Halogenated oxabicyclo[3.2.1]octadiene building blocks: Elaboration of the dibromoenone

Article abstract of DOI:10.1002/ejoc.200500529

We have been interested in exploiting the highly functionalized oxabicyclo[3.2.1]octadienes that are produced by the cycloaddition of furan and tetrabromocyclopropene as synthetic building blocks. As part of this program, we have prepared non-racemic deri

Full text of DOI:10.1002/ejoc.200500529

FULL PAPER
Halogenated Oxabicyclo[3.2.1]octadiene Building Blocks: Elaboration
of the Dibromoenone
Phillip M. Pelphrey,[a] Ravi S. Orugunty,[b] Richard J. Helmich,[b] Merle A. Battiste,[b] and
Dennis L. Wright*[a]
Keywords: Cross-coupling / Dibromoenone / Oxygen heterocycles / Palladium
We have been interested in exploiting the highly function-
alized oxabicyclo[3.2.1]octadienes that are produced by the
cycloaddition of furan and tetrabromocyclopropene as syn-
thetic building blocks. As part of this program, we have pre-
pared non-racemic derivatives of these adducts containing
an α,β-dibromoenone moiety embedded in the bicyclic
framework. Elaboration of this unit has been realized
through substitution and palladium-catalyzed cross-coupling
reactions. Formation of bicyclodecenes has also been ac-
complished by a chromium-nickel-mediated ring closure.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Results and Discussion
Tobey and Law disclosed in 1968 that tetrabromocy-
clopropene undergoes a facile cycloaddition reaction with
furan to generate the halogenated oxabicyclo[3.2.1]oc-
tadiene derivative 1 in excellent yield.[1] Over the past se-
veral years we have studied the utility of this highly func-
tionalized bicyclic nucleus as a versatile building block and
have been interested in using this system in both target-
oriented and diversity-oriented manifolds.[2] Recently, we
developed a direct route to the chiral enones 2a/b from 1
involving the resolution of the corresponding tartrate ketals
(Scheme 1).[3]
Functionalization of the β-Bromine by Substitution Reac-
tions: Because of conjugation of the C4 bromide to the car-
bonyl at C2, it seemed relatively straightforward to selec-
tively exchange this halogen through nucleophilic addition/
elimination reactions (Table 1).
We examined a variety of synthetically relevant nucleo-
philes to effect substitution of this bromide. A vinylogous
Finkelstein reaction[6] occurred in excellent yield by heating
2 with sodium iodide in acetone. Morpholine reacted in
very high yield to give the vinylogous amide 3b while cya-
nide added in much lower yield to give the nitrile 3c. The
lower yield of the nitrile seemed to relate to the instability
of 3c, which is prone to decomposition. The copper-cata-
lyzed addition of organometallic species was also studied as
a way to append carbon chains onto the bicyclic enone.
Although the Gilman-type cuprate added in very good yield
to give 3d, attempts to add Grignard reagents with substo-
ichiometric copper salts was frustrated by rapid 1,2-ad-
dition to the carbonyl group. The ketone in 2 can be re-
garded as a vinylous acid bromide and appears to be highly
reactive. Only with a stoichiometric amount of copper(i)
iodide could the acetal derivative 3e be obtained in reason-
able yield. The addition of functionalized units to the enone
occurred smoothly utilizing the Knochel conditions,[7]
which produced the ester 3f in very good overall yield.
Functionalization of the β-Bromine by Palladium-Cata-
lyzed Cross-Coupling Reactions: Another attractive strategy
for elaborating the dibromoenone found in 2 was to utilize
palladium-catalyzed cross-coupling chemistry to substitute
this system. Although the literature contained abundant ex-
amples of cross-coupling on both α- and β-bromoenones[8]
there are few examples with enones containing adjacent re-
active groups.[9] Examining a variety of palladium-catalyzed
Scheme 1. Bicyclic building blocks containing a dibromoenone.
These enantiomeric building blocks possess an α,β-dibro-
moenone moiety which should allow for the straightfor-
ward introduction of a variety of groups. We have studied
the reactivity and selectivity of this uncommon function-
ality[4] and herein report a range of transformations that
can be utilized to elaborate this skeleton.[5]
[a] Department of Chemistry, Dartmouth College,
Hanover, NH 03755, USA
Fax: +1-603-646-3946
E-mail: dwright@dartmouth.edu
[b] Department of Chemistry, University of Florida,
Gainesville, FL 32611, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
4296
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500529
Eur. J. Org. Chem. 2005, 4296–4303

Halogenated Oxabicyclo[3.2.1]octadiene with Dibromoenone-Based Building Blocks
FULL PAPER
Table 1. Direct substitution of the β-bromide of ( )-2.
reactions showed that preferential reaction took place at the product. Under these conditions, phenyl, 4-methoxyphenyl
β position in agreement with the higher reactivity of these and naphthylboronic acids were coupled exclusively to the
moieties in relation to α-haloenone systems (Table 2).
β position to give 4a–c. No coupling at the α position or
Initial attempts to effect Suzuki cross-coupling with 2 double coupling was observed in these systems. Attempted
were frustrated by low yields and prolonged reaction times. Sonagashira coupling under these conditions or with cop-
Standard conditions employing the use of palladium(ii) ace- per additives was unsuccessful, although good yields of the
tate/triphenylphosphane as the source of palladium and po- alkyne could be obtained with an amine base present. In-
tassium phosphate as the base gave essentially only reco- stallation of a vinyl substituent by a Stille coupling was
vered starting materials or after prolonged heating, pro- moderately successful, producing the diene 4f, while Heck
ducts of decomposition. Eventually, it was found that the and Negishi couplings were completely unsuccessful even
addition of silver salts was critical to obtain high yields of with the more reactive iodide 3a. Interestingly, the bromide
Eur. J. Org. Chem. 2005, 4296–4303
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4297

Dennis L. Wright et al.
FULL PAPER
Table 2. Cross-coupling reactions of ( )-2.
[a] Condition A: Pd(OAc)2, PPh3, Et3N, Ag2CO3, MeCN, 25 °C, 12 h. [b] Condition B: Pd(PhCN)2Cl2, CuI, Et3N, MeCN, 25 °C, 10 min.
[c] Condition C: Pd(PhCN)2Cl2, AsPh3, DMF, 25 °C, 30 min. [d] Condition D: Pd(OAc)2, PPh3, Ag2CO3, Et3N, MeCN, 25 °C Ǟ reflux.
and iodide showed almost the same reaction profile includ-
Functionalization of the α-Bromine by Metal-Mediated Re-
ing rate and product yield in all of the palladium reactions actions: Building upon the success of palladium-mediated
examined. The formation of single regioisomers in the cross-coupling of the β position, we made attempts to effect
above reactions shows that the β position is significantly a second cross-coupling at the α position (see Scheme 2). To
more reactive than the α-bromide. To further elaborate this end, compound 4d was subjected to a fresh batch of
these building blocks, a second coupling seemed possible.
phenylacetylene and palladium. Changing the palladium
4298
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4296–4303

Halogenated Oxabicyclo[3.2.1]octadiene with Dibromoenone-Based Building Blocks
FULL PAPER
source to a more reactive palladium species effected the de-
sired coupling in good yield. Furthermore, addition of two
equivalents of the desired acetylene with dichloro[1,1Ј-bis(di-
phenylphosphanyl)ferrocene]palladium(ii) and compound 2
gave the bis-coupled product 10 in good yield as the only
isolable product. The lower reactivity of these systems has
been appreciated,[10] however, effective functionalization of
the α position has been accomplished.
Scheme 3. Annulation by a Nozaki–Hiyama–Kishi closure .
Conclusions
The direct condensation of furan and tetrabromocy-
clopropene leads to heavily functionalized synthetic build-
ing blocks for seven-membered carbocyclic and five- and
six-membered oxacyclic systems. To effectively utilize these
building blocks for the preparation of complex molecules,
it is important to develop reactions to elaborate the skel-
eton. We have shown that the dibromoenone unit can be
readily derivatized at the β position through a nucleophilic
addition/elimination sequence or palladium-mediated cross-
coupling reactions. The α-bromide proved equally as reac-
tive towards similar coupling reaction and is amenable to
metallation and electrophilic trapping. The application of
these building blocks in target and diversity-oriented syn-
theses is ongoing.
Experimental Section
General: The 1H and 13C spectra were recorded at 500 and
125 MHz, respectively. All melting points are uncorrected. High-
resolution mass spectrometry was provided by the University of
Illinois Urbana-Champaigne Mass Spectrometry laboratory. All
reagents were used directly from commercial sources, unless other-
wise stated. All reported yields are the average of at least two inde-
pendent runs. Compound 2 was prepared according to the litera-
ture procedure.[2d]
Scheme 2. Functionalization of the α-bromide.
To further enhance our strategy of functionalizing the
α position, we pursued different metallating protocols (see
Scheme 2). Low-temperature metallation of 6a gave the
organolithium 7, which could be simply protonated with
(1S,5R)-3-Bromo-4-iodo-8-oxabicylo[3.2.1]octa-3,6-dien-2-one (3a):
To a 50 mL round-bottomed flask was added sodium iodide (1.3 g,
8.9 mmol). Acetone (20 mL) was added and the reaction was
stirred at 25 °C until all material was dissolved. Compound 2
acetic acid to yield the reduced derivative 8 or reacted with (1.0 g, 3.6 mmol) was added and the flask placed into a preheated
oil bath (60 °C). The reaction was stirred at 60 °C for 18 hours.
The flask was removed from the oil bath and cooled to room tem-
perature. The reaction mixture was filtered through a pad of celite.
The solvent was removed under reduced pressure and the residue
purified by column chromatography (SiO2, 100 g) using 10% ethyl
acetate in hexanes as the eluent to afford 3a as a white solid (1.12 g,
electrophiles such as methyl iodide to give the tetrasubsti-
tuted olefin 9. It also proved possible to apply a related
metallation of the vinyl bromide to effect a net annulation
of the dibromoenone.
Conversion of the previously described 3f to 11b by re-
duction (85%) and silylation (85%) preceded two-step
transformation to the unstable aldehyde 12 and a chro-
mium/nickel-promoted ring closure[11] to give the hy-
droazulene 13a/b in good overall yield and high diastereose-
lectivity (Scheme 3).
1
95%): Rf = 0.51 (hexane/EtOAc, 2:1). M.p. 138–140 °C. H NMR
(500 MHz, CDCl3): δ = 7.07 (dd, J = 2.0, 0.7 Hz, 1 H), 6.57 (ddd,
J = 5.9, 2.4, 0.5 Hz, 1 H), 5.50 (dd, J = 2.0, 0.7 Hz, 1 H), 5.18 (dd,
J = 2.2, 0.7 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
182.8, 138.7, 131.0, 129.5, 127.3, 90.6, 87.1 ppm. IR (thin film,
Eur. J. Org. Chem. 2005, 4296–4303
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4299

Dennis L. Wright et al.
FULL PAPER
cm–1): ν = 3054, 2985, 1706, 1543, 1285, 1175. HRMS: m/z
325.8444 (calcd. C7H4BrIO2, 325.8439).
added magnesium turnings (97 mg, 4.0 mmol) and THF
(0.900 mL). (Bromoethyl)dioxolane (0.240 mL, 2.0 mmol) in THF
(0.900 mL) was added dropwise over 5 minutes. The suspension
was stirred at room temperature for 3 hours. The solution was then
cooled to –10 °C and copper(i) iodide (381 mg, 2.0 mmol) was
added at once. The suspension was stirred at –10 °C for 30 minutes
and then cooled to –78 °C. Compound 2 (280 mg, 1.0 mmol) in
THF (0.900 mL) was added dropwise over 5 minutes. The solution
was stirred at –78 °C for 3 hours. Saturated ammonium chloride
(1.0 mL) was added and the solution allowed to warm to room
temperature. The solution was extracted with dichloromethane
(3×5 mL). The combined organics were dried with sodium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (SiO2, 30 g) using 20% ethyl acetate in
hexanes as eluent to afford 3e as a colorless oil (166 mg, 55%): Rf
= 0.18 (hexane/EtOAc, 2:1). 1H NMR (500 MHz, CDCl3): δ = 6.88
(dd, J = 5.6, 1.5 Hz, 1 H), 6.53 (dd, J = 5.6, 2.2 Hz, 1 H), 5.22 (d,
J = 2.0 Hz, 1 H), 5.10 (d, J = 1.7 Hz, 1 H), 4.96 (t, J = 4.1 Hz, 1
H), 4.04–3.97 (m, 2 H), 3.93–3.88 (m, 2 H), 2.64–2.50 (m, 2 H),
2.16–1.91 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 186.0,
164.7, 140.1, 131.0, 115.5, 103.0, 86.9, 83.3, 65.3, 65.3, 30.1, 28.4
˜
(1S,5R)-3-Bromo-4-morpholino-8-oxabicylco[3.2.1]octa-3,6-dien-2-
one (3b): To a 25 mL round-bottomed flask was added compound
2 (200 mg, 0.72 mmol). Dichloromethane (10 mL) was added and
the reaction was stirred at 25 °C until all material was dissolved.
Potassium carbonate (200 mg, 1.43 mmol) was added followed by
morpholine (0.125 mL, 1.43 mmol). The reaction mixture was
stirred at 25 °C for 1 hour. Water (0.100 mL) was added and the
reaction stirred for 30 minutes. The reaction mixture was diluted
with dichloromethane (25 mL), washed with saturated sodium hy-
drogen carbonate (25 mL) and then washed with brine (25 mL).
The organics were taken, dried with sodium sulfate and concen-
trated. The residue was purified by column chromatography (SiO2,
20 g) using 50% ethyl acetate in hexanes as the eluent to afford 3b
as a white solid (180 mg, 88%): Rf = 0.13 (hexane/EtOAc, 1:1).
1
M.p. 135–137 °C. H NMR (500 MHz, CDCl3): δ = 6.71–6.67 (m,
2 H), 5.47 (d, J = 2.0 Hz, 1 H), 5.12 (d, J = 2.0 Hz, 1 H), 3.8 (t, J
= 4.9 Hz, 4 H), 3.66–3.64 (m, 4 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 186.1, 164.2, 136.0, 134.6, 89.6, 87.0, 81.6, 67.3, 50.1
ppm. IR (thin film, cm–1): ν = 3053, 2982, 2919, 2858, 1656, 1547,
˜
ppm. IR (thin film, cm–1): ν = 2960, 2884, 1703, 1596, 1139.
˜
1265. HRMS: m/z 284.9992 (calcd. C11H12BrNO3, 285.0000).
HRMS: m/z 229.9988 (calcd. C12H13BrO4, 299.9997).
(1R,5S)-3-Bromo-4-oxo-8-oxabicyclo[3.2.1]octa-2,6-diene-2-carbo-
nitrile (3c): To a 10 mL round-bottomed flask was added dimethyl
sulfoxide (2 mL) and sodium cyanide (54 mg, 1.1 mmol). The reac-
tion mixture was heated to 40 °C and stirred until all material was
dissolved. The flask was removed and the solution cooled to room
temperature. Compound 2 (280 mg, 1.0 mmol) was added and the
reaction stirred at 25 °C for 30 minutes. Water (10 mL) was added
and the solution extracted with diethyl ether (4×20 mL). The com-
bined organics were dried with sodium sulfate and concentrated
under reduced pressure. The residue was purified by column
chromatography (SiO2, 30 g) using 10% ethyl acetate in hexanes as
the eluent to afford 3c as a yellow solid (79 mg, 35%): Rf = 0.42
(hexane/EtOAc, 2:1). M.p. 115–117 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.03 (ddd, J = 5.6, 2.0, 0.7 Hz, 1 H), 6.58 (dd, J =
5.6, 2.4 Hz, 1 H), 5.34 (d, J = 2.0 Hz, 1 H), 5.25 (dd, J = 2.2,
0.7 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 182.0, 140.1,
134.4, 130.4, 129.6, 113.5, 87.1, 81.9 ppm. IR (thin film, cm–1):
Methyl 3-{(1R,5S)-3-Bromo-4-oxo-8-oxabicyclo[3.2.1]octa-2,6-dien-
2-yl}propanoate (3f): To a 10 mL round-bottomed flask was added
lithium chloride (91 mg, 2.1 mmol) and copper(i) cyanide (96 mg,
1.1 mmol). THF (1.0 mL) was added and the solution stirred at
25 °C for 30 minutes. The light green solution was cooled to 0 °C
and the organozinc reagent[12] (0.850 mL, 1.1 mmol, 1.26 m) was
added. The solution was stirred at 0 °C for 30 minutes and then
cooled to –78 °C. BF3–OEt2 (0.270 mL, 2.1 mmol) was added, fol-
lowed by compound 2 (100 mg, 0.36 mmol) in THF (1.0 mL). The
solution was warmed to –30 °C and stirred for 3 hours. Saturated
ammonium chloride (2.0 mL) and liquid ammonia (aqueous 25%,
0.500 mL) were added and the solution warmed to room tempera-
ture and stirred for 30 minutes. The layers were separated and the
aqueous layer was extracted with ethyl acetate (3×5 mL). The com-
bined organics were washed with brine, dried with sodium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (SiO2, 10 g), using 33% ethyl acetate
in hexanes as the eluent to afford 3f as a white solid (93 mg, 90%):
ν = 3054, 2986, 1721, 1572, 1265. HRMS: m/z 224.9422 (calcd.
˜
C8H4BrNO2, 224.9425).
(1S,5R)-3-Bromo-4-methyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one Rf = 0.30 (hexane/EtOAc, 2:1). M.p. 80–82 °C. 1H NMR
(3d): To a 10 mL round-bottomed flask was added copper(i) iodide
(82 mg, 0.43 mmol) and ether (2 mL). The suspension was cooled
to –78 °C and methyllithium (0.79 mmol) was added dropwise over
5 minutes. The reaction was warmed to –10 °C and stirred for 30
minutes. The resulting cuprate was cooled to –78 °C and a solution
of 2 (100 mg, 0.36 mmol) in diethyl ether (2 mL) was added drop-
wise over 5 minutes. The reaction was stirred at –78 °C for 3 hours.
Saturated ammonium chloride (2 mL) was added and the solution
allowed to warm to room temperature. The solution was extracted
with diethyl ether (3×10 mL). The combined organics were dried
with sodium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (SiO2, 10 g) using
10% ethyl acetate in hexanes as the eluent to afford the 3d as a
(500 MHz, CDCl3): δ = 6.88 (ddd, J = 5.6, 2.0, 0.7 Hz, 1 H), 6.51
(dd, J = 5.6, 2.2 Hz, 1 H), 5.26 (d, J = 2.0 Hz, 1 H), 5.09 (dd, J =
2.2, 0.7 Hz, 1 H), 3.72 (s, 3 H), 2.63–2.60 (m, 2 H), 2.79–2.69 (m,
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 185.8, 172.5, 163.3,
140.3, 130.8, 116.5, 86.8, 83.7, 52.3, 30.6, 29.4 ppm. IR (thin film,
cm–1): ν = 2953, 1735, 1700, 1597, 1438, 1201, 1169. HRMS: m/z
˜
285.9844 (calcd. C11H11BrO4, 285.9841).
General Procedure for Suzuki Couplings of Arylboronic Acids: In a
dry screw-cap tube, acetonitrile (1.0 mL) was degassed. Palladium
acetate (8.1 mg, 0.036 mmol), triethylamine (0.018 mL,
0.017 mmol) and triphenylphosphane (37.5 mg, 0.014 mmol) were
added and stirred for 15 minutes. To the resulting solution was
added 2 (100 mg, 0.36 mmol), boronic acid (0.36 mmol) and silver
carbonate (108.4 mg, 0.36 mmol). The solution was stirred over-
night at 25 °C. The crude reaction mixture was subjected to Soxhlet
extraction using ethyl acetate (25 mL). The crude extract was sub-
jected to column chromatography using 5% ethyl acetate in hex-
anes to afford the desired products.
1
brown semisolid (65 mg, 84%): H NMR (300 MHz, CDCl3): δ =
6.92 (dd, J = 5.7, 2.1 Hz, 1 H), 6.56 (dd, J = 5.2, 2.1 Hz, 1 H), 5.16
(d, J = 2.1 Hz, 1 H), 5.12 (d, J = 2.1 Hz, 1 H), 2.12 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 185.8, 162.0, 139.4, 131.5, 115.5,
86.8, 84.3, 20.4 ppm. IR (thin film, cm–1): ν = 2980, 1707, 1603,
˜
1240, 1068. HRMS: m/z 213.9619 (calcd. C8H7BrO2, 213.9629).
(1S,5R)-3-Bromo-4-[2-(1,3-dioxolan-2-yl)ethyl]-8-oxabicylo[3.2.1]-
octa-3,6-dien-2-one (3e): To a 10 mL round-bottomed flask was
(1S,5R)-3-Bromo-4-phenyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one
(4a): Compound 2 (50 mg) was subjected to the coupling condi-
4300
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4296–4303

Halogenated Oxabicyclo[3.2.1]octadiene with Dibromoenone-Based Building Blocks
FULL PAPER
tions with phenylboronic acid to afford 4a (39.8 mg, 80%) as a
colorless solid. 1H NMR (300 MHz, CDCl3): δ = 7.45 (s, 5 H), 6.96
(d, J = 2.0 Hz, 1 H), 3.91 (s, 3 H), 3.90 (s, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 184.9, 153.5, 145.6, 139.9, 132.7, 131.0,
(dd, J = 5.7, 1.9 Hz, 1 H), 6.62 (dd, J = 5.7, 2.4 Hz, 1 H), 5.46 (d, 128.6, 120.4, 116.4, 112.6, 109.6, 87.2, 84.1, 61.2, 56.4 ppm. IR
J = 1.9 Hz, 1 H), 5.20 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR (thin film, cm–1): ν = 2940, 2184, 1696, 1575, 1501, 1238, 1130.
˜
(75 MHz, CDCl3): δ = 186.3, 161.1, 140.4, 134.7, 131.1, 130.3, HRMS: m/z 390.0095 (calcd. C18H15BrO5, 390.0103).
128.9, 127.9, 114.8, 86.9, 85.2 ppm. IR (thin film, cm–1): ν = 2979,
1699, 1585, 1186, 1072. HRMS: m/z 275.9762 (calcd. C8H7BrO2,
275.9786).
˜
(1S,5R)-3-Bromo-4-vinyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (4f):
To a 10 mL round-bottomed flask was added either 2 (100 mg,
0.36 mmol) or 3a (100 mg. 0.31 mmol). DMF (2 mL) was added,
(1S,5R)-3-Bromo-4-(4-methoxyphenyl)-8-oxabicyclo[3.2.1]octa-3,6-
dien-2-one (4b): Compound 2 (100 mg) was subjected to the coup-
ling conditions with (4-methoxyphenyl)boronic acid to afford 4b
(80 mg, 73 %) as a colorless solid; m.p. 122–123 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.50 (d, J = 8.8 Hz, 2 H), 6.98 (d, J =
8.8 Hz, 2 H), 6.92 (dd, J = 5.7, 1.7 Hz, 1 H), 6.60 (dd, J = 5.7,
2.4 Hz, 1 H), 5.49 (d, J = 1.7 Hz, 1 H), 5.18 (d, J = 2.4 Hz, 1 H),
3.86 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 186.4, 161.3,
160.5, 140.3, 131.1, 130.0, 126.6, 114.3, 113.7, 86.9, 85.1, 55.6 ppm.
followed by Pd(PhCN)2Cl2 (14 mg, 0.036 mmol for 2; 12 mg,
0.031 mmol for 3a) and triphenylarsane (22 mg, 0.072 mmol for 2;
14 mg, 0.061 mmol for 3a). The reaction mixture was stirred at
25 °C until all material was dissolved. Vinyltributyltin (0.115 mL,
0.39 mmol for 2; 0.098 mL, 0.34 mmol for 3a) was added and the
solution stirred at 25 °C for 1 hour. The solvent was removed under
reduced pressure and the residue was purified by column
chromatography (SiO2, 10 g) using pentane (100 mL), followed by
10% ethyl acetate in hexanes as eluent to afford 4f as a yellow solid
(34 mg, 42% for 2; 21 mg, 30% for 3a): Rf = 0.44 (hexane/EtOAc,
IR (thin film, cm–1): ν = 2974, 2839, 1694, 1604, 1302, 1253, 1179,
˜
1
1072. HRMS: m/z 305.9854 (calcd. C14H11BrO3, 305.9891).
2:1). M.p. 63–65 °C. H NMR (500 MHz, CDCl3): δ = 6.92–6.85
(m, 2 H), 6.53 (dd, J = 5.9, 2.2 Hz, 1 H), 5.79 (d, J = 17.6 Hz, 1
H), 5.73 (d, J = 11.2 Hz, 1 H), 5.59 (d, J = 2.0 Hz, 1 H), 5.17 (dd,
J = 2.2, 0.7 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
186.6, 156.1, 139.5, 133.3, 131.4, 124.6, 117.5, 87.2, 80.3 ppm. IR
(1S,5R)-3-Bromo-4-(naphthalen-1-yl)-8-oxabicyclo[3.2.1]octa-3,6-
dien-2-one (4c): Compound 2 (100 mg) was subjected to the coup-
ling conditions with 1-napthylboronic acid to afford 4c (92 mg,
1
78%) as a colorless solid. H NMR (300 MHz, CDCl3): δ = 8.00–
(thin film, cm–1): ν = 3054, 2986, 1697, 1545, 1421, 1265. HRMS:
˜
7.86 (m, 5 H), 7.62–7.50(m, 4 H), 7.00 (dd, J = 5.7, 1.9 Hz, 1 H),
6.65 (dd, J = 5.7, 2.4 Hz, 1 H), 5.58 (d, J = 1.9 Hz, 1 H), 5.24 (d,
J = 2.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 186.3,
140.5, 133.6, 133.0, 132.0, 131.2, 130.9, 128.8, 128.7, 128.1, 128.1,
m/z 225.9630 (calcd. C9H7BrO2, 225.9629).
(1S,5R)-3,4-Bis(2-phenylethynyl)-8-oxabicyclo[3.2.1]octa-3,6-dien-2-
one (5): To a 10 mL round-bottomed flask was added 4d (205 mg,
0.68 mmol). Acetonitrile (3 mL) was added and the reaction mix-
ture stirred at 25 °C until all material was dissolved. Triethylamine
(3 mL) was added followed by copper(i) iodide (9.1 mg,
0.048 mmol) and Pd(dppf)2Cl2 (39 mg, 0.048 mmol). Phenylacety-
lene (0.083 mL, 0.75 mmol) was then added and the solution stirred
under argon for 1 hour. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(SiO2, 10 g) using 20% ethyl acetate in hexanes as the eluent to
afford 5 as a yellow oil (132 mg, 60%): Rf = 0.44 (hexane/EtOAc,
127.9, 127.2, 124.8, 87.0, 85.3 ppm. IR (thin film, cm–1): ν = 3057.
˜
2979, 1699, 1575, 1195, 1072; Analysis calcd. for C17H13BrO3: C,
62.41, H, 3.39. Found: C, 62.41, H, 3.25.
General Procedure of the Sonogashira Reaction: To a 10 mL round-
bottomed flask was added either 2 (100 mg, 0.36 mmol) or 3a
(100 mg, 0.31 mmol). Acetonitrile (2 mL) was added and the reac-
tion mixture stirred at 25 °C until all material was dissolved. Trieth-
ylamine (2 mL) was added followed by copper(i) iodide
(0.07 equiv.) and Pd(PhCN)2Cl2 (0.07 equiv.). The acetylene
(1.1 equiv.) was then added and the solution stirred under argon
for 10 minutes. The solvent was removed under reduced pressure
and the residue was purified by column chromatography.
1
4:1). H NMR (500 MHz, CDCl3): δ = 7.57–7.55 (m, 4 H), 7.45–
7.39 (m, 3 H), 7.36–7.35 (m, 3 H), 6.98 (dd, J = 5.6, 2.0 Hz, 1 H),
6.57 (dd, J = 5.8, 2.2 Hz, 1 H), 5.34 (d, J = 2.0 Hz, 1 H), 5.08 (d,
J = 2.2 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 188.16,
146.0, 139.6, 132.3, 132.1, 130.8, 130.4, 129.2, 128.9, 128.6, 122.8,
122.0, 120.5, 112.2, 99.3, 87.1, 85.4, 83.5, 82.9 ppm. IR (thin film,
(1S,5R)-3-Bromo-4-(2-phenylethynyl)-8-oxabicyclo[3.2.1]octa-3,6-
dien-2-one (4d): Compound 2 or 3a (100 mg) was subjected to the
coupling conditions using phenylacetylene. The residue was puri-
fied by column chromatography (SiO2, 10 g) using 15% ethyl ace-
tate in hexanes as eluent to afford 4d as a yellow oil which solidified
upon standing (85 mg, 79% for 2; 69 mg, 75% for 3a): Rf = 0.48
(hexane/EtOAc, 2:1). M.p. 86–88 °C. 1H NMR (500 MHz, CDCl3):
δ = 7.59–7.57 (m, 2 H), 7.48–7.44 (m, 1 H), 7.43–7.39 (m, 2 H),
7.01 (ddd, J = 5.6, 2.0, 0.7 Hz, 1 H), 6.58 (dd, J = 5.6, 2.2 Hz, 1
H), 5.35 (d, J = 2.0 Hz, 1 H), 5.20 (dd, J = 2.2, 0.7 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 184.9, 145.7, 140.0, 132.4, 131.0,
130.6, 128.9, 121.6, 120.8, 112.2, 87.2, 84.8, 84.1 ppm. IR (thin
cm–1): ν = 3063, 2980, 2179, 1704, 1543, 1491, 1443, 1364, 1209,
˜
1063. HRMS: m/z 322.1000 (calcd. C23H14O2, 322.0994).
(1S,2R,5R)-3-Bromo-4-(2-phenylethynyl)-8-oxabicyclo[3.2.1]octa-
3,6-dien-2-ol (6): To a 25 mL round-bottomed flask was added 4d
(200 mg, 0.66 mmol). Methanol (13 mL, 0.05 m) was added and the
reaction mixture was stirred at 25 °C until all material was dis-
solved. Cerium chloride (247 mg, 0.66 mmol) was added and
stirred to dissolve. The solution was cooled to –10 °C and sodium
borohydride (28 mg, 0.73 mmol) was added. The solution was
stirred at –10 °C for 1 hour and quenched with water (2.0 mL). The
solution was warmed to room temperature and the solvent re-
film, cm–1): ν = 3054, 2985, 2189, 1698, 1557, 1265, 1194. HRMS:
˜
m/z 299.9788 (calcd. C15H9BrO2, 299.9786).
(1S,5R)-3-Bromo-4-[2-(3,4,5-trimethoxyphenyl)ethynyl]-8-oxabicyclo- moved. The residue was taken up in ethyl acetate (10 mL) and
[3.2.1]octa-3,6-dien-2-one (4e): Compound 2 or 3a (100 mg) was
subjected to the coupling conditions using (3,4,5-trimethoxy-
phenyl)acetylene. The residue was purified by column chromatog-
raphy (SiO2, 10 g) using 20% ethyl acetate in hexanes as the eluent
to afford 4e as a yellow solid (123 mg, 88% for 2; 104 mg, 87% for
3a): Rf = 0.30 (hexane/EtOAc, 2:1). M.p. 145–147 °C. 1H NMR
washed with water (5 mL). The aqueous layer was extracted with
ethyl acetate (3×10 mL). The combined organics were washed with
brine, dried with sodium sulfate and concentrated. The residue was
purified by column chromatography (SiO2, 20 g) using 20% ethyl
acetate in hexanes as eluent to afford 6 as a colorless oil (170 mg,
85 %): Rf = 0.30 (hexane/EtOAc, 2:1). 1H NMR (500 MHz,
(500 MHz, CDCl3): δ = 7.01 (dd, J = 5.6, 1.5 Hz, 1 H), 6.79 (s, 2 CDCl3): δ = 7.52–7.50 (m, 2 H), 7.39–7.34 (m, 3 H), 6.90 (dd, 6.1,
H), 6.59 (dd, J = 5.6, 2.2 Hz, 1 H), 5.35 (d, J = 2.0 Hz, 1 H), 5.20 1.7 Hz, 1 H), 6.24 (dd, J = 6.1, 2.0 Hz, 1 H), 5.26 (dd, J = 6.1,
Eur. J. Org. Chem. 2005, 4296–4303
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4301

Dennis L. Wright et al.
FULL PAPER
1.7 Hz, 1 H), 4.92 (d, J = 1.7 Hz, 1 H), 4.60 (t, J = 5.9 Hz, 1 H),
dium sulfate and concentrated. The residue was purified by column
2.16 (d, J = 5.4 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = chromatography (SiO2, 10 g) using 10% ethyl acetate in hexanes as
141.1, 131.9, 131.5, 129.6, 129.4, 129.3, 128.6, 122.6, 100.0, 84.7,
eluent to afford 9 as a yellow oil (64 mg, 80%): Rf = 0.42 (hexane/
81.8, 81.1, 68.0 ppm. IR (thin film, cm–1): ν = 3418, 3080, 2967,
EtOAc, 4:1). 1H NMR (500 MHz, CDCl3): δ = 7.45–7.42 (m, 2 H),
˜
2916, 2200, 1307, 1052. HRMS: m/z 301.9945 (calcud C15H11BrO2, 7.37–7.33 (m, 3 H), 6.83 (dd, J = 6.1, 1.7 Hz, 1 H), 6.12 (dd, J =
301.9942).
6.1, 2.0 Hz, 1 H), 5.33 (dd, J = 5.6, 1.7 Hz, 1 H), 4.68 (s, 1 H), 4.09
(d, J = 5.6 Hz, 1 H), 3.44 (s, 3 H), 0.98 (t, J = 7.8 Hz, 9 H), 0.88–
0.72 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 142.5, 140.2,
138.0, 131.4, 129.2, 128.6, 123.5, 97.3, 87.9, 81.6, 79.6, 72.5, 57.5,
(1S,2R,5R)-3-Bromo-4-(2-phenylethynyl)-2-triethylsilyloxy-8-oxabi-
cyclo[3.2.1]octa-3,6-diene (6a): To a 10 mL round-bottomed flask
was added 6 (130 mg, 0.43 mmol). Dichloromethane (2 mL) was
added and the reaction mixture was stirred at 25 °C until all mate-
rial was dissolved. The solution was cooled to 0 °C and 2,6-lutidine
(0.100 mL, 0.86 mmol) was added followed by TESOTf (0.145 mL,
0.64 mmol). The solution was warmed to room temperature over-
night. Saturated sodium hydrogen carbonate (5 mL) was added and
the layers separated. The aqueous layer was extracted with dichlo-
romethane (3×10 mL). The combined organics were dried with so-
dium sulfate and concentrated under reduced pressure. The residue
was purified by column chromatography (SiO2, 20 g) using 5 %
ethyl acetate in hexanes as eluent to afford 6a as a colorless oil
7.8, 3.8 ppm. IR (thin film, cm–1): ν = 2952, 2873, 2820, 2200,
˜
1458, 1314, 1190, 1100. HRMS: m/z 352.1866 (calcd. C22H28O2Si,
352.1859).
(1S,5R)-3,4-Bis[2-(trimethylsilyl)ethynyl]-8-oxabicyclo[3.2.1]octa-
3,6-dien-2-one (10): To a 20 mL round-bottomed flask was added
compound 2 (500 mg, 1.79 mmol). Acetonitrile (9 mL) was added
and the reaction mixture stirred at 25 °C until all material was dis-
solved. Triethylamine (9 mL) was added followed by copper(i) io-
dide (48 mg, 0.25 mmol) and Pd(dppf)2Cl2 (205 mg, 0.25 mmol).
Trimethylsilylacetylene (0.56 mL, 3.93 mmol) was then added and
(143 mg, 80 %): Rf = 0.52 (hexane/EtOAc, 4:1). 1H NMR the solution stirred under argon for 1 hour. The solvent was re-
(500 MHz, CDCl3): δ = 7.50–7.47 (m, 2 H), 7.37–7.32 (m, 3 H), moved under reduced pressure and the residue was purified by col-
6.86 (dd, J = 5.9, 1.5 Hz, 1 H), 6.20 (dd, J = 5.9, 1.7 Hz, 1 H), 5.10
umn chromatography (SiO2, 50 g) using 10% ethyl acetate in hex-
(dd, J = 6.1, 1.5 Hz, 1 H), 4.87 (d, J = 1.7 Hz, 1 H), 4.60 (d, J = anes as the eluent to afford 10 as a yellow oil (350 mg, 62%): Rf =
1
6.1 Hz, 1 H), 1.03 (t, J = 7.8 Hz, 9 H), 0.79–0.67 (m, 6 H) ppm.
0.44 (hexane/EtOAc, 9:1 ). H NMR (500 MHz, CDCl3): δ = 6.89
13C NMR (125 MHz, CDCl3): δ = 140.3, 131.8, 131.1, 130.0, 130.0, (ddd, J = 5.6, 2.0, 0.7 Hz, 1 H), 6.47 (ddd, J = 5.6, 2.2, 0.7 Hz, 1
129.0, 128.9, 122.9, 99.3, 85.2, 82.8, 81.7, 68.6, 7.1, 5.1 ppm. IR
H), 5.15 (dd, J = 2.0, 0.5 Hz, 1 H), 4.98 (dd, J = 2.2, 0.7 Hz, 1 H),
0.28 (s, 9 H), 0.23 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 187.9, 147.0, 139.5, 130.6, 121.3, 120.0, 105.6, 99.1, 97.5, 87.0,
(thin film, cm–1): ν = 2956, 2911, 2876, 2201, 1339, 1238, 1117.
˜
HRMS: m/z 416.0814 (calcd. C21H25BrO2Si, 416.0807).
82.7, 0.08, –0.18 ppm. IR (thin film, cm–1): ν = 2962, 2901, 2254,
˜
(1S,2R,5R)-4-(2-Phenylethynyl)-2-triethylsilyloxy-8-oxabicyclo-
[3.2.1]octa-3,6-diene (8): To a dry screw-cap vial, was added 6a
(89 mg, 0.21 mmol). THF (1 mL) was added and the solution was
2159, 1707, 1540, 1332, 1300, 1252, 1064. HRMS: m/z 314.1161
(calcd. C17H22O2Si2, 314.1158).
cooled to –78 °C. n-Butyllithium (0.174 mL, 0.28 mmol, 1.6 m in Methyl 3-[(1R,4R,5S)-3-Bromo-4-triethylsilyloxy-8-oxabicy-
pentane) was added and the solution stirred at –78 °C for 1 hour.
Acetic acid (0.049 mL, 0.85 mmol) was added and the solution
warmed to room temperature. The solution was stirred at 25 °C for
15 min and then diluted with diethyl ether (10 mL). The solution
was washed with saturated sodium hydrogen carbonate (5 mL). The
aqueous layer was extracted with diethyl ether (2 ×10 mL). The
combined organics were washed with brine (5 mL), dried with so-
dium sulfate and concentrated. The residue was purified by column
chromatography (SiO2, 10 g) using 10% ethyl acetate in hexanes as
eluent to afford 8 as a yellow oil that solidified upon standing
clo[3.2.1]octa-2,6-dien-2-yl]propanoate (11b): To a flame-dried
50 mL round-bottomed flask, was added compound 3f (1.10 g,
3.83 mmol). Methanol (30 mL) was added followed by cerium chlo-
ride (1.43 g, 3.83 mmol). The solution was cooled to 0 °C. Sodium
borohydride (160 mg, 4.21 mmol) was added and the solution
stirred at 0 °C for 30 minutes. The reaction was quenched by ad-
dition of water (5.0 mL). The solution was warmed to room tem-
perature and the solvent removed. The residue was taken up in
ethyl acetate (30 mL) and washed with water (10 mL). The aqueous
layer was extracted with ethyl acetate (3×20 mL). The combined
organics were washed with brine, dried with sodium sulfate and
concentrated. The residue was purified by column chromatography
(SiO2, 50 g) using 33% ethyl acetate in hexanes as eluent to afford
the alcohol 11a as a colorless oil (982 mg, 88%): Rf = 0.18 (hexane/
1
(65 mg, 90%): Rf = 0.44 (hexane/EtOAc, 2:1). M.p. 80–82 °C. H
NMR (500 MHz, CDCl3): δ = 7.46–7.43 (m, 2 H), 7.38–7.34 (m, 3
H), 6.97 (dd, J = 5.9, 1.7 Hz, 1 H), 6.16 (dd, J = 6.1, 1.7 Hz, 1 H),
5.15 (dd, J = 6.1, 1.7 Hz, 1 H), 4.69 (d, J = 1.2 Hz, 1 H), 4.51 (dd,
J = 6.3, 10.0 Hz, 1 H), 1.3 (d, J = 10.0 Hz, 1 H), 1.01–0.98 (m, 9
1
EtOAc, 2:1). H NMR (500 MHz, CDCl3): δ = 6.71 (dd, J = 6.1,
H), 0.92–0.79 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 1.7 Hz, 1 H), 6.18 (dd, J = 6.1, 2.0 Hz, 1 H), 5.15 (dd, J = 6.1,
143.4, 142.8, 139.3, 131.4, 129.4, 128.8, 128.7, 123.2, 98.1, 87.6,
2.0 Hz, 1 H), 4.71 (d, J = 1.5 Hz, 1 H), 4.44 (d, J = 5.6 Hz, 1 H),
81.8, 81.7, 64.2, 7.9, 3.8 ppm. IR (thin film, cm–1): ν = 2952, 2907,
3.70 (s, 3 H), 2.55–2.43 (m, 5 H) ppm. 13C NMR (125 MHz,
˜
2873, 2193, 1488, 1236, 1041. HRMS: m/z 338.1704 (calcd. CDCl3): δ = 173.0, 144.9, 140.8, 129.4, 122.6, 81.9, 81.3, 68.1, 52.1,
C21H26O2Si, 338.1702).
31.5, 28.4 ppm. IR (thin film, cm–1): ν = 3436, 2954, 1737, 1640,
˜
1439, 1367, 1305, 1199, 1055. HRMS: m/z 288.0005 (calcd.
C11H13BrO4, 287.9997).
(1S,2R,5R)-3-Methyl-4-(2-phenylethynyl)-2-triethylsilyloxy-8-oxabi-
cyclo[3.2.1]octa-3,6-diene (9): To a dry screw-cap vial, was added
6a (95 mg, 0.23 mmol). THF (1 mL) was added and the solution
To a 25 mL round-bottomed flask was added 11a (982 mg,
cooled to –78 °C. n-Butyllithium (0.185 mL, 0.30 mmol, 1.6 m in 3.40 mmol). Dichloromethane (11 mL) was added and the reaction
pentane) was added and the solution stirred at –78 °C for 1 hour.
Methyl iodide (0.060 mL, 0.91 mmol) was added and the solution
warmed to room temperature overnight. The solution was diluted
with diethyl ether (10 mL) and washed with water (5 mL). The
aqueous layer was extracted with diethyl ether (2 ×10 mL). The
combined organics were washed with brine (5 mL), dried with so-
mixture was stirred at 25 °C until all material was dissolved. The
solution was cooled to 0 °C and 2,6-lutidine (0.947 mL, 8.15 mmol)
was added followed by TESOTf (0.922 mL, 4.08 mmol). The solu-
tion was warmed to room temperature overnight. Saturated sodium
hydrogen carbonate (5 mL) was added and the layers separated.
The aqueous layer was extracted with dichloromethane
4302
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4296–4303

Halogenated Oxabicyclo[3.2.1]octadiene with Dibromoenone-Based Building Blocks
FULL PAPER
(3×10 mL). The combined organics were dried with sodium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (SiO2, 40 g) using 5% ethyl acetate in
hexanes as eluent to afford compoud 11b as a colorless oil (1.10 g,
6.1, 1.7 Hz, 1 H), 6.03 (dd, J = 6.1, 2.0 Hz, 1 H), 5.05 (dd, J = 5.9,
2.0 Hz, 1 H), 4.83– 4.81 (m, 1 H), 4.79 (d, J = 6.6 Hz, 1 H), 4.77
(s, 1 H), 2.60–2.54 (m, 1 H), 2.40–2.34 (m, 1 H), 2.12–2.05 (m, 1
H), 1.85–1.80 (m, 1 H), 1.04–1.00 (m, 9 H), 0.74–0.68 (m, 6 H)
80 %): Rf = 0.32 (hexane/EtOAc, 4:1). 1H NMR (500 MHz, ppm. 13C NMR (125 MHz, CDCl3): δ = 148.4, 140.9, 131.9, 128.6,
CDCl3): δ = 6.71 (dd, J = 6.1, 1.7 Hz, 1 H), 6.13 (dd, J = 6.1, 81.7, 78.3, 78.0, 67.8, 32.3, 30.6, 6.8, 4.9 ppm. IR (thin film, cm–1):
2.0 Hz, 1 H), 5.02 (dd, J = 5.9, 2.0 Hz, 1 H), 4.69 (d, J = 1.7 Hz,
1 H), 4.48 (d, J = 5.9 Hz, 1 H), 3.71 (s, 3 H), 2.61–2.42 (m, 4 H),
1.03–1.00 (m, 9 H), 0.75–0.68 (m, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 173.1, 144.5, 140.1, 129.7, 122.6, 82.9, 81.1, 68.8, 52.0,
ν = 3552, 2953, 2876, 1238, 1077, 1041, 1004. HRMS: m/z 294.1656
˜
(calculated C16H26O3Si, 294.1651). 13b: Rf = 0.26 (hexane/EtOAc,
1
2:1). H NMR (500 MHz, CDCl3): δ = 6.70 (dd, J = 6.1, 1.7 Hz,
1 H), 6.06 (dd, J = 6.1, 2.0 Hz, 1 H), 5.05 (dd, J = 6.1, 2.0 Hz, 1
H), 4.79 (d, J = 6.1 Hz, 1 H), 4.72–4.71 (m, 2 H), 2.65–2.56 (m, 1
H), 2.32–2.24 (m, 2 H), 1.73–1.67 (m, 1 H), 1.00 (t, J = 8.0 Hz, 9
H), 0.72–0.67 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
148.0, 140.2, 135.8, 129.3, 81.4, 78.2, 76.5, 64.0, 33.2, 30.6, 7.0, 4.9
31.5, 28.6, 7.1, 5.0 ppm. IR (thin film, cm–1): ν = 2954, 2877, 1739,
˜
1438, 1241, 1117. HRMS: m/z 402.0852 (calcd. C17H27BrO4Si,
402.0862).
(1S,2S,8R)-2-Triethylsilyloxy-11-oxatricyclo[6.2.1.03,7]undeca-
3(7),9-dien-4-ol (13a/b): To a 50 mL round-bottomed flask was
added lithium aluminum hydride (89 mg, 2.25 mmol). THF
(15 mL) was added and the reaction mixture was stirred and cooled
to 0 °C. Compound 11b (860 mg, 2.13 mmol) in THF (5 mL) was
added dropwise. After complete addition the reaction was warmed
to 25 °C and stirred for 30 minutes. Water (0.500 mL) was added.
The solids were filtered off and washed with ethyl acetate
(4 × 25 mL). The combined organics were washed with water
(10 mL) and brine 10 mL). The organics were dried with anhydrous
sodium sulfate, filtered and concentrated to give the crude alcohol
as a colorless oil (720 mg, 90%). The crude alcohol was dissolved
in dichloromethane (20 mL). Dess–Martin periodinane (1.22 g,
2.88 mmol) was added and the solution stirred at 25 °C for 1 hour.
Saturated sodium hydrogen carbonate/saturated sodium thiosulfate
(10 mL, 1:1, v/v) was added and the solution stirred for 1 hour.
The layers were separated and the organics washed with saturated
sodium hydrogen carbonate (10 mL) and water (10 mL). The or-
ganics were washed with brine, dried with anhydrous sodium sul-
fate, and concentrated to give the crude aldehyde 12 as a colorless
oil (957 mg, 89 %): Rf = 0.18 (hexane/EtOAc, 4:1). 1H NMR
(500 MHz, CDCl3): δ = 9.81–9.80 (m, 1 H), 6.70 (dd, J = 5.9,
1.7 Hz, 1 H), 6.13 (dd, J = 6.1, 2.0 Hz, 1 H), 5.01 (dd, J = 6.1,
2.0 Hz, 1 H), 4.67 (d, J = 1.7 Hz, 1 H), 4.47 (d, J = 5.9 Hz, 1 H),
2.67–2.64 (m, 2 H), 2.58–2.53 (m, 1 H), 2.46–2.40 (m, 1 H), 1.00
(t, J = 7.8 Hz, 9 H), 0.72–0.67 (m, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 200.9, 144.6, 140.0, 129.7, 122.5, 82.9, 81.1, 68.8, 41.4,
ppm. IR (thin film, cm–1): ν = 3421, 2953, 2876, 1037. HRMS:
˜
m/z 294.1650 (calcd. C16H26O3Si, 294.1651).
1
Supporting Information: Copies of H and 13C spectra for all new
compounds are provided and are available via the www; see also
the footnote on the first page of this article.
Acknowledgments
The authors would like to thank the National Science Foundation,
the Petroleum Research Fund and Dartmouth College for support
of this work.
[1] a) D. C. F. Law, S. W. Tobey, J. Am. Chem. Soc. 1968, 90, 2376–
2386; b) S. W. Tobey, D. C. F. Law, US Patent 3,538,117, Nov.
3, 1970.
[2] a) R. S. Orugunty, D. L. Wright, M. A. Battiste, K. A. Abboud,
Org. Lett. 2002, 4, 1997–2000; b) R. S. Orugunty, I. Ghiviriga,
K. Abboud, M. A. Battiste, D. L. Wright, J. Org. Chem. 2004,
69, 570–572; c) W. A. Batson, K. A. Abboud, M. A. Battiste,
D. L. Wright, Tetrahedron Lett. 2004, 45, 2093–2096; d) R. S.
Orugunty, D. L. Wright, M. A. Battiste, R. J. Helmich, K. Ab-
boud, J. Org. Chem. 2004, 69, 406–416.
[3] P. M. Pelphrey, K. A. Abboud, D. L. Wright, J. Org. Chem.
2004, 69, 6931–6933.
[4] J. Zhang, P. G. Balzecka, J. G. Davidson, Org. Lett. 2002, 4,
4559 –4561.
[5] For examples of reactions of other transformations of oxabicy-
clo[3.2.1]octanes see: a) J. Högermeier, H.-U. Reissig, I.
Brüdgam, H. Hartl, Adv. Synth. Catal. 2004, 346, 1868–1879;
b) H. Zinser, S. Henkel, B. Föhlisch, Eur. J. Org. Chem. 2004,
6, 1344–1346; c) I. V. Hartung, H. M. R. Hoffmann, Angew.
Chem. Int. Ed. Eng. 2004, 43, 1934–1949.
[6] For an example on a β-bromo ester see: S. Caddick, V. M. Del-
isser, V. E. Doyle, S. Khan, A. G. Avent, S. Vile, Tetrahedron
1999, 55, 2737–2754.
[7] P. Knochel, R. D. Singer, Chem. Rev. 1993, 93, 2117–2188.
[8] For examples involving β-haloenones see: a) X. Zhang, R. C.
Larock, Org. Lett. 2003, 5, 2993–2996; b) C. Savarin, L. S. Lie-
beskind, Org. Lett. 2001, 3, 2149–2152.
[9] A. de Meijere has demonstrated sequentional coupling with
adjacent vinyl bromides and enol triflates. P. von Zezchwitz, F.
Pety, A. de Meijere, Chem. Eur. J. 2001, 7, 4035–4046.
[10] E. Negishi, Z. Owczarczyk, D. R. Swanson, Tetrahedron Lett.
1991, 32, 4453–4456.
25.8, 7.0, 5.0 ppm. IR (thin film, cm–1): ν = 2955, 2876, 1725, 1459,
˜
1412, 1343, 1240, 1120.
In a glove box was weighed chromium(ii) chloride (567 mg,
4.61 mmol) and nickel(ii) chloride (6.0 mg, 0.08 mmol). DMF
(10.0 mL) was added and the solution stirred at 25 °C for 1 hour.
A solution of 12 (200 mg, 0.536 mmol) in DMF (3.0 mL) was
added and the flask placed into a preheated oil bath at 45 °C. The
solution was heated at 45 °C for 18 hours and cooled to 25 °C. The
solution was diluted with hexanes/ethyl acetate (15 mL, 1:1, v:v)
and d/l-serinate (10 mL, 1.0 m in satd. NaHCO3) was added drop-
wise. The reaction was stirred vigorously for 30 min. The layers
were separated and the aqueous layer was extracted with hexanes/
ethyl acetate (3×15 mL, 1:1, v:v). The combined organics were
washed with water (10 mL) and brine (10 mL). The organics were
dried with anhydrous sodium sulfate, filtered, and concentrated.
The residue was purified by column chromatography (SiO2, 10 g)
using 20% ethyl acetate in hexanes as eluent to afford 13a (13 mg,
8%) and 13b (105 mg, 67%) as colorless oils: 13a: Rf = 0.24 (hex-
[11] A. Fürstner, Chem. Rev. 1999, 99, 991–1046.
[12] J. Talbert, P. Knochel, M. C. P. Yeh, S. C. Berk, J. Org. Chem.
1988, 53, 2392–2394.
Received: July 13, 2005
Published Online: September 1, 2005
1
ane/EtOAc, 4:1). H NMR (500 MHz, CDCl3): δ = 6.78 (dd, J =
Eur. J. Org. Chem. 2005, 4296–4303
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4303