An Exploratory Study of Type II [3 + 4] Cycloadditions between Vinylcarbenoids and Dienes

Article abstract of DOI:10.1021/jo991959b

The intramolecular type II [3 + 4] cycloaddition between vinylcarbenoids and furans is a practical method for the construction of 5-oxo-10-oxatricyclo[6.2.1.0^4,9]undeca-3,8(11)-dienes, containing two anti-Bredt double bonds. These tricyclic systems are well functionalized for eventual elaboration to the natural product CP-263,114. The rhodium-stabilized vinylcarbenoids are generated by dirhodium tetracarboxylate catalyzed decomposition of vinyldiazoacetates. The [3 + 4] cycloaddition is generally considered to occur by a tandem cyclopropanation/Cope rearrangement, although evidence is presented that with these substrates the [3 + 4] cycloaddition may occur in a concerted manner.

Full text of DOI:10.1021/jo991959b

J . Org. Chem. 2000, 65, 4261-4268
4261
An Exp lor a tor y Stu d y of Typ e II [3 + 4] Cycloa d d ition s betw een
Vin ylca r ben oid s a n d Dien es
Huw M. L. Davies,* Rebecca L. Calvo, Robert J . Townsend, Pingda Ren, and
R. Melvyn Churchill
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260-3000
hdavies@acsu.buffalo.edu
Received December 23, 1999
The intramolecular type II [3 + 4] cycloaddition between vinylcarbenoids and furans is a practical
method for the construction of 5-oxo-10-oxatricyclo[6.2.1.04,9]undeca-3,8(11)-dienes, containing two
anti-Bredt double bonds. These tricyclic systems are well functionalized for eventual elaboration
to the natural product CP-263,114. The rhodium-stabilized vinylcarbenoids are generated by
dirhodium tetracarboxylate catalyzed decomposition of vinyldiazoacetates. The [3 + 4] cycloaddition
is generally considered to occur by a tandem cyclopropanation/Cope rearrangement, although
evidence is presented that with these substrates the [3 + 4] cycloaddition may occur in a concerted
manner.
For some time we have studied the synthetic utility of
the [3 + 4] cycloaddition between rhodium-stabilized
vinylcarbenoids and dienes.1,2 Recently, CP-263,114 (1)
has become a synthetic target of great interest on account
of its novel structure and promising biological activity.3,4
The research activity in this area has included numerous
model studies5-18 and two recent reports of total synthe-
ses of racemic CP-263,114 by Nicolaou19,20 and Danishef-
sky.21,22 Intrigued by the possibility that the [3 + 4]
cycloaddition could be a novel disconnection for the
synthesis of CP-263,114, we have explored the utility of
type II [3 + 4] cycloadditions between vinylcarbenoids
and various dienes.23 In this paper, we describe the scope
of this chemistry, with particular emphasis on the
stability and subsequent chemistry of the resulting [3 +
4] cycloaddition products which contain two anti-Bredt
double bonds.
(1) Davies, H. M. L. Curr. Org. Chem. 1998, 2, 463.
(2) Davies, H. M. L. In Advances in Cycloaddition; Haramata, M.
E., Ed.; J AI Press Inc.: Greenwich, CT, 1999; Vol. 5, pp 119-164.
(3) Dabrah, T. T.; Kaneko, T.; Massefski, W.; Whipple, E. B. J . Am.
Chem. Soc. 1997, 119, 1594.
(4) Dabrah, T. T.; Harwood: H. J .; Huang, L. H.; J ankovich, N. D.;
Kaneko, T.; Li, J . C.; Lindsey, S.; Moshier, P. M.; Subashi, T. A.;
Therrien, M.; Watts, P. C. J . Antibiot. 1997, 50, 1.
(5) Baldwin, J . E.; Beyeler, A.; Cox, R. J .; Keats, G.; Pritchard, G.
J .; Adlington, R. M.; Watkin, D. J . Tetrahedron 1999, 55, 7363.
(6) Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett.1999,
40, 5215.
(7) Clive, D. L. J .; Sun, S. Y.; He, X.; Zhang, J . H.; Gagliardini, V.
Tetrahedron Lett. 1999, 40, 4605.
(8) Nicolaou, K. C.; Baran, P. S.; J autelat, R.; He, Y.; Fong, K. C.;
Choi, H. S.; Yoon, W. H.; Zhong, Y. L. Angew. Chem., Int. Ed. Engl.
1999, 38, 549.
(9) Bio, M. M.; Leighton, J . L. J . Am. Chem. Soc. 1999, 121, 890.
(10) Chen, C.; Layton, M. E.; Shair, M. D. J . Am. Chem. Soc. 1998,
120, 10784.
(11) Frontier, A. J .; Danishefsky, S. J .; Koppel, G. A.; Meng, D. F.
Tetrahedron 1998, 54, 12721.
(12) Kwon, O. Y.; Su, D. S.; Meng, D. F.; Deng, W.; Damico, D. C.;
Danishefsky, S. J . Angew. Chem., Int. Ed. Engl. 1998, 37, 1877.
(13) Kwon, O. Y.; Su, D. S.; Meng, D. F.; Deng, W.; Damico, D. C.;
Danishefsky, S. J . Angew. Chem., Int. Ed. Engl. 1998, 37, 1880.
(14) Waizumi, N.; Itoh, T.; Fukuyama, T. Tetrahedron Lett. 1998,
39, 6015.
To study the feasibility of type II intramolecular
cyclopropanations, the isoprenyl-functionalized vinyl-
diazoacetate 2 was initially prepared. Rhodium(II) oc-
tanoate catalyzed decomposition of the vinyldiazoacetate
2 resulted in the formation of the cis-divinylcyclopropane
3 (eq 1). Even though cis-divinylcyclopropanes tend to
readily rearrange to cycloheptadienes, 3 was not prone
to ring expansion to 4 by a Cope rearrangement. The
failure of this rearrangement is presumably due to the
strain that exists in the transition-state for the Cope
rearrangement24 or in the doubly anti-Bredt product 4.
To determine if structural variations in the divinylcy-
clopropane could favor the Cope rearrangement,24 explor-
atory studies were extended to include the diazoacetoac-
etate system 5 (eq 2). Rh2(OAc)4-catalyzed decomposition
of 5 resulted in the formation of the cyclopropane 6. Silyl-
ation of 6 generated the divinylcyclopropane 7, which
(15) Armstrong, A.; Critchley, T. J .; Mortlock, A. A. Synlett 1998,
552 ff.
(16) Nicolaou, K. C.; Postema, M. H. D.; Miller, N. D.; Yang, G.
Angew. Chem., Int. Ed. Engl. 1998, 36, 22821.
(17) Sgarbi, P. W. M.; Clive, D. L. J . J . Chem. Soc., Chem. Commun.
1997, 2157.
(18) Nicolaou, K. C.; Harter, M. W.; Boulton, L.; J andeleit, B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1194.
(19) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Choi, H. S.; Yoon,
W. H.; He, Y.; Fong, K. C. Angew. Chem., Int. Ed. Engl. 1999, 38, 1669.
(20) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Fong, K. C.; He, Y.;
Yoon, W. H.; Choi, H. S. Angew. Chem., Int. Ed. Engl. 1999, 38, 1676.
(21) Meng, D. F.; Danishefsky, S. J . Angew. Chem., Int. Ed. Engl.
1999, 38, 1485.
(22) Meng, D.; Tan, Q.; Danishefsky, S. J . Angew. Chem., Int. Ed.
Engl. 1999, 38, 3197.
(23) For a preliminary account of a portion of this work, see: Davies,
H. M. L.; Calvo, R.; Ahmed, G. Tetrahedron Lett. 1997, 38, 1737.
(24) Hudlicky, T.; Fan, R.; Reed, J . W.; Gadamasetti, K. G. Org.
React. 1992, 41, 1.
10.1021/jo991959b CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/13/2000

4262 J . Org. Chem., Vol. 65, No. 14, 2000
Davies et al.
Overall, the type II [3 + 4] cycloaddition between
vinylcarbenoids and dienes was not a very robust trans-
formation, primarily due to the relative instability of the
cycloaddition products. To improve the stability of the
products, cycloaddition reactions were carried out with
furan as the diene component. Since the diene component
is constrained within a ring, transannular reactions of
the [3 + 4] cycloaddition products were expected to be
highly unlikely because they would lead to excessively
strained products. Decomposition of phenylvinyldiazoac-
etate 15 failed to generate the required [3 + 4] cycload-
dition product, but instead afforded the unstable triene
16 (eq 4). The unraveling of a furan ring to a triene on
reaction with a metal-stabilized vinylcarbenoid is a
common reaction that is usually formed from zwitterionic
intermediates.25,26
on heating to 65 °C underwent a novel rearrangement
to the fused cyclobutane 9. Most likely, this reaction
proceeds via the desired product 8, but due to the
presence of the two anti-Bredt double bonds in 8, this
compound is unstable and undergoes a transannular
rearrangement to form cyclobutane 9.
In contrast to the phenylvinyldiazoacetate 15, a series
of siloxyvinyldiazoacetates of general structure 17 gave
the desired bicyclic products 18 in moderate to good yields
(eq 5). Previous results obtained for intermolecular
reactions of vinyldiazoacetates with furans,27 pyrroles,28
and intramolecular reactions of vinyldiazoacetates with
pyrroles29 have also shown that silyloxyvinyldiazoac-
etates are exceptional substrates for this type of [3 + 4]
cycloaddition.
The transannular rearrangement to form fused cy-
clobutanes would not be possible if a ketone linkage was
used instead of an ester. Consequently, the chemistry of
diazodiketone 10 was explored (eq 3). The diazodiketone
10 underwent very effective intramolecular cyclopropa-
nation to form cyclopropane 11. Attempts to form a cis-
divinylcyclopropane from 11 using 1 equiv of a silylating
agent were unsuccessful because preferential silylation
of the cyclopentanone occurred. Consequently, the reac-
tion was carried out with two equivalents of the silylating
agent and this resulted in the formation of the rather
unstable monosilylated product 13. Presumably, the
desired rearrangement occurred to form 12, but 12 was
unstable and underwent desilylation of the anti-Bredt
silyl enol ether to form 13. Further verification of the
structure of 13 was obtained by conversion of 13 to
diketone 14, which was sufficiently stable for complete
structural characterization.
The next series of experiments were carried out on
ketone derivatives instead of esters because these com-
pounds would ultimately be required in a synthesis of
CP-263,114. The general synthesis of these compounds
is shown in (eq 6). Reaction of aldehyde 19 with the
dianion of acetoacetone generated the aldol product 20,
(25) Davies, H. M. L.; McAfee, M. J .; Oldenburg, C. E. M. J . Org.
Chem. 1989, 54, 930.
(26) Davies, H. M. L.; Clark, D. M.; Alligood, D. B.; Eiband, G. R.
Tetrahedron 1987, 43, 4265.
(27) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J . Am. Chem.
Soc. 1996, 118, 10774.
(28) Davies, H. M. L.; Matasi, J . J .; Hodges, L. M.; Huby, N. J . S.;
Thornley, C.; Kong, N.; Houser, J . H. J . Org. Chem. 1997, 62, 1095.
(29) Davies, H. M. L.; Matasi, J . J .; Ahmed, G. J . Org. Chem. 1996,
61, 2305.

Cycloadditions between Vinylcarbenoids and Dienes
J . Org. Chem., Vol. 65, No. 14, 2000 4263
which was directly converted to diazodiketone 21 without
purification. Treatment of 21 with 2 equiv of triisopro-
pylsilyl triflate and triethylamine generated the vinyl-
diazoketone 22. Gratifyingly, excellent regiocontrol was
achieved in the silyl enol ether formation, where only 22
was formed.
(eq 8). This result further demonstrated the lability of
these compounds, which contain two anti-Bredt double
bonds.
If the [3 + 4] cycloaddition methodology was to figure
in a viable synthesis of CP-263,114, the initially formed
doubly anti-Bredt products would have to be transformed
to more stable compounds. Since the anti-Bredt silyl enol
ether 23 was prone to migration away from the bridge-
head position, 23 was reacted with N-bromosuccinimide.
This resulted in bromination with enol migration to form
bromide 27 (eq 9). It was envisioned that the bridgehead
bromo functionality would be a useful structural motif
for late stage introduction of an anti-Bredt double bond
by a zinc-induced elimination of an appropriately func-
tionalized â-bromo acetate. A remarkable feature of the
bridgehead bromination was that even though 23 existed
as a 3:1 mixture of diastereomers, 27 was formed as a
single diastereoisomer, indicating that only the major C7
exo diastereomer of 23 was undergoing reaction. It was
apparent from molecular models of 23, that the C7 endo
silyloxy group, sterically inhibited bromination. The
relative stereochemistry in 27 was established using
NOE difference analysis and then confirmed by X-ray
crystallography (Supporting Information). Further trans-
formations on 27 were readily achieved by reduction to
the alcohol 28 and selective desilylation of the silyl enol
ether in 28 to form 29.
The chemoselectivity of the rhodium(II) carbenoid
mediated reaction was found to be dependent on the
reaction solvent employed. When the reaction was carried
out using hexane as solvent a 61:37:2 mixture of [3 + 4]
cycloaddition products 23 and 24 and the triene 25 was
obtained (eq 7). However, when the reaction was carried
out in CH2Cl2 the ratio of 23 to 24 was improved to 73:
17 and the amount of triene 25 increased to 10% of the
product mixture. Under both sets of reaction conditions,
23 and 24 were formed as a 3:1 diastereomeric mixture.
If the [3 + 4] cycloaddition strategy was actually used
in a planned synthesis of CP-263,114, it would be
advantageous if the chemistry could be extended to more
elaborate furans. The 3-furanylester derivative 30 would
be especially useful, because it could enable the introduc-
tion of the maleic anhydride moiety in CP-263,114.
Rhodium(II) octanoate catalyzed decomposition of 22b in
CH2Cl2 resulted in the formation of 30 in 68% yield as a
4:1 diastereomeric mixture favoring the C7 exo isomer
(eq 10). The reaction of 22b was much cleaner than that
of the unsubstituted derivative 22a . Treatment of 30 with
N-bromosuccinimide resulted in the formation of 31 in
74% yield as a single diastereomer. Once again, the minor
C7 endo isomer of 30 does not appear to undergo
bromination. Attempts to reduce the ketone group in 31
with a variety of reagents were initially unsuccessful.
Even though 23 could be isolated by chromatography
in 44% yield, on standing in solution from 1 to 48 h, it
rearranged to a new silyl enol ether 26 in which the
alkene had migrated away from the anti-Bredt position

4264 J . Org. Chem., Vol. 65, No. 14, 2000
Davies et al.
Sch em e 1
However, finally, it was discovered that reduction with
lithium aluminum hydride at -78 °C resulted in the
formation of the alcohol 32. Under these conditions the
ester group in 31 was left unchanged.
verely curtailed if a hydrocarbon solvent is used. The
formation of trienes from the reaction of vinylcarbenoids
with furans is considered to occur from fully formed
zwitterionic intermediates obtained via electrophilic
attack of the carbenoid at the 2-position of the furan.25
This mechanism is consistent with the increased forma-
tion of triene 25 in the reaction of 22a when the reaction
solvent is changed from hexanes to CH2Cl2.
The more subtle issue in this chemistry is the effect of
solvent on formation of the two [3 + 4] cycloaddition
products 23 and 24. On changing the solvent from hexane
to CH2Cl2 the ratio of 23 to 24 changes from 61:37 to 73:
17. It is plausible that the Cope rearrangement of the
fully formed cyclopropane 33 is difficult to achieve and
that instead an alternative ring expansion mechanism
with silyl transfer occurs to form 24 (Scheme 1). The
direct formation of 23 could more reasonably occur from
a partially zwitterionic transition state or even the fully
zwitterionic intermediate 34.33 Thus, even though the
reaction of vinylcarbenoids with dienes has been gener-
ally considered as a cyclopropanation followed by a Cope
rearrangement, in certain systems, it may be that the
reaction is a stepwise or even a concerted [3 + 4] cyclo-
addition. It has been previously proposed that certain
intramolecular reactions between vinylcarbenoids and
pyrroles may be stepwise [3 + 4] cycloadditions.29
In summary, these studies further extend the range
of transformations that are possible between vinylcar-
benoids and dienes. The model studies described here
demonstrate that the intramolecular type II [3 + 4]
cycloadditions with furans are sufficiently robust that
such an approach for the total synthesis of CP-263,114
is reasonable. Further studies to use this chemistry for
the synthesis of CP-263,114 are in progress.
Discu ssion
The Cope rearrangement of cis-divinylcyclopropanes,
which are formed from intramolecular type II cyclopro-
panations, is a demanding transformation that is only
successful when a silyl enol ether is one of the vinyl com-
ponents. Due to the presence of two anti-Bredt double
bonds in the [3 + 4] cycloaddition products, transannular
rearrangements are potentially a problem, but these can
be avoided when furans are used as the diene component.
Even though the initial [3 + 4] cycloaddition products
are quite labile, they can be converted to stable com-
pounds that are appropriately functionalized for further
elaboration toward CP-263,114.
One of the most interesting features of this [3 + 4]
cycloaddition chemistry is that three products can be
formed in the reaction with furan, depending on the
reaction solvent used. A reasonable explanation for this
effect is shown in Scheme 1. It is well established that
solvent has a major effect on vinylcarbenoid transfor-
mations.30-32 The use of CH2Cl2 can lead to products
derived from zwitterionic intermediates rather than
cyclopropanation, but such transformations can be se-
(30) Davies, H. M. L.; Saikali, E.; Clark, T. J .; Chee, E. H.
Tetrahedron Lett. 1990, 31, 6299.
(31) Davies, H. M. L.; Saikali, E.; Young, W. B. J . Org. Chem. 1991,
56, 5696.
(32) Davies, H. M. L.; Clark, T. J .; Kimmer, G. F. J . Org. Chem.
1991, 56, 6440.
(33) In Scheme 1, 34 is indicated to be formed directly from the
carbene insertion, although it cannot be ruled out that 34 could have
been formed by spontaneous or metal-mediated opening of 33.

Cycloadditions between Vinylcarbenoids and Dienes
J . Org. Chem., Vol. 65, No. 14, 2000 4265
109.4, 55.6, 52.1, 37.0, 36.9, 25.9, 25.3, 17.4, -5.1, -5.3; MS
m/z (relative intensity) 266 (1), 265 (2), 223 (100). Due to the
relative instability of this compound, no further characteriza-
tion was obtained. However, full data was obtained for the free
acid derived from 9 (See Supporting Information).
Exp er im en ta l Section
Gen er a l In for m a tion . 1H NMR spectra were run at either
300, 400, or 500 MHz and 13C NMR at either 75 or 125 MHz
in CDCl3. Mass spectral determinations were carried out at
70 eV. Melting points are uncorrected. IR spectra were
obtained using a Nicolet Impact series 420 IR. Elemental
analyses were performed by Atlantic Microlabs Inc., Norcross,
GA.
Reactions were performed using heat-gun dried glassware
under an atmosphere of argon. Tetrahydrofuran (THF), diethyl
ether (Et2O), and hexanes were distilled from sodium ben-
zophenone ketyl prior to use. Acetonitrile (CH3CN), toluene,
diisopropylamine, and dichloromethane (CH2Cl2) were distilled
from calcium hydride. Column chromatography was carried
out on Merck silica gel 60 (230-400 mesh). Rhodium(II)
octanoate was purchased from Degussa Chemical Corporation.
Commercially available reagents were used without additional
purification unless otherwise stated.
1-Acetyl-5-vin ylbicyclo[3.1.0]h exa n -2-on e 11. A solution
of diazo 10 (1.55 g, 8.07 mmol) in CH2Cl2 (40 mL) was added
dropwise over 2 h to a solution of rhodium(II) octanoate (63
mg, 81 µmol) in CH2Cl2 (60 mL). The reaction was stirred at
room temperature overnight and then concentrated in vacuo.
Purification by silica gel column chromatography (petroleum
ether/Et2O, 4:1) afforded cyclopropane 11 (1.1 g, 83%): Rf 0.43
(petroleum ether/Et2O, 4:1); IR (neat) 3094, 3012, 2955, 2872,
1734, 1687, 1646, 1418, 1367 (cm-1); 1H NMR (300 MHz,
CDCl3) δ 5.72 (dd, 1 H, J ) 17.7, 10.8 Hz), 5.27 (d, 1 H, J )
17.7 Hz), 5.20 (d, 1 H, J ) 10.8 Hz), 2.41 (d, 1 H, J ) 5.1 Hz),
2.37-2.30 (m, 2 H), 2.34 (s, 3 H), 2.17-2.13 (m, 2 H), 1.60 (d,
1 H, J ) 5.1 Hz); 13C NMR (75 MHz, CDCl3) δ 208.5, 199.5,
134.3, 115.9, 52.9, 48.2, 33.3, 29.9, 25.2, 23.6; MS m/z (relative
intensity) 165 (11), 164 (100). Anal. Calcd for C10H12O2: C,
73.15; H, 7.37. Found: C, 73.03; H, 7.35.
7-(ter t-Bu t yld im et h ylsilyloxy)b icyclo[4.3.1]d eca -1,7-
d ien -5-on e 13. n-BuLi (2.5 M in hexanes, 0.88 mL, 2.2 mmol)
was added to a solution of diisopropylamine (0.32 mL, 2.4
mmol) in THF (4 mL) at 0 °C. After 30 min, the reaction
mixture was cooled to -78 °C, and a solution of 11 (164 mg,
1.00 mmol) in THF (1 mL) was added. After 10 min, tert-
butyldimethylsilyl chloride (0.30 g, 2.0 mmol) was added, and
the reaction mixture was allowed to warm to room tempera-
ture overnight. The reaction mixture was poured into satu-
rated aqueous NaHCO3 and Et2O, washed with water, dried
(Na2SO4), and concentrated in vacuo. Purification by silica gel
column chromatography (petroleum ether/Et2O, 4:1) afforded
silyl enol ether 13 (123 mg, 44%): Rf 0.74 (petroleum ether/
Et2O, 4:1); IR (neat) 3048, 2955, 2934, 2887, 2856, 1703, 1646,
1486, 1191 (cm-1);1H NMR (300 MHz, CDCl3) δ 5.70 (t, 1 H, J
) 6.9 Hz), 5.08 (dd, 1 H, J ) 5.1, 1.8 Hz), 3.12-3.07 (m, 1 H),
2.87 (d, 1 H, J ) 15.3 Hz), 2.72 (d, 1 H, J ) 12.0 Hz), 2.68-
2.51 (m, 3 H), 2.29-2.14 (m, 3 H), 0.88 (s, 9 H), 0.11 (s, 3 H),
0.06 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 208.3, 150.1, 141.9,
122.3, 109.3, 58.9, 42.5, 33.9, 28.6, 25.5, 22.6, 17.8, -4.5, -5.0;
HRMS (EI) m/z calcd for C12H17O2Si (-C4H9, loss of tert-butyl
group) 221.0995, found 221.0998.
1,5-Divin yl-3-oxa bicyclo[3.1.0]h exa n -2-on e 3. A solution
of diazo 2 (178 mg, 1.00 mmol) in hexanes (20 mL) was added
dropwise over 2 h to a solution of rhodium(II) octanoate (8.0
mg, 10 µmol) in hexanes (40 mL) heated at reflux. The reaction
mixture was heated at reflux for a further 1 h and then allowed
to cool to room temperature overnight and concentrated in
vacuo. Purification by silica gel column chromatography
(petroleum ether/Et2O, 4:1) afforded cyclopropane 3 (67 mg,
45%): Rf 0.37 (petroleum ether/Et2O, 4:1); IR (neat) 3089, 2965,
2923, 2851, 1770, 1728, 1588 (cm-1); 1H NMR (300 MHz,
CDCl3) δ 5.78-5.65 (m, 2 H), 5.45-5.19 (m, 4 H), 4.38 (d, 1 H,
J ) 9.1 Hz), 4.28 (d, 1 H, J ) 9.1 Hz), 1.70 (d, 1 H, J ) 4.8
Hz), 1.42 (d, 1 H, J ) 4.8 Hz); 13C NMR (75 MHz, CDCl3) δ
195.1, 131.9, 128.3, 119.3, 117.9, 70.0, 37.2, 25.7, 22.5; HRMS
(EI) m/z calcd for C9H10O2 150.0681, found 150.0681.
1-Acetyl-5-vin yl-3-oxa bicyclo[3.1.0]h exa n -2-on e 6. A
solution of diazo 5 (1.68 g, 8.66 mmol) in CH2Cl2 (40 mL) was
added dropwise over 1.5 h to a solution of rhodium(II)
octanoate (24 mg, 31 µmol) in CH2Cl2 (60 mL) at room
temperature. The reaction mixture was stirred at room tem-
perature overnight and then concentrated in vacuo. Purifica-
tion by silica gel column chromatography (petroleum ether/
Et2O, 3:2) afforded cyclopropane 6 (286 mg, 20%): Rf 0.22
(petroleum ether/Et2O, 4:1); IR (neat) 3089, 2965, 2924, 1786,
1693, 1646, 1589, 1429, 1367, 1093 (cm-1); 1H NMR (300 MHz,
CDCl3) δ 5.81 (dd, 1 H, J ) 17.6, 10.9 Hz), 5.37 (d, 1 H, J )
10.9 Hz), 5.30 (d, 1 H, J ) 17.6 Hz), 4.50 (d, 1 H, J ) 10.3 Hz),
4.28 (d, 1 H, J ) 10.3 Hz), 2.45 (s, 3 H), 2.42 (d, 1 H, J ) 4.7
Hz), 1.55 (d, 1 H, J ) 4.7 Hz); 13C NMR (75 MHz, CDCl3) δ
197.9, 172.9, 128.9, 118.5, 68.0, 43.2, 42.6, 29.3, 24.4. Anal.
Calcd for C9H10O3: C, 65.05; H, 6.07. Found: C, 64.89; H, 6.11.
ter t-Bu tyldim eth ylsilyl 6-Meth ylen e-2-oxobicyclo[3.2.0]-
h ep ta n e-1-ca r boxyla te 9. Triethylamine (0.15 mL, 1.1 mmol)
and tert-butyldimethylsilyl trifluoromethanesulfonate (0.22
mL, 0.94 mmol) were added to a solution of cyclopropane 6
(120 mg, 0.72 mmol) in CH2Cl2 (3 mL) at 0 °C. The reaction
was stirred for 20 min at 0 °C and then poured into saturated
aqueous NaHCO3 and hexanes. The organic phase was washed
with brine, dried (Na2SO4), and concentrated in vacuo to afford
cyclopropane 7 (210 mg), which was used in the next step
without further purification: 1H NMR (300 MHz, CDCl3) δ 5.72
(dd, 1 H, J ) 18.2, 10.9 Hz), 5.25 (d, 1 H, J ) 10.9 Hz), 5.17
(d, 1 H, J ) 18.2 Hz), 4.41-4.39 (m, 3 H), 4.24 (d, 1 H, J ) 8.8
Hz), 1.80 (d, 1 H, J ) 4.9 Hz), 1.33 (d, 1 H, J ) 4.9 Hz), 0.88
(s, 9 H), 0.20 (s, 3 H), 0.17 (s, 3 H).
Bicyclo[4.3.1]d ec-1-en e-5,7-d ion e 14. TBAF (1 M in THF,
0.36 mL, 0.36 mmol) was added to a solution of silyl enol ether
13 (100 mg, 0.36 mmol) in THF (5 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 2 h and then poured into
saturated aqueous NH4Cl, extracted with Et2O and EtOAc,
dried (Na2SO4), and concentrated in vacuo. Purification by
silica gel column chromatography (petroleum ether/Et2O, 1:1)
afforded diketone 14 (20 mg, 34%): Rf 0.34 (petroleum ether/
1
Et2O, 1:1); IR (neat) 2950, 2918, 2815, 1718, 1687 (cm-1); H
NMR (300 MHz, CDCl3) δ 5.74 (dd, 1 H, J ) 7.2, 5.4 Hz), 3.50-
3.46 (m, 1 H), 3.04 (dd, 1 H, J ) 12.9, 2.7 Hz), 2.81-2.62 (m,
3 H), 2.57-2.49 (m, 2 H), 2.45-2.32 (m, 4 H); 13C NMR (75
MHz, CDCl3) δ 206.0, 204.9, 142.4, 122.7, 67.3, 41.8, 38.8, 31.5,
29.2, 21.5; HRMS (EI) m/z calcd for C10H12O2 164.0837, found
164.0840.
[4-Meth yl-6-oxo-(E)-5-(2-ph en ylvin yl)-6H-pyr an -3-ylide-
n e]a ceta ld eh yd e 16. A solution of diazo 15 (132 mg, 0.468
mmol) in CH2Cl2 (20 mL) was added dropwise over 1 h to a
solution of rhodium(II) octanoate (3.6 mg, 4.7 µmol) in CH2-
Cl2 (10 mL) heated at reflux. The reaction mixture was heated
at reflux for a further 2 h, allowed to cool to room temperature
overnight, and concentrated in vacuo. Purification by silica gel
column chromatography (hexane/EtOAc, 4:1) afforded alde-
hyde 16 (83 mg, 70%) as a 5: 1 inseparable mixture of double
bond isomers: Rf 0.55 (hexane/EtOAc, 1:1); IR (neat) 3063,
3026, 2931, 2851, 1713, 1665, 1607, 1581, 1570, 1491; 1H NMR
(300 MHz, CDCl3) δ 10.22 (d, 1 H, J ) 8.1 Hz), 7.60 (d, 1 H, J
) 16.0 Hz), 7.54-7.25 (m, 5 H), 6.99 (d, 1 H, J ) 16.0 Hz),
6.04 (d, 1 H, J ) 8.1 Hz), 4.85 (s, 2 H), 2.50 (s, 3 H); 13C NMR
(75 MHz, CDCl3) δ 190.4, 161.7, 146.7, 141.3, 139.2, 136.6,
129.7, 129.4, 129.1 (2C), 128.7, 127.1, 119.7, 71.0, 22.0; HRMS
(EI) m/z calcd for C16H14O3 254.0943, found 254.0963.
A solution of cyclopropane 7 (210 mg, 0.72 mmol) in toluene
(10 mL) was heated at 65 °C overnight. The solvent was
evaporated in vacuo, and purification by silica gel column
chromatography (petroleum ether/Et2O, 4:1) afforded silyl ester
9 (110 mg, 55% from 6): Rf 0.77 (petroleum ether/Et2O, 4:1);
IR (neat) 2961, 2928, 2858, 2890, 1748, 1721, 1302, 1259
(cm-1); 1H NMR (500 MHz, CDCl3) δ 5.04 (d, 1 H, J ) 2.4 Hz),
5.01 (d, 1 H, J ) 2.4 Hz), 3.77 (d, 1 H, J ) 4.3 Hz), 3.35 (d, 1
H, J ) 16.8 Hz), 2.72-2.65 (m, 2 H), 2.43 (dd, 1 H, J ) 18.7,
8.3 Hz), 2.22-2.14 (m, 1H), 2.09-2.04 (m, 1 H), 0.91 (s, 9 H),
0.28 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 214.9, 170.4, 145.5,

4266 J . Org. Chem., Vol. 65, No. 14, 2000
Davies et al.
Typ ica l P r oced u r e for th e P r ep a r a tion of Dioxa tr i-
cycles 18a-e. 3-(ter t-Bu tyldim eth ylsilyloxy)-6,10-dioxatr i-
cyclo[6.2.1.04,9]u n d eca -3,8(11)-d ien -5-on e 18a . Triethy-
lamine (0.50 mL, 3.6 mmol) and tert-butyldimethylsilyl trif-
luoromethanesulfonate (0.60 mL, 2.6 mmol) were added to a
solution of 3-furanylmethyl 2-diazo-3-oxobutanoate (0.44 g, 2.1
mmol) in CH2Cl2 (35 mL) at 0 °C. The reaction mixture was
stirred for 20 min at 0 °C and then poured into dilute aqueous
NaHCO3 and hexanes. The organic phase was washed with
brine, dried (Na2SO4), and concentrated in vacuo to afford diazo
17a (0.68 g). The material was used in the subsequent reaction
without purification: IR (neat) 2957, 2931, 2886, 2858, 2102,
25.3, 18.0, 8.9, -4.4, -5.2; HRMS (EI) m/z calcd for C17H26O4-
Si 322.1600, found 322.1518. 18d (minor endo diastereomer):
Rf 0.40 (petroleum ether/Et2O, 4:1); IR (neat) 2955, 2928, 2858,
1743, 1607, 1465, 1346, 1259 (cm-1); 1H NMR (300 MHz,
CDCl3) δ 5.28 (s, 1 H), 5.27 (d, 1 H, J ) 6.3 Hz), 5.12 (t, 1 H,
J ) 5.7 Hz), 4.91 (s, 1 H), 2.79 (dd, 1 H, J ) 17.6, 6.3 Hz),
2.00-1.93 (m, 1 H), 1.81-1.72 (m, 1 H), 1.68 (d, 1 H, J ) 17.6
Hz), 0.98 (t, 3 H, J ) 7.5 Hz), 0.90 (s, 9 H), 0.23 (s, 3 H), 0.19
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 163.5, 149.8, 149.6, 114.4,
114.2, 78.4, 76.9, 76.5, 33.4, 27.5, 24.8, 17.6, 8.2, -4.7, -5.3;
HRMS (EI) m/z calcd for C17H26O4Si 322.1600, found 322.1598.
3-(t er t -Bu t yld im e t h ylsilyloxy)-6,11-d ioxa t r ic yc lo-
[7.2.1.04,10]d od eca -3,9(12)-d ien -5-on e 18e. Purification by
silica gel column chromatography (petroleum ether/Et2O, 1:1)
afforded 18e in 26% yield from 2-(3-furanyl)ethyl 2-diazo-3-
oxobutanoate: Rf 0.33 (petroleum ether/Et2O, 1:1); IR (neat)
2955, 2934, 2898, 2867, 1739, 1646, 1263, 1191 (cm-1); 1H NMR
(300 MHz, CDCl3) δ 5.46 (dd, 1 H, J ) 1.5, 1.5 Hz), 5.03 (ddd,
1 H, J ) 5.3, 1.5, 1.5 Hz), 4.73 (s, 1 H), 4.38 (ddd, 1 H, J )
12.1, 2.9, 3.9 Hz), 3.85 (ddd, 1 H, J ) 12.1, 12.0, 1.8 Hz), 2.77
(ddddd, 1 H, J ) 16.8, 3.9, 1.8, 1.5, 1.5 Hz), 2.76 (dd, 1 H, J )
17.3, 5.3 Hz), 2.60 (ddd, 1 H, J ) 16.8, 12.0, 2.9 Hz), 1.80 (d,
1
1710, 1607 (cm-1); H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H),
7.40 (s, 1H), 6.44 (s, 1H), 5.11 (s, 2H), 4.99 (s, 1H), 4.99 (d,
1H, J ) 1.9 Hz), 4.24 (d, 1H, J ) 1.9 Hz), 0.91 (s, 9H), 0.22 (s,
6H).
A solution of diazo 17a (680 mg, 2.1 mmol) in hexanes (50
mL) was added dropwise over 25 min to a solution of rhodium-
(II) octanoate (17 mg, 22 µmol) in hexanes heated at reflux.
The reaction mixture was heated at reflux for a further 1 h,
then concentrated in vacuo. Purification by silica gel column
chromatography (petroleum ether/Et2O, 1:1) afforded 18a (520
mg, 83% from 3-furanylmethyl 2-diazo-3-oxobutanoate): IR
(neat) 2954, 2929, 2858, 1732, 1600; 1H NMR (300 MHz,
CDCl3) δ 0.20 (s, 3 H), 0.23 (s, 3 H), 0.90 (s, 9 H), 1.75 (d, 1 H,
J ) 17.6 Hz), 2.81 (dd, 1 H, J ) 5.4, 17.6 Hz), 4.95 (d, 1 H, J
) 12.6 Hz), 4.97 (s, 1 H), 5.04 (d, 1 H, J ) 12.6 Hz), 5.28 (d, 1
H, J ) 5.4 Hz), 5.36 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ
163.7, 150.6, 146.3, 117.2, 115.2, 79.0, 76.9, 65.2, 34.1, 25.5,
18.2, -4.1, -4.9. Anal. Calcd for C15H22O4Si: C, 61.19; H, 7.53.
Found: C, 61.06; H, 7.50.
1 H, J ) 17.3 Hz), 0.89 (s, 9 H), 0.21 (s, 3 H), 0.18 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 167.9, 151.4, 148.6, 117.6, 114.2, 78.2,
77.7, 71.4, 34.2, 29.0, 25.4, 17.9, -4.2, -4.3. Anal. Calcd for
C
16H24O4Si: C, 62.30; H, 7.84. Found: C, 62.15; H, 7.89.
Typ ica l P r oced u r e for t h e P r ep a r a t ion of Dia zos
21a ,b. 3-Dia zo-6-h yd r oxy-6-(3-fu r a n yl)-2,4-h exa n ed ion e
21a . 2,4-Pentanedione (3.29 mL, 32.0 mmol, distilled) and
DMPU (5.80 mL, 48.0 mmol) were added to a solution of LDA
[(diisopropylamine (10.8 mL, 76.8 mmol) and n-BuLi (2.56 M
in hexanes, 27.5 mL, 70 mmol)] in THF (120 mL) at -78 °C.
The reaction mixture was stirred at -78 °C for 30 min,
3-furaldehyde 19a (2.77 mL, 32.0 mmol, distilled) was then
added, and the reaction mixture was allowed to warm to 0 °C
over 2 h. Saturated aqueous NH4Cl and water were added,
and the reaction mixture was extracted with Et2O. The organic
phase was washed with brine, dried (Na2SO4), and concen-
trated in vacuo to afford diketo alcohol 20a (exists as mixture
of diketone and enol tautomer, 9.30 g). The material was used
in the subsequent reaction without purification: IR (neat)
3416, 3145, 2959, 2873, 1712, 1611, 1500 (cm-1); 1H NMR (400
MHz, CDCl3) δ 15.35 (s), 7.43-7.38 (m, 2 H), 6.41-6.39 (s, 1
H), 5.53 (s), 5.29-5.24 and 5.15-5.10 (dd, 1 H), 2.97-2.54 (m,
2 H), 2.04 and 2.01 (s, 3 H); MS m/z (relative intensity) 196
(21), 138 (23), 110 (17).
p-Acetamidobenzenesulfonyl azide (p-ABSA) (7.68 g, 32.0
mmol) was added to a solution of diketo alcohol 20a (9.3 g, 32
mmol) in CH3CN (160 mL) and stirred for 15 min. Triethyl-
amine (9.12 mL, 64.0 mmol) was added, and the reaction
mixture was stirred at room temperature for a further 4 h.
The reaction mixture was concentrated in vacuo, and the
residue was slurried in Et2O, filtered, and concentrated in
vacuo. Purification by silica gel column chromatography (hex-
anes/EtOAc, 3:1) afforded diazo 21a (5.14 g, 72% from 19a ):
Rf 0.49 (hexanes/EtOAc, 1:2); IR (neat): 3451, 3141, 2981,
2924, 2132, 1656, 1506, 1367 (cm-1); 1H NMR (300 MHz,
CDCl3) δ 7.41 (d, 1 H, J ) 1.7 Hz), 7.38 (d, 1 H, J ) 1.7 Hz),
6.39 (s, 1 H), 5.19 (dt, 1 H, J ) 8.8, 8.1 Hz), 3.24 (d, 1 H, J )
8.1 Hz), 3.17 (d, 2 H, J ) 8.8 Hz), 2.41 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 190.4, 188.0, 143.4, 139.0, 127.5, 108.4, 70.3,
47.9, 29.3, 28.3; MS m/z (relative intensity) 194 (37), 176 (1).
Anal. Calcd for C10H10O4N2: C, 54.05; H, 4.54. Found: C,
53.80; H, 4.47.
3-(ter t-Bu t yld im et h ylsilyloxy)-11-b en zyloxym et h yl-
6,10-dioxatr icyclo[6.2.1.04,9]u n deca-3,8(11)-dien -5-on e 18b.
Purification by silica gel column chromatography (petroleum
ether/Et2O, 1:1) afforded 18b in 66% yield from 4-benzyloxym-
ethyl-3-furanylmethyl 2-diazo-3-oxobutanoate: Rf 0.48 (petro-
leum ether/Et2O, 1:1); IR (neat) 3058, 3022, 2965, 2929, 2856,
2882, 2360, 2334, 1744, 1600, 1346, 1263, 1155 (cm-1); 1H NMR
(300 MHz, CDCl3) δ 7.38-7.28 (m, 5 H), 5.31 (d, 1 H, J ) 6.4
Hz), 4.96 (s, 2 H), 4.90 (s, 1 H), 4.48 (d, 1 H, J ) 11.7 Hz), 4.44
(d, 1 H, J ) 11.7 Hz), 4.14 (d, 1 H, J ) 12.7 Hz), 4.07 (d, 1 H,
J ) 12.7 Hz), 2.78 (dd, 1 H, J ) 17.2, 6.4 Hz), 1.98 (d, 1 H, J
) 17.2 Hz), 0.92 (s, 9 H), 0.25 (s, 3 H), 0.20 (s,3 H); 13C NMR
(75 MHz, CDCl3) δ 163.1, 150.6, 141.4, 137.3, 127.9, 127.4,
127.3, 127.0, 114.6, 79.5, 77.0, 71.9, 63.2, 63.0, 33.6, 24.8, 17.5,
-4.8, -5.9; MS m/z (relative intensity) 251 (19), 208 (6); HRMS
(EI) m/z calcd for C11H11O5Si 251.0376, found 251.0750.
3-(ter t-Bu t yld im et h ylsilyloxy)-9-m et h yl-6,10-d ioxa -
tr icyclo[6.2.1.04,9]u n d eca -3,8(11)-d ien -5-on e 18c. Purifica-
tion by silica gel column chromatography (petroleum ether/
Et2O, 4:1) afforded 18c in 29% yield from 2-methyl-3-fur-
anylmethyl 2-diazo-3-oxobutanoate as a white solid: Rf 0.33
(petroleum ether/Et2O, 4:1); mp 124-126 °C; IR (neat) 2960,
2934, 2828, 2856, 1739, 1594, 1150, 1000 (cm-1); 1H NMR (300
MHz, CDCl3) δ 5.35 (s, 1 H), 5.23 (d, 1 H, J ) 5.7 Hz), 4.95 (s,
2 H), 2.81 (dd, 1 H, J ) 17.2, 5.7 Hz), 1.76 (d, 1 H, J ) 17.2
Hz), 1.55 (s, 3 H), 0.91 (s, 9 H), 0.24 (s, 3 H), 0.21(s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 163.8, 149.9, 147.5, 119.2, 118.1, 81.3,
77.3, 64.2, 33.9, 25.2, 18.2, 17.0, -4.5, -5.2. Anal. Calcd for
C
16H24O4Si: C, 62.30; H, 7.84. Found: C, 62.19; H, 7.63.
3-(ter t-Bu t yld im et h ylsilyloxy)-7-et h yl-6,10-d ioxa t r i-
cyclo[6.2.1.04,9]u n d eca -3,8(11)-d ien -5-on e 18d . Purification
by silica gel column chromatography (petroleum ether/Et2O,
4:1) afforded 18d in 48% yield from 1-(3-furanyl)propyl 2-diazo-
3-oxobutanoate as a 2:1 mixture of separable diastereomers.
18d (major exo diastereomer): Rf 0.50 (petroleum ether/Et2O,
4:1); IR (neat) 2961, 2934, 2858, 1737, 1601, 1471, 1346, 1259
Meth yl 4-(4-Dia zo-1-h yd r oxy-3,5-d ioxoh exyl)-3-fu r a n -
ca r boxyla te 21b. Purification by silica gel column chroma-
tography (petroleum ether/Et2O, 1:1) afforded 21b in 71% yield
from 19b: Rf 0.70 (Et2O); IR (neat) 3462, 3146, 3001, 2960,
2929, 2856, 2132, 1729, 1677, 1656, 1553 (cm-1); 1H NMR (400
MHz, CDCl3) δ 7.97 (s, 1 H), 7.44 (s, 1 H), 5.35 (ddd, 1 H, J )
11.7, 7.1, 6.6 Hz), 4.32 (d, 1 H, J ) 6.6 Hz), 3.84 (s, 3 H), 3.24-
3.14 (m, 2 H), 2.44 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 191.5,
190.4, 164.8, 149.7, 141.0, 127.3, 116.8, 63.1, 52.0, 47.3, 29.7,
28.7; HRMS (EI) m/z calcd for C12H12O6 (M+ - N2) 252.0643,
found 252.0634.
1
(cm-1); H NMR (300 MHz, CDCl3) δ 5.30 (s, 1 H), 5.27 (d, 1
H, J ) 4.6 Hz), 4.96 (t, 1 H, J ) 6.1 Hz), 4.93 (s, 1 H), 2.79
(dd, 1 H, J ) 17.7, 4.6 Hz), 2.01-1.94 (m, 1 H), 1.83-1.78 (m,
1 H), 1.73 (d, 1 H, J ) 17.7 Hz), 1.00 (t, 3 H, J ) 7.5 Hz), 0.91
(s, 9 H), 0.24 (s, 3 H), 0.21 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 163.9, 150.5, 149.7, 116.8, 115.8, 78.9, 78.2, 75.7, 33.5, 27.1,

Cycloadditions between Vinylcarbenoids and Dienes
J . Org. Chem., Vol. 65, No. 14, 2000 4267
3,7-Di(t r iisop r op ylsilyloxy)-10-oxa t r icyclo[6.2.1.04,9]-
u n d eca -3,8(11)-d ien -5-on e 23 a n d 5,7-d i(tr iisop r op ylsi-
lyloxy)-10-oxa t r icyclo[6.2.1.04,9]u n d eca -4,8(11)-d ien -3-
on e 24. Triisopropylsilyl trifluoromethanesulfonate (0.93 mL,
3.5 mmol) was added dropwise over 10 min to a solution of
diazo 21a (350 mg, 1.6 mmol) and triethylamine (0.57 mL, 4.1
mmol) in CH2Cl2 (15 mL) at 0 °C. The reaction mixture was
stirred for 3 h at 0 °C, diluted with hexanes, washed succes-
sively with water and brine, dried (Na2SO4), and concentrated
in vacuo to afford diazo 22a (1.0 g). The material was used in
the subsequent reaction without purification: 1H NMR (300
MHz, CDCl3) δ 7.34 (s, 2 H), 6.39 (s, 1 H), 5.35 (t, 1 H, J ) 6.5
Hz), 5.15 (s, 1 H), 4.35 (d, 1 H, J ) 2.1 Hz), 3.02 (dd, 1 H, J )
14.3, 6.8 Hz), 2.71 (dd, 1 H, J ) 14.3, 6.8 Hz), 1.20 (m, 6 H),
1.08 (t, 18 H, J ) 7.2 Hz), 1.00 (d, 18 H, J ) 7.2 Hz).
A solution of diazo 22a (1.07 g, 2.00 mmol) in hexanes (15
mL) was added dropwise over 30 min to a solution of rhodium-
(II) octanoate (16 mg, 20 µmol) in hexanes (20 mL). The
reaction mixture was stirred at room temperature for 1 h and
then concentrated in vacuo. Purification by silica gel column
chromatography (petroleum ether/Et2O, 9:1) afforded two
regioisomeric oxatricycles 23 (397 mg, 39% from 21a , 3:1
inseparable mixture of diastereomers) and 24 (320 mg, 32%
from 21a , 3:1 inseparable mixture of diastereomers). A trace
amount of aldehyde 25 was also formed according to the 1H
NMR spectrum of the crude reaction mixture. The ratio of 23:
24:25 in the crude reaction mixture was found to be 61:37:2
according to the 1H NMR spectrum.
H), 1.03-1.01 (m, 36 H); 13C NMR (125 MHz, CDCl3) δ 203.7
(s), 147.8 (s), 139.4 (s), 131.3 (d), 105.5 (d), 78.8 (d), 77.8 (d),
67.4 (d), 58.4 (d), 52.2 (t), 17.9 (q), 17.8 (q), 12.5 (d), 11.9 (d);
MS m/z (relative intensity) 506 (1), 463 (40), 435 (19), 349 (2);
HRMS (EI) m/z calcd for C28H50O4Si2 (-C3H7, loss of isopropyl
group) 463.2700, found 463.2699.
4-Br om o-3,7-d i(t r iisop r op ylsilyloxy)-10-oxa t r icyclo-
[6.2.1.04,9]u n d eca -2,8(11)-d ien -5-on e 27. N-Bromosuccinim-
ide (1.8 g, 9.9 mmol) was added to a solution of oxatricycle 23
(5.0 g, 9.9 mmol) in THF (150 mL) in a flask covered with
aluminum foil. The reaction mixture was stirred at 0 °C for 2
h, diluted with Et2O, washed successively with saturated
aqueous NaHCO3 and water, dried (Na2SO4), and concentrated
in vacuo. Purification by silica gel column chromatography
(petroleum ether/Et2O, 19:1) afforded bromoketone 27 (2.4 g,
41%): Rf 0.47 (petroleum ether/Et2O, 4:1); mp 108-110 °C
(MeOH); IR (neat) 2950, 2893, 2867, 1744, 1625, 1470 (cm-1);
1H NMR (300 MHz, CDCl3) δ 6.41 (s, 1 H), 5.40 (s, 1 H), 5.29
(d, 1 H, J ) 4.4 Hz), 5.11-5.10 (m, 2 H), 2.84 (dd, 1 H, J )
13.9, 2.6 Hz), 2.67 (dd, 1 H, J ) 13.9, 3.3 Hz), 1.20-1.00 (m,
42 H); 13C NMR (125 MHz, CDCl3) δ 194.3 (s), 147.5 (s), 138.3
(s), 134.2 (d), 105.9 (d), 87.3 (d), 78.2 (d), 72.3 (s), 67.0 (d), 50.1
(t), 17.9 (q), 17.8 (q), 12.6 (d), 11.8 (d); HRMS (EI) m/z calcd
for C25H42O4Si2Br (-C3H7, loss of an isopropyl group) 541.1833,
found 541.1805.
4-Br om o-3,7-d i(t r iisop r op ylsilyloxy)-10-oxa t r icyclo-
[6.2.1.04,9]u n d eca -2,8(11)-d ien -5-ol 28. Sodium borohydride
(93 mg, 2.5 mmol) was added to a solution of bromoketone 27
(481 mg, 0.822 mmol) in methanol (1.5 mL) and THF (4.5 mL)
at 0 °C. The reaction mixture was allowed to warm to room
temperature overnight, quenched with water, and extracted
with EtOAc. The organic phase was washed with brine, dried
(Na2SO4), and concentrated in vacuo. Purification by silica gel
column chromatography (petroleum ether/Et2O, 19:1) afforded
alcohol 28 (426 mg, 88%): Rf 0.51 (petroleum ether/Et2O, 1:1);
23: Rf 0.23 (petroleum ether/Et2O, 9:1); IR (neat) 2943, 2892,
1
2866, 1719, 1693, 1567 (cm-1); H NMR (400 MHz, CDCl3) δ
5.30 (s, 1 H), 5.21 (s, 1 H), 5.18 (d, 1 H, J ) 6.2 Hz), 4.92 (t, 1
H, J ) 6.2 Hz), 2.89-2.50 (m, 3 H), 1.69 (d, 1 H, J ) 17.2 Hz),
1.27-1.16 (m, 6 H), 1.11-0.99 (m, 36 H); 13C NMR (125 MHz,
CDCl3) δ 192.7, 154.2, 146.1, 126.2, 115.6, 78.1, 46.8, 62.8, 53.8,
33.4, 17.8, 17.7, 12.8, 11.9; HRMS (EI) m/z calcd for C28H50O4-
Si2 506.3248, found 506.3250.
1
IR (neat) 3542, 2950, 2871, 1630, 1475 (cm-1); H NMR (300
24: Rf 0.15 (petroleum ether/Et2O, 9:1); IR (neat) 2945, 2887,
2865, 1688, 1560, 1465, 1390, 1353, 879, 676 (cm-1); 1H NMR
(400 MHz, CDCl3) δ 5.42 (s, 1 H), 5.17 (d, 2 H, J ) 6.2 Hz),
4.88 (s, 1 H), 2.95 (dd, 1 H, J ) 16.7, 6.2 Hz), 2.80 (dd, 1 H, J
) 17.4, 6.2 Hz), 2.51 (d, 1 H, J ) 16.7 Hz), 1.77. 13C NMR
(125 MHz, CDCl3) δ 191.8, 156.9, 148.5, 130.8, 114.9, 78.5,
77.8, 65.1, 34.7, 22.6, 17.9, 17.7, 12.4, 12.2; HRMS (EI) m/z
calcd for C28H50O4Si2 506.3248, found 506.3217.
[6-(Tr iisop r op ylsilyloxy)-3-(1-(tr iisop r op ylsilyloxy)vi-
n yl)-4-oxocycloh ex-2-en ylid en e]a ceta ld eh yd e 25. A solu-
tion of diazo 22a (1.0 g, 1.6 mmol) in CH2Cl2 (30 mL) was
added dropwise over 1 h to a solution of rhodium(II) octanoate
(13 mg, 17 µmol) in CH2Cl2 (15 mL) at room temperature. The
reaction mixture was stirred at room temperature for a further
30 min and then concentrated in vacuo. Purification by silica
gel column chromatography (petroleum ether/Et2O, 19:1) af-
forded 23 (355 mg, 44% from 21a , 3:1 inseparable mixture of
diastereomers), 24 (200 mg, 25% from 21a , 3:1 inseparable
mixture of diastereomers), and 25 (65 mg, 8% from 21a ). The
ratio of 23:24:25 in the crude reaction mixture was found to
be 73:17:10 according to the 1H NMR spectrum.
MHz, CDCl3) δ 6.19 (s, 1 H), 5.30 (d, 1 H, J ) 4.6 Hz), 5.28 (s,
1 H), 4.95 (d, 1 H, J ) 4.6 Hz), 4.87 (t, 1 H, J ) 2.6 Hz), 4.30
(ddd, 1 H, J ) 8.2, 4.0, 4.0 Hz), 3.51 (d, 1 H, J ) 8.2 Hz), 2.36
(ddd, 1 H, J ) 13.0, 4.0, 4.0 Hz), 1.54 (dd, 1 H, J ) 13.0, 2.6
Hz), 1.27-1.18 (m, 3 H), 1.17-1.07 (m, 18 H), 1.07-1.02 (m,
18 H), 0.89-0.83 (m, 3 H); 13C NMR (125 MHz, CDCl3) δ 148.8,
139.4, 12.8, 108.9, 85.9, 77.6, 72.2, 66.9, 66.3, 43.9, 18.0, 17.9,
12.7, 11.9; HRMS (EI) m/z calcd for C25H44O4Si2Br (-C3H7, loss
of an isopropyl group) 543.1962, found 543.1901.
4-B r o m o -5-h y d r o x y -7-(t r i i s o p r o p y ls i ly lo x y )-10-
oxa tr icyclo[6.2.1.04,9]u n d ec-8(11)-en -3-on e 29. TBAF (0.24
mL, 0.24 mmol, 1 M in THF) was added to a solution of alcohol
28 (140 mg, 0.24 mmol) in THF (10 mL) at -78 °C. The
reaction mixture was stirred at -78 °C for 15 min and then
poured into ice-water and extracted with CH2Cl2. The organic
phase was dried (Na2SO4) and concentrated in vacuo. Purifica-
tion by silica gel column chromatography (petroleum ether/
Et2O, 3:1) afforded bromoketone 29 (100 mg, 95%): Rf 0.34
(petroleum ether/Et2O, 1:1); IR (neat) 2956, 2897, 2871, 1710,
1
1470 (cm-1); H NMR (300 MHz, CDCl3) δ 5.89 (s, 1 H), 5.12
(d, 1 H, J ) 4.2 Hz), 5.03 (s, 1 H), 4.87 (s, 1 H), 4.18 (m, 1 H),
3.74 (d, 1 H, J ) 11.3 Hz), 3.14 (dd, 1 H, J ) 16.3, 4.2 Hz),
2.46 (dd, 1 H, J ) 13.9, 3.1 Hz), 2.19 (d, 1 H, J ) 16.3 Hz),
2.84 (dt, 1 H, J ) 13.9, 3.1 Hz), 1.13-0.84 (m, 21 H); 13C NMR
(125 MHz, CDCl3) δ 203.9, 146.5, 123.7, 83.2, 79.0, 71.9, 65.6,
45.5, 42.4, 29.6, 17.8, 11.8; HRMS (EI) m/z calcd for C16H24O4-
SiBr (-C3H7, loss of an isopropyl group) 387.0627, found
387.0662.
25: Rf 0.35 (petroleum ether/Et2O, 9:1); IR (neat) 2946, 2866,
2722, 1726, 1678, 1598, 1550, 1460, 885 (cm-1); 1H NMR (300
MHz, CDCl3) δ 10.28 (d, 1 H, J ) 7.7 Hz), 8.44 (s, 1 H), 6.42
(d, 1 H, J ) 7.7 Hz), 5.66 (s, 1 H), 4.83 (dd, 1 H, J ) 10.6, 5.0
Hz), 4.80 (s, 1 H), 2.99 (dd, 1 H, J ) 15.2, 5.0 Hz), 2.82 (dd, 1
H, J ) 15.2, 10.6 Hz), 1.31-1.23 (m, 6 H), 1.12-0.98 (m, 36
H). 13C NMR (75 MHz, CDCl3) 216.6, 189.6, 149.0, 134.5, 132.5,
130.9, 128.8, 101.2, 68.1, 30.3, 17.9, 17.8, 12.9, 12.7; HRMS
(EI) m/z calcd for C28H50O4Si2 506.3248, found 506.3285.
3,7-Di(t r iisop r op ylsilyloxy)-10-oxa t r icyclo[6.2.1.04,9]-
u n d eca 2,8(11)-d ien -5-on e 26. Upon standing, 23 rearranged
to 26, which was purified by silica gel column chromatography
(petroleum ether/Et2O, 4:1): Rf 0.54 (petroleum ether/Et2O,
Meth yl 3,7-Di(tr iisopr opylsilyloxy)-5-oxo-10-oxatr icyclo-
[6.2.1.04,9]u n d eca -3,8(11)-d ien e-11-ca r boxyla te 30. Trieth-
ylamine (0.36 mL, 0.26 mmol) and then triisopropylsilyl
trifluoromethanesulfonate (0.59 mL, 0.22 mmol) were added
to a solution of diazo 21b (55 mg, 0.21 mmol) in CH2Cl2 (10
mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C,
and then additional triethylamine (0.36 mL, 0.26 mmol) and
triisopropylsilyl trifluoromethanesulfonate (0.59 mL, 0.22
mmol) were added and the mixture stirred at 0 °C for a further
1 h. The reaction mixture was then diluted with hexanes and
poured into saturated aqueous NaHCO3 and hexanes. The
1
9:1); IR (neat) 2955, 2893, 2867, 1734, 1631, 1470 (cm-1); H
NMR (300 MHz, CDCl3) δ 6.22 (s, 1 H), 5.35 (d, 1 H, J ) 5.6
Hz), 5.29 (d, 1 H, J ) 4.8 Hz), 5.06 (t, 1 H, J ) 3.5 Hz), 5.01
(d, 1 H, J ) 4.8 Hz), 3.49 (d, 1 H, J ) 5.6 Hz), 2.77 (dd, 1 H,
J ) 13.9, 3.5 Hz), 2.55 (d, 1 H, J ) 13.9 Hz), 1.18-1.05 (m, 6

4268 J . Org. Chem., Vol. 65, No. 14, 2000
Davies et al.
organic phase was washed with brine, dried (Na2SO4), and
concentrated in vacuo to afford diazo 22b (128 mg). The
material was used in the subsequent reaction without purifi-
cation: 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1 H), 7.45 (s, 1
H), 5.72 (dd, 1 H, J ) 7.5, 3.9 Hz), 5.18 (s, 1 H), 4.33 (d, 1 H,
J ) 2.2 Hz), 3.81 (s, 3 H), 3.00 (dd, 1 H, J ) 13.9, 7.5 Hz), 2.86
(dd, 1 H, J ) 13.9, 3.9 Hz), 1.26-1.18 (m, 6 H), 1.07-0.97 (m,
36 H).
A solution of diazo 22b (1.95 g, 3.29 mmol) in hexanes
(60 mL) was added dropwise over 30 min to a solution of
rhodium(II) octanoate (26 mg, 33 µmol) in CH2Cl2 (100 mL).
The reaction mixture was stirred for a further 10 min and then
concentrated in vacuo. Purification by silica gel column chro-
matography (petroleum ether/Et2O, 19:1) afforded oxatricycle
30 (1.27 g, 68%) as a 4:1 inseparable mixture of diastereomers.
30: Rf 0.68 (petroleum ether/Et2O, 4:1); IR (neat): 2943, 2868,
1720, 1571, 1462 (cm-1); 1H NMR (300 MHz, CDCl3) δ 5.51
(dd, 1 H, J ) 5.7, 4.1 Hz), 5.45 (d, 1 H, J ) 5.7 Hz), 5.35 (s, 1
H), 3.75 (s, 3 H), 2.85-2.78 (m, 3 H), 1.97 (d, 1 H, J ) 17.4
Hz), 1.24-1.09 (m, 6 H), 1.06-1.03 (m, 36 H); 13C NMR (75
MHz, CDCl3) δ 193.7 (s), 164.4 (s), 163.4 (s), 146.8 (s), 124.0
(s), 118.0 (s), 79.0 (d), 78.5 (d), 62.4 (d), 54.6 (t), 51.3 (q), 33.0
(t), 17.8 (q), 17.6 (q), 12.7 (d), 11.9 (d); HRMS (EI) m/z calcd
for C30H52O6Si2 564.3348, found 564.3302.
(125 MHz, CDCl3) δ 193.3, 162.6, 149.5, 147.2, 138.1, 105.8,
88.8, 78.6, 70.8, 65.9, 51.9, 49.0, 17.7, 17.6, 12.5, 11.8; HRMS
(EI) m/z calcd for C27H44O6Si2Br (-C3H7, loss of an isopropyl
group) 599.1860, found 599.1889.
Meth yl 4-Br om o-5-h yd r oxy-3,7-(tr iisop r op ylsilyloxy)-
10-oxa tr icyclo[6.2.1.04,9]u n d eca -2,8(11)-d ien e-11-ca r boxy-
la te 32. A solution of lithium aluminum hydride (823 µL, 0.823
mmol, 1 M in THF) was added dropwise over 5 min to a
solution of bromoketone 31 (530 mg, 0.823 mmol) in THF (15
mL) at -78 °C. The reaction mixture was stirred at -78 °C
for 1 h, acetone (1.0 mL) was added, and stirring was continued
for a further 10 min. The reaction mixture was poured into
saturated aqueous NH4Cl solution and extracted with Et2O.
The organic phase was washed successively with water and
brine, dried (Na2SO4), and concentrated in vacuo. Purification
by silica gel chromatography (pentane/Et2O, 20:1) afforded
alcohol 32 (437 mg, 82%): Rf 0.36 (pentane/Et2O, 20:1); IR
(neat) 3542, 2951, 2871, 1737, 1657, 1625, 1476, 1438, 1337,
1
1247, 1225 (cm-1); H NMR (300 MHz, CDCl3) δ 5.45 (s, 1H),
5.44 (d, 1H, J ) 4.8 Hz), 5.38 (s, 1H), 5.06 (d, 1H, J ) 4.8 Hz),
4.29 (ddd, 1H, J ) 12.1, 8.8, 4.4 Hz), 3.71 (s, 3H), 3.46 (d, 1H,
J ) 8.8 Hz), 2.32 (dt, 1H, J ) 13.6, 4.1 Hz), 1.46 (dt, 1H, J )
12.8, 2.2 Hz), 0.84-1.26 (br m, 42H); 13C NMR (75 MHz,
CDCl3) 162.7, 150.7, 148.5, 137.0, 108.8, 87.5, 78.0, 71.8, 65.3,
65.0, 51.6, 42.8, 17.8, 17.7, 12.5, 11.7. Anal. Calcd for C30H53O6-
Si2Br: C, 55.79; H, 8.27. Found: C, 55.93; H, 8.25.
Meth yl 4-Br om o-3,7-d i(tr iisop r op ylsilyloxy)-5-oxo-10-
oxa t r icyclo[6.2.1.04,9]u n d eca -2,8(11)-d ien e-11-ca r b oxy-
la te 31. N-Bromosuccinimide (47.6 mg, 0.277 mmol) was added
to a solution of oxatricycle 30 (151 mg, 0.267 mmol) in THF (6
mL) at 0 °C, in a flask covered with aluminum foil. The
reaction mixture was stirred at 0 °C for 2 h, diluted with Et2O,
and washed successively with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), and concentrated in vacuo. Purification
by silica gel column chromatography (petroleum ether/Et2O,
19:1) afforded bromoketone 31 (127 mg, 74%): Rf 0.29 (petro-
leum ether/Et2O, 19:1); IR (neat) 2956, 2897, 2876, 1726, 1630
Ack n ow led gm en t. Financial support of this work
by the National Institutes of Health (GM57425) is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for 2, 5, 10, 15, 19, and precursors to 17, 1H NMR spectral
data for 2, 3, 5, 10, 13-16, 18b, 18d (endo), 18d (exo), 21b,
and 23-31, and X-ray crystallographic data for 27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
(cm-1); H NMR (300 MHz, CDCl3) δ 5.67 (dd, 1 H, J ) 3.3,
2.9 Hz), 5.54 (s, 1 H), 5.44 (d, 1 H, J ) 4.8 Hz), 5.23 (d, 1 H,
J ) 4.8 Hz), 3.75 (s, 3 H), 2.82 (dd, 1 H, J ) 14.3, 3.3 Hz), 2.59
(dd, 1 H, J ) 14.3, 2.9 Hz), 1.14-0.94 (m, 42 H); 13C NMR
J O991959B