Highly stereoselective synthesis of furano-oxepanes: Intramolecular nitrone cycloaddition (INC) reactions on sugar derived 2-substituted allylic ethers

Article abstract of DOI:10.1016/j.tetasy.2003.10.006

The stereoselective synthesis of furano-oxepanes has been achieved from sugar ethers by an intramolecular nitrone cycloaddition (INC) reaction. The substitution at the 2-position of the allylic group aided in the exclusive formation of oxepanes.

Full text of DOI:10.1016/j.tetasy.2003.10.006

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3899–3905
Highly stereoselective synthesis of furano-oxepanes:
intramolecular nitrone cycloaddition (INC) reactions on sugar
derived 2-substituted allylic ethersꢀ
G. V. M. Sharma,a,* Asra Begum,a K. Ravinder Reddy,a A. Ravi Sankarb and A. C. Kunwarb
aD-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
bNMR Group, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 August 2003; accepted 4 October 2003
Abstract—The stereoselective synthesis of furano-oxepanes has been achieved from sugar ethers by an intramolecular nitrone
cycloaddition (INC) reaction. The substitution at the 2-position of the allylic group aided in the exclusive formation of oxepanes.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
furano-oxepanes as exclusive products from the sugar
derived 2-substituted allylic ethers (Fig. 1).
Seven-membered oxacycles are structural fragments of
a variety of bioactive natural products,1 besides their
use in pharmacological applications.2 The presence of
these systems in complex molecules such as ciguatoxin3
and others make them challenging synthetic targets,
thus resulting in the development of number of syn-
thetic methods.4 Nitrone–alkene cycloaddition5 reac-
tions are powerful synthetic routes for the preparation
of isoxazolidines that can be converted into a variety of
compounds. The intramolecular nitrone cycloaddition
(INC) of O-allyl saccharides give furano-pyran,
pyrano-pyran and furano-oxepane systems. Collins et
al.,6 Bhattacharjya et al.6 and Shing et al.6 reported the
synthesis of tetrahydro-pyrans and oxepanes using INC
reactions on sugar derived 3-O-allyl ethers. Further,
Shing et al. discovered the detrimental effect of steric
congestion on the formation of oxepane rings. Earlier
we reported7 substituent effects on the intramolecular
2. Results and discussion
The requisite 3-O-allyl ether–aldehydes 6 and 7 were
obtained from diacetone glucose (DAG) 1 (Scheme 1).
Accordingly 1 on reaction with allyl bromides C and D
in the presence of NaH in DMF resulted in the forma-
tion of ethers 2 (66%) and 3 (68%), respectively. Acid
hydrolysis of 2 and 3 with 60% aq. acetic acid at room
temperature furnished the diols 4 and 5, respectively,
which on oxidative cleavage with NaIO4 gave 6 and 7.
The thus made aldehydes 6 and 7 were independently
subjected to INC reaction with CH3NHOH·HCl in the
presence of Et3N to give 8 (75%) and 9 (50%), respec-
tively, as exclusive products, whose structures were
unambiguously assigned from NMR spectroscopic
studies.
1,3-dipolar cycloaddition reaction of
D-glucose-derived
3-O-prenyl and allylic ethers, which resulted new sugar-
derived furano-pyranes as exclusive products. In con-
tinuation of our studies on the substituent effects on
INC reactions, herein, we report the synthesis of chiral
ꢀ IICT Communication No. 030703.
* Corresponding
esmvee@iict.res.in
author.
E-mail:
esmvee@iict.ap.nic.in,
Figure 1.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.006

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G. V. M. Sharma et al. / Tetrahedron: Asymmetry 14 (2003) 3899–3905
Scheme 1.
NMR studies on compound 9 showed NOE between
H7b and H3 indicating their diaxial disposition in the
seven-membered ring, which takes a chair form. Fur-
ther long-range v coupling JH4–H6b=1.0 Hz and
JH5–H6a:0 Hz and weak NOE between H7a and H6a
support the proposed conformation for the oxepane
ring. Other characteristic NOE’s as shown in Figure 2
confirmed the envelope conformation for isopropylidine
ring and NOE between N-CH3 with H4 confirmed that
azoxy ring is pointing below the average plane of
seven-membered ring. The same was further confirmed
from the energy minimized8 structure as shown in
Figure 2.
gave 14 (75%) and 15 (64%), which on hydrolysis with
TFA in CH2Cl2 furnished 16 and 17, respectively.
Swern oxidation of 16 and 17 afforded 18 (84%) and 19
(60%), respectively, which on INC reaction under stan-
dard reaction conditions furnished oxepanes 20 (80%)
and 21 (53%), respectively. Structures of 20 and 21 were
unambiguously assigned from the spectral studies.
NMR studies on compound 21 (Fig. 3) showed NOE
between H7a and H3 indicating their diaxial disposition
in a seven-membered ring, which is in a chair confor-
mation. Further long-range v coupling JH4–H6a=1.1 Hz
and JH5–H6a:0 Hz, and a weak NOE between H6b and
H7b supported the proposed conformation for the
seven-membered ring. Other characteristic NOE’s
between H4 and CH3(a) confirmed an envelope confor-
mation for isopropylidine ring and NOE between N-
CH3 with H4 confirms that the azoxy ring is pointing
above the average plane of the seven-membered ring,
which was further supported from the minimum energy
structure (Fig. 3).
Thus, from the preceding discussion, it was evident that
the substituent on the 2-position of allylic group, influ-
ences the cyclisation, resulting in oxepanes as exclusive
products.
Therefore, the study on INC reactions was extended to
the allyl ethers 18 and 19 derived from sorbose,
wherein, in contrast to the case of 6 and 7, the 1,2-O-
isopropylidine group is on the top side, while the
aldehyde/allyl ether groups are on the bottom side of
furan ring. Accordingly, the known diacetonide 10,9
obtained from sorbose, was subjected to alkylation with
CH3I in dioxane in presence of KOH to give 11
(Scheme 2). Hydrolysis of 11 with aq. acetic acid fol-
lowed by selective protection of diol 12 with TrCl gave
13 (87%). Allylation of 13 with C and D independently
3. Conclusion
In conclusion, it is well demonstrated that the sub-
stituent on the 2-position of allylic group has a promi-
nent role in defining the regiochemical outcome, thus
resulting in seven-membered oxepane ring systems as
exclusive products.
Figure 2. Characteristic NOE’s and minimum energy structure for 9.

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 14 (2003) 3899–3905
3901
Scheme 2.
Figure 3. Characteristic NOE’s and minimum energy structure for 21.
over anhydrous Na2SO4 and concentrated below 40°C
in vacuo.
4. Experimental
NMR spectra were recorded on Varian Gemini FT-200
MHz (21°C) with 7–10 mM solutions in appropriate
solvents using TMS as internal standard. Solvents were
dried over standard drying agents and freshly distilled
prior to use. IR spectra were taken with a Perkin–
Elmer 1310 spectrometer. Mass spectra were recorded
on CEC-21-11013 or Finnigan Mat 1210 double focus-
ing mass spectrometers operating at a direct inlet sys-
tem and FABMS was measured using VG AUTOSPEC
mass spectrometers at 5 or 7 k resolution using
perflurokerosene as an internal reference. Nomencla-
ture mentioned in this section was adopted from ACD/
Name Version 1.0b, Advanced Chemistry Development
Inc., Toronto, Canada, Organic solutions were dried
4.1. 5-[2,2-Dimethyl-(4R)-1,3-dioxolan-4-yl]-2,2-
dimethyl-(3aR,5R,6S,6aR)-perhydrofuro[2,3-d][1,3]-
dioxol-6-yl 2-methylallyl ether 2
To a stirred solution of 1 (5 g, 19.23 mmol) in DMF
(10 mL), sodium hydride (1.11 g, 46.15 mmol, 50%
suspension) was added slowly at 0°C. After stirring at
room temperature for 30 min, b-methyl allyl chloride
(1.9 mL, 19.23 mmol) was added and reaction mixture
was stirred for further 1 h. It was quenched with
aqueous ammonium chloride solution (20 mL) and
extracted with ether (3×50 mL). The ether layer was
washed with water (25 mL), brine (25 mL) and dried

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G. V. M. Sharma et al. / Tetrahedron: Asymmetry 14 (2003) 3899–3905
(Na2SO4). The organic layer was evaporated and
residue obtained purified by column chromatography
(silica gel, hexane–EtOAc, 19:1) to afford 2 (4 g, 66%)
as a pale yellow syrup; [h]D=−24.3 (c 1.0, CHCl3); IR
(neat): 880, 1045, 1100, 1200, 1365, 2980 cm−1; 1H
NMR (200 MHz, CDCl3): l 5.80 (d, 1H, J=3.7 Hz,
H-1), 4.90–4.88 (2s, 2H, olefinic), 4.48 (d, 1H, J=3.7
Hz, H-2), 4.32–4.20 (m, 1H, H-4), 4.10–3.90 (m, 5H,
H-5, 6a, 6b, 7a, 7b), 3.85 (d, 1H, J=1.70 Hz, H-3), 1.70
(s, 3H, CH3), 1.50 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.32
(s, 3H, CH3), 1.29 (s, 3H, CH3); EIMS (m/z, %): 299
(M+−15, 20), 127 (10), 101 (43), 85 (11), 55 (100). Anal.
calcd for C16H26O6: C, 61.13; H, 8.34. Found: C, 61.07;
H, 8.30.
aq. acetic acid (10 mL) was stirred at room temperature
for 12 h, it was worked-up and purified as described for
4 to afford 5 (1.49 g, 86%) as a pale yellow syrup;
[h]D=−14.5 (c 6.45, CHCl3); IR (neat): 1024, 1072,
1168, 1376, 1712, 2976, 3488 cm−1; 1H NMR (200
MHz, CDCl3): l 6.32–5.90 (2s, 2H, olefinic), 5.85 (d,
1H, J=3.72 Hz, H-1), 4.50 (d, 1H, J=3.72 Hz, H-2),
4.30–4.18 (m, 3H, H-4, -OCH
H-3, 5), 4.0–3.57 (m, 4H, H-6a, 6b, 7a, 7b), 1.48 (s, 3H,
6 2CH3), 4.16–4.0 (m, 2H,
CH3), 1.39–1.22 (m, 6H, CH3, -OCH2CH6 3); FABMS
(m/z, %): 355 (M++23, 12), 332 (M+, 4), 275 (24), 127
(46), 85 (100), 59 (76).
4.2. Ethyl 2-[5-[2,2-dimethyl-(4R)-1,3-dioxolan-4-yl]-2,2-
dimethyl-(3aR,5R,6S,6aR)-perhydrofuro[2,3-d][1,3]di-
oxol-6-yloxymethyl]acrylate 3
4.5. 6,6,12,14-Tetramethyl-(1S,2R,4R,8R,9S,12R)-
3,5,7,10,13-pentaoxa-14-azatetracyclo[10.2.1.02,9.04,8]-
pentadecane 8
To a stirred solution of 1 (2.00 g, 7.69 mmol) in DMF
(5 mL), sodium hydride (0.44 g, 18.46 mmol, 50%
suspension) was added slowly at 0°C. After stirring at
room temperature for 30 min, ethyl 2-bromo methyl
acrylate (1.48 g, 7.69 mmol) was added and after 1 h, it
was worked-up and purified as described for 2 to afford
3 (1.94 g, 68%) as a pale yellow syrup; [h]D=−20.1 (c
5.65, CHCl3); IR (neat): 848, 1024, 1056, 1168, 1376,
1712, 2993 cm−1; 1H NMR (200 MHz, CDCl3): l
6.31–5.94 (2s, 2H, olefinic), 5.8 (d, 1H, J=3.5 Hz, H-1),
4.58 (d, 1H, J=3.5 Hz, H-2), 4.39–4.20 (m, 5H, H-3, 5,
To a stirred solution of 4 (0.90 g, 3.28 mmol) in CH2Cl2
(10 mL), sat. sodium bicarbonate solution (0.4 mL) was
added followed by sodium periodate (1.40 g, 6.56
mmol) at 0°C and reaction mixture stirred for 5 h.
After completion of the reaction (TLC analysis), solid
Na2SO4 (0.50 g) was added, stirred for further 20 min
and extracted with CH2Cl2. Organic layer was dried
(Na2SO4) and evaporated to afford 2,2-dimethyl-6-(2-
methylallyloxy)-(3aR,5S,6R,6aR)-perhydrofuro[2,3-d]-
[1,3]dioxole-5-carbaldehyde 6 (0.65 g, 82%) as a colour-
less syrup, which was used as such for the next reaction.
4, -OCH
1.52 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.40–1.25 (m, 9H,
CH3, CH3, OCH2CH3
); FABMS (m/z, %): 372 (M+, 8),
357 (48), 281 (12), 147 (100), 127 (36), 101 (52), 73 (76).
Anal. calcd for C18H28O8: C, 58.05; H, 7.58. Found: C,
58.01; H, 7.53.
6 2CH3), 4.10–3.93 (m, 4H, H-6a, 6b, 7a, 7b),
A mixture of 6 (0.65 g, 2.68 mmol), N-methyl hydroxyl-
amine hydrochloride (0.22 g, 2.68 mmol) and Et3N
(0.75 mL, 5.37 mmol) in toluene (6 mL) was heated at
reflux for 5 h. Toluene was removed and the residue
obtained was purified by column chromatography (sil-
ica gel, hexane–EtOAc, 9:1) to afford 8 (0.545 g, 75%)
as a white solid; mp 94–96°C; [h]D=−17.25 (c 0.75,
CHCl3); IR (KBr): 815, 1011, 1100, 1216, 1372, 1455,
6
4.3. 1-[2,2-Dimethyl-6-(2-methylallyloxy)-(3aR,5R,6S,
6aR)-perhydrofuro[2,3-d][1,3]dioxol-5-yl]-(1R)-ethane-
1,2-diol 4
1
2969 cm−1; H NMR (500 MHz, CDCl3): l 5.88 (d, 1H,
J=3.7 Hz, H-1), 4.41 (d, 1H, J=3.7 Hz, H-2), 4.16
(ddd, 1H, J=1.0, 1.7, 3.5 Hz, H-4), 4.09 (d, 1H, J=1.7
Hz, H-3), 3.60 (dd, 1H, J=3.5, 6.5 Hz, H-5), 3.44 (q,
2H, J=12.5 Hz, H-7a, 7b), 2.76 (s, 3H, N-CH3), 2.72
(d, 1H, J=12.5 Hz, H-6a), 2.20 (ddd, 1H, J=1.0, 6.5,
12.5 Hz, H-6b), 1.48 (s, 3H, CH3), 1.39 (s, 3H, CH3),
1.32 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) 111.57,
104.26, 85.80, 84.44, 82.35, 79.18, 76.65, 66.63, 46.58,
33.49, 26.56, 26.07, 25.34; EIMS (m/z, %): 271 (M+,
10), 256 (8), 98 (40), 69 (36), 57 (30), 43 (100). Anal.
calcd for C13H21NO5: C, 57.55; H, 7.80. Found: C,
57.49; H, 7.77.
A solution of compound 2 (3 g, 9.55 mmol) in 60% aq.
acetic acid (15 mL) was stirred at room temperature for
12 h. It was neutralized with solid sodium bicarbonate
(15 g), extracted into ethyl acetate (2×75 mL) and the
organic layer was dried (Na2SO4). Evaporation of the
solvent and purification of residue by column chro-
matography (silica gel, hexane–EtOAc, 3:2) afforded 4
(2.1 g, 80%) as a pale yellow syrup; [h]D=−34.4 (c 1.0,
CHCl3); IR (neat): 830, 1075, 1170, 2970, 3480 cm−1; 1H
NMR (200 MHz, CDCl3): l 5.85 (d, 1H, J=3.65 Hz,
H-1), 4.98–4.90 (2s, 2H, olefinic), 4.51 (d, 1H, J=3.65
Hz, H-2), 4.12–3.90 (m, 5H, H-4, 6a, 6b, 7a, 7b),
3.82–3.65 (m, 2H, H-3, 5), 2.86 (bs, 1H, -OH), 2.61 (bs,
1H, -OH), 1.78 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.25 (s,
3H, CH3); EIMS (m/z, %): 259 (M+−15, 4), 155 (10),
127 (50), 113 (60), 71 (57), 43 (100).
4.6. Ethyl 6,6,14-trimethyl-(1S,2R,4R,8R,9S,12R)-
3,5,7,10,13-pentaoxa-14-azatetracyclo[10.2.1.02,9.04,8]-
pentadecane-12-carboxylate 9
4.4. Ethyl 2-[5-[1,2-dihydroxy-(1R)-ethyl]-2,2-dimethyl-
(3aR,5R,6S,6aR)-perhydrofuro[2,3-d][1,3]dioxol-6-
yloxymethyl]acrylate 5
To a stirred solution of 5 (1.48 g, 4.46 mmol) in CH2Cl2
(15 mL), sat. sodium bicarbonate solution (0.6 mL) was
added followed by sodium periodate (1.91 g, 8.92
mmol) at 0°C and reaction mixture stirred for 5 h. It
A solution of compound 3 (1.94 g, 5.20 mmol) in 60%

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 14 (2003) 3899–3905
3903
was worked-up as described for 6 to afford ethyl 2-[5-
formyl - 2,2 - dimethyl - (3aR,5S,6R,6aR) - perhydrofuro-
[2,3-d][1,3]dioxol-6-yloxymethyl]acrylate 7 (0.99 g, 74%)
as a colourless syrup, which was used as such for the
next reaction.
matography (silica gel, hexane–EtOAc, 1:1) afforded 12
(8.13 g, 80%) as a pale yellow syrup; [h]D=+29.9 (c
8.85, CHCl3); IR (neat): 1104, 1200, 1360, 2944, 3424
cm−1; 1H NMR (500 MHz, CDCl3): l 4.42 (s, 1H, H-2),
4.35 (dt, 1H, J=2.7, 5.2, 5.2 Hz, H-4), 4.19 (dd, 1H,
J=2.7, 10.5 Hz, H-3), 3.94 (m, 2H, H-5a, 5b), 3.82 (d,
1H, J=10.5, -OH), 3.66 (abq, 2H, J=10.1 Hz,
A mixture of 7 (0.99 g, 3.3 mmol), N-methyl hydroxyl-
amine hydrochloride (0.275 g, 3.3 mmol) and Et3N
(0.92 mL, 6.6 mmol) in toluene (10 mL) was heated at
reflux for 5 h. It was worked-up and purified as
described for 8 to afford 9 (0.54 g, 50%) as a white
solid; mp 65–67°C; [h]D=+71.0 (c 0.5, CHCl3); IR
(KBr): 1015, 1092, 1246, 1384, 1738, 2910, 2992 cm−1;
1H NMR (500 MHz, CDCl3): l 5.89 (d, 1H, J=3.7 Hz,
H-1), 4.44 (d, 1H, J=3.7 Hz, H-2), 4.23 (q, 2H, J=7.1
-CH6 2OCH3), 3.48 (s, 3H, -OCH3), 1.52 (s, 3H), 1.35 (s,
3H); FABMS (m/z, %): 280 (M++46, 20), 257 (M++23,
40), 235 (M++1, 12), 217 (38), 147 (44), 127 (54), 85
(89), 73 (100).
4.9. 3a-Methoxymethyl-2,2-dimethyl-5-trityloxymethyl-
(3aS,5S,6R,6aS)-perhydrofuro[2,3-d][1,3]dioxol-6-ol 13
Hz, OCH6 2CH3), 4.17 (ddd, 1H, J=1.0, 1.8, 3.5 Hz,
To a stirred solution of 12 (2.5 g, 10.6 mmol) in CH2Cl2
(10 mL), Et3N (2.96 mL, 21.3 mmol) followed by trityl
chloride (3.54 g, 12.72 mmol) were added at 0°C. After
6 h, it was diluted with CH2Cl2 (50 mL) and the organic
layer was washed with water (50 mL), brine (50 mL)
and dried (Na2SO4). Evaporation of the solvent and
purification of residue by column chromatography (sil-
ica gel, hexane–EtOAc 19:1) afforded 13 (4.43 g, 87%)
as a pale yellow syrup; [h]D=+20.75 (c 4.90, CHCl3);
H-4), 4.09 (d, 1H, J=1.8 Hz, H-3), 3.68 (dd, 1H,
J=3.5, 6.4 Hz, H-5), 3.94 (d, 1H, J=12.7 Hz, H-7a),
3.65 (d, 1H, J=12.7 Hz, H-7b), 2.77 (s, 3H, N-CH3),
2.88 (d, 1H, J=12.6 Hz, H-6a), 2.68 (ddd, 1H, J=1.0,
6.4, 12.6 Hz, H-6b), 1.49 (s, 3H, CH3), 1.30 (s, 3H,
CH3), 1.30 (t, 3H, J=7.1 Hz, OCH2CH6 3
); 13C NMR
(75 MHz, CDCl3) 170.87, 111.80, 104.26, 87.86, 84.39,
82.27, 79.91, 72.81, 66.52, 61.88, 45.81, 31.45, 26.60,
26.10, 13.99; FABMS (m/z, %): 330 (M++1, 100), 156
(20), 109 (15), 95 (26), 83 (27), 55 (50). Anal. calcd for
C15H23NO7: C, 54.70; H, 7.04. Found: C, 54.61; H,
6.99.
1
IR (neat): 704, 1120, 1232, 1440, 2944, 3440 cm−1; H
NMR (500 MHz, CDCl3): l 7.48 (m, 6H, Ar-H), 7.29
(m, 6H, Ar-H), 7.22 (m, 3H, Ar-H), 4.41 (s, 1H, H-2),
4.36 (dt, 1H, J=2.4, 5.6 Hz, H-4), 4.14 (dd, 1H, J=2.4,
10.5 Hz, H-3), 3.63 (abq, 2H, J=10.1 Hz, -CH6 2OCH3),
3.42 (s, 3H, -OCH3), 3.40 (m, 2H, H-5a, 5b), 1.53 (s,
3H), 1.35 (s, 3H); FABMS (m/z, %): 233 (M+−243, 6),
243 (100), 165 (16).
4.7. 3a-Methoxymethyl-2,2,7,7-tetramethyl-(3aS,4aS,
8aR,8bS)-perhydro[1,3]dioxolo[4%,5%:4,5]furo[3,2-d]-
[1,3]dioxine 11
To a solution of 10 (13.0 g, 50.0 mmol) in 1,4-dioxane
(65 mL), solid KOH (8.41 g, 150.0 mmol) was added
and heated at reflux for 2 h. The reaction mixture was
cooled to 0°C and CH3I (6.4 mL, 100.0 mmol) was
added. After 5 h, 1,4-dioxane was removed on rotava-
por, the reaction mixture was treated with water (50
mL) and extracted with ether (3×75 mL). Ethereal layer
was washed with water (50 mL), brine (50 mL), dried
(Na2SO4) and evaporated. The residue obtained was
purified by column chromatography (silica gel, hexane–
EtOAc, 9:1) to afford 11 (11.91 g, 87%) as a pale yellow
syrup; [h]D=−5.25 (c 6.35, CHCl3); IR (neat): 1120,
1200, 1376, 2928, 2992 cm−1; 1H NMR (500 MHz,
CDCl3): l 4.53 (s, 1H, H-2), 4.44 (ddd, 1H, J=2.2, 5.3
Hz, H-4), 4.31 (d, 1H, J=2.2 Hz, H-3), 3.96 (abq, 2H,
4.10. 3a-Methoxymethyl-2,2-dimethyl-6-(2-methylallyl-
oxy)-5-trityloxymethyl-(3aS,5S,6R,6aS)-perhydro-
furo[2,3-d][1,3]dioxole 14
To a stirred solution of 13 (2 g, 4.2 mmol) in DMF (5
mL), sodium hydride (0.24 g, 10.00 mmol, 50% suspen-
sion) was added slowly at 0°C. After stirring at room
temperature for 30 min, b-methyl allyl chloride (0.41 g,
4.2 mmol) was added and after 1 h, it was worked-up
as described for 2 to afford 14 (1.67 g, 75%) as a white
solid; mp 128–130°C; [h]D=+29.6 (c 6.30, CHCl3); IR
(KBr): 704, 1088, 1200, 1376, 1456, 2848, 2928 cm−1; 1H
NMR (500 MHz, CDCl3): l 7.49 (m, 6H, Ar-H), 7.25
(m, 6H, Ar-H), 7.18 (m, 3H, Ar-H), 4.95–4.75 (m, 2H,
olefinic), 4.42 (s, 1H, H-2), 4.39 (dt, 1H, J=3.4, 4.9, 4.9
Hz, H-4), 3.90 (td, 1H, J=12.7, 1.3 Hz, H-7a), 3.85 (d,
1H, J=3.4 Hz, H-3), 3.75 (td, 1H, J=1.3, 12.5, Hz,
H-7b), 3.50 (dd, 1H, J=5.4, 9.1 Hz, H-5a), 3.42 (abq,
J=8.6 Hz, -CH6 2OCH3), 3.74 (m, 2H, H-5a, 5b), 3.48 (s,
3H, -OCH3), 1.49 (s, 3H), 1.44 (s, 3H), 1.41 (s, 3H),
1.28 (s, 3H); EIMS (m/z, %): 259 (M+−15, 20), 210 (10),
171 (15), 101 (40), 85 (43), 45 (100).
2H, J=12.4 Hz, -CH6 2OCH3), 3.40 (s, 3H, -OCH3), 3.2
(dd, 1H, J=9.1, 7.7 Hz, H-5b), 1.60 (s, 3H, CH3), 1.57
(s, 3H), 1.37 (s, 3H); FABMS (m/z, %): 287 (M+−243,
4), 243 (10), 109 (45), 95 (62), 55 (100).
4.8. 5-Hydroxymethyl-3a-methoxymethyl-2,2-dimethyl-
(3aS,5S,6R,6aS)-perhydrofuro[2,3-d][1,3]dioxol-6-ol 12
A solution of compound 11 (11.9 g, 43.4 mmol) in 80%
aq. acetic acid (80 mL) was stirred at room temperature
for 12 h. It was neutralised with solid sodium bicarbon-
ate (90 g), extracted into ethyl acetate (2×75 mL) and
the organic layer dried (Na2SO4). Evaporation of the
solvent and purification of residue by column chro-
4.11. Ethyl 2-[3a-methoxymethyl-2,2-dimethyl-5-trityl-
oxymethyl-(3aS,5S,6R,6aS)-perhydrofuro[2,3-d][1,3]-
dioxol-6-yloxymethyl]acrylate 15
To a stirred solution of 13 (1.6 g, 3.35 mmol) in DMF
(5 mL), sodium hydride (0.19 g, 8.05 mmol, 50% sus-

3904
G. V. M. Sharma et al. / Tetrahedron: Asymmetry 14 (2003) 3899–3905
pension) was added slowly at 0°C. After stirring at
room temperature for 30 min, ethyl 2-bromo methyl
acrylate (0.65 g, 3.35 mmol) was added. After 1 h, it
was worked-up and purified as described for 2 to afford
15 (1.265 g, 64%) as a pale yellow syrup; [h]D=+43.0 (c
3.45, CHCl3); IR (neat): 720, 1088, 1376, 1712, 2928
cm−1; 1H NMR (500 MHz, CDCl3): l 7.42 (m, 6H,
Ar-H), 7.27 (m, 6H, Ar-H), 7.21 (m, 3H, Ar-H), 6.16
(dt, 1H, J=2.9, 1.3, 1.3 Hz, olefinic), 5.58 (dt, 1H,
J=2.9, 1.3, 1.3 Hz, olefinic), 4.52 (s, 1H, H-2), 4.47
(ddd, 1H, J=3.1, 5.5, 7.8 Hz, H-4), 4.31(td, 1H, J=
14.0, 1.3, 1.3 Hz, H-7a), 4.17 (q, 2H, J=7.2 Hz,
5.5, 7.7 Hz, H-4), 4.35 (td, 1H, J=12.9, 1.2, 1.2 Hz,
H-7a), 4.24 (q, 2H, J=7.1 Hz, -OCH2CH3), 4.18 (td,
1H, J=12.9, 1.1, 1.1 Hz, H-7b), 4.05 (d, 1H, J=3.3 Hz,
H-3), 3.84 (m, 2H, H-5a, 5b), 3.57 (abq, 2H, J=10.5
6
Hz, -CH6 2OCH3), 3.43 (s, 3H, -OCH3), 1.50 (s, 3H,
-CH3), 1.41 (s, 3H), 1.23 (t, 3H, J=7.1 Hz, OCH2CH6 3);
FABMS (m/z, %): 346 (M+, 4), 355 (8), 281 (29), 242
(40), 147 (60), 73 (100), 55 (60). Anal. calcd for
C16H26O8: C, 55.48; H, 7.57. Found: C, 55.40; H, 7.52.
4.14. 4-Methoxymethyl-6,6,12,14-tetramethyl-(1R,2S,4S,
8S,9R,12S)-3,5,7,10,13-pentaoxa-14-azatetracyclo-
[10.2.1.02,9.04,8]pentadecane 20
-OCH
4.05 (d, 1H, J=3.1 Hz, H-3), 3.49 (abq, 2H, J=11.0
Hz, -CH2OCH3), 3.45 (dd, 1H, J=5.5, 9.2 Hz H-5a),
6 2CH3), 4.12 (td, 1H, J=14.0, 1.3, 1.3 Hz, H-7b),
6
3.38 (s, 3H, -OCH3), 3.28 (dd, 1H, J=9.2, 7.8 Hz,
H-5b), 1.55 (s, 3H), 1.40 (s, 3H), 1.26 (t, 3H, J=7.2 Hz,
To a stirred solution of oxalyl chloride (0.20 mL, 2.28
mmol) in dry CH2Cl2 (5 mL), dry DMSO (0.32 mL,
4.57 mmol) was added at −78°C. After stirring at the
same temperature for 20 min, a solution of 16 (0.60 g,
2.08 mmol) in dry CH2Cl2 (5 mL) was added dropwise
and the reaction mixture stirred for further 3 h. It was
quenched with Et3N (1.73 mL, 12.48 mmol) and stirred
till reaction mixture comes to room temperature. It was
diluted with CH2Cl2 (25 mL) and organic layer was
washed with water (25 mL), brine (25 mL), dried
(Na2SO4) and evaporated to afford 3a-methoxymethyl-
2,2-dimethyl-6-(2-methylallyloxy)-(3aS,5R,6R,6aS)-per-
hydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde 18 (0.50 g,
84%) as a light brown syrup, which was used as such
for the next reaction.
OCH2CH6 3
); FABMS (m/z, %): 345 (M+−243, 10), 380
(20), 243 (100), 165 (24).
4.12. 3a-Methoxymethyl-2,2-dimethyl-6-(2-methylallyl-
oxy)-(3aS,5S,6R,6aS)-perhydrofuro[2,3-d][1,3]dioxol-5-
ylmethanol 16
To a stirred solution of 14 (1.67 g, 3.1 mmol) in CH2Cl2
(15 mL), trifluoroacetic acid (1.64 mL) was added at
0°C and stirred at room temperature for 1 h. It was
quenched with aq. sodium bicarbonate solution (25
mL) and extracted with CH2Cl2 (3×30 mL). Organic
layer was washed with water (25 mL), brine (25 mL)
and dried (Na2SO4). Evaporation of solvent and purifi-
cation of residue by column chromatography (silica gel,
hexane–EtOAc, 3:2) afforded 16 (0.6 g, 66%) as a pale
yellow syrup; [h]D=+32.4 (c 5.50, CHCl3); IR (neat):
A mixture of 18 (0.50 g, 1.75 mmol), N-methyl hydrox-
ylamine hydrochloride (0.146 g, 1.75 mmol) and Et3N
(0.49 mL, 3.50 mmol) in toluene (5 mL) was heated at
reflux for 5 h and worked-up as described for 8 to
afford 20 (0.44 g, 80%) as a white solid; mp 113–115°C;
[h]D=+21.3 (c 0.5, CHCl3); IR (KBr): 1030, 1107, 1369,
1
880, 1040, 1120, 1200, 1360, 1456, 2920, 3456 cm−1; H
NMR (500 MHz, CDCl3): l 5.0–4.88 (m, 2H, olefinic),
4.54 (s, 1H, H-2), 4.40 (dt, 1H, J=3.3, 4.8, 4.8 Hz,
H-4), 4.04 (td, 1H, J=12.5, 1.1 Hz, H-7a), 3.99 (d, 1H,
J=3.3 Hz, H-3), 3.94 (td, 1H, J=4.8, 12.1 Hz, H-5a),
3.88 (td, 1H, J=12.5, 1.1 Hz, H-7b), 3.86 (dd, 1H,
J=4.8, 12.1 Hz, H-5b), 3.61 (abq, 2H, J=12.4 Hz,
1
2912, 2995 cm−1; H NMR (500 MHz, CDCl3): l 4.34
(s, 1H, H-2), 4.26 (ddd, 1H, J=1.1, 1.8, 3.1 Hz, H-4),
4.09 (d, 1H, J=1.8 Hz, H-3), 3.64 (d, 1H, J=10.8 Hz,
H-7a), 3.57 (dd, 1H, J=3.1, 6.4 Hz, H-5), 3.57 (d, 1H,
J=10.8 Hz, H-7b), 3.45 (s, 2H, CH6 2OCH3), 3.45 (s,
3H, -OCH3), 2.75 (s, 3H, N-CH3), 2.67 (d, 1H, J=12.7
Hz, H-6a), 2.19 (ddd, 1H, J=1.1, 6.4, 12.7 Hz, H-6b),
1.50 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.38 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3) 112.78, 112.22, 85.83,
84.42, 82.32, 79.81, 77.07, 72.75, 66.80, 59.72, 46.59,
33.58, 27.36, 26.26, 25.35; FABMS (m/z, %): 316 (M++
1, 96), 258 (22), 185 (40), 133 (22), 93 (84), 55 (100).
Anal. calcd for C15H25NO6: C, 57.13; H, 7.99. Found:
C, 58.06; H, 7.93.
-CH6 2OCH3), 3.44 (s, 3H, -OCH3), 1.73 (s, 3H, CH3),
1.51 (s, 3H), 1.41 (s, 3H); FABMS (m/z, %): 289
(M++1, 20), 231 (12), 109 (32), 95 (45), 69 (62), 55 (100).
Anal. calcd for C14H24O6: C, 58.32; H, 8.39. Found: C,
58.25; H, 8.33.
4.13. Ethyl 2-[5-hydroxymethyl-3a-methoxymethyl-2,2-
dimethyl-(3aS,5S,6R,6aS)-perhydrofuro[2,3-d][1,3]dioxol-
6-yloxymethyl]acrylate 17
4.15. Ethyl-4-methoxymethyl-6,6,14-trimethyl-(1R,2S,4S,
8S,9R,12S)-3,5,7,10,13-pentaoxa-14-azatetracyclo-
[10.2.1.02,9.04,8]pentadecane-12-carboxylate 21
To a stirred solution of 15 (1.26 g, 2.13 mmol) in
CH2Cl2 (10 mL), trifluoroacetic acid (1.2 mL) was
added at 0°C, stirred at room temperature for 1 h and
worked-up and purified as described for 16 to afford 17
(0.52 g, 70%) as a pale yellow syrup; [h]D=+14.8 (c
5.30, CHCl31); IR (neat): 1120, 1200, 1376, 1712, 2944,
3472 cm−1; H NMR (500 MHz, CDCl3): l 6.32 (dt,
1H, J=2.8, 1.2 Hz, olefinic), 5.82 (dt, 1H, J=2.8, 1.2
Hz, olefinic), 4.57 (s, 1H, H-2), 4.43 (ddd, 1H, J=3.3,
To a stirred solution of oxalyl chloride (0.12 mL, 1.43
mmol) in dry CH2Cl2 (5 mL), dry DMSO (0.2 mL, 2.86
mmol) was added at −78°C. After 20 min, a solution of
17 (0.45 g, 1.30 mmol) in dry CH2Cl2 (5 mL) was added
dropwise. After 3 h, it was quenched with Et3N (1.08
mL, 7.8 mmol) and worked-up as described for 18 to

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 14 (2003) 3899–3905
3905
afford
ethyl
2-[5-formyl-3a-methoxymethyl-2,2-di-
2. (a) Crawley, G. C.; Dowell, R. I.; Edwards, P.; Foster, S.
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863–909; (b) Torssell. K. B. G. In Organic Synthesis.
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methyl - (3aS,5R,6R,6aS) - perhydrofuro[2,3 - d][1,3]-
dioxol-6-yloxymethyl]acrylate 19 (0.27 g, 60%) as a
light brown syrup, which was used as such for the next
reaction.
A mixture of 19 (0.27 g, 0.78 mmol), N-methyl hydrox-
ylamine hydrochloride (0.066 g, 0.78 mmol) and Et3N
(0.22 mL, 1.57 mmol) in toluene (5 mL) was heated at
reflux for 5 h. It was worked-up as described for 8 to
afford 21 (0.155 g, 53%) as a white solid; mp 66–68°C;
[h]D=−26.3 (c 0.5, CHCl3); IR (KBr): 1050, 1200, 1250,
1500, 1720, 2905, 2998 cm−1; 1H NMR (500 MHz,
CDCl3): l 4.36 (s, 1H, H-2), 4.27 (ddd, 1H, J=1.1, 2.1,
3.1 Hz, H-4), 4.22 (q, 2H, J=7.2 Hz, OCH6 2CH3), 4.09
(d, 1H, J=2.1 Hz, H-3), 3.95 (d, 1H, J=12.8 Hz,
H-7a), 3.64 (dd, 1H, J=3.1, 6.5 Hz, H-5), 3.62 (d, 1H,
J=12.8 Hz, H-7b), 3.61 (q, 2H, J=10.7 Hz,
CH6 2OCH3), 3.45 (s, 3H, -OCH3), 2.76 (s, 3H, N-CH3),
2.83 (d, 1H, J=12.6 Hz, H-6a), 2.66 (ddd, 1H, J=1.1,
6.5, 12.6 Hz, H-6b), 1.50 (s, 3H, CH3), 1.38 (s, 3H,
CH3), 1.29 (t, 3H, J=7.2 Hz, OCH2CH6 3
); 13C NMR
(75 MHz, CDCl3) 170.90, 112.80, 112.41, 87.86, 84.33,
82.58, 79.48, 72.83, 72.67, 66.63, 61.86, 59.76, 45.79,
31.53, 27.36, 26.25, 13.99; FABMS (m/z, %): 374 (M++
1, 100), 316 (62), 270 (10), 188 (20), 129 (18), 113 (28).
Anal. calcd for C17H27NO8: C, 54.68; H, 7.29. Found:
C, 54.62; H, 7.24.
Acknowledgements
The authors, K.R.R. and A.R.S. would like to thank
the CSIR, New Delhi, for financial support.
References
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