A facile synthesis of fused aromatic spiroacetals based on the 3,4,3′,4′-tetrahydro-2,2′-spirobis(2H-1-benzopyran) skeleton

Article abstract of DOI:10.1016/j.tet.2006.04.026

The facile synthesis of a series of aromatic 6,6-spiroacetals based on the parent 3,4,3′,4′-tetrahydro-2,2′-spirobis(2H-1-benzopyran) heterocyclic system is reported. Key steps included the use of a Sonogashira coupling for the synthesis of an aryl acetylene that was coupled to an aryl aldehyde to form a propargyl alcohol intermediate. Hydrogenation of the alkynol followed by oxidation produced a masked dihydroxy ketone that upon treatment with trimethylsilyl bromide underwent deprotection and cyclisation to the fused aromatic spiroacetal.

Full text of DOI:10.1016/j.tet.2006.04.026

Tetrahedron 62 (2006) 5883–5896
A facile synthesis of fused aromatic spiroacetals based on the
3,4,30,40-tetrahydro-2,20-spirobis(2H-1-benzopyran) skeleton
*
Margaret A. Brimble, Christopher L. Flowers, Michael Trzoss and Kit Y. Tsang
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Received 14 February 2006; revised 20 March 2006; accepted 6 April 2006
Available online 2 May 2006
Abstract—The facile synthesis of a series of aromatic 6,6-spiroacetals based on the parent 3,4,30,40-tetrahydro-2,20-spirobis(2H-1-benzo-
pyran) heterocyclic system is reported. Key steps included the use of a Sonogashira coupling for the synthesis of an aryl acetylene that
was coupled to an aryl aldehyde to form a propargyl alcohol intermediate. Hydrogenation of the alkynol followed by oxidation produced
a masked dihydroxy ketone that upon treatment with trimethylsilyl bromide underwent deprotection and cyclisation to the fused aromatic
spiroacetal.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
antibiotics isolated from cultures of Streptomyces2 that ex-
hibit activity against Gram-positive bacteria. b-Rubromycin
2 and g-rubromycin 3 exhibit potent inhibition of human
telomerase3 with IC50 values of 3 mM and are active against
the reverse transcriptase of human immunodeficiency virus-
1.4 These compounds possess a unique aromatic spiroace-
tal ring system in which benzannelated furan and pyran rings
share one carbon atom to form a spiroacetal system. The fact
that a-rubromycin 1, which lacks this aryl spiroacetal
moiety, exhibits substantially decreased inhibitory potency
towards telomerase (IC50>200 mM), suggests that this
The presence of spiroacetals as key sub-units in a wide range
of biologically active natural products has prompted a range
of synthetic methods for their preparation largely based on
the acid catalysed cyclisation of dihydroxyketones or com-
pounds containing a masked carbonyl group.1 However, the
occurrence of spiroacetals in which the oxygen atoms are
derived from two aromatic hydroxy groups is less common
and therefore fewer methods have been reported for their
synthesis. The rubromycins 1–3 (Fig. 1) are a class of
O
O
CO2Me
HO
O
HO
HO
O
O
HO
OH
O
O
MeO
HO
MeO
MeO
O
O
O
CO2Me
O
MeO
O
α-
-
rubromycin 2
rubromycin 1
β
O
O
O
CO2Me
O
CO2Me
HO
HO
OH
O
OH
O
O
MeO
O
O
R
R3
OH OH
OH
R1 R2
O
OH
O
R1 = H; R2 = H; R3 = H
griseorhodin C 6: R = OH
γ-rubromycin 3:
purpuromycin 4: R1 = H; R2 = H; R3 = OH
heliquinomycin 5: R1 = O-cymarose; R2 = OH; R3 = H
Figure 1. The rubromycin family of antibiotics.
* Corresponding author. Tel.: +64 9 3737599; fax: +64 9 3737422; e-mail: m.brimble@auckland.ac.nz
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.026

5884
M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
spiroacetal system plays an essential role in the observed
inhibition of telomerase. Structurally related to the rubro-
mycins are purpuromycin 4,5 a potential topical agent for
vaginal infections,6 heliquinomycin 5,7 an inhibitor of DNA
helicase and griseorhodin C 6.8 All these compounds
can act as bioreductive alkylating agents as postulated by
Moore.9
chromans where the oxygen atoms were derived from two
aromatic hydroxy groups. Our strategy for the synthesis
of the 3,4,30,40-tetrahydro-2,20-spirobis(2H-1-benzopyran)
skeleton was amenable to the preparation of unsymmetrical
analogues.
COMe
OH
COMe
HO
OH
OH
To date the only synthesis of a naturally occurring bis-
benzannelated spiroacetal is the elegant total synthesis of
heliquinomycin 5 reported by Danishefsky et al.10 In this
case the key aromatic 5,6-spiroacetal ring system was
assembled via electrophilic spiroacetalization of a naphtho-
furan bearing a phenolic hydroxyl group as the nucleophilic
partner. The only other synthesis of the bisbenzannelated
spiroacetal ring system present in g-rubromycin 3 was
reported by de Koning et al.11 in which a Henry reaction
allowed union of two aryl moieties and a Nef reaction was
used to liberate the masked carbonyl group that induces
the spiroacetalization step.
O
O
O
O
HO2C
Me
CO2H
Me
O
O
O
O
COMe MeOC
cynantetrone 7
2. Results and discussion
Our research group has also reported12 the synthesis of
several bisbenzannelated aromatic 5,6-spiroacetal analogues
of the naturally occurring antibiotic g-rubromycin 3. We
now herein report the synthesis of a series of aromatic 6,6-
spiroacetals as found in the novel cytotoxic acetophenone,
cynantetrone 7.13 These aryl 6,6-spiroacetals are homolo-
gous to the aryl 5,6-spiroacetal present in g-rubromycin 3.
Extension of the central core spiroacetal ring system pro-
vides an opportunity to probe the effect of the conformation
of the spiroacetal ring system on the inhibition of human tel-
omerase. Previous syntheses of the 3,4,30,40-tetrahydro-2,20-
spirobis(2H-1-benzopyran) heterocyclic system involved
hydrogenation and acid catalysed cyclisation of a disalicyli-
deneacetone,14 acid catalysed reaction of resorcinol with
2,6-dimethyl-2,5-heptadien-4-one or 1,5-diphenyl-1,4-pen-
tadien-3-one,15 or Michael reaction between dimedone
and a 1,5-diaryl-1,4-pentadien-3-one16 followed by intra-
molecular cyclisation of the Michael 1:2 adduct. These latter
approaches however, only afforded C2-symmetric spiro-
As a part of our synthetic programme directed towards the
synthesis of bioactive spiroacetal-containing natural prod-
ucts we prepared the tetracyclic aryl spiroacetals 8–12 via
disconnection to the protected diphenolic ketones 13–17
(Scheme 1). The strategy for assembly of these spiroacetal
precursors 13–17 focussed on reaction of the aryl acetalde-
hydes 18–20 with the acetylides derived from acetylenes
21 and 22.
The synthesis of the aryl aldehydes 18–20 required for cou-
pling with the acetylenes 21,22 is outlined in Scheme 2.
Aldehydes 18–20 were prepared from the readily available
phenols 23–25 via Claisen rearrangement of the derived
allylphenols 26–28. After protection of the Claisen rear-
rangement products 29–31 as either a methoxymethyl
(MOM), a methoxyethoxymethyl (MEM) or an ethoxy-
methyl (EM) ether, hydroboration of the alkenes 32–34
using borane–dimethylsulfide complex at 0 ꢀC afforded the
R3
R2
O
R2
R1
OP1
P2O
R1
O
R3
O
8: R1 = H; R2 = H; R3 = H
13: R1 = H; R2 = H; R3 = H; P1 = MOM; P2 = MEM
14: R1 = H; R2 = OMe; R3 = H; P1 = MEM; P2 = MEM
15: R1 = H; R2 = H; R3 = OMe; P1 = EM; P2 = MEM
16: R1 = OMe; R2 = H; R3 = OMe; P1 = EM; P2 = MOM
17: R1 = OMe; R2 = OMe; R3 = H; P1 = MEM; P2 = MOM
9: R1 = H; R2 = OMe; R3 = H
10: R1 = H; R2 = H; R3 = OMe
11: R1 = OMe; R2 = H; R3 = OMe
12: R1 = OMe; R2 = OMe; R3 = H
R1
R1
PO
OP
+
H
R2
O
21: R1 = H; P = MEM
18: R1 = H; R2 = H; P = MOM
19: R1 = OMe; R2 = H; P = MEM
20: R1 = H; R2 = OMe; P = EM
22: R1 = OMe; P = MOM
Scheme 1.

M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
5885
R1
R1
R1
OH
O
OH
i
ii
R2
R2
R2
23: R1 = H; R2 = H
26: R1 = H; R2 = H
29: R1 = H; R2 = H
24: R1 = OMe; R2 = H
25: R1 = H; R2 = OMe
27: R1 = OMe; R2 = H
28: R1 = H; R2 = OMe
30: R1 = OMe; R2 = H
31: R1 = H; R2 = OMe
R1
R1
R1
OP
OP
OP
iii
iv
v
H
R2
OH
R2
R2
O
18: R1 = H; R2 = H; P = MOM
19: R1 = OMe; R2 = H; P = MEM
20: R1 = H; R2 = OMe; P = EM
32: R1 = H; R2 = H; P = MOM 35: R1 = H; R2 = H; P = MOM
33: R1 = OMe; R2 = H; P = MEM 36: R1 = OMe; R2 = H; P = MEM
34: R1 = H; R2 = OMe; P = EM 37: R1 = H; R2 = OMe; P = EM
Scheme 2. Reagents, conditions and yields: (i) allyl bromide, K2CO3, acetone, reflux, 26, 86%; 27, 83%; 28, 97%; (ii) 180 ꢀC, N2, 29, 72%; 30, 87%; 31, 99%;
(iii) MOMCl/MEMCl/EMCl, iPr2NEt, CH2Cl2, 0 ꢀC, 32, 50%; 33, 37%; 34, 74%; (iv) BH3$SMe2, NaOH, H2O2, 35, 60%; 36, 55%; 37, 70%; (v) TPAP, NMO,
˚
4 A MS, CH2Cl2, 18, 51%; 19, 70%; 20, 40%.
primary alcohols 35–37 that underwent oxidation to the
desired aldehydes 18–20 in moderate yield using tetrapropyl-
ammonium perruthenate (TPAP) and 4-methylmorpholine
N-oxide (NMO).
The resulting secondary alcohols 47–51 were isolated in
nearly quantitative yield after purification by flash chroma-
tography. Oxidation of the secondary alcohols 47–51 using
tetra-n-propylammonium perruthenate (TPAP), 4-methyl-
morpholine N-oxide (NMO) and 4 A molecular sieves in
dichloromethane provided the ketones 13–17 required for
the final spirocyclisation step.
˚
Acetylenes 21 and 22 were prepared (Scheme 3) via
Sonogashira reaction of iodides 38 (prepared directly by
MEM protection of 2-iodophenol) and 39 (prepared from
2-methoxyphenol 24 via MOM protection followed by
ortholithiation and iodination) with 2-methyl-3-butyn-2-ol
followed by pyrolysis of the resultant tertiary acetylenic
alcohols 40 and 41 under basic conditions.
The final step in the synthesis of the aryl 6,6-spiroacetals
8–12 involved deprotection of the phenolic hydroxyl groups
of the ketones 13–17 and subsequent Lewis acid catalysed
cyclisation (Scheme 4). The ketones 13–17 were treated
with trimethylsilyl bromide (10 equiv) in dichloromethane
˚
With both acetylenes 21, 22 and aldehydes 18–20 in hand,
the synthesis continued with the coupling of these two
sub-units to construct the desired 6,6-spiroacetals 8–12
(Scheme 4). The coupling step involved generation of the
acetylide by treatment of the appropriate acetylene 21 or
22 with butyllithium at ꢁ78 ꢀC under nitrogen. After allow-
ing time for the complete formation of the acetylide (40 min)
the appropriate aldehyde 18, 19 or 20 was added dropwise in
tetrahydrofuran. After 1 h the reaction was allowed to warm
to room temperature and stirred for a further 2 h. Aqueous
workup followed by flash chromatography gave the desired
propargyl alcohols 42–46 in good yield.
in the presence of 4 A molecular sieves to effect both depro-
tection of the methoxyethoxymethyl, or equivalent group,
and the cyclisation step.
The 1H NMR spectra of the aryl 6,6-spiroacetals 8–12 were
much simpler than those of the ketone precursors 13–17 due
to the symmetrical, or almost, symmetrical nature of the
products. The electronic differences induced by the presence
of methoxy substituents on the aryl ring did not exhibit an
effect on the central spiroacetal ring system. Additionally,
the loss of the ether protecting groups led to cleaner NMR
spectra. The most characteristic feature in the 13C NMR
spectra of the spiroacetals 8–12 was the presence of a charac-
teristic quaternary spirocarbon at dC 96.2–96.4 ppm. In
Hydrogenation of the alkyne was then effected by stirring
the propargyl alcohols 42–46 in ethyl acetate with potassium
carbonate over 10% palladium on carbon under hydrogen.
1
the H NMR spectra four sets of doublets of doublets of
doublets could be assigned to the diastereotopic protons of
R1
R1
R1
R1
PO
PO
PO
HO
i
ii
iii
I
24: R1 = OMe
38: R1 = H; P = MEM
21: R1 = H; P = MEM
HO
39: R1 = OMe; P = MOM
22: R1 = OMe; P = MOM
40: R1 = H; P = MEM
41: R1 = OMe; P = MOM
Scheme 3. Reagents, conditions and yields: (i) MOMCl, iPr2EtN, CH2Cl2, 0 ꢀC then BuLi, THF, rt, 2 h then ꢁ45 ꢀC, I2, 1 h, 39, 14%; (ii) PPh3, PdCl2(PPh3)2,
2-methyl-3-butyn-2-ol, Et3N, CuI, 40, 95%; 41, 99%; (iii) NaOH, toluene, reflux, 21, 86%; 22, 72%.

5886
M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
R1
P2O
R1
R2
R1
OP1
PO
OP
i
+
H
R3
R2
OH
O
21: R1 = H; P = MEM
42: R1 = H; R2 = H; R3 = H; P1 = MOM; P2 = MEM
43: R1 = H; R2 = OMe; R3 = H; P1 = MEM; P2 = MEM
44: R1 = H; R2 = H; R3 = OMe; P1 = EM; P2 = MEM
45: R1 = OMe; R2 = H; R3 = OMe; P1 = EM; P2 = MOM
46: R1 = OMe; R2 = OMe; R3 = H; P1 = MEM; P2 = MOM
18: R1 = H; R2 = H; P = MOM
19: R1 = OMe; R2 = H; P = MEM
20: R1 = H; R2 = OMe; P = EM
22: R1 = OMe; P = MOM
R2
R1
R2
R1
OP1
P2O
OP1
P2O
ii
iii
R3
R3
OH
O
13: R1 = H; R2 = H; R3 = H; P1 = MOM; P2 = MEM
14: R1 = H; R2 = OMe; R3 = H; P1 = MEM; P2 = MEM
15: R1 = H; R2 = H; R3 = OMe; P1 = EM; P2 = MEM
16: R1 = OMe; R2 = H; R3 = OMe; P1 = EM; P2 = MOM
17: R1 = OMe; R2 = OMe; R3 = H; P1 = MEM; P2 = MOM
47: R1 = H; R2 = H; R3 = H; P1 = MOM; P2 = MEM
48: R1 = H; R2 = OMe; R3 = H; P1 = MEM; P2 = MEM
49: R1 = H; R2 = H; R3 = OMe; P1 = EM; P2 = MEM
50: R1 = OMe; R2 = H; R3 = OMe; P1 = EM; P2 = MOM
51: R1 = OMe; R2 = OMe; R3 = H; P1 = MEM; P2 = MOM
R3
R2
R1
iv
O
O
8: R1 = H; R2 = H; R3 = H
9: R1 = H; R2 = OMe; R3 = H
10: R1 = H; R2 = H; R3 = OMe
11: R1 = OMe; R2 = H; R3 = OMe
12: R1 = OMe; R2 = OMe; R3 = H
Scheme 4. Reagents, conditions and yields: (i) nBuLi, THF, ꢁ78 ꢀC to rt, 42, 57%; 43, 51%; 44, 88%; 45, 73%; 46, 54%; (ii) 10% Pd/C, K2CO3, EtOAc, 47,
ꢀ
˚
71%; 48, 77%; 49, 70%; 50, 99%; 51, 83%; (iii) TPAP, NMO, 4 A MS, CH2Cl2, 13, 99%; 14, 91%; 15, 99%; 16, 95%; 17, 99%; (iv) TMSBr, CH2Cl2, ꢁ30 C to
rt, 8, 97%; 9, 96%; 10, 99%; 11, 96%; 12, 96%.
the methylene groups in the spiroacetal ring system. The two
methylene groups were distinguished using 2D spectroscopy
(COSY). Long distance coupling between the aromatic
protons of the outer aryl-rings with four protons in the inner
spiroacetal rings allowed conclusive assignment of the
benzylic CH2 groups (Fig. 2).
inhibitor g-rubromycin 3 have been prepared using tri-
methylsilyl bromide to effect cyclisation of a suitably
protected diphenolic ketone precursor. The cyclisation pre-
cursors in turn were readily available via coupling of an
aryl acetylene to an aryl aldehyde fragment. A Sonogashira
reaction was used to prepare the acetylene precursors. The
6,6-spiroacetals thus prepared adopted a flattened chair–
chair bis-axial conformation.
An X-ray crystal structure was also obtained17 for aryl
spiroacetal 11. The ORTEP diagram for spiroacetal 11
(Fig. 3) clearly shows that the spiroacetal rings adopt a flat-
tened chair–chair arrangement with two anomeric effects
stabilising the bis-axial conformation.
In summary five aryl 6,6-spiroacetals that are homologous to
the aryl 5,6-spiroacetal ring system present in the telomerase
7
8
6
δC152.2
δH 6.60-7.30
1
5
8a
2
O
O
4a
8'
4
7'
6'
2
8'a
3
21.1
2.75, 3.27
δC
δH
3'
4'
4'a
5'
96.2
δC
δC 31.2
δH 1.97, 2.21
δC122.2
Figure 2. Characteristic 1H and 13C NMR chemical shifts for the parent 6,6-
spiroacetal 8.
Figure 3. ORTEP diagram for 6,6-spiroacetal 11.17

M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
5887
3. Experimental
(15 mL), water (15 mL) and brine (15 mL). The organic
layer was dried over magnesium sulfate and concentrated
in vacuo. The resultant residue was purified by flash chroma-
tography using the specified solvent system.
3.1. General details
Dichloromethane, toluene and triethylamine were distilled
from calcium hydride prior to use. Tetrahydrofuran was
dried over sodium/benzophenone and distilled before use.
Glassware was oven or flame-dried under an atmosphere of
nitrogen. Reactions were carried out under an atmosphere of
nitrogen unless otherwise specified. Infrared spectra (IR)
were obtained using Perkin Elmer Spectrum 1000 Fourier
Transform Infrared spectrometer from thin films between
sodium chloride plates. Absorbtion peaks are expressed
in wave numbers (cmꢁ1) and were measured between
450 cmꢁ1 and 4000 cmꢁ1. The signal strengths are expressed
by the abbreviations: s¼strong, m¼medium, w¼weak, and
br¼broad. NMR spectra were recorded on a Bruker
3.2.2. Claisen rearrangement of allyl ether. Neat allyl
phenyl ether (475 mg, 3.5 mmol) was placed in an oven
dried flask or a sealed tube and heated at 200 ꢀC under a
nitrogen atmosphere for 16 h. The reaction mixture changed
from colourless oil to pale brown oil. The reaction mixture
was allowed to cool and the thick oil was subjected to
column chromatography using the specified solvent system.
3.2.3. Protection of allylated phenols as methoxymethyl,
methoxyethoxymethyl or ethoxymethyl ethers. A stirred
solution of the appropriate 2-allylphenol (344 mg, 2.56
mmol) in dry dichloromethane (5 mL) was cooled to
0 ꢀC under nitrogen. Diisopropylethylamine (0.803 mL,
4.61 mmol) was added followed by methoxyethoxymethyl
chloride (0.270 mL, 3.59 mmol) dropwise. The cooling
bath was removed after 30 min and the mixture was warmed
to room temperature over 12 h. Dichloromethane was
removed in vacuo and the residue was taken up in diethyl
ether (10 mL) and washed sequentially with water
(10 mL), 10% aqueous sodium hydroxide (10 mL) and brine
(10 mL). The organic layer was dried over magnesium
sulfate and concentrated in vacuo. The resultant residue
was purified by column chromatography using the specified
solvent system.
1
DRX300 spectrometer operating at 300 MHz for H nuclei
and 75 MHz for 13C nuclei or on a Bruker DRX400 spectro-
photometer operating at 400 MHz for 1H nuclei and
100 MHz for 13C nuclei. Chemical shifts are recorded as
parts per million (ppm) downfield from tetramethylsilane
(TMS) as the internal standard or relative to the 1H in
CDCl3. The 13C values were referenced to the residual
chloroform peak at d 77.0 ppm. 13C shifts are reported as
1
chemical shift and assignment. H shifts are reported as
chemical shift, relative integral, multiplicity, coupling con-
stant and assignment. H MNR data are reported as s (sin-
1
glet); d (doublet); dd (doublet of doublets); dt (doublet of
triplets); ddd (doublet of doublets of doublets); t (triplet);
q (quartet); m (multiplet); br (broad). J values are given in
Hertz. All assignments were made with the aid of DEPT
135, COSY and HSQC experiments where required. Low
resolution mass spectra were recorded using a VG70-SE
spectrometer operating at nominal accelerating voltage of
70 eV. High resolution mass spectra were recorded using
a VG70-SE spectrometer operating at nominal resolution
of 5000–10,000 as appropriate. Fragmentation was induced
using desorptive electron impact (DEI+), electron impact
(EI) or fast atom bombardment (FAB+). Fast atom bombard-
ment (FAB) mass spectra were obtained using 3-nitrobenzyl
alcohol as the matrix. Major and significant fragments are
quoted in the form x(y), where x is the mass to charge ratio
and y is the percentage abundance relative to the base
peak. Purification by flash chromatography was performed
using Merck silica gel 0.0063–0.10 mm with the solvent sys-
tems indicated. Thin layer chromatography (TLC) was run
on silica precoated aluminium plates (Merck Kieselgel
F254). Compounds were visualised under UV fluorescence
and by staining with vanillin in methanolic acid followed
by heating. Melting points were determined on a Kofler
hot-stage apparatus and are uncorrected.
3.2.4. Hydroborationofprotectedallylphenol. Allylphenol
(100 mg, 0.45 mmol) was dissolved in tetrahydrofuran
(6 mL) and the solution was cooled to 0 ꢀC. Borane–
dimethyl sulfide complex (0.09 mL, 0.9 mmol) was added
dropwise and the mixture was stirred at 0 ꢀC for 5 h then
warmed to room temperature and stirred overnight. The
excess borane was quenched by the addition of methanol
(0.5 mL). Sodium hydroxide (1 M, 0.5 mL) was added
carefully followed by the dropwise addition of hydrogen
peroxide (30%, 0.5 mL) and the resultant mixture stirred
overnight. The mixture was extracted with diethyl ether
(5 mL) and the combined organic extracts were dried over
magnesium sulfate. The solvents were concentrated in vacuo
and the resultant residue was purified by flash chromato-
graphy using the specified solvent system.
3.2.5. TPAP oxidation of the alcohol. To a mixture of the
alcohol (294 mg, 1.5 mmol) in dichloromethane (5 mL)
˚
with 4 A molecular sieves (300 mg) were added tetra-n-
propylammonium perruthenate (30 mg, 0.075 mmol) and
4-methylmorpholine N-oxide (263 mg, 2.25 mmol) and the
reaction was stirred at room temperature for 1 h. The mix-
ture was filtered through a plug of flash silica and concen-
trated in vacuo. The resultant residue was purified by flash
chromatography using the specified solvent system.
3.2. Standard procedures
3.2.1. Allylation of phenols. To a stirred solution of the
appropriate phenol (5.0 g, 53 mmol) in acetone (30 mL)
were added potassium carbonate (9.23 g, 159 mmol) and
allyl bromide (4.58 mL, 54 mmol). The mixture was heated
under reflux at 65 ꢀC for 16 h, cooled to room temperature,
filtered and the filtrate concentrated under reduced pressure.
The residue was dissolved in dichloromethane (50 mL) and
washed sequentially with 1 M aqueous sodium hydroxide
3.2.6. Sonogashira coupling. A mixture of the protected
iodophenol (308 mg, 1.0 mmol), 2-methyl-3-butyn-2-ol
(0.154 mL, 1.6 mmol), triphenylphosphine (5 mg, 0.02 mmol)
and bis(triphenylphosphine)palladium(II) dichloride (7 mg,
0.01 mmol) in dry triethylamine (5 mL) was stirred under
nitrogen at 80 ꢀC for 15 min. Copper(I) iodide (4 mg,
0.002 mmol) was then added and the reaction was heated

5888
M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
overnight at 80 ꢀC. The reaction mixture was filtered through
a plug of CeliteÒ and concentrated under reduced pressure.
The resultant residue was purified by column chromato-
graphy using the specified solvent system.
3.3. Spectroscopic data for individual compounds
3.3.1. Allyl phenyl ether (26). The allylation reaction was
carried out according to the standard procedure using phenol
23 (5.0 g, 53 mmol), allyl bromide (4.58 mL, 54 mmol) and
potassium carbonate (9.23 g, 159 mmol). The product was
purified by column chromatography using hexane–ethyl
acetate (90:10) as eluent to give the title compound 26
(6.09 g, 86%) as colourless oil. dH (400 MHz, CDCl3) 4.52
(2H, d, J 5.5, OCH2CH]CH2), 5.28 (1H, dd, Jgem 1.6,
J 7.8, OCH2CH]CHAHB), 5.43 (1H, dd, Jgem 1.6, J 13.8,
OCH2CH]CHAHB), 6.06 (1H, m, OCH2CH]CH2), 7.3–
6.9 (5H, m, Ar-H); dC (75 MHz, CDCl3) 68.6 (OCH2CH]
CH2), 117.5 (OCH2CH]CH2), 133.3 (OCH2CH]CH2),
114.7, 120.8, 129.4 (Ar-CH), 158.5 (q, Ar-C). The spectro-
scopic data were in agreement with the literature.18
3.2.7. Pyrolysis of the tertiary alcohol. A mixture of the
alcohol (101 mg, 0.384 mmol) and solid sodium hydroxide
(468 mg, 1.92 mmol) in dry toluene (10 mL) was heated
under reflux for 3.5 h. The reaction was quenched by the
addition of saturated ammonium chloride solution (4 mL)
and extracted with diethyl ether (10 mL). The solvents
were removed under reduced pressure and the resultant
residue was purified by column chromatography using the
specified solvent system.
3.2.8. Coupling of the acetylene with the aldehyde.
n-Butyllithium (0.18 mL, 1.6 M in hexane, 0.29 mmol) was
added dropwise to a stirred solution of the acetylene
(75 mg, 0.31 mmol) in tetrahydrofuran (1 mL) at ꢁ78 ꢀC
under nitrogen. The solution was stirred at ꢁ78 ꢀC for
40 min then a solution of the aldehyde (50 mg, 0.26 mmol)
in tetrahydrofuran (0.5 mL) was added dropwise and the
mixture was stirred for 1 h. The mixture was allowed to
warm to room temperature and stirred for 2.5 h. Water
(3 mL) was added and the mixture was extracted with ethyl
acetate (3ꢂ2 mL). The combined organic extracts were
washed with brine (1 mL), dried over magnesium sulfate
and concentrated in vacuo. The resultant residue was puri-
fied by flash chromatography using the specified solvent
system.
3.3.2. 2-Allylphenol (29). The Claisen rearrangement reac-
tion was carried out according to the standard procedure
using allyl phenyl ether 26 (475 mg, 3.5 mmol). The product
was purified by column chromatography using hexane–ethyl
acetate (80:20) as eluent to give the title compound 29
(338 mg, 72%) as colourless oil. dH (400 MHz, CDCl3)
3.42 (2H, d, J 6.7, CH2CH]CH2), 4.95 (1H, br s, OH),
5.17 (1H, m, CH2CH]CHAHB), 5.18 (1H, t, J 1.5,
CH2CH]CHAHB), 6.03 (1H, m, CH2CH]CH2), 7.3–6.9
(4H, Ar-H); dC (75 MHz, CDCl3) 35.0 (CH2CH]CH2),
116.3 (CH2CH]CH2), 115.7, 120.8 (Ar-CH), 125.2 (q,
C2), 127.8, 136.2 (Ar-CH), 136.2 (CH2CH]CH2), 154.0
(q, C1). The spectroscopic data were in agreement with
the literature.19
3.2.9. Hydrogenation of acetylene. A mixture of the acetyl-
ene (80 mg, 0.17 mmol), 10% palladium on carbon (67 mg,
0.63 mmol) and potassium bicarbonate (86 mg, 0.63 mmol)
in ethyl acetate (2 mL) was stirred under an atmosphere
of hydrogen at room temperature for 2 h. The resulting
mixture was filtered through a plug of CeliteÒ and the filtrate
was concentrated in vacuo. The resulting residue was puri-
fied by flash chromatography using the specified solvent
system.
3.3.3. 1-Allyl-2-(methoxymethoxy)benzene (32). The pro-
tection step was carried out according to the standard
procedure using 2-allylphenol 29 (344 mg, 2.56 mmol), di-
isopropylamine (0.803 mL, 4.61 mmol) and methoxymethyl
chloride (0.270 mL, 3.59 mmol). The product was purified
by column chromatography using hexane–ethyl acetate
(80:20) as eluent to give the title compound 32 (226 mg,
50%) as colourless oil. dH (400 MHz, CDCl3) 3.41 (2H, d,
J 6.2, CH2CH]CH2), 3.48 (3H, s, OCH3), 5.02 (1H, m,
CH2CH]CHAHB), 5.07 (1H, m, CH2CH]CHAHB), 5.20
(2H, s, OCH2O), 5.98 (1H, m, CH2CH]CH2), 7.3–6.9
(4H, m, Ar-H); dC (75 MHz, CDCl3) 34.4 (CH2CH]
CH2), 56.0 (OCH3), 94.4 (OCH2O), 115.4 (CH2CH]
CH2), 137.0 (CH2CH]CH2), 115.4, 121.7, 127.3, 130.0
(Ar-CH), 137.0 (q, C2), 154.0 (q, C1). The spectroscopic
data were in agreement with the literature.20
3.2.10. Oxidation of the secondary alcohol to a ketone.
Tetra-n-propylammonium perruthenate (0.3 mg, 0.008 mmol)
was added to a stirred mixture of the secondary alcohol
(74 mg, 0.16 mmol), 4-methylmorpholine N-oxide (3 mg,
˚
0.24 mmol) and 4 A molecular sieves (45 mg) in dichloro-
methane (1 mL). The reaction was stirred at room tem-
perature for 1.5 h then filtered through a plug of silica gel
and the filtrate concentrated in vacuo. The resultant residue
was purified by flash chromatography using the specified
solvent system.
3.3.4. 3-(2-(Methoxymethoxy)phenyl)propan-1-ol (35).
The hydroboration reaction was carried out according to
the standard procedure using 1-allyl-2-(methoxymethoxy)-
benzene 32 (100 mg, 0.45 mmol) and borane–dimethyl sul-
fide complex (0.09 mL, 0.9 mmol). The product was purified
by column chromatography using hexane–ethyl acetate
(80:20) as eluent to give the title compound 35 (65 mg,
60%) as colourless oil. (Found: M+, 196.1098, C11H16O3
requires 196.1099); nmax (film)/cmꢁ1 3368 (br, O–H), 2934
(s, ArC–H), 2358 (w, O–CH2–O), 1233 (m, C–O), 1151
(w, C–OH); dH (400 MHz, CDCl3) 1.68 (1H, br s, OH),
1.86 (2H, quintet, J 7.4, 6.2, CH2CH2CH2OH), 2.75 (2H, t,
J 7.4, CH2CH2CH2OH), 3.50 (3H, s, OCH3), 3.64 (2H, t,
J 6.2, CH2CH2CH2OH), 5.21 (2H, s, OCH2O), 7.3–6.9
3.2.11. Cyclisation of the ketone to a 6,6-spiroacetal. To a
˚
mixture of ketone (70 mg, 0.15 mmol), 4 A molecular sieves
(50 mg) in dichloromethane (1.5 mL) at ꢁ30 ꢀC was added
trimethylsilyl bromide (0.20 mL, 1.5 mmol) and the reaction
was stirred under nitrogen for 1 h. The reaction was warmed
to 0 ꢀC stirred for 1 h, then poured into water (1 mL) and ex-
tracted with ethyl acetate (3ꢂ5 mL). The combined organic
extracts were washed with brine (1 mL), dried over magne-
sium sulfate and concentrated in vacuo. The resultant residue
was purified by flash chromatography using the specified
solvent system.

M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
5889
(4H, m, Ar-H); dC (75 MHz, CDCl3) 26.1 (CH2, C-2), 33.0
(CH2, C-3), 56.0 (OCH3), 62.0 (CH2OH), 94.6 (OCH2O),
113.9, 121.8, 127.2, 130.2 (Ar-CH), 130.6 (q, C10), 155.2
(q, C20); m/z (EI, %) 196 (M+, 4), 164 (15), 134 (71), 121
(7), 119 (12), 91 (11), 45 (100).
OCH2CH2OCH3), 5.32 (2H, s, OCH2O), 6.90–7.40 (4H,
m, Ar-H); dC (75 MHz, CDCl3) 31.0 (C(CH3)2), 59.0
(OCH3), 65.6 (q, COH), 67.9 (OCH2CH2OCH3), 71.6
(OCH2CH2OCH3), 78.3 (q, Ar–C^C), 94.4 (OCH2O),
97.9 (Ar–C]C), 113.7 (q, C10), 115.8, 122.0, 129.6,
133.4, (Ar–CH), 157.7 (q, C20); m/z (EI, %) 264 (M+, 0.5),
158 (100), 143 (8), 131 (7), 115 (5), 89 (24), 59 (85), 43 (24).
3.3.5. 3-(2-(Methoxymethoxy)phenyl)propanal (18). The
oxidation was carried out according to the standard proce-
dure using [3-(2-(methoxymethoxy)phenyl)]propan-1-ol
(35) (294 mg, 1.5 mmol), tetra-n-propylammonium
perruthenate (30 mg, 0.075 mmol), 4-methylmorpholine
3.3.8. 1-Ethynyl-2-((2-methoxyethoxy)methoxy)benzene
(21). The reaction was carried out according to the stan-
dard procedure using 4-(2-((2-methoxyethoxy)-methoxy)-
phenyl)-2-methylbut-3-yn-2-ol (40) (101 mg, 0.384 mmol)
and sodium hydroxide (468 mg, 1.92 mmol). The product
was purified by column chromatography using hexane–ethyl
acetate (70:30) as the eluent to give the title compound 21
(68 mg, 86%) as a colourless oil. (Found: M+, 206.0941,
C12H14O3 requires 206.0943); nmax (film)/cmꢁ1 3235 (s,
C^C–H), 2970 (s, ArC–H), 2930 (m, O–CH2–O), 2100
(w, C^C), 1489 (w, C–O–C); dH (400 MHz, CDCl3) 3.27
(1H, s, C^CH), 3.37 (3H, s, OCH3), 3.56 (2H, t, J 4.7,
OCH2CH2OCH3), 3.88 (2H, t, J 4.7, OCH2CH2OCH3),
5.32 (2H, s, OCH2O), 6.90–7.40 (4H, m, Ar-H); dC
(75 MHz, CDCl3) 30.9 (C^CH), 59.0 (OCH3), 67.9
(OCH2CH2OCH3), 71.5 (OCH2CH2OCH3), 80.0 (q, Ar-
C^C), 81.0 (q, C1), 94.4 (OCH2O), 115.0, 121.7, 130.2,
134.1, (Ar-CH), 158.3 (q, C2); m/z (EI, %) 206 (M+, 3),
131 (15), 118 (5), 103 (4), 89 (70), 77 (8), 100 (85), 45 (5).
˚
N-oxide (263 mg, 2.25 mmol) and 4 A molecular sieves
(500 mg). The product was purified by column chromato-
graphy using hexane–ethyl acetate (70:30) as the eluent to
give the title compound 18 (148 mg, 51%) as a colourless
oil. (Found: M+, 194.0940, C11H14O3 requires 194.0943);
nmax (film)/cmꢁ1 2932 (m, ArC–H), 2826 (m, CH2–O–
CH2), 2724 (w, CHO), 1722 (s, C]O), 1492 (w, C–O–C),
1235 (w, C–O); dH (400 MHz, CDCl3) 2.76 (2H, dt, J 7.8,
1.6, CH2CHO), 2.98 (2H, t, J 7.8, ArCH2), 3.50 (3H,
s, OCH3), 5.20 (2H, s, OCH2O), 7.3–6.9 (4H, m, Ar-H),
9.83 (1H, t, J 1.6, CHO); dC (75 MHz, CDCl3) 23.5
(CH2CH2CHO), 44.0 (CH2CHO), 56.1 (OCH3), 114.2
(OCH2O), 114.0, 121.9, 127.2, 130.2 (Ar-CH), 129.2, (q,
C10), 155.1 (q, C20), 202.3 (CHO); m/z (EI, %) 194 (M+,
3), 162 (4), 132 (16), 121 (6), 91 (6), 77 (5), 45 (100).
3.3.6. 1-Iodo-2-((2-methoxyethoxy)methoxy)benzene
(38). The protection step was carried out according to the
standard procedure using 2-iodophenol (1.07 g, 4.9 mmol),
diisopropylethylamine (1.65 mL, 9.4 mmol) and methoxy-
ethoxymethyl chloride (0.81 mL, 7.2 mmol). The product
was purified by column chromatography using hexane–ethyl
acetate (85:15) as the eluent to give the title compound 38
(1.14 g, 75%) as a colourless oil. (Found: M+, 307.9912,
C10H13IO3 requires 307.9909); nmax (film)/cmꢁ1 2923 (s,
ArC–H), 2879 (m, O–CH2–O), 1472 (s, C–O–C), 1229
(s, C–O), 644 (w, C–I); dH (400 MHz, CDCl3) 3.35 (3H,
s, OCH3), 3.57 (2H, t, J 4.7, OCH2CH2OCH3), 3.87 (2H, t,
J 4.7, OCH2CH2OCH3), 5.36 (2H, s, OCH2O), 6.65–7.80
(4H, m, Ar-H); dC (75 MHz, CDCl3) 58.9 (OCH3), 68.1
(OCH2CH2OCH3), 71.4 (OCH2CH2OCH3), 87.1 (q, C-1),
93.9 (OCH2O), 115.0, 123.7, 129.5, 139.4 (Ar-CH), 156.0
(q, C-2); m/z (EI, %) 308 (M+, 6), 233 (5), 220 (5), 106
(6), 89 (99), 76 (7), 59 (100), 45 (6).
3.3.9. 1-[((2-Methoxyethoxy)methoxy)phenyl]-5-[2-
(methoxymethoxy)phenyl]-pent-1-yn-3-ol (42). The
coupling reaction was carried out according to the standard
procedure using 3-(2-(methoxymethoxy)phenyl)propanal
(18) (25 mg, 0.124 mmol), 1-ethynyl-2-((2-methoxyethoxy)-
methoxy) benzene (21) (20 mg, 0.102 mmol) and n-butyl-
lithium (0.064 mL, 0.122 mmol). The product was purified
by column chromatography using hexane–ethyl acetate
(50:50) as the eluent to give the title compound 42 (23 mg,
57%) as a colourless oil. (Found: M+, 400.1874, C23H28O6
requires 400.1886); nmax (film)/cmꢁ1 3428 (br, O–H), 2925
(s, ArC–H), 2920 (m, O–CH2–O), 1491 (s, C–O–C), 1078
(m, C–O); dH (400 MHz, CDCl3) 2.10 (2H, q, J 7.8, 6.2,
CH2CH2Ar), 2.41 (1H, br s, OH), 2.89 (2H, t, J 7.8,
CH2CH2Ar), 3.31 (3H, s, CH2CH2OCH3), 3.45 (3H, s,
OCH2OCH3), 3.57 (2H, t, J 4.7, OCH2CH2OCH3), 3.88
(2H, t, J 4.7, OCH2CH2OCH3), 4.61 (1H, t, J 6.2, CHOH),
5.18 (2H, s, OCH2OCH3), 5.32 (2H, s, CH2OCH2O),
6.90–7.5 (8H, m, Ar-H); dC (75 MHz, CDCl3) 26.2 (CH2,
C-5), 38.0 (CH2, C-4), 56.1 (OCH3), 59.0 (OCH2CH2O
CH3), 62.5 (CHOH), 67.9 (OCH2CH2OCH3), 71.6
(OCH2CH2OCH3), 81.3 (q, Ar-C^C), 94.1 (q, Ar-C^C),
94.2 (OCH2OCH2), 94.5 (OCH2OCH3), 112.6 (q, C10),
113.4 (q, C100), 114.0, 115.5, 121.8, 121.9, 127.4, 129.8,
130.3, 133.5 (Ar-CH), 155.2 (q, C200), 157.9 (q, C20); m/z
(EI, %) 400 (M+, <0.5), 262 (20), 250 (18), 131 (19), 121
(15), 89 (44), 59 (100), 45 (65).
3.3.7. 4-[(2-Methoxyethoxy)methoxy)phenyl]-2-methyl-
but-3-yn-2-ol (40). The Sonogashira reaction was carried
out according to the standard procedure using 1-iodo-2-
((2-methoxyethoxy)methoxy) benzene (38) (308 mg,
1.0 mmol), 2-methyl-3-butyn-2-ol (0.154 mL, 1.6 mmol),
triphenylphosphine (5 mg, 0.02 mmol), bis(triphenylphos-
phine)palladium(II) dichloride (7 mg, 0.01 mmol), triethyl-
amine (5 mL) and copper(I) iodide (4 mg, 0.002 mmol).
The product was purified by column chromatography using
hexane–ethyl acetate (70:30) as the eluent to give the title
compound 40 (247 mg, 95%) as a colourless oil. (Found:
M+, 264.1356, C15H20O4 requires 264.1362); nmax (film)/
cmꢁ1 3423 (br, O–H), 2980 (s, ArC–H), 2930 (s, O–CH2–
O), 2228 (w, C]C), 1489 (s, C–O–C), 1449, 1372 (w,
geminal CH3); dH (400 MHz, CDCl3) 1.63 (6H, 2ꢂs,
2ꢂCH3), 3.81 (3H, s, OCH3), 2.47 (1H, br s, OH), 3.59
(2H, t, J 4.7, OCH2CH2OCH3), 3.91 (2H, t, J 4.7,
3.3.10. 1-[((2-Methoxyethoxy)methoxy)phenyl]-5-[(2-
(methoxymethoxy)phenyl]-pentan-3-ol (47). The hydro-
genation was carried out according to the standard procedure
using 1-[(2-methoxyethoxy)methoxy)phenyl]-5-[2-(meth-
oxymethoxy)-phenyl]-pent-1-yn-3-ol (42) (7 mg, 0.0175
mmol), 10% palladium on carbon (7 mg, 0.0063 mmol)
and potassium carbonate (9 mg, 0.063 mmol). The product

5890
M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
was purified by column chromatography using hexane–ethyl
acetate (50:50) as the eluent to give the title compound
42 (5 mg, 71%) as a colourless oil. (Found: M+(+NH4),
422.2537, C23H32O6(+NH4) requires 422.2543); nmax
(film)/cmꢁ1 3459 (br, O–H), 2928 (s, ArC–H), 1493 (s,
C–O–C), 1078 (m, C–O); dH (400 MHz, CDCl3) 1.76 (4H,
m, CH2CH2Ar), 2.25 (1H, br s, OH), 2.75 (4H, m,
CH2CH2Ar), 3.37 (3H, s, CH2CH2OCH3), 3.47 (3H, s,
OCH2OCH3), 3.47 (1H, m, CHOH), 3.58 (2H, m,
OCH2CH2OCH3), 3.82 (2H, m, OCH2CH2OCH3), 5.20
(2H, s, OCH2OCH3), 5.29 (2H, s, CH2OCH2O), 6.90–7.50
(8H, m, Ar-H); dC (75 MHz, CDCl3) 26.4 (CH2Ar), 37.8
(CH2CHOH), 56.1 (OCH2OCH3), 59.0 (OCH3), 67.7
(OCH2CH2OCH3), 70.4 (CHOH), 71.6 (OCH2CH2OCH3),
93.6 (OCH2OCH2), 94.5 (OCH2OCH3), 114.0, 114.1,
121.9, 121.9, 127.1, 127.1, 130.1, 130.3 (Ar-CH), 131.1,
(q, C10 and C100), 155.1, 155.1 (q, C200 and C20); m/z
(DEI+, %) 422 (M+, 8), 405 (3), 329 (30), 314 (27), 297
(80), 284 (35), 267 (100), 107 (22).
40-Hax), 6.60–7.30 (8H, m, Ar-H); dC (75 MHz, CDCl3)
21.0 (CH2, C-4 and C-40), 31.2 (CH2, C-3 and C-30), 96.2
(q, C2), 117.1, 120.8, (Ar-CH), 122.2 (q, C4a and C4a0),
127.2, 129.0 (Ar-CH), 152.2 (q, C8a and C8a0); m/z (EI,
%) 252 (M+, 60), 158 (14), 145 (40), 131 (100), 107 (40),
77 (13), 57 (6), 43 (4).
3.3.13. 1-(Allyloxy)-2-methoxybenzene (27). The allyla-
tion reaction was carried out according to the standard pro-
cedure using 2-methoxyphenol (24) (5.0 g, 40 mmol), allyl
bromide (4.87 mL, 40 mmol) and potassium carbonate
(16.58 g, 120 mmol). The product was purified by column
chromatography using hexane–ethyl acetate (90:10) as the
eluent to give the title compound 27 (5.46 g, 83%) as a
colourless oil. dH (400 MHz, CDCl3) 3.89 (3H, s, OCH3),
4.58 (2H, d, J 5.5, OCH2CH]CH2), 5.27 (1H, m,
OCH2CH]CHAHB), 5.40 (1H, m, OCH2CH]CHAHB),
6.06 (1H, m, OCH2CH]CH2), 6.90–7.30 (4H, m, Ar-H);
dC (75 MHz, CDCl3) 55.7 (OCH3), 69.7 (OCH2CH]
CH2), 111.7, 113.5 (Ar-CH), 117.7 (CH]CH2), 120.6,
121.1 (Ar-CH), 133.3 (OCH2CH]CH2), 147.9 (q, C2),
149.4 (q, C1). The spectroscopic data were in agreement
with the literature.11
3.3.11. 1-[((2-Methoxyethoxy)methoxy)phenyl]-5-[2-
(methoxymethoxy)phenyl]-pentan-3-one (13). The reac-
tion was carried out according to the standard procedure
using 1-[((2-methoxyethoxy)methoxy)phenyl]-5-[2-(methoxy-
methoxy)phenyl]pentan-3-ol (47) (5 mg, 0.0124 mmol), tetra-
n-propylammonium perruthenate (0.2 mg, 0.0062 mmol),
4-methylmorpholine N-oxide (2 mg, 0.0186 mmol) and
3.3.14. 2-Allyl-6-methoxyphenol (30). The Claisen rear-
rangement was carried out according to the standard proce-
dure using 1-(allyloxy)-2-methoxybenzene (27) (3.664 g,
22.3 mmol). The product was purified by column chromato-
graphy using hexane–ethyl acetate (70:30) as the eluent to
give the title compound 30 (3.20 g, 87%) as a colourless
oil. dH (400 MHz, CDCl3) 3.40 (2H, m, CH2CH]CH2),
3.80 (3H, s, OCH3), 4.65 (1H, br s, OH), 5.04 (1H, m,
CH2CH]CHAHB), 5.08 (1H, m, CH2CH]CHAHB), 6.00
(1H, m, CH2CH]CH2), 6.60–6.80 (3H, m, Ar-H); dC
(75 MHz, CDCl3) 33.6 (CH2CH]CH2), 55.6 (OCH3),
108.5 (Ar-CH), 115.1 (CH2CH]CH2), 119.2, 122.0 (Ar-
CH), 125.8 (q, C2), 136.5 (CH2CH]CH2), 143.2 (q, C1),
146.2 (q, C6).11
˚
4 A molecular sieves (100 mg). The product was purified
by column chromatography using hexane–ethyl acetate
(50:50) as the eluent to give the title compound 13 (5 mg,
>99%) as a colourless oil. (Found: M+(+NH4), 420.2390,
C23H30O6(+NH4) requires 420.2386); nmax (film)/cmꢁ1
2925 (s, ArC–H), 1714 (s, C]O), 1494 (m, C–O–C), 1079
(m, C–O); dH (400 MHz, CDCl3) 2.70 (4H, m, CH2CO),
2.89 (4H, m, CH2CH2Ar), 3.37 (3H, s, CH2CH2OCH3),
3.46 (3H, s, OCH2OCH3), 3.55 (2H, t, J 4.4, OCH2CH2
OCH3), 3.80 (2H, t, J 4.4, OCH2CH2OCH3), 5.18 (2H, s,
OCH2OCH3), 5.28 (2H, s, OCH2OCH2), 6.80–7.30 (8H,
m, Ar-H); dC (75 MHz, CDCl3) 24.9 (CH2CH2Ar), 42.9
(CH2CO), 56.0 (CH2CH2OCH3), 59.0 (OCH3), 67.7 (OCH2
CH2OCH3), 71.6 (OCH2CH2OCH3), 93.4 (OCH2OCH2),
94.3 (OCH2OCH3), 113.9, 114.0, 121.7, 125.5, 127.4,
127.5 (Ar-CH), 129.9 (q, C100 and C10), 130.0, 130.1 (Ar-
CH), 155.08, 155.14 (q, C200 and C20), 210.0 (CHO); m/z
(DCl+, %) 420 (68), 297 (44), 295 (25), 282 (28), 265
(100), 253 (62), 131 (24), 89 (14).
3.3.15. 1-Allyl-3-methoxy-2-((2-methoxyethoxy)methoxy)-
benzene (33). The protection step was carried out according
to the standard procedure using 2-allyl-6-methoxyphenol
(30) (1.13 g, 7.9 mmol), diisopropylethylamine (2.48 mL,
14.70 mmol) and methoxyethoxymethyl chloride (0.90 mL,
7.9 mmol). The product was purified by column chromato-
graphy using hexane–ethyl acetate (70:30) as the eluent to
give the title compound 33 (761 mg, 37%) as a colourless
oil. nmax (film)/cmꢁ1 3077 (w, CH]CH2), 2934 (s, ArC–
H), 1285 (w, C–O), 1150 (m, C–O–C); dH (400 MHz,
CDCl3) 3.33 (3H, s, CH2CH2OCH3), 3.38 (2H, m,
CH2CH]CH2), 3.54 (2H, m, OCH2CH2OCH3), 3.89 (3H,
s, OCH3), 3.90 (2H, m, OCH2CH2OCH3), 5.04 (1H, m,
CH2CH]CHAHB), 5.04 (1H, m, CH2CH]CHAHB), 5.15
(2H, s, OCH2O), 5.97 (1H, m, CH2CH]CH2), 6.70–7.00
(3H, m, Ar-H); dC (75 MHz, CDCl3) 33.8 (CH2CH]CH2),
55.1 (OCH3), 58.5 (CH2CH2OCH3), 68.6 (CH2CH2OCH3),
71.3 (CH2CH2OCH3), 97.3 (OCH2O), 109.93 (Ar-CH),
115.2 (CH2CH]CH2), 121.5, 123.7 (Ar-CH), 133.7 (q,
C1), 136.7 (CH2CH]CH2), 143.6 (q, C3), 151.8 (q, C2);
m/z (EI, %) 163 (M+, 5), 131 (25), 93 (52), 63 (100), 51 (9).
3.3.12. 3,4,30,40,-Tetrahydro-2,20-spirobis(2H-1-benzo-
pyran) (8). The reaction was carried out according to the
standard procedure using 1-[((2-methoxyethoxy)-methoxy)-
phenyl]-5-[2-(methoxymethoxy)phenyl]pentan-3-one (13)
(15 mg, 0.0373 mmol), trimethylsilyl bromide (0.05 mL,
˚
0.373 mmol) and 4 A molecular sieves (50 mg). The product
was purified by column chromatography using hexane–ethyl
acetate (50:50) as the eluent to give the title compound 13
(9 mg, 97%) as a colourless solid, mp 63–65 ꢀC. (Found:
M+, 252.1145, C17H16O2 requires 252.1150); nmax (film)/
cmꢁ1 2925 (s, ArC–H), 1455 and 1488 (m, C–O–C), 1094
(w, C–O); dH (400 MHz, CDCl3) 1.97 (2H, ddd, Jgem 13.0,
J3ax,4ax 13.0, J3ax,4eq 5.9, 3 and 30-Hax), 2.21 (2H, ddd,
Jgem 13.0, J3eq,4ax 5.9, J3eq,4eq 2.6, 3 and 30-Heq), 2.75 (2H,
ddd, Jgem 16.2, J4eq,3ax 5.9, J4eq,3eq 2.6, 4 and 40-Heq), 3.27
(2H, ddd, Jgem 16.2, J4ax,3ax 13.0, J4ax,3eq 5.9, 4 and
3.3.16. 3-[(3-Methoxy)-2-((2-methoxyethoxy)methoxy)-
phenyl]propan-1-ol (36). The hydroboration reaction was

M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
5891
carried out according to the standard procedure using
1-allyl-3-methoxy-2-((2-methoxyethoxy)methoxy)benzene
(33) (730 mg, 2.9 mmol) and borane–dimethyl sulfide com-
plex (0.600 mL, 6.0 mmol). The product was purified by col-
umn chromatography using hexane–ethyl acetate (10:90) as
the eluent to give the title compound 36 (430 mg, 55%) as
a colourless oil. (Found: M+, 270.1468, C14H22O5 requires
270.1467); nmax (film)/cmꢁ1 3431 (br, O–H), 2935 (s,
ArC–H), 1264 (s, C–O), 1159 (w, C–OH); dH (400 MHz,
CDCl3) 1.86 (2H, m, CH2CH2CH2OH), 2.60 (1H, br s,
OH), 2.77 (2H, t, J 6.3, CH2CH2CH2OH), 3.38 (3H, s,
CH2OCH3), 3.59 (4H, m, CH2OH and OCH2CH2OCH3),
3.80 (3H, s, OCH3), 3.94 (2H, t, J 5.1, OCH2CH2OCH3),
5.17 (2H, s, OCH2O), 6.75–7.00 (3H, m, Ar-H); dC
(75 MHz, CDCl3) 26.1 (CH2, C-2), 33.0 (CH2, C-3), 55.5
(OCH3), 58.9 (CH2CH2OCH3), 61.7 (CH2OH), 69.0
(CH2CH2OCH3), 71.70 (CH2CH2OCH3), 98.0 (OCH2O),
109.9, 121.9, 124.2 (Ar-CH), 135.8 (q, C10), 144.2 (q,
C30), 151.9 (q, C20); m/z (EI, %) 270 (M+, <0.5), 194 (20),
149 (5), 137 (5), 89 (21), 59 (100), 45 (4).
4.65 (1H, t, J 5.9, CHOH), 5.20 (2H, s, 200-OCH2OCH2),
5.30 (2H, s, 20-OCH2OCH2), 6.70–7.50 (7H, m, Ar-H); dC
(75 MHz, CDCl3) 25.8 (CH2, C-5), 38.7 (CH2, C-4), 55.5
(OCH3), 58.7 (200-OCH2CH2OCH3), 58.8 (CHOH), 62.3
(20-OCH2CH2OCH3), 67.7 (20-OCH2CH2OCH3), 68.9
(200-OCH2CH2OCH3), 71.4 (20-OCH2CH2OCH3), 71.7 (200-
OCH2CH2OCH3), 80.7 (q, Ar-C]C), 94.3 (q, Ar-C]C),
94.0 (20-OCH2OCH2), 98.0 (200-OCH2OCH2), 110.1 (Ar-
CH), 113.4 (q, C100), 115.3, 121.7, 122.1, 124.1, 129.5,
133.4 (Ar-CH), 135.5 (q, C10), 144.4 (q, C30), 152.0 (q,
C20), 157.7 (q, C200); m/z (EI, %) 400 (M+, <0.5), 262 (25),
250 (21), 173 (5), 89 (45), 59 (100), 45 (65).
3.3.19. 1-[(3-Methoxy)-2-((2-methoxyethoxy)methoxy)-
phenyl]-5-[2-((2-methoxyethoxy)methoxy)phenyl]-
pentan-3-ol (48). The hydrogenation was carried out
according to the standard procedure using 5-[(3-methoxy)-
2-((2-methoxyethoxy)methoxy)phenyl]-1-[2-((2-methoxy-
ethoxy)methoxy)phenyl]-pent-1-yn-3-ol (43) (116 mg,
0.253 mmol), 10% palladium on carbon (100 mg, 0.0912
mmol), potassium carbonate (126 mg, 0.912 mmol). The
product was purified by column chromatography using hex-
ane–ethyl acetate (50:50) as the eluent to give the title com-
pound 48 (90 mg, 77%) as a colourless oil. (Found: M+,
479.2648, C26H39O8 requires 479.2645); nmax (film)/cmꢁ1
3435 (br, O–H), 2928 (s, ArC–H), 1474 (m, C–O–C), 1077
(m, C–O); dH (400 MHz, CDCl3) 1.76 (4H, quintet, J 7.6,
13.9, CH2CH2Ar), 2.79 (4H, m, CH2CH2Ar), 3.36, 3.37
(6H, each s, 20- and 200-CH2CH2OCH3), 3.55 (5H, m, 20-
or 200-OCH2CH2OCH3 and CHOH), 3.80 (3H, s, OCH3),
3.81 (2H, m, 20- or 200-OCH2CH2OCH3), 3.93 (2H, m,
20- or 200-OCH2CH2OCH3), 5.17 (2H, s, 20-OCH2OCH2),
5.27 (2H, s, 200-OCH2OCH2), 6.70–7.20 (7H, m, Ar-H);
dC (75 MHz, CDCl3) 26.2, 26.4 (CH2-Ar), 37.7, 38.2
(CH2CHOH), 55.5 (ArOCH3), 58.8, 58.9 (OCH2CH2O
CH3), 67.6, 69.0 (OCH2CH2OCH3), 70.3 (CHOH), 71.4,
71.7 (OCH2CH2OCH3), 93.5 (200-OCH2OCH2), 98.0
(20-OCH2OCH2), 109.9, 114.0, 121.7, 121.9, 124.1, 126.9,
130.0 (Ar-CH), 131.2 (q, C300), 136.2 (q, C100), 144.2 (q,
C10), 152.0 (q, C20), 155.0 (q, C200); m/z (FAB+, %) 479
(M+, 3), 402 (2), 372 (4), 219 (3), 165 (5), 154 (100), 136
(70), 89 (46).
3.3.17. 3-[(3-Methoxy-2-((2-methoxyethoxy)methoxy)-
phenyl]propanal (19). The oxidation was carried out
according to the standard procedure using [3-(3-methoxy)-
2-((2-methoxyethoxy)-methoxy)phenyl]propan-1-ol (36)
(430 mg, 1.6 mmol), tetra-n-propylammonium perruthenate
(3 mg, 0.08 mmol), 4-methylmorpholine N-oxide (200 mg,
˚
2 mmol) and 4 A molecular sieves (750 mg). The product
was purified by column chromatography using hexane–ethyl
acetate (50:50) as the eluent to give the title compound 19
(301 mg, 70%) as a colourless oil. (Found: M+, 268.1310,
C14H20O5 requires 268.1311); nmax (film)/cmꢁ1 2932 (s,
ArC–H), 2838 (m, CH2–O–CH2), 2724 (w, CHO), 1722 (s,
C]O), 1476 (s, C–O–C), 1265 (m, C–O); dH (400 MHz,
CDCl3) 2.77 (2H, q, J 1.6, 7.0, CH2CH2CHO), 3.00 (2H,
t, J 7.0, ArCH2), 3.38 (3H, s, CH2OCH3), 3.57 (2H, t,
J 6.3 OCH2CH2OCH3), 3.81 (3H, s, OCH3), 3.90 (2H, t,
J 6.3, OCH2CH2OCH3), 5.19 (2H, s, OCH2O), 6.70–7.00
(3H, m, Ar-H), 9.81 (1H, t, J 1.6, CHO); dC (75 MHz,
CDCl3) 23.0 (CH2, C-3), 44.3 (CH2, C-2), 55.5 (OCH3),
58.8 (CH2CH2OCH3), 69.0 (CH2CH2OCH3), 71.6 (CH2
CH2OCH3), 97.8 (OCH2O), 110.5, 121.6, 124.2 (Ar-CH),
134.4 (q, C10), 144.2 (q, C30), 152.0 (q, C20), 201.9
(CHO); m/z (EI, %) 268 (M+, 6), 151 (4), 136 (5), 89 (64),
77 (4), 65 (3), 59 (100), 45 (4).
3.3.20. 1-[(3-Methoxy)-2-((2-methoxyethoxy)methoxy)-
phenyl]-5-[2-((2-methoxyethoxy)methoxy)phenyl]pen-
tan-3-one (14). The oxidation was carried out according
to the standard procedure using 1-[(3-methoxy-2-((2-
methoxyethoxy)methoxy)phenyl]-5-[2-((2-methoxyethoxy)-
methoxy)phenyl] pentan-3-ol (48) (90 mg, 0.195 mmol),
tetra-n-propylammonium perruthenate (0.3 mg, 0.0097
mmol), 4-methylmorpholine N-oxide (3.4 mg, 0.29 mmol)
3.3.18. 5-[(3-Methoxy)-2-((2-methoxyethoxy)methoxy)-
phenyl]-1-([2-((2-methoxyethoxy)methoxy)phenyl]pent-
1-yn-3-ol (43). The coupling reaction was carried out
according to the standard procedure using 3-[(3-methoxy)-2-
((2-methoxyethoxy)methoxy)phenyl]propanal (19) (162 mg,
0.79 mmol), 1-ethynyl-2-((2-methoxyethoxy)methoxy)benz-
ene (21) (165 mg, 0.654 mmol) and butyllithium (0.5 mL,
0.785 mmol). The product was purified by column chromato-
graphy using hexane–ethyl acetate (20:80) as the eluent to
give the title compound 43 (152 mg, 51%) as a colourless
oil. (Found: M+, 400.1875, C23H28O6 requires 400.1886);
nmax (film)/cmꢁ1 3435 (br, O–H), 2928 (m, ArC–H), 1474
(m, C–O–C), 1077 (m, C–O); dH (400 MHz, CDCl3) 2.12
(2H, q, J 7.3, 5.9, CH2CH2Ar), 2.45 (1H, br s, OH), 2.96
(2H, t, J 7.3, CH2CH2Ar), 3.36, 3.54 (6H, each s,
2ꢂCH2CH2OCH3), 3.54 (4H, m, 2ꢂOCH2CH2OCH3),
3.81 (3H, s, OCH3), 3.88 (4H, m, 2ꢂOCH2CH2OCH3),
˚
and 4 A molecular sieves (100 mg). The product was puri-
fied by column chromatography using hexane–ethyl acetate
(50:50) as the eluent to give the title compound 14 (82 mg,
91%) as a colourless oil. (Found: M+, 476.2406, C26H36O8
requires 476.2410); nmax (film)/cmꢁ1 2930 (s, ArC–H),
1712 (s, C]O), 1492 (s, C–O–C), 1078 (s, C–O); dH
(400 MHz, CDCl3) 2.70 (4H, t, J 8.1, CH2CO), 2.91 (4H,
m, CH2Ar), 3.35 (6H, each s, 2ꢂCH2CH2OCH3), 3.55
(4H, m, 2ꢂOCH2CH2OCH3), 3.80 (3H, s, OCH3), 3.82
(2H, m, 20- or 200-OCH2CH2OCH3), 3.93 (2H, m, 20- or 200-
OCH2CH2OCH3), 5.17 (2H, s, 20-OCH2OCH2), 5.27 (2H,
s, 200-OCH2OCH2), 6.70–7.35 (7H, m, Ar-H); dC (75 MHz,

5892
M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
CDCl3) 24.8, 24.9 (CH2CH2-Ar), 42.8, 43.2 (CH2CH2-Ar),
55.5 (ArOCH3), 58.8, 58.9 (OCH2CH2OCH3), 67.6, 69.0
(OCH2CH2OCH3), 71.5, 71.6 (OCH2CH2OCH3), 93.3 (200-
OCH2OCH2), 97.8 (20-OCH2OCH2), 110.3, 113.9, 121.6,
121.8, 124.1, 127.3, 129.8 (Ar-CH), 129.8 (q, C100), 135.2
(q, C10), 144.2 (q, C30), 152.0 (q, C20), 155.0 (q, C200),
209.6 (q, CO); m/z (FAB+, %) 476 (M+, 1), 400 (2), 325
(10), 295 (52), 282 (30), 154 (55), 89 (100), 77 (17).
147.9 (q, C1), 153.5 (q, C4). The spectroscopic data were
in agreement with the literature.22
3.3.24. 2-Allyl-1-(ethoxymethoxy)-4-methoxybenzene
(34). The protection step was carried out according to the
standard procedure using 2-allyl-4-methoxyphenol (31)
(6.37 g, 39 mmol), diisopropylamine (12.2 mL, 70 mmol)
and ethoxymethyl chloride (4.87 mL, 43 mmol). The prod-
uct was purified by column chromatography using hexane–
ethyl acetate (80:20) as the eluent to give the title compound
34 (6.41 g, 74%) as a colourless oil. (Found: M+, 222.1255,
C13H18O3 requires 222.1256); nmax (film)/cmꢁ1 3077 (w,
CH]CH2), 2934 (s, ArC–H), 1285 (w, C–O), 1150 (m,
C–O–C); dH (400 MHz, CDCl3) 1.23 (3H, t, J 7.0,
OCH2CH3), 3.37 (2H, d, J 6.7, CH2CH]CH2), 3.71 (2H,
q, J 7.0, OCH2CH3), 3.74 (OCH3), 5.03 (1H, m, CH2CH]
CHAHB), 5.07 (1H, m, CH2CH]CHAHB), 5.15 (2H, s,
OCH2O), 5.98 (1H, m, CH2CH]CH2), 6.60–7.10 (3H,
m, Ar-H); dC (75 MHz, CDCl3) 15.1 (OCH2CH3), 34.4
(CH2CH]CH2), 55.5 (OCH3), 64.1 (OCH2CH3), 94.1
(OCH2O), 115.8 (CH2CH]CH2), 111.6, 115.4, 115.7 (Ar-
CH), 132.7 (CH2CH]CH2), 136.7 (q, C2), 149.2 (q, C1),
154.4 (q, C4); m/z (EI, %) 222 (M+, 65), 192 (22), 163
(36), 149 (31), 103 (11), 77 (10), 59 (100), 41 (10).
3.3.21. 8-Methoxy-3,4,30,40-tetrahydro-2,20-spirobis(2H-1-
benzopyran) (9). The cyclisation was carried out according
to the standard procedure using 1-[(3-methoxy)-2-((2-
methoxyethoxy)-methoxy)phenyl]-5-[2-((2-methoxyethoxy)-
methoxy)phenyl]pentan-3-one (14) (82 mg, 0.178 mmol),
˚
trimethylsilyl bromide (0.23 mL, 1.78 mmol) and 4 A molec-
ular sieves (50 mg). The product was purified by column
chromatography using hexane–ethyl acetate (50:50) as the
eluent to give the title compound 9 (48 mg, 96%) as a colour-
less solid, mp 125–126 ꢀC. (Found: M+, 282.1256, C18H18O3
requires 282.1256); nmax (film)/cmꢁ1 3054 (w, ArC–H), 1482,
1421 (w, C–O–C); dH (400 MHz, CDCl3) 1.98 (2H, ddd, Jgem
13.3, J3ax,4ax 13.1, J3ax,4eq 5.7, 3 and 30-Hax), 2.31 (2H, ddd,
Jgem 13.3, J3eq,4ax 5.9, J3eq,4eq 2.6, 3 and 30-Heq), 2.75 (2H,
ddd, Jgem 16.2, J4eq,3ax 5.7, J4eq,3eq 2.6, 4 and 40-Heq), 3.35
(2H, ddd, Jgem 16.2, J4ax,3ax 13.1, J4ax,3eq 5.9, 4 and 40-Hax),
3.63 (3H, s, OCH3), 6.60–7.20 (7H, m, Ar-H); dC (75 MHz,
CDCl3) 21.0, 21.2 (CH2CH2Ar), 30.9, 31.3 (CH2CH2Ar),
56.5 (OCH3), 96.3 (q, C2), 111.0, 117.0, 120.2, 121.3,
122.5 (Ar-H), 122.3, 123.1 (q, C4a and C4a0), 127.0, 128.9
(Ar-CH), 142.14 (q, C8), 148.6 (q, C8a), 152.2 (q, C8a0);
m/z (EI, %) 282 (M+, 80), 161 (28), 145 (42), 138 (50), 131
(100), 107 (25), 77 (14), 73 (22).
3.3.25. 3-[2-(Ethoxymethoxy)-5-methoxyphenyl]propan-
1-ol (37). The hydroboration reaction was carried out
according to the standard procedure using 2-allyl-1-(ethoxy-
methoxy)-4-methoxybenzene (34) (3.0 g, 13.5 mmol) and
borane–dimethyl sulfide complex (2.7 mL, 27 mmol). The
product was purified by column chromatography using
hexane–ethyl acetate (80:20) as the eluent to give the title
compound 37 (2.28 g, 70%) as a colourless oil. (Found:
M+, 240.1362, C13H20O4 requires 240.1362); nmax (film)/
cmꢁ1 3411 (br, O–H), 2936 (s, ArC–H), 2834 (m, O–CH2–
O), 1278 (w, C–O), 1151 (m, C–OH); dH (400 MHz,
CDCl3) 1.23 (3H, t, J 7.0, OCH2CH3), 1.84 (2H, quintet,
J 6.2, 7.7, CH2CH2CH2OH), 2.60 (1H, br s, OH), 2.70
(2H, t, J 7.7, CH2CH2CH2OH), 3.70 (2H, t, J 6.2,
CH2OH), 3.71 (OCH2CH3), 3.80 (3H, s, OCH3), 5.13 (2H,
s, OCH2O), 6.60–7.10 (3H, m, Ar-H); dC (75 MHz,
CDCl3) 15.0 (OCH2CH3), 26.1 (CH2, C2), 32.9 (CH2, C3),
55.4 (OCH3), 61.6 (CH2OH), 64.2 (OCH2CH3), 94.0
(OCH2O), 111.3, 115.5, 115.9 (Ar-CH), 132.6 (q, C10),
149.3 (q, C20), 154.3 (q, C50); m/z (EI, %) 240 (M+, 10),
194 (10), 164 (100), 149 (25), 137 (16), 77 (9), 59 (35),
41 (10).
3.3.22. 1-(Allyloxy)-4-methoxybenzene (28). The allyla-
tion reaction was carried out according to the standard pro-
cedure using 4-methoxyphenol (25) (5.0 g, 40 mmol), allyl
bromide (3.5 mL, 40 mmol) and potassium carbonate
(11.0 g, 80 mmol). The product was purified by column
chromatography using hexane–ethyl acetate (90:10) as the
eluent to give the title compound 28 (6.38 g, 97%) as a col-
ourless oil. dH (400 MHz, CDCl3) 3.74 (3H, s, OCH3), 4.56
(2H, d, J 5.1, OCH2CH]CH2), 5.41 (1H, dq, Jgem 1.5,
J 10.6, OCH2CH]CHAHB), 5.42 (1H, m, OCH2CH]
CHAHB), 6.10 (1H, m, OCH2CH]CH2), 6.80–6.95 (4H,
m, Ar-H); dC (75 MHz, CDCl3) 55.5 (OCH3), 69.3
(OCH2CH]CH2), 114.5, 115.6 (Ar-CH), 117.4 (CH]
CH2), 133.5 (OCH2CH]CH2), 152.6 (q, C1), 153.8 (q,
C4). The spectroscopic data were in agreement with the
literature.21
3.3.26. 3-[2-(Ethoxymethoxy)-5-methoxyphenyl]propa-
nal (20). The oxidation was carried out according to the
standard procedure using 3-[2-(ethoxymethoxy)-5-meth-
oxyphenyl]propan-1-ol (37) (1.28 g, 5.3 mmol), tetra-n-
propylammonium perruthenate (100 mg, 0.267 mmol),
3.3.23. 2-Allyl-4-methoxyphenol (31). The Claisen rear-
rangement was carried out according to the standard proce-
dure using 1-(allyloxy)-4-methoxybenzene (28) (6.37 g,
39 mmol). The product was purified by column chromato-
graphy using hexane–ethyl acetate (50:50) as the eluent to
give the title compound 31 (6.37 g, >99%) as a colourless
oil. dH (400 MHz, CDCl3) 3.36 (2H, d, J 6.2, CH2CH]
CH2), 3.74 (3H, s, OCH3), 5.10 (1H, dq, Jgem 1.5, J 10.6,
CH2CH]CHAHB), 5.16 (1H, m, CH2CH]CHAH2B), 5.20
(1H, br s, OH), 6.00 (1H, m, 6.2, CH2CH]CH2), 6.60–
6.80 (3H, m, Ar-H); dC (75 MHz, CDCl3) 35.0 (CH2CH]
CH2), 55.7 (OCH3), 112.5, 115.9, 116.3 (Ar-CH), 116.7
(CH2CH]CH2), 126.7 (q, C2), 136.1 (CH2CH]CH2),
˚
4-methylmorpholine N-oxide (900 mg, 8.0 mmol) and 4 A
molecular sieves (1 g). The product was purified by column
chromatography using hexane–ethyl acetate (50:50) as the
eluent to give the title compound 20 (506 mg, 40%) as
a colourless oil. (Found: M+, 238.1206, C13H18O4 requires
238.1205); nmax (film)/cmꢁ1 2975 (s, ArC–H), 2834 (m,
CH2–O–CH2), 2724 (w, CHO), 1725 (s, C]O), 1504
(m, C–O–C), 1280 (w, C–O); dH (400 MHz, CDCl3) 1.23
(3H, t, J 7.0, OCH2CH3), 2.72 (2H, dt, J 1.5, 7.6,
CH2CH2CHO), 2.92 (2H, t, J 7.6, ArCH2), 3.67 (2H, q,

M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
5893
J 7.0, OCH2CH3), 3.73 (3H, s, OCH3), 5.17 (2H, s, OCH2O),
6.70–7.00 (3H, m, Ar-H), 9.80 (1H, t, J 1.5, CHO);
dC (75 MHz, CDCl3) 15.0 (OCH2CH3), 23.5 (CH2, C-3),
43.9 (CH2, C-2), 55.4 (OCH3), 64.1 (OCH2CH3), 93.7
(OCH2O), 111.7, 115.2, 115.8 (Ar-CH), 130.5 (q, C10),
149.3 (q, C20), 154.2 (q, C50), 202.0 (CHO); m/z (EI, %)
238 (M+, 43), 208 (30), 180 (14), 151 (17), 136 (24), 77
(7), 59 (100), 41 (6).
(q, C200); m/z (EI, %) 448 (M+, <0.5), 402 (14), 372 (25),
296 (30), 284 (16), 137 (25), 89 (45), 59 (100).
3.3.29. 1-[2-(Ethoxymethoxy)-5-methoxyphenyl]-5-[2-
((2-methoxyethoxy)methoxy)phenyl]pentan-3-one (15).
The oxidation was carried out according to the standard
procedure using 1-[2-(ethoxymethoxy)-5-methoxyphenyl]-
5-[2-((2-methoxyethoxy)methoxy)phenyl]pentan-3-ol (49)
(43 mg, 0.096 mmol), tetra-n-propylammonium perruthen-
ate (0.2 mg, 0.0048 mmol), 4-methylmorpholine N-oxide
3.3.27. 5-[2-(Ethoxymethoxy)-5-methoxyphenyl]-1-[2-
((2-methoxyethoxy)methoxy)phenyl]pent-1-yn-3-ol (44).
The coupling reaction was carried out according to
the standard procedure using 3-[2-(ethoxymethoxy)-5-
methoxyphenyl]propanal (20) (40 mg, 0.17 mmol), 1-ethy-
nyl-2-((2-methoxyethoxy)methoxy)benzene (21) (42 mg,
0.20 mmol) and n-butyllithium (0.13 mL, 0.20 mmol). The
product was purified by column chromatography using
hexane–ethyl acetate (50:50) as the eluent to give the title
compound 44 (75 mg, 88%) as a colourless oil. (Found:
M+, 444.2146, C25H32O7 requires 444.2148); nmax (film)/
cmꢁ1 3428 (br, O–H), 2930 (m, ArC–H), 1495 (m, C–O–
C); dH (400 MHz, CDCl3) 1.23 (3H, m, OCH2CH3), 2.11
(2H, m, CH2COH), 2.65 (1H, br s, OH), 2.87 (2H, m,
CH2CH2Ar), 3.34 (3H, s, CH2CH2OCH3), 3.55 (2H, t, J
4.7, OCH2CH2OCH3), 3.75 (2H, q, J 7.4, OCH2CH3), 3.75
(3H, s, OCH3), 3.88 (2H, t, J 4.7, OCH2CH2OCH3), 4.61
(1H, t, J 6.7, CHOH), 5.18 (2H, s, OCH2OCH2CH3), 5.32
(2H, s, OCH2OCH2), 6.60–7.50 (7H, m, Ar-H); dC
(75 MHz, CDCl3) 15.1 (CH2CH3), 26.3 (CH2, C-5), 38.0
(CH2, C-4), 55.5 (OCH3), 58.9 (CH2CH3), 60.3 (CHOH),
62.3 (OCH2CH2OCH3), 64.17 (2ꢂOCH2O), 67.8
(OCH2CH2OCH3), 71.5 (OCH2CH2OCH3), 81.2 (q, Ar-
C^C), 94.1 (q, Ar-C^C), 111.4 (Ar-CH), 113.4 (q, C10),
115.4, 115.6, 116.2, 121.8, 129.7 (Ar-CH), 131.8 (q, C100),
133.5 (Ar-CH), 149.5 (q, C500), 154.4 (q, C20), 157.8 (q,
C200); m/z (EI, %) 444 (M+, 1), 292 (20), 277 (8), 222 (29),
180 (25), 89 (27), 59 (100), 45 (4).
˚
(17 mg, 0.14 mmol) and 4 A molecular sieves (100 mg).
The product was purified by column chromatography using
hexane–ethyl acetate (60:40) as the eluent to give the title
compound 15 (43 mg, >99%) as a colourless oil. (Found:
M+, 446.2303, C25H34O7 requires 446.2305); nmax (film)/
cmꢁ1 2931 (s, ArC–H), 1713 (s, C]O), 1495 (s, C–O–C),
1083 (m, C–O); dH (400 MHz, CDCl3) 1.22 (3H, t, J 7.1,
OCH2CH3), 2.69 (2H, t, J 8.2, CH2CH2Ar), 2.87 (2H, m,
CH2CH2Ar), 3.37 (3H, s, CH2CH2OCH3), 3.55 (2H, t,
J 4.5, OCH2CH2OCH3), 3.73 (3H, s, OCH3), 3.75 (2H, q,
J 7.1, CH2CH3), 3.80 (2H, t, J 4.5, OCH2CH2OCH3),
5.15 (2H, s, OCH2OCH2CH3), 5.28 (2H, s, OCH2OCH2),
6.60–7.20 (7H, m, Ar-H); dC (75 MHz, CDCl3) 15.1
(CH2CH3), 24.9, 25.0 (CH2Ar), 42.9, 42.9 (CH2CO), 55.5
(OCH3), 59.0 (OCH2CH2OCH3), 64.1 (CH2CH3), 67.7
(OCH2CH2OCH3), 71.6 (OCH2CH2OCH3), 93.4, 93.9
(2ꢂOCH2O), 111.6, 113.9, 115.5, 115.9, 121.7, 127.4,
129.9 (Ar-CH), 130.0 (q, C10), 131.44 (q, C100), 149.4 (q,
C500), 154.3 (q, C20), 155.1 (q, C200), 209.9 (q, CO); m/z
(EI, %) 446 (M+, 4), 400 (5), 294 (5), 282 (51), 161 (13),
107 (10), 89 (32), 59 (100).
3.3.30. 6-Methoxy-3,4,30,40-tetrahydro-2,20-spirobis(2H-1-
benzopyran) (10). The cyclisation was carried out according
to the standard procedure using 1-([2-(ethoxymethoxy-5-
methoxyphenyl]-5-[2-((2-methoxyethoxy)methoxy)phenyl]-
pentan-3-one (15) (40 mg, 0.09 mmol), trimethylsilyl
˚
bromide (0.12 mL, 0.9 mmol) and 4 A molecular sieves
3.3.28. 1-[2-(Ethoxymethoxy)-5-methoxyphenyl]-5-[2-
((2-methoxyethoxy)methoxy)phenyl]pentan-3-ol (49).
The hydrogenation was carried out according to the standard
procedure using 5-[2-(ethoxymethoxy)-5-methoxyphenyl]-1-
[2-((2-methoxyethoxy)methoxy)phenyl]pent-1-yn-3-ol (44)
(60 mg, 0.14 mmol), 10% palladium on carbon (51 mg,
0.049 mmol) and potassium carbonate (70 mg, 0.49 mmol).
The product was purified by column chromatography using
hexane–ethyl acetate (80:20) as the eluent to give the title
compound 49 (48 mg, 70%) as a colourless oil. (Found:
M+, 448.2461, C25H36O7 requires 448.2461); nmax (film)/
cmꢁ1 3584 (br, O–H), 2929 (s, ArC–H), 1495 (m, C–O–C);
dH (400 MHz, CDCl3) 1.24 (3H, t, J 7.0, OCH2CH3),
1.75 (2H, q, J 7.8, CH2Ar), 2.73 (3H, m, CH2COH and
CHOH), 3.37 (3H, s, CH2CH2OCH3), 3.55 (2H, m,
OCH2CH2OCH3), 3.55 (1H, m, CHOH), 3.75 (2H, m,
CH2CH3), 3.75 (3H, s, OCH3), 3.82 (2H, t, J 4.4,
OCH2CH2OCH3), 5.16 (2H, s, OCH2OCH2CH3), 5.29 (2H,
s, OCH2OCH2), 6.60–7.30 (7H, m, Ar–H); dC (75 MHz,
CDCl3) 15.1 (CH2CH3), 26.3, 26.4 (CH2Ar), 37.8, 37.8
(CH2CHOH), 55.5 (OCH3), 58.9 (CH2CH3), 62.3
(OCH2CH2OCH3), 67.7 (OCH2CH2OCH3), 70.1 (CHOH),
71.6 (OCH2CH2OCH3), 93.6, 94.2 (2ꢂOCH2O), 111.3,
114.1, 115.7, 115.9, 121.8, 127.1, 130.1 (Ar–CH), 131.1 (q,
C10), 132.6 (q, C100), 149.4 (q, C500), 154.5 (q, C20), 155.1
(50 mg). The product was purified by column chromato-
graphy using hexane–ethyl acetate (60:40) as the eluent to
give the title compound 10 (25 mg, >99%) as a colourless
solid, mp 87.5–89.0 ꢀC. (Found: M+, 282.1252, C18H18O3 re-
quires 282.1256); nmax (film)/cmꢁ1 2958 (w, ArC–H), 1488
and 1455 (w, C–O–C); dH (400 MHz, CDCl3) 1.95 (2H,
ddd, Jgem 13.2, J3ax,4ax 13.2, J3ax,4eq 5.6, 3 and 30-Hax), 2.19
(2H, ddd, Jgem 13.2, J3eq,4ax 6.0, J3eq,4eq 2.6, 3 and 30-Heq),
2.72 (2H, ddd, Jgem 16.5, J4eq,3ax 5.6, J4eq,3eq 2.6, 4 and 40-
Heq), 3.35 (2H, ddd, Jgem 16.5, J4ax,3ax 13.2, J4ax,3eq 6.0, 4
and 40-Hax), 3.74 (3H, s, OCH3), 6.60–7.30 (7H, m, Ar-H);
dC (75 MHz, CDCl3) 21.3, 22.0 (CH2CH2Ar), 31.1, 31.1
(CH2CH2Ar), 55.6 (OCH3), 96.2 (q, C2), 113.1, 113.6,
117.1, 117.6, 120.7 (Ar-CH), 122.2, 122.7 (q, C4a and
C4a0), 127.1, 129.0 (Ar-CH), 146.2 (q, C8 and C80), 152.2
(q, C8a), 153.7 (q, C8a0); m/z (EI, %) 282 (M+, 100), 175
(21), 161 (60), 145 (42), 131 (38), 107 (23), 77 (11), 73 (20).
3.3.31. 1-Iodo-3-methoxy-2-(methoxymethoxy)benzene
(39). The protection step was carried out according to the
standard procedure using 1-methoxyphenol (24) (0.996 g,
8.03 mmol), diisopropylethylamine (2.52 mL, 14.4 mmol)
and methoxymethyl chloride (0.92 mL, 8.03 mmol). The
product was purified by column chromatography using
hexane–ethyl acetate (90:10) as the eluent to give the MOM

5894
M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
ether23 (1.19 g, 88%) as a colourless oil that was used di-
rectly in the iodination step; dH (400 MHz, CDCl3) 3.50
(3H, s, OCH3), 3.86 (3H, s, OCH3), 5.21 (2H, s, OCH2O),
6.84–7.15 (4H, m, Ar-H); dC (75 MHz, CDCl3) 55.6
(OCH3), 56.0 (OCH3), 95.4 (OCH2O), 111.7, 116.5, 120.8,
122.4 (Ar-CH), 146.5 (q, C-1), 149.8 (q, C-2). To a solution
of the MOM ether (1.00 g, 5.93 mmol) in tetrahydrofuran
(5 mL) cooled to ꢁ15 ꢀC under nitrogen was added n-butyl-
lithium (4.08 mL, 6.53 mmol) dropwise with stirring. The
reaction mixture was allowed to warm to room temperature
over 2 h then cooled to ꢁ45 ꢀC and a solution of iodine was
(0.825 g, 6.53 mmol) in tetrahydrofuran (1 mL) added drop-
wise over 1 h. The cooling bath was removed and the solu-
tion was warmed to room temperature and stirred for 2 h.
The reaction mixture was concentrated under reduced pres-
sure and the residue was taken up with diethyl ether (10 mL)
and then washed with 20% sodium thiosulfate (5 mL) and
aqueous saturated sodium bicarbonate (5 mL). The organic
extract was dried over magnesium sulfate and concentrated
under reduced pressure. The resultant residue was purified
by flash chromatography using hexane–ethyl acetate
(90:10) as eluent to give the title compound 39 (0.236 g,
14%) as a colourless oil. (Found: M+, 293.9755, C9H11IO3
requires 293.9753); nmax (film)/cmꢁ1 2938 (w, ArC–H),
1569 (C–O), 1580 (O–C–O), 1290 (C–O); dH (400 MHz,
CDCl3) 3.67 (3H, s, OCH3), 3.82 (3H, s, OCH3), 5.16 (2H,
s, OCH2O), 6.75–7.37 (3H, m, Ar-H); dC (75 MHz,
CDCl3) 55.9 (OCH3), 58.3 (OCH3), 92.6 (q, C1), 98.7
(OCH2O), 112.8, 125.9, 131.0 (Ar-CH), 145.9 (q, C2),
152.4 (q, C3). m/z (EI, %) 294 (M+, 20), 264 (30), 249 (7),
167 (21), 107 (6), 94 (4), 51 (7), 45 (100).
compound 22 (109 mg, 72%) as a colourless oil. (Found:
M+, 192.0797, C11H12O3 requires 192.0780); nmax (film)/
cmꢁ1 3075 (Ar-CH), 2268 (C^C), 1469 (OCH2O), 1265,
1208, 1160 (CO); dH (400 MHz, CDCl3) 3.25 (1H, s,
C^CH), 3.64 (3H, s, OCH2OCH3), 3.84 (3H, s, OCH3),
5.24 (2H, s, OCH2OCH3), 6.90–7.10 (3H, m, Ar-CH);
dC (75 MHz, CDCl3) 55.9 (OCH3), 57.5 (OCH2OCH3),
80.1 (C^CH), 81.1 (q, C^CH), 98.5 (OCH2O), 113.4
(Ar-CH), 117.3 (q, C-1), 124.1, 125.7 (Ar-CH), 147.6 (q,
C-30), 152.4 (q, C-20). m/z (EI, %) 192 (M+, 5), 191 (6),
162 (30), 161 (22), 147 (6), 131 (11), 119 (8), 91 (7), 76
(7), 45 (100).
3.3.34. 5-[2-(Ethoxymethoxy)-5-methoxyphenyl]-1-[3-
methoxy-2-(methoxymethoxy)phenyl]pent-1-yn-3-ol
(45). The coupling reaction was carried out according to the
standard procedure using 3-[5-methoxy-2-((2-methoxy-
ethoxy)methoxy)phenyl]propanal (20) (75 mg, 0.31 mmol),
1-ethynyl-3-methoxy-2-(methoxymethoxy)benzene
(22)
(50 mg, 0.26 mmol) and n-butyllithium (0.18 mL, 0.29
mmol). The product was purified by column chromato-
graphy using hexane–ethyl acetate (60:40) as the eluent to
give the title compound 45 (87 mg, 73%) as a colourless
oil. (Found: M+, 430.1985, C24H30O7 requires 430.1992);
nmax (film)/cmꢁ1 3435 (br, O–H); dH (400 MHz, CDCl3)
1.23 (3H, m, CH2CH3), 2.07 (2H, quintet, J 6.6, 8.6,
CH2CH2Ar), 2.70 (1H, br s, OH), 2.84 (2H, m,
CH2CH2Ar), 3.63 (2H, m, OCH2CH3), 3.71 (3H, s,
OCH2OCH3), 3.73 (3H, s, 500-OCH3), 3.83 (3H, s, 30-
OCH3), 4.60 (1H, t, J 6.6, CHOH), 5.17 (2H, s,
OCH2OCH2), 5.22 (2H, s, OCH2OCH3), 6.60–7.30 (7H,
m, Ar-H); dC (75 MHz, CDCl3) 15.1 (CH2CH3), 26.2
(CH2, C-5), 37.9 (CH2, C-4), 55.5, 55.8 (2ꢂOCH3), 57.4
(OCH2OCH3), 62.3 (CHOH), 64.2 (OCH2CH3), 81.3 (q,
Ar-C^C), 94.0 (OCH2OCH2), 94.1 (q, Ar-C^C), 98.5
(OCH2OCH3), 117.8 (q, C10), 111.6, 112.9, 115.6, 116.0,
124.0, 125.2 (Ar-CH), 131.6 (q, C100), 147.0 (q, C30), 149.5
(q, C500), 152.5 (q, C20), 154.4 (q, C200); m/z (EI, %) 430
(M+, 4), 322 (46), 310 (35), 180 (55), 161 (52), 151 (44),
59 (64), 45 (100).
3.3.32. 4-[(3-Methoxy)-2-(methoxymethoxy)phenyl]-2-
methylbut-3-yn-2-ol (41). The Sonogashira reaction was
carried out according to the standard procedure using
1-iodo-3-methoxy-2-[(methoxymethoxy)]benzene
(39)
(200 mg, 0.68 mmol), 2-methyl-3-butyn-2-ol (0.106 mL,
1.09 mmol), triphenylphosphine (4 mg, 0.014 mmol),
bis(triphenylphosphine)palladium(II) dichloride (5 mg,
0.0068 mmol), triethylamine (5 mL) and copper(I) iodide
(2 mg, 0.0013 mmol). The product was purified by column
chromatography using hexane–ethyl acetate (60:40) as the
eluent to give the title compound 41 (170 mg, >99%) as
a colourless oil. (Found: M+, 250.1208, C14H18O4 requires
250.1205); nmax (film)/cmꢁ1 3689 (br, OH), 3053 (Ar-
CH), 2305 (C^C), 1469 (OCH2O), 1265, 1208, 1160
(CO); dH (400 MHz, CDCl3) 1.60 (6H, each s, 2ꢂCH3),
2.88 (1H, br s, OH), 3.65 (3H, s, OCH3), 3.84 (3H, s,
OCH3), 5.22 (2H, s, OCH2O), 6.84–7.00 (3H, m, Ar-CH);
dC (75 MHz, CDCl3) 31.0, 31.4 (C(CH3)2), 55.9 (OCH3),
57.5 (OCH3), 65.6 (q, C-2), 84.0 (q, Ar-C^C), 98.0 (q,
Ar-C^C-3), 98.5 (OCH2O), 112.8, 115.4 (Ar-CH), 117.8
(q, C10), 124.0 (Ar-CH), 146.8 (q, C30), 152.4 (q, Ar-C20).
m/z (EI, %) 250 (M+, 2), 188 (100), 175 (5), 173 (7), 160
(14), 145 (14), 131 (15), 115 (7), 45 (49), 43 (29).
3.3.35. 1-[2-(Ethoxymethoxy)-5-methoxyphenyl]-5-[3-
methoxy-2-(methoxymethoxy)phenyl]pentan-3-ol (50).
The hydrogenation was carried out according to the standard
procedure using 5-[2-(ethoxymethoxy)-5-methoxyphenyl]-
1-[3-methoxy-2-(methoxymethoxy)phenyl]pent-1-yn-3-ol
(45) (80 mg, 0.17 mmol), 10% palladium on carbon (67 mg,
0.063 mmol) and potassium carbonate (86 mg, 0.63 mmol).
The product was purified by column chromatography using
hexane–ethyl acetate (60:40) as the eluent to give the title
compound 50 (80 mg, 99%) as a colourless oil. (Found:
M+, 434.2309, C24H34O7 requires 434.2305); nmax (film)/
cmꢁ1 3584 (br, O–H), 2933 (s, ArC–H), 1499 (m, C–O–
C), 1080 (w, C–O); dH (400 MHz, CDCl3) 1.23 (3H, t, J
7.1, CH2CH3), 1.74 (4H, m, CH2CH2Ar), 2.70 (1H, br s,
OH), 2.70 (4H, m, CH2Ar), 2.80 (1H, m, CHOH), 3.70
(2H, q, J 7.1, OCH2CH3), 3.72 (3H, s, OCH2OCH3), 3.72
(3H, s, 50-OCH3), 3.81 (3H, s, 300-OCH3), 5.09 (2H, s,
OCH2OCH2), 5.15 (2H, s, OCH2OCH3), 6.60–7.10 (6H,
m, Ar-H); dC (75 MHz, CDCl3) 15.0 (CH2CH3), 26.1, 26.5
(CH2Ar), 37.8, 38.2 (CH2CHOH), 55.4, 55.5 (2ꢂOCH3),
57.5 (OCH2OCH3), 64.1 (OCH2CH3), 69.9 (CHOH), 94.0
(OCH2OCH2), 99.0 (OCH2OCH3), 109.9, 111.3, 115.5,
3.3.33. 1-Ethynyl-3-methoxy-2-(methoxymethoxy)benz-
ene (22). The reaction was carried out according to
the standard procedure using 4-[(3-methoxy-2-(methoxy-
methoxy)phenyl]-2-methylbut-3-yn-2-ol (41) (198 mg,
0.79 mmol) and sodium hydroxide (158 mg, 3.96 mmol).
The product was purified by column chromatography using
hexane–ethyl acetate (60:40) as the eluent to give the title

M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
5895
115.7, 121.9, 124.2 (Ar-CH), 132.6 (q, C00), 136.1 (q, C100),
144.1 (q, C300), 149.3 (q, C50), 152.0 (q, C200), 154.3 (q, C20);
m/z (DEI, %) 434 (M+, 1), 388 (38), 314 (50), 189 (46), 177
(43), 137 (100), 59 (44), 45 (95).
benzene (22) (40 mg, 0.21 mmol) and n-butyllithium
(0.14 mL, 0.23 mmol). The product was purified by column
chromatography using hexane–ethyl acetate (60:40) as the
eluent to give the title compound 46 (52 mg, 54%) as a
colourless oil. (Found: M+, 460.2102, C25H32O8 requires
460.2097); nmax (film)/cmꢁ1 3426 (br, O–H), 2934 (s,
ArC–H), 1471 (s, C–O–C), 1076 (m, C–O); dH (400 MHz,
CDCl3) 2.11 (2H, m, CH2CH2Ar), 2.92 (2H, m,
CH2CH2Ar), 2.94, (1H, br s, OH), 3.37 (3H, s,
CH2CH2OCH3), 3.47 (2H, t, J 4.5, OCH2CH2OCH3), 3.58
(3H, s, OCH2OCH3), 3.81, 3.83 (2ꢂOCH3), 3.92 (2H, m,
OCH2CH2OCH3), 4.60 (1H, t, J 6.0, CHOH), 5.19 (2H, s,
OCH2OCH3), 5.21 (2H, s, CH2OCH2O), 6.70–7.10 (6H,
m, Ar-H); dC (75 MHz, CDCl3) 25.9 (CH2, C-5), 38.7
(CH2, C-4), 55.6, 55.8 (OCH3), 57.4 (OCH2CH2OCH3),
58.9 (OCH2OCH3), 62.3 (CHOH), 69.0 (OCH2CH2OCH3),
71.8 (OCH2CH2OCH3), 81.0 (q, Ar-C^C), 94.4 (q, Ar-
C^C), 98.1 (OCH2OCH2), 98.5 (OCH2OCH3), 110.2,
112.8, (Ar-CH), 117.9 (q, C10), 122.1, 124.0, 124.2, 125.3
(Ar-CH), 135.4 (q, C100), 144.5, 147.0 (q, C30 and C500),
152.0, 152.5 (q, C200 and C20); m/z (EI, %) 460 (M+,
<0.5), 322 (14), 310 (31), 174 (20), 161 (23), 89 (25), 59
(100), 45 (50).
3.3.36. 1-[2-(Ethoxymethoxy)-5-methoxyphenyl]-5-[3-
methoxy-2-(methoxymethoxy)phenyl]pentan-3-one (16).
The oxidation was carried out according to the standard
procedure using 1-[2-(ethoxymethoxy)-5-methoxyphenyl]-
5-[3-methoxy-2-(methoxymethoxy)phenyl]pentan-3-ol (50)
(74 mg, 0.16 mmol), tetra-n-propylammonium perruthenate
(0.3 mg, 0.008 mmol), 4-methylmorpholine N-oxide (3 mg,
˚
0.24 mmol) and 4 A molecular sieves (20 mg). The product
was purified by column chromatography using hexane–ethyl
acetate (60:40) as the eluent to give the title compound 16
(74 mg, 95%) as a colourless oil. (Found: M+, 432.2148,
C24H32O7 requires 432.2148); nmax (film)/cmꢁ1 2931 (s,
ArC–H), 1713 (s, C]O), 1495 (s, C–O–C), 1160 (m, C–
O); dH (400 MHz, CDCl3) 1.22 (3H, t, J 7.0, CH2CH3),
2.72 (4H, m, CH2CO), 2.86, 2.93 (4H, m, CH2CH2Ar),
3.54 (3H, s, OCH2OCH3), 3.70 (2H, q, J 7.0, OCH2CH3),
3.71 (3H, s, 50-OCH3), 3.82 (3H, s, 300-OCH3), 5.08 (2H, s,
OCH2OCH2), 5.15 (2H, s, OCH2OCH3), 6.60–7.30 (6H,
m, Ar-H); dC (75 MHz, CDCl3) 15.1 (CH2CH3), 24.7, 25.0
(CH2CH2Ar), 42.9, 43.4 (CH2CO), 55.5, 55.6 (2ꢂOCH3),
57.4 (OCH2OCH3), 64.1 (OCH2CH3), 93.8 (OCH2OCH2),
98.9 (OCH2OCH3), 110.4, 111.7, 115.4, 115.8, 121.9,
124.2 (Ar-CH), 131.4 (q, C10), 135.3 (q, C100), 144.3 (q,
C300), 149.4 (q, C50), 152.1 (q, C200), 154.3 (q, C20), 209.7
(q, CO); m/z (EI, %) 432 (M+, 0.5), 386 (38), 312 (50),
187 (46), 175 (43), 137 (100), 59 (44), 45 (95).
3.3.39. 1-[3-Methoxy-2-((2-methoxyethoxy)methoxy)-
phenyl]-5-[(3-methoxy)-2-(methoxymethoxy)phenyl]-
pentan-3-ol (51). The hydrogenation was carried out
according to the standard procedure using 5-[3-methoxy-
2-((2-methoxyethoxy)methoxy)phenyl]-1-[(3-methoxy)-2-
(methoxymethoxy)phenyl]pent-1-yn-3-ol (46) (52 mg, 0.11
mmol), 10% palladium on carbon (43 mg, 0.041 mmol)
and potassium carbonate (56 mg, 0.41 mmol). The product
was purified by column chromatography using hexane–ethyl
acetate (50:50) as the eluent to give the title compound 51
(43 mg, 83%) as a colourless oil. (Found: M+, 465.2502,
C25H37O8 requires 465.2489); nmax (film)/cmꢁ1 3469 (br,
O–H), 2932 (s, ArC–H), 1474 (m, C–O–C), 1072 (w, C–
O); dH (400 MHz, CDCl3) 1.76 (4H, m, CH2CO), 2.80
(4H, m, CH2Ar), 2.80 (1H, m, CHOH), 3.37 (3H, s,
CH2CH2OCH3), 3.57 (3H, s, OCH2OCH3), 3.57 (2H, m,
OCH2CH2OCH3), 3.81, 3.82 (6H, s, 2ꢂOCH3), 3.93 (2H,
m, OCH2CH2OCH3), 5.08 (2H, s, OCH2OCH3), 5.16 (2H,
s, OCH2OCH2), 6.70–7.30 (6H, m, Ar-H); dC (75 MHz,
CDCl3) 26.3, 26.3 (CH2Ar), 38.2, 38.3 (CH2CHOH),
55.6, 55.6 (OCH3), 57.4 (OCH2CH2OCH3), 59.0
(OCH2OCH3), 69.0 (OCH2CH2OCH3), 70.1 (CHOH),
71.8 (OCH2CH2OCH3), 98.0 (OCH2OCH2), 99.0
(OCH2OCH3), 109.9, 110.0, 122.0, 122.0, 124.2, 124.2
(Ar-CH), 136.3, 136.3 (q, C100 and C10), 144.2, 144.2 (q,
C30 and C500), 151.0, 152.0 (q, C200 and C20); m/z (FAB+,
%) 465 (M+, <0.5), 307 (20), 289 (14), 154 (100), 136
(68), 107 (22), 89 (21), 77 (20).
3.3.37. 6,80-Dimethoxy-3,4,30,40,-tetrahydro-2,20-
spirobis(2H-1-benzopyran) (11). The cyclisation reaction
was carried out according to the standard procedure using
1-[2-(ethoxymethoxy)-5-methoxyphenyl]-5-[3-methoxy-
2-(methoxymethoxy)phenyl]pentan-3-one (16) (70 mg,
0.15 mmol), trimethylsilyl bromide (0.20 mL, 1.5 mmol)
˚
and 4 A molecular sieves (50 mg). The product was purified
by column chromatography using hexane–ethyl acetate
(50:50) as the eluent to give the title compound 11 (45 mg,
96%) as a colourless solid, mp 146–147 ꢀC. (Found: M+,
312.1358, C19H20O4 requires 312.1362); nmax (film)/cmꢁ1
2931 (m, ArC–H), 1482 and 1421 (w, C–O–C); dH
(400 MHz, CDCl3) 1.98 (2H, ddd, Jgem 13.1, J3ax,4ax 13.1,
J3ax,4eq 5.7, 3 and 30-Hax), 2.19 (2H, ddd, Jgem 13.1,
J3eq,4ax 5.9, J3eq,4eq 2.6, 3 and 30-Heq), 2.90 (2H, ddd, Jgem
16.2, J4eq,3ax 5.7, J4eq,3eq 2.6, 4 and 40-Heq), 3.30 (2H, ddd,
Jgem 16.3, J4ax,3ax 13.1, J4ax,3eq 5.9, 4 and 40-Hax), 6.60–
7.30 (6H, m, Ar-H); dC (75 MHz, CDCl3) 20.9, 21.5
(CH2CH2Ar), 30.8, 31.2 (CH2CH2Ar), 55.6 (6-OCH3),
56.5 (80-OCH3), 96.2 (q, C2), 111.0, 113.0, 113.6, 117.5,
120.2, 121.3 (Ar-CH), 122.8 (q, C4a), 123.2 (q, C40a),
142.2 (q, C80a,), 146.2 (q, C8a), 148.6 (q, C8 and C80),
153.6 (q, C6); m/z (EI, %) 312 (M+, 80), 188 (6), 176 (55),
174 (32), 161 (100), 137 (40), 91 (6), 77 (10).
3.3.40. 1-[3-Methoxy-2-((2-methoxyethoxy)methoxy)-
phenyl]-5-[3-methoxy-2-(methoxymethoxy)phenyl]pen-
tan-3-one (17). The oxidation was carried out according to
the standard procedure using 1-[3-methoxy-2-((2-methoxy-
ethoxy)methoxy)phenyl)]-5-[(3-methoxy)-2-(methoxy-
methoxy)phenyl)pentan-3-ol (51) (43 mg, 0.09 mmol),
tetra-n-propylammonium perruthenate (0.01 mg, 0.005
mmol), 4-methylmorpholine N-oxide (0.1 mg, 0.01 mmol)
3.3.38. 5-[(3-Methoxy)-2-((2-methoxyethoxy)methoxy)-
phenyl]-1-[3-methoxy-2-(methoxymethoxy)phenyl]pent-
1-yn-3-ol (46). The coupling reaction was carried out
according to the standard procedure using 3-[(3-methoxy)-2-
((2-methoxyethoxy)methoxy)phenyl]propanal (19) (50 mg,
0.21 mmol), 1-ethynyl-3-methoxy-2-(methoxymethoxy)-
˚
and 4 A molecular sieves (50 mg). The product was purified
by column chromatography using hexane–ethyl acetate

5896
M. A. Brimble et al. / Tetrahedron 62 (2006) 5883–5896
Heterocycles 1986, 24, 1699; (d) Jacobs, M. F.; Kitching, W.
Curr. Org. Chem. 1998, 2, 395; (e) Mead, K. T.; Brewer,
B. N. Curr. Org. Chem. 2003, 7, 227.
(50:50) as the eluent to give the title compound 17 (43 mg,
>99%) as a colourless oil. (Found: M+(+NH4), 480.2594,
C25H38NO8 requires 480.2597); nmax (film)/cmꢁ1 2936 (s,
ArC–H), 1712 (s, CO), 1476 (s, C–O–C), 1073 (s, C–O);
dH (400 MHz, CDCl3) 2.73 (4H, m, CH2CO), 2.95
(4H, m, CH2CH2Ar), 3.36 (3H, s, CH2CH2OCH3), 3.56
(3H, s, OCH2OCH3), 3.56 (2H, t, J 4.7, OCH2CH2O
CH3), 3.81, 3.82 (6H, s, 2ꢂOCH3), 3.89 (2H, t, J 4.7,
OCH2CH2OCH3), 5.08 (2H, s, OCH2OCH3), 5.17 (2H, s,
CH2OCH2O), 6.70–7.30 (6H, m, Ar-H); dC (75 MHz,
CDCl3) 24.6, 24.7 (CH2CH2Ar), 43.3, 43.3 (CH2CO), 55.6,
55.6 (OCH3), 57.4 (OCH2CH2OCH3), 58.9 (OCH2OCH3),
69.0 (OCH2CH2OCH3), 71.7 (OCH2CH2OCH3), 97.8
(OCH2OCH2), 98.9 (OCH2OCH3), 110.3, 110.4, 121.8,
121.85, 124.1, 124.13 (Ar-CH), 135.2, 135.2 (q, C100 and
C10), 144.2, 144.3 (q, C30 and C500), 152.1, 152.1 (q, C200
and C20), 209.6 (CO); m/z (DEI, %) 462 (M+, <0.5), 324
(14), 312 (71), 161 (55), 137 (30), 89 (28), 59 (100), 45 (62).
2. (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A.
Tetrahedron Lett. 1966, 3525; (b) Brockmann, H.; Lenk, W.;
Schwantje, G.; Zeeck, A. Chem. Ber. 1969, 102, 126; (c)
Brockmann, H.; Zeeck, A. Chem. Ber. 1970, 103, 1709.
3. Ueno, T.; Takahashi, H.; Oda, M.; Mizunuma, M.; Yokoyama,
A.; Goto, Y.; Mizushina, Y.; Sakaguchi, K.; Hayashi, H.
Biochemistry 2000, 39, 5995.
4. Goldman, M. E.; Salituro, G. S.; Bowen, J. A.; Williamson,
J. M.; Zink, L.; Schleif, W. A.; Emini, E. A. Mol. Pharmacol.
1990, 38, 20.
5. (a) Coronelli, C.; Pagani, H.; Bardone, M. R.; Lancini, G. C.
J. Antibiot. 1974, 27, 161; (b) Bardone, M. R.; Martinelli, E.;
Zerilli, L. F.; Cornelli, C. Tetrahedron 1974, 30, 2747.
6. Trani, A.; Dallanoce, C.; Pranzone, G.; Ripamonti, F.;
Goldstein, B. P.; Ciabatti, R. J. Med. Chem. 1997, 40, 967.
7. (a) Chino, M.; Nishikawa, K.; Umekia, M.; Hayashi, C.;
Yamazaki, T.; Tsuchida, T.; Sawa, T.; Hamada, M.; Takeuchi,
T. J. Antibiot. 1996, 49, 752; (b) Chino, M.; Nishikawa, K.;
Tsuchida, T.; Sawa, R.; Nakamura, H.; Nakamura, K. T.;
Muraoka, Y.; Ikeda, D.; Naganawa, H.; Sawa, T.; Takeuchi,
T. J. Antibiot. 1997, 50, 143.
3.3.41. 8,80-Dimethoxy-3,4,40,30-tetrahydro-2,20-
spirobis(2H-1-benzopyran) (12). The reaction was carried
out according to the standard procedure using 1-[3-methoxy-
2-((2-methoxyethoxy)-methoxy)phenyl]-5-[3-methoxy-
2-(methoxymethoxy)phenyl]pentan-3-one (17) (39 mg,
0.08 mmol), trimethylsilyl bromide (0.11 mL, 0.84 mmol)
8. Stroshane, R. M.; Chan, J. A.; Rubalcaba, E. A.; Garetson,
A. L.; Aszalos, A. A.; Roller, P. P. J. Antibiot. 1979, 32, 197.
9. (a) Moore, H. W. Science 1977, 197, 527; (b) Moore, H. W.;
Czerniak, R. Med. Res. Rev. 1981, 1, 249.
˚
and 4 A molecular sieves (50 mg). The product was purified
by column chromatography using hexane–ethyl acetate
(50:50) as the eluent to give the title compound 12 (25 mg,
96%) as a colourless solid, mp 195–196 ꢀC. (Found: M+,
312.1358, C19H20O4 requires 312.1358); nmax (film)/cmꢁ1
2934 (w, ArC–H), 1478 and 1440 (m, C–O–C); dH
(400 MHz, CDCl3) 2.00 (2H, ddd, Jgem 13.1, J3ax,4ax 13.1,
J3ax,4eq 5.8, 3-Hax), 2.32 (2H, ddd, Jgem 13.1, J3eq,4ax 5.9,
J3eq,4eq 2.6, 3-Heq), 2.76 (2H, ddd, Jgem 16.2, J4eq,3ax
5.8, J4eq,3eq 2.6, 4-Heq), 3.35 (2H, ddd, Jgem 16.2, J4ax,3ax
13.1, J4ax,3eq 5.9, 4-Hax), 3.66 (6H, s, 2ꢂOCH3), 6.60–7.30
(6H, m, Ar-H); dC (75 MHz, CDCl3) 21.1 (CH2CH2Ar),
31.1 (CH2CH2Ar), 56.4 (2ꢂOCH3), 96.4 (q, C2), 110.9,
120.2, 121.3 (Ar-CH), 123.3 (q, C4a and C4a0), 142.14 (q,
C8 and C80), 148.5 (q, C8a and C8a0); m/z (EI, %) 312
(M+, 75), 295 (5), 188 (12), 175 (44), 161 (100), 137 (44),
115 (3), 77 (8).
10. (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4709; (b) Siu, T.; Qin, D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4713.
11. (a) Capecchi, T.; de Koning, C. B.; Michael, J. P. Tetrahedron
Lett. 1998, 39, 5429; (b) Capecchi, T.; de Koning, C. B.;
Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000, 2681.
12. Brimble, M. A.; Tsang, K. Org. Lett. 2003, 5, 4425.
13. Huang, P.-L.; Won, S.-J. Helv. Chim. Acta 1999, 82, 1716.
14. Mora, P. T.; Szeki, T. J. Am. Chem. Soc. 1950, 72, 3009.
15. Livant, P.; Xu, W. J. Org. Chem. 1998, 63, 636.
16. Giasuddin, M.; Ahmed, S. A.; Uddin, Md. K.; Rahman, Md. T.;
Romman, U. K. R.; Fujio, M.; Tsuda, Y. Tetrahedron Lett.
2005, 46, 8217.
17. Clark, G. R.; Flowers, C. L.; Brimble, M. A. Acta Crystallogr.
2005, E61, 910.
18. Crosby, J.; Stirling, C. J. J. Chem. Soc. 1970, 671.
19. Schaefer, T.; Sebastian, R.; Wildman, T. A. Can. J. Chem.
1979, 57, 3005.
20. Kaufman, T. S.; Sindelar, S. Magn. Reson. Chem. 1989, 12,
1178.
Acknowledgements
The authors thank the University of Auckland for financial
support of this work.
21. El-Qisairi, A. K.; Qaseer, H. A.; Henry, P. M. J. Organomet.
Chem. 2002, 656, 168.
References and notes
22. Darling, S. D.; Wills, K. D. J. Org. Chem. 1967, 32, 2794.
23. Pardini, V. L.; Vargas, R. R.; Viertler, H.; Utley, J. H. P.
Tetrahedron 1992, 48, 7221.
1. (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617; (b)
Boivin, T. L. B. Tetrahedron 1987, 43, 3309; (c) Kluge, A. F.