Unified syntheses of cavicularin and riccardin C: Addressing the synthesis of an arene adopting a boat configuration

Article abstract of DOI:10.1002/chem.201101550

Concise syntheses of the natural products cavicularin (ten steps) and riccardin C (seven steps) are reported. Key features of the new synthetic route are a convergent strategy to assemble acyclic precursors and a sequence of regioselective reduction and h

Full text of DOI:10.1002/chem.201101550

DOI: 10.1002/chem.201101550
Unified Syntheses of Cavicularin and Riccardin C: Addressing the Synthesis
of an Arene Adopting a Boat Configuration
Sarah L. Kostiuk,[a] Timothy Woodcock,[a] Leo F. Dudin,[b] Peter D. Howes,[b] and
David C. Harrowven*[a]
Abstract: Concise syntheses of the natural products cavicularin (ten steps) and ric-
cardin C (seven steps) are reported. Key features of the new synthetic route are a
convergent strategy to assemble acyclic precursors and a sequence of regioselec-
tive reduction and halogenation steps to facilitate Wittig macrocyclisation and
transannular ring contraction reactions.
Keywords: natural products · radi-
cal reactions · strained molecules ·
synthetic methods · total synthesis
Introduction
hibit activity in various pharmacological screens, including
antimycotic and antibacterial effects,[5–7] and cytotoxicity
against P-388 mouse leukaemia and KB cell lines from naso-
pharyngeal carcinomas.[8] Recently, riccardin C (4) gained
prominence as a partial liver X receptor (LXR) a agonist
and LXRb antagonist,[3,9,10] these playing a critical role in
maintaining lipid homeostasis through the regulation of sev-
eral genes involved in the efflux, transport and excretion of
cholesterol.
From a structural perspective, cavicularin (5), from the
Japanese liverwort Cavicularia densa, is unusual in having
an additional linkage between arenes C and D.[11] This im-
parts such strain on the paracyclophane core that it induces
a boat conformation in arene A.[12] Moreover, though
devoid of any stereogenic carbon centres, natural cavicularin
is chiral as a result of restricted conformational freedom.[12]
Herein, we present a fuller account of our first generation
synthesis of riccardin C (4) and cavicularin (5),[13] and a new
strategy offering rapid access through a combination of con-
vergence and telescoping.
Macrocyclic bisbibenzyls are common constituents of liver-
worts and other bryophytes,[1] the earliest land plants.[2] To
date riccardin C (4) is the only compound of this class to
have been found in a higher flowering plant; that is, it is a
constituent of Primula macrocalyx Bge. (Primulaceae).[3,4]
Natural macrocyclic bisbibenzyls are thought to share a
common origin in Nature, being derived by the dimerisation
of lunularin.[1] Consequently, the vast majority conform to
one of three structural motifs, 1–3, which are sub-divided
into familial groups by the nature of the linkage between
the arenes B and D.[1] Siblings are further discriminated
through variations in the two-carbon chains linking the
arenes A and B, as well as C and D, and with respect to the
substituents decorating the constituent arenes.
From a biological perspective, liverworts have long been
used in traditional Japanese medicine as antibacterial and
antifungal agents, and as diuretics.[1] Their constituent mac-
rocyclic bisbibenzyl natural products have been found to ex-
Results and Discussion
[a] Dr. S. L. Kostiuk, Dr. T. Woodcock, Prof. D. C. Harrowven
Chemistry, University of Southampton, Highfield
Southampton, Hampshire, SO17 1BJ (UK)
Fax : (+44)23-8059-6805
Development of a first-generation synthesis: In our first
total synthesis of cavicularin, the acyclic precursor 6 was as-
sembled in a convergent manner from the constituent start-
ing materials 7–10 with a longest linear sequence of nine
E-mail: dch2@soton.ac.uk
[b] Dr. L. F. Dudin, Dr. P. D. Howes
steps (Scheme 1). Key features included an SnAr reaction to
c/o GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage, SG1 2NY (UK)
0
ꢀ
conjoin arenes A and C, a Pd -catalysed C H insertion reac-
tion to conjoin arenes B and D, and a Wittig reaction to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101550.
unite these subunits.[13] Following a McMurry-induced mac-
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FULL PAPER
Figure 1. X-ray crystal structure for phenanthrene 16, showing the boat-
configured arene.
erating the boat-configured arene A, which displayed a 168
bend away from planarity in the solid state (Figure 1).
From this juncture, two tasks remained to complete the
ꢀ
first total synthesis of cavicularin: the reduction of the C9
C10 phenanthrene bond and the global deprotection of the
aryl methyl ethers. The former proved an intractable prob-
lem as all attempts to effect reduction of 16 to 15 either re-
turned the starting material or gave complex product mix-
tures, presumed to be derived from reduction of the boat-
configured arene. Consequently, we decided to explore the
impact of reducing the cis-alkene in 11 before inducing the
transannular ring contraction. Our hope was that the macro-
cyclic architecture of 13 would restrict conformational free-
dom and promote reactive conformers favouring the 6-exo/
endo-trig cyclisation mode. Indeed, when 13 was exposed to
TTMSS under standard radical-forming conditions it gave
an inseparable 1:2 mixture of cavicularin trimethyl ether 15
and riccardin C trimethyl ether 17 in high yield. With the in-
itiator now employed at substoichiometric levels we saw no
evidence for addition of the isobutyronitrile radical to the
product.[17] However, in removing the cis-alkene tether we
undoubtedly slowed the rate of the transannular ring con-
traction significantly, allowing hydrogen-atom abstraction
from the silane to become competitive. Thus, treatment of
the product mixture with boron tribromide provided syn-
thetic samples of cavicularin (5) and riccardin C (4) in 32
and 63% yield, respectively, each displaying spectral charac-
teristics identical to those reported for the natural prod-
ucts.[3,4,10,11]
Scheme 1. Summary of the first-generation synthesis and a previously un-
reported approach through stilbene 11. Ts=tosyl, AIBN=azobisisobu-
tyronitrile, Ac=acyl, TTMSS=tris(trimethylsilyl)silane.
rocyclisation, our plan was to effect a transannular ring con-
traction through the addition of an aryl radical intermediate
to its proximal arene, that is, 12![14]!16.[14] Prior art sug-
gested that the cis-alkene linking the radical donor and ac-
ceptor was crucial to promote the desired ortho-cyclisation
pathway over ipso-substitution, as with saturated two-
carbon tethers the ubiquitous 5-exo-trig cyclisation mode
usually predominates.[15] Pleasingly, cyclisation of iodostil-
bene 11 to phenanthrene 16 was successful, though its effi-
ciency was compromised by an unexpected affinity of the
product for the isobutyronitrile radical (and arising from the
need to use a full equivalent of AIBN as initiator).[16] X-ray
analysis of 16 showed that we had achieved our goal of gen-
It is interesting to note that for riccardin C (4), there are
many variations in the reported H NMR data, which have
1
been
variously
recorded
in
CDCl3,
[D6]DMSO,
[D6]DMSO+CDCl3 and [D6]acetone.[3,4,10,11] In CDCl3 at
1
258C the H NMR spectrum shows significant broadening of
all ArCH2 signals and those of the A ring. Consequently, the
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D. C. Harrowven et al.
region around d=6.82–6.72 ppm has typically been de-
scribed as a 6H or 7H multiplet. Three peaks are discerna-
ble, attributed to the protons H12 (d=6.81 ppm, dd, J=8.3,
2.6 Hz), H11’ (d=6.79 ppm, d, J=7.5 Hz) and H5’ (d=
6.75 ppm, dd, J=8.3, 1.9 Hz). The same phenomenon was
found in [D6]benzene and [D8]toluene, solvents in which the
signals are better resolved. This broadness can be attributed
to restricted rotation within the molecule. By recording the
NMR spectra at lower temperatures in [D8]toluene, we
found that the resonances for the A ring began to resolve
into four distinct doublets of doublets, whereas at elevated
temperatures they resolved into an AB quartet (Figure 2).
Scheme 2. A new strategy for riccardin C (4).
Scheme 3. Construction of the acyclic precursors 26 and 27. SPhos=2-di-
cyclohexylphosphino-2’,6’-dimethoxybiphenyl.
Figure 2. 1H NMR data (dH =7.15–6.00 ppm) for riccardin C recorded in
CDCl3 and [D8]toluene at 243, 298 and 363 K.
suitably primed biaryl ether 24 (Scheme 3). Contemporane-
ously, triflation of phenol 18 (arene D) to compound 19 ena-
bled a Suzuki–Miyaura coupling with the commercially
available boronic acid 20 (arene B), thereby giving our
second key building block, styrene 21.[18,19] Next, a Heck re-
action facilitated union of these subunits,[20] providing tet-
raarene 25 in excellent overall yield and with a longest
linear sequence of three steps from commercially available
starting materials. Catalytic hydrogenation of 25 proceeded
smoothly to give either the dialdehyde 26 in 95 or the alco-
hol 27 in 89% yield, depending on the reaction time em-
ployed.[21]
Although efficient telescoping of the hydrogenation steps
was easily realised, attempts to sequence the Pd0-catalysed
Suzuki–Miyaura and Heck coupling reactions met with lim-
ited success (ꢁ20% for 19+20+24!25), due to an incom-
patibility of the catalyst systems. Cross-coupling of the elec-
tron-rich triflate 19 and boronic acid 20 proved particularly
challenging, giving the corresponding product in poor yields
with conventional ligand and base combinations.[19] Though
Combining the principles of convergence and telescoping:
In seeking improvements to the aforementioned syntheses,
we noted three low-yielding transformations (macrocyclisa-
tion 6!11, ring contraction 13!15 and the Pd0-catalysed
ꢀ
C H insertion reaction used to conjoin arenes B and D)
and a high step count. To address these concerns, we formu-
lated a new strategy based on robust coupling procedures
and employment of the principles of convergence and tele-
scoping to reduce the step count. The tactic, summarised in
Scheme 2, included a switch in the site of macrocyclisation
to between arenes A and B, as this allowed the constituent
arenes to be assembled by using a series of palladium-cata-
lysed coupling reactions and hydrogenation reactions. In
principle, these might then be sequenced on establishing an
appropriate catalyst system.
To that end, 4-fluorobenzaldehyde (arene A) and guaiacol
(22, arene C) were coupled by nucleophilic aromatic substi-
tution to give compound 23, which, on iodination, gave the
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Syntheses of Cavicularin and Riccardin C
FULL PAPER
this could be overcome by the use of the SPhos ligand of
Buchwald in conjunction with caesium carbonate,[22] this
combination proved to be a poor mediator of the subse-
quent Heck reaction with iodide 24 as this favoured ligand-
less conditions.[23]
The use of ring-closing metathesis for the macrocyclisa-
tion of compound 26 to 29 (via 32) was also examined but
without success. Exposure of bis-styrene 32 to the Grubbs II
catalyst gave rise to a complex product mixture from which
the dimer (E,E)-31 was isolated in 32% yield
(Scheme 5).[25,26] This failure can be attributed to the strain
in macrocycle 29 (see below) and related intermediates,
leading to reversibility and the promotion of the cross-meta-
thesis to stilbene 37.
Total synthesis of riccardin C: With a short entry to tetraar-
enes 26 and 27 in hand, we were well-placed to complete a
total synthesis of riccardin C. From the former it was possi-
ble to induce macrocyclisation directly by using a McMurry
reaction, with this giving the strained trans-stilbene 29 as the
main product in modest yield. Diol 28 was also recovered,
albeit heavily contaminated with copolar byproducts pre-
sumed to be derived from the reduction of THF
(Scheme 4).[24] Thus, the erythro stereochemistry ascribed to
compound 28 is based on its return following re-exposure to
the McMurry reagent, as the threo product would be expect-
ed to give (E)-29. From a synthetic perspective, either stil-
bene 29 or the crude product mixture could be transformed
into riccardin C through exposure to H2/Pd–C and global de-
protection of the aryl methyl ethers.
Total synthesis of cavicularin: Our final task was to develop
a second-generation synthesis of cavicularin with a linear
step count reduced to around half that employed previously.
Efficient macrocyclisation and a selective bromination pro-
cedure were therefore needed to enable transannular ring
contraction. Our plan was to facilitate both through a selec-
tive double halogenation of compound 27 to benzyl bromide
39. Though this seemed ambitious, we had observed a
marked preference for the para halogenation of anisoles in
related reactions involving linked aromatic ring systems.[27]
Scheme 4. New total syntheses of riccardin C.
The modest yields and capricious nature of the McMurry-
induced macrocyclisation prompted an exploration of alter-
native routes to compound 29. The phosphonium salt 30 was
readily obtained from alcohol 27 and smoothly underwent
macrocyclisation to (E)-29 on treatment with sodium meth-
oxide under pseudo-high dilution conditions (Scheme 4).[24]
Interestingly, when conducted at higher concentrations the
Wittig reaction gave the (Z,Z)-dimer 31 as a significant by-
product, with the alternative stereochemical preference.
Scheme 5. Ring-closing metathesis leading to (E,E)-31 by using the
Grubbs second-generation catalyst (1,3-bis(2,4,6-trimethylphenyl)-2-imi-
dazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ru-
thenium.
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D. C. Harrowven et al.
Of the thirteen unsubstituted aromatic carbons in tetraarene
27, only the desired site for bromination met this criterion.
Thus, exposure of 27 to bromine in glacial acetic acid gener-
ated dibromide 39 in 81% yield, with the tribromide 41
being formed as a minor byproduct. The latter, which could
be formed in higher yield by using bromine in excess, shows
how this preference for para bromination can even be
extend to diaryl ethers when in competition with ortho bro-
mination of an anisole.
Next, treatment of dibromide 39 with triphenylphosphine
gave phosphonium salt 40, which, on exposure to NaOMe
under conditions of pseudo-high dilution, afforded macrocy-
cle 43 in 69% yield (Scheme 6). The high yield is impressive
given the intrinsic strain in the product. As with trans-stil-
bene 29, an X-ray crystal structure of compound 43 revealed
a boat configuration in arene A akin to that in cavicularin
itself.[10] Furthermore, its trans-stilbene displays a torsional
angle of 1678 across the double bond, which in turn has
bond angles ranging from 115–1298 (Figure 3).
Figure 3. X-ray crystal structure of compound 43, showing the boat-con-
figured arene and the distorted trans-alkene.
Reduction of this alkene by catalytic hydrogenation addi-
tionally induced hydrogenolysis of the aryl bromide to give
riccardin C trimethyl ether 17. Over-reduction was eliminat-
ed by using diimide, allowing aryl bromide 42 to be formed
under microwave irradiation, conversion was complete
within 30 min to afford cavicularin trimethyl ether 15 and
riccardin C trimethyl ether 17 as an inseparable 2:5 mix-
ture.[28] Finally, removal of all six aryl methyl ethers with
boron tribromide gave cavicularin (5) and riccardin C (4), in
22 and 52% yield (over two steps), respectively.
in 96% yield. Attempts to transform this product into cavi-
0
ꢀ
cularin trimethyl ether 15 by a Pd -catalysed C H insertion
reaction failed, whereas its treatment under standard radi-
cal-forming conditions (Bu3SnH, VAZO, toluene, heating to
reflux) gave poor conversion even after prolonged heating
to reflux. However, by conducting the reaction at 1508C
Conclusion
In summary, short and practicable total syntheses of cavicu-
larin and riccardin C have been developed. The early stages
feature a sequence of four Pd0-catalysed coupling and hy-
drogenation reactions that enable the construction of the
acyclic precursors 26 and 27 in four linear steps and comple-
tion of the total synthesis of riccardin C in as few as seven
linear steps. For cavicularin, a short endgame involving mac-
rocyclisation (Wittig) and a radical-induced transannular
ring contraction is made possible by a humble double bro-
mination.
Experimental Section
Reagents were obtained commercially and used without further purifica-
tion unless indicated otherwise. Solvents were purified by standard proce-
dures prior to use. Reactions were performed under an argon atmosphere
in oven-dried glassware containing a Teflon-coated stirrer bar. Flash
column chromatography was carried out on silica gel (60 ꢁ, particle size
30–70 micron) with the solvent system used given in parentheses. TLC
analyses were performed on commercial 60 F254 silica gel plates. Melting
points were recorded on Reichert Austria apparatus and are uncorrected.
1H NMR spectra were recorded on either a Bruker AV-300 (300 MHz) or
DPX-400 (400 MHz) spectrometer operating at 298 K. Chemical shifts
are quoted in parts per million downfield of tetramethylsilane with resid-
ual solvent as the internal standard. Assignments were made on the basis
of chemical shift, coupling constants, aided in some cases by COSY,
HMQC, HMBC and comparison of spectra with that of related com-
Scheme 6. Second-generation total synthesis of cavicularin. VAZO=1,1’-
azobis(cyanocyclohexane).
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Syntheses of Cavicularin and Riccardin C
FULL PAPER
pounds. Coupling constants (J) are reported in hertz and are round to
the nearest 0.1 Hz. Infrared spectra were recorded neat as an oil film or
solid compression using the ATR/golden gate method. Absorption
maxima (n˜max) are quoted in wavenumbers (cmꢀ1). ESI mass spectra were
recorded using a ZMD quadrupole mass spectrometer measuring mono-
isotopic masses (mode: ES+ or ESꢀ). EI mass spectra were measured
on a Thermoquest Trace MS. m/z values are reported with their percent-
age abundance relative to the most intense signal. Values for the most
abundant isotope combination are reported.
Alternative procedure: To a solution of triflate 3 (4.00 g, 14.2 mmol) and
boronic acid 4 (2.54 g, 14.2 mmol) in dioxane (80 mL) LiCl (6.016 mg,
140.8 mmol), Cs2CO3 (23.10 g, 70.9 mmol) and SPhos (404 mg,
1.14 mmol) were added. The reaction mixture was degassed by sonication
under argon for 10 min, then PdACTHNUTRGNE(UNG OAc)2 (128 mg, 0.57 mmol) was added.
The reaction mixture was heated at reflux for 3 h, then cooled to RT and
partitioned between water (80 mL) and CH2Cl2 (100 mL). The aqueous
phase was separated and extracted with CH2Cl2 (2ꢂ100 mL). The com-
bined organic phases were concentrated in vacuo and purified by flash
column chromatography (2:1 petroleum ether/CH2Cl2) to afford the title
compound (1.96 g, 52%) as a yellow crystalline solid. M.p. (heptane/ethyl
acetate) 118–1208C; 1H NMR (300 MHz, CDCl3): d=9.75 (s, 1H), 7.50
(d, J=2.7 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.22 (d=7.7 Hz, 1H), 7.19
(dd=8.4, 2.8 Hz, 1H), 7.12 (dd, J=7.8, 1.4 Hz, 1H), 7.00 (d, J=1.2 Hz,
1H), 6.77 (dd, J=17.6, 10.9 Hz, 1H), 5.82 (d, J=17.6 Hz, 1H), 5.33 (d,
J=10.9 Hz, 1H), 3.90 (s, 3H), 3.77 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=192.6 (C), 159.4 (C), 156.9 (C), 139.4 (C), 136.5 (CH), 135.1
(C), 134.5 (C), 132.4 (CH), 131.9 (CH), 126.3 (C), 121.4 (CH), 119.3
(CH), 114.8 (CH2), 109.6 (CH), 108.4 (CH), 55.7 (CH3), 55.6 ppm (CH3);
IR (solid): n˜ =3004, 2936, 2838, 1686, 1603, 1486, 1393, 1266, 1246,
1035 cmꢀ1; MS (ES+): m/z (%): 559 [2M+Na]+ (9), 291 [M+Na]+ (100);
HRMS (ES+): m/z calcd for C17H16O3Na: 282.0173; found: 291.0994.
15,16-Dihydro-1,12,23-trimethoxy-6,8:17,20-dietheno-21-oxa-
benzo[g]naphthaACHTUNGTRENNUNG
[1,8-bc]cyclotetradecine (16):[13] A solution of iodide 11
(65 mg, 0.11 mmol) and tributyltin hydride (0.036 mL, 0.13 mmol) in tolu-
ene (30 mL) was heated to 908C, then AIBN (32 mg, 0.20 mmol) was
added. After 2.5 h the reaction mixture was cooled and stirred vigorously
with an aqueous solution of KF (10%, 20 mL) for 30 min. The aqueous
phase was separated and extracted with diethyl ether (3ꢂ30 mL). The
combined organic phases were then dried (MgSO4), filtered and concen-
trated in vacuo. Purification by column chromatography (9:1 petroleum
ether/diethyl ether then separately CH2Cl2). HPLC (1:4 EtOAc/hexane
and recrystallisation (EtOH) afforded the title compound (12 mg,
0.026 mmol, 24%) as a white solid. M.p. (EtOH) 218–2208C; 1H NMR
(400 MHz, CDCl3): d=7.72 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H),
7.49 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.41 (s, 1H), 7.03 (s,
1H), 6.93 (d, J=2.0 Hz, 1H), 6.89 (dd, J=8.3, 2.5 Hz, 1H), 6.79–6.76 (m,
1H), 6.32 (dd, J=8.5, 2.3 Hz, 1H), 6.21 (dd, J=8.3, 2.0 Hz, 1H), 5.73
(dd, J=8.3, 2.5 Hz, 1H), 4.07 (s, 3H), 3.92 (s, 3H), 3.82 (s, 3H), 2.99 (dt,
J=12.8, 3.7 Hz, 1H), 2.85 (dt, J=12.8, 3.7 Hz, 1H), 2.63 (td, J=12.8,
3.7 Hz, 1H), 2.01 ppm (td, J=12.8, 3.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=159.0 (C), 155.6 (C), 154.9 (C), 152.1 (C), 142.7 (C), 139.8
(C), 134.7 (C), 133.8 (C), 132.0 (C), 131.3 (CH), 130.6 (CH), 130.2 (CH),
129.1 (C), 128.3 (CH), 128.2 (C), 127.8 (CH), 125.5 (CH), 124.9 (CH),
122.7 (C), 121.0 (C), 117.9 (CH), 115.2 (CH), 113.1 (2ꢂCH), 111.5 (CH),
106.5 (CH), 57.5 (CH3), 55.6 (CH3), 38.3 (CH2), 38.3 ppm (CH2); UV
4-(2-Methoxyphenoxy)benzaldehyde (23):[29] To a solution of 2-methoxy-
phenol (22) (5.00 g, 40.3 mmol) and 4-fluorobenzaldehyde (5.50 g,
44.4 mmol, 4.78 mL) in DMF (25 mL) K2CO3 (6.12 g, 44.4 mmol) was
added. The reaction mixture was heated at reflux for 24 h, then cooled to
RT and poured onto ice (50 mL). The resultant emulsion was extracted
with ethyl acetate (3ꢂ50 mL), then the combined organic phases were
washed with brine (50 mL), dried over MgSO4 and concentrated in
vacuo. Purification by flash column chromatography (chloroform) afford-
1
ed the title compound (8.40 g, 91%) as a yellow oil. H NMR (400 MHz,
CDCl3): d=9.90 (s, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.24 (ddd, J=8.1, 7.4,
1.8 Hz, 1H), 7.10 (dd, J=8.1, 1.5 Hz, 1H), 7.05 (dd, J=8.3, 1.3 Hz, 1H),
7.00 (obscured m, 1H), 6.99 (d, J=8.5 Hz, 2H), 3.79 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=191.0 (C), 163.9 (C), 152.0 (C), 143.2
(C), 132.1 (2ꢂCH), 131.2 (C), 126.7 (CH), 122.9 (CH), 121.7 (CH), 116.5
(2ꢂCH), 113.4 (CH), 56.2 ppm (CH3); IR (neat): n˜ =1692, 1599, 1570,
1487, 1261, 1222, 1176, 1152, 1131 cmꢀ1; MS (EI, 70 eV): m/z (%): 228
[M+] (100), 207 (30), 185 (20), 184 (18), 128 (42), 114 (38), 77 (55), 51
(42).
(CH2Cl2):
l
(emax)=320
(15000),
274
(50700),
230 nm
(42600 molꢀ1 dm3 cmꢀ1); IR (solid): n˜ =2920, 1600, 1498, 1275, 1228, 1104,
1040, 930, 845 cmꢀ1; MS (ES+): m/z (%): 949 [2M+Na]+ (20), 485
[M+Na]+ (100), 236 (70), 227 (70); HRMS (ES+): m/z calcd for
C31H26NaO4: 485.1723; found: 485.1726; X-ray: see Figure 1.
2-Methoxy-4-vinylphenyltrifluoromethane sulfonate (19): To a solution of
trifluoromethanesulfonic anhydride (2.45 g, 16.3 mmol) in CH2Cl2
(30 mL) at 08C, a solution of 4-hydroxy-3-methoxystyrene 18 (5.07 g,
18.0 mmol) and pyridine (1.55 g, 19.6 mmol) in CH2Cl2 (30 mL) was
added over 1 h, while keeping the reaction temperature at 08C. After a
further 3 h, ice water (50 mL) was added and the phases were separated.
The organic phase was washed with saturated aqueous NaHCO3 (50 mL)
then dried over MgSO4 and concentrated in vacuo. Purification by flash
column chromatography (CH2Cl2) afforded the title compound (4.03 g,
88%) as colourless oil. 1H NMR (300 MHz, CDCl3): d=7.18 (d, J=
8.3 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 7.01 (dd, J=8.3, 1.9 Hz, 1H), 6.69
(dd, J=17.5, 10.8 Hz, 1H), 5.77 (d, J=17.5 Hz, 1H), 5.35 (d, J=10.8 Hz,
1H), 3.94 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=151.6 (C), 139.1
4-(5-Iodo-2-methoxyphenoxy)benzaldehyde (24): To a solution of 4-(me-
thoxyphenoxy)benzaldehyde (23) (2.00 g, 9.4 mmol) in CH2Cl2 (20 mL)
was added a solution of ICl (1.83 g, 11.3 mmol) in CH2Cl2 (5 mL). Light
was excluded for seven days, then saturated aqueous solution of Na2S2O3
(15 mL) was added. After 1 h the biphasic solution was separated and
the aqueous phase was extracted with diethyl ether (10 mL + 50 mL).
The combined organic phases were washed with water (50 mL) and brine
(50 mL), then dried over MgSO4 and concentrated in vacuo to afford the
title compound (3.31 g, quantitative) as an orange gum, which crystallised
1
on standing. M.p. (CH2Cl2) 488C sharp; H NMR (400 MHz, CDCl3): d=
9.82 (s, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.43 (dd, J=8.6, 2.1 Hz, 1H), 7.30
(d, J=2.1 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.70 (d, J=8.6 Hz, 1H),
3.68 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=190.7 (C), 163.0 (C),
152.0 (C), 143.9 (C), 135.3 (CH), 132.0 (2ꢂCH), 131.4 (C), 131.2 (CH),
116.5 (2ꢂCH), 115.0 (CH), 82.0 (C), 56.1 ppm (CH3); IR (solid): n˜ =
1682, 1598, 1582, 1495, 1464, 1264, 1227, 1175, 1162, 1153, 1110, 1041,
1024, 769 cmꢀ1; MS (EI, 70 eV): m/z (%): 354 [M+] (100), 207 (19), 184
(24), 128 (14), 79 (31), 51 (18).
(C), 138.3 (C), 135.7 (CH), 122.6 (CH), 119.0 (CH), 118.9 (q, JACTHNUTRGNEU(GN C,F)=
320.7 Hz, CF3), 116.1 (CH2), 110.7 (CH), 56.3 ppm (CH3); 19F NMR
(282 MHz, CDCl3): d=ꢀ74.13 ppm (CF3); IR (neat): n˜ =1601, 1502,
1415, 1200, 1135, 1104, 858, 819 cmꢀ1; MS (EI, 70 eV): m/z (%): 282 [M]+
(23), 149 (82), 121 (34), 103 (28), 91 (67), 69 (100%); HRMS (ES+): m/z
calcd for C10H9O4F3S: 282.0173; found: 282.0167.
2’,4-Dimethoxy-4’-vinylbiphenyl-2-carbaldehyde (21): To a solution of tri-
flate 19 (78 mg, 0.28 mmol) and boronic acid 20 (10 mg, 0.55 mmol) in di-
oxane (2 mL), LiCl (117 mg, 2.77 mmol), Cs2CO3 (326 mg, 1.11 mmol)
and SPhos (44 mg, 0.11 mmol) were added. The reaction mixture was de-
gassed by sonication under argon for 5 min. PdCl2 (5 mg, 0.027 mmol)
was added and the reaction mixture was heated at reflux for 3 h. The re-
action mixture was cooled to RT, filtered through a glass sinter, then
silica (ꢁ1 g) was added to the filtrate and the solvent was removed in
vacuo. Purification by flash column chromatography (4:1 petroleum
ether/diethyl ether) afforded the title compound (55 mg, 76%) as an off-
white solid.
2’,4-Dimethoxy-4’-[3-(4-formyl-phenoxy)-4-methoxy-phenyl-vinyl]-bi-
phenyl-2-carbaldehyde (25): To
a solution of the biaryl 21 (1.30 g,
4.49 mmol) and ether 24 (1.64 g, 4.49 mmol) in dioxane (30 mL) triethyla-
mine (1.96 g, 19.40 mmol) was added. The reaction mixture was degassed
by sonication for 10 min under argon then PdACTHNURGTNEUNG(OAc)2 (43 mg,
0.019 mmol) was added. The reaction mixture was heated at reflux for
19 h, then cooled to RT and the solvent was removed in vacuo. Purifica-
tion of the residue by flash column chromatography (9:1!3:2 heptane/
ethyl acetate) afforded the title compound (2.00 g, 83%) as a white solid.
M.p. (petroleum ether) 94–958C; 1H NMR (400 MHz, CDCl3): d=9.94
Chem. Eur. J. 2011, 17, 10906 – 10915
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10911

D. C. Harrowven et al.
(s, 1H), 9.77 (s, 1H), 7.86 (d, J=8.9 Hz, 2H), 7.51 (d, J=2.8 Hz, 1H),
7.40 (dd, J=8.5, 1.9 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.30 (d, J=8.5 Hz,
1H), 7.25 (d, J=7.9 Hz, 1H), 7.23–7.18 (m, 3H), 7.10 (d, J=16.3 Hz,
1H), 7.07–7.04 (m, 3H), 7.01 (d, J=16.3 Hz, 1H), 3.91 (s, 3H), 3.84 (s,
3H), 3.79 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=192.5 (C), 190.9
(C), 163.6 (C), 159.4 (C), 157.1 (C), 151.7 (C), 143.4 (C), 139.1 (C), 135.1
(C), 134.4 (C), 132.6 (CH), 132.1 (2ꢂCH), 132.1 (CH), 131.3 (C), 128.2
(CH), 127.6 (CH), 126.2 (C), 125.3 (CH), 121.4 (CH), 120.3 (CH), 119.5
(CH), 116.5 (2ꢂCH), 113.4 (CH), 109.7 (CH), 108.5 (CH), 56.3 (CH3),
55.8 (CH3), 55.6 ppm (CH3), one carbon atom was not observed; IR
(solid): n˜ =2934, 2839, 1689, 1600, 1501, 1271, 1227, 1155, 1032 cmꢀ1; MS
(ES+): m/z (%): 1011 [2M+Na]+ (37), 517 [M+Na]+ (100), 183 (99), 192
(70); HRMS (ES+): m/z calcd for C31H26NaO6: 517.1622; found:
517.1615.
The aqueous phase was separated and extracted with chloroform
(15 mL). The combined organic phases were dried (Na2SO4), filtered and
concentrated in vacuo. The residue was dissolved in CH2CL2 (15 mL) and
methanol (15 mL) then palladium on carbon (5%, 150 mg) was added.
The flask was evacuated and purged with argon three times, then evacu-
ated and purged with hydrogen twice. After 1 h, the reaction mixture was
filtered through Celite. The filtrate was concentrated in vacuo then puri-
fied by flash column chromatography (3:7 diethyl ether/petroleum ether)
to afford the title compound (30 mg, 40%) as a viscous oil, which crystal-
lised on trituration with petroleum ether. M.p. (petroleum ether) 153–
1548C (Lit. 1558C (EtOH);[10c] 155–1568C (solvent not specified);[13] Lit.
1948C (EtOH);[10c] 199–2008C (EtOH)[13] 205–2068C (solvent not speci-
fied;[10d] 1648C (solvent not specified;[10f])); 1H NMR (400 MHz, CDCl3):
d=7.07 (d, J=8.5 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H), 6.89 (d, J=8.1 Hz,
1H), 6.86–6.70 (m, 7H), 6.45 (d, J=1.3 Hz, 1H), 6.25 (dd, J=7.6, 1.6 Hz,
1H), 5.37 (d, J=2.0 Hz, 1H), 3.95 (s, 3H), 3.98 (s, 3H), 3.68 (s, 3H),
3.01–2.75 (m, 5H), 2.71–2.54 ppm (m, 3H); 13C NMR (100 MHz, CDCl3):
d=159.3 (C), 156.1 (C), 152.9 (C), 148.8 (C), 147.1 (C), 143.4 (C), 141.4
(C), 139.9 (C), 134.0 (C), 132.6 (2ꢂCH), 131.1 (C), 129.5 (CH, heavily at-
tenuated), 129.4 (CH, heavily attenuated), 127.8 (C), 122.5 (2ꢂCH),
121.9 (CH), 121.6 (CH), 116.8 (CH), 115.6 (CH), 112.0 (CH), 111.6
(CH), 111.3 (CH), 56.3 (CH3), 55.4 (2ꢂCH3), 38.4 (CH2), 38.3 (CH2),
37.4 (CH2), 35.8 ppm (CH2); IR (solid): n˜ =2926, 1604, 1505, 1463, 1261,
1231, 1164, 1128, 1040 cmꢀ; MS (ES+): m/z (%): 956 [2M+Na]+ (23),
489 [M+Na]+ (100).
2’,4-Dimethoxy-4’-{2-[3-(4-formylphenoxy)-4-methoxyphenyl]-ethyl}-bi-
phenyl-2-carbaldehyde (26): To solution of the dialdehyde 25 (140 mg,
0.28 mmol) in THF (30 mL) palladium on carbon (5%, 280 mg) was
added. The flask was evacuated/purged with argon three times, then
evacuated/purged with hydrogen twice under vigorous stirring. After
10 min the reaction mixture was filtered through Celite and the filtrate
was concentrated in vacuo. Purification by flash column chromatography
(2:3 diethyl ether/petroleum ether) afforded the title compound (133 mg,
1
95%) as a white solid. M.p. (EtOAc/petroleum ether) 38–398C; H NMR
(400 MHz, CDCl3): d=9.78 (s, 1H), 9.60 (s, 1H), 7.70 (d, J=8.8 Hz,
2H), 7.39 (d, J=2.6 Hz, 1H), 7.18–7.12 (m, 2H), 7.09 (dd, J=8.4, 2.8,
1H), 7.05 (d, J=7.7 Hz, 1H), 6.98 (dd, J=8.4, 2.0 Hz, 1H), 6.90–6.85 (m,
3H), 6.81 (d, J=2.0 Hz, 1H), 6.76 (dd, J=7.6, 1.3 Hz, 1H), 3.81 (s, 3H),
3.69 (s, 3H), 3.60 (s, 3H), 2.87 ppm (apparent s, 4H); 13C NMR
(100 MHz, CDCl3): d=192.9 (C), 191.1 (C), 164.0 (C), 159.5 (C), 157.0
(C), 150.4 (C), 143.8 (C), 143.0 (C), 135.3 (C), 135.3 (C), 135.0 (C), 132.9
(CH), 132.3 (2 x CH), 131.9 (CH), 131.3 (C), 126.7 (CH), 124.7 (C), 123.2
(CH), 121.6 (CH), 121.5 (CH), 116.6. (CH), 116.5 (CH), 113.5 (CH),
111.4 (CH), 109.9 (CH), 56.5 (CH3), 56.0 (CH3), 55.8 (CH3), 38.5 (CH2),
37.2 ppm (CH2); IR (solid): n˜ =2938, 1689, 1602, 1578, 1509, 1488, 1273,
AHCTUNGTRENNUNG
a
(15 mg, 0.27 mmol) in CH2Cl2 (5 mL) a solution of phosphonium salt 30
(112 mg, 0.137 mmol) in CH2Cl2 (10 mL) was added dropwise over 4 h.
After 18 h at RT, the reaction mixture was heated at reflux for 1 h, then
cooled to RT and filtered. Silica (ꢁ4 g) was added and the solvent was
removed in vacuo. Purification by flash column chromatography (7:3!
2:3 petroleum ether/diethyl ether) firstly afforded trans-stilbene 29
1227, 1156 cmꢀ1
;
MS (ES+): m/z (%): 1015 [2M+Na]+ (97), 519
(30 mg, 47%) as
a
white solid. M.p. (CHCl3) 139–1408C; 1H NMR
[M+Na]+ (100).
(400 MHz, CDCl3): d=7.24 (d, J=8.5 Hz, 1H), 7.22–7.11 (m, 2H), 7.02
(d, J=3.0 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 6.92–6.88 (m, 2H), 6.86 (d,
J=8.0 Hz, 1H), 6.79 (dd, J=8.5, 2.0 Hz, 1H), 6.63 (d, J=7.5 Hz, 1H),
6.58 (d, J=16.1 Hz, 1H), 6.52 (s, 1H), 6.04 (d, J=16.1 Hz, 1H), 5.77 (d,
J=2.0 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.66 (s, 3H), 2.97–2.75 ppm
(m, 4H); 13C NMR (100 MHz, CDCl3): d=158.9 (C), 156.6 (C), 155.4
2’,4-Dimethoxy-4’-{2-[3-(4-hydroxymethylphenoxy)-4-methoxyphenyl]-
ethyl}-biphenyl-2-carbaldehyde (27): To solution of dialdehyde 25
(230 mg, 0.47 mmol) in CH2Cl2 (20 mL) and methanol (20 mL) palladium
on carbon (10%, 460 mg) was added. The flask was evacuated/purged
with argon three times, then evacuated/purged with hydrogen twice with
vigorously stirring. After 20 min the reaction mixture was filtered
through Celite and the filtrate was concentrated in vacuo. Purification by
flash column chromatography (2:3 diethyl ether/petroleum ether) afford-
ed the title compound (206 mg, 89%) as
a
white foam. 1H NMR
(300 MHz, CDCl3): d=9.66 (s, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.29–7.23
(m, 2H), 7.19 (dd, J=8.4, 2.6 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.98–6.88
(m, 3H), 6.89 (d, J=8.8 Hz, 2H), 6.83 (dd, J=7.7, 1.5 Hz, 1H), 6.78 (d,
J=1.8 Hz, 1H), 6.69 (d, J=1.5 Hz, 1H), 4.62 (s, 2H), 3.90 (s, 3H), 3.83
(s, 3H), 3.68 (s, 3H), 2.95–2.88 ppm (m, 4H); 13C NMR (75 MHz,
CDCl3): d=192.7 (C), 159.0 (C), 157.6 (C), 156.4 (C), 149.8 (C), 144.5
(C), 143.5 (C), 134.9 (C), 134.8 (C), 134.7 (C), 134.5 (C), 132.5 (CH),
131.4 (CH), 128.5 (2ꢂCH), 124.8 (CH), 124.1 (C), 121.5 (CH), 121.3
(CH), 121.1 (CH), 117.0 (2ꢂCH), 112.8 (CH), 111.0 (CH), 109.3 (CH),
64.9 (CH2), 56.1 (CH3), 55.6 (CH3), 55.3 (CH3), 38.1 (CH2), 36.8 ppm
(CH2); IR (neat): n˜ =3434, 2935, 2837, 1686, 1605, 1505, 1269, 1222, 1163,
1125, 1035, 1002 cmꢀ1; MS (ES+): m/z (%): 1019 [2M+Na]+ (33), 521
[M+Na]+ (100); HRMS (ES+): m/z calcd for C31H30NaO6: 521.1935;
found: 521.1935.[21]
1,2,13,14-Tetrahydro-9,17,22-trimethoxy-3,6-etheno-15,18-etheno-8,12-
metheno-12H-7-benzooxacycloeicosine (17): To an aliquot of THF
(5 mL) at ꢀ788C containing magnesium (80 mg, 3.29 g) titanium tetra-
chloride (666 mg, 3.51 mmol, 0.39 mL) was added dropwise over 5 min.
The reaction was allowed to warm to RT over 2 h then the resultant
black solution was re-cooled to ꢀ788C. A solution of bisaldehyde 26
(81 mg, 0.163 mmol) in THF (10 mL) was added dropwise over 10 min
then the cooling bath was removed. After 19 h at RT the reaction mix-
ture was partitioned between water (15 mL) and chloroform (15 mL).
10912
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10906 – 10915

Syntheses of Cavicularin and Riccardin C
FULL PAPER
(C), 150.4 (C), 147.4 (C), 142.5 (C), 139.4 (C), 138.6 (C), 137.9 (CH),
135.8 (C), 131.9 (CH), 131.5 (C), 130.7 (C), 130.1 (CH), 127.4 (CH),
127.2 (CH), 127.0 (CH), 122.6 (CH), 122.6 (CH), 122.5 (CH), 119.6
(CH), 116.0 (CH), 112.5 (CH), 111.9 (CH), 110.4 (CH), 110.3 (CH), 56.2
(CH3), 55.4 (CH3), 55.3 (CH3), 36.2 (CH2), 33.7 ppm (CH2); IR (solid):
n˜ =2933, 1602, 1510, 1500, 1260, 1227, 1161, 1126 cmꢀ; MS (ES+): m/z
(%): 953 [2M+H]+ (34), 505 (57), 483 [M+H]+ (100); HRMS (ES+):
m/z calcd for C31H29O4: 465.2050; found: 465.2054.
0.38 mmol) was added. After 20 min, bisaldehyde 26 (47 mg, 0.097 mmol)
was added as a solution in THF (1 mL). The reaction was allowed to
warm to RT and after 1.5 h the reaction mixture was partitioned between
saturated aqueous NH4Cl solution (1 mL) and CH2Cl2 (2 mL). The
phases were separated and the aqueous phase was extracted with CH2Cl2
(2ꢂ2 mL). The combined organic phases were washed with brine (5 mL),
dried over MgSO4, filtered and concentrated in vacuo. Purification by
flash column chromatography (9:1 petroleum ether/ethyl acetate) afford-
ed the title compound (34 mg, 73%) as
a
colourless oil. 1H NMR
Then the title compound (12 mg, 19%) was obtained as a crystalline
solid. M.p. (CH2Cl2/petroleum ether) 114–1168C; 1H NMR (300 MHz,
CDCl3): d=7.17–7.06 (m, 6H), 6.94–6.61 (m, 14H), 6.49 (s, 2H), 6.21 (d,
J=12.1 Hz, 2H), 6.15 (d, J=12.1 Hz, 2H), 3.82 (s, 6H), 3.62 (s, 6H), 3.51
(s, 6H), 2.91–2.84 ppm (brs, 6H); 13C NMR (100 MHz, CDCl3): d=156.6
(2ꢂC), 156.1 (2ꢂC), 148.9 (2ꢂC), 145.3 (2ꢂC), 141.6 (2ꢂC), 138.2 (2ꢂ
C), 134.2 (2ꢂC), 131.9 (2ꢂCH), 131.5 (2ꢂCH), 131.3 (2ꢂCH), 130.7 (2ꢂ
C), 130.7 (2ꢂC), 103.4 (4ꢂCH), 129.6 (2ꢂCH), 128.7 (2ꢂC), 127.3 (2ꢂ
C), 123.8 (2ꢂCH), 120.6 (2ꢂCH), 120.1 (2ꢂCH), 117.7 (4ꢂCH), 113.7
(2ꢂCH), 113.5 (2ꢂCH), 112.7 (2ꢂCH), 111.3 (2ꢂCH), 56.1 (2ꢂCH3),
55.2 (2ꢂCH3), 55.1 (2ꢂCH3), 37.8 (2ꢂCH2), 36.6 ppm (2ꢂCH2); IR
(solid): n˜ =2933, 1602, 1504, 1463, 1422, 1270, 1227, 1167, 1125,
1038 cmꢀ1; MS (ES+): m/z (%): 952 [M+H]+ (13), 268 (13), 217 (100);
HRMS (ES+): m/z calcd for C62H56NaO8: 951.3867; found: 951.3865.
(400 MHz, CDCl3): d=7.35 (d, J=8.5 Hz, 2H), 7.19 (d, J=2.5 Hz, 1H),
7.13 (d, J=8.5 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H); 6.99 (dd, J=8.0, 2.0 Hz,
1H); 6.97–6.93 (m, 2H); 6.91–6.85 (m, 3H), 6.79 (dd, J=7.5, 1.5 Hz,
1H), 6.71 (s, 1H), 6.70 (dd, J=17.6, 11.0 Hz, 1H), 6.49 (dd, J=17.6,
11.0 Hz, 1H), 5.65 (dd, J=17.6, 1.0 Hz, 1H), 5.64 (dd, J=17.6, 1.0 Hz,
1H), 5.17 (d, J=11.0 Hz, 1H), 5.11 (dd, J=11.0, 1.0 Hz, 1H), 3.88 (s,
3H), 3.83 (s, 3H), 3.70 (s, 3H), 2.91 ppm (apparent s, 4H); 13C NMR
(100 MHz, CDCl3): d=150.0 (C), 144.5 (C), 142.2 (C), 137.5 (C), 136.1
(CH), 135.8 (CH), 135.7 (C), 135.7 (C), 134.9 (C), 132.0 (C), 131.7 (CH),
131.7 (CH), 130.3 (C), 130.0 (C), 127.4 (2ꢂCH), 127.1 (C), 124.7 (CH),
121.4 (CH), 120.4 (CH), 117.2 (C), 117.0 (2ꢂCH), 113.8 (CH2), 113.4
(CH), 112.9 (CH), 112.3 (CH2), 111.2 (CH), 109.7 (CH), 56.1 (CH3), 55.5
(CH3), 55.3 (CH3), 38.1 (CH2), 36.9 ppm (CH2); IR (neat): n˜ =2933, 1603,
1505, 1271, 1225, 1166, 1032, 1002, 908 cmꢀ1; MS (ES+): m/z (%): 515
[M+Na]+ (100); HRMS (ES+): m/z calcd for C33H32NaO4: 515.2193;
found: 515.2189.
3’-Bromo-4,6’-dimethoxy-2-formyl-4’-{2-[3-(4-bromomethylphenoxy)-4-
methoxyphenyl]ethyl}biphenyl (39): To
a solution of tetraarene 27
(95 mg, 0.19 mmol) in glacial acetic acid (2 mL) a solution of bromine
(34 mg, 0.23 mmol) in glacial acetic acid (1 mL) was added. After 64 h at
RT, water (2 mL) and then saturated aqueous Na2S2O3 solution (2 mL)
were added. the obtained solution was extracted with CH2Cl2 (3ꢂ10 mL)
and the combined organic phases were dried over MgSO4. The solvent
was removed in vacuo to give the title compound (99 mg, 81%) as a col-
ourless oil, which was used without further purification.
4-(5-[2-{5-Bromo-2,4’-dimethoxy-2-formylbiphenyl}-ethyl]-2-methoxy
phenoxy)-benzyl triphenylphosphonium bromide (40): A solution of di-
bromide 39 (99 mg, 0.16 mmol) and triphenylphosphine (81 mg,
0.31 mmol) in toluene (10 mL) was heated at reflux for 18 h, then cooled
to 08C. Filtration of the reaction mixture gave the title compound
(129 mg, 93%) as a white solid. 1H NMR (400 MHz, CDCl3): d=9.70 (s,
1H), 7.80–7.69 (m, 7H), 7.67–7.60 (m, 4H), 7.55–7.38 (m, 5H), 7.28–7.14
(m, 5H), 7.07–6.97 (m, 2H), 6.92 (d, J=7.5 Hz, 1H), 6.85–6.75 (m, 1H),
6.72 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 5.40 (br. s, 2H), 3.88 (s, 3H), 3.80
(s, 3H), 3.63 (s, 3H), 3.04–2.83 ppm (m, 4H); IR (neat): n˜ =3382, 2930,
2849, 1689, 1604, 1505, 1438, 1270, 1225, 1112 cmꢀ1; MS (ES+) m/z (%):
ACHTUNGTRENNUNG(1E,25E)-13,14,37,38-Tetrahydro-9,17,22,33,41,46-hexamethoxy-
3,7:15,18:27,30:39,42-tetraethano-8,12:32,36-dimethano-dibenzo-[7,31-
dioxa-s-m]-cyclo-tetracontine ((E,E)-31): A solution of bis-styrene 32
(179 mg, 0.37 mmol) and the Grubbs second generation catalyst (5 mg,
0.06 mmol) in CH2Cl2 was heated at reflux for 1 h and then cooled to RT.
Further catalyst was added (5 mg, 0.06 mmol) and the resulting solution
was heated at reflux for another 17 h. A third batch of catalyst (5 mg,
0.06 mmol) was added and after a further 2 h heating at reflux the reac-
tion mixture was cooled to RT and concentrated in vacuo. Purification by
flash column chromatography (7:3 petroleum ether/diethyl ether) afford-
ed the title compound (38 mg, 20%) as a white crystalline solid in addi-
tion to unidentified higher oliogmers and isomers. M.p. (CH2Cl2/MIBK/
petroleum ether; MIBK=methyl isobutyl ketone) 139–1408C; 1H NMR
(400 MHz, CDCl3): d=7.29–7.27 (m, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.17
(d, J=9.0 Hz, 2H), 7.10–7.00 (obscured m, 2H), 7.08 (d, J=7.5 Hz, 2H),
7.03 (dd, J=8.5, 2.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 2H), 6.92–6.80 (m,
10H), 6.77 (d, J=1.5 Hz, 2H), 6.72 (d, J=16.6 Hz, 2H), 3.91 (s, 6H),
3.83 (s, 6H), 3.70 (s, 6H), 2.89 pm (s, 8H); 13C NMR (100 MHz, CDCl3):
d=158.9 (2ꢂC), 157.5 (2ꢂC), 156.9 (2ꢂC), 149.7 (2ꢂC), 144.7 (2ꢂC),
142.4 (2ꢂC), 137.2 (2ꢂC), 135.0 (2ꢂCH), 132.2 (2ꢂC), 131.9 (2ꢂCH),
131.9 (2ꢂC), 130.5 (2ꢂC), 127.9 (2ꢂCH), 127.6 (4ꢂCH), 127.3 (2ꢂCH),
124.6 (2ꢂCH), 121.2 (2ꢂCH), 120.5 (2ꢂCH), 117.1 (4ꢂCH), 113.1 (2ꢂ
CH), 113.1 (2ꢂCH), 111.2 (2ꢂCH), 109.5 (2ꢂCH), 56.2 (2ꢂCH3), 55.6
(2ꢂCH3), 55.3 (2ꢂCH3), 38.8 (2ꢂCH2), 37.5 ppm (2ꢂCH2), two carbon
atoms were not observed; IR (solid): n˜ =2932, 1600, 1504, 1463, 1271,
1226, 1166, 1125, 1038, 810, 731 cmꢀ1; MS (ES+): m/z (%): 951 [M+Na]+
(7), 426 (46), 219 (100).
823 [M
N
U
calcd for C49H43BrO5P: 821.2026; found: 821.2026.
(E)-13,14-Dihydro-9,17,22-trimethoxy-3,6-etheno-15,18-bromoetheno-
8,12-metheno-12H-7-benzooxacycloeicosine (43): To
a
solution of
NaOMe (2 mg, 0.04 mmol) in CH2Cl2 (0.5 mL) a solution of phosphoni-
um salt 40 (18 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) was added dropwise
over 20 min. After 4 h, the reaction mixture was heated at reflux for 18 h,
then cooled to RT and silica (ꢁ1 g) was added. Concentration in vacuo
and purification by column chromatography (4:1 petroleum ether/diethyl
ether) afforded the title compound (7.5 mg, 69%) as a white crystalline
solid. M.p. (CH2Cl2/petroleum ether) 196–1978C; 1H NMR (300 MHz,
CDCl3): d=7.25 (obscured m, 1H), 7.24 (s, 1H), 7.20 (d, J=8.4 Hz, 1H),
7.16 (dd, J=8.5, 2.7 Hz, 1H), 7.03–6.95 (m, 3H), 6.89 (d, J=8.2 Hz, 1H),
6.92–6.86 (m, 1H), 6.80 (dd, J=8.2, 2.0 Hz, 1H), 6.58 (d, J=16.1 Hz,
1H), 6.43 (s, 1H), 6.10 (d, J=16.1 Hz, 1H), 5.73 (d, J=2.0 Hz, 1H), 3.97
(s, 3H), 3.86 (s, 3H), 3.56 (s, 3H), 3.15–2.94 (m, 2H), 2.87–2.70 ppm (m,
2H); 13C NMR (100 MHz, CDCl3): d=159.5 (C), 156.1 (C), 155.5 (C),
150.5 (C), 147.6 (C), 141.1 (C), 139.7 (C), 138.6 (C), 136.4 (CH), 135.5
(C), 134.9 (CH), 131.5 (CH), 130.2 (C), 130.0 (CH), 129.9 (C), 127.7
(CH), 127.5 (CH), 123.7 (CH), 122.9 (CH), 122.1 (CH), 116.0 (CH),
114.7 (C), 112.9 (CH), 112.1 (CH), 111.4 (CH), 110.8 (CH), 56.4 (CH3),
55.8 (CH3), 55.5 (CH3), 37.1 (CH2), 33.21 ppm (CH2); IR (solid): n˜ =
2921, 2810, 1505, 1437, 1260, 1217, 1161, 1120, 1028, 718 cmꢀ1; MS (ES+):
2’,4-Dimethoxy-2-vinyl-4’-{2-[3-(4-vinylphenoxy)-4-methoxyphenyl]-eth-
yl}biphenyl (32): To a stirred suspension of methyltriphenylphosphonium
bromide (135 mg, 0.38 mmol) in THF (1 mL) at 08C KOtBu (42 mg,
Chem. Eur. J. 2011, 17, 10906 – 10915
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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10913

D. C. Harrowven et al.
m/z (%): 1107 [2M+Na]+ (23), 565 [M+Na]+ (86), 301 (27), 183 (71);
HRMS (ES+): m/z calcd for C31H27BrNaO4: 565.0985; found: 565.0970.
For the X-ray crystal structure see Figure 3.
133.1 (CH), 131.6 (CH), 129.4 (2ꢂCH, heavily attenuated), 128.5 (C),
124.5 (C), 122.4 (2ꢂCH, heavily attenuated), 122.4 (CH), 121.9 (CH),
117.7 (CH), 116.2 (CH), 116.2 (CH), 115.1 (CH), 114.5 (CH), 38.3 (CH2),
38.0 (CH2), 37.3 (CH2), 35.2 ppm (CH2); IR (solid): n˜ =3408, 2926, 1605,
1,2,13,14-Tetrahydro-9,17,22-trimethoxy-3,6-etheno-15,18-bromoetheno-
8,12-metheno-12H-7-benzooxacycloeicosine (42): A solution of trans-stil-
bene 43 (163 mg, 0.30 mmol), tosylhydrazone (559 mg, 3.00 mmol) and
NaOAc (246 mg, 3.00 mmol) in aqueous THF (1:1 v/v, 20 mL) was
heated at reflux for 7 days and then cooled to RT. A saturated aqueous
K2CO3 solution (10 mL) was added followed after 3 h stirring by the ad-
dition of CH2Cl2 (10 mL). The aqueous phase was separated and extract-
ed with CH2Cl2 (3ꢂ10 mL), then the combined organic phases were
dried over Na2SO4 and concentrated in vacuo. Purification by flash
column chromatography (4:1 petroleum ether/diethyl ether) afforded the
title compound (157 mg, 96%) as a white foam. 1H NMR (400 MHz,
CDCl3): d=7.15 (s, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.96 (d, J=2.7 Hz,
1H), 6.90 (d, J=8.2 Hz, 1H), 6.87–6.78 (m, 5H), 6.72 (brdd, J=8.5,
2.1 Hz, 1H), 6.34 (s, 1H), 5.37 (d, J=2.1 Hz, 1H), 3.96 (s, 3H), 3.89 (s,
3H), 3.63 (s, 3H), 3.16–3.00 (m, 2H), 2.94–2.81 (m, 3H), 2.78–2.61 ppm
(m, 3H); 13C NMR (100 MHz, CDCl3): d=159.4 (C), 157.2 (C), 155.2
(C), 154.7 (C), 153.7 (C), 152.8 (C), 149.1 (C), 143.1 (C), 139.8 (C), 139.6
(C), 136.1 (CH), 132.6 (CH), 129.5 (CH), 129.4 (CH), 122.5 (CH), 122.0
(CH), 121.6 (CH), 115.9 (CH), 115.6 (CH), 114.7 (C), 113.7 (C), 113.6
(CH), 111.9 (CH), 111.5 (CH), 56.1 (CH3), 55.4 (CH3), 55.2 (CH3), 38.2
(CH2), 37.8 (CH2), 36.3 (CH2), 35.4 ppm (CH2); IR (neat): n˜ =2929, 2849,
1512, 1506, 1481, 1464, 1262, 1231, 1047, 1017 cmꢀ1; MS (ES+): m/z (%):
1111 [2M+Na]+, 10%), 599 (39), 583 (13), 567 ([M+Na]+, 30), 318
(100); HRMS (ES+): m/z calcd for C31H29BrNaO4: 567.1141; found:
567.1131.
Cavicularin (5) and Riccardin C (4)[3]: A solution of aryl bromide 42
(155 mg, 0.284 mmol) and tributyltin hydride (273 mg, 0.405 mmol) in tol-
uene (4 mL) was degassed by sonication for 10 min, then VAZO (69 mg,
0.284 mmol) was added. The solution was heated by microwave irradia-
tion (1208C, 300 W) for 30 min. Silica (ꢁ3 g) was added and the solvent
was removed in vacuo. Purification by column chromatography (19:1!
9:1 petroleum ether/diethyl ether, 10% K2CO3/silica stationary phase) af-
forded an inseparable 2:5 mixture of cavicularin trimethyl ether 15 and
riccardin C trimethyl ether 17. After addition of CH2Cl2 (5 mL) the reac-
tion mixture was cooled to 08C, then BBr3 (1.4 mL, 1.4 mmol, 1m in
CH2Cl2) was added over 2 min. After 18 h at RT, water (5 mL) was
added. The aqueous phase was separated and extracted with CH2Cl2 (3ꢂ
10 mL), then the combined organic phases were washed with brine
(20 mL). Silica (ꢁ2 g) was added and the solvent was removed in vacuo.
Purification by column chromatography (98:2 CH2Cl2/methanol, 10% an-
hydrous K2CO3/silica) firstly afforded cavicularin (5) (26 mg, 22%) as a
white solid. M.p. (diethyl ether/petroleum ether) 214–2158C; 1H NMR
(400 MHz, CDCl3): d=6.99 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H),
6.88 (d, J=2.5 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.76 (dd, J=8.3, 2.5 Hz,
1H), 6.72 (dd, J=8.3, 2.5 Hz, 1H), 6.69 (s, 1H), 6.47 (dd, J=8.5, 2.3 Hz,
1H), 6.41 (s, 1H), 6.16 (dd, J=8.3, 2.3 Hz, 1H), 6.12 (dd, J=8.5, 2.5 Hz,
1H), 6.11 (s, 1H), 4.82 (s, 1H), 4.74 (s, 1H), 2.99–2.92 (m, 2H), 2.79–2.63
(m, 4H), 2.56 (apparent td, J=13.0, 3.7 Hz, 1H), 2.29 ppm (apparent td,
J=13.0, 3.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=155.6 (C), 153.8
(C), 150.2 (C), 147.9 (C), 141.6 (C), 140.5 (C), 138.5 (C), 135.0 (C), 131.7
(C), 131.7 (CH), 131.1 (CH), 130.1 (CH), 128.9 (C), 127.8 (CH), 124.0
(C), 124.0 (C), 123.3 (C), 123.0 (CH), 117.8 (CH), 116.9 (CH), 115.1
(CH), 114.7 (CH), 113.3 (CH), 113.0 (CH), 38.1 (CH2), 37.4 (CH2), 30.5
(CH2), 30.2 ppm (CH2); IR (solid): n˜ =3298, 2922, 1605, 1584, 1501, 1259,
1237, 1072, 907, 732 cmꢀ1; MS (ES+): m/z (%): 867 [2M+Na]+ (12), 445
[M+Na]+ (100), 236 (82), 142 (90).
1505, 1432, 1270, 1223, 1189, 907 cmꢀ1
;
MS (ES+): m/z (%): 871
[2M+Na]+ (10), 447 [M+Na]+ (100).
CCDC-808507 ((E)-43), 821664 (Z,Z-31) and 821665 ((E)-29) contain the
supplementary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We gratefully acknowledge the EPSRC, ERDF (IS:CE-Chem & Inter-
Reg IVa program 4061) and GSK for funding, Dr. Gary Kelly is thanked
for assistance with the sequential hydrogenation steps and Dr. Mark
Light for the X-ray crystal structures.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 10906 – 10915

Syntheses of Cavicularin and Riccardin C
FULL PAPER
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Received: May 19, 2011
Published online: August 17, 2011
Chem. Eur. J. 2011, 17, 10906 – 10915
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10915