CP-263,114 synthetic studies. Construction of an isotwistane ring system via rhodium carbenoid C-H insertion

Article abstract of DOI:10.1016/S0040-4020(02)00664-6

Described is a rhodium carbenoid C-H insertion strategy for the construction of an isotwistane ring system needed for a late-stage fragmentation en route to the total synthesis of CP-263,114.

Full text of DOI:10.1016/S0040-4020(02)00664-6

Tetrahedron 58 (2002) 6545–6554
CP-263,114 synthetic studies. Construction of an isotwistane
ring system via rhodium carbenoid C–H insertion
*
´
David A. Spiegel, Jon T. Njardarson and John L. Wood
Sterling Chemistry Laboratory, Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA
Received 18 April 2002; accepted 14 May 2002
Dedicated to Professor Yoshito Kishi in honor of his receipt of the Tetrahedron Prize and his inspirational contributions to the field of organic chemistry
Abstract—Described is a rhodium carbenoid C–H insertion strategy for the construction of an isotwistane ring system needed for a late-
stage fragmentation en route to the total synthesis of CP-263,114. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
led us to postulate that of the possible products derived from
C–H insertion, the desired one would predominate (Fig. 1).3
Additionally, rhodium carbenoids have been shown to favor
insertion into C–H bonds on highly substituted carbon
atoms, and are particularly prone to insertion at C–H bonds
adjacent to heteroatoms. In a preliminary study, we explored
the feasibility of the C–H insertion approach on a model
substrate (i.e. 8, Scheme 1).
Since their isolation in 1995, CP-263,114 (1, Phomoidride
B, Fig. 1) and CP-225,917 (Phomoidride A) have received
enormous attention from the synthetic community.1 In line
with these efforts, our laboratories have been interested in
developing methods to construct the carbocyclic core of
CP-263,114, and applying these methods to a total synthesis
of the natural product. In our approach, we envision the late-
stage fragmentation of a heavily functionalized isotwistane
skeleton (2) to generate the carbocyclic core of the
phomoidrides (2!1). In order to employ this fragmentation
strategy, we explored a rhodium carbenoid-mediated C–H
insertion reaction to construct the isotwistane skeleton, and
a subsequent alkylation to construct the quaternary center
found in the natural product (3!2).
2. Results and discussion
As illustrated in Scheme 1, the synthesis commenced with
known ketone 4.4 Dihydroxylation of 4 with osmium
tetroxide resulted in exclusive formation of the desired
diol 5, which was protected as the corresponding acetonide
(6), and then homologated to its b-ketoester 7. Treatment of
b-ketoester 7 with p-acetamidobenzenesulfonyl azide
( p-ABSA) according to the procedure of Davies5 furnished
desired diazo ester 8. After screening several rhodium
catalysts and solvents, it was found that rhodium(II) acetate
in methylene chloride at room temperature gave the desired
insertion product 9 in excellent yield. Interestingly, only one
Active research in the area of rhodium carbenoids has
illustrated a diverse pattern of reactivity for these species.2
With regard to the C–H insertion strategy planned for
constructing the isotwistane skeleton, the known propensity
of rhodium carbenoids to generate 5-membered rings in
preference to 4- and 6-membered rings was encouraging and
Figure 1. Retrosynthetic analysis.
Keywords: rhodium carbenoid; b-ketoester; isotwistane; CP-263,114; phomoidrides; C–H insertion; diazo.
*
Corresponding author. Tel.: þ1-203-432-5991; fax: þ1-203-432-6144; e-mail: john.wood@yale.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00664-6

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D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
Scheme 1.
of the two possible diastereomeric products was observed
(the structure of 9 was assigned using NOE difference
experiments). Following the successful rhodium carbenoid
C–H insertion, attention was focused on constructing the
quaternary center. Thus, alkylation of b-ketoester 9 with
methyl bromoacetate furnished 10 in excellent yield.
Single-crystal X-ray analysis confirmed that 10 possessed
the stereochemistry required for the natural product. The
observed selectivity can be attributed to substrate control,
in which the electrophile traps only from the less hindered
a-face.
were eventually overcome by the use of high concentrations
and moderate reaction temperatures to produce 14 in good
yield. As anticipated, the cycloadduct generated was
derived from endo attack of the dienophile on the side
opposite to the acetonide on the sterically more accessible
diene face.9 Structural assignment of the product was
secured using X-ray crystallography. Unfortunately, for-
mation of the corresponding b-ketoester via a Birch
reduction–ozonolysis sequence on 14 was unsuccessful.
Despite being unable to advance 14, the Diels–Alder
cycloaddition remained an attractive strategy and attention
was turned to an alternate route. Propargyl ether 15 was
subjected to oxidative dicarbonylation conditions10 to give
maleate 16, which was then hydrolyzed and dehydrated to
produce maleic anhydride 17 (Scheme 3). Subsequent
Diels–Alder reaction with acetonide 13 yielded 18 as a
single cycloadduct, which was ring-opened to the corre-
sponding diester 19. Chemoselective removal of the benzyl
ether furnished alcohol 20, which was then converted to 21
in a three-step sequence. Treatment of 21 with p-ABSA
gave diazo compound 22 (Scheme 4). Unfortunately,
Applying this method to the total synthesis of the
phomoidrides required that the C–H insertion chemistry
be compatible with the functional groups present in 3; of
particular concern was the neighboring maleic anhydride
unit or an appropriate precursor. To investigate the issues of
functional group tolerance, a more advanced model system
was constructed from acetonide 136 and anhydride 127
(Scheme 2). In the event, the propensity of 13 to undergo
dimerization8 and aromatization made it difficult to effect
the desired Diels–Alder cycloaddition. These problems
Scheme 2.

D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
6547
Scheme 3.
exposure of 22 to a variety of reaction conditions produced
none of the desired C–H insertion product 23. In all cases,
intractable mixtures were obtained.
protected as its bis-triisopropyl silyl (TIPS) ether (25,
Scheme 5). Reductive removal of the benzyl ether was
accomplished in high yield to provide primary alcohol 26,
which, after a three step oxidation–enolate addition–
oxidation sequence, was converted to b-ketoester 27.
Finally, smooth diazotization to provide C–H insertion
substrate 28 was accomplished using p-ABSA and DBU.
Based on the success of the simpler model system 8, it is
believed that the difficulties with 22 are likely the result of
competing carbonyl ylide formation.11 It was therefore
envisioned that removal of the ester groups in 22 might
minimize these undesired side reactions. Thus, anhydride 18
was exhaustively reduced to its corresponding diol (24) and
Initial attempts to produce a C–H insertion product by
treating 28 with various rhodium(II) catalysts in a variety of
Scheme 4.
Scheme 5.

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D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
Scheme 6.
solvents yielded side-products from oxonium ylide for-
mation-[1,4]-silyl migration and oxidative decarbonylation
processes, 29 and 30, respectively (Scheme 5).12 Early
experiments revealed that the electron-poor rhodium(II)
trifluoroacetate or rhodium(II) perfluorobutyrate catalysts
led almost exclusively to the formation of 30. The desired
compound (31)13 was observed only as a minor product.
Additionally, a substantial solvent effect was noted whereby
utilization of chlorinated solvents (CH2Cl2, 1,2-dichloro-
ethane) clearly favored the formation of compounds 29 and
30 over compound 31. Formation of these side products was
suppressed by employing the rhodium(II) pivalate
(Rh2(piv)4) catalyst system in benzene at 508C, to yield 32
as a single diastereomer in 46% overall yield after alkylation
with methyl bromoacetate (Scheme 6).14 It is worth noting
that in the C–H insertion step, decreasing the reaction
temperature from refluxing benzene to 508C gave rise to a
substantial increase in the yield of the desired product. As in
earlier systems (see 10, Scheme 1), subsequent electrophile
trapping occurred exclusively on the less hindered a-face of
the molecule. Compound 32 contains both the complete
isotwistane core and the succinate-derived quaternary center
found in the natural product.
High-resolution mass spectra were performed at the
University of Illinois Mass Spectrometry Center. Single-
crystal X-ray analyses were performed by Susan DeGala of
Yale University.
3.1.1. 1-(5,6-Dihydroxy-bicyclo[2.2.2]oct-2-yl)-ethanone
(5). To a stirred solution of 4 (7.38 g, 49.1 mmol, 1 equiv.)
and NMO (12.7 g, 108.1 mmol, 2.2 equiv.) in a mixture of
acetone (74 mL) and water (1.5 mL) was added OsO4
(2.5 wt% solution in 2-methyl-2-propanol: 2.3 mL,
0.2 mmol, 0.004 equiv.). After stirring the reaction mixture
at room temperature for 10 h, sodium bisulfite (1 g) was
added and stirring continued for an additional 1 h. The
resulting slurry was filtered through a Celite cake,
thoroughly washed with acetone, and concentrated. The
crude mixture was diluted with CH2Cl2 (200 mL) and
washed with 1N HCl. The aqueous phase was saturated with
NaCl and extracted with CH2Cl2 (3£30 mL). The organic
phases were combined, dried over Na2SO4, and concen-
trated in vacuo. The resulting oil was purified using silica
gel chromatography, yielding 5 as a clear oil (8.73 g, 95%
yield). FTIR (thin film/NaCl) 3389 (s), 2938 (s), 2870 (m),
1704 (s), 1454 (w), 1399 (w), 1355 (m), 1185 (w), 1149 (w),
1
1065 (m), 1017 (m), 975 (w), 953 (w), 830 (w) cm21; H
NMR (500 MHz, CDCl3) d 3.85–3.83 (m, 1H), 3.73–3.71
(m, 1H), 2.84 (d, J¼4.5 Hz, 1H), 2.74–2.70 (m, 1H), 2.68
(d, J¼4.0 Hz, 1H), 2.18 (s, 3H), 2.10–2.09 (m, 1H), 2.01–
1.96 (m, 1H), 1.93–1.87 (m, 2H), 1.65–1.59 (m, 1H), 1.40–
1.25 (m, 3H); 13C NMR (125 MHz, CDCl3) d 210.1, 67.8,
65.0, 49.0, 34.2, 31.6, 28.8, 24.4, 18.9, 17.9; HRMS (EI) m/z
184.1103 [calcd for C10H16O3 (Mþ) 184.1099].
3. Experimental
3.1. General
Unless stated otherwise, reactions were performed in flame
dried glassware under a nitrogen atmosphere, using freshly
distilled solvents. Diethyl ether (Et2O) and tetrahydrofuran
(THF) were distilled from sodium/benzophenone ketyl.
Methylene chloride (CH2Cl2) and triethylamine (Et3N) were
distilled from calcium hydride. All other commercially
obtained reagents were used as received.
3.1.2. 1-(4,4-Dimethyl-3,5-dioxa-tricyclo[5.2.2.02,6]un-
dec-8-yl)-ethanone (6). To a stirred solution of 5 (3.31 g,
17.97 mmol, 1 equiv.) in CH2Cl2 (100 mL) was added 2,2-
dimethoxypropane (6.63 mL, 53.91 mmol, 1 equiv.) and
PPTS (100 mg, 0.40 mmol, 0.02 equiv.). The reaction
mixture was stirred overnight at room temperature, diluted
with CH2Cl2 (100 mL), and washed with saturated NaHCO3
(3£50 mL). The organic layer was dried over Na2SO4 and
purified using silica gel chromatography with 10% EtOA-
c/hexanes as eluant to furnish 6 as a white crystalline solid
(3.43 g, 85% yield). Mp 81–838C; FTIR (thin film/NaCl)
2986 (m), 2937 (s), 2869 (m), 1708 (s), 1453 (w), 1379 (m),
1262 (m), 1207 (m), 1163 (m), 1145 (w), 1096 (w), 1058 (s),
965 (w), 875 (m) cm21; 1H NMR (500 MHz, CDCl3) d 4.05
(ddd, J¼7.5, 4.0, 1.0 Hz, 1H), 3.91 (ddd, J¼8.0, 4.0, 1.0 Hz,
1H), 2.80–2.76 (m, 1H), 2.25 (t, J¼3.0 Hz, 1H), 2.19 (s,
3H), 1.99–1.92 (m, 3H), 1.87–1.80 (m, 1H), 1.61 (ddd,
J¼13.5, 11.0, 4.0 Hz, 1H), 1.50 (s, 3H), 1.33–1.20 (m, 2H),
1.30 (s, 3H); 13C NMR (125 MHz, CDCl3) d 209.8, 107.8,
75.0, 72.4, 48.5, 31.7, 29.0, 28.8, 25.9, 24.3, 23.5, 19.0,
17.9; HRMS (EI) m/z 224.1414 [calcd for C13H20O3 (Mþ)
224.1412].
Unless stated otherwise, all reactions were magnetically
stirred and monitored by thin-layer chromatography (TLC)
using E. Merck silica gel 60 F254 precoated plates
(0.25 mm). Column or flash chromatography was performed
with the indicated solvents using silica gel (230–400 mesh)
purchased from Bodman. In general, the chromatography
guidelines reported by Still et al. were followed.15 When
reactions were adsorbed onto silica gel, the amount of silica
gel used was equal to two times the weight of the reagents.
All melting points were obtained on a Gallenkamp capillary
melting point apparatus and are uncorrected. Infrared
spectra were recorded on a Midac M1200 FTIR. H and
13C NMR spectra were recorded on a Bruker AM-500,
Bruker Avance DPX-500 or Bruker Avance DPX-400
spectrometer. Chemical shifts are reported relative to
internal chloroform (1H, d 7.26 ppm; 13C, d 77.0 ppm).
1

D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
6549
3.1.3. 3-(4,4-Dimethyl-3,5-dioxa-tricyclo[5.2.2.02,6]un-
dec-8-yl)-3-oxo-propionic acid methyl ester (7). To a
stirred (2788C) solution of 6 (5.76 g, 25.68 mmol, 1 equiv.)
in THF (25 mL) was added LiHMDS (1.0 M solution in
THF: 77.1 mL, 77.1 mmol, 3 equiv.). After stirring the
reaction mixture at 2788C for 1.5 h, methyl chloroformate
(4 mL, 51.36 mmol, 2 equiv.) was added and the reaction
mixture was allowed to warm to room temperature
overnight. The reaction was quenched by the addition of
saturated ammonium chloride (20 mL) solution and
extracted with Et2O (3£30 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo.
The crude oil was subjected to silica gel chromatography
(gradient elution, 0–10% EtOAc/hexanes) yielding analyti-
cally pure 7 as a crystalline white solid (5.1 g, 70% yield).
Mp 61–648C; FTIR (thin film/NaCl) 2985 (m), 2938 (s),
2870 (m), 1749 (s), 1710 (s), 1453 (w), 1438 (w), 1380 (m),
1316 (m), 1263 (s), 1207 (s), 1163 (s), 1090 (m), 1060 (s),
982 (w), 875 (m) cm21; 1H NMR (500 MHz, CDCl3) d 4.06
(dd, J¼8.0, 4.0 Hz, 1H), 3.96 (app dd, J¼8.0, 4.0 Hz, 1H),
3.73 (s, 3H), 3.53 (s, 2H), 2.92 (dq, J¼5.5, 2.0 Hz, 1H), 2.23
(app t, J¼2.5 Hz, 1H), 2.02–1.82 (m, 3H), 1.67 (ddd,
J¼11.0, 9.0, 4.0 Hz, 1H), 1.52–1.49 (m, 1H), 1.50 (s, 3H),
1.37–1.23 (m, 2H), 1.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 204.0, 167.8, 107.9, 74.9, 72.2, 52.6, 48.1, 47.7,
31.4, 28.9, 25.9, 242.3, 23.7, 18.9, 17.7; HRMS (EI) m/z
282.1470 [calcd for C15H22O5 (Mþ) 282.1467].
(m), 1033 (w), 996 (w), 920 (w), 873 (w), 750 (w) cm21; 1H
NMR (500 MHz, CDCl3) d 4.67 (d, J¼5.0 Hz, 1H), 3.76 (s,
3H), 3.62 (d, J¼1.5 Hz, 1H), 2.65–2.62 (m, 1H), 2.16–2.15
(m, 1H), 2.03–1.91 (m, 4H), 1.65–1.58 (m, 2H), 1.54 (s, 3H),
1.26 (s, 3H), 1.21 (ddt, J¼14.0, 2.0, 1.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 208.4, 168.9, 109.3, 86.0, 75.2, 62.3,
52.4, 47.2, 39.1, 29.0, 27.0, 26.4, 25.8, 18.8, 14.3; HRMS (EI)
m/z 280.1312 [calcd for C15H20O5 (Mþ) 280.1311].
3.1.6. Methyl (9R )-9-(2-methoxy-2-oxoethyl)-2,2-
dimethyl-8-oxooctahydro-4,7-methanoindeno[3a,4-
d ][1,3]dioxole-9-carboxylate (10). To a stirred suspension
of NaH (157 mg, 3.92 mmol, 3 equiv.) in DMF (10 mL) at
08C was added dropwise 9 (366 mg, 1.31 mmol, 1 equiv.)
dissolved in DMF (3 mL). After 1 h, methyl bromoacetate
(310 mL, 3.26 mmol, 2.5 mmol) was added and stirring was
continued for 12 h at room temperature. The reaction
mixture was quenched by the addition of saturated
ammonium chloride (20 mL), diluted with benzene
(100 mL) and washed sequentially with saturated CuSO4
(3£30 mL) and brine (2£10 mL). The organic layer was
dried over Na2SO4 and concentrated in vacuo. The resultant
oil was purified using silica gel chromatography employing
15% EtOAc/hexanes as the eluant to furnish 10 as a white
solid (387 mg, 84% yield). Mp 108–1118C (recrystallized
from hexanes); FTIR (thin film/NaCl) 2990 (w), 2947 (m),
2871 (w), 1759 (s), 1740 (s), 1434 (w), 1373 (w), 1283 (w),
1254 (w), 1214 (m), 1152 (m), 1117 (m), 1080 (w), 1057
(m), 1036 (m), 1015 (m), 968 (m), 884 (m) cm21; 1H NMR
(500 MHz, CDCl3) d 4.07 (d, J¼5.0 Hz, 1H), 3.81 (s, 3H),
3.69 (s, 3H), 3.33 (d, J¼16.0 Hz, 1H), 2.61 (ddd, J¼10.0,
4.5, 3.5 Hz, 1H), 2.53 (d, J¼16.0 Hz, 1H), 2.16–2.13 (m,
1H), 2.04–1.99 (m, 2H), 1.92–1.75 (m, 2H), 1.64 (ddt,
J¼15.0, 11.0, 3.5 Hz, 1H), 1.55 (s, 3H), 1.40 (s, 3H), 1.25–
1.17 (m, 2H); 13C NMR (125 MHz, CDCl3) d 208.3, 170.9,
170.5, 113.3, 87.7, 78.7, 61.8, 52.5, 52.2, 46.9, 37.0, 36.3,
28.9, 27.6, 27.1, 24.1, 19.2, 14.8; HRMS (EI) m/z 352.1528
[calcd for C18H24O7 (Mþ) 352.1522].
3.1.4. 2-Diazo-3-(4,4-dimethyl-3,5-dioxa-tricyclo-
[5.2.2.02,6]undec-8-yl)-3-oxo-propionic acid methyl
ester (8). To a stirred solution of 7 (1962 mg, 6.95 mmol,
1.0 equiv.) and p-ABSA (1838 mg, 7.65 mmol, 1.1 equiv.)
in CH2Cl2 (35 mL) was added dropwise DBU (1150 mL,
7.65 mmol, 1.1 equiv.). After stirring the reaction mixture
for 1 h at room temperature, it was concentrated, poured
onto a silica gel column, and chromatographed using 15%
EtOAc/hexanes as the eluant to furnish 8 as a yellow oil
(1840 mg, 86% yield). FTIR (thin film/NaCl) 2940 (m),
2870 (w), 2138 (s), 1721 (s), 1650 (m), 1437 (m), 1380 (m),
1360 (m), 1306 (s), 1262 (m), 1207 (s), 1164 (m), 1132 (m),
1102 (w), 1060 (m), 973 (m), 876 (m), 812 (w), 763 (w), 739
3.1.7. 3-(3-Methoxy-phenyl)-furan-2,5-dione (12).
A
mixture of 3-iodoanisole (4 mL, 33.6 mmol, 1 equiv),
diethyl fumarate (11 mL, 67.2 mmol, 2 equiv.), Pd(OAc)2
(380 mg, 1.68 mmol, 0.05 equiv.), P(o-tol)3 (1020 mg,
3.36 mmol, 0.1 equiv.) and Et3N (10 mL, 67.2 mmol,
2 equiv.) was heated in a sealed tube at 908C for 1 h. The
crude reaction mixture was cooled to room temperature,
concentrated, and purified using silica gel chromatography
employing a gradient of 5–25% EtOAc/hexanes as eluant to
yield the corresponding aryl diester (6.1 g, 65%). This
material was carried on directly to the next step. A solution
of the diester (6.1 g, 21.8 mmol, 1 equiv.) and LiOH (9.2 g,
218.3 mmol, 10 equiv.) in a mixture of THF (925 mL) and
water (220 mL) was heated to 408C for 24 h. The crude
reaction mixture was cooled, concentrated in vacuo,
acidified to pH 4, and extracted with EtOAc (3£100 mL),
dried over MgSO4 and evaporated. The resulting crude oil
was dissolved acetic anhydride (100 mL) and heated at 608C
for 12 h. The acetic anhydride was evaporated and the
resulting solid was recrystallized from EtOAc/hexanes to
furnish 12 (2858 mg, 64% yield).
(w) cm21 1H NMR (400 MHz, CDCl3) d 4.14 (ddd,
;
J¼10.1, 5.0, 1.0 Hz, 1H), 4.03 (ddd, J¼10.1, 4.5, 2.0 Hz,
1H), 3.82 (s, 3H), 3.74 (ddd, J¼12.5, 8.0, 3.0 Hz, 1H),
2.09–1.81 (m, 5H), 1.65 (ddd, J¼17.5, 13.0, 6.0 Hz, 1H),
1.49 (s, 3H), 1.44–1.31 (m, 1H), 1.31 (s, 3H), 1.27–1.23
(m, 1H); 13C NMR (100 MHz, CDCl3) d 194.1, 161.6,
107.7, 75.1, 72.4, 52.4, 43.7, 32.4, 29.2, 25.9, 24.3, 23.6,
18.7, 17.8; HRMS (CI) m/z 309.1451 [calcd for C15H20N2O5
(MþH) 309.1451].
3.1.5. Methyl (9S )-2,2-dimethyl-8-oxooctahydro-4,7-
methanoindeno[3a,4-d ][1,3]dioxole-9-carboxylate (9).
To a stirred solution of 8 (96 mg, 0.31 mmol, 1 equiv.) in
CH2Cl2 (40 mL) at room temperature was added Rh2(OAc)4
(2 mg, 0.005 mmol, 0.015 equiv.). This suspension was
stirred overnight at room temperature, concentrated, and
purified by silica gel chromatography using 10% EtOA-
c/hexanes as the eluant to give 9 as a white solid (83 mg,
95% yield). Mp 93–958C (recrystallized from hexanes);
FTIR (thin film/NaCl) 2988 (w), 2935 (m), 2887 (w), 1761
(s), 1721 (s), 1455 (w), 1439 (w), 1383 (m), 1373 (w), 1343
(m), 1272 (m), 1252 (w), 1215 (m), 1192 (m), 1134 (s), 1073
3.1.8. 4a-(3-Methoxyphenyl)-2,2-dimethylhexahydro-
4,8-ethenofuro[3,4-f ][1,3]benzodioxole-5,7-dione (14).

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D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
Anhydride 12 (93 mg, 0.46 mmol, 1 equiv.) and acetonide
13 (140 mg, 0.92 mmol, 2 equiv.) were dissolved in
benzene (0.5 mL) and heated in a sealed tube at 758C for
20 h. The crude reaction mixture was cooled to room
temperature and purified by silica gel chromatography using
1% HCOOH/15% EtOAc/hexanes as the eluant, yielding 14
as a white solid (125 mg, 76% yield). Mp 183–1858C
(recrystallized from hexanes/EtOAc); FTIR (thin film/
NaCl) 2978 (w), 2937 (w), 2915 (w), 1853 (w), 1779 (s),
1600 (w), 1583 (w), 1495 (w), 1382 (w), 1293 (w), 1263
(m), 1224 (m), 1208 (m), 1162 (m), 1088 (w), 1066 (m), 989
(m), 961 (w), 937 (w), 912 (w), 874 (w), 764 (w) cm21; 1H
NMR (500 MHz, CDCl3) d 7.37 (t, J¼8.0 Hz, 1H), 7.12 (t,
J¼2.5 Hz, 1H), 1.05 (dd, J¼8.0, 1.5 Hz, 1H), 6.93 (dd,
J¼8.0, 2.5 Hz, 1H), 6.38 (t, J¼7.0 Hz, 1H), 6.28 (t,
J¼7.0 Hz, 1H), 4.30 (dd, J¼7.0, 3.0 Hz, 1H), 4.10 (dd,
J¼7.0, 3.0 Hz, 1H), 3.85 (s, 3H), 3.84–3.82 (m, 1H), 3.62–
3.60 (m, 1H), 3.48 (d, J¼3.0 Hz, 1H), 1.31 (s, 3H), 1.18 (s,
3H); 13C NMR (125 MHz, CDCl3) d 172.3, 171.0, 160.7,
135.2, 132.5, 130.7, 130.5, 118.5, 114.0, 113.4, 110.2, 76.9,
74.3, 55.9, 55.6, 46.6, 42.7, 38.6, 25.5, 25.2; HRMS (EI) m/z
356.1254 [calcd for C20H20O6 (Mþ) 356.1260].
5H), 6.88 (t, J¼2.0 Hz, 1H), 4.66 (s, 2H), 4.43 (d, J¼2.0 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 164.3, 163.5, 150.5,
136.7, 129.7, 128.9, 128.6, 128.1, 74.0, 63.5; HRMS (CI)
m/z 219.0656 [calcd for C12H10O4 (MþH) 219.0657].
3.1.11. 4a-[(Benzyloxy)methyl]-2,2-dimethylhexahydro-
4,8-ethenofuro[3,4-f ][1,3]benzodioxole-5,7-dione (18).
Prepared in the same manner as 14, yielding 18 as an
amorphous white solid (72% yield). FTIR (thin film/NaCl)
2987 (w), 2935 (w), 2871 (w), 1857 (m), 1780 (s), 1455 (w),
1382 (m), 1364 (w), 1266 (m), 1226 (m), 1208 (m), 1164
(m), 1065 (s), 1022 (w), 978 (m), 916 (m), 825 (w), 757 (m),
1
740 (m), 697 (m) cm21; H NMR (500 MHz, CDCl3) d
7.39–7.30 (m, 3H), 7.24–7.22 (m, 2H), 6.23 (app t,
J¼7.0 Hz, 1H), 6.16 (app t, J¼7.0 Hz, 1H), 4.52 (dd,
J¼12.0 Hz, 2H), 4.30 (ddd, J¼7.5, 3.0, 1.0 Hz, 1H), 4.25
(ddd, J¼7.5, 3.0, 1.0 Hz, 1H), 3.81 (d, J¼8.5 Hz, 1H), 3.56
(d, J¼8.5 Hz, 1H), 3.45–3.43 (m, 1H), 3.25 (ddd, J¼6.0,
3.5, 1.5 Hz, 1H), 2.93 (d, J¼2.5 Hz, 1H), 1.30 (s, 3H), 1.24
(s, 3H); 13C NMR (125 MHz, CDCl3) d 173.5, 171.3, 136.7,
132.1, 130.3, 129.0, 128.8, 128.4, 127.8, 127.7, 110.2, 76.8,
74.7, 74.0, 70.9, 54.4, 45.4, 38.7, 37.8, 25.4, 25.1; HRMS
(EI) m/z 370.1418 [calcd for C21H22O6 (Mþ) 370.1416].
3.1.9. 2-Benzyloxymethyl-but-2-enedioic acid dimethyl
ester (16). To a solution of benzyl ether 15 (2924 mg,
20 mmol, 1 equiv.) in MeOH (100 mL) was added
potassium iodide (45 mg, 0.2 mmol, 0.01 equiv.) and
palladium(II) iodide (10 mg, 0.02 mmol, 0.001 equiv.).
This mixture was transferred to a stainless steel autoclave
(300 mL). The autoclave was pressurized with CO (400 psi)
and air (560 psi). The reaction mixture was stirred and
heated at 658C for 20 h. The autoclave was cooled to room
temperature, the mixture diluted with CH2Cl2 (150 mL) and
filtered first through a Celite cake with a thin charcoal layer
on top, and then through a short silica plug to give 16 (5.1 g,
96% yield) as a clear oil. FTIR (thin film/NaCl) 3030 (w),
2952 (m), 2860 (w), 1731 (s), 1658 (m), 1497 (w), 1453 (m),
1436 (s), 1373 (m), 1331 (m), 1270 (s), 1200 (s), 1170 (s),
3.1.12. 8-[(Benzyloxy)methyl]-2,2-dimethyl-3a,4,7,7a-
tetrahydro-4,7-ethano-1,3-benzodioxole-8,9-dicarboxyl-
ate (19). Anhydride 18 (1080 mg, 2.92 mmol, 1 equiv.) was
dissolved in MeOH (50 mL) and heated at reflux overnight.
The reaction mixture was cooled to room temperature and
the MeOH was evaporated. To the crude reaction mixture
was added THF (10 mL) and an excess of an etheral solution
of diazomethane and stirred for 5 h. The excess diazo-
methane was quenched by the addition of acetic acid.
Evaporation yielded diester 19 (1200 mg, 99% yield) as an
amorphous white solid. FTIR (thin film/NaCl) 3064 (w),
2985 (m), 2949 (m), 2872 (w), 1746 (s), 1496 (w), 1454 (m),
1434 (m), 1370 (m), 1283 (m), 1262 (m), 1206 (s), 1165
(m), 1123 (m), 1088 (m), 1065 (m), 1030 (m), 891 (w), 736
1
1
1132 (m), 1087 (s), 913 (w), 874 (w), 742 (m) cm21; H
(w), 699 (w) cm21; H NMR (500 MHz, CDCl3) d 7.37–
NMR (500 MHz, CDCl3) d 7.37–7.30 (m, 5H), 6.22 (t,
J¼2.0 Hz, 1H), 4.57 (s, 2H), 4.25 (d, J¼2.0 Hz, 2H), 3.81
(s, 3H), 3.75 (s, 3H); 13C NMR (125 MHz, CDCl3) d 167.0,
165.6, 145.1, 137.4, 128.6, 128.0, 127.8, 121.3, 72.9, 69.0,
52.5, 52.1; HRMS (CI) m/z 265.1071 [calcd for C14H16O5
(MþH) 265.1076].
7.26 (m, 5H), 6.27 (t, J¼7.0 Hz, 1H), 6.12 (t, J¼7.0 Hz,
1H), 4.58 (d, J¼12.5 Hz, 1H), 4.65 (d, J¼12.5 Hz, 1H), 4.44
(dd, J¼7.0, 3.0 Hz, 1H), 4.10 (dd, J¼7.0, 2.5 Hz, 1H), 3.88
(d, J¼9.5 Hz, 1H), 3.61 (s, 3H), 3.60 (s, 3H), 3.47–3.45 (m,
2H), 3.07–3.05 (m, 1H), 2.44 (d, J¼1.0 Hz, 1H), 1.32 (s,
3H), 1.21 (s, 3H); 13C NMR (125 MHz, CDCl3) d 173.1,
172.9, 137.8, 131.8, 128.8, 128.6, 128.0, 127.7, 108.9, 77.9,
74.9, 73.5, 73.4, 55.8, 52.4, 52.1, 46.7, 40.0, 38.4, 25.4,
25.3; HRMS (EI) m/z 416.1831 [calcd for C23H28O7 (Mþ)
416.1835].
3.1.10. 3-Benzyloxymethyl-furan-2,5-dione (17). A sol-
ution of maleate 16 (5390 mg, 20.4 mmol, 1 equiv.) in a
mixture of EtOH (18 mL) and 2N NaOH (31 mL) was
heated to 758C for 3 h. The reaction mixture was cooled to
room temperature and 1N HCl (63 mL) was added. The
biphasic mixture was extracted with EtOAc (4£50 mL) and
combined organic layers were dried over Na2SO4 and
evaporated, to yield a crude oil which was dissolved in
Ac2O (100 mL) and heated at 758C for 1 h. Removal of the
excess acetic anhydride on a rotary evaporator, the mixture
was purified using column chromatography (10% EtOAc/
hexanes) to furnish 17 (3.71 g, 83% yield) as a white solid.
FTIR (thin film/NaCl) 3109 (m), 3064 (w), 3030 (w), 2873
(m), 2803 (w), 1860 (w), 1841 (m), 1765 (s), 1655 (m), 1498
(m), 1453 (m), 1369 (m), 1312 (w), 1281 (m), 1229 (m),
1125 (m), 1032 (m), 982 (s), 893 (s), 884 (s), 839 (m), 745
3.1.13. Dimethyl 8-(hydroxymethyl)-2,2-dimethyl-
3a,4,7,7a-tetrahydro-4,7-ethano-1,3-benzodioxole-8,9-
dicarboxylate (20). To a stirred solution of 19 (94 mg,
0.225 mmol, 1 equiv.) in methanol (5 mL) was added 10%
Pd/C (90 mg) and HCOOH (200 mL). The stirred solution
was kept under an atmosphere of hydrogen (balloon) for 5 h
at room temperature, filtered through Celite washing
thoroughly with EtOAc, and concentrated in vacuo to
yield 20 (66 mg, 90% yield) as a white crystalline solid. Mp
125–1288C; IR (thin film/NaCl) 3466 (m), 2985 (m), 2951
(m), 1741 (s), 1435 (m), 1373 (m), 1283 (m), 1206 (s), 1165
(s), 1107 (w), 1062 (s), 1027 (m), 888 (w), 832 (w), 723 (w)
1
1
(s) cm21; H NMR (500 MHz, CDCl3) d 7.41–7.34 (m,
cm21; H NMR (500 MHz, CDCl3) d 6.23 (t, J¼6.5 Hz,

D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
6551
1H), 6.11 (t, J¼6.5 Hz, 1H), 4.46 (ddd, J¼6.5, 3.5, 1.0 Hz,
1H), 4.20 (dd, J¼7.0, 3.0 Hz, 1H), 4.05 (d, J¼11.0 Hz, 1H),
3.82–3.69 (m, 1H), 3.68 (s, 3H), 3.65 (s, 3H), 3.30 (ddd,
J¼6.0, 3.5, 1.0 Hz, 1H), 3.28–3.26 (m, 1H), 3.13 (d,
J¼8.0 Hz, 1H), 2.27 (s, 1H), 1.32 (s, 3H), 1.26 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 173.4, 173.1, 130.5, 130.2,
109.4, 78.0, 74.8, 68.1, 56.4, 52.6, 52.5, 48.5, 40.4, 37.4,
25.4, 25.3; HRMS (EI) m/z 326.1368 [calcd for C16H22O7
(Mþ) 326.1366].
1435 (m), 1371 (m), 1316 (s), 1253 (m), 1208 (s), 1165 (m),
1135 (m), 1069 (m), 1021 (m), 917 (m), 881 (m), 833 (w),
736 (m) cm21 1H NMR (500 MHz, CDCl3) d 6.35 (t,
;
J¼6.5 Hz, 1H), 6.20 (t, J¼6.5 Hz, 1H), 4.30–4.23 (m, 3H),
4.19 (dd, J¼7.0, 3.0 Hz, 1H), 3.91 (ddd, J¼6.5, 3.5, 1.0 Hz,
1H), 3.88 (ddd, J¼6.5, 3.5, 1.0 Hz, 1H), 3.60 (s, 3H), 3.59
(s, 3H), 3.29–3.27 (m, 1H), 1.32 (t, J¼6.5 Hz, 3H), 1.31 (s,
3H), 1.21 (s, 3H); 13C NMR (125 MHz, CDCl3) d 187.7,
172.0, 169.6, 160.6, 130.0, 128.4, 109.3, 78.8, 76.7, 75.3,
65.3, 62.2, 52.6, 52.4, 45.4, 39.3, 39.0, 25.4, 25.3, 14.4.
3.1.14. Dimethyl 8-(3-ethoxy-3-oxopropanoyl)-2,2-
dimethyl-3a,4,7,7a-tetrahydro-4,7-ethano-1,3-benzo-
dioxole-8,9-dicarboxylate (21). To a stirred solution of 20
(1380 mg, 4.23 mmol, 1 equiv.) in acetone at 08C (120 mL)
was added Jones’ reagent (12.3 mL). The reaction mixture
was stirred for 3.5 h at room temperature. At that point,
MeOH (20 mL) and water (40 mL) were added and the
mixture was concentrated to remove most of the acetone and
methanol. The crude reaction mixture was extracted with
EtOAc (3£50 mL) and dried over Na2SO4 to yield the crude
acid (1125 mg, 78% yield). The crude acid was dissolved in
CH2Cl2 (30 mL) and to this solution was added (COCl)2
(375 mL, 4.30 mmol, 1.3 equiv.) followed by 2 drops of
DMF. The reaction mixture was stirred for 12 h and
concentrated to yield pure acid chloride that was carried
on directly to the next step. In a separate flask, EtOAc
(970 mL, 9.9 mmol, 3 equiv.) was dissolved in dry THF
(11 mL) and treated with LiHMDS (1.0 M solution in THF:
9.9 mL, 9.9 mmol, 3 equiv.) at 2788C. After 3 h at 2788C,
a solution of the acid chloride dissolved in THF (10 mL)
was added and stirring was continued for another 1.5 h
before quenching with 1N HCl (20 mL) and extracting with
EtOAc (3£30 mL). The combined organic phases were
washed with water (10 mL) and brine (10 mL), dried over
Na2SO4, and concentrated to yield a crude oil. This crude oil
was purified using silica gel chromatography using 20%
EtOAc/hexanes as eluant to give 21 as a pale brown oil
(1350 mg, 78% yield over 3 steps). IR (thin film/NaCl) 2984
(m), 2953 (m), 2907 (w), 1745 (s), 1718 (s), 1436 (m), 1326
(m), 1259 (s), 1224 (s), 1206 (s), 1109 (m), 1067 (s), 1048
(m), 1031 (m), 912 (w), 889 (w), 833 (w), 726 (w), 651 (w)
3.1.16. (8-Benzyloxymethyl-9-hydroxymethyl-4,4-di-
methyl-3,5-dioxa-tricyclo[5.2.2.02,6]undec-10-en-8-yl)-
methanol (24). To a stirred solution of 18 (5.0 g,
13.5 mmol, 1 equiv.) in THF (135 mL) was added LAH
(9.7 g, 54 mmol, 4 equiv.). The reaction was allowed to stir
for 5 min at room temperature at which time a saturated
aqueous solution of Na2SO4 (15 mL) was added dropwise
over 5 min. This solution was left to stir for another 40 min,
at which time it was filtered over a Celite plug. After the
filter cake washed thoroughly with EtOAc, the filtrate was
concentrated in vacuo to yield analytically pure 24 (4.6 g,
95% yield) as a pale yellow oil. 1H NMR (500 MHz,
CDCl3) d 1.25 (brs, 1H), 1.21 (s, 3H), 1.33 (s, 3H), 2.67–
2.69 (m, 1H), 3.04 (dd, J¼2.5, 6.5 Hz, 1H), 3.26 (d,
J¼9.5 Hz, 1H), 3.44 (dd, J¼4, 11.5 Hz, 1H), 3.57–3.71 (m,
4H), 4.15 (dd, J¼3, 7 Hz, 1H), 4.33 (dd, J¼3, 7 Hz, 1H),
4.53 (d, J¼12 Hz, 1H), 4.57 (d, J¼12 Hz, 1H), 6.00 (t,
J¼7 Hz, 1H), 6.08 (t, J¼7 Hz, 1H), 7.27–7.39 (m, 5H); 13C
NMR (500 MHz, CDCl3) d 25.4, 25.7, 39.9, 40.0, 45.2,
46.5, 65.0, 65.48, 72.9, 73.6, 75.5, 78.4, 108.6, 128.2, 128.4,
129.0, 129.5, 131.9, 138.2; IR (thin film/NaCl) 885 (m), 967
(w), 1027 (m), 1065 (s), 1165 (m), 1206 (s), 1264 (m), 1314
(w), 1374 (m), 1455 (m), 1496 (w), 1734 (w), 2873 (m),
2926 (s), 3053 (w), 3383 (brs) cm21; HRMS (FAB) m/z
found: 361.2016 [calcd for C21H28O5 (MþH) 361.2015].
3.1.17. 10-Benzyloxymethyl-4,4-dimethyl-10,11-bis-tri-
isopropylsilanyloxymethyl-3,5-dioxa-tricyclo[5.2.2.02,6]-
undec-8-ene (25). To a stirred solution of 24 (2.0 g,
5.6 mmol, 1 equiv.) in DMF (25 mL) was added imidazole
(1.9 g, 27.8 mmol, 5 equiv.) and TIPSCl (5.9 mL,
27.8 mmol, 5 equiv.). This solution was allowed to stir at
room temperature for 5 days at which time the reaction was
diluted with EtOAc (250 mL), and the combined organic
phase was washed with water (100 mL) and brine (100 mL).
The aqueous phase was then back extracted with EtOAc
(2£200 mL), and the combined organic phases were dried
over Na2SO4 and concentrated in vacuo to yield a crude oil
which was chromatographed over a column of silica gel
(gradient elution, 0–2.5% EtOAc/hexanes). The early-
eluting product-containing fractions were further purified
via Kugelrohr distillation (50 Torr, 1258C) of low-boiling
impurities to yield pure 25 (3.6 g, 96% yield) as a clear oil.
Rf 0.65, 4:1 hexanes/ethyl acetate; 1H NMR (500 MHz,
CDCl3) d 1.00–1.05 (m, 42H), 1.23 (s, 3H), 1.33 (s, 3H),
1.16 (dd, J¼4.5, 10 Hz, 1H), 3.09 (dd, J¼2.5, 6 Hz, 1H),
3.19–3.20 (m, 1H), 3.26 (t, J¼10 Hz, 1H), 3.47 (d, J¼9 Hz,
1H), 3.49 (d, J¼2 Hz, 2H), 3.68 (d, J¼9 Hz, 1H), 3.84 (dd,
J¼4.5, 9.5 Hz, 1H), 4.18 (dd, J¼3, 7 Hz, 1H), 4.41 (dd,
J¼3, 7 Hz, 1H), 4.45 (d, J¼11.5 Hz, 1H), 4.50 (d,
J¼11.5 Hz, 1H), 6.03 (t, J¼7 Hz, 1H), 6.15 (t, J¼7 Hz,
1H), 7.24–7.33 (m, 5H); 13C NMR (500 MHz, CDCl3) d
1
cm21; H NMR (500 MHz, CDCl3) d 6.33 (t, J¼6.5 Hz,
1H), 6.12 (t, J¼6.5 Hz, 1H), 4.21–4.16 (m, 3H), 4.03 (ddd,
J¼6.0, 3.0, 1.0 Hz, 1H), 3.74 (d, J¼1.5 Hz, 1H), 3.62 (s,
6H), 3.60–3.53 (m, 3H), 3.19–3.17 (m, 1H), 1.29 (s, 3H),
1.27 (t, J¼7.0 Hz, 3H), 1.19 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 196.3, 172.5, 169.4, 166.3, 129.5, 129.4, 109.4,
76.7, 74.2, 67.8, 61.9, 53.0, 52.4, 45.2, 44.3, 40.0, 39.2,
25.3, 25.2, 14.2; HRMS (EI) m/z 410.1577 [calcd for
C20H26O9 (Mþ) 410.1577].
3.1.15. 8-(2-Diazo-2-ethoxycarbonyl-acetyl)-4,4-di-
methyl-3,5-dioxa-tricyclo[5.2.2.02,6]undec-10-ene-8,9-
dicarboxylic acid methyl ester (22). Triethylamine
(22 mL, 0.15 mmol, 3 equiv.) was added dropwise to a
stirred solution of 21 (21 mg, 0.051 mmol, 1.0 equiv.) and
p-ABSA (14 mg, 0.056 mmol, 1.1 equiv.) in CH3CN
(1 mL). After stirring for 2 h at room temperature, the
reaction mixture was concentrated, poured onto basic
alumina column and chromatographed using 25% EtOAc/
hexanes as the eluant to furnish 22 as a yellow oil (15 mg,
67% yield). FTIR (thin film/NaCl) 3071 (w), 2986 (m),
2951 (m), 2908 (m), 2148 (s), 1752 (s), 1721 (s), 1638 (m),

6552
D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
11.9, 11.97, 12.3, 17.7, 18.0, 25.0, 25.3, 37.6, 39.5, 44.3,
46.1, 62.4, 63.0, 73.2, 73.8, 75.5, 78.7, 107.7, 127.3, 127.4,
128.1, 129.7, 132.0, 138.5; IR (thin film/NaCl) 809 (m), 884
(m), 918 (w), 996 (w), 1013 (w), 1066 (s), 1087 (s), 1140
(m), 1164 (w), 1206 (m), 1264 (m), 1379 (m), 1463 (m),
1497 (w), 1727 (w), 2866 (s), 2890 (m), 2942 (s), 3055 (w)
cm21; HRMS (FAB) m/z found: 673.4684 [calcd for
C39H69O5 (MþH) 673.4684].
film/NaCl) 996 (w), 1014 (w), 1065 (s), 1098 (s), 1142
(w), 1164 (w), 1207 (m), 1262 (m), 1369 (m), 1380 (m),
1463 (m), 1723 (m), 2725 (w), 2866 (s), 2891 (m), 2942 (s)
cm21
.
This material was dried azeotropically with benzene,
redissolved in THF (8 mL), and added via cannula over
15 min to a 2788C solution of EtOAc (1.1 mL, 11.3 mmol),
and LiHMDS (10 mL of 1 M solution in THF) which had
been stirring for 0.5 h. The mixture was allowed to stir at
2788C for 1.5 h at which time it was quenched with 1N HCl
(10 mL) and warmed to room temperature. This solution
was then diluted with EtOAc (200 mL), poured into a
separatory funnel, and washed with brine (150 mL). The
aqueous layer was back extracted with EtOAc (100 mL£4),
and the combined organic phases were dried over Na2SO4
and concentrated in vacuo to yield a yellow oil. This residue
was dissolved in CH2Cl2 (30 mL) and treated with Dess–
Martin periodinane (1.5 g, 3.6 mmol) for 11 h. Workup with
Na2S2O3 and K2CO3 (see above), extraction with CH2Cl2,
drying over Na2SO4, and evaporation of organic phases
3.1.18. (4,4-Dimethyl-8,9-bis-triisopropylsilanoxy-
methyl-3,5-dioxa-tricyclo[5.2.2.02,6]undec-10-en-8-yl)-
methanol (26). A flame-dried 50 mL three-necked round-
bottom flask was equipped with a mechanical stirrer and dry
ice condenser and cooled to 2788C in a dry ice–acetone
bath. The flask was then charged with anhydrous ammonia
(20 mL) and freshly cut Li metal (38 mg, 5.5 mmol,
10 equiv.) and allowed to stir for 30 min. At this time, a
solution of 25 (374 mg, 0.55 mmol, 1 equiv.) in THF (5 mL)
was added dropwise via cannula and stirring was continued
for another 30 min at 2788C at which time the reaction was
quenched with solid NH4Cl (1 g). EtOAc (20 mL) was
added at this point, and the solution was allowed to warm to
room temperature. After stirring at room temperature for
2 h, the reaction mixture was filtered through a Celite plug,
which was washed thoroughly with EtOAc, and the filtrate
was concentrated in vacuo to yield analytically pure 26
1
yielded 27 (1.3 g, 95% yield) as a yellow oil. H NMR
(500 MHz, CDCl3) d 0.86–1.10 (m, 50.4H), 1.23–1.38 (m,
10.8), 2.04 (brs, 0.2H), 3.04–3.04 (brs, 1H), 3.042 (brs,
1.2H), 3.36–3.51 (m, 3.6H), 3.58–3.62 (m, 1.2H), 3.67–
3.75 (m, 2.4H), 3.87–3.97 (m, 1.2H), 4.02–4.12 (m, 1.2H),
4.17–4.17 (m, 3.6H), 4.33 (dd, J¼2.8, 7.2 Hz, 1H), 4.41
(dd, J¼2.8, 7.2 Hz, 0.2H), 5.32 (s, 0.2H), 6.10–6.19 (m,
2.4H), 12.51 (brs, 0.2H); 13C NMR (500 MHz, CDCl3) d
11.9, 11.9, 11.9, 11.9, 12.1, 12.4, 17.7, 17.7, 17.7, 17.8,
17.9, 18.0, 18.0, 18.0, 25.0, 25.2, 38.4, 39.7, 40.5, 46.5,
59.3, 61.1, 63.4, 75.3, 78.2, 108.3, 130.2, 130.7, 168.0,
205.0; IR (thin film/NaCl) 1014 (s), 1065 (s), 1096 (s),
1165 (m), 1207 (s), 1224 (m), 1259 (m), 1368 (m),
1380 (m), 1463 (m), 1619 (w), 1709 (m), 1746 (s), 2867
(s), 2892 (m), 2942 (s), 3055 (w) cm21; HRMS (FAB)
m/z found: 667.4426 [calcd for C36H67O7Si2 (MþH)
667.4425].
1
(220 mg, 99% yield) as a clear oil. H NMR (500 MHz,
CDCl3) d 1.01–1.09 (m, 42H), 1.27 (s, 3H), 1.33 (s, 3H),
2.70 (m, 1H), 3.36–3.63 (m, 7H), 3.80 (d, J¼10 Hz, 1H),
4.07 (d, J¼10 Hz, 1H), 4.26 (dd, J¼3, 7 Hz, 1H), 4.57 (dd,
J¼3, 7 Hz, 1H), 6.05 (t, J¼7 Hz, 1H), 6.21 (t, J¼7 Hz, 1H);
13C NMR (500 MHz, CDCl3) d 11.7, 11.8, 12.2, 17.6, 18.0,
24.9, 25.3, 37.2, 38.8, 45.1, 45.5, 63.9, 67.5, 70.1, 75.3,
78.6, 108.0, 129.2, 132.3; IR (thin film/NaCl) 997 (m), 1012
(m), 1042 (m), 1063 (m), 1081 (m), 1114 (m), 1163 (m),
1206 (m), 1259 (m), 1379 (m), 1463 (m), 2726 (w), 2867 (s),
2890 (s), 2942 (s), 3054 (w), 3483 (brs) cm21; HRMS
(FAB) m/z found: 583.4212 [calcd for C32H63O5Si2 (MþH)
583.4214].
3.1.20. 2-Diazo-3-(4,4-dimethyl-8,9-bis-triisopropyl-
silanoxymethyl-3,5-dioxa-tricyclo[5.2.2.02,6]undec-10-
en-8-yl)-3-oxo-propionic acid ethyl ester (28). To a stirred
solution of 27 (20 mg, 0.03 mmol, 1.0 equiv.) in CH2Cl2
(0.7 mL) was added dropwise DBU (15.5 mL, 0.09 mmol,
3 equiv.) and p-ABSA (9 mg, 0.036 mmol, 1.2 equiv.).
After stirring the reaction mixture for 1 h at room
temperature, it was evaporated onto silica gel, poured onto
a column of type III basic alumina and chromatographed
(gradient elution, 0–5% EtOAc/hexanes) to yield 28 as a
yellow oil (18 mg, 86% yield). 1H NMR (500 MHz, CDCl3)
d 0.98–1.06 (m, 42H), 1.23 (s, 3H), 1.31–1.34 (m, 6H),
2.85 (dd, J¼3.6, 10.4 Hz, 1H), 3.27–3.33 (m, 1H), 3.48–
3.51 (m, 2H), 3.97 (dd, J¼3.2, 7.2 Hz, 1H), 4.05 (dd, J¼3.2,
7.2 Hz, 1H), 4.16–4.30 (m, 4H), 4.53 (d, J¼11 Hz, 1H),
6.07 (t, J¼7 Hz, 1H), 6.20 (t, J¼7 Hz, 1H); 13C NMR
(500 MHz, CDCl3) d 11.9, 12.1, 12.1, 14.3, 17.4, 17.9, 17.9,
18.0, 18.1, 18.1, 25.1, 25.3, 29.7, 37.0, 39.2, 40.6, 60.6,
61.4, 62.6, 64.5, 76.1, 78.1, 108.3, 129.6, 132.4, 160.9,
192.6; IR (thin film/NaCl) 1013 (m), 1065 (s), 1098 (s),
1167 (w), 1196 (m), 1206 (m), 1268 (m), 1288 (m), 1368
(m), 1379 (m), 1463 (m), 1639 (m), 1717 (s), 2139 (m),
2866 (s), 2941 (s) cm21; HRMS (ESI) m/z found: 715.4150
[calcd for C36H64N2O7Si2 (MþNa) 715.4150].
3.1.19. 3-(4,4-Dimethyl-8,9-bis-triisopropylsilanoxy-
methyl-3,5-dioxa-tricyclo[5.2.2.02,6]undec-10-en-8-yl)-3-
oxo-propionic acid ethyl ester (27). To a stirred solution of
26 (1.2 g, 2 mmol, 1 equiv.) in CH2Cl2 (20 mL) was added
Dess–Martin periodinane (3.4 g, 8 mmol, 4 equiv.), and the
solution was allowed to stir at room temperature for 2 h. At
this time, a saturated aqueous solution of Na2S2O3 (15 mL)
was added, and the reaction was allowed to stir for another
2 h at which point a saturated aqueous solution of K2CO3
was added and the reaction was stirred for another 15 min.
This biphasic mixture was transferred to a separatory funnel
containing brine (50 mL), and the aqueous layer was
extracted with CH2Cl2 (50 mL£4). The combined organic
layers were dried over Na2SO4, and evaporated in vacuo to
yield an amorphous yellow solid. 1H NMR (500 MHz,
CDCl3) d 1.04–1.08 (m, 42H), 1.23 (s, 3H), 1.36 (s, 3H),
2.33 (t, J¼7.5 Hz, 1H), 3.07 (m, 1H), 3.41 (dd, J¼7.5,
10 Hz, 1H), 3.49–3.50 (m, 1H), 3.65 (dd, J¼7.5, 10 Hz,
1H), 3.83 (d, J¼10 Hz, 1H), 3.95 (d, J¼10 Hz, 1H), 4.18 (s,
2H), 6.16 (t, 2H), 9.84 (s, 1H); 13C NMR (500 MHz, CDCl3)
d 11.8, 11.8, 11.9, 17.6, 17.7, 17.7, 17.7, 17.8, 17.9,
18.0, 18.0, 18.0, 24.9, 25.2, 38.2, 38.2, 39.0, 56.7, 63.0,
63.8, 75.2, 78.1, 108.3, 129.3, 131.5, 204.9; IR (thin

D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
6553
3.2. General procedure for catalyst and solvent
screening
The organic layer was dried over Na2SO4, concentrated in
vacuo, and azeotroped with toluene (2 mL) to yield a clear
oil. Purification via preparative thin-layer chromatography
eluting with 24:1 hexanes/ethyl acetate yielded 32 (34 mg,
To a stirred solution of 28 (0.01 M) in the desired solvent
was added 10 mol% of rhodium(II) catalyst. This reaction
mixture was either stirred with heating or at room
temperature until reaction monitoring via TLC or NMR
indicated disappearance of starting material. If necessary,
additional catalyst was added in 10 mol% increments. The
solvent was then evaporated in vacuo, and the products
purified using preparative thin-layer chromatography.
1
46% yield) as a clear oil. H NMR (500 MHz, CDCl3) d
0.93–1.14 (m, 42H), 1.21–1.45 (m, 9H), 2.06–2.09 (m,
1H), 2.68 (d, J¼16.5 Hz, 1H), 3.15 (d, J¼10 Hz, 1H), 3.28–
3.30 (m, 1H), 3.33–3.36 (m, 2H), 3.46–3.49 (m, 3.633H, s,
3H), 4.18–4.25 (m, 2H), 4.30 (d, J¼4 Hz, 1H), 4.34–4.37
(m, 1H), 6.21 (t, J¼7.0 Hz, 1H), 6.28 (t, J¼7.0 Hz, 1H),;
13C NMR (500 MHz, CDCl3) d 12.2, 12.2, 14.4, 18.3, 18.33
18.4, 27.5, 28.1, 30.1, 36.0, 39.1, 42.2, 52.0, 58.8, 59.3,
61.6, 61.7, 62.0, 81.4, 90.0, 111.8, 127.43, 133.4, 169.9,
170.5, 206.6; IR (thin film/NaCl) 1064 (m), 1098 (s), 1163
(m), 1196 (m), 1217 (m), 1246 (m), 1287 (w), 1369 (m),
1381 (m), 1462 (m), 1738 (s), 1747 (s), 1764 (s), 2866 (s),
2941 (s) cm21; HRMS (FAB) m/z found: 737.4482 [calcd
for C39H69O9Si2 (MþH) 737.4480].
3.2.1. Spiro[(2-carboxyethyl-3-silyloxy-4,5-dihydro-
furan)-4,100-(40,40-dimethyl-110-triisopropylsilanyloxy-
methyl-30,50-dioxa-tricyclo[5.2.2.02,6]undec-80-ene)] (29).
Rf 0.30, 4:1 hexanes/ethyl acetate; 1H NMR (500 MHz,
CDCl3) d 0.97–1.06 (m, 21H), 1.14 (dd, J¼7, 11 Hz, 18H),
1.24–1.25 (m, 3H), 1.31–1.34 (m, 6H), 1.39–1.83 (m, 3H),
2.16 (dd, J¼6.5, 9 Hz, 1H), 3.12 (dd, J¼4, 9 Hz, 1H), 3.26–
3.28 (m, 1H), 3.31 (t, J¼11.5 Hz, 1H), 3.72 (dd, J¼5.5,
11.5 Hz, 1H), 3.80 (d, J¼11 Hz, 1H), 3.92 (d, J¼11 Hz,
1H), 4.24 (q, J¼9 Hz, 2H), 4.33 (dd, J¼4, 9 Hz, 1H), 4. 64
(dd, J¼3.5, 9 Hz, 1H), 6.18 (t, J¼5 Hz, 2H); 13C NMR
(500 MHz, CDCl3) d 10.85, 13.58, 16.96, 17.09, 17.13,
24.14, 24.28, 28.68, 36.98, 39.89, 43.75, 52.29, 59.36,
61.82, 72.63, 73.56, 77.47, 107.04, 125.98, 130.07, 131.01,
150.94, 159.35; IR (thin film/NaCl) 967 (m), 995 (m), 1065
(s), 1105 (s), 1151 (m), 1223 (s), 1260 (m), 1379 (m), 1407
(w), 1464 (m), 1620 (m), 1713 (s), 2139 (w), 2866 (s), 2893
(s), 2942 (s), 3054 (w) cm21; HRMS (FAB) m/z found:
665.4261 [calcd for C36H65O7Si2 (MþH) 665.4269].
Acknowledgments
We acknowledge the support of this work by Bristol-Myers
Squibb, Eli Lilly, Glaxo-Wellcome, Yamanouchi and
Zeneca through their Faculty Awards Programs and the
Camille and Henry Dreyfus Foundation for a Teacher–
Scholar Award. We thank Susan de Gala for securing the
X-ray crystallographic analyses.
References
3.2.2. 4,4-Dimethyl-8,9-bis-triisopropylsilanyloxy-
methyl-3,5-dioxa-tricyclo[5.2.2.02,6]undeca-8,10-diene
(30). Rf 0.75, 4:1 hexanes/ethyl acetate; 1H NMR
(500 MHz, CDCl3) d 1.05–1.11 (m, 42H), 1.26 (s, 3H),
1.34 (s, 3H), 4.00 (brs, 2H), 4.20 (dd, J¼4, 12.5 Hz, 2H),
4.29 (d, J¼2 Hz, 2H), 4.33 (dd, J¼4, 12.5 Hz, 2H), 6.33–
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12.4, 18.1, 18.1, 18.4, 18.4, 25.9, 26.4, 44.4, 60.5, 79.5,
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6554
D. A. Spiegel et al. / Tetrahedron 58 (2002) 6545–6554
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