27 (dd, J = 15 Hz, 2.6 Hz, 1H), 2.31-1.91 (m, 1H); 13C NMR (50 MHz, CDCl3) δ 139.2, 137.9,
129.1, 128.4, 128.3, 127.6, 127.3, 126.4, 102.3, 98.0, 80.5, 77.9, 77.2, 76.6, 72.2, 70.4, 69.7,
58.3, 55.7, 34.6. HRMS (TOF MS ES+) found [M+H]+ 357.1697, C21H25O5 calcd 357.1702.
4-Benzyloxy-6-methoxy-2-methyltetrahydropyran-3-ol (25)11a To a solution of 23 (5.1 g, 19
mmol) in dry pyridine (50 mL) was added a solution of tosyl chloride (4.40 g, 23 mmol ) at 0 °C
in drop wise manner and stirred at rt for 2 h. The reaction mixture was cooled to 0 °C, quenched
by adding water, extracted with ethyl acetate (100 × 3 mL). The organic part was washed with
dil aq CuSO4 and work up using usual manner to obtain 24 as yellow semisolid. The crude 24
was dissolved in dry THF (100 mL) was added LiAlH4 (440 mg, 122 mmol) at 0 °C in portion
under inert atmosphere. The reaction mixture was refluxed for 2 h, cooled to 0 °C and quenched
with aq Na2SO4. It was passed through celite, washed with ether and concentrated under reduced
pressure. The crude 25 was purified by flash column chromatography (using 20%
EtOAc/hexanes as eluent) to obtain 2512 (2.5 g, 52%) as yellow semisolid. 1H NMR (200 MHz,
CDCl3) δ 7.38-7.31 (m, 5H), 4.82 (d, J = 11.4 Hz, 1H), 4.70 (d, J = 4.4 Hz, 1H), 4.41 (d, J =
11.4 Hz, 1H), 4.07-3.93 (m, 1H), 3.83 (d, J = 3 Hz, 1H), 3.39 (s, 3H), 3.34-3.26 (m, 1H), 2.67 (d,
J = 10.4 Hz, 1H), 2.33 (d, J = 15 Hz, 1H), 1.82-1.71 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δ 138.2, 128.5, 128.0, 127.8, 97.3, 73.0, 72.3, 70.4, 64.6, 55.2, 31.5, 17.9.
4-Benzyloxy-6-methoxy-2-methyltetrahydropyran-3-yl-acetate (26)11bAcetylation of 25 was
carried out using standard procedure (Ac2O-Py at 0 °C to rt) to obtain 26 in quantitative yield. .
1H NMR (200 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 4.73-4.65 (m, 3H), 4.58 (d, J = 12.2 Hz, 1H),
4.41-4.27 (m, 1H), 3.96-3.90 (m, 1H), 3.41 (s, 3H), 2.27-2.17 (m, 1H), 2.09 (s, 3H), 1.91-1.82
(m, 1H), 1.22 (d, J = 6.6 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 170.5, 138.6, 128.4, 127.8,
127.6, 97.7, 74.0, 71.0, 70.8, 62.9, 55.5, 32.5, 21.1, 17.6.
4-Hydroxy-6-methoxy-2-methyltetrahydropyran-3-yl-acetate (27) To a solution of 26 (2 g,
6.8 mmol) in DCM (20 mL) at - 90 °C, was added BBr3 (40.8 mL, 1 M in DCM, 40.8 mmol) and
stirred at for 10 min. After which MeOH (15 mL) and saturated aq NaHCO3 (15 mL) were
added, extracted with DCM (15 × 3 mL) and work up in usual manner. The reaction mixture was
purified by flash column chromatography (using 30% EtOAc/hexanes as eluent) to obtain 27
15

ACCEPTED MANUSCRIPT
(1.36 g, 98%)) was prepared as a yellow semisolid. 1H NMR (200 MHz, CDCl3, mixture of two
anomers) δ 4.72-4.67 (m), 4.52-4.41 (m), 4.14-3.85 (m), 3.40 (s), 3.31 (s), 2.04-1.61 (m), 1.14 (d,
13
J = 6.4 Hz, 3H); C NMR (50 MHz, CDCl3) δ 170.5, 170.2, 98.9, 98.5, 75.2, 75.0, 67.3, 65.7,
65.6, 61.2, 56.5, 55.2, 37.4, 35.3, 21,1, 17.9, 17.6. HRMS (TOF MS ES+) found [M+H]+
205.1081, C9H17O5 calcd 205.1076.
4-Methanesulfonyloxy-6-methoxy-2-methyltetrahydropyran-3-yl-acetate
(15)
The
compound 15 (1.7 g, 95%) was prepared as a yellow semisolid from 27 (1.3 g, 6.4 mmol),
following the standard mesylation procedure using mesyl chloride (1.2 mL) in pyridine (20 mL).
1H NMR (200 MHz, CDCl3, mixture of two anomers) δ 5.14-5.10 (m), 5.06-5.01 (m), 4.70-4.65
(m), 4.56-4.46 (m), 4.21-4.10 (m), 3.98-3.84 (m), 3.43 (s), 3.29 (s), 2.99 (s), 2.24-1.79 (m), 1.20-
1.10 (m); 13C NMR (50 MHz, CDCl3) δ 170.2, 170.1, 98.4, 96.6, 76.1, 74.1, 72.2, 71.9, 67.7,
61.1, 56.6, 55.3, 38.9, 38.6, 36.6, 34.3, 20.9. 17.8, 17.3; HRMS (TOF MS ES+) found [M+H]+
283.0844, C10H19O7S calcd 283.0852.
6-(2-Hydroxy-naphthalen-1-yl)-4-methanesulfonyloxy-2-methyltetrahydropyran-3-yl-
acetate (28) To a stirred solution of 2-naphthol (19) (180 mg, 1.25 mmol) and hexopyranoside
15 (300 mg, 1.06 mmol) in methylene chloride (20 mL) were added TMSOTf (50 µL, 2.7 mmol)
and AgClO4 (260 mg, 2.7 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and
then the temperature was gradually increased to rt and stirred for 1 h. The reaction was quenched
with triethyl amine (0.2 mL) and DCM was evaporated under reduced pressure. The reaction
mixture was purified by flash column chromatography (using 20% EtOAc/hexanes as eluent) to
obtain 28 (268 mg, 64%) as yellow semisolid. 1H NMR (200 MHz, CDCl3) δ 8.65 (s, 1H), 7.78-
7.64 (m, 3H), 7.48 (t, J = 7.0 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 5.89 (dd,
J = 10.6 Hz, J = 3.2 Hz, 1H), 5.29 (d, J = 2.6 Hz, 1H), 4.83 (dd, J = 10.2 Hz, J = 2.8 Hz, 1H),
13
4.34-4.20 (m, 2H), 3.15 (s, 3H), 2.43-2.25 (m, 2H), 2.17 (s, 3H), 1.39 (d, J = 6.2 Hz, 3H); C
NMR (50 MHz, CDCl3) δ 170.2, 154.0, 130.8, 130.4, 129.2, 129.0, 127.4, 123.4, 120.5, 120.0,
113.9, 76.1, 72.9, 72.3, 72.0, 38.9, 36.6, 21.8, 18.2. HRMS (TOF MS ES+) found [M+Na]+
417.0994, C19H22O7SNa calcd 417.0984.
6-Methoxy-3-methyl-1,2-dihydronaphthalene (33) To a solution of 31 (5 g, 26.3 mmol) in dry
MeOH, was added sodium borohydride (1.12 g, 31.6 mmol) at 0 °C in portion and stirred at rt
16

ACCEPTED MANUSCRIPT
for 12 h. The reaction was quenched by adding water (5 mL) at 0 °C and MeOH was evaporated
under reduced pressure. Water (50 mL) was added and it was extracted with ethyl acetate (3 x
100 mL) and worked up in usual manner to obtain the crude alcohol 31 (4.3 g, 85%). The crude
alcohol 31 (4 g, 20.8 mmol) was dissolved in dry benzene (80 mL), p-toluenesulfonic acid (200
mg) was added and the reaction mixture was refluxed for 2 h using a Dean-Stark apparatus. The
reaction mixture was concentrated under reduced pressure, water (50 mL) was added, extracted
with EtOAc (3 x 100 mL) and work up in usual manner. The crude product was purified by
column chromatography on silica gel (using 20% EtOAc/hexanes as eluent) to afford 33 (2.6 g,
72%) as clear oil. 1H NMR (200 MHz, CDCl3) δ 7.06 (d, J = 8 Hz, 1H), 6.70 (dd, J = 8 Hz, J =
2.6 Hz 1H), 6.62 (d, J = 2.6 Hz, 1H), 6.25 (s, 1H), 3.84 (s, 3H), 2.82 (t, J = 8 Hz, 2H), 2.29 (t, J
= 8.2 Hz, 2H), 1.98 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 158.5, 139.2, 136.3, 128.0, 126.4,
123.0, 111.1, 111.0, 55.4, 29.4, 27.4, 23.7. HRMS (TOF MS ES+) found [M+H]+ 175.1120,
C12H15O calcd 175.1123.
2-Methoxy-7-methylnaphthalene (34)13a To a solution of 33 (500 mg, 1.63 mmol) in dry DCM
(20 mL), DDQ (450 mg, 2 mmol) was added and the reaction mixture was stirred at rt for 30
min. The reaction mixture was passed through basic alumina column to obtain pure ether 31 (395
1
mg, 80%, pale yellow solid). mp 96 - 98 °C; H NMR (200 MHz, CDCl3) δ 8.03 (d, J = 9 Hz,
1H), 7.75 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7 Hz, 1H), 7.37-7.29 (m, 3H), 4.03 (s, 3H), 2.80 (s,
3H); 13C NMR (50 MHz, CDCl3) δ 157.5, 135.0, 134.4, 128.2, 126.4, 126.9, 125.5, 124.7, 118.4,
106.6, 55.3, 19.5.
7-Methylnaphthalen-2-ol (27)12b To a solution of 31 (110 mg, 0.64 mmol) in DCM (10 mL) at
0 °C, was added BBr3 (1.3 mL, 1 M in DCM, 1.3 mmol) and stirred at rt for 12 h. The reaction
mixture was cooled to 0 °C and quenched with aq NaHCO3, extracted with DCM (15 × 3 mL)
and work up in usual manner. The reaction mixture was purified by flash column
chromatography (using 10% EtOAc/hexanes as eluent) to obtain 27 (91 mg, 90%) was prepared
as a yellow semisolid. 1H NMR (200 MHz, CDCl3) δ 7.73-7.69 (m, 2H), 7.44 (s, 1H), 7.21 (d, J
= 6.4 Hz, 1H), 7.11-7.07 (m, 2H), 5.36 (s, 1H), 2.51 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
153.4, 136.4, 135.0, 129.8, 127.7, 127.4, 126.1, 125.7, 117.0, 109.3, 21.9.
17

ACCEPTED MANUSCRIPT
5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl-acetate (37)13b A solution of 36 (900 mg, 4.4 mmol)
in dry pyridine (20 mL) at 0 °C, was added acetic anhydride (0.63 mL, 6.6 mmol) and the
reaction mixture was stirred at rt for 12 h. The reaction mixture was cooled to 0 °C, quenched by
adding water, extracted with ethyl acetate (3 x 50 mL). The organic part was washed with dil aq
CuSO4 and work up using usual manner to obtain 37 (1.08 g, 96%) as yellow semisolid. 1H
NMR (200 MHz, CDCl3) δ 8.02 (dd, J = 8.2 Hz, J = 2 Hz, 1H), 7.00-6.86 (m, 2H), 2.91 (t, J = 6
13
Hz, 2H), 2.60 (t, J = 6 Hz, 2H), 2.26 (s, 3H), 2.15-2.02 (m, 2H); C NMR (50 MHz, CDCl3) δ
197.2, 168.9, 154.4, 146.4, 130.4, 129.1, 121.5, 120.2, 38.9, 29.8, 23.1, 21.1.
5-Methoxynaphthalen-2-yl-acetate (38) To a solution of 37 (1.0 g, 4.9 mmol) in dry CCl4 (40
mL), were added NBS (850 mg, 4.75 mmol) and AIBN (10 mg) and refluxed for 4 h in the
presence of 200 W electric bulb. The reaction mixture was cooled to 0 °C, filtered through
regular filter paper and the filtrate was evaporated under reduced pressure to obtain the crude
naphthol. The crude naphthol was dissolved in dry acetone (30 mL), were added DBU (0.9 mL, 6
mmol) and MeI (0.6 mL, 10 mmol) and stirred at rt for 12 h. Acetone was evaporated under
reduced pressure, extracted with ethyl acetate (3 x 50 mL) and work up in usual manner to obtain
the crude 38. The crude product was purified by column chromatography on silica gel (using
1
20% EtOAc/hexanes as eluent) to afford 38 (790 mg, 75%) as yellow semisolid. H NMR (200
MHz, CDCl3) δ 8.14 (d, J = 9 Hz, 1H), 7.36 (s, 1H), 7.25 (d, J = 4.4 Hz, 2H), 7.07 (dd, J = 8.6
Hz, J = 1.2 Hz, 1H), 6.58 (t, J = 4.4 Hz, 1H), 3.77 (s, 3H), 2.15 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ 169.6, 155.6, 149.1, 135.11, 127.0, 123.9, 123.6, 120.2, 119.9, 118.2, 103.7, 55.5, 21.2.
HRMS (TOF MS ES+) found [M+H]+ 217.0858, C13H13O3 calcd 217.0865.
5-Methoxynaphthalen-2-ol (35) To a solution of 38 (864 mg, 4 mmol) in methanol (20 mL),
was added NaOMe (20 mg) and the reaction mixture was stirred at rt for 1 h. The reaction was
quenched by adding amberlyst-15, filtered through regular filter paper and concentrated under
reduced pressure. The crude product was purified by column chromatography on silica gel (using
1
10% EtOAc/hexanes as eluent) to afford 35 (690 mg, 99%) as pale yellow semisolid. H NMR
(200 MHz, CDCl3) δ 8.03 (d, J = 9.8 Hz, 1H), 7.22-7.06 (m, 2H), 6.96-6.91 (m, 2H), 6.51 (d, J =
7.4 Hz, 1H), 3.81 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 155.8, 154.2, 136.1, 126.9, 124.3, 121.0,
119.1, 117.0, 109.6, 102.1, 55.6; HRMS (TOF MS ES+) found [M+Na]+ 197.0570, C11H10O2Na
calcd 197.0578.
18

ACCEPTED MANUSCRIPT
4-Azido-6-(2-hydroxy-5-methoxy-naphthalen-1-yl)-2-methyltetrahydropyran-3-yl-acetate
(39) To a stirred solution of naphthol 35 (100 mg, 0.57 mmol) and azido acetate 13 (300 mg,
1.15 mmol)) and 4A0 molecular sieves in methylene chloride (40 mL) was added tin (IV)
chloride (3.5 mL, 1 M in DCM, 3.5 mmol) at - 78 °C. The reaction mixture was stirred at - 78 °C
for 10 min and then the temperature was gradually increased to - 35 °C and kept overnight. The
reaction was quenched with saturated sodium sulfate and the mixture was extracted with
methylene chloride. The organic phase was dried and concentrated and purified by flash column
chromatography (using 20% EtOAc/hexanes as eluent) to obtain 39 (43 mg, 20%) as yellow
semisolid. [α]35D = + 56.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.16 (d, J
= 9.2 Hz, 1H), 7.39 (t, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 9.2 Hz, 1H), 6.69
(d, J = 7.6 Hz, 1H), 5.72 (dd, J = 6.8 Hz, 1H), 4.90 (dd, J = 9.6 Hz, J = 3.2 Hz, 1H), 4.31-4.22
(m, 2H), 3.97 (s, 3H), 2.21-2.15 (m, 5H), 1.36 (d, J = 6.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ
170.3, 156.5, 154.6, 132.3, 127.5, 124.2, 120.8, 118.9, 114.2, 113.4, 101.9, 74.9, 73.6, 72.1, 58.7,
55.8, 35.8, 20.9, 18.3; HRMS (TOF MS ES+) found [M+Na]+ 394.1370, C19H21O5NNa calcd
394.1379.
2-Fluoro-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl-acetate (42) The compound 42 (585
mg, 80%) was prepared as a white semisolid from 41 (600 mg, 3 mmol), following the procedure
for the preparation of compound 32 from 31 using NaBH4 (130 mg, 3.6 mmol) followed by
1
acetylation using acetic anhydride (0.43 mL, 4.5 mmol) and pyridine (10 mL). H NMR (200
MHz, CDCl3, mixture of four isomers) δ 7.07-7.05 (m, 1H), 6.86-6.75 (m, 2H), 6.16-6.08 (m,
1H), 5.07-4.79 (m, 1H), 3-68 (s, 3H), 3.05-2.75 (m, 2H), 2.39-1.95 (m, 5H); 13C NMR (50 MHz,
CDCl3, mixture of four isomers) δ 170.9, 158.4, 133.4, 133.3, 129.8, 129.7, 128.4, 115.7, 115.1,
113.9, 113.6, 91.0, 89.6, 87.8, 71.7, 71.5, 70.1, 69.9, 55.56, 55.5, 26.3, 26.1, 25.6, 25.5, 25.0,
24.8, 24.7,24.6, 21.4; 19F NMR ( 188 MHz, CDCl3, mixture of four isomers) δ - 198.1, - 202.6, -
203.6, - 204.0; HRMS (TOF MS ES+) found [M-HOAc+H]+ 179.0847, C11H12OF calcd
179.0872.
2-Fluoro-7-methoxynaphthalene (43) The compound 42 (500 mg, 2.6 mmol) was dissolved in
dry benzene (20 mL), p-toluenesulfonic acid (30 mg) was added and the reaction mixture was
refluxed for 2 h using a Dean-Stark apparatus. The reaction mixture was concentrated under
reduced pressure, diluted with water (50 mL), extracted with EtOAc (3 x 100 mL) and work up
19

ACCEPTED MANUSCRIPT
in usual manner. The crude product was dissolved in DCM (20 mL), DDQ (450 mg, 2 mmol)
was added and the reaction mixture was stirred at rt for 30 min. The reaction mixture was passed
through basic alumina column to obtain pure 43 (147 mg, 40%) as a brown solid. m.p. 126 °C;
1H NMR (400 MHz, CDCl3) δ 7.75-7.71 (m, 2H), 7.35 (d, J = 10 Hz, 1H), 7.13-7.07 (m, 2H),
13
3.92 (s, 3H); C NMR (100 MHz, CDCl3) δ 161.5 (d, JC-F = 243.8 Hz), 158.7, 135.8 (d, JC-F
=
9.8 Hz), 130.2 (d, JC-F = 9.6 Hz), 129.6, 126.1, 118.1 (d, JC-F = 2.8 Hz), 113.8 (d, JC-F = 25 Hz),
110.2 (d, JC-F = 21 Hz), 105.5 (d, JC-F = 5 Hz). 55.5; HRMS (TOF MS ES+) found [2M-H]+
351.1181, C22H17O2F2 calcd 351.1197.
7-Fluoronaphthalen-2-ol (40) The compound 40 (125 mg, 85%) was prepared as a yellow
semisolid from 43 (160 mg, 0.91 mmol), following the procedure for the preparation of
compound 30 from 34 using BBr3 (2.0 mL, 1 M in DCM, 2.0 mmol) in DCM (10 mL). 1H NMR
(200 MHz, CDCl3) δ 7.75-7.71 (m, 2H), 7.28-7.25 (m, 1H), 7.15-7.08 (m, 3H), 6.02 (s, 1H); 13C
NMR (50 MHz, CDCl3) δ 161.5 (d, JC-F = 244 Hz), 154.2, 135.7 (d, JC-F = 9.5 Hz), 130.3 (d, JC-F
= 10 Hz), 130.1, 126.1, 117.1 (d, JC-F = 2.5 Hz), 114.0 (d, JC-F = 25.5 Hz), 109.9, 109.4 (d, JC-F
=
9 Hz); 19F NMR ( 188 MHz, CDCl3) δ - 115.2; HRMS (TOF MS ES+) found [M+H]+ 163.0560,
C10H8OF calcd 163.0559.
4-(R)-Azido-6-(7-fluoro-2-hydroxynaphthalen-1-yl)-2-methyltetrahydropyran-3-yl-
methylester (45a) The compound 45a (54 mg, 30%) was prepared as a yellow semisolid from
the reaction of 40 (81 mg, 0.5 mmol) with 13 (250 mg, 1.0 mmol) following the procedure for
the preparation of compound 39 from 35 using SnCl4 (1.7 mL, 1 M in DCM, 1.7 mmol) in DCM
(10 mL). [α]35 = + 62.6 (c 0.5, CHCl3); IR (KBr, cm-1) 3367, 2099, 1744, 1630, 1220, 1048,
D
772; 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.75 (dd, J = 8.8 Hz, JH-F = 6 Hz, 1H), 7.69 (d,
J = 8.8 Hz, 1H), 7.24 (d, J = 10 Hz, 1H), 7.13-7.05 (m, 2H), 5.36 (dd, J = 11.6 Hz, J = 1.6 Hz,
1H), 4.90 (t, J = 9.6 Hz, 1H), 3.86-3.73 (m, 2H), 2.41-2.36 (m, 1H), 2.20 (s, 3H), 2.10-2.00 (m,
13
1H), 1.37 (d, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 170.2, 162.0 (d, JC-F = 244 Hz),
154.9, 131.89 (d, JC-F = 9 Hz), 131.6 (d, JC-F = 9.8 Hz), 130.4, 125.9, 119.4 (d, JC-F = 2.6 Hz),
113.7 (d, JC-F = 5.5 Hz), 113.3 (d, JC-F = 24.8 Hz), 77.6, 76.7, 76.4, 75.1, 61.0, 35.98, 21.0, 18.1;
19F NMR (376 MHz, CDCl3) δ - 113.5; HRMS (TOF MS ES+) found [M+Na]+ 382.1183,
C18H18FN3O4Na calcd 382.1179.
20

ACCEPTED MANUSCRIPT
4-(S)-Azido-6-(7-fluoro-2-hydroxynaphthalen-1-yl)-2-methyltetrahydropyran-3-yl-
methylester (45b) The compound 45b (18 mg, 10%) was obtained along with 45a as a yellow
semisolid. [α]35 = + 98.4 (c 0.5, CHCl3); IR (KBr, cm-1) 3353, 217, 1744, 1629, 1220, 1050,
D
772; 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.73 (dd, J = 8.8 Hz, JH-F = 6 Hz, 1H), 7.66 (d,
J = 9.2 Hz, 1H), 7.28 (d, J = 12 Hz, 1H), 7.11-7.03 (m, 2H), 5,58 (dd, J = 10.4 Hz, J = 3.6 Hz,
1H), 4.91 (dd, J = 10 Hz, J = 3.2 Hz, 1H), 4.31-4.23 (m, 2H), 2.20-2.16 (m, 5H), 1.37 (d, J = 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.3, 161.9 (d, JC-F = 243.9 Hz), 155.0, 132.1 (d, JC-F
=
8.8 Hz), 131.5 (d, JC-F = 9.6 Hz), 130.2, 125.9, 119.3, 114.0 (d, JC-F = 5.2 Hz), 113.3 (d, JC-F = 25
Hz), 105.1 (d, JC-F = 22.6 Hz), 74.8, 73.3, 72.2, 58.5, 35.7, 20.9, 18.3; 19F NMR (376 MHz,
CDCl3) δ - 113.3; HRMS (TOF MS ES+) found [M+Na]+ 382.1188, C18H18FN3O4Na calcd
382.1179.
4-(S)-Azido-6-(2-hydroxy-6-methyl-naphthalen-1-yl)-2-methyltetrahydropyran-3-yl-
methylester (47a)
The compound 47a (28 mg, 35%) was prepared as a yellow semisolid from the reaction of 46 (36
mg, 0.23 mmol) with 13 (100 mg, 0.39 mmol) following the procedure for the preparation of
compound 39 from 35 using SnCl4 (1.3 mL, 1 M in DCM, 1.3 mmol) in DCM (10 mL). [α]35
=
D
1
+ 60.4 (c 0.5, CHCl3); IR (KBr, cm-1) 3369, 2098, 1744, 1606, 1375, 1227, 1046, 913, 744; H
NMR (600 MHz, CDCl3) δ 8.47 (s, 1H), 7.65 (d, J = 9 Hz, 1H), 7.57 (s, 1H), 7.55 (d, J = 9 Hz,
1H), 7.34 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 9 Hz, 1H), 5.52 (d, J = 11.4 Hz, 1H), 4.91 (t, J = 9.6
Hz, 1H), 3.86-3.77 (m, 2H), 2.49 (s, 3H), 2.44-2.41 (m, 1H), 2.21 (s, 3H), 2.19-2.06 (m, 1H),
1.39 (d, J = 6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170, 153, 132.6, 129.6, 129.1, 129.0,
128.7, 128.2, 120.2, 119.9, 113.7, 76.5, 76.1, 75, 61, 35.9, 21.1, 20.9, 18. HRMS (TOF MS ES+)
found [M+Na]+ 378.1431, C19H21N3O4Na calcd 378.1430.
4-(R)-Azido-6-(2-hydroxy-6-methyl-naphthalen-1-yl)-2-methyltetrahydropyran-3-yl-
methylester (47b, major) and (3S,4R,6S)-4-azido-6-(2-hydroxy-6-methylnaphthalen-1-yl)-2-
methyltetrahydro-2H-pyran-3-yl acetate (47c, minor)
47b + 47c (29 mg) were obtained along with 47a as yellow semisolid. IR (KBr, cm-1) 3356,
2116, 1743, 1376, 1227, 1051, 813, 744; 1H NMR (600 MHz, CDCl3) δ 8.63 (s, major), 8.59 (s,
minor), 7.64 - 7.55 (m), 7.34 (d, J = 8.4 Hz), 7.09 - 7.07 (m), 5.92 (dd, J = 10.8 Hz, J = 4.8 Hz,
21

ACCEPTED MANUSCRIPT
minor), 5.75 (dd, J = 10.2 Hz, J = 3 Hz, major), 5.30 (d, J = 3 Hz, minor), 4.92 (dd, J = 10.2 Hz,
J = 3.6 Hz, major), 4.40 (d, J = 3.6 Hz, minor), 4.39 (s, major), 4.38 - 4.27 (m, major), 4.05-4.04
(m, minor), 2.48 (s), 2.23 - 2.18 (m), 1.45 (d, J = 6.6 Hz, minor), 1.39 (d, J = 6.6 Hz, major); 13C
NMR (150 MHz, CDCl3) δ 170.4, 170.0, 153.2, 153.0, 132.53, 132.5, 129.4, 129.3, 129.1,
129.08, 128.9, 128.8, 128.0, 120.6, 120.5, 119.8, 119.8, 114.0, 112.3, 96.1, 87.1, 79.2, 74.6, 73.0,
71.8, 69.3, 61.4, 58.4, 39.5, 35.6, 21.2, 21.1, 20.7, 18.1, 16.5. HRMS (TOF MS ES+) found
[M+Na]+ 378.1432, C19H21N3O4Na calcd 378.1430.
Supplementary data
Copies of 1H and 13C NMR spectra of all new compounds associated with this article.
Acknowledgement
We gratefully acknowledge Indian Institute of Technology Kharagpur and the Department of
Science and Technology (DST), New Delhi and the Counsil of Scientific and Industrial research
(CSIR) for instrumental facilities and financial support. PM and SM are thankful to University
Grants Commission, New Delhi for their fellowship and SC is thankful to CSIR India for his
fellowship.
References and notes
1. (a) Schneemann, I.; Kajahn, I.; Ohlendorf, B.; Zinecker, H.; Erhard, A.; Nagel, K.; Wiese, J.;
Imhoff, J. F. J. Nat. Prod. 2010, 73, 1309-1312. (b) We, K.; Wang, M.; Yao, Q.; Zhang, A. Chin.
J. Chem. 2013, 31, 93-99.
2. Mitra, P.; Behera, B.; Maiti, T. K.; Mal, D. J. Org. Chem. 2013, 78, 9748-9757.
3. (a) Hauser, F. M.; Dorsch, W. A.; Mal, D. Org. Lett. 2002, 4, 2237-2239. (b) Dorsch, W. A.
(Doctoral dissertation). 2002, Retrieved from ProQuest/UMI Dissertations and Theses. (UMI
Number 3058967)
4. (a) Zhang, Y-H.; Shi, B-F.; Yu, J-Q. Angew. Chem. Int. Ed. 2009, 48, 6097-6100. (b) Broom,
N. J. P.; Sammes, P. G. J. Chem. Soc.; Perkin Trans. 1 1981, 465-470.
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5. Negoro, N.; Sasaki, S.; Ito, M.; Kitamura, S.; Tsujihata, Y.; Ito, R.; Suzuki, M.; Takeuchi, K.;
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2323.
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Deleterious effect of 7-methyl group on glycosylation of 2-naphthols
Prithiba Mitra, Subhajit Mandal, Soumen Chakraborty and Dipakranjan Mal1,*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
E-mail: dmal@chem.iitkgp.ernet.in
Supporting Information
Contains
Page no
1. 1H and 13C NMR spectra of selected compounds
2-20
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1. 1H and 13C NMR spectra of selected compounds
5-Methoxy-7-methylnaphthalen-2-ol (6)
1H NMR (200 MHz, CDCl3) and 13C NMR (50 MHz, CDCl3)
O
OH
6
2

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6-Acetoxy-4-(tert-butoxycarbonyl-methyl-amino)-2-methyltetrahydropyran-3-yl-acetate
(14)
1H NMR (400 MHz, CDCl3) and 13C NMR (100 MHz, CDCl3)
3

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8-(Benzyloxy)-6-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine (22)
1H NMR (200 MHz, CDCl3) and 13C NMR (50 MHz, CDCl3)
O
Ph
O
O
OBn O
22
4

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4-Benzyloxy-6-methoxy-2-methyltetrahydropyran-3-yl-acetate (26)
1H NMR (200 MHz, CDCl3) and 13C NMR (50 MHz, CDCl3)
O
AcO
OBn O
26
5

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4-Hydroxy-6-methoxy-2-methyltetrahydropyran-3-yl-acetate (27)
1H NMR (200 MHz, CDCl3) and 13C NMR (50 MHz, CDCl3)
O
AcO
OH
O
27
6