Synthesis of an enantiomerically pure 2,2,4-trisubstituted cyclobutanone building block by zirconocene-promoted deoxygenative ring contraction of structurally modified 4-vinylfuranosides

Article abstract of DOI:10.1016/j.tet.2003.07.012

A route to an enantiopure trisubstituted cyclobutanone has been devised. The pursuit of this building block begins with D-glucose and features a zirconocene-promoted ring contraction.

Full text of DOI:10.1016/j.tet.2003.07.012

Tetrahedron 60 (2004) 1353–1358
Synthesis of an enantiomerically pure 2,2,4-trisubstituted
cyclobutanone building block by zirconocene-promoted
deoxygenative ring contraction of structurally modified
4-vinylfuranosides
†
*
Leo A. Paquette and Ho-Jung Kang
Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA
Received 24 January 2003; revised 15 July 2003; accepted 15 July 2003
Abstract—A route to an enantiopure trisubstituted cyclobutanone has been devised. The pursuit of this building block begins with D-glucose
and features a zirconocene-promoted ring contraction.
q 2003 Elsevier Ltd. All rights reserved.
The Taguchi/Hanzawa team1 and our own group2 have
previously reported several studies dealing with diastereo-
selectivity control in the zirconocene-mediated ring con-
traction of 4-vinylfuranosides to enantiopure cyclobutanes.
Multiply functionalized four-membered ring products are
formed with the absolute configuration at each constituent
carbon being fully definable under normal circumstances.2
The potential importance of this process to natural products
synthesis2 and to the elaboration of useful organic scaffolds3
has been recognized. The initial work with readily
accessible modified carbohydrates has shown that transition
state models typified by 2 can play a useful role in the
concise rationalization of the stereochemical outcome of
the deoxygenative transformations.2 The predictability is
thought to be associated with the interplay of nonbonded
steric interactions during intramolecular cyclization within
the allylzirconocene–aldehyde complex (Scheme 1).
scenario led us to consider the possibility that one or both of
the diastereomers 5 and 6 might qualify as a suitable
precursor. At least two major concerns surfaced immedi-
ately. Despite the fact that no prior attention had yet been
accorded to 4,4-disubstituted systems of this type, we
speculated that reaction with the zirconocene reagent4
would materialize, particularly at more elevated tempera-
tures, and lead to an intermediate such as 2. Less certain was
the issue of whether the additional substituent on the
nucleophilic carbon would serve to retard formation of the
C–C cyclobutane bond and to what degree. Also, in light of
available precedent, the lack of substitution at C-3 was
likely to present itself as a deterrent to high-level
diastereoselectivity (Scheme 2).2
Our path to the targeted cyclobutanone commenced with the
known D-glucose-derived tosylate 7.5,6 In order to facilitate
elimination of the sulfonate ester, 7 was stirred in acidic
methanol at rt to produce regioselectively the side chain
diol,7 oxidative cleavage of which with sodium periodate
proceeded well, giving rise to the aldehyde. When the direct
In the course of another investigation, the need arose to
prepare the 2,2,4-trisubstituted cyclobutanone of generic
formula 4 having the (2S,4R) configuration as depicted. This
Scheme 1.
Keywords: Zirconocene; Cyclobutanes; Diastereoselectivity; D-Glucose; Ring contraction.
*
Corresponding author. Tel.: þ1-614-292-2520; fax: þ1-614-292-1685; e-mail address: paquette.1@osu.edu
†
Permanent address: Department of Chemistry, Kyung Hee University, 1 Hoe Ki-Dong, Dong Dae Moon-Gu, Seoul 130-701, Korea.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.07.012

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L. A. Paquette, H.-J. Kang / Tetrahedron 60 (2004) 1353–1358
Scheme 2.
Scheme 3. (a) Hþ, MeOH, rt, (b) NalO4, H2O, THF, (c) NaClO2, H2O, CH3CN, rt, (d) CH2N2, ether, (e) DBU, CH2Cl2, (f) H2, 10% Pd/C, EtOH (90% for 6
steps), (g) TsCl, DMAP, Et3N, CH2Cl2, rt, (h) Hþ, MeOH, reflux, (i) PMB imidate, CSA, CH2Cl2, rt (88% for 2 steps), (j) LDA, THF, 2788C; CH2O (93%).
oxidation of this intermediate to ester 8 with bromine in
methanol8 met with failure, recourse was made to sequential
treatment with sodium chlorite9 and diazomethane.
Although these conditions were met with partial detosyla-
tion, it proved a simple matter to return from 9 to 8
(Scheme 3). At this stage, the intended E2 elimination
occurred smoothly in the presence of DBU, making
possible a stereocontrolled catalytic hydrogenation to
generate 10. The six-step conversion of 7 is not
demanding of chromatographic purification in its inter-
mediary stages and delivers the saturated ester 10 in 92%
overall yield.
following 1D NMR analysis and NOE studies as
summarized in A and B.
With these successes as a platform, the focus was next
placed on chemical modification of the carbomethoxy
substituent in both series. For this purpose, the primary
carbinol was masked with tert-butyldiphenylsilyl chloride
in advance of diisobutylaluminum hydride reduction to the
aldehyde level and Wittig olefination (Scheme 4). It will be
appreciated that the conversion of 13 to 16 and of 14 to 18
by this means is not accompanied by any concern regarding
epimerization. The reactivity of both 4-vinylfuranosides
toward the zirconocene reagent was independently probed
and found to deliver the cyclobutanols 19 and 20 in an
identical 1.9:1 ratio. The co-addition of boron trifluoride
etherate as promoter gave rise to lower yields, messier
reaction mixtures, and inverted product ratios. Magnesium
bromide was also tested, with similar consequences. We
The latter was subjected to acidic methanol at the reflux
temperature to effect removal of the remaining acetonide
unit and allow for protection of the C-2 hydroxyl as its
p-methoxybenzyl ether via the trichloroacetimidate
option.10 As expected on steric grounds, methyl glycoside
11 predominated over 12 by a factor of 3.5:1 (88% yield).
The major anomer was readily separated by means of silica
gel chromatography and its enolate anion was condensed
with formaldehyde in ether.11 The implementation of this
reaction resulted in the formation of 13 and 14. The
diastereomeric ratio of 1.7:1 indicated that p-facial
discrimination for electrophilic capture by the conjugate
base of 11 was not pronounced. The distinctive
structural features of the aldol isomers were apparent

L. A. Paquette, H.-J. Kang / Tetrahedron 60 (2004) 1353–1358
1355
Scheme 4. (a) TBDPSCl, imid, DMF, rt (94%), (b) Dibal-H, CH2Cl2, 2208C, (c) Swern, (d) Ph3PvCH2, THF, 2308C!rt (68% for 4 steps), (e) ‘Cp2Zr’, THF,
658C (56–70%), (f) IBX, DMSO, rt (92%).12
offer no explanation of these effects at this time. The relative
and absolute configurations of 19 and 20 were deduced by
detailed NOE measurements. In particular, the observed
proximity of H-2 to H-8 in 20 requires that the C-2 hydroxyl
be b-oriented as shown in C. The a-projection of C-7
follows from the integral enhancement noted between both
of its attached methylene protons and H-2. Further
confirmation was derived from the interaction of H-1 with
H-5 and H-6.
in a NOESY experiment was used to differentiate the
methylene pair. Following that assignment, it was possible
to define the C-2 hydroxyl as a on the strength of the
H-2$H-4b interaction. The b-orientation of C-7 was
similarly deciphered. The readily recognized proximity of
H-4a to H-5 and H-6 provided additional compelling
confirmatory evidence.
These results bring into focus several mechanistic facets
of this fascinating ring contraction. The stereochemical
predisposition of the OPMB substituent at C-2 in either
reactant has a low-level impact on the distribution of
cyclobutanols 19 and 20 as foreshadowed by less
substituted congeners. The possibility that the product
ratio may depend on the steric bulk of the oxygen
protecting group at C-2 was not examined. Significantly,
however, the p-facial selectivity of attack by the
zirconocene reagent on the vinyl double bond has no
major product-determining consequences. This phenom-
enon may be the result of a substantive kinetic bias for
the subsequent ring opening that leads to the
E-configured allylzirconocene intermediate. The possible
operation of a ZYE isomerization cannot be ruled out,
but the cis arrangement of the vinyl and hydroxyl groups
in 19 and 20 is almost certain to stem from transition
states 22 and 23. Finally, the combined yield of 19 and
20 (56–70%) under purely thermal conditions indicates
that the added CH2OTBDPS substituent is not a deterrent
to four-membered ring closure, although kinetic
retardation was evident relative to the ring-contracting
reactions performed with similar but less crowded
examples.
In the case of 19, the effect observed between H-8 and H-4a

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L. A. Paquette, H.-J. Kang / Tetrahedron 60 (2004) 1353–1358
in CH2Cl2 (400 mL), treated with DBU (25.2 g, 166 mmol),
stirred at rt for 5 h, concentrated to a volume of 100 mL, and
diluted with ethyl acetate (200 mL) prior to filtration
through a pad of silica gel. Solvent evaporation furnished
the unsaturated ester, which was taken up in ethanol
(100 mL), and hydrogenated over 5% Pd/C (1.3 g) under an
atmosphere of H2 (40 psi). After 1 h, the reaction mixture
was filtered through Celite, concentrated, and subjected to
chromatography on silica gel. Elution with 3:2 hexanes/
ethyl acetate afforded pure 10 as a colorless oil (29.4 g, 90%
over six steps); IR (neat, cm21) 1757, 1734; 1H NMR
(300 MHz, CDCl3) d 5.78 (d, J¼3.4 Hz, 1H), 4.63 (t, J¼
4.2 Hz, 1H), 4.55 (dd, J¼0.9, 9.2 Hz, 1H), 3.69 (s, 3H), 2.59
(dd, J¼0.5, 14.1 Hz, 1H), 2.23 (ddd, J¼4.8, 9.2, 14.1 Hz,
1H), 1.38 (s, 3H), 1.21 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 172.0, 112.4, 106.8, 79.3, 76.9, 51.8, 34.8, 25.5 (2C);
ES HRMS m/z (MþNa)þ calcd 225.0733, obsd 225.0740;
[a]2D0¼263.3 (c 1.03, CHCl3).
1. Experimental13
Anal. calcd for C9H14O5: C, 53.46; H, 6.98. Found: C,
53.28; H, 7.03.
1.1. General
1.1.1. Conversion of tosylate 7 to ester 10. A solution of
75,6 (67.0 g, 162 mmol) in methanol (1650 mL) was treated
with sulfuric acid (84 mL of 2.5 M), stirred at rt for 16 h,
neutralized with concentrated sodium hydroxide, and freed
of solvent. The residue was slurried with CH2Cl2 (1 L) and
the organic phase was dried and evaporated to provide the
diol. The latter was directly dissolved in THF (500 mL),
cooled to 0 8C, and treated with a solution of sodium
periodate (52 g, 243 mmol) in water (700 mL). The reaction
mixture was stirred overnight, the THF was removed under
reduced pressure, and ethyl acetate (500 mL) was intro-
duced. The separated organic phase was washed with water
(200 mL) and brine (200 mL), the aqueous layers were
combined and extracted with ethyl acetate (3£200 mL),
and the unified organic phases were dried and evaporated
to furnish the aldehyde that was directly submitted to
oxidation.
1.1.2. Transformation of 10 into esters 11 and 12. A
solution of 10 (5.00 g, 24.7 mmol) in methanol (100 mL)
was treated with concentrated HCl (1.3 mL), refluxed for
1 h, neutralized with solid NaHCO3 (5 g), and freed of
methanol under reduced pressure. The residue was taken up
in CH2Cl2 (300 mL), dried, and evaporated to leave a
mixture of hydroxy methyl glycosides. This material was
dissolved in CH2Cl2 (100 mL), treated with p-methoxyben-
zyl trichloroacetimidate (9.21 g, 32.6 mmol), and cooled to
0 8C. Camphorsulfonic acid (380 mg, 1.63 mmol) was
introduced and the reaction mixture was stirred for 24 h at
0 8C and 2 days at rt, quenched with saturated NaHCO3
solution, diluted with CH2Cl2 (300 mL), and worked up in
the predescribed manner. Medium-pressure liquid chroma-
tography on silica gel (elution with 7:3 hexanes/ethyl
acetate) afforded 11 (3.88 g) and 12 (1.10 g) in 88% overall
yield for 2 steps. The minor product remained contaminated
with minor impurities and was not fully characterized.
The above material dissolved in acetonitrile (440 mL) was
treated sequentially with a solution of sodium dihydrogen
phosphate (33.7 g, 244 mmol) in water (120 mL) and 30%
hydrogen peroxide (25 mL). This mixture was cooled to
0 8C prior to the introduction of sodium chlorite (22.1 g,
244 mmol) dissolved in water (120 mL). The reaction
mixture was allowed to warm to rt, stirred overnight, and
freed of acetonitrile under reduced pressure. The resulting
aqueous solution was extracted with ethyl acetate
(2£200 mL). The aqueous layer was acidified with citric
acid to pH 1–2 and extracted with ethyl acetate
(2£200 mL). The combined organic phases were washed
with brine (300 mL), dried, concentrated to a volume of
300 mL, and treated with an excess of diazomethane until
N2 effervescence stopped. The solvent was evaporated and
the residual ester was dissolved in CH2Cl2 (200 mL). To this
solution was added 4-(dimethylamino)pyridine (2.0 g,
16 mmol), triethylamine (3.5 mL, 25 mmol), and tosyl
chloride (5.0 g, 26 mmol), and the resulting mixture was
stirred overnight at rt prior to dilution with ether (500 mL),
filtration, and sequential washing with saturated calcium
sulfate, sodium bicarbonate, and sodium chloride solutions
(200 mL of each). The organic layer was dried and
evaporated to give ester 8. The latter was directly dissolved
For 11: colorless oil; IR (neat, cm21) 1759, 1731, 1613; 1H
NMR (300 MHz, CDCl3) d 7.21 (m, 2H), 6.86 (m, 2H), 5.10
(s, 1H), 4.63 (dd, J¼4.5, 9.0 Hz, 1H), 4.43 (s, 2H), 3.93 (dd,
J¼2.1, 5.5 Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.37 (s, 3H),
2.46 (ddd, J¼5.5, 9.0, 13.5 Hz, 1H), 2.27 (ddd, J¼2.1, 4.5,
13.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 172.4, 159.3,
129.7, 129.2, 113.8, 108.0, 81.1, 75.9, 70.8, 55.2, 55.0, 52.2,
34.0; ES HRMS m/z (MþNa)þ calcd 319.1152, obsd
319.1161; [a]2D0¼227.4 (c 1.96, CHCl3).
Anal. calcd for C15H20O6: C, 60.80; H, 6.80. Found: C,
61.00; H, 6.77.
1.1.3. Hydroxymethylation of 11. n-Butyllithium (36.4 mL
of 1.5 M in hexanes, 54.6 mmol) was added to a cold
(230 8C) solution of diisopropylamine (10.2 mL, 72.8 mmol)
in dry THF (80 mL). The reaction mixture was stirred for
20 min at this temperature, then cooled to 278 8C in advance
of the introduction of a solution of 11 (10.8 g, 36.4 mmol) in
THF (30 mL). After 1 h of stirring, a solution of excess
formaldehyde dissolved in THF was added until the color of
the reaction mixture turned light brown. Subsequent

L. A. Paquette, H.-J. Kang / Tetrahedron 60 (2004) 1353–1358
1357
warming to 210 8C was followed by a quench with saturated
NH4Cl solution (50 mL) and subsequent dilution with ethyl
acetate (500 mL) and water (200 mL). The resulting organic
phase was dried and concentrated to leave a residue that was
chromatograhed on silica gel. Elution with 2:3 hexanes/ethyl
acetate gave 13 (7.03 g, 59%) and 14 (4.08 g, 34%).
stirring, the alcohol from above was introduced as a solution
in CH2Cl2 (7 mL). The reaction mixture was stirred for 1 h
at 278 8C, quenched with triethylamine (3 mL), and
warmed to rt before being treated with saturated NaHCO3
solution (20 mL) and diluted with CH2Cl2 (100 mL). The
separated organic phase was dried and evaporated to furnish
the aldehyde that was carried forward without delay.
For 13: colorless oil; IR (neat, cm21) 3480, 1733, 1613; 1H
NMR (300 MHz, CDCl3) d 7.16 (m, 2H), 6.82 (m, 2H), 5.05
(s, 1H), 4.38 (ABq, J¼11.4 Hz, Dn¼14.2 Hz, 2H), 3.91 (d,
J¼4.3 Hz, 1H), 3.80 (d, J¼11.4 Hz, 1H), 3.74 (s, 3H), 3.67
(s, 3H), 3.61 (d, J¼11.4 Hz, 1H), 3.36 (s, 3H), 2.52 (br s,
1H), 2.43 (d, J¼13.8 Hz, 1H), 2.21 (dd, J¼4.9, 13.8 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 172.9, 159.1, 129.4,
129.0, 113.6, 108.4, 88.3, 81.4, 70.4, 67.0, 55.2, 55.0, 52.4,
34.8; ES HRMS m/z (MþNa)þ calcd 349.1258, obsd,
349.1249; [a]2D0¼239.1 (c 1.71, CHCl3).
For 14: colorless oil; IR (neat, cm21) 3490, 1737, 1613; 1H
NMR (300 MHz, CDCl3) d 7.22 (m, 2H), 6.86 (m, 2H), 5.01
(s, 1H), 4.44 (ABq, J¼11.3 Hz, Dn¼15.5 Hz, 2H), 3.96 (d,
J¼5.0 Hz, 1H), 3.80 (ABq, J¼11.3 Hz, Dn¼19.9 Hz, 2H),
3.78 (s, 3H), 3.75 (s, 3H), 3.39 (s, 3H), 2.63 (br s, 1H), 2.50
(dd, J¼5.6, 14.3 Hz, 1H), 2.18 (d, J¼14.3 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 173.3, 159.4, 129.3, 129.2, 113.9,
107.9, 87.3, 81.7, 70.9, 67.0, 55.2, 54.8, 52.3, 35.1; ES
HRMS m/z (MþNa)þ calcd 349.1258, obsd 349.1235.
To a solution of methyltriphenylphosphonium bromide
(1.53 g, 4.28 mmol) in THF (15 mL) was added n-butyl-
lithium (2.3 mL of 1.5 M in hexanes, 3.45 mmol) at 230 8C
and this mixture was stirred for 20 min before the aldehyde
was introduced as a solution in THF (8 mL) and for 3 h at rt
before being quenched with saturated NaHCO3 solution
(5 mL), diluted with ethyl acetate (300 mL) and washed
with brine (100 mL). The organic phase was dried and
evaporated to leave a residue that was chromatographed on
silica gel. Elution with 15:1 hexanes/ethyl acetate gave 16
as a colorless oil (847 mg, 74% over three steps); IR (neat,
1
cm21) 1613, 1588, 1514; H NMR (300 MHz, CDCl3) d
7.67 (m, 4H), 7.40 (m, 6H), 7.24 (m, 2H), 6.87 (m, 2H), 6.10
(dd, J¼10.8, 17.4 Hz, 1H), 6.34 (dd, J¼1.6, 17.4 Hz, 1H),
6.13 (dd, J¼1.6, 10.8 Hz, 1H), 5.01 (s, 1H), 4.44 (s, 2H),
3.97 (ddd, J¼1.0, 2.6, 6.1 Hz, 1H), 3.80 (s, 3H), 3.62 (s,
2H), 3.28 (s, 3H), 2.35 (dd, J¼6.1, 13.5 Hz, 1H), 2.01 (dd,
J¼2.6, 13.5 Hz, 1H), 1.07 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 159.2, 141.0, 135.7, 133.5, 130.1, 129.6, 129.2,
127.6, 113.8, 113.3, 108.2, 87.0, 83.2, 70.8, 69.8, 55.3, 54.7,
37.2, 26.8, 19.3; ES HRMS m/z (MþNa)þ calcd 555.2537,
obsd 555.2537; [a]2D0¼214.8 (c 2.04, CHCl3).
1.1.4. Conversion of 13 to 16. To a solution of 13 (810 mg,
2.48 mmol) and imidazole (835 mg, 12.2 mmol) in DMF
(10 mL) was added tert-butyldiphenylsilyl chloride (823 mg,
3.0 mmol). The reaction mixture was stirred at rt for 3 h
before being quenched with water (30 mL) and diluted with
ethyl acetate (200 mL). The separated organic layer was
washed with brine, dried, and evaporated to leave a residue,
chromatography of which on silica gel (elution with 7:1
hexanes/ethyl acetate) provided pure silyl ether (1.30 g,
94%) as a colorless oil; IR (neat, cm21) 1730, 1514, 1250;
1H NMR (300 MHz, CDCl3) d 7.73–7.65 (m, 4H), 7.41 (m,
6H), 7.22 (m, 2H), 6.86 (m, 2H), 5.15 (s, 1H), 4.43 (s, 2H),
3.98 (d, J¼10.1 Hz, 1H), 3.90 (d, J¼4.1 Hz, 1H), 3.80 (s,
3H), 3.74 (d, J¼10.1 Hz, 1H), 3.73 (s, 3H), 3.33 (s, 3H),
2.55 (d, J¼13.7 Hz, 1H), 2.06 (dd, J¼4.7, 13.7 Hz, 1H),
1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) d 173.3, 159.2,
135.6 (2C), 133.1, 133.0, 129.8, 129.7, 129.1, 127.7, 127.6,
113.7, 108.0, 88.6, 81.1, 70.3, 69.5, 55.2, 54.8, 52.3, 35.6,
26.6, 19.2; ES HRMS m/z (MþNa)þ calcd 587.2436, obsd
587.2410; [a]2D0¼213.8 (c 2.68, CHCl3).
Anal. calcd for C32H40O5Si: C, 72.14; H, 7.57. Found: C,
71.90; H, 7.59.
1.1.5. Conversion of 14 to 18. A 763 mg (2.34 mmol)
sample of 14 was reacted with tert-butyldiphenylsilyl
chloride (820 mg, 3.00 mmol) and imidazole (820 mg,
12.0 mmol) in DMF (10 mL) as described above to give
1.21 g (92%) of the silyl ether as a colorless oil; IR (neat,
1
cm21) 1738, 1614, 1586; H NMR (300 MHz, CDCl3) d
7.65 (m, 4H), 7.37 (m, 6H), 7.13 (m, 2H), 6.82 (m, 2H), 4.96
(s, 1H), 4.37 (s, 2H), 4.03 (d, J¼9.5 Hz, 1H), 3.96 (dd,
J¼1.4, 6.0 Hz, 1H), 3.88 (d, J¼9.5 Hz, 1H), 3.80 (s, 3H),
3.75 (s, 3H), 3.36 (s, 3H), 2.72 (dd, J¼6.0, 14.2 Hz, 1H),
2.11 (dd, J¼1.4, 14.2 Hz, 1H), 1.04 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 173.2, 159.2, 135.7, 135.6, 133.4,
133.2, 129.8, 129.6, 129.1, 127.6 (2C), 113.8, 108.0, 87.2,
82.3, 70.9, 68.9, 55.3, 54.7, 52.1, 35.4, 26.7, 19.3; ES
HRMS m/z (MþNa)þ calcd 587.2436, obsd 587.2477;
[a]2D0¼231.7 (c 3.29, CHCl3).
A cold (278 8C) solution of the above ester (1.21 g,
2.14 mmol) in CH2Cl2 (15 mL) was treated with diisobutyl-
aluminum hydride (6.3 mL of 1.0 M in hexanes, 6.3 mmol).
The reaction mixture was warmed to 220 8C, stirred for 1 h,
and quenched with sodium potassium tartrate solution
(20%, 20 mL). Stirring was maintained until a clear phase
separation had been achieved. The aqueous phase was
extracted with CH2Cl2 (2£100 mL) and the combined
organic phases were washed with brine (100 mL) prior to
drying and evaporation. The resulting alcohol was used
directly.
Reduction of the above ester (1.21 g, 2.14 mmol) with
diisobutylaluminum hydride (6.3 mL of 1.0 M in hexanes,
6.3 mmol) at 278 to 220 8C in the predescribed manner
provided the primary alcohol that was directly oxidized by
the Swern method detailed above. The resulting unpurified
aldehyde 17 was treated with the ylide prepared from
n-butyllithium (2.3 mL of 1.5 M in hexanes, 3.45 mmol)
and methyltriphenylphosphonium bromide (1.53 g,
4.28 mmol). There was isolated 847 mg (74% over three
steps) of 18 as a colorless oil; IR (neat, cm21) 1613, 1514,
1470; 1H NMR (300 MHz, CDCl3) d 7.67 (m, 4H), 7.34 (m,
6H), 7.18 (m, 2H), 6.84 (m, 2H), 6.12 (dd, J¼10.8, 17.4 Hz,
To CH2Cl2 (20 mL) containing 1.0 mL of DMSO was added
oxalyl chloride (280 mL) at 278 8C. After 20 min of

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L. A. Paquette, H.-J. Kang / Tetrahedron 60 (2004) 1353–1358
1H), 5.33 (dd, J¼1.6, 17.4 Hz, 1H), 5.11 (dd, J¼1.6,
10.8 Hz, 1H), 4.95 (d, J¼1.1 Hz, 1H), 4.42 (s, 2H), 3.99
(ddd, J¼1.1, 3.3, 6.1 Hz, 1H), 3.81 (s, 3H), 3.77 (d, J¼
9.5 Hz, 1H), 3.64 (d, J¼9.5 Hz, 1H), 3.38 (s, 3H), 2.40 (dd,
J¼3.3, 13.5 Hz, 1H), 2.10 (dd, J¼6.1, 13.5 Hz, 1H), 1.07 (s,
9H); 13C NMR (75 MHz, CDCl3) d 159.2, 141.6, 135.7
(2C), 133.6 (2C), 130.1, 129.5 (2C), 129.1, 127.5, 113.8,
113.2, 108.4, 87.0, 83.1, 71.0, 69.3, 55.3, 55.1, 36.5, 26.9,
19.4; ES HRMS m/z (MþNa)þ calcd 555.2537, obsd
255.2537; [a]2D0¼251.8 (c 1.70, CHCl3).
1.1.7. Oxidation of 20 to 21. To a DMSO solution (2 mL)
of 20 (241 mg, 0.479 mmol) was added 1-hydroxy-1,2-
benziodoxol-3(1H)-one 1-oxide (IBX, 364 mg, 1.30 mmol)
dissolved in DMSO (2 mL) and the reaction mixture was
stirred overnight at rt prior to the introduction of ethyl
acetate (4 mL) and water (4 mL), and filtration through a
cotton plug. The organic phase was washed with brine,
dried, and concentrated to leave a residue that was chromato-
graphed on silica gel. Elution with 10:1 hexanes/ethyl
acetate provided 220 mg (92%) of 21 as a colorless oil; IR
(neat, cm21) 1782, 1613, 1514; 1H NMR (300 MHz,
CDCl3) d 7.68 (m, 4H), 7.41 (m, 6H), 7.30 (m, 2H), 6.89
(m, 2H), 5.73 (dd, J¼10.4, 17.3 Hz, 1H), 5.16 (d, J¼
17.3 Hz, 1H), 5.12 (d, J¼10.4 Hz, 1H), 4.79 (dd, J¼8.3,
9.9 Hz, 1H), 4.74 (d, J¼11.3 Hz, 1H), 4.58 (d, J¼11.3 Hz,
1H), 3.96 (d, J¼10.3 Hz, 1H), 3.82 (s, 3H), 3.52 (d, J¼
10.3 Hz, 1H), 2.62 (dd, J¼8.3, 11.3 Hz, 1H), 2.40 (dd,
J¼9.9, 11.3 Hz, 1H), 1.06 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 207.6, 159.4, 135.7, 135.6, 134.6, 133.3, 132.9,
129.7 (2C), 129.6 (2C), 127.7, 116.4, 113.8, 84.0, 71.6,
66.3, 64.8, 55.2, 27.6, 26.7, 19.3; ES HRMS m/z (MþNa)þ
calcd 523.2275, obsd 523.2242; [a]2D0¼22.9 (c 1.2, CHCl3).
Anal. calcd for C32H40O5Si: C, 72.14; H, 7.57. Found: C,
72.02; H, 7.56.
1.1.6. Ring contraction of 16. To a THF solution (4 mL) of
zirconocene dichloride (82.4 mg, 0.282 mmol) was added
n-butyllithium (0.38 mL of 1.5 M, 0.57 mmol) at 278 8C
and the reaction mixture was stirred for 1 h prior to the
introduction of 16 (100 mg, 0.188 mmol) dissolved in THF
(3 mL) and warming to rt. After 9 h, the reaction
temperature was raised to 55 8C and stirring was maintained
overnight prior to quenching with 1N HCl (1 mL) and
extraction with ethyl acetate (3£50 mL). The combined
organic layers were washed with saturated NaHCO3
solution (30 mL), dried, and evaporated. The residue was
chromatographed on silica gel (elution with 5:1 hexanes/
ethyl acetate) to deliver 19 (29 mg) and 20 (21 mg) in 70%
combined yield based on 25% recovered starting material.
Acknowledgements
We thank the Yamanouchi USA Foundation and the
National Science Foundation for their support of our
research program.
For 19: colorless oil; IR (neat, cm21) 3544, 1612, 1514; 1H
NMR (300 MHz, CDCl3) d 7.65 (m, 4H), 7.41 (m, 6H), 7.27
(m, 2H), 6.89 (m, 2H), 5.95 (dd, J¼10.9, 17.6 Hz, 1H), 5.26
(dd, J¼1.3, 10.9 Hz, 1H), 5.09 (dd, J¼1.3, 17.6 Hz, 1H),
4.46 (s, 2H), 4.41(m, 1H), 4.17 (m, 1H), 3.81 (s, 3H), 3.64
(d, J¼10.1 Hz, 1H), 3.46 (d, J¼10.1 Hz, 1H), 2.57 (br s,
1H), 2.27 (ddd, J¼2.3, 6.8, 12.7 Hz, 1H), 2.10 (dd, J¼4.9,
12.7 Hz, 1H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3) d
159.3, 137.6, 135.6, 133.3, 133.2, 129.9, 129.7, 129.5,
127.7, 116.5, 113.8, 71.6, 71.3, 70.8, 67.9, 55.2, 49.9, 31.1,
26.8, 19.3; ES HRMS m/z (MþNa)þ calcd 525.2432, obsd
525.2429; [a]2D0¼225.6 (c 1.28, CHCl3).
References and notes
1. Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem.
Soc. 1993, 115, 8835. Hanzawa, Y.; Ito, H.; Taguchi, T.
Synlett 1995, 299.
´
2. Paquette, L. A.; Cuniere, N. Org. Lett. 2002, 4, 1927.
´
3. Paquette, L. A.; Kim, I. H.; Cuniere, N. Org. Lett. 2003, 5.
4. Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron
Lett. 1986, 27, 2829.
For 20: colorless oil; IR (neat, cm21) 3440, 1613, 1587; 1H
NMR (300 MHz, CDCl3) d 7.66 (m, 4H), 7.40 (m, 6H), 7.29
(m, 2H), 6.88 (m, 2H), 5.89 (dd, J¼11.0, 17.7 Hz, 1H), 5.30
(dd, J¼1.1, 11.0 Hz, 1H), 5.19 (dd, J¼1.1, 17.7 Hz, 1H),
4.49 (s, 2H), 4.22 (d, J¼6.4 Hz, 1H), 3.81 (s, 3H), 3.77 (dt,
J¼6.4, 8.4 Hz, 1H), 3.65 (d, J¼10.2 Hz, 1H), 3.50 (d, J¼
10.2 Hz, 1H), 2.13 (dd, J¼8.4, 11.2 Hz, 1H), 1.79 (dd, J¼
8.4, 11.2 Hz, 1H), 1.72 (br s, 1H), 1.09 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 159.1, 137.0, 135.6, 133.4, 130.4,
129.7, 129.4, 127.7, 117.1, 113.7, 78.0, 75.1, 70.5, 67.3,
55.2, 45.4, 27.7, 26.9, 19.4; ES HRMS m/z (MþNa)þ calcd
525.2432, obsd 525.2423; [a]2D0¼þ10.2 (c 0.66, CHCl3).
5. Schmidt, O. Th. Methods Carbohydr. Chem. 1963, 2, 318.
6. Hwang, C. K.; Li, W. S.; Nicolaou, K. C. Tetrahedron Lett.
1984, 25, 2295.
7. Just, G.; Luthe, C. Can. J. Chem. 1980, 58, 2286.
8. Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler,
F. W. Tetrahedron Lett. 1988, 29, 5087.
¨ ¨ ¨
9. Hase, T.; Wahala, K. Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol.
7, pp 4533–4534.
10. Overman, L. E. Acc. Chem. Res. 1980, 13, 218, and references
cited therein. Patil, V. J. Tetrahedron Lett. 1996, 37, 1481.
11. Schlosser, M.; Jenny, T.; Guggisberg, Y. Synlett 1990, 704.
12. Boeckman, Jr. R. K.; Shao, P.; Mullins, J. J. Org. Synth. 2000,
77, 141.
The entirely comparable treatment of 17 with the zircono-
cene reagent prepared from the same quantity of reagents
resulted in the isolation of 24 mg of 19 and 18 mg of 20
(56% yield based on 19% recovered starting material).
13. For a prior listing of general experimental conditions, consult
Paquette, L.; Arbit, R.; Funel, J.-A.; Bolshakov, S. Synthesis
2002, 2105.