Asymmetric oxidopyrylium-alkene [5+2] cycloaddition: A divergent approach for the synthesis of enantiopure oxabicyclo[5.4.0]undecanes

Article abstract of DOI:10.1016/j.tet.2004.04.003

A Chiron approach to the synthesis of enantiomeric oxabicyclic adducts 16 and 32 has been developed employing an intramolecular [5+2] cycloaddition of 3-oxidopyrylium with unsaturated sugars.

Full text of DOI:10.1016/j.tet.2004.04.003

Tetrahedron 60 (2004) 4829–4836
Asymmetric oxidopyrylium-alkene [512] cycloaddition:
a divergent approach for the synthesis of enantiopure
oxabicyclo[5.4.0]undecanesq;qq
*
U. Murali Krishna, Kodand D. Deodhar and Girish K. Trivedi
*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Received 5 January 2004; revised 8 March 2004; accepted 1 April 2004
Abstract—A Chiron approach to the synthesis of enantiomeric oxabicyclic adducts 16 and 32 has been developed employing an
intramolecular [5þ2] cycloaddition of 3-oxidopyrylium with unsaturated sugars.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
little attention in an efficient [5þ2] annulation method, is
the asymmetric version of the cycloaddition reaction,
despite numerous applications of this class of reactions in
organic synthesis. Taking into account the various
approaches reported in the literature in this context,3 we
embarked on the development of novel routes to access
chiral oxabicyclo adducts. We wish to report here a chiral
pool approach for the asymmetric synthesis of oxabicyclic
adducts. We demonstrate that the reactions of optically
active unsaturated aldehydes derivable from the appropriate
sugar derivatives, with 2-lithiofuran provides useful 2-furyl-
carbinol intermediates and suitable manipulations of these
systems lead to a convenient and flexible route to the
asymmetric synthesis of oxabicyclo[m.n.0]adducts. We also
3-Oxidopyrylium-alkene [5þ2] cycloaddition provides an
interesting and potentially versatile entry into highly
functionalized oxabicyclo[3.2.1]octane frameworks from
simple precursors. The rapid generation of molecular
complexity in a relatively easy manner, has made this
approach a highly useful tool in the synthesis of seven-
membered ring containing complex natural products.
Notably, Wender and coworkers have successfully applied
this strategy, in an intramolecular fashion, to the total
synthesis of natural products phorbol and resiniferatoxin.1,2
However, compared to other cycloaddition strategies, one of
the most important aspects that have received relatively
Scheme 1.
q CDRI Communication No. 6414.
qq Supplementary data associated with this article can be found in the online version, at doi: 10.1016/j.tet.2004.04.003
Keywords: D-Ribose; 3-Oxidopyrylium; Asymmetric synthesis; [5þ2] Cycloaddition.
*
Corresponding authors. Tel.: þ91-2225767169; fax: þ91-2225723480; e-mail address: chgktia@chem.iitb.ac.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.003

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U. Murali Krishna et al. / Tetrahedron 60 (2004) 4829–4836
Scheme 2. (a) Me2CO, H2SO4 (cat); (b) NaBH4, MeOH, 2 h; (c) NaIO4, H2O, 84% (3 steps); (d) allylMgBr, 278 8C; (e) TBDMSCl, imidazole, THF, 72%
(2 steps); (f) NaH, BnBr, THF, 0 8C; (g) Bu4NF, THF, rt, 2 h.
demonstrate that exploitation of the pseudo-symmetry of
chosen sugar starting material, leads to the synthesis of the
enantiomeric partners of the oxabicyclic adducts.4
Isopropylidenation of D-ribose 6 with acetone in the
presence of catalytic amount of sulfuric acid gave 2,3-O-
isopropylidene-D-ribose 7. Compound 7 on reduction with
sodium borohydride afforded the triol, which on oxidative
cleavage with sodium periodate (NaIO4) gave 2,3-O-
isopropylidene-L-erythrose 8 in 84% yield from 7 (Scheme
2).6 Grignard reaction of compound 8, using allylmagne-
sium bromide at 278 8C, afforded the diol 9. Selective
monoprotection of primary alcohol (TBDMSCl/imid.) in 9
provided the compound 10 in 72% yield over 2 steps. The
diastereomers (96:4, anti/syn) were separated by column
chromatography and the major isomer was carried forward.
The secondary hydroxyl group in 10 was protected as benzyl
ether using BnBr/NaH in THF/DMF (4:1) and removal of
the TBS group using tetrabutylammonium fluoride (TBAF)
afforded the aldehyde precursor 11.
2. Results and discussion
We devised a strategy with an expectation of preparing the
optically active oxabicyclo[5.4.0]undecanes. Our approach
involves the synthesis of cycloadduct of general type 1 by
intramolecular cycloaddition of the 3-oxidopyrylium 2 with
the tethered olefin. The pyrylium species 2 could be
obtained from the acetoxypyranone 3, which in turn could
be obtained from the 2-furylcarbinol 4, with requisite
stereogenic centers within the tether joining the reacting
partners. The synthesis of furylcarbinol (4) could be possible
by the reaction of 2-lithiofuran with the unsaturated
aldehyde 5 (Scheme 1).
Swern oxidation of alcohol 11 furnished the corresponding
aldehyde 12. Addition of 2-lithiofuran (generated in situ by
treating furan with n-BuLi at 0 8C) to aldehyde 12 at 278 8C
afforded the furylcarbinol 13 (Scheme 3). Oxidative
rearrangement of 13 using VO(acac)2/t-BuOOH7 in
CH2Cl2 gave the hydroxypyranone 14 and acetylation of
the anomeric hydroxyl gave the acetoxypyranone 15 in 88%
yield from 13. Oxidopyrylyum-alkene cycloaddition
occurred upon treatment of the acetoxypyranone (15) with
Et3N (4 equiv.) in CH3CN under reflux, affording the
The importance of carbohydrates as versatile sources of
chiral information in the asymmetric synthesis of various
complex organic molecules is well recognized.5 Our initial
efforts were focused on the synthesis of optically active
unsaturated aldehydes from the appropriate sugar starting
material. After scrutinizing various cheap and commercially
available carbohydrates, we chose ribose for our purpose.
Scheme 3. (a) (COCl)2, DMSO, Et3N, 278 8C; (b) n-BuLi, furan, THF,
278 8C, 70%; (c) VO(acac)2, t-BuOOH, CH2Cl2; (d) Ac2O, pyridine,
DMAP, CH2Cl2, 88% (2 steps).
Scheme 4.

U. Murali Krishna et al. / Tetrahedron 60 (2004) 4829–4836
4831
Scheme 5. (a) Diallylzinc, Et2O, 0 8C, 5 h; (b) NaIO4, water, 85% (2 steps); (c) Ac2O, pyridine, CH2Cl2, 0 8C, 92%; (d) n-BuLi, furan, THF, 278 8C, 85%; (e)
VO(acac)2, t-BuOOH, CH2Cl2, rt, 3.5 h; (f) Ac2O, pyridine, CH2Cl2.
cycloadducts 16 and 17 as an inseparable mixture of
1
diastereomers (93:7, H NMR) in 65% yield (Scheme 4).
The observed diastereoselectivity of the reaction is in
accordance with that reported, which is attributed to the
stereogenic center present on the tether, next to the pyrylium
moiety.1b,e,3d
addition of diallylzinc to 7 (diastereoselectivity 96:4 anti/
syn), followed by sodium periodate cleavage of the resultant
triol 18.8 Addition of 2-lithiofuran to the lactol 19 yielded
the furylcarbinol 21, which was then oxidatively rearranged
to the hydroxypyranone 22. However, our attempts to
transform the pyranone 22 to the corresponding pyrylium
ylide precursor (acetoxypyranone) (23), were unsuccessful.
The reaction resulted in the formation of a complex mixture,
which is presumably due to existence of the hydroxy-
pyranone in the form of hemiketals (24) and/or spiroketals
(25) (Scheme 6).9
In order to synthesize other stereo-analogous [5þ2]
cycloadducts, we decided to exploit the pseudo-symmetry
of ribose. It was envisioned that the introduction of the furyl
unit on the lactol 19 (Scheme 5) would provide us an
intermediate which facilitates the reversal of the sense of the
asymmetric induction as compared to our previous intra-
molecular cycloaddition. Accordingly 2,3-O-isopropyl-
idine-D-ribose 7 was transformed to the lactol 19 by
In the light of these results we have modified our synthetic
strategy, which is outlined in Scheme 7. The lactol 19 was
oxidized to the lactone 26 by Swern oxidation conditions.
Scheme 6.
Scheme 7. (a) (COCl)2, DMSO, Et3N, 278 8C, 90%; (b) n-BuLi, furan, THF, 278 8C, 6 h, 75%; (c) AcCl, pyridine, CH2Cl2, 0 8C-rt, 96%; (d) NaBH4, MeOH,
0 8C, 93%.

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U. Murali Krishna et al. / Tetrahedron 60 (2004) 4829–4836
Figure 2.
(OBn, OAc), with diverse functionality around the ring
(Fig. 2).
Scheme 8. (a) VO(acac)2, t-BuOOH, CH2Cl2; (b) Ac2O, pyridine, DMAP,
0 8C; (c) Et3N, CH3CN, reflux, 83%.
Reaction of 2-lithiofuran on lactone 26 at 278 8C for 6 h
afforded the monoaddition product 27 in 75% yield. The
hydroxyl group in 27 was protected as acetate (AcCl/py),
and the keto group was reduced with sodium borohydride to
give compound 29 in 89% yield. Oxidative ring expansion
of 29 using VO(acac)2/t-BuOOH generated the pyranone 30
(Scheme 8). The pyranone 30 was transformed to the
acetoxypyranone 31, which upon treatment with Et3N in
CH3CN under reflux conditions smoothly underwent highly
diastereoselective cycloaddition to yield the cycloadduct 32
(83% yield) and the stereochemistry was unambiguously
established by single-crystal X-ray analysis (Fig. 1).
The presence of enone groups in the cycloadducts would
permit introduction of other functional groups in stereo-
controlled fashion by virtue of their rigid molecular
architecture. It seems reasonable to believe that by choosing
an appropriate sugar and its suitable manipulations the
methodology might find applicability in the synthesis of
various important natural products.
4. Experimental
4.1. X-ray diffraction data of 32
Crystals of 32 were obtained by slow evaporation of a
solution of 32 in a mixture of petroleum ether and ethyl
acetate at room temperature.
Chemical formula: C16H20O6; formula weight: 308.32;
crystal system: monoclinic; unit cell dimensions and
volume with estimated standard deviations: a:
˚
˚
˚
9.5590(6) A; b¼8.8780(9) A; c¼10.2790(7) A; a: 908; b:
3
˚
114.082(5)8; g: 908; volume: 796.40(11) A ; temperature
293(2) K; space group P21; number of molecules in the unit
˚
cell (Z): 2; wavelength of radiation (l): 0.70930 A; linear
absorption coefficient (m): 0.098 mm21; number of reflec-
tions measured: 1311; number of independent reflections:
1311 [Rint¼0.0000]; final R indices [I.2s(I)]: R1¼0.0404,
wR2¼0.0880. Crystallographic data (excluding structure
factors) for the structure 32 in this paper have been
deposited with the Cambridge Crystallographic Data Center
as supplementary publication number CCDC-212708.
Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: þ44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Figure 1. ORTEP drawing of the X-ray structure of 32.
4.2. Materials and general experimental procedures
3. Conclusion
The following general procedures were used in all reactions
unless otherwise noted. Oxygen- and moisture-sensitive
reactions were carried out in flame-dried glassware sealed
with a rubber septum under a positive pressure of dry
nitrogen or argon. Sensitive liquids and solutions were
transferred by syringe or cannula through rubber septa
In summary, the synthesis of optically active oxabicyclo-
[5.4.0]undecanes have been accomplished using D-ribose
as a Chiron for asymmetric induction. We have observed
that the cycloadducts 16 and 32 are pseudo enantiomers,
having variation in the hydroxyl protection groups

U. Murali Krishna et al. / Tetrahedron 60 (2004) 4829–4836
4833
through which a positive pressure of nitrogen was main-
tained. THF and Et2O were distilled from sodium-
benzophenone ketyl under nitrogen. Methylene chloride,
acetonitrile and triethylamine were distilled from calcium
hydride. Pyridine was refluxed over KOH pellets and
distilled. Melting points were determined with a veego
apparatus of Buchi type and are uncorrected. NMR spectra
were measured in a Fourier transform mode on a Varian
mercury-400 (1H at 400 MHz, 13C at 100 MHz), and Varian
VXR-300s (1H at 300 MHz, 13C at 75 MHz) magnetic
resonance spectrometer. Infrared spectra were recorded on a
Nicolet Impact 400 and Thermo Nicolet Avatar 320 series
Fourier transform spectrometer (FTIR) and are reported in
wavenumbers (cm21). Optical rotations were determined
with a JASCO DIP-370 digital polarimeter at ambient
temperature.
5.07 (m, 2H), 4.25–4.18 (m, 1H), 4.09–4.04 (m, 1H), 3.89–
3.75 (m, 3H), 3.60–3.56 (m, 1H), 2.53–2.51 (m, 1H), 2.29–
2.24 (m, 1H), 1.36 (s, 3H), 1.32 (s, 3H), 0.89 (s, 9H), 0.11 (s,
3H), 0.10 (s, 3H).
HRMS (FAB) calculated for C16H32O4SiNa: 339.1968
(MNaþ), found 339.1975.
syn Isomer: [a]2D5¼þ8.9 (c 0.56, CHCl3).
IR (neat) nmax 3420, 1645 cm21
.
1H NMR (300 MHz, CDCl3) d: 5.92–5.83 (m, 1H), 5.18–
5.10 (m, 2H), 4.18–4.13 (m, 1H), 4.09–4.06 (m, 1H), 3.95–
3.86 (m, 2H), 3.76–3.71 (m, 1H), 2.87–2.86 (d, J¼5.1 Hz,
1H), 2.37 (m, 2H), 1.48 (s, 3H), 1.37 (s, 3H), 0.90 (s, 9H),
0.10 (s, 6H).
4.2.1. 1-(5-Hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-
4-yl)-but-3-en-1-ol (9). A dry, 100 ml, three-necked,
round-bottomed flask is charged with excess of Mg (1.8 g,
0.075 g-atom) and 40 ml anhydrous Et2O. To the stirred
mixture was added dropwise a solution of allyl bromide
(7.4 g, 5.3 ml, 61 mmol) in 61 ml of Et2O at such a rate to
maintain gentle reflux. After the addition is over the mixture
was refluxed for 30 min. To this a solution of 8 (0.974 g,
6.1 mmol) in ether (20 ml) at 278 8C was added dropwise.
The resulting mixture was stirred for 1 h at 278 8C and then
allowed to warm to room temperature over 4 h. The reaction
mixture was quenched by adding cold saturated NH4Cl
(100 ml) and extracted with ethyl acetate. The organic phase
was washed with brine and dried over Na2SO4. The crude
reaction mixture was filtered and concentrated under
reduced pressure. The crude mixture can be used directly
in the next step.
13C NMR (75 MHz, CDCl3) d: 135.0, 117.4, 108.1, 78.9,
77.3, 68.5, 61.9, 39.0, 27.4, 25.9, 25.2, 18.4, 25.3.
4.2.3. [5-(1-Benzyloxy-but-3-enyl)-2,2-dimethyl-[1,3]-
dioxolan-4-yl]-methanol (11). To a solution of anti-isomer
10 (0.3 g, 0.95 mmol) in THF (5 ml) at 0 8C was added NaH
(60 mg, 60%) and benzyl bromide (0.2 ml) and the resulting
mixture was stirred for 3 h. The reaction mixture was
quenched by addition of saturated NH4Cl and extracted with
ether. The organic phase was washed with water, brine and
dried over Na2SO4. The crude reaction mixture was filtered
and concentrated under reduced pressure. Purification of the
resultant residue by flash chromatography afforded the
product.
[a]2D5¼215.7(c 0.83, CHCl3).
[a]2D5¼þ51.7 (c 0.6, CHCl3). IR (neat) nmax 3422,
IR (neat) nmax 3420, 1645 cm21
.
1645 cm21
.
1H NMR (300 MHz, CDCl3) d: 7.38–7.30 (m, 5H), 5.98–
5.94 (m, 1H), 5.20 (m, 2H), 4.65 (d, J¼11.1 Hz, AB system,
1H), 4.44 (d, J¼11.1 Hz, AB system, 1H) 4.23–4.12 (m,
2H), 3.90 (dd, J¼3.6, 11 Hz, 1H), 3.79–3.68 (m, 2H), 2.63–
2.40 (m, 2H), 1.46 (s, 3H), 1.35 (s, 3H), 0.95 (s, 9H), 0.89 (s,
6H).
1H NMR (300 MHz, CDCl3) d: 5.89–5.82 (m, 1H), 5.22–
5.18 (m, 2H), 4.34–4.30 (m, 1H), 4.0–3.96 (m, 1H), 3.89–
3.76 (m, 3H), 2.85 (br s, 1H), 2.61 (m, 2H), 2.20 (m, 1H),
1.41 (s, 3H), 1.35 (s, 3H).
HRMS (EI) calculated for C10H18O5: 202.1205 (Mþ), found
202.1205.
To this compound in THF (13 ml) at 0 8C was added
n-Bu4NF (0.75 ml, 1 M in THF, 0.75 mmol). After being
stirred for 2 h at room temperature, water (10 ml) was
added. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate. The combined
organic layers were washed with brine and dried over
Na2SO4. The crude reaction mixture was filtered and
concentrated under reduced pressure. Purification of the
resultant residue by flash chromatography afforded the
desired product 11 (0.174 g, 63% in 2 steps).
4.2.2. 1-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-2,2-
dimethyl-[1,3]dioxolan-4-yl]-but-3-en-1-ol (10). To the
solution of the diol 9 (0.5 g, 2.5 mmol) in THF/DMF (3:1,
5 ml) at 0 8C was added TBDMSCl (0.45 g, 2.9 mmol) and
imidazole (0.43 g, 6.25 mmol). After 1 h, the mixture was
poured into ether and the ether layer was washed with water,
saturated NaHCO3, and dried over Na2SO4. The crude
reaction mixture was filtered and concentrated under
reduced pressure. Purification of the resultant residue by
flash chromatography afforded the diastereomers 10 (anti/
syn 96:4) in 72% yield over 2 steps.
[a]2D5¼241.38 (c 0.63, CHCl3).
IR (neat) nmax 3425, 1645 cm21
.
anti Isomer: [a]2D5¼28.3 (c 0.6, CHCl3).
1H NMR (300 MHz, CDCl3) d: 7.34–7.30 (m, 5H), 6.0–
5.89 (m, 1H), 5.23–5.14 (m, 2H), 4.71 (d, J¼11 Hz, AB
system, 1H), 4.45 (d, J¼11 Hz, AB system, 1H), 4.30 (dd,
J¼6, 11.7 Hz 1H), 4.15 (dd, J¼6, 8.7 Hz, 1H), 3.79 (m, 1H),
IR (neat) nmax 3420, 1645 cm21
.
1H NMR (300 MHz, CDCl3) d: 6.19–5.91 (m, 1H), 5.18–

4834
U. Murali Krishna et al. / Tetrahedron 60 (2004) 4829–4836
3.70 (br m, 2H), 2.65 (m, 1H), 2.51 (m, 2H), 1.45 (s, 3H),
1.35 (s, 3H).
1 h and then at room temperature for 3 h. The pale yellow
solution was diluted with CH2Cl2, washed with water brine
and dried over Na2SO4. The crude reaction mixture was
filtered and concentrated under reduced pressure (nmax
3415, 1694, 1639 cm21). The resultant residue was taken in
CH2Cl2 (2 ml) containing pyridine (0.06 ml) at 0 8C, and
treated with acetic anhydride (0.24 ml) and 4-dimethyl-
aminopyridine (DMAP) (catalytic). The resulting mixture
was stirred for 1 h at 0 8C. CH2Cl2 was added and the
organic layer was treated with 5% hydrochloric acid,
saturated NaHCO3, water and dried over Na2SO4. Evapo-
ration of the solvent followed by flash column chroma-
tography afforded the desired compound 15 in quantitative
yield. This crude material was used as such in the next step.
13C NMR (75 MHz, CDCl3) d: 137.3, 133.2, 128.7, 128.2,
118.3, 108.3, 77.5, 76.3, 71.3, 61.2, 34.2, 28.0, 25.5.
HRMS (FAB) calculated for C17H24O4Na: 315.1573
(MNaþ), found 315.1567.
4.2.4. [5-(1-Benzyloxy-but-3-enyl)-2,2-dimethyl-[1,3]-
dioxolan-4-yl]-furan-2-yl-methanol (13). To a solution
of oxalyl chloride (0.044 ml, 0.63 mmol) in CH2Cl2 (1 ml)
at 278 8C was added dropwise a solution of DMSO
(0.094 ml, 1.26 mmol) in CH2Cl2 (0.5 ml). After 5 min, a
solution of the alcohol 11 (0.14 g, 0.48 mmol) in CH2Cl2
(1 ml) was added. Stirring was continued for 20 min at
278 8C and Et3N (0.33 ml, 2.39 mmol) was added drop-
wise. The resulting mixture was slowly allowed to warm to
room temperature and stirred for 1 h. Water (5 ml) was
added, and the organic layer was separated and concentrated
under reduced pressure. The residue was diluted with ether
(50 ml) and washed with water, brine and dried over
Na2SO4. The crude reaction mixture was filtered and
concentrated under reduced pressure to give the crude
aldehyde 12 (0.139 g), which was immediately used in the
next step without further purification.
IR (neat) nmax 1749, 1701 cm21
.
1H NMR (400 MHz, CDCl3) d: 7.33–7.25 (m, 5H), 6.90
(dd, J¼10, 3.6 Hz, 1H), 6.58 (d, J¼3.6 Hz, 1H), 6.22 (d,
J¼10 Hz, 1H), 5.72 (m, 1H), 5.15 (m, 2H), 4.88 (d, J¼
6.4 Hz, 1H), 4.74 (m, 2H), 4.35 (m, 2H), 4.0 (m, 1H), 2.76
(m, 1H), 2.45 (m, 1H), 2.1 (s, 3H), 1.32 (s, 3H), 1.25 (s, 3H).
To a solution of pyranone acetate 15 (0.38 g, 0.09 mmol) in
CH3CN (0.5 ml) was added Et3N (0.005 ml) at room
temperature. The reaction mixture was heated at reflux
for 20 h. After being cooled to 25 8C, the solvent was
evaporated under reduced pressure and the residue was
purified by flash chromatography to afford the cycloadduct
16 and 17 as 93:7 inseparable mixtures of diastereomers in
65% yield.
In a different flask, a solution of furan (0.33 ml, 4.32 mmol,
freshly distilled over KOH) in THF (2.86 ml) was added
dropwise a solution of n-BuLi (0.7 ml, 15% in hexane,
2.3 mmol) at 278 8C. After stirring for 3 h at 0 8C under
argon, the mixture was cooled to 278 8C and a solution of
aldehyde 12 (0.139 mg, 0.479 mmol) in THF (1 ml) was
added dropwise. The resulting mixture was stirred for 3 h
before being quenched by addition of saturated NH4Cl
solution (5 ml). The organic layer was separated and the
aqueous layer was extracted with ether. The combined
organic phases were washed with brine and dried over
Na2SO4. The crude reaction mixture was filtered and
concentrated under reduced pressure. Purification of the
resultant residue by flash chromatography afforded the
desired compound 13 (0.86 g, 70%) as yellow oil.
[a]2D5¼þ38.58 (c 0.91, CHCl3). IR (neat) nmax 1693 cm21
.
1H NMR (400 MHz, CDCl3) d: 7.4–7.2 (m, 5H), 7.2 (dd,
J¼9.6, 4.4 Hz, 1H), 5.9 (d, J¼9.6 Hz, 1H), 5.0 (d, J¼
6.8 Hz, 1H), 4.9 (m, 1H), 4.70 (d, J¼12 Hz, AB system,
1H), 4.59 (d, J¼12.4 Hz, AB system, 1H), 4.65 (m, 1H),
3.40 (m, 1H), 1.9–1.7 (m, 5H), 1.4 (s, 3H), 1.3 (s, 3H).
13C NMR (100 MHz, CDCl3) d: 197.0, 152.3, 138.0, 128.3,
127.6, 127.5, 125.5, 109.6, 84.1, 75.1, 72.9, 72.6, 70.6, 38.5,
35.5, 28.2, 26.3, 24.9.
[a]2D5¼2978 (c 0.33, CHCl3).
HRMS (EI) calculated for C21H25O5: 356.1624 (Mþ), found
356.1628.
IR (neat) nmax 3460, 1645 cm21
.
1H NMR (300 MHz, CDCl3) d: 7.35–7.25 (m, 6H), 6.30 (m,
2H), 5.94 (m, 1H), 5.2 (m, 2H), 4.92 (dd, J¼7.6, 2.4 Hz,
1H), 4.67 (d, J¼11.2 Hz, AB system, 1H), 4.5 (m, 1H), 4.40
(d, J¼10.8 Hz, AB system, 1H), 4.26 (m, 1H), 4.06 (m, 1H),
2.92 (d, J¼7.6 Hz, 1H), 2.67 (m, 1H), 2.5 (m, 1H), 1.54 (s,
3H), 1.37 (s, 3H).
4.2.6. 6-Allyl-2,2-dimethyl-dihydro-furo[3,4-d][1,3]-
dioxol-4-one (26). To a solution of oxalyl chloride
(1.56 ml, 17.94 mmol) in CH2Cl2 (40 ml) at 278 8C was
added dropwise a solution of DMSO (3.12 ml, 44.1 mmol)
in CH2Cl2 (14 ml). (3.13 g, 15.63 mmol). After 5 min, a
solution of the lactol 198 in CH2Cl2 (24 ml) was added.
Stirring was continued for 20 min at 278 8C and Et3N
(11.5 ml) was added dropwise. The resulting mixture was
allowed to warm to room temperature and stirred for 1 h.
Water (25 ml) was added, and the organic layer was
separated and concentrated under reduced pressure. The
residue was diluted with ether (50 ml) and washed with
water, brine and dried over Na2SO4. The crude reaction
mixture was filtered and concentrated under reduced
pressure. Purification of the resultant residue by flash
chromatography afforded the lactone 26 (2.8 g, 90%) as oil.
13C NMR (75 MHz, CDCl3) d: 154.9, 141.9, 137.8, 133.4,
128.8, 128.6, 128.5, 127.9, 127.8, 118.1, 110.3, 108.4,
106.9, 77.9, 77.5, 76.7, 71.1, 65.8, 34.6, 26.9, 24.7.
4.2.5. Synthesis of cycloadducts 16 and 17. To a solution
of furylcarbinol 13 (0.48 g, 0.134 mmol) in dry CH2Cl2
(1 ml) at 220 8C was added t-BuOOH (0.03 ml) and
VO(acac)2 (1.69 mg, 0.008 mmol)) under argon atmos-
phere. The resulting dark solution was stirred at 220 8C for

U. Murali Krishna et al. / Tetrahedron 60 (2004) 4829–4836
4835
[a]2D5¼þ52.58 (c 0.4, CHCl3).
IR (neat) nmax 3446, 1785, 1641 cm21
dimethyl-[1,3]dioxolan-4-yl]-but-3-enyl ester (29). To a
solution of furyl ketone 28 (0.2 g, 0.65 mmol) in MeOH
(3 ml) at 0 8C was added sodium borohydride (40 mg,
1.05 mmol). The reaction mixture was stirred at 0 8C for 1 h,
and then quenched by addition of water and extracted with
CH2Cl2. The organic phase was washed with brine and dried
over Na2SO4, filtered and evaporated. Purification of the
resultant residue by flash chromatography afforded the
desired adduct 29 (0.193 g, 93%) as yellow oil.
.
1H NMR (400 MHz, CDCl3) d: 5.76–5.69 (m, 1H), 5.24 (m,
2H), 4.71 (d, J¼6.1 Hz, 1H), 4.65 (t, J¼6.1 Hz, 1H), 4.58
(d, J¼6.1 Hz, 1H), 2.5 (m, 2H), 1.47 (s, 3H), 1.38 (s, 3H).
13C NMR (100 MHz, CDCl3) d 173.6, 130.3, 120.8, 113.7,
81.9, 78.8, 74.9, 37.5, 26.9, 25.8.
[a]2D5¼41.28 (c 0.34, CHCl3).
HRMS (FAB) calculated for C10H14NaO4: 199.0970
(MNaþ), found 199.0982.
IR (neat) nmax 3466, 1737, 1641 cm21
.
4.2.7. Acetic acid 1-[5-(furan-2-carbonyl)-2,2-dimethyl-
[1,3]dioxolan-4-yl]-but-3-enyl ester (28). To a solution of
furan (0.29 ml, 3.795 mmol) in ether (8 ml) was added
dropwise a solution of n-BuLi (1.25 ml, 15% in hexane) at
278 8C. After stirring for 3 h at 0 8C under argon, the
mixture was cooled to 278 8C and a solution of lactone 26
(0.5 g, 2.53 mmol) in ether (10 ml) was added dropwise.
The resulting mixture was stirred at 278 8C for 6 h before
being quenched by addition of methanol (1 ml). After
warming to room temperature the solution was extracted
with ether. The organic phases were washed with NH4Cl
and dried over Na2SO4. The crude reaction mixture was
filtered and concentrated under reduced pressure to afford
the furyl ketone 27 along with some amount of unreacted
lactone 26. This mixture was difficult to separate by column
chromatography and hence it was carried through the next
step.
1H NMR (300 MHz, CDCl3) d: 7.41 (s, 1H), 6.34 (m, 2H),
5.98–5.74 (m, 1H), 5.27–5.07 (m, 3H), 4.7 (d, J¼8.4 Hz,
1H), 4.5 (m, 1H), 4.43 (m, 1H), 2.5 (m, 1H), 2.3–2.2 (m,
2H), 2.1 (s, 3H), 1.4 (s, 3H), 1.3 (s, 3H).
13C NMR: (75 MHz, CDCl3) d: 170.0, 153.8, 142.2, 132.8,
118.1, 110.2, 108.6, 107.9, 78.0, 76.9, 70.4, 65.7, 35.9, 27.6,
25.4, 21.2.
HRMS (FAB) calculated for C16H23O6: 311.1494 (MHþ),
found 311.1511.
4.2.9. Synthesis of cycloadduct 32. To a solution of
furylmethanol 29 (0.1 g, 0.32 mmol) in dry CH2Cl2 (2.4 ml)
at 220 8C was added t-BuOOH (0.074 ml) and VO(acac)2
(2.69 mg, 0.012 mmol) under argon atmosphere. The
resulting dark solution was stirred at 220 8C for 1 h and
then at room temperature for 3 h. The pale yellow solution
was diluted with CH2Cl2, washed with water brine and dried
over Na2SO4. The crude reaction mixture was filtered and
concentrated under reduced pressure (nmax 3453, 1738,
1702, 1641 cm21). The resultant residue was (0.135 g,
0.41 mmol) was taken in CH2Cl2 (2 ml) containing pyridine
(0.07 ml, 0.85 mmol) at 0 8C, was treated with acetic
anhydride (0.47 ml) and 4-dimethylaminopyridine (cata-
lytic). The resulting mixture was stirred for 1 h at 0 8C.
CH2Cl2 was added and the organic layer was treated with
5% hydrochloric acid, saturated NaHCO3, water and dried
over Na2SO4. Evaporation of the solvent followed by flash
column chromatography afforded the desired compound 31
(nmax 1738, 1699, 1647 cm21) which was carried to the next
step without further purification.
To a solution of 26 (0.25 g, 0.94 mmol) in dry CH2Cl2
(4 ml) at 0 8C was added pyridine (0.27 ml, 3.29 mmol) and
freshly distilled acetyl chloride (0.14 ml, 1.9 mmol). The
resulting suspension was stirred at 0 8C for 1 h, then warmed
to room temperature and stirred for a further 2 h. The
reaction was diluted with CH2Cl2 and the organic layer was
washed with saturated sodium bicarbonate solution, 5%
hydrochloric acid, brine and dried over Na2SO4. The crude
reaction mixture was filtered and concentrated under
reduced pressure. Purification of the resultant residue by
flash chromatography afforded the desired product 28 in
72% over 2 steps.
[a]2D5¼223.48 (c 0.47, CHCl3).
IR (neat) nmax 1741, 1685 cm21
.
To a solution of pyranone acetate 31 (0.1 g, 0.27 mmol) in
CH3CN (1.5 ml) was added Et3N (0.05 ml) at room
temperature. The reaction mixture was heated at reflux
for 6 h. after being cooled to 25 8C, the solvent was evapo-
rated under reduced pressure and the residue was purified
by flash chromatography to afford the cycloadduct 32
(0.70 g, 83%).
1H NMR (300 MHz, CDCl3) d: 7.61 (d, J¼1.5 Hz, 1H), 7.36
(d, J¼3.9 Hz, 1H), 6.55 (dd, J¼3.9, 1.5 Hz, 1H), 5.74–5.60
(m, 1H), 5.31 (d, J¼6.9 Hz, 1H), 5.0 (m, 2H), 4.79 (m, 1H),
4.61 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 1.7 (s, 3H), 1.68 (s,
3H), 1.43 (s, 3H).
13C NMR (75 MHz, CDCl3) d 182.5, 168.9, 151.5, 146.7,
132.5, 118.5, 118.2, 112.5, 110.4, 78.7, 77.7, 70.7, 34.7,
27.2, 25.3, 20.5.
[a]2D5¼2183.38 (c 0.42, CHCl3).
IR (CHCl3) nmax 1738, 1693 cm21
.
HRMS (FAB) calculated for C16H20NaO6: 331.1158
(MNaþ), found 331.1172.
1H NMR (400 MHz, CDCl3) d: 7.22 (dd, J¼9.6, 4 Hz, 1H),
5.97 (d, J¼9.6 Hz, 1H), 5.0 (m, J¼6.4, 3.2 Hz, 1H), 4.93
(dd, J¼4.8, 4 Hz, 1H), 4.64 (m, 2H), 2.20–1.87 (m, 5H), 2.1
(s, 3H), 1.56 (s, 3H), 1.40 (s, 3H).
4.2.8. Acetic acid 1-[5-(furan-2-yl-hydroxy-methyl)-2,2-

4836
U. Murali Krishna et al. / Tetrahedron 60 (2004) 4829–4836
13C NMR (100 MHz, CDCl3) d: 196.3, 170.0, 151.9, 125.3,
109.6, 109.5, 83.7, 72.9, 72.8, 72.0, 70.6, 37.8, 35.3, 27.8,
26.2, 24.9, 21.0.
Lett. 2001, 3, 623–625. (c) Lopez, F.; Castedo, L.; Mascarenas,
J. L. Org. Lett. 2000, 2, 1005–1007. (d) Bauta, W. E.; Booth, J.;
Bos, M. E.; DeLuca, M.; Diorazio, L.; Donohoe, T. J.; Frost, C.;
Magnus, N.; Magnus, P.; Mendoza, J.; Pye, P.; Tarrant, J. G.;
Thom, S.; Ujjainwalla, F. Tetrahedron 1996, 52, 14081–14102.
(e) Ohmori, N.; Yoshimura, M.; Ohkata, K. Heterocycles 1997,
45, 2097–2099. (f) Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc.
1999, 121, 5811–5812, Also see: Ref. 1b,c.
HRMS (EI) calculated for C16H20O6: 308.1260 (Mþ), found
308.1271.
4. Preliminary communication: Murali Krishna, U.; Srikanth, G. S.
C.; Trivedi, G. K.; Deodhar, K. D. Synlett 2003, 2383–2385.
5. (a) Hanessian, S. Total Synthesis of Natural Products: the
Chiron Approach; Baldwin, J. E., Ed.; Pergamon: Oxford,
1983; Vol. 3. (b) In Carbohydrate Mimics: Concepts and
Methods; Chapleur, Y., Ed.; Wiley: Weinheim, 1998. (c) Bols,
M. Carbohydrate Building Blocks; Wiley: New York, 1996.
6. (a) Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala,
B. R. Synthesis 1990, 1031–1032. (b) Shah, R. H. Carbohydr.
Res. 1986, 155, 212–216. (c) Hough, L.; Jones, J. K. N.;
Mitchell, D. L. Can. J. Chem. 1958, 36, 1720–1728.
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