Palladium-catalyzed couplings to nucleophilic heteroarenes: The total synthesis of (-)-frondosin B

Article abstract of DOI:10.1016/j.tet.2004.07.041

The total synthesis of (-)-frondosin B, the enantiomer of naturally-occuring (+)-frondosin B, is described, wherein a palladium-catalyzed cyclization is used to establish the tetracyclic ring system of the natural product. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.07.041

Tetrahedron 60 (2004) 9675–9686
Palladium-catalyzed couplings to nucleophilic heteroarenes:
the total synthesis of (K)-frondosin B
*
Chambers C. Hughes and Dirk Trauner
Department of Chemistry, Center for New Directions in Organic Synthesis, University of California, 419 Latimer Hall, Berkeley,
CA 94720, USA
Received 23 June 2004; revised 1 July 2004; accepted 2 July 2004
Available online 27 August 2004
Abstract—The total synthesis of (K)-frondosin B, the enantiomer of naturally-occuring (C)-frondosin B, is described, wherein a
palladium-catalyzed cyclization is used to establish the tetracyclic ring system of the natural product.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Several mechanisms have been proposed for the reaction,
including those that involve migratory insertion onto the
heteroarene or oxidative addition of Pd(II) into one of the
heteroarene C–H bonds. Miura and co-workers first
suggested a mechanism wherein the organopalladium(II)
species 1, formed from initial oxidative addition of Pd(0), is
nucleophilically attacked at the Pd(II) center by the
electron-rich heteroarene (Scheme 2).2a Loss of a proton
from the resulting cationic intermediate 2, followed by
reductive elimination of Pd(0), then affords the coupled
product. Further discussion of this mechanism has been
provided by Sharp2b and Gevorgyan.2c
The direct, palladium-catalyzed coupling of nucleophilic
heteroarenes to halides (or triflates) is an emerging synthetic
tool in heterocyclic chemistry (Scheme 1). Furans, pyrroles,
indoles, and thiophenes—among others—have been shown
to participate in the reaction, which, at least formally,
represents a ‘heteroaryl Heck reaction’.1 Uniquely, this
method of carbon–carbon bond formation does not require
prior functionalization of the heterocycle via halogenation
or metallation. In combination with the mildness and
functional group tolerance of palladium-catalyzed cross
couplings, this reaction offers significant advantages in the
synthesis of complex heteroarenes, for instance, certain
natural products and pharmaceuticals.
The literature is replete with examples of Heck couplings to
C2 of the heteroarenes.3 Some selected examples are shown
Scheme 1.
Scheme 2. Miura’s mechanism.
Keywords: Frondosin; Heck reaction; Palladium catalysis; Total synthesis.
* Corresponding author. Tel.: C1-510-643-5507; fax: C1-510-643-9480; e-mail: trauner@cchem.berkeley.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.041

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Scheme 3. Palladium-catalyzed coupling to C2. Reagents and conditions: Pd(PPh3)4, KOAc, 120–160 8C.
in Scheme 3 (Eqs. 1–4).3a–d Notably, only aryl halides and
triflates are known to couple to C2.
compounds, especially frondosin A (3), have been found to
be inhibitors of interleukin-8 (IL-8) in the low micromolar
range. IL-8 receptor antagonists interfere with the inflam-
matory cascade and could potentially be used to prevent
autoimmune disorders. Equally important, members of the
frondosin family have been shown to exhibit HIV-inhibitory
properties.7
Relatively few examples exist showing coupling to C3.4
Nevertheless, furan, pyrrole, indole, and thiophene have all
been demonstrated to couple at C3, and some notable
examples are depicted below (Scheme 4, Eqs. 1–4).4a–d As a
whole, efficient Heck coupling to C3 of these heteroarenes
requires elevated temperatures and is realized only in an
intramolecular sense. That selective C3-arylation/vinylation
is accomplished, in most cases, only when C2 is either
already substituted or geometrically unaccessible lends
credence to the electrophilic palladation mechanism dis-
cussed above, as C2 of these heteroarenes is usually more
nucleophilic than C3.
Frondosin B (4) has attracted much attention from the
synthetic community. The first asymmetric total synthesis by
the Danishefsky group confirmed the structure and led to the
assignment of an absolute configuration.8b Our communi-
cation describing the synthesis of (K)-frondosin B soon
followed,5 and Flynn and co-workers have recently disclosed
an expedient, three-component racemic synthesis.9
Our own interest in this chemistry emerged during efforts
toward the total synthesis of a marine natural product
frondosin B (Fig. 1, 4). In 2002, we described an
enantioselective total synthesis of this norsesquiterpenoid
in a short communication.5 We now report the full details of
our synthesis and give an account of its evolution.
Our original plan foresaw the implementation of the
Arcadi–Cacchi reaction to form the key C10–C11 bond
(Scheme 5).10 According to this proposal, oxidative addition
of Pd(0) to phenol 8 produces species 9, in which the
palladium is coordinated to the internal alkyne. This
coordination event promotes the nucleophilic attack of the
electron-deficient alkynyl ligand by the neighboring phen-
oxide. Subsequent reductive elimination furnishes tetra-
cycle 10.
Frondosin B is one of a family of marine terpenoids isolated
from the Micronesian sponge Dysidea frondosa.6 These

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9677
undertaken, in the hope that its reactivity would model that
of its chiral analogue (8) (Scheme 6). In this case,
commercially available 4-pentyn-1-ol (12) would be
coupled to 4-methoxyphenol (13) via Sonogashira coupling
and to cyclohexa-1,3-dione (14) via nucleophilic displace-
ment of a leaving group on the alkyne.
The synthesis of 11 required careful choice of protecting
groups. Though it had been previously demonstrated that
the phenol functionality in frondosin B could be efficiently
protected as a methyl ether throughout its synthesis,8 the
choice of protecting group for the free phenol in 11, which is
to be revealed directly before the key step, needed to be
thoroughly considered. The tetrahydropyanyl (THP) pro-
tecting group was initially chosen for this purpose, as the
strong tendency of this group to direct ortho-lithiation
would also facilitate the synthesis. The selective hydrolysis
of similar ether protecting groups in the presence of a vinyl
triflate had been previously reported.11
Treatment of 4-methoxyphenol (13) with dihydropyran
(DHP) and TFA was followed by regioselective lithiation at
the ortho position and iodination to afford 15 (Scheme 7).
Sonogashira coupling gave 16a in good yield.12 The alcohol
was converted to the iodide and subsequently reacted with
dimethoxylithiocyclohexadiene using the Piers protocol to
afford a mixture of adduct 17a and the adduct resulting from
hydrolysis of one enol ether.13 Selective hydrolysis of the
enol ethers to procure compound 18a, however, could not be
achieved. Various conditions resulted in the formation of a
complex mixture of deprotected phenols.
Scheme 4. Palladium-catalyzed coupling to C3. Reagents and conditions:
(a) Pd(OAc)2, PPh3, Tl2CO3, 110 8C; (b) Pd(OAc)2, KOAc, t-BuNH3Cl,
100 8C; (c) Pd(PPh3)4, Et3N, 100 8C; (d) Pd(OAc)2, PPh3, TlOAc, MeCN,
80 8C.
Believing a methoxymethyl (MOM) protecting group would
exhibit greater stability than the THP protecting group,14 the
former was used in a second attempt to synthesize the model
cyclization precursor. 4-Methoxyphenol was protected as
the MOM ether, and the resulting intermediate was then
lithiated and iodinated as before. Interestingly, however, the
MOM ether was not able to effect selective ortho-lithiation,
and a 1:1 mixture of regioisomeric products was formed.
Since the selectivity of this reaction remained low, another
method for making the ortho halide needed to be devised.
2. Model studies
In order to gain rapid insight into the feasibility of the key
cyclization, the synthesis of achiral phenol 11 was initially
To this end, 4-methoxyphenol was treated with tetrabutyl-
ammonium tribromide (TBABr3) to yield the brominated
phenol in good yield (see Scheme 7). After protection of the
phenol, bromide 19 was subjected to the same conditions as
those described for the THP-protected iodide 15, that is,
Sonogashira coupling followed by nucleophilic displace-
ment of the iodide with dimethoxylithiocyclohexadiene.
Again, however, the protecting group was not stable to the
conditions required to hydrolyze the enol ethers, and the
crude product was composed of a mixture of deprotected
phenol, from which none of 18b could be isolated.
Realizing that an acid-labile protecting group would not
survive the conditions required to hydrolyze the enol ethers,
we were compelled to consider an alternative. Accordingly,
alcohol 16b was deprotected directly after Sonogashira
coupling to produce phenol 20, which was then reprotected
as allyl ether 21 (Scheme 8). The dimethoxycyclohexa-
dienyl moiety was introduced as before. 22 was successfully
hydrolyzed to the protected diketone, and since the material
Figure 1. The frondosins. The absolute stereochemistry of frondosin A and
C-E (3, 5–7) is based on that determined for B (4) and has not been
independently established.

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Scheme 5. The proposed key cyclization.
Despite efforts to convert 11 into 24 with a range of
palladium reagents, however, we were unable to effect the
desired cyclization. Instead, extensive decomposition of the
starting material took place.
Contemplating the mechanism of the Arcadi–Cacchi
reaction we wondered whether base-catalyzed benzofuran
formation might actually precede formation of an organo-
palladium(II) species. In this case, benzofuran 25 would be
a distinct intermediate along the reaction pathway
(Scheme 9). The missing C–C bond would be formed
from this intermediate through a Heck-type process.
Scheme 6. Retrosynthetic analysis of the model cyclization precursor 11.
Luckily, benzofuran 25 was already in our hands at this
time. Formed serendipitously from 23 when the crude de-
allylation reaction mixture was left standing at room
temperature, 25 was subjected to a catalytic amount of
palladium(II) acetate [Pd(OAc)2]. Much to our delight, the
desired cyclization occurred. Thus, we found that efficient,
palladium-catalyzed bond formation could indeed be
readily decomposed on standing, it was immediately treated
with sodium bis(trimethylsilyl)amide (NaHMDS) and
N-phenyltrifluoromethanesulfonimide (PhNTf2) to afford
triflate 23. Deprotection of the phenol using tetrakis(tri-
phenylphosphine)palladium(0) [Pd(PPh3)4] and tributyltin
hydride (Bu3SnH) gave the model cyclization precursor 11.
Scheme 7. Reagents and conditions: (a) DHP, TFA, 0 8C to rt, 32%; (b) n-BuLi, THF, K78 8C to rt, then I2, K30 8C, 70%; (c) TBABr3, MeOH, CH2Cl2, rt,
81%; (d) NaH, DMF, 0 8C, then MOMCl, 98%; (e) 4-pentyn-1-ol, Pd(PPh3)2Cl2, CuI, n-BuNH2, reflux, 16a: 75%, 16b: 67%; (f) MsCl, Et3N, THF, 0 8C; NaI,
Me2CO, reflux, from 16a: 66%, from 16b: 94%; (e) 1,5-dimethoxylithiocyclohexa-1,4-diene, HMPA, THF, K78 8C, 17a: 37% (mono-enol ether: 8%), 17b:
53% (mono-enol ether: 13%).

C. C. Hughes, D. Trauner / Tetrahedron 60 (2004) 9675–9686
9679
Scheme 8. Reagents and conditions: (a) HCl, H2O, MeOH, rt, 65%; (b) allyl bromide, K2CO3, DMF, rt, 82%; (c) MsCl, Et3N, THF, 0 8C; NaI, Me2CO, reflux,
97%; (d) 1,5-dimethoxylithiocyclohexa-1,4-diene, HMPA, THF, K78 8C, 57% (mono-enol ether: 13%); (e) HCl, Me2CO, 0 8C; (f) NaHMDS, THF, 0 8C, then
PhNTf2, 62% (two steps); (g) Pd(PPh3)4, p-nitrophenol, Bu3SnH, CH2Cl2, rt, 58%.
achieved provided the benzofuran moiety was already in
place. This reaction, representing the first known Heck-type
cyclization onto C3 of a benzofuran, closed the central
seven-membered ring of 24 and assembled the tetracyclic
ring system found in frondosin B.
31 followed by hydrolysis afforded cyclohexa-1,3-dione 32.
As before, the diketone decomposed on standing and was
therefore immediately converted into enol triflate 33, setting
the stage for the key cyclization.
Treatment of 33 with a catalytic amount of Pd(PPh3)4 and
Hu¨nig’s base in dimethyl acetamide (DMA) at 90 8C
resulted in the formation of the strategic C10–C11 bond.
Importantly, no detectable racemization of the C8 stereo-
center occurred under these conditions.19 The conversion of
the carbonyl group into a gem-dimethyl moiety was
achieved by using a protocol developed by Reetz et al.20
Reaction of ketone 10 with MeMgBr gave the correspond-
ing crude, highly acid-sensitive tertiary alcohol, which was
subsequently subjected to the action of Me2TiCl2 (formed in
situ from Me2Zn and TiCl4). Upon addition of the reagent,
an intense dark violet color was observed, which presum-
ably originates from the stabilized carbocation 34 formed as
an intermediate. Overall, this procedure afforded O-methyl
frondosin B (35) in good yield without contamination by
double bond isomers. Finally, O-demethylation following a
previously reported procedure gave frondosin B (4) in high
optical purity.8
3. The natural product
Encouraged by the success of the model studies, we began
work toward the asymmetric total synthesis of (C)-
frondosin B, starting with the known R-configured alkyne
26 (obtained in 91% ee by means of a Sharpless
epoxidation) and the known aryl bromide 27.
(Scheme 10).15,16 An acetate ester, 27 is well-suited for
Sonogashira coupling relative to 15 and 19 since oxidative
addition of Pd(0) should be enhanced by the electron-
withdrawing nature of this substituent. Indeed, coupling of
these two components was achieved in high yield, provided
alkyne 26 was added slowly to the reaction mixture with a
syringe pump. Following acidic deprotection to yield
primary alcohol 29,17 treatment with K2CO3 in methanol
effected saponification of the phenolic acetate and con-
comitant cyclization to afford benzofuran 30 directly.18
Alkylation of dimethoxylithiocyclohexadiene with iodide
To our surprise, however, the optical rotation of the
Scheme 9. Reagents and conditions: (a) Pd(PPh3)4, p-nitrophenol, Bu3SnH, CH2Cl2, rt, 28%; (b) Pd(OAc)2, PPh3, Et3N, MeCN, reflux, 54%.

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Scheme 10. The total synthesis of (K)-frondosin B. Reagents and conditions: (a) Pd(PPh3)4, CuI, Et3N, MeCN, reflux, 94%; (b) TFA, CH2Cl2, rt, 83%; (c)
K2CO3, MeOH, reflux, 92%; (d) MsCl, Et3N, THF, 0 8C; NaI, Me2CO, reflux, 93%; (e) 1,5-dimethoxylithiocyclohexa-1,4-diene, HMPA, THF, K78 8C to rt,
67% (mono-enol ether: 17%); (f) ion-exchange resin, Me2CO, H2O, reflux; (g) NaHMDS, THF, Et2O, 0 8C, then PhNTf2, 75% (2 steps); (h) Pd(PPh3)4,
i-Pr2NEt, DMA, 90 8C, 70%; (i) MeMgBr, THF, K78 8C to rt; (j) Me2Zn, TiCl4, CH2Cl2, K78 8C to rt, 82% (2 steps); (k) NaSEt, DMF, reflux, 90%.
R-configured material thus obtained was opposite to that of
the natural product ([a]DZK16.8 compared to [a]DZC
18.6). Though the natural product had been assigned the R
configuration in the synthesis by Danishefsky et al.,
according to our work, (C)-frondosin B is S-configured.
To reconcile this discrepancy, we put forward the notion
that Danishefsky’s material underwent an unnoticed
inversion of configuration at an early stage of the synthesis
(Scheme 11).
The most likely candidate for such a switch is the
nucleophilic opening of an epoxy alcohol 36 with
trimethylaluminum (AlMe3), which probably proceeded
with unwanted retention of configuration through
Scheme 11. Double inversion of a stereocenter.

C. C. Hughes, D. Trauner / Tetrahedron 60 (2004) 9675–9686
9681
participation of the ester carbonyl group to produce 38
(via transition state 37).21 This diol was elaborated to
S-configured alkyne 39 and ultimately to the S-configured
natural product. Presumably, this double inversion of
configuration did not occur when, in our case, epoxy
alcohol 40 was likewise treated with AlMe3 to give 41.
Here, the resulting diol was elaborated to R-configured
alkyne 26, as expected.
5.09 mmol) in n-BuNH2 (10.2 mL) was added 4-pentyn-1-
ol (0.52 mL, 5.6 mmol), CuI (97 mg, 0.51 mmol), and
Pd(PPh3)2Cl2 (179 mg, 0.255 mmol). The solution, initially
green, was heated at reflux for 2 h, cooled, diluted with
water (100 mL), and extracted with ether (3!50 mL). The
combined organic extracts were washed once with brine
(20 mL), dried, filtered, and concentrated. The product was
purified by column chromatography (50% EtOAc in
hexanes) to afford 1.11 g (75%) of 16a as a yellowish-
brown oil: IR (film): 3422 (br), 2944 cmK1; 1H NMR: d 7.02
(d, JZ9.2 Hz, 1H), 6.89 (d, JZ3.2 Hz, 1H), 6.77 (dd, JZ
9.2, 3.2 Hz, 1H), 5.37 (t, JZ3.2 Hz, 1H), 4.00 (m, 1H),
3.87–3.78 (m, 2H), 3.75 (s, 3H), 3.62–3.55 (m, 1H), 2.58 (t,
JZ6.8 Hz, 2H), 2.11–1.79 (m, 6H), 1.75–1.55 (m, 3H); 13C
NMR: d 154.1, 151.7, 117.8, 117.4, 115.2, 115.0, 97.7, 93.2,
77.4, 61.9, 61.7, 55.6, 31.3, 30.2, 25.2, 18.6, 16.2; HRMS
(EIC): m/z (MC) calcd for C17H22O4, 290.1518; found
290.1515.
4. Conclusion
We have achieved a facile, asymmetric total synthesis of
(K)-frondosin B [(K)-4] from simple starting materials
(22% overall yield from the known alkyne 26) by means of a
novel, intramolecular Heck reaction onto a benzofuran. The
previously proposed absolute configuration of the natural
product was reassigned through our synthesis. The key
coupling reaction, which can effect substitution at C3 (and
C2) of a variety of aromatic heterocycles, might be
successfully employed in other total syntheses as well. In
fact, studies toward the total synthesis of rhazinilam, an
axially chiral phenylpyrrole isolated from Rhazya stricta,22
using a similar methodology are currently underway in our
laboratories and will be reported in due course.
5.2.2. 2-[2-(5-Iodo-pent-1-ynyl)-4-methoxy-phenyoxy]-
tetrahydro-pyran (43a). To a solution of 16a (1.01 g,
3.48 mmol) in THF (12 mL) at 0 8C was added Et3N
(0.53 mL, 3.8 mmol) followed by MsCl (0.29 mL,
3.5 mmol). After 1 h at 0 8C, the solution was filtered
through Celite with ether washings and then concentrated.
The mesylated alcohol was dissolved in dry acetone
(17 mL), and NaI (2.09 g, 13.9 mmol) was added. The
solution was heated at reflux for 2 h, cooled, and filtered
through Celite with acetone washings. The product was
purified by column chromatography (10% EtOAc in
hexanes) to yield 919 mg (66%) of 43a as a pale yellow
5. Experimental
5.1. General
1
oil: IR (film): 2942 cmK1; H NMR: d 7.00 (d, JZ9.2 Hz,
Tetrahydrofuran (THF) was distilled from Na/benzo-
quinone, triethylamine (Et3N) and Hu¨nig’s base (i-Pr2NEt)
were distilled from CaH2, and dichloromethane (CH2Cl2)
and ether (Et2O) were dried by passing through a column of
activated alumina prior to use. Hexamethylphosphoramide
(HMPA) was distilled from CaH2 and stored in a Schlenk
1H), 6.87 (d, JZ3.2 Hz, 1H), 6.75 (dd, JZ9.2, 3.2 Hz, 1H),
5.35 (t, JZ3.2 Hz, 1H), 3.93 (m, 1H), 3.70 (s, 3H), 3.60–
3.51 (m, 1H), 3.36 (t, JZ6.8 Hz, 2H), 2.56 (t, JZ6.4 Hz,
2H), 2.11–1.95 (m, 3H), 1.95–1.77 (m, 2H), 1.73–1.52 (m,
3H); 13C NMR: d 154.0, 151.7, 117.6, 117.4, 115.0, 97.4,
91.5, 78.0, 61.7, 55.5, 32.2, 30.4, 25.3, 20.6, 18.7, 5.6, 5.5;
HRMS (EIC): m/z (MC) calcd for C17H21IO3, 400.0535;
found 400.0538.
˚
tube over 4 A molecular sieves. 2-(2-Iodo-4-methoxy-
phenoxy)-tetrahydro-pyran (15) and 2-bromo-4-methoxy-
phenol (42) were synthesized according to literature
methods.23,24 Acetic acid 2-bromo-4-methoxy-phenyl ester
(27) was made by treating a solution of 42 in pyridine with
acetic anhydride. 1,5-Dimethoxy-cyclohexa-1,4-diene was
prepared via Birch reduction of 1,5-dimethoxybenzene.13
Pd(PPh3)4 was triturated repeatedly with DMSO, rinsed
with MeOH, and dried under vacuum. n-Butyllithium
(n-BuLi) and t-butyllithium (t-BuLi) were titrated periodi-
cally with diphenylacetic acid. All other starting materials
and solvents are commercially available and were used
without further purification. Chromatography was carried
5.2.3. 2-{2-[5-(2,6-Dimethoxy-cyclohexa-2,5-dienyl)-
pent-1-ynyl]-4-methoxy-phenoxy}-tetrahydro-pyran
(17a) and 3-methoxy-2-{5-[5-methoxy-2-(tetrahydro-
pyran-2-yloxy)-phenyl]-pent-4-ynyl}-cyclohex-3-enone
(44a). To a solution of t-BuLi in pentane (1.5 mL, 1.5 M,
2.3 mmol) at K78 8C was added THF (11.5 mL). A solution
of 1,5-dimethoxy-cyclohexa-1,4-diene (311 mg,
2.22 mmol) in THF (2.2 mL) was added dropwise via
syringe. After 1 h at K78 8C, HMPA (0.45 mL, 2.7 mmol)
was added, followed 15 min later by a solution of 43a
(810 mg, 2.02 mmol) in THF (2.2 mL). After an additional
15 min, the solution was allowed to warm to rt for 1.5 h,
then poured into brine (100 mL) and extracted with ether
(3!40 mL). The combined organic extracts were washed
once with brine (20 mL), dried, filtered, and concentrated.
The product was purified by column chromatography (10%
EtOAc to 60% EtOAc in hexanes) to give 309 mg (37%) of
17a and 65 mg (8%) of 44a, both as colorless oils: 17a: IR
˚
out with ICN SiliTech 32-63 D 60 A silica gel. Reactions
and chromatography fractions were analyzed with Merck
silica gel 60 F254 plates. Extracts were dried over MgSO4,
and solvents were removed with a rotary evaporator at
aspirator pressure. Melting points were determined with an
1
electrothermal apparatus and are uncorrected. H and 13C
NMR spectra were recorded in CDCl3 (7.27 ppm) on a
Bruker AM 400 MHz spectrometer.
1
(film): 2942, 1692, 1661 cmK1; H NMR: d 7.00 (d, JZ
5.2. Compounds
9.2 Hz, 1H), 6.89 (d, JZ3.2 Hz, 1H), 6.76 (dd, JZ9.2,
3.2 Hz, 1H), 5.39 (t, JZ3.2 Hz, 1H), 4.71 (t, JZ3.6 Hz,
2H), 4.07–3.98 (m, 1H), 3.74 (s, 3H), 3.61–3.48 (m, 7H),
5.2.1. 5-[5-Methoxy-2-(tetrahydro-pyran-2-yloxy)-phe-
nyl]-pent-4-yn-1-ol (16a). To a solution of 15 (1.70 g,

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C. C. Hughes, D. Trauner / Tetrahedron 60 (2004) 9675–9686
2.96 (m, 1H), 2.83–2.76 (m, 2H), 2.39 (t, JZ7.2 Hz, 2H),
2.15–1.78 (m, 5H), 1.76–1.42 (m, 5H); 13C NMR: d 154.2,
151.6, 118.4, 117.4, 116.0, 114.6, 97.7, 94.5, 91.5, 76.4,
61.6, 55.5, 542, 40.5, 30.2, 29.2, 25.3, 24.4, 24.1, 19.8, 18.5;
HRMS (EIC): m/z (MC) calcd for C25H32O5, 412.2250;
found 412.2245. 44a: IR (film): 2942, 1649, 1602 cmK1; 1H
NMR: d 6.98 (d, JZ9.2 Hz, 1H), 6.86 (d, JZ3.2 Hz, 1H),
6.74 (dd, JZ9.2, 3.2 Hz, 1H), 5.37–5.32 (m, 1H), 5.30 (s,
1H), 4.01–3.92 (m, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.59–
3.50 (m, 1H), 2.52–2.21 (m, 5H), 2.12–1.50 (m, 12H); 13C
NMR: d 199.2, 180.9, 154.1, 151.5, 118.0, 118.0, 117.5,
115.4, 114.8, 101.8, 97.5, 97.5, 93.3, 77.2, 61.7, 61.7, 55.5,
55.5, 37.8, 30.3, 30.2, 25.9, 25.2, 18.5; HRMS (EIC) m/z
(MC) calcd for C24H30O5, 398.2093; found 398.2088.
pent-4-ynyl]-cyclohex-3-enone (44b). The procedure fol-
lowed was the same as described above for 17a/44a. The
product was purified by column chromatography (15%
EtOAc to 60% EtOAc in hexanes) to give 1.06 g (53%) of
17b and 257 mg (13%) of 44b, both as colorless oils: 17b:
1
IR (film): 2948, 2903, 2827, 1691 cmK1; H NMR: d 6.96
(d, JZ9.2 Hz, 1H), 6.89 (d, JZ3.2 Hz, 1H), 6.72 (dd, JZ
9.2, 3.2 Hz, 1H), 5.12 (s, 2H), 4.67 (t, JZ3.2 Hz, 2H), 3.69
(s, 3H), 3.50 (s, 6H), 3.48 (s, 3H), 2.94 (m, 1H), 2.81–2.72
(m, 2H), 2.37 (t, JZ7.2 Hz, 2H), 1.90–1.79 (m, 2H), 1.54–
1.41 (m, 2H); 13C NMR: d 154.4, 154.2, 151.7, 117.9, 117.8,
115.9, 114.5, 96.0, 94.6, 91.5, 76.5, 55.9, 55.3, 54.0, 40.5,
29.1, 24.4, 24.0, 19.7; HRMS (EIC): m/z (MC) calcd for
C22H28O5, 372.1937; found 372.1946. 44b: IR (film): 2941,
1649, 1602 cmK1; 1H NMR: d 6.94 (d, JZ9.2 Hz, 1H), 6.83
(d, JZ3.2 Hz, 1H), 6.70 (dd, JZ9.2, 3.2 Hz, 1H), 5.26 (s,
1H), 5.07 (s, 2H), 3.67 (s, 3H), 3.61 (s, 3H), 3.43 (s, 3H),
2.49–2.32 (m, 4H), 2.27–2.17 (m, 1H), 2.08–1.94 (m, 1H),
191–1.73 (m, 2H), 1.73–1.50 (m, 3H); 13C NMR: d 199.1,
180.9, 154.2, 151.7, 117.8, 117.6, 115.3, 114.7, 101.7, 95.9,
93.5, 77.1, 56.0, 55.5, 55.5, 37.8, 33.9, 30.2, 26.4, 25.8,
19.6; HRMS (EIC): m/z (MC) calcd for C21H26O5,
358.1780; found 358.1783.
5.2.4. 2-Bromo-4-methoxy-1-methoxymethyl-benzene
(19). To a solution of 42 (11.7 g, 57.8 mmol) in DMF
(200 mL) at 0 8C was added NaH (2.54 g, 60% dispersion in
oil, 63.5 mmol) over 5 min. After 10 min at 0 8C, the
solution was allowed to warm to rt over 30 min. The mixture
was cooled again to 0 8C, and MOMCl (4.40 mL,
57.9 mmol) was slowly added via syringe. The solution,
after being stirred at rt for 2 h, was diluted with water (1 L)
and extracted with ether (4!200 mL). The combined
organic extracts were washed with 1 M NaOH (2!
100 mL) and brine (100 mL), then dried, filtered, and
concentrated to afford 14.0 g (98%) of 19 as a colorless oil,
which was taken on into the next step without further
purification: IR (film): 2957, 2905 cmK1; 1H NMR: d 7.12–
7.04 (m, 2H), 6.81–6.75 (m, 1H), 5.15 (s, 2H), 3.74 (s, 3H),
3.52 (s, 3H); 13C NMR: d 155.0, 147.8, 118.4, 117.8, 113.8,
113.5, 96.0, 56.2, 55.7; HRMS (EIC): m/z (MC) calcd for
C9H11BrO3, 245.9892; found 245.9891.
5.2.8. 2-(5-Hydroxy-pent-1-ynyl)-4-methoxy-phenol (20).
To a solution of 16b (2.34 g, 9.34 mmol) in MeOH (46 mL)
was added conc. HCl (1.8 mL) dropwise. After 4 h the
reaction mixture was diluted with water (200 mL) and
extracted with ether (3!100 mL). The combined organic
extracts were washed once with brine (50 mL), dried,
filtered, and concentrated. The product was purified by
column chromatography (50% EtOAc in hexanes) and
recrystallized from ether to yield 1.26 g (65%) of 20 as a
white solid: mp 80–82 8C; IR (KBr): 3423, 3079 (br),
1
2954 cmK1; H NMR: d 6.83–6.72 (m, 3H), 3.83 (t, JZ
5.2.5. 5-(5-Methoxy-2-methoxymethoxy-phenyl)-pent-4-
yn-1-ol (16b). The procedure followed was the same as
described above for 16a. The product was purified by
column chromatography (50% EtOAc in hexanes) to afford
1.90 g (67%) of 16b as a yellowish-brown oil: IR (film):
3427 (br), 2949 cmK1; 1H NMR: d 6.99 (d, JZ9.2 Hz, 1H),
6.88 (d, JZ3.2 Hz, 1H), 6.76 (dd, JZ9.2, 3.2 Hz, 1H), 5.14
(s, 2H), 3.80 (t, JZ5.6 Hz, 2H), 3.72 (s, 3H), 3.49 (s, 3H),
2.60–2.46 (m, 3H), 1.89–1.79 (m, 2H); 13C NMR: d 154.2,
151.8, 117.6, 117.2, 115.1, 114.9, 95.7, 93.6, 77.2, 61.7,
56.1, 55.5, 31.2, 16.4; HRMS (EIC): m/z (MC) calcd for
C14H18O4, 250.1205; found 250.1203.
5.6 Hz, 2H), 3.72 (s, 3H), 2.94 (br s, 1H), 2.57 (t, JZ6.8 Hz,
2H), 1.90–1.79 (m, 2H), phenolic –OH group exchanged;
13C NMR: d 152.7, 151.3, 116.3, 115.5, 115.4, 110.2, 96.2,
75.8, 61.8, 55.7, 30.9, 16.5; HRMS (EIC): m/z (MC) calcd
for C12H14O3, 206.0943; found 206.0940.
5.2.9. 5-(2-Allyloxy-5-methoxy-phenyl)-pent-4-yn-1-ol
(21). To a solution of 20 (1.19 g, 5.77 mmol) in DMF
(30 mL) was added K2CO3 (2.39 g, 17.3 mmol) followed by
allyl bromide (0.65 mL, 7.5 mmol). The mixture was
diluted 12 h later with water (200 mL) and extracted with
CH2Cl2 (3!50 mL). The combined organic extracts were
dried, filtered, and concentrated. The product was purified
by column chromatography (50% EtOAc in hexanes) to
afford 1.16 g (82%) of 21 as a colorless oil: IR (film): 3374
(br), 2948 cmK1; 1H NMR: d 6.91–6.86 (m, 1H), 6.78–6.70
(m, 2H), 6.04 (m, 1H), 5.40 (m, 1H), 5.25 (m, 1H), 4.52 (m,
2H), 3.80 (t, JZ6.0 Hz, 2H), 3.72 (s, 3H), 2.55 (t, JZ
6.8 Hz, 2H), 2.52 (br s, 1H), 1.84 (m, 2H); 13C NMR: d
153.3, 153.3, 133.4, 117.8, 117.2, 114.7, 114.2, 114.2, 93.7,
76.7, 70.2, 61.7, 55.6, 31.2, 16.4; HRMS (EIC): m/z (MC)
calcd for C15H18O3, 246.1256; found 246.1251.
5.2.6. 2-(5-Iodo-pent-1-ynyl)-4-methoxy-1-methoxy-
methoxy-benzene (43b). The procedure followed was the
same as described above for 43a. The product was purified
by column chromatography (10% EtOAc in hexanes) to
furnish 2.76 g (94%) of 43b as a pale yellow oil: IR (film):
2952, 2903 cmK1; 1H NMR: d 6.99 (d, JZ9.2 Hz, 1H), 6.89
(d, JZ3.2 Hz, 1H), 6.77 (dd, JZ9.2, 3.2 Hz, 1H), 5.15 (s,
2H), 3.72 (s, 3H), 3.50 (s, 3H), 3.38 (t, JZ6.8 Hz, 2H), 2.58
(t, JZ6.8 Hz, 2H), 2.11–2.01 (m, 2H); 13C NMR: d 154.2,
151.9, 117.7, 117.3, 115.0, 95.8, 91.8, 77.9, 56.1, 55.6, 32.1,
20.6, 5.5, 5.4; HRMS (EIC): m/z (MC) calcd for
C14H17IO3, 360.0222; found 360.0215.
5.2.10. 1-Allyloxy-2-(5-iodo-pent-1-ynyl)-4-methoxy-
benzene (45). The procedure followed was the same as
described above for 43a. The product was purified by
column chromatography (10% EtOAc in hexanes) to
furnish 1.57 g (97%) of 45 as a pale yellow oil: IR (film):
5.2.7. 2-[5-(2,6-Dimethoxy-cyclohexa-2,5-dienyl)-pent-1-
ynyl]-4-methoxy-1-methoxymethoxy-benzene (17b) and
3-methoxy-2-[5-(5-methoxy-2-methoxymethoxy-phenyl)-

C. C. Hughes, D. Trauner / Tetrahedron 60 (2004) 9675–9686
9683
1
2936 cmK1; H NMR: d 6.93–6.89 (m, 1H), 6.80–6.73 (m,
5.2.13. Trifluoro-methanesulfonic acid 2-[5-(2-hydroxy-
5-methoxy-phenyl)-pent-4-ynyl]-3-oxo-cyclohex-1-enyl
ester (11). To a solution of Pd(PPh3)4 (59 mg, 0.051 mmol)
in CH2Cl2 (8 mL) was added a solution of 23 (240 mg,
0.508 mmol) in CH2Cl2 (2 mL). p-Nitrophenol (707 mg,
5.08 mmol) was added, followed by Bu3SnH (0.47 mL,
1.8 mmol) dropwise via syringe. After 30 min the solution
was diluted with water (50 mL) and extracted with CH2Cl2
(3!20 mL). The combined organic extracts were washed
once with brine (20 mL), dried, filtered, and concentrated.
The product was purified by preparative HPLC (20% EtOAc
in hexanes) to furnish 127 mg (58%) of 11 as a pale yellow
2H), 6.06 (m, 1H), 5.44 (m, 1H), 5.28 (m, 1H), 4.52 (m, 2H),
3.74 (s, 3H), 3.40 (t, JZ6.8 Hz, 2H), 2.60 (t, JZ6.8 Hz,
2H), 2.09 (m, 2H); 13C NMR: d 153.5, 153.3, 133.4, 117.9,
117.3, 114.8, 114.62, 114.1, 92.0, 77.9, 70.2, 55.6, 32.2,
20.7, 5.6; HRMS (EIC): m/z (MC) calcd for C15H17IO2,
356.0273; found 356.0277.
5.2.11. 1-Allyloxy-2-[5-(2,6-dimethoxy-cyclohexa-2,5-
dienyl)-pent-1-ynyl]-4-methoxy-benzene (22) and 2-[5-
(2-allyloxy-5-methoxy-phenyl)-pent-4-ynyl]-3-methoxy-
cyclohex-3-enone (46). The procedure followed was the
same as described above for 17a/44a. The product was
purified by column chromatography (10% EtOAc to 60%
EtOAc in hexanes) to give 2.05 g (57%) of 22 and 458 mg
(13%) of 46, both as colorless oils: 22: IR (film): 2937,
1
oil: IR (film): 3500 (br), 2942, 1687 cmK1; H NMR: d
6.92–6.73 (m, 3H), 6.03 (br s, 1H), 3.74 (s, 3H), 2.76 (t, JZ
6.0 Hz, 2H), 2.61–2.43 (m, 6H), 2.08 (m, 2H), 1.73 (m, 2H);
13C NMR: d 197.6, 162.5, 152.7, 151.1, 131.2, 118.1 (q, JZ
320 Hz), 116.5, 115.4, 115.4, 110.0, 96.0, 75.7, 55.6, 36.6,
28.5, 26.9, 22.7, 20.4, 19.4; HRMS (FABC): m/z (MC)
calcd for C19H19F3O6S 432.0854; found 432.0858.
2832, 1692, 1661 cmK1; H NMR: d 6.93 (d, JZ2.8 Hz,
1
1H), 6.81–6.71 (m, 2H), 6.07 (m, 1H), 5.44 (m, 1H), 5.26
(m, 1H), 4.72 (t, JZ3.2 Hz, 2H), 4.55 (m, 2H), 3.75 (s, 3H),
3.55 (s, 6H), 3.01–2.93 (m, 1H), 2.85–2.78 (m, 2H), 2.41 (t,
JZ7.2 Hz, 2H), 1.90–1.80 (m, 2H), 1.57–1.45 (m, 2H); 13C
NMR: d 154.2, 153.5, 153.3, 133.6, 118.1, 117.0, 114.9,
114.7, 144.4, 95.0, 91.5, 76.3, 70.5, 55.6, 54.2, 40.5, 29.2,
24.4, 24.1, 19.9; HRMS (EIC): m/z (MC) calcd for
C23H28O4, 368.1988; found 368.1983. 46: IR (film): 2940,
5.2.14. Trifluoro-methanesulfonic acid 2-[3-(5-methoxy-
benzofuran-2-yl)-propyl]-3-oxo-cyclohex-1-enyl ester
(25). To a solution of Pd(PPh3)4 (470 mg, 0.406 mmol) in
CH2Cl2 (70 mL) was added a solution of 23 (1.92 g,
4.06 mmol) in CH2Cl2 (10 mL). p-Nitrophenol (2.82 g,
20.3 mmol) was added, followed by Bu3SnH (3.70 mL,
13.8 mmol) dropwise via syringe. After 6 h the solution was
diluted with brine (100 mL) and extracted with CH2Cl2 (4!
50 mL). The combined organic extracts were dried, filtered,
and concentrated. The crude product was left standing at rt
for w2 d and was then diluted with CH2Cl2 (300 mL). The
solution was washed successively with 1 M NaOH (3!
100 mL), water (100 mL), brine (50 mL), dried, filtered, and
concentrated. The product was purified by column chroma-
tography (20% EtOAc in hexanes), then by preparative
HPLC (15% EtOAc in hexanes) to give 448 mg (28%) of 25
as a pale yellow oil: IR (film): 2940, 1687 cmK1; 1H NMR:
d 7.28 (d, JZ9.2 Hz, 1H), 6.95 (d, JZ2.4 Hz, 1H), 6.80 (dd,
JZ9.2, 2.4 Hz, 1H), 6.36 (s, 1H), 3.83 (s, 3H), 2.77 (t, JZ
7.2 Hz, 2H), 2.71 (t, JZ6.4 Hz, 2H), 2.50–2.40 (m, 4H),
2.00 (m, 2H), 1.86 (m, 2H); 13C NMR: d 197.2, 162.1,
159.3, 155.6, 149.5, 131.3, 129.4, 118.3 (q, JZ320 Hz),
111.4, 110.9, 103.0, 102.3, 55.8, 36.6, 28.5, 28.3, 25.9, 23.3,
20.4; HRMS (EIC): m/z (MC) calcd for C19H19F3O6S
432.0854; found 432.0857.
2865, 1650, 1602 cmK1; H NMR: d 6.90 (d, JZ2.4 Hz,
1
1H), 6.80–6.72 (m, 2H), 6.03 (m, 1H), 5.42 (m, 1H), 5.32 (s,
1H), 5.24 (m, 1H), 4.53 (m, 2H), 3.74 (s, 3H), 3.67 (s, 3H),
2.56–2.39 (m, 4H), 2.34–2.23 (m, 1H), 2.13–2.01 (m, 1H),
1.96–1.80 (m, 2H), 1.80–1.60 (m, 3H); 13C NMR: d 199.3,
181.0, 153.4, 153.3, 133.5, 118.1, 117.0, 114.6, 114.4,
114.3, 101.8, 93.7, 77.1, 70.2, 55.6, 55.6, 37.9, 34.0, 30.3,
26.5, 25.9, 19.7; HRMS (EIC): m/z (MC) calcd for
C22H26O4, 354.1831; found 354.1828.
5.2.12. Trifluoro-methanesulfonic acid 2-[5-(2-allyloxy-
5-methoxy-phenyl)-pent-4-ynyl]-3-oxo-cyclohex-1-enyl
ester (23). To a solution of 22 (3.47 g, 9.42 mmol) and 46
(0.730 g, 2.06 mmol) in acetone (120 mL) at 0 8C was added
1 M HCl (5.7 mL, 5.7 mmol). After 3.5 h the solution was
neutralized to pH 7 with a saturated NaHCO3 solution and
diluted with water (200 mL). The mixture was extracted
with CH2Cl2 (3!50 mL), and the combined organic
extracts were then dried, filtered, and concentrated in an
ice bath. The crude diketone was immediately dissolved in
THF (115 mL) and cooled to 0 8C. A solution of NaHMDS
in THF (13.7 mL, 1.0 M, 13.7 mmol) was added dropwise
via syringe, followed 30 min later by a solution of PhNTf2
(4.89 g, 13.7 mmol) in THF (12 mL). After 2 h at 0 8C, the
solution was diluted with brine (100 mL) and extracted with
ether (3!100 mL). The combined organic extracts were
washed once with brine (50 mL), dried, filtered, and
concentrated. The product was purified by column chroma-
tography (20% EtOAc in hexanes) to yield 3.32 g (62% over
two steps) of 23 as a pale yellow oil: IR (film): 2940,
1690 cmK1; 1H NMR: d 6.94 (d, JZ2.4 Hz, 1H), 6.81–6.73
(m, 2H), 6.06 (m, 1H), 5.42 (m, 1H), 5.25 (m, 1H), 4.55 (m,
2H), 3.75 (s, 3H), 2.76 (t, JZ6.4 Hz, 2H), 2.58–2.41 (m,
6H), 2.06 (m, 2H), 1.74 (m, 2H); 13C NMR: d 197.1, 162.1,
153.4, 153.4, 133.5, 131.4, 118.1 (q, JZ320 Hz), 117.9,
117.0, 114.9, 114.6, 114.50, 93.4, 77.2, 70.4, 55.6, 36.7,
28.6, 27.2, 23.2, 20.5, 19.7; HRMS (FABC): m/z (MC)
calcd for C22H23F3O6S 472.1167; found 472.1170.
5.2.15. 11-Methoxy-1,2,3,5,6,7-hexahydro-8-oxa-di-
benzo[a,h]azulen-4-one (24). To a solution of 25
(448 mg, 1.04 mmol) in MeCN (26 mL) was added
Pd(OAc)2 (37 mg, 0.16 mmol), PPh3 (55 mg, 0.21 mmol),
and Et3N (0.29 mL, 2.1 mmol). The reaction mixture was
heated at reflux for 14 h, cooled, diluted with water
(100 mL), and extracted with CH2Cl2 (3!50 mL). The
combined organic extracts were washed once with brine
(50 mL), dried, filtered, and concentrated. The product was
purified by preparative HPLC (15% EtOAc in hexanes) to
afford 160 mg (54%) of 24 as a white solid: mp 133–135 8C;
IR (KBr) 2940, 1645 cmK1; 1H NMR: d 7.30 (d, JZ9.2 Hz,
1H), 7.13 (d, JZ2.4 Hz, 1H), 6.85 (dd, JZ9.2, 2.4 Hz, 1H),
3.84 (s, 3H), 3.05 (t, JZ7.2 Hz, 2H), 2.99 (t, JZ6.0 Hz,
2H), 2.60 (m, 2H), 2.53 (t, JZ6.4 Hz, 2H), 2.10 (m, 2H),
1.94 (m, 2H); 13C NMR: d 197.5, 161.1, 155.8, 149.2, 148.8,
136.4, 128.2, 116.5, 111.4, 111.2, 105.5, 56.0, 37.6, 30.5,

9684
C. C. Hughes, D. Trauner / Tetrahedron 60 (2004) 9675–9686
29.5, 25.6, 23.4, 22.7; HRMS (EIC): m/z (MC) calcd for
C18H18O3 282.1256; found 282.1252.
30.5, 19.3; HRMS (EIC): m/z (MC) calcd for C13H16O3
220.1099; found 220.1099.
5.2.19. 2-((R)-3-Iodo-1-methyl-propyl)-5-methoxy-
benzofuran (31). The procedure followed was the same
as described above for 43a. The product was purified by
column chromatography (5% EtOAc in hexanes) to yield
1.18 g (93%) of 31 as a light brown oil: [a]DZK86.8 (cZ
1.00, CHCl3); IR (film): 2966, 2933, 1616, 1602 cmK1; 1H
NMR: d 7.32 (d, JZ8.8 Hz, 1H), 6.99 (d, JZ2.4 Hz, 1H),
6.85 (dd, JZ8.8, 2.4 Hz, 1H), 6.40 (s, 1H), 3.85 (s, 3H),
3.28–3.19 (m, 1H), 3.17–3.06 (m, 2H), 2.36–2.23 (m, 1H),
2.17–2.05 (m, 1H), 1.37 (d, JZ7.2 Hz, 3H); 13C NMR: d
162.4, 156.0, 149.8, 129.3, 112.0, 111.4, 103.5, 102.2, 56.2,
39.2, 34.8, 18.7, 4.3; HRMS (EIC): m/z (MC) calcd for
C13H15IO2 330.0117; found 330.0116.
5.2.16. Acetic acid 4-methoxy-2-[(R)-5-(4-methoxy-
benzyloxy)-3-methyl-pent-1-ynyl]-phenyl ester (28). A
solution of 27 (4.40 g, 18.0 mmol) in Et3N (15 mL) and
MeCN (15 mL) was purged for 15 min with a gentle stream
of argon. Pd(PPh3)4 (518 mg, 0.448 mmol) and CuI
(171 mg, 0.898 mmol) were then added. The mixture was
heated at reflux, and a solution of 26 (1.96 g, 8.98 mmol) in
MeCN (5 mL), previously purged with argon as well, was
added via syringe pump over 6 h. The solution was heated at
reflux for an additional 16 h, cooled, poured into a saturated
NaHCO3 solution (200 mL), and extracted with ether (3!
100 mL). The combined organic extracts were washed once
with brine (50 mL), dried, filtered, and concentrated. The
product was purified by column chromatography (20%
EtOAc in hexanes) to furnish 3.24 g (94%) of 28 as a pale
yellow oil: [a]DZK70.0 (cZ1.00, CHCl3); IR (film): 2935,
5.2.20. 2-[(R)-3-(2,6-Dimethoxy-cyclohexa-2,5-dienyl)-1-
methyl-propyl]-5-methoxy-benzofuran (47) and 3-meth-
oxy-2-[(R)-3-(5-methoxy-benzofuran-2-yl)-butyl]-cyclo-
hex-3-enone (48). The procedure followed was the same as
described above for 17a/44a. The product was purified by
column chromatography (8% EtOAc to 60% EtOAc in
hexanes) to furnish 743 mg (67%) of 47 and 182 mg (17%)
of 48, both as colorless oils: 47: [a]DZC17.6 (cZ1.00,
CHCl3); IR (film): 2935, 2830, 1692 cmK1; 1H NMR: d 7.30
(d, JZ8.8 Hz, 1H), 6.97 (d, JZ2.4 Hz, 1H), 6.81 (dd, JZ
8.8, 2.4 Hz, 1H), 6.28 (m, 1H), 4.74 (t, JZ3.6 Hz, 2H), 3.84
(s, 3H), 3.54 (s, 3H), 3.52 (s, 3H), 3.00–2.71 (m, 4H), 1.85–
1.69 (m, 2H), 1.69–1.56 (m, 1H), 1.49–1.37 (m, 1H), 1.29
(d, JZ6.8 Hz, 3H); HRMS (FABC): m/z (MC) calcd for
C21H26O4 342.1831; found 342.1825. 48: [a]DZK34.6
1
2861, 1765, 1612 cmK1; H NMR: d 7.31–7.26 (m, 2H),
6.99–6.81 (m, 5H), 4.48 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H),
3.69–3.60 (m, 2H), 2.95–2.84 (m, 1H), 2.92 (s, 3H), 1.89–
1.71 (m, 2H), 1.27 (d, JZ6.8 Hz, 3H); 13C NMR: d 169.4,
159.4, 157.2, 145.4, 130.8, 129.4, 122.9, 118.6, 117.5,
115.1, 114.0, 99.2, 76.1, 72.9, 68.0, 55.8, 55.4, 37.1, 23.8,
21.3, 21.0; HRMS (FABC): m/z (MC) calcd for C23H26O5
382.1780; found 382.1786.
5.2.17. Acetic acid 2-((R)-5-hydroxy-3-methyl-pent-1-
ynyl)-4-methoxy-phenyl ester (29). To a solution of 28
(1.04 g, 2.72 mmol) in CH2Cl2 (25 mL) was added TFA
(2.7 mL) dropwise via syringe. After 10 min the mixture
was poured into a saturated NaHCO3 solution (200 mL) and
extracted with ether (3!100 mL). The combined organic
extracts were washed once with brine (50 mL), dried,
filtered, and concentrated. The product was purified by
column chromatography (50% EtOAc in hexanes) to furnish
591 mg (83%) of 29 as a pale yellow oil: [a]DZK37.1 (cZ
(cZ1.00, CHCl3); IR (film): 2939, 1737, 1659, 1602 cmK1
;
1H NMR: d 7.30 (d, JZ8.8 Hz, 1H), 6.98 (d, JZ2.4 Hz,
1H), 6.82 (dd, JZ8.8, 2.4 Hz, 1H), 6.33 (s, 1H), 5.31 (t, JZ
3.6 Hz, 1H), 3.84 (s, 3H), 3.66 (s, 3H), 3.00–2.85 (m, 1H),
2.49–2.33 (m, 2H), 2.33–2.21 (m, 1H), 2.11–2.00 (m, 1H),
1.94–1.45 (m, 5H), 1.34 (d, JZ6.8 Hz, 3H); HRMS (FABC):
m/z (MHC) calcd for C20H25O4 329.1753; found 329.1749.
1
1.00, CHCl3); IR (film): 3449 (br), 2935, 1765 cmK1; H
NMR: d 6.98–6.91 (m, 2H), 6.86–6.80 (m, 1H), 3.89–3.79
(m, 2H), 3.78 (s, 3H), 2.86 (m, 1H), 2.31 (s, 3H), 1.91–1.65
(m, 3H), 1.29 (d, JZ6.8 Hz, 3H); 13C NMR: d 169.5, 157.2,
145.4, 123.0, 118.4, 117.4, 115.3, 98.9, 76.5, 61.1, 55.8,
39.6, 23.7, 21.3, 21.0; HRMS (EIC): m/z (MC) calcd for
C15H18O4 262.1205; found 262.1205.
5.2.21. Trifluoro-methanesulfonic acid 2-[(R)-3-(5-meth-
oxy-benzofuran-2-yl)-butyl]-3-oxo-cyclohex-1-enyl ester
(33). To a solution of 47 (743 mg, 2.17 mmol) and 48
(182 mg, 0.55 mmol) in acetone (46 mL) and water (9 mL)
was added a strongly acidic cation exchange resin (400 mg,
Bio-Radw AG MP-50, 100-200 mesh), and the mixture was
heated at reflux for 18 h. Additional resin (800 mg) was
added in increments, and after continued refluxing for 24 h,
the solution was filtered through Celite, diluted with brine
(50 mL), and extracted with ether (5!100 mL). The
combined organic extracts were dried, filtered, and
concentrated to about 20 mL: HRMS (EIC): m/z (MC)
calcd for C19C22O4 314.1518; found 314.1517. The solution
was passed through a plug of silica, concentrated again to
about 20 mL, and then diluted with THF (27 mL). A
solution of NaHMDS in THF (3.5 mL, 1.0 M, 3.5 mmol)
was added via syringe. After 30 min, a solution of PhNTf2
(1.07 g, 3.00 mmol) in THF (6.0 mL) was added dropwise
via cannula. After 2 h, the solution was diluted with water
(100 mL) and extracted with ether (3!100 mL). The
combined organic extracts were washed once with brine
(50 mL), dried, filtered, and concentrated. The product was
purified by column chromatography (15% EtOAc in
5.2.18. (R)-3-(5-Methoxy-benzofuran-2-yl)-butan-1-ol
(30). To a solution of 29 (580 mg, 2.21 mmol) in MeOH
(22 mL) was added K2CO3 (733 mg, 5.30 mmol), and the
mixture was heated at reflux for 5 h. The solution was
cooled, poured into a saturated NH4Cl solution (200 mL),
and extracted with CH2Cl2 (3!100 mL). The combined
organic extracts were dried, filtered, and concentrated. The
product was purified by column chromatography (40%
EtOAc in hexanes) to yield 450 mg (92%) of 30 as a
colorless oil: [a]DZK33.0 (cZ1.00, CHCl3); IR (film):
3349 (br), 2936, 1615, 1602 cmK1; 1H NMR: d 7.31 (d, JZ
9.2 Hz, 1H), 6.98 (d, JZ2.4 Hz, 1H), 6.83 (dd, JZ9.2,
2.4 Hz, 1H), 6.35 (s, 1H), 3.84 (s, 3H), 3.69 (m, 2H), 3.14
(m, 1H), 2.08–1.98 (m, 1H), 1.92–1.81 (m, 1H), 1.62 (br s,
1H), 1.37 (d, JZ7.2 Hz, 3H); 13C NMR: d 164.1, 156.0,
149.7, 129.5, 111.8, 111.4, 103.5, 101.4, 60.9, 56.1, 38.5,

C. C. Hughes, D. Trauner / Tetrahedron 60 (2004) 9675–9686
9685
hexanes) to afford 892 mg (74%) of 33 as a colorless oil:
[a]DZK8.4 (cZ1.00, CHCl3); IR (film): 2967, 2938,
5.2.24. (R)-Frondosin B [(K)-4]. (K)-4 was prepared from
35 according to the literature:8 [a]DZK16.8 (cZ1.00,
CHCl3).
1
1690 cmK1; H NMR: d 7.30 (d, JZ8.8 Hz, 1H), 6.97 (d,
JZ2.4 Hz, 1H), 6.81 (dd, JZ8.8, 2.4 Hz, 1H), 6.38 (s, 1H),
3.84 (s, 3H), 2.95 (m, 1H), 2.66 (m, 2H), 2.45–2.37 (m, 4H),
2.00–1.83 (m, 3H), 1.76–1.65 (m, 1H), 1.35 (d, JZ7.2 Hz,
3H); 13C NMR: d 197.5, 163.9, 162.2, 156.0, 149.8, 131.8,
129.6, 118.5 (q, JZ320 Hz), 111.8, 111.4, 103.4, 101.5,
56.2, 37.0, 34.1, 33.5, 28.8, 21.9, 20.6, 19.2; HRMS (FABC):
m/z (MC) calcd for C20H21F3O6S 446.1011; found 446.1005.
References and notes
1. (a) Malleron, J.-L.; Fiaud, J.-C.; Legros, J.-Y. Handbook of
Palladium-Catalyzed Organic Reactions; Academic: San
Diego, 1997. (b) Li, J. J.; Gribble, G. W. Palladium in
Heterocyclic Chemistry; Pergamon: Amsterdam, 2000.
2. (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. (b) Glover,
B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko,
M. F. Org. Lett. 2003, 5, 301. (c) Park, C.-H.; Ryabova, V.;
Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett.
2004, 6, 1159.
5.2.22. (R)-11-Methoxy-7-methyl-1,2,3,5,6,7-hexahydro-
8-oxa-dibenzo[a,h]azulen-4-one [(K)-10]. To a degassed
solution of i-Pr2NEt (0.78 mL, 4.5 mmol) in DMA
(110 mL) was added Pd(PPh3)4 (65 mg, 0.056 mmol), and
the mixture was heated to 90 8C. A solution of 33 (500 mg,
1.12 mmol) in DMA (5 mL), previously degassed as well,
was then added via syringe pump over 3 h. The mixture was
stirred at 90 8C for an additional 36 h, cooled, diluted with a
saturated NaHCO3 solution (500 mL) and water (200 mL),
and extracted with ether (4!200 mL). The combined
organic extracts were washed with water (2!100 mL),
brine (50 mL), dried, filtered, and concentrated. The product
was purified by column chromatography (15% EtOAc in
hexanes) to give 234 mg (70%) of (K)-10 as a colorless
oil: [a]DZK36.1 (cZ1.00, CHCl3); IR (film): 2934,
3. (a) Anbazhagan, M.; Saulter, J. Y.; Hall, J. E.; Boykin,
D. W. Heterocycles 2003, 60, 1133. (b) Klunder, J. M.;
Hoermann, M.; Cywin, C. L.; David, E.; Brickwood,
J. R.; Schwartz, R.; Barringer, K. J.; Pauletti, D.; Shih, C.-K.;
Erickson, D. A.; Sorge, C. L.; Joseph, D. P.; Hattox,
S. E.; Adams, J.; Grob, P. M. J. Med. Chem. 1998, 41, 2960.
(c) Ruediger, F.; Garratt, P. J.; Jones, R.; Teh, M.-T.; Tsotinis,
A.; Panoussopoulou, M.; Calogeropoulou, T.; Teh, M.-Y.;
Sugden, D. J. Med. Chem. 2000, 43, 1050. (d) Dahlgren, A.;
Kvarnstroem, I.; Vrang, L.; Hamelink, E.; Hallberg, A.;
Rosenquist, A.; Samuelsson, B. Bioorg. Med. Chem. 2003, 11,
827. See also: (e) Sezen, B.; Sames, D. J. Am. Chem. Soc.
2003, 125, 5274.
1
1656 cmK1; H NMR: d 7.34 (d, JZ8.8 Hz, 1H), 7.17 (d,
JZ2.4 Hz, 1H), 6.88 (dd, JZ8.8, 2.4 Hz, 1H), 3.86 (s, 3H),
3.29 (m, 1H), 3.10–2.93 (m, 2H), 2.86–2.76 (m, 1H), 2.63–
2.46 (m, 2H), 2.41–2.31 (m, 1H), 2.20–2.03 (m, 3H), 1.56
(m, 1H), 1.39 (d, JZ6.8 Hz, 3H); 13C NMR: d 197.6, 164.5,
156.0, 149.3, 149.1, 137.2, 128.3, 115.8, 111.7, 111.5,
105.9, 56.3, 37.9, 36.1, 35.1, 30.9, 23.7, 21.4, 20.6; HRMS
(EIC): m/z(MC) calcd for C19H20O3 296.1412; found
296.1414. The enantiomeric excess was determined by
HPLC [Chiralpak ADTM column, 2% i-PrOH in hexanes at
1.0 mL/min; tR (major enantiomer)Z25.8 min, tR (minor
enantiomer)Z33.8 min] to be 91%.
4. (a) Burwood, M.; Davies, B.; Diaz, I.; Grigg, R.; Molina, P.;
Sridharan, V.; Hughes, M. Tetrahedron Lett. 1995, 36, 9053.
(b) Padwa, A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem.
´
2001, 66, 1716. (c) Malapel-Andrieu, B.; Merour, J.-Y.
Tetrahedron 1998, 54, 11079. (d) Fishwick, C. W. G.;
Grigg, R.; Sridharan, V.; Virica, J. Tetrahedron 2003, 59,
4451. See also: (e) Kozikowski, A. P.; Ma, D. Tetrahedron
Lett. 1991, 32, 3317. (f) Smet, M.; Van Dijk, J.; Dehaen, W.
Syn lett 1999, 4, 495. (g) Okazawa, T.; Satoh, T.; Miura, M.;
Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286. (h) Matsuda,
Y.; Kohra, S.; Katou, K.; Uemura, T.; Yamashita, K.
Heterocycles 2003, 60, 405.
5.2.23. (R)-11-Methoxy-4,4,7-trimethyl-2,3,4,5,6,7-hexa-
hydro-1HK8-oxa-dibenzo[a,h]azulene (35). To a solution
of (K)-10 (274 mg, 0.925 mmol) in THF (9.3 mL) at
K78 8C was added a solution of MeMgBr in ether (1.2 mL,
3.0 M, 3.6 mmol) dropwise via syringe. After 20 min at
K78 8C, the solution was allowed to warm to rt for 1 h. The
mixture was cooled to 0 8C, and the reaction was quenched
with MeOH. The solution was diluted with water (200 mL)
and brine (100 mL) and extracted with ether (3!100 mL).
The combined organic extracts were washed once with brine
(50 mL), dried, filtered, and concentrated. To a solution of
TiCl4 in CH2Cl2 (0.93 mL, 1.0 M, 0.93 mmol) at 0 8C was
added a solution of ZnMe2 in toluene (0.93 mL, 2.0 M,
1.8 mmol) dropwise via syringe. After 10 min a solution of
the crude alcohol in CH2Cl2 (9.3 mL) was added dropwise
via cannula, and after 10 min the solution was allowed to
warm to rt. 2 h later the mixture was cooled to 0 8C, and the
reaction was again quenched with MeOH. The mixture was
diluted with water (200 mL) and brine (100 mL) and
extracted with ether (3!100 mL). The product was purified
by column chromatography (3% EtOAc in hexanes) to yield
236 mg (82%) of 35 as a pale yellow oil: [a]DZK36.1 (cZ
1.00, CHCl3); IR, NMR, and HRMS are consistent with the
literature.8
5. Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41,
1569. Erratum: Angew. Chem., Int. Ed. 2002, 41, 2227.
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Jurewicz, A. J.; Johnson, R. K. Tetrahedron 1997, 53, 5047.
7. Hallock, Y. F.; Cardellina, J. H.; Boyd, M. R. Nat. Prod. Lett.
1998, 11, 153.
8. (a) Inoue, M.; Frontier, A. J.; Danishefsky, S. J. Angew. Chem.,
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¨
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observed.