A chemoenzymatic synthesis of the carbobicyclic core associated with CP-225,917 and CP-263,114 (phomoidrides A and B)

Article abstract of DOI:10.1039/b105376k

The chemoenzymatic synthesis of bicyclo[4.3.1]dec-6(7)-ene-5-carboxylic acid was reported. The synthesis involved the Diels-Alder cycloaddition of bromobenzene-derived and enantiopure cis-1,2-dihydrocatechol along with the anionic oxy-Cope rearrangement a

Full text of DOI:10.1039/b105376k

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A chemoenzymatic synthesis of the carbobicyclic core associated
with CP-225,917 and CP-263,114 (phomoidrides A and B)
Martin G. Banwell,* Kenneth J. McRae and Anthony C. Willis
1
Research School of Chemistry, Institute of Advanced Studies, The Australian National
University, Canberra, ACT 0200, Australia. E-mail: mgb@rsc.anu.edu.au
Received (in Cambridge, UK) 19th June 2001, Accepted 19th July 2001
First published as an Advance Article on the web 29th August 2001
The bromobenzene-derived and enantiopure cis-1,2-dihydrocatechol 3 has been converted, via a reaction sequence
involving Diels–Alder cycloaddition, anionic oxy-Cope rearrangement and Wolff ring-contraction steps, into
compound 4 and epimer 24, which embody key structural elements associated with the nonadride-type natural
products CP-225,917 (1) and CP-263,114 (2).
cis-1,2-dihydrocatechol 3, which is obtained in large quantity
Introduction
and in enantiopure form by microbial cis-dihydroxylation of
In 1997 Kaneko et al. at Pfizer Central Research (USA) detailed
the isolation of CP-225,917 (1) and CP-263,114 (2) from
an unidentified fungus.1 The same group reported2 that com-
pounds 1 and 2 inhibit Ras farnesyl transferase (from rat’s
brains) with IC50 values of 20 and 6 µM, respectively. The latter
compound also inhibits squalene synthase (SQS) with an IC50
of 43 µM.2 These natural products are probably biogenetically
related to the nonadrides2 and, by virtue of their structural
complexity and biological activities, have been described as
“milestone compounds”.3
bromobenzene,8 into the highly functionalised and monochiral
bicyclo[4.3.1]dec-6(7)-ene
4 (phomoidride core numbering
shown4m). The chemistry detailed herein was commenced before
the absolute stereochemistries of compounds 1 and 2 had been
established and, for convenience, we chose to use the readily
available diol 3 as starting material. However, the enantiomer
of compound 3 (viz. ent-3) is known9 so the work described
herein can be employed for the preparation of ent-4 and related
systems possessing the same absolute stereochemistry as CP-
225,917 and CP-263,114. Compound 4 embodies key structural
elements associated with the carbobicyclic core of the title
natural products and the strategy used to obtain this material is
sufficiently flexible that it should serve as a means for making
useful analogues of compounds 1 and 2 and, perhaps, the
natural products themselves.
A central objective associated with the present work was to
capitalise on our earlier experience with converting, via Diels–
Alder cycloaddition and anionic oxy-Cope rearrangement
steps, a cis-1,2-dihydrocatechol into the AB-ring substructure
(a bicyclo[5.3.1]undec-7(8)-ene) associated with taxoids.10
It was anticipated that through application of Wolff ring-
contraction techniques, such a ring system could be converted
into the required bicyclo[4.3.1]dec-6(7)-ene-5-carboxylic acid.
Results and discussion
The early stages of the reaction sequence leading, via the above-
mentioned strategy, from compound 3 to target 4 are shown
in Scheme 1. Thus, the readily available and epimerically pure
benzylidene acetal of diol 3 was subjected to Diels–Alder
reaction with α-chloroacryloyl chloride11 (which serves as a
ketene equivalent).12 The resulting epimeric mixture of acid
chlorides was immediately treated with sodium azide and the
ensuing α-chlorinated acyl azides underwent smooth Curtius
rearrangement and subsequent hydrolysis to afford ketone 5
(70% from compound 3). The ∆5,6-double bond associated with
Not surprisingly CP-225,917 and CP-263,114 have attracted
significant attention as targets for synthesis. Various
approaches,3,4 including a biomimetic one,5 have been reported
with total syntheses having recently been achieved by
Nicolaou,6a,b Shair,6c Danishefsky6d and Fukuyama.6e The last6e
and related studies7 have allowed the assignment of the
absolute stereochemistries of the title compounds which are
opposite to those implied by structures 1 and 2. It is against
this background that we now report on the conversion of the
2194
J. Chem. Soc., Perkin Trans. 1, 2001, 2194–2203
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105376k

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Scheme 1 Reagents and conditions: i, benzaldehyde dimethyl acetal (BDMA), (ϩ)-CSAؒH2O, CH2Cl2, Ϫ20 to Ϫ10 ЊC, 1 h; ii, a. α-chloroacryloyl
chloride, K2CO3, benzene, 70 ЊC, 16 h; b. NaN3, DME, 18 ЊC, 3 h; c. DME, reflux, 3 h; d. 5% v/v AcOH–H2O, 0 ЊC, 0.5 h; iii, (TMSOCH2)2,
TMSOTf, CH2Cl2, 18 ЊC, 24 h; iv, Pd/C, H2, THF, 18 ЊC, 26 h; v, PMBDMA, (ϩ)-CSAؒH2O, CH2Cl2, Ϫ20 ЊC, 3 h; vi, DIBAL-H, CH2Cl2, Ϫ50 to
0 ЊC, 10 h; vii, n-Bu3SnH, AIBN, benzene, hν, 18 ЊC, 6 h; viii, oxalyl chloride, DMSO, CH2Cl2, Ϫ78 ЊC, 4 h then NEt3, Ϫ78 ЊC, 0.5 h then Ϫ78
to 18 ЊC, 0.5 h; ix, (H2C᎐CH)MgBr, THF, Ϫ40 ЊC, 3 h; x, PPTS, 95% v/v acetone–H2O, reflux, 24 h; xi, NaH, ethyl formate, THF, 0 to 18 ЊC, 2.5 h;
᎐
xii, DBU, MEM-Cl, DMF, Ϫ55 to Ϫ20 ЊC, 5.66 h (PMP = p-methoxyphenyl).
compounds such as 5 and 6 corresponds to the sites of attach-
ment of the side chains at C-8 and C-9 in targets 1 and 2. It
is our intention, in future studies (vide infra), to exploit this
double bond as a platform for the regio- and diastereo-selective
introduction of these moieties. However, for the purposes of the
present work, the primary focus of which was to establish the
feasibility of the above-mentioned anionic oxy-Cope–Wolff
rearrangement sequence, this double bond was deleted. Thus,
the readily obtained ethylene acetal derivative, 6 (91%), of
ketone 5 was converted into the corresponding saturated
diol (97%) upon treatment with dihydrogen in the presence
of palladium on carbon, before transformation into the
p-methoxybenzylidene acetal 7 (97%). In principle, this p-
methoxybenzylidene acetal moiety could have been introduced
at the beginning of the reaction sequence, thereby avoiding the
protecting group interconversion described here. However,
attempts to prepare such an acetal by reaction of diol 3 with
p-methoxybenzaldehyde dimethyl acetal (PMBDMA) in the
presence of appropriate acid catalysts invariably led to epimeric
mixtures of the target compounds. Since, in contrast, the
corresponding reaction leading to the simple benzylidene acetal
always afforded a single epimeric product the reaction sequence
just described proved the more serviceable. Reductive cleavage
of acetal 7 could be achieved in a regioselective manner
using DIBAL-H and a 2 : 7 mixture of the p-methoxybenzyl
(PMB) mono-ethers 8 (21%) and 9 (70%), respectively, was
obtained. The required regioisomer 9 was subjected to reduc-
tive debromination with tri-n-butyltin hydride and the single
product 10 (70%) thereby obtained was submitted to oxidation
with the Dess–Martin periodinane.13 The ensuing ketone
(96%) reacted in a diastereofacially selective fashion with vinyl-
magnesium bromide to give compound 11 (85%) which was
then subjected to acetal hydrolysis using pyridinium toluene-
p-sulfonate (PPTS) as catalyst. The ketone 12 (90%) thus
obtained was subjected to a Claisen condensation reaction with
ethyl formate to provide the hydroxymethylenated product 13
(75%) with the Z-configuration about the newly introduced
double bond, such that the vinylogous acid residue can engage
in intramolecular hydrogen-bonding. Reaction of compound
13 with (2-methoxyethoxy)methyl chloride (MEM-Cl) in the
presence of DBU at low temperature produced an 8 : 1 mixture
of the expected ether 14 (80%) and the isomeric aldehyde 15
(5%) resulting from electrophilic attack of MEM-Cl at the
alternate end of the ambident anion derived from the conjugate
acid 13. The illustrated E-configuration about the enol ether
moiety within compound 14 follows from an X-ray crystal-
lographic study on a derivative (vide infra).
All attempts to engage compound 14 in an anionic oxy-Cope
rearrangement process failed and in each instance the
hydrolysis product 13 was the only characterisable reaction
product. On the basis that suppression of the hydrolysis
process, which presumably involves a nucleophilic addition–
elimination sequence, would allow for the desired arrangement
to occur, enone 14 was subjected to modified Luche reduction
conditions14 (Scheme 2) and in this manner an 8 : 1 mixture of
unstable allylic alcohols 16 (85%) and 17 (5%) was obtained.
The illustrated stereochemistries at the newly installed stereo-
genic centre within these products follow from the subsequent
chemistry. Thus, the major product, 16, underwent smooth
anionic oxy-Cope rearrangement on treatment with potassium
hydride and 18-crown-6 (18-C-6) at 60 ЊC and, after work-up
with aqueous ammonium chloride, the lactol 18 (83%) was
obtained. Subjection of this last compound to Purdie–Irvine
methylation conditions resulted in the formation of the desired
acetal 20 (92%) together with small amounts of the crystalline
by-product 19 (<5%), the structure of which was determined
by single-crystal X-ray analysis (Fig. 1). This X-ray study
effectively serves to confirm the structures of all the com-
pounds described to this point. By-product 19 is presumed
to result from contamination of the silver oxide used in the
methylation process by silver carbonate which serves as the
source of the carbon dioxide residue incorporated during
the conversion 18
19. Support for this proposition follows
from the observation that when freshly prepared, and presum-
ably carbonate-free, silver oxide is used in the O-methylation
process then acetal 20 is the exclusive product of reaction.
With the acquisition of compound 20 the introduction of
functionality necessary for carrying out the key Wolff ring-
contraction step was pursued. To these ends the MEM ether
moiety within substrate 20 was cleaved under conditions
J. Chem. Soc., Perkin Trans. 1, 2001, 2194–2203
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Scheme 2 Reagents and conditions: i, NaBH4, CeCl3, 2,6-lutidine, EtOH, 0 ЊC, 1 h; ii, KH, 18-C-6, DME, 60 ЊC, 2 h then 5% aqueous HCl, 0 ЊC,
5 min; iii, CH3I, Ag2O, DMF, reflux, 30 min; iv, PPTS, tert-BuOH, reflux, 4 h; v, Dess–Martin periodinane, CH2Cl2, 0 ЊC, 3 h; vi, NaH, ethyl formate,
THF, 0 to 18 ЊC, 1.5 h; vii, p-nitrobenzenesulfonyl azide, NEt3, CH2Cl2, 0 ЊC, 45 min; viii, MeOH, hv, 18 ЊC, 45 min.
C-5-epimer 24 (42%). The stereochemistries associated with C-5
in each of epimers 4 and 24 were readily discerned by 1H NMR
spectroscopic methods. In particular, in the spectrum of the
minor epimer the geminally-related and diastereotopic protons
at C-4 show mutual coupling (Jgem = 13.7 Hz) but only one
of them shows vicinal coupling (J = 7.8 Hz) to the adjacent
methine proton, H-5, which resonates, as a doublet, at δ 3.04.
In contrast, in the analogous spectrum of the major isomer
the equivalent methylene protons are not only coupled to
one another (Jgem = 13.3 Hz) but each are now also coupled to
H-5 (J = 11.1 and 7.4 Hz). Inspection of molecular models and
consideration of the relationship between coupling constants
and dihedral angle suggest that such observations are best
accommodated by the illustrated stereochemical assignments
for compounds 4 and 24.
The lack of any significant level of diastereoselection in the
Wolff ring-contraction of diazoketone 23 is likely to be of little
consequence because upon deprotonation each of products 4
and 24 would lead to a common ester enolate that will be used
to introduce the acetic acid side-chain required at C-5.
Conclusion
Application of the strategy detailed herein to the total synthesis
of the title compounds as well as various analogues is now
underway in these laboratories. As noted earlier, the double-
bond within Diels–Alder adducts such as 5 and 6 could serve as
a means by which to introduce the C-8 and C-9 side-chains
associated with targets 1 and 2. A possible scenario is shown
in Fig. 2 and relies on conversion of acetal 6, via standard
functional group interconversions (FGIs), into the Se-phenyl-
selenocarbonate 25. Reaction of such a species with tri-n-
butyltin hydride under conditions defined by Bachi and Bosch19
should result in formation of radical 26 which might be expected
to engage in a 5-exo-trig cyclisation onto the proximate double
bond more rapidly than it would engage in decarboxylation.19
If so, then the newly formed alkyl radical, 27, would be
expected to engage in a diastereofacially selective radical allyl-
ation reaction with, for example, an allyl sulfone20 such that
compound 28 would be obtained. Reduction of this lactone
to the corresponding lactol and subjection of the latter to
Wittig-type olefination would enable ready introduction of
the C-8 side chain associated with the phomoidrides. Similarly,
the allyl residue could be exploited in establishing the C-9
Fig. 1 ORTEP derived from single-crystal X-ray analysis of carbonate
19.
defined by Monti et al.15 and the ensuing 2Њ-alcohol 21 (85%)
was oxidised to the corresponding ketone 22 (96%) using the
Dess–Martin periodinane. In anticipation of a diazo-transfer
reaction,16 α-formylation of this last compound was achieved
under standard conditions and the product of this reaction was
immediately treated with p-nitrobenzenesulfonyl azide.17 In this
fashion the yellow-coloured α-diazoketone 23 (70% from 22)
was obtained and irradiation of a methanolic solution of this
compound, using a medium pressure mercury lamp fitted with
a Pyrex filter, then afforded a chromatographically separable
18
mixture of the Wolff rearrangement product 4 (25%) and its
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Mass spectral data are listed as: mass-to-charge ratio (m/z);
assignment (where possible); intensity relative to the base
peak. Optical rotations were measured with a Perkin-Elmer
241 polarimeter at the sodium D-line (589 nm) using the
spectroscopic grade solvents specified at 20 ЊC and at the
concentrations (c) (g 100 mLϪ1) indicated. The measurements
were carried out in a cell with a path length of 1 dm. Specific
rotations ([α]2D0) were calculated using the equation [α]D = (100α)/
(cl ) and are given in 10Ϫ1 deg cm2 gϪ1. Melting points were
recorded on a Reichert hot-stage apparatus and are uncorrected
except where otherwise stated. Elemental analyses were per-
formed by the Australian National University Microanalytical
Services Unit based in the Research School of Chemistry,
The Australian National University, Canberra, Australia.
Analytical thin layer chromatography (TLC) was conducted
on aluminium-backed 0.2 mm thick silica gel 60 F254 plates
(Merck) and the chromatograms were visualised under a
254 nm UV lamp and/or by treatment with an anisaldehyde–
sulfuric acid–ethanol (3 mL : 4.5 mL : 200 mL) dip or,
occasionally, with a phosphomolybdic acid–ceric sulfate–
sulfuric acid–water (37.5 g : 7.5 g : 37.5 mL : 720 mL) dip,
followed by heating. The retention factor (Rf) quoted is
rounded to the nearest 0.1. Flash chromatography was con-
ducted according to the method of Still and co-workers21
using silica gel 60 (mesh size 0.040–0.063 mm) as the stationary
phase and the analytical reagent (AR) grade solvents indicated.
Many starting materials and reagents were available from the
Aldrich Chemical Company or EGA-Chemie and were used as
supplied or simply distilled. Drying agents and other inorganic
salts were purchased from AJAX or BDH Chemicals. Reactions
employing air- and/or moisture-sensitive reagents and inter-
mediates were carried out under an atmosphere of dry, oxygen-
free nitrogen in flame-dried apparatus. Room temperature is
assumed to be ca. 18 ЊC. Tetrahydrofuran (THF) and diethyl
ether were dried using sodium metal and then distilled, as
required, from sodium benzophenone ketyl. Methanol was
distilled from magnesium methoxide. Dichloromethane
(CH2Cl2) was distilled from calcium hydride. Ethylene glycol
dimethyl ether (DME) was refluxed over calcium hydride
then distilled, as required, from sodium benzophenone ketyl.
N,N-Dimethylformamide (DMF) was heated at reflux over
calcium hydride for 16 h then distilled and stored over 3 Å
molecular sieves. Organic solutions obtained from work-up of
reaction mixtures were dried with magnesium sulfate (MgSO4).
Petrol refers to petroleum spirits boiling in the range 40–60 ЊC
unless otherwise specified. Organic solutions were concentrated
under reduced pressure on a rotary evaporator with the water
bath generally not exceeding 40 ЊC.
Fig. 2 Possible strategy for the regio- and diastereo-selective incor-
poration of the phomoidride side-chain synthons into a bicyclo[2.2.2]-
octanyl precursor.
side-chain, while the bicyclo[2.2.2]octane moiety could be
elaborated to the phomoidride core by the anionic oxy-Cope
and Wolff rearrangement chemistries detailed above. Work by
others2–4 has demonstrated that the so-called maleic anhydride
moiety associated with targets 1 and 2 can be installed rather
easily. Work aimed at amalgamating and implementing these
chemistries is currently underway in these laboratories. Results
will be reported in due course.
Experimental
Unless otherwise specified, proton (1H) and carbon (13C) NMR
spectra were recorded on a Varian Gemini 300 or a Varian
Mercury 300 spectrometer operating at 300 MHz for proton
and 75 MHz for carbon nuclei. Chemical shifts were recorded
as δ values in parts per million (ppm). Spectra were acquired in
deuteriochloroform (CDCl3) at 20 ЊC unless otherwise stated.
1
For H NMR spectra recorded in CDCl3, the peak due to
residual CHCl3 (δH 7.26) was used as the internal reference. 1H
NMR data are recorded as follows: chemical shift (δH) [multi-
plicity, coupling constant(s) J/Hz, relative integral, assignment
(where possible)] where multiplicity is defined as: s = singlet;
d = doublet; t = triplet; q = quartet; m = multiplet or com-
binations of the above. The central peak (δ 77.0) of the CDCl3
triplet was used as the reference for proton-decoupled
13C NMR spectra. For 13C NMR spectra, the data are given
as: chemical shift (δC) (protonicity), where protonicity is
defined as: C = quaternary; CH = methine; CH2 = methylene;
CH3 = methyl; C or CH2 = quaternary or methylene; CH or
CH3 = methine or methyl. The assignments of signals observed
in various NMR spectra were often assisted by conducting
attached proton test (APT), homonuclear (1H–1H) correlation
spectroscopy (COSY), nuclear Overhauser effect (NOE), and/
(2S,3aR,7aS)-4-Bromo-3a,7a-dihydro-2-phenyl-1,3-benzodioxole
Benzaldehyde dimethyl acetal (BDMA) (7.50 mL, 0.05 mol)
was added, dropwise, to a magnetically stirred suspension of
compound 3 (9.50 g, 0.05 mol) and (1S)-(ϩ)-camphor-10-
sulfonic acid monohydrate (CSAؒH2O) (260 mg, 1 mmol) in
anhydrous CH2Cl2 (400 mL) maintained at Ϫ20 ЊC under a
nitrogen atmosphere. The reaction mixture was allowed to
warm to 10 ЊC over 1 h then treated with NaOH (300 mL of
a 1 M aqueous solution). The separated aqueous layer was
extracted with CH2Cl2 (3 × 200 mL) and the combined organic
phases were washed with brine (1 × 400 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
afford the title acetal (ca. 14.1 g) as a white solid. This material
proved somewhat unstable and was therefore subjected, without
purification, to the next step of the reaction sequence. δH 7.49
(2H, m), 7.38 (3H, m), 6.41 (1H, d, J 6.0), 6.04 (1H, dd, J 9.6
and 3.2), 5.93 (1H, dd, J 9.6 and 6.0), 5.76 (1H, s), 4.79 (2H, m);
δC 135.9 (C), 129.6 (CH), 128.2 (CH), 127.0 (CH), 126.0 (CH),
124.2 (CH), 123.3 (CH), 122.9 (C), 99.4 (CH), 76.0 (CH), 73.4
(CH).
1
or H–13C correlation spectroscopy (HETCOR) experiments.
Infrared spectra (νmax) were recorded on either a Perkin-Elmer
1800 Fourier Transform infrared spectrophotometer or a Perkin-
Elmer Spectrum One instrument. Samples were analysed
as KBr discs (for solids) or as thin films on KBr plates (for
liquids/oils). Low and high resolution mass spectra were
recorded on a VG Fisons AutoSpec three sector (E/B/E) double
focussing mass spectrometer, using positive-ion electron impact
techniques (unless otherwise specified) at the voltages indicated.
J. Chem. Soc., Perkin Trans. 1, 2001, 2194–2203
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(2S,3aS,4R,7R,7aR)-7-Bromo-3a,4,7,7a-tetrahydro-2-phenyl-
4,7-ethano-1,3-benzodioxol-8-one (5)
(1H, s), 4.77 (1H, d, J ca. 7.5), 4.47 (1H, dd, J ca. 7.5 and 3.2),
4.27–4.20 (2H, complex m), 4.03–3.96 (2H, complex m), 3.10
(1H, m), 1.94 (1H, dd, J 13.8 and 3.8), 1.84 (1H, dd, J 13.8
and 2.2); δC 135.5 (C), 133.7 (CH), 132.0 (CH), 129.5 (CH),
128.0 (CH), 127.3 (CH), 110.7 (C), 103.7 (CH), 81.0 (CH), 79.1
(CH), 69.2 (C), 66.0 (CH2), 65.6 (CH2), 38.1 (CH2), 34.8 (CH);
(2S,3aR,7aS)-4-Bromo-3a,7a-dihydro-2-phenyl-1,3-benzodi-
oxole (10.0 g, 35.83 mmol) was added to a magnetically stirred
mixture of α-chloroacryloyl chloride (11.2 g, 89.56 mmol)
and potassium carbonate (495 mg, 3.58 mmol) in anhydrous
benzene (143 mL) maintained at room temperature under a
nitrogen atmosphere. The reaction mixture was then heated to
70 ЊC for 16 h, cooled to room temperature and concentrated
under reduced pressure. The residue thus obtained was immedi-
ately dissolved in DME and the resulting solution treated with
sodium azide (9.3 g, 143.3 mmol) while being maintained under
an atmosphere of nitrogen. The resulting suspension was
stirred at 18 ЊC for 3 h after which time the remaining solids
were removed by filtration. The filtrate was heated at reflux for
3 h then cooled to 0 ЊC and treated with cold (0 ЊC) acetic acid
(20 mL of a 5% v/v aqueous solution). After 0.5 h at 0 ЊC, the
solution was extracted with diethyl ether (3 × 200 mL) and
the combined organic phases washed with NaOH (2 × 300 mL
of a 1 M aqueous solution) and brine (1 × 300 mL) before
being dried (MgSO4), filtered and concentrated under reduced
pressure to afford a pale yellow semi-solid (ca. 10 g). Subjection
of this material to flash chromatography (silica, 15% v/v ethyl
acetate–petrol elution) provided, after concentration of the
appropriate fractions (Rf 0.4 in 25% v/v ethyl acetate–petrol),
the title compound 5 (8.0 g, 70% from compound 3) as a white
solid. Recrystallisation (ethyl acetate–petrol) of a portion of
this material afforded an analytically pure sample of the title
compound as fine white crystals, mp 160–162 ЊC, [α]D ϩ312
(c 0.3, CHCl3) (Found: C, 56.00; H, 3.93; Br, 24.74%. C15H13-
BrO3 requires C, 56.10; H, 4.08; Br, 24.88%); νmax/cmϪ1 1743,
1460, 1405, 1106, 1094, 983, 760, 702; δH 7.71–7.36 (3H, com-
plex m), 7.52 (2H, m), 6.42 (1H, m), 6.26 (1H, m), 5.85 (1H, s),
4.62 (1H, m), 4.53 (1H, m), 3.44 (1H, m), 2.44 (1H, dd, J 18.8
ϩ
ϩ
ؒ
ؒ
m/z 365 and 363 [(M Ϫ H ) , 2 and 2%], 285 [(M Ϫ Br ) , 2],
ϩ
ϩ
ؒ
ؒ
86 (C4H6O2 , 100). Found (HRMS): (M Ϫ H ) , 363.0240.
79
ϩ
ؒ
C17H17 BrO4 (M Ϫ H ) requires 363.0232.
(1R,4S,5S,6S)-1-Bromo-5,6-dihydroxybicyclo[2.2.2]octan-2-one
ethylene acetal
A magnetically stirred mixture of compound 6 (7.35 g, 20.13
mmol) and 10% Pd/C (1.2 g) in THF (100 mL), maintained at
18 ЊC, was placed under an atmosphere of hydrogen for 26 h.
After this time, the reaction mixture was filtered through a
short pad of Celite which was subsequently washed with ethyl
acetate (200 mL). The combined filtrates were concentrated
under reduced pressure to afford a pale yellow oil (ca. 7.4 g)
which was subjected to flash chromatography (silica, 50–80%
v/v ethyl acetate–petrol elution). Concentration of the appro-
priate fractions (Rf 0.4 in 60% v/v ethyl acetate–petrol), then
provided the title compound (5.45 g, 97%) as a clear, colourless
and viscous oil, [α]D ϩ1 (c 1.5, CHCl3) (Found: C, 42.49; H,
5.44; Br, 28.35%. C10H15BrO4 requires C, 43.03; H, 5.42; Br,
28.63%); νmax/cmϪ1 3400, 2950, 1325, 1155, 1089, 1027, 984;
δH 4.25 (1H, ddd, J 8.3, 3.4 and 1.7), 4.20–4.03 (3H, complex
m), 4.02–3.90 (2H, complex m), 3.35 (1H, d, J 4.6), 2.85 (1H,
d, J 3.4), 2.35 (1H, m), 2.21–2.10 (1H, complex m), 2.08–1.90
(4H, m), 1.53–1.45 (1H, m); δC 108.9 (C), 76.6 (C), 69.3 (CH),
68.4 (CH), 65.5 (CH2), 65.4 (CH2), 41.1 (CH2), 32.3 (CH),
ϩ
ؒ
26.2 (CH2), 20.7 (CH2); m/z 280 and 278 (M , 6 and 6%), 263
ϩ
ϩ
ؒ
ؒ
ؒ
and 261 [(M Ϫ HO ) , 35 and 36], 199 [(M Ϫ Br ) , 40], 181
ϩ
ϩ
ؒ
ؒ
[(M Ϫ H2O Ϫ Br ) , 100]. Found (HRMS): M , 278.0153.
C10H15 BrO4 requires M , 278.0154.
79
ϩ
ؒ
and 3.8), 2.15 (1H, dd, J 18.8 and 1.9); δ 199.8 (C᎐O), 135.6
᎐
C
(CH), 134.8 (CH), 132.3 (CH), 130.7 (CH), 129.0 (CH), 128.0
(CH), 105.8 (CH), 81.9 (CH), 80.2 (CH), 71.5 (C), 35.4 (CH),
(2S,3aS,4R,7R,7aS)-7-Bromo-3a,4,7,7a-tetrahydro-2-(4Ј-
methoxyphenyl)-4,7-ethano-1,3-benzodioxol-8-one ethylene
acetal (7)
ϩ
ؒ
34.2 (CH2); m/z 322 and 320 (M , 28 and 29%), 216 and 214
ϩ
ϩ
ؒ
ؒ
[(M Ϫ C7H6O) , 74 and 78], 174 and 172 [(M Ϫ C9H8O2) ,
ϩ
ϩ
ؒ
90 and 93], 77 (C6H5 , 100). Found (HRMS): M , 320.0049.
p-Methoxybenzaldehyde dimethyl acetal (PMBDMA) (8.77
mL, 46.67 mmol) was added, dropwise, to a magnetically stirred
solution of the above-mentioned diol (10.86 g, 38.91 mmol)
and (ϩ)-CSAؒH2O (452 mg, 1.95 mmol) in anhydrous CH2Cl2
(450 mL) maintained at Ϫ20 ЊC under a nitrogen atmosphere.
After 3 h at Ϫ20 ЊC the reaction mixture was treated with
NaOH (200 mL of a 1 M aqueous solution). The separated
aqueous layer was extracted with CH2Cl2 (3 × 250mL) and the
combined organic phases were washed with brine (1 × 400 mL)
before being dried (MgSO4), filtered and concentrated under
reduced pressure to afford a white solid. Subjection of this
material to flash chromatography (silica, 30% v/v ethyl acetate–
petrol elution) provided, after concentration of the appropriate
fractions (Rf 0.7 in 40% v/v ethyl acetate–petrol), the title
compound (14.9 g, 97%) as a white solid. Recrystallisation
(ethyl acetate–petrol) of a portion of this material afforded an
analytically pure sample of acetal 7 as clear, colourless platelets,
mp 150–152 ЊC; [α]D ϩ80 (c 0.5, CHCl3) (Found: C, 54.38; H,
5.25; Br, 20.01%. C18H21BrO5 requires C, 54.42; H, 5.33; Br,
20.11%); νmax/cmϪ1 1614, 1516, 1398, 1245, 1081, 1065, 1030;
δH 7.51 (2H, d, J 8.7), 6.93 (2H, d, J 8.7), 5.82 (1H, s), 4.62
(1H, dd, J 8.4 and 1.6), 4.32 (1H, dd, J 8.4 and 1.7), 4.20 (2H,
m), 4.04 (2H, m), 3.82 (3H, s), 2.53 (1H, m), 2.28–2.12 (4H,
complex m), 1.98 (1H, m), 1.55 (1H, m); δC 160.5 (C), 128.2
(CH), 127.9 (C), 113.6 (CH), 108.7 (C), 103.4 (CH), 78.3 (CH),
77.2 (CH), 70.6 (C), 65.7 (CH2), 65.6 (CH2), 55.1 (CH3), 40.8
(CH2), 30.0 (CH), 25.9 (CH2), 20.9 (CH2); m/z 398 and 396
C15H1379BrO3 Mϩ requires 320.0048.
ؒ
(2S,3aS,4R,7R,7aS)-7-Bromo-3a,4,7,7a-tetrahydro-2-phenyl-
4,7-ethano-1,3-benzodioxol-8-one ethylene acetal (6)
1,2-Bis(trimethylsilyoxy)ethane (20.2 mL, 82.7 mmol) was
added, dropwise, to a magnetically stirred solution of ketone 5
(8.85 g, 27.55 mmol) in anhydrous CH2Cl2 containing TMSOTf
(0.21 mL, 1.1 mmol) maintained at 18 ЊC and under a nitrogen
atmosphere. After 24 h the reaction mixture was treated with
pyridine (1 mL) then NaHCO3 (100 mL of a saturated aqueous
solution). The resulting mixture was extracted with diethyl
ether (3 × 100 mL) and the combined organic phases were
washed with NaOH (1 × 100 mL of a 1 M aqueous solution)
and brine (1 × 200 mL) before being dried (MgSO4), filtered
and concentrated under reduced pressure to afford a pale
yellow oil. Subjection of this material to flash chromatography
(silica, 20% v/v ethyl acetate–petrol elution) provided, after
concentration of the appropriate fractions (Rf 0.5 in 25% v/v
ethyl acetate–petrol), the title compound 6 (9.15 g, 91%) as a
white solid which was contaminated with trace amounts
(<10%) of the epimeric acetal. This material could be used,
without further purification, in the next step of the reaction
sequence. Recrystallisation (chloroform–petrol) of a portion of
this material afforded an analytically pure sample of compound
6 as white crystalline masses, mp 146–149 ЊC, [α]D ϩ140 (c 1.0,
CHCl3) (Found: C, 55.58; H, 4.56; Br, 21.97%. C17H17BrO4
requires C, 55.91; H, 4.69; Br, 21.88%); νmax/cmϪ1 2923, 2886,
1458, 1404, 1150, 1091, 1068, 978, 760; δH 7.49 (2H, m), 7.34
(3H, m), 6.35 (1H, d, J 8.7), 6.23 (1H, dd, J 8.7 and ca. 6), 5.74
ϩ
ϩ
ؒ
ؒ
(M , 9 and 9%), 397 and 395 [(M Ϫ H) , 14 and 12], 262
ϩ
ؒ
and 260 [(M Ϫ C8H8O2) , 31 and 33], 261 and 259 [(M Ϫ
C8H8O2 Ϫ H ) , 32 and 30], 181 [(M Ϫ C8H8O2 Ϫ Br ) , 100].
ϩ
ϩ
ؒ
ؒ
2198
J. Chem. Soc., Perkin Trans. 1, 2001, 2194–2203

View Article Online
ϩ
79
ϩ
ؒ
ؒ
Found (HRMS): M , 396.0562. C18H21 BrO5 requires M ,
396.0572.
complex m), 1.56 (1H, m), 1.32 (1H, m); δC 159.2 (C), 129.7 (C),
129.3 (CH), 113.7 (CH), 106.6 (C), 71.9 (CH2), 71.8 (CH), 66.7
(CH), 63.8 (CH2), 63.6 (CH2), 55.1 (CH3), 38.3 (CH2), 36.7
ϩ
ؒ
(1R,4R,5S,6S)-1-Bromo-6-hydroxy-5-[(4Ј-methoxyphenyl)-
methoxy]bicyclo[2.2.2]octan-2-one ethylene acetal (8) and
(1R,4R,5S,6S)-1-bromo-5-hydroxy-6-[(4Ј-methoxyphenyl)-
methoxy]bicyclo[2.2.2]octan-2-one ethylene acetal (9)
(CH), 33.1 (CH), 17.0 (CH2), 14.4 (CH2); m/z 320 (M , 7%),
ϩ
ϩ
ؒ
ؒ
302 [(M Ϫ H2O) , 4], 183 [(M Ϫ p-CH3OC6H4CH2O ) , 30],
ϩ
ؒ
ϩ
138 [(p-CH3OC6H4CH2OH) , 53], 121 (p-CH3OC6H4CH2 ,
100). Found (HRMS): M , 320.1626. C18H24O5 requires M ,
320.1624.
ϩ
ϩ
ؒ
ؒ
DIBAL-H (150.0 mL of a 1 M solution in hexane, 150.0 mmol)
was added, dropwise over 1 h, to a magnetically stirred solution
of acetal 7 (14.9 g, 37.5 mmol) in CH2Cl2 (200 mL) maintained
at Ϫ50 ЊC under a nitrogen atmosphere. The resulting mixture
was allowed to warm to 0 ЊC over 10 h, then treated with
tartaric acid (500 mL of a 1 M aqueous solution). The mixture
thus obtained was partitioned between diethyl ether (300 mL)
and brine (200 mL). The separated aqueous layer was extracted
with diethyl ether (3 × 400 mL) and the combined organic
phases were washed with brine (1 × 500 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
afford a clear, colourless oil. Subjection of this material to flash
chromatography (silica, 1 : 1.5 : 7.5 v/v/v ethyl acetate–CH2Cl2–
petrol elution) provided two fractions, A (Rf 0.3) and B (Rf 0.2).
Concentration of fraction A afforded the title compound 8
(3.16 g, 21%) as a clear, colourless oil, [α]D ϩ1 (c 0.6, CHCl3);
νmax/cmϪ1 3494, 1612, 1585, 1514, 1249, 1088, 1030; δH 7.27 (2H,
d, J 8.5), 6.89 (2H, d, J 8.5), 4.55 (2H, s), 4.28 (1H, m), 4.18
(2H, m), 3.96 (2H, m), 3.83 (1H, partially obscured m), 3.82
(3H, s), 3.46 (1H, d, J 4.2), 2.36 (1H, m), 2.13–1.86 (5H, com-
plex m), 1.48 (1H, m); δC 159.3 (C), 129.3 (CH), 129.2 (C), 113.8
(CH), 108.8 (C), 75.4 (CH), 74.9 (C or CH2), 72.1 (C or CH2),
69.0 (CH), 65.5 (2 × CH2, coincident), 55.1 (CH3), 41.1 (CH2),
(1S,3R,4S)-3-[(4Ј-Methoxyphenyl)methoxy]bicyclo[2.2.2]-
octane-2,5-dione 5-(ethylene acetal)
Dimethyl sulfoxide (10.1 mL, 143 mmol) was added, dropwise,
to a magnetically stirred solution of oxalyl chloride (6.1 mL,
69 mmol) in dry CH2Cl2 (88 mL) maintained at Ϫ78 ЊC under
an atmosphere of nitrogen. After 20 min, a solution of com-
pound 10 (7.05 g, 22.0 mmol) in dry CH2Cl2 (88 mL) was
added, dropwise and via cannula, to the reaction mixture. After
a further 4 h, triethylamine (20 mL, 143 mmol) was added,
dropwise, and the resulting homogeneous solution was stirred
at Ϫ78 ЊC for 30 min and for a further 30 min while warming
to 18 ЊC. The reaction mixture was then diluted with CH2Cl2
(500 mL) and NaHCO3 (200 mL of a saturated aqueous solu-
tion). The separated organic phase was washed with water
(1 × 200 mL) and brine (1 × 200 mL) then dried (MgSO4),
filtered and concentrated under reduced pressure to afford a
pale yellow oil. Subjection of this material to flash chrom-
atography (silica, 1 : 9 : 10 v/v/v ethyl acetate–CH2Cl2–petrol
elution) provided, after concentration of the appropriate
fractions (Rf 0.2 in 20% v/v ethyl acetate–petrol), the title
compound (6.72 g, 96%) as a clear, colourless oil, [α]D ϩ72
(c 1.8, CHCl3); νmax/cmϪ1 2951, 1733, 1612, 1585, 1512, 1464,
1356, 1301, 1247, 1092, 824, 758; δH 7.30 (2H, d, J 8.7), 6.88
(2H, d, J 8.7), 4.83 (1H, d, J 11.5), 4.62 (1H, d, J 11.5), 4.00–
3.81 (5H, complex m), 3.80 (3H, s), 2.42 (1H, m), 2.25 (1H, m),
ϩ
ؒ
30.0 (CH), 26.1 (CH2), 21.2 (CH2); m/z 400 and 398 (M , 3
ϩ
ϩ
ؒ
and 3%), 319 [(M Ϫ Br ) , <1], 121 (p-CH3OC6H4CH2 , 100).
ϩ
ؒ
79
ϩ
ؒ
Found (HRMS): M , 398.0733. C18H23 BrO5 requires M ,
398.0729.
Concentration of fraction B afforded the title compound 9
(9.90 g, 70%) as a clear, colourless oil, [α]D Ϫ9 (c 0.5, CHCl3);
νmax/cmϪ1 3494, 1612, 1585, 1514, 1249, 1086, 1028, 823; δH 7.37
(2H, d, J 8.6), 6.90 (2H, d, J 8.6), 4.93 (1H, d, J 10.4), 4.60 (1H,
d, J 10.4), 4.21–4.11 (3H, complex m), 4.02–3.97 (3H, complex
m), 3.82 (3H, s), 3.47 (1H, d, J 6.5), 2.38 (1H, m), 2.18 (1H, m),
2.04–1.86 (4H, complex m), 1.46 (1H, m); δC 159.4 (C), 129.8
(CH), 129.5 (C), 113.8 (CH), 108.9 (C), 77.9 (CH), 76.0 (CH2),
74.4 (C), 68.3 (CH), 65.5 (CH2), 65.4 (CH2), 55.1 (CH3), 41.0
(CH2), 32.7 (CH), 26.8 (CH2), 20.6 (CH2); m/z 400 and 398
2.05 (2H, m), 1.83 (4H, m); δC 214.3 (C᎐O), 159.1 (C), 129.9
᎐
(C), 129.4 (CH), 113.6 (CH), 108.3 (C), 77.5 (CH), 72.4 (CH2),
64.1 (CH2), 63.9 (CH2), 55.1 (CH3), 44.0 (CH), 41.9 (CH),
ϩ
ؒ
37.7 (CH2), 23.6 (CH2), 14.9 (CH2); m/z 318 (M , <1%), 197
ϩ
ؒ
[(M Ϫ p-CH3OC6H4CH2O ) , 23], 182 [(M Ϫ p-CH3OC6H4-
ϩ
ϩ
ؒ
CHO) , 33], 121 (p-CH3OC6H4CH2 , 100). Found (HRMS):
ϩ
ϩ
ؒ
ؒ
M , 318.1466. C18H22O5 requires M , 318.1467.
(1S,4S,5S,6R)-5-Ethenyl-5-hydroxy-6-[(4Ј-methoxyphenyl)-
methoxy]bicyclo[2.2.2]octan-2-one ethylene acetal (11)
ϩ
ϩ
ؒ
ؒ
(M , 8 and 8%), 263 and 261 [(M Ϫ p-CH3OC6H4CH2O ) , 19
Vinylmagnesium bromide (31.8 mL of a 1 M solution in THF,
31.8 mmol) was added, dropwise, to a magnetically stirred solu-
tion of the above-mentioned ketone (5.05 g, 15.9 mmol) in THF
(159 mL) maintained at Ϫ40 ЊC under a nitrogen atmosphere.
The reaction mixture was held at Ϫ40 ЊC for 3 h, then treated
with NH4Cl (100 mL of a saturated aqueous solution). The
mixture thus obtained was partitioned between diethyl ether
(300 mL) and brine (200 mL). The separated aqueous layer was
extracted with diethyl ether (3 × 200 mL) and the combined
organic phases were washed with brine (1 × 300 mL) before
being dried (MgSO4), filtered and concentrated under reduced
pressure to afford a pale yellow oil. Subjection of this material
to flash chromatography (silica, 40% v/v ethyl acetate–petrol
elution) provided, after concentration of the appropriate frac-
tions (Rf 0.5), the title compound 11 (4.68 g, 85%) as a clear,
colourless oil, [α]D ϩ23 (c 1.2, CHCl3); νmax/cmϪ1 3513, 2932,
1612, 1514, 1251, 1079; δH 7.23 (2H, d, J 8.7), 6.88 (2H, d,
J 8.7), 6.05 (1H, dd, J 17.2 and 10.7), 5.33 (1H, dd, J 17.2
and 1.6), 5.07 (1H, dd, J 10.7 and 1.6), 4.50 (2H, s), 3.99–3.82
(4H, complex m), 3.81 (3H, s), 3.73 (1H, app t, J 2.0), 2.08–1.98
(1H, complex m), 1.94–1.87 (2H, complex m), 1.85–1.70 (3H,
m), 1.56 (1H, m), 1.30 (1H, m) [signal due to OH not observed];
δC 159.3 (C), 143.5 (CH), 129.8 (C), 129.4 (CH), 113.7 (CH),
112.3 (CH2), 109.7 (C), 75.8 (CH), 72.3 (CH2), 71.3 (C), 63.8
(CH2), 63.6 (CH2), 55.1 (CH3), 38.0 (CH), 37.6 (CH), 37.2
ϩ
ؒ
and 20], 138 [(p-CH3OC6H4CH2OH) , 75], 121 (p-CH3OC6H4-
ϩ
ϩ
CH2 , 100). Found (HRMS): M , 398.0730. C18H2379BrO5,
ؒ
Mϩ requires 398.0729.
ؒ
(1S,4S,5S,6R)-5-Hydroxy-6-[(4Ј-methoxyphenyl)methoxy]-
bicyclo[2.2.2]octan-2-one ethylene acetal (10)
n-Bu3SnH (3.9 mL, 13.0 mmol) was added, dropwise, to a
magnetically stirred solution of compound 9 (4.0 g, 10.0 mmol)
and azoisobutyronitrile (AIBN) (33 mg, 0.2 mmol) in degassed
benzene (10 mL) maintained at room temperature under an
atmosphere of nitrogen. The reaction mixture was then sub-
jected to irradiation, using a medium-pressure mercury-vapour
lamp (125 W) contained within a water-cooled quartz jacket,
for 6 h during which time (after 3 h) a second equivalent of
AIBN (33 mg, 0.2 mmol) was added. The solvents were then
removed under reduced pressure and the residue thus obtained
was subjected to flash chromatography (silica, 20–50% v/v ethyl
acetate–petrol elution). Concentration of the appropriate
fractions (Rf 0.2 in 20% v/v ethyl acetate–petrol) then afforded
the title compound 10 (2.24 g, 70%) as a clear, colourless oil,
[α]D Ϫ20 (c 1.6, CHCl3); νmax/cmϪ1 3508, 2932, 1612, 1514, 1250,
1079, 1032, 1020; δH 7.27 (2H, d, J 8.5), 6.89 (2H, d, J 8.5), 4.50
(2H, ABq, J 11.4), 3.97–3.82 (6H, complex m), 3.81 (3H, s),
2.97 (1H, br s), 1.96–1.87 (2H, complex m), 1.86–1.71 (4H,
J. Chem. Soc., Perkin Trans. 1, 2001, 2194–2203
2199

View Article Online
ϩ
ϩ
ϩ
ؒ
ؒ
ؒ
(CH2), 19.4 (CH2), 13.9 (CH2); m/z 346 (M , <1%), 319
<1%), 312 [(M Ϫ H2O) , 1], 209 [(M Ϫ p-CH3OC6H4CH2 ) ,
ϩ
ϩ
ϩ
ϩ
ؒ
ؒ
ؒ
[(M Ϫ C2H3 ) , <1], 225 [(M Ϫ p-CH3OC6H4CH2 ) , 37], 121
(p-CH3OC6H4CH2 , 100). Found (HRMS): M , 346.1780.
8), 121 (p-CH3OC6H4CH2 , 100). Found (HRMS): M ,
330.1468. C19H22O5 requires M , 330.1467.
ϩ
ϩ
ϩ
ؒ
ؒ
ϩ
ؒ
C20H26O5 requires M , 346.1780.
(1S,3E,4S,5S,6R)-5-Ethenyl-5-hydroxy-3-(2Ј-methoxyethoxy-
methoxymethylene)-6-[(4Ј-methoxyphenyl)methoxy]bicyclo-
[2.2.2]octan-2-one (14) and (1S,4S,5R,6S)-6-ethenyl-6-hydroxy-
3-(2Ј-methoxyethoxymethoxy)-5-[(4Ј-methoxyphenyl)methoxy]-
bicyclo[2.2.2]oct-2-ene-2-carbaldehyde (15)
(1S,4S,5S,6R)-5-Ethenyl-5-hydroxy-6-[(4Ј-methoxyphenyl)-
methoxy]bicyclo[2.2.2]octan-2-one (12)
Pyridinium toluene-p-sulfonate (PPTS) (1.13 g, 4.50 mmol)
was added to a magnetically stirred solution of ketal 11 (5.2 g,
15.0 mmol) in acetone (156 mL of a 95% v/v aqueous solution)
maintained at ambient temperature. The reaction mixture was
heated at reflux for 24 h then cooled to 18 ЊC and partitioned
between diethyl ether (400 mL) and NaHCO3 (100 mL of a
saturated aqueous solution). The separated aqueous layer was
extracted with diethyl ether (3 × 100 mL) and the combined
organic phases were washed with brine (1 × 300 mL) before
being dried (MgSO4), filtered and concentrated under reduced
pressure to afford a white solid. Subjection of this material
to flash chromatography (silica, 20% v/v ethyl acetate–petrol
elution) provided, after concentration of the appropriate
fractions (Rf 0.5), the title compound 12 (1.22 g, 90%) as a white
solid. Recrystallisation (diethyl ether) of a portion of this
material afforded an analytically pure sample of ketone 12 as
colourless prisms, mp 102–103 ЊC; [α]D ϩ11 (c 0.9, CHCl3)
(Found: C, 71.48; H, 7.50%. C18H22O4 requires C, 71.50; H,
7.33%); νmax/cmϪ1 3552, 1717, 1611, 1516, 1243, 1101, 1030,
995, 921, 821; δH 7.23 (2H, d, J 8.7), 6.87 (2H, d, J 8.7), 5.91
(1H, dd, J 17.2 and 10.7), 5.27 (1H, br d, J 17.2), 5.13 (1H, dd,
J 10.7 and 1.3), 4.57 (1H, d, J 11.3), 4.47 (1H, d, J 11.3), 3.81
(3H, s), 3.68 (1H, br s), 3.59 (1H, m), 2.62 (1H, app q, J ca. 2.6),
2.36–2.13 (5H, complex m), 1.56 (1H, m), 1.38 (1H, m);
δC 213.9 (C), 159.4 (C), 142.3 (CH), 129.4 (CH), 128.7 (C),
113.7 (CH), 113.2 (CH2), 74.4 (CH), 72.0 (CH2), 71.2 (C), 55.0
(CH3), 47.9 (CH), 41.2 (CH2), 38.4 (CH), 19.8 (CH2), 15.4
DBU (2.08 mL, 13.94 mmol) was added, dropwise, to a mag-
netically stirred solution of compound 13 (3.07 g, 9.29 mmol)
in DMF (93 mL), maintained at 0 ЊC under an atmosphere
of nitrogen. After 10 min, the reaction mixture was cooled to
Ϫ55 ЊC and a solution of MEM-Cl (2.12 mL, 18.58 mmol) in
DMF (93 mL) was added dropwise over 40 min. The reaction
mixture thus obtained was allowed to warm to Ϫ20 ЊC over 5 h,
then treated with NH4Cl (100 mL of a saturated aqueous solu-
tion) and water (50 mL). The separated aqueous layer was
extracted with diethyl ether (3 × 200 mL) and the combined
organic phases were washed with water (3 × 100) and brine
(1 × 300 mL) before being dried (MgSO4), filtered and con-
centrated under reduced pressure to afford a pale yellow oil.
Subjection of this material to flash chromatography (silica,
30% v/v ethyl acetate–petrol elution) provided two fractions,
A (Rf 0.2) and B (Rf 0.1).
Concentration of fraction A afforded the title compound 14
(3.11 g, 80%) as a clear, colourless oil, [α]D ϩ14 (c 1.4, CHCl3);
νmax/cmϪ1 3500, 1703, 1624, 1514, 1302, 1249, 1078, 960, 832;
δH 7.44 (1H, s), 7.22 (2H, d, J 8.6), 6.86 (2H, d, J 8.6), 5.80
(1H, dd, J 17.0 and 10.6), 5.33 (1H, dd, J 17.0 and 1.6), 5.08
(2H, s), 4.96 (1H, dd, J 10.6 and 1.6), 4.53 (1H, d, J 11.2), 4.45
(1H, d, J 11.2), 3.81 (3H, s), 3.71 (3H, m), 3.51 (3H, m), 3.38
(3H, s), 3.05 (1H, m), 2.64 (1H, m), 2.30 (1H, m), 2.09 (1H, m),
1.54 (1H, m), 1.34 (1H, m); δC 201.4 (C), 159.4 (C), 150.7 (CH),
143.2 (CH), 129.5 (CH), 128.9 (C), 118.6 (C or CH2), 113.8
(CH), 111.9 (C or CH2), 97.1 (CH2), 76.1 (CH), 72.3 (C or
CH2), 71.3 (C or CH2), 71.2 (C or CH2), 68.2 (C or CH2),
59.0 (CH3), 55.2 (CH3), 47.9 (CH), 38.6 (CH), 19.7 (CH2),
ϩ
ϩ
ؒ
ؒ
(CH2); m/z 302 (M , <1%), 284 [(M Ϫ H2O) , 2], 181
ϩ
ϩ
ؒ
[(M Ϫ p-CH3OC6H4CH2 ) , 18], 121 (p-CH3OC6H4CH2 , 100).
Found (HRMS): (M Ϫ H2O) , 284.1410. C18H22O4 requires
(M Ϫ H2O) , 284.1412.
ϩ
ؒ
ϩ
ؒ
ϩ
ϩ
ؒ
15.2 (CH2); m/z 419 [(M ϩ H) , <1%], 312 [(M Ϫ C4H10O3 ) ,
ϩ
(1S,3Z,4S,5S,6R)-5-Ethenyl-5-hydroxy-3-(hydroxymethylene)-
6-[(4Ј-methoxyphenyl)methoxy]bicyclo[2.2.2]octan-2-one (13)
37], 121 (p-CH3OC6H4CH2 , 100). Found (HRMS): (M ϩ H)ϩ,
419.2072. C23H30O7 requires (M ϩ H)ϩ, 419.2070.
Concentration of fraction B afforded the title compound 15
(194 mg, 5%) as a clear, colourless oil, νmax/cmϪ1 3498, 2935,
1703, 1654, 1615, 1514, 1248, 1102, 978, 838; δH 9.97 (1H, s),
7.25 (2H, d, J ca. 8.5), 6.89 (2H, d, J ca. 8.5), 5.65 (1H, dd,
J 17.0 and 10.6), 5.26 (1H, dd, J 17.0 and 1.6), 5.24 (1H, d,
J 7.0), 5.12 (1H, d, J 7.0), 4.92 (1H, dd, J 10.6 and 1.6), 4.54
(2H, m), 3.81 (3H, s), 3.78 (2H, m), 3.51 (2H, m), 3.42 (1H, m),
3.34 (3H, s), 3.19 (2H, m), 2.20 (1H, m), 2.02 (1H, m), 1.31 (1H,
m), 1.06 (1H, m) [signal due to OH not observed]; δC 184.5
(CH), 170.6 (C), 159.5 (C), 144.1 (CH), 129.6 (CH), 129.2 (C),
121.4 (C), 113.9 (CH), 111.9 (CH2), 92.2 (CH2), 77.5 (CH), 72.7
(C or CH2), 71.3 (C or CH2), 70.4 (C or CH2), 68.5 (C or CH2),
58.9 (CH3), 55.3 (CH3), 36.8 (CH), 36.1 (CH), 20.3 (CH2),
A solution of compound 12 (2.92 g, 9.66 mmol) in THF (50
mL) was added, dropwise, to a magnetically stirred suspension
of NaH (966 mg, ca. 60% dispersion in mineral oil, 24.1 mmol)
in THF (46 mL) maintained at 0 ЊC under an atmosphere of
nitrogen. After 30 min, ethyl formate (7.12 mL, 96.6 mmol) was
added, dropwise, and the reaction mixture was allowed to warm
to 18 ЊC over 2 h before being treated with H2SO4 (50 mL of a
2 M aqueous solution). The resulting mixture was extracted
with diethyl ether (3 × 100 mL) and the combined organic
phases were washed with brine (1 × 200 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
afford the title compound 13 (2.39 g, 75%) as a white solid. This
material could be used, without purification, in the next step
of the reaction sequence. Recrystallisation (DME–petrol) of a
portion of this material afforded an analytically pure sample of
the vinylogous acid 13 as pale pink crystals, mp 114–115 ЊC;
[α]D Ϫ25 (c 1.1, CHCl3) (Found: C, 69.03; H, 6.61%. C19H22O5
requires C, 69.07; H, 6.71%); νmax/cmϪ1 3522, 1672, 1611, 1517,
1246, 1091, 831, 823; δH 7.22 (2H, d, J 8.7), 7.15 (1H, s), 6.88
(2H, d, J 8.7), 5.82 (1H, dd, J 17.0 and 10.5), 5.30 (1H, dd,
J 17.0 and 1.6), 5.04 (1H, br d, J 10.5), 4.55 (1H, d, J 11.2), 4.47
(1H, d, J 11.2), 3.81 (3H, s), 3.65 (1H, br s), 3.44 (1H, br s), 2.72
(1H, app q, J ca. 2.6), 2.45 (1H, app t, J ca. 2.8), 2.36 (1H, m),
2.08 (1H, m), 1.46 (1H, m), 1.33 (1H, m) [signal due to enolic
OH not observed]; δC 203.7 (C), 162.2 (CH), 159.6 (C), 143.4
(CH), 129.6 (CH), 128.8 (C), 114.1 (C or CH2), 113.9 (CH),
112.5 (C or CH2), 76.2 (CH), 72.6 (CH2), 71.2 (C), 55.2 (CH3),
ϩ
ϩ
ؒ
ؒ
16.5 (CH2); m/z 418 (M , <1%), 312 [(M Ϫ C4H10O3 ) , 6], 121
ϩ
ϩ
ؒ
(p-CH3OC6H4CH2 , 100). Found (HRMS): M , 418.1993.
ϩ
ؒ
C23H30O7 requires M , 418.1992.
(1S,2S,3R,4R,5R,6E )-2-Ethenyl-6-(2Ј-methoxyethoxymethoxy-
methylene)-3-[(4Ј-methoxyphenyl)methoxy]bicyclo[2.2.2]octane-
2,5-diol (16) and (1S,2S,3R,4R,5S,6E )-2-ethenyl-6-(2Ј-meth-
oxyethoxymethoxymethylene)-3-[(4Ј-methoxyphenyl)methoxy]-
bicyclo[2.2.2]octane-2,5-diol (17)
Sodium borohydride (90 mg, 2.38 mmol) was added to a
magnetically stirred suspension of cerium() chloride (586 mg,
2.38 mmol) in EtOH (25 mL) maintained at 0 ЊC under a
nitrogen atmosphere. After 30 min, a solution of compound 14
(500 mg, 1.19 mmol) in ethanol (12 mL) containing 2,6-lutidine
(2.4 mL) was added, dropwise, to the reaction mixture. After
ϩ
ؒ
46.6 (CH), 41.5 (CH), 21.0 (CH2), 14.7 (CH2); m/z 330 (M ,
2200
J. Chem. Soc., Perkin Trans. 1, 2001, 2194–2203

View Article Online
ϩ
ؒ
1 h at 0 ЊC the reaction mixture was diluted with water (30 mL)
and the resulting solution was extracted with diethyl ether
(3 × 50 mL). The combined organic phases were washed with
brine (1 × 100 mL) before being dried (MgSO4), filtered and
concentrated under reduced pressure to afford a pale yellow
oil which was immediately subjected to flash chromatography
(silica, 30% v/v ethyl acetate–petrol containing 1% triethyl-
amine elution). In this way two fractions, A (Rf 0.5 in 60% v/v
ethyl acetate–petrol) and B (Rf 0.4 in 60% v/v ethyl acetate–
petrol) were obtained.
(CH2), 22.4 (CH2), 18.5 (CH2); m/z 402 [(M-H2O) , <1%], 314
ϩ
(5), 121 (p-CH3OC6H4CH2 , 100). Found (HRMS): (M Ϫ
ϩ
ϩ
ؒ
ؒ
H2O) , 402.2042. C23H32O7 requires (M Ϫ H2O) , 402.2042.
(1S,2R,6R,11R)-6-(2Ј-Methoxyethoxymethoxy)-2-[(4Ј-methoxy-
phenyl)methoxy]-3-oxobicyclo[5.3.1]undec-7(8)-en-11-yl methyl
carbonate (19) and (2R,5R,9S,9aR,10R)-2,3,4,5,7,8,9,9a-octa-
hydro-2-methoxy-5-(2Ј-methoxyethoxymethoxy)-10-[(4Ј-
methoxyphenyl)methoxy]-2,9-methano-1-benzoxepine (20)
A magnetically stirred suspension of compound 18 (42 mg,
0.1 mmol) in DMF (2 mL) and iodomethane (2 mL) con-
taining silver() oxide (231 mg, 1.0 mmol) was heated at reflux
(ca. 43 ЊC) while being maintained under a nitrogen atmos-
phere. After 30 min, the reaction mixture was cooled to 18 ЊC
and filtered through a short (2 cm) plug of Celite which was
washed with ethyl acetate (5 mL). The combined filtrates were
concentrated under reduced pressure to afford a pale yellow
oil which was immediately subjected to flash chromatography
(silica, 30% v/v ethyl acetate–petrol elution) and which provided
two fractions, A (Rf 0.1) and B (Rf 0.2).
Concentration of fraction A afforded the title compound 19
(2.5 mg, <5%) as a colourless solid. Recrystallisation (diethyl
ether–hexane) of this material afforded an analytically pure
sample of carbonate 19 as colourless needles, mp 99–100 ЊC;
[α]D ϩ61(c 1.1, CHCl3); νmax/cmϪ1 1754, 1697, 1613, 1517, 1270,
1253, 1033; δH 7.22 (2H, d, J 8.7), 6.83 (2H, d, J 8.7), 5.81 (1H,
m), 5.31 (1H, m), 4.63 (2H, s), 4.38 (1H, partially obscured m),
4.36 (2H, ABq, J 11.2), 4.31 (1H, d, J 4.7), 3.85 (3H, s), 3.79
(3H, s), 3.73 (1H, m), 3.61–3.48 (3H, complex m), 3.38 (3H, s),
Concentration of fraction A afforded the title compound 16
(425 mg, 85%) as a clear, colourless oil, [α]D Ϫ35 (c 1.4, CHCl3).
νmax/cmϪ1 3480, 2937, 1684, 1612, 1514, 1463, 1248, 1182, 1091,
1055, 992, 921, 831; δH 7.24 (2H, d, J 8.6), 6.86 (2H, d, J 8.6),
6.46 (1H, s), 6.05 (1H, dd, J 17.1 and 10.6), 5.40 (1H, dd, J 17.1
and 2.0), 4.98 (1H, dd, J 10.6 and 2.0), 4.90 (2H, s), 4.51 (2H, s),
4.39 (1H, br s), 3.80 (3H, s), 3.78 (1H, s), 3.76–3.65 (3H, com-
plex m), 3.53 (2H, m), 3.38 (3H, s), 2.80 (1H, m), 2.15–2.01 (2H,
m), 1.91 (1H, m), 1.29–1.14 (2H, m) [signal due to OH not
observed]; δC 159.2 (C), 144.1 (CH), 141.7 (CH), 129.8 (C),
129.4 (CH), 121.3 (C), 113.7 (CH), 111.1 (CH2), 95.4 (CH2),
75.5 (CH), 72.5 (C or CH2), 71.8 (C or CH2), 71.4 (C or CH2),
69.2 (CH), 67.2 (CH2), 58.9 (CH3), 55.2 (CH3), 38.9 (CH),
ϩ
ؒ
37.5 (CH), 19.0 (CH2), 16.0 (CH2); m/z 344 [(M Ϫ C3H8O2) ,
ϩ
3%], 121 (p-CH3OC6H4CH2 , 100). Found (HRMS): (M Ϫ C3-
ϩ
ϩ
ؒ
ؒ
H8O2) , 344.1625. C23H32O7 requires (M-C3H8O2) , 344.1624.
Concentration of fraction B afforded the title compound 17
(25 mg, 5%) as a clear, colourless oil, νmax/cmϪ1 3480, 2938,
1682, 1612, 1514, 1249, 1052; δH 7.23 (2H, d, J 8.6), 6.87 (2H, d,
J 8.6), 6.46 (1H, s), 5.84 (1H, dd, J 17.0 and 10.6), 5.35 (1H, dd,
J 17.0 and 1.8), 4.95 (1H, dd, J 10.6 and 1.8), 4.89 (2H, ABq,
J 6.7), 4.50 (2H, s), 4.18 (1H, m), 3.81 (3H, s), 3.80–3.53 (5H,
complex m), 3.39 (3H, s), 3.17 (1H, br s), 2.77 (1H, m), 2.15–
2.10 (2H, complex m), 1.75–1.59 (3H, complex m), 1.37–1.33
(1H, complex m); δC 159.4 (C), 144.1 (CH), 143.2 (CH), 129.5
(C), 129.4 (CH), 121.1 (C), 113.8 (CH), 111.4 (CH2), 95.5
(CH2), 77.3 (CH), 72.2 (C or CH2), 71.5 (C or CH2), 71.4 (C or
CH2), 68.2 (CH), 67.4 (C or CH2), 59.0 (CH3), 55.3 (CH3), 37.5
2.91 (1H, m), 2.38–1.71 (8H, complex m); δ 211.9 (C᎐O), 159.3
᎐
C
(C), 154.8 (C), 136.8 (C), 129.7 (C), 129.5 (CH), 127.4 (CH),
113.7 (CH), 93.5 (CH2), 79.6 (CH), 75.4 (CH), 71.7 (CH2),
71.2 (CH), 70.8 (CH2), 67.0 (CH2), 59.0 (CH3), 55.2 (CH3),
55.1 (CH3), 44.2 (CH), 38.5 (CH2), 33.1 (CH2), 20.5 (CH2),
ϩ
ؒ
17.0 (CH2); m/z 434 [(M Ϫ C2H4O ) , <1%], 372 (13), 121 (p-
ϩ
ϩ
ؒ
CH3OC6H4CH2 , 100). Found (HRMS): (M Ϫ C2H4O ) ,
ϩ
ؒ
434.1938. C25H34O9 requires (M Ϫ C2H4O ) , 434.1941.
Concentration of fraction B afforded the title compound 20
(40 mg, 92%) as a clear, colourless oil, [α]D ϩ80 (c 1.1, CHCl3);
νmax/cmϪ1 1612, 1514, 1248, 1110, 1037; δH 7.18 (2H, d, J 8.6),
6.85 (2H, d, J 8.6), 5.85 (1H, m), 4.71 (2H, s), 4.64 (1H, m), 4.45
(2H, ABq, J 11.5), 4.41 (1H, partially obscured m), 3.91 (1H,
d, J 9.3), 3.83–3.76 (1H, partially obscured m), 3.80 (3H, s),
3.67–3.54 (3H, complex m), 3.39 (3H, s), 3.30 (3H, s), 2.70 (1H,
m), 2.19–2.00 (3H, complex m), 1.93–1.59 (5H, complex m);
δC 158.9 (C), 142.1 (C), 130.2 (C), 128.6 (CH), 120.6 (CH),
113.6 (CH), 112.1 (C), 93.5 (CH2), 83.0 (CH), 75.7 (CH), 73.2
(CH), 73.1 (CH2), 71.7 (CH2), 66.8 (CH2), 58.9 (CH3), 55.1
(CH3), 49.2 (CH3), 41.0 (CH), 33.4 (CH2), 31.4 (CH2), 22.4
(CH2), 18.5 (CH2); m/z 358 (<1%), 345 (<1), 328 [(M Ϫ C4-
ϩ
ؒ
(CH), 36.7 (CH), 19.4 (CH2), 11.9 (CH2); m/z 420 (M , 2%),
ϩ
ؒ
344 [(M Ϫ C3H8O2) , 5], 223 (40), 193 (100). Found (HRMS):
ϩ
ؒ
M , 420.2138.
(2R,5R,9S,9aR,10R)-2,3,4,5,7,8,9,9a-Octahydro-5-(2Ј-
methoxyethoxymethoxy)-10-[(4Ј-methoxyphenyl)methoxy]-2,9-
methano-1-benzoxepin-2-ol (18)
Potassium hydride (95 mg, 2.37 mmol) was added, in portions,
to a magnetically stirred solution of compound 16 (200 mg,
0.48 mmol) and 18-crown-6 (253 mg, 0.95 mmol) in DME
(16 mL) maintained at 0 ЊC under an atmosphere of nitrogen.
The resulting pale orange solution was heated to 60 ЊC for 2 h
then cooled to 0 ЊC and treated with HCl (15 mL of a 5% v/v
aqueous solution). The resulting solution was extracted with
diethyl ether (3 × 50 mL) and the combined organic phases
were washed with brine (1 × 50 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
afford a pale yellow oil. Subjection of this material to flash
chromatography (silica, 60% v/v ethyl acetate–petrol elution)
provided, after concentration of the appropriate fractions
(Rf 0.4 in 80% v/v ethyl acetate–petrol), the title compound 18
(168 mg, 83%) as a clear, colourless oil, [α]D ϩ90 (c 1.1, CHCl3);
νmax/cmϪ1 3388, 1611, 1513, 1456, 1247, 1033; δH 7.20 (2H, d,
J 8.7), 6.85 (2H, d, J 8.7), 5.86 (1H, m), 4.73 (2H, m), 4.63 (1H,
m), 4.50 (2H, ABq, J 11.5), 4.37 (1H, m), 3.83 (2H, m), 3.79
(3H, s), 3.66–3.54 (3H, complex m), 3.39 (3H, s), 2.80 (1H, m),
2.70 (1H, s), 2.23–2.11 (3H, complex m), 2.01 (1H, m), 1.79–
1.57 (4H, complex m); δC 158.9 (C), 142.0 (C), 130.3 (C), 128.6
(CH), 120.8 (CH), 113.6 (CH), 109.2 (C), 93.5 (CH2), 87.0
(CH), 76.0 (CH), 73.2 (CH2), 73.2 (CH), 71.7 (CH2), 66.8
(CH2), 58.9 (CH3), 55.2 (CH3), 40.6 (CH), 34.4 (CH2), 33.3
ϩ
ϩ
ؒ
H10O3) , 10], 121 (p-CH3OC6H4CH2 , 100). Found (HRMS):
ϩ
ؒ
(M Ϫ C4H10O3) , 328.1672. C24H34O7 requires (M Ϫ C4H10-
O3) , 328.1674.
ϩ
ؒ
(2R,5R,9S,9aR,10R)-2,3,4,5,7,8,9,9a-Octahydro-2-methoxy-10-
[(4Ј-methoxyphenyl)methoxy]-2,9-methano-1-benzoxepin-5-ol
(21)
A solution of compound 20 (204 mg, 0.47 mmol) in t-BuOH
(4.7 mL) containing pyridinium toluene-p-sulfonate (586 mg,
2.35 mmol) was heated at reflux under an atmosphere of nitro-
gen for 4 h. The cooled reaction mixture was then diluted with
water (20 mL) and the resulting solution extracted with diethyl
ether (3 × 30 mL). The combined organic phases were washed
with brine (1 × 50 mL) before being dried (MgSO4), filtered
and concentrated under reduced pressure to afford a pale
yellow oil. Subjection of this material to flash chromatography
(silica, 30% v/v ethyl acetate–petrol elution) provided, after
concentration of the appropriate fractions (Rf 0.7 in 45% ethyl
acetate–petrol), the title compound 21 (138 mg, 85%) as a clear,
J. Chem. Soc., Perkin Trans. 1, 2001, 2194–2203
2201

View Article Online
colourless oil, [α]D ϩ20 (c 1.3, CHCl3) (Found: C, 69.21; H,
7.49%. C20H26O5 requires C, 69.34; H, 7.56%); νmax/cmϪ1 3438,
1612, 1585, 1513, 1247, 1111, 1091, 1062, 1034; δH 7.21 (2H, d,
J 8.7), 6.85 (2H, d, J 8.7), 5.91 (1H, m), 4.67 (1H, br d, J ca. 8),
4.48 (2H, ABq, J 11.5), 4.44 (1H, br d, J ca. 8), 3.93 (1H, d,
J 9.2), 3.80 (3H, s), 3.30 (3H, s), 2.86 (1H, m), 2.18–1.59 (8H,
complex m); δC 158.9 (C), 145.4 (C), 130.2 (C), 128.7 (CH),
119.2 (CH), 113.6 (CH), 112.4 (C), 82.6 (CH), 75.8 (CH), 73.2
(CH2), 69.2 (CH), 55.2 (CH3), 49.1 (CH3), 41.2 (CH), 35.5
(CH2), 31.9 (CH2), 22.4 (CH2), 18.6 (CH2) [signal due to OH
afford a yellow oil. Subjection of this material to flash chrom-
atography (silica, 1 : 29 : 70 v/v/v triethylamine–ethyl acetate–
petrol elution) provided, after concentration of the appropriate
fractions (Rf 0.4), the title compound 23 (45 mg, 70%) as a clear,
yellow oil, νmax/cmϪ1 2077, 1626, 1514, 1337, 1248, 1109, 1030;
δH 7.25 (2H, d, J 8.5), 6.88 (2H, d, J 8.5), 6.42 (1H, m), 4.56
(1H, partially obscured m), 4.50 (2H, ABq, J 11.5), 4.07 (1H,
d, J 10.3), 3.81 (3H, s), 3.39 (1H, d, J 16.7), 3.38 (3H, s), 2.92
(1H, m), 2.60 (1H, d, J 16.7), 2.30 (1H, m), 1.80–1.61 (3H,
complex m); δC 190.7 (C), 159.3 (C), 142.1 (C), 133.7 (CH),
129.8 (C), 129.0 (CH), 113.8 (CH), 107.3 (C), 80.6 (CH), 72.8
(CH), 72.3 (CH2), 62.0 (C), 55.3 (CH3), 50.4 (CH3), 38.7 (CH),
ϩ
ϩ
ؒ
ؒ
not observed]; m/z 346 (M , <1%), 328 [(M Ϫ H2O) , 5], 121
ϩ
ϩ
ؒ
(p-CH3OC6H4CH2 , 100). Found (HRMS): M , 346.1774.
ϩ
ϩ
ؒ
ؒ
C20H26O5 requires M , 346.1780.
29.7 (CH2), 23.4 (CH2), 20.5 (CH2); m/z 342 [(M Ϫ N2) , 2%],
ϩ
ϩ
ؒ
121 (p-CH3OC6H4CH2 , 100). Found (HRMS): (M Ϫ N2) ,
ϩ
ؒ
(2R,9S,9aR,10R)-2,3,4,5,7,8,9,9a-Octahydro-2-methoxy-10-
[(4Ј-methoxyphenyl)methoxy]-2,9-methano-1-benzoxepin-5-one
(22)
342.1463. C20H22N2O5 requires, (M Ϫ N2) , 342.1467.
Methyl (2R,4R,8S,8aR,9R)-3,4,6,7,8,8a-hexahydro-2-methoxy-
9-[(4Ј-methoxyphenyl)methoxy]-2,8-methano-2H-1-benzopyran-
4-carboxylate (24) and methyl (2R,4S,8S,8aR,9R)-3,4,6,7,8,8a-
hexahydro-2-methoxy-9-[(4Ј-methoxyphenyl)methoxy]-2,8-
methano-2H-1-benzopyran-4-carboxylate (4)
Dess–Martin periodinane (327 mg, 0.80 mmol) was added,
in portions, to a magnetically stirred solution of alcohol 21
(138 mg, 0.40 mmol) in CH2Cl2 (5 mL) maintained at 0 ЊC
under an atmosphere of nitrogen. After 3 h the reaction
mixture was diluted with CH2Cl2 (10 mL) then treated with
sodium thiosulfate (5mL of a 1 M aqueous solution) and
sodium bicarbonate (5 mL of a saturated aqueous solution).
After being stirred vigorously for 15 min, the reaction mixture
was extracted with CH2Cl2 (3 × 15 mL) and the combined
organic phases were washed with brine (1 × 50 mL) before
being dried (MgSO4), filtered and concentrated under reduced
pressure to afford a pale yellow oil. Subjection of this material
to flash chromatography (silica, 30% v/v ethyl acetate–petrol
elution) provided, after concentration of the appropriate frac-
tions (Rf 0.8 in 50% v/v ethyl acetate–petrol), the title compound
22 (132 mg, 96%) as a clear, colourless oil, [α]D Ϫ123 (c 1.2,
CHCl3); νmax/cmϪ1 1687, 1612, 1513, 1248, 1116, 1035; δH 7.21
(2H, d, J 8.6), 6.84 (2H, d, J 8.6), 6.48 (1H, m), 4.48 (1H,
partially obscured m), 4.45 (2H, ABq, J 11.4), 4.04 (1H, d,
J 10.5), 3.77 (3H, s), 3.36 (3H, s), 2.92–2.74 (2H, complex m),
2.45 (1H, br d, J ca. 15), 2.38–2.25 (2H, complex m), 1.87 (1H,
A solution of compound 23 (35 mg, 0.09 mmol) in anhydrous
methanol (7 mL) (contained in a Pyrex round-bottom flask)
maintained at 18 ЊC under a nitrogen atmosphere was subjected
to external irradiation using a medium-pressure mercury
vapour lamp (125 W) contained within a water-cooled
quartz jacket. After 45 min the solution became colourless and
irradiation was discontinued. The solvent was removed under
reduced pressure and the clear, colourless oil thus obtained
was subjected to flash chromatography (silica, 20% v/v ethyl
acetate–toluene elution) which afforded two fractions, A (Rf
0.6) and B (Rf 0.5).
Concentration of fraction A afforded the title compound 24
(15 mg, 42%) as a clear, colourless oil, [α]D ϩ17 (c 0.9, CHCl3);
νmax/cmϪ1 1737, 1612, 1513, 1437, 1246, 1116, 1035, 755; δH 7.24
(2H, d, J 8.6), 6.85 (2H, d, J 8.6), 5.64 (1H, m), 4.55 (2H, ABq,
J 11.8), 4.36 (1H, m), 3.80 (3H, s), 3.79 (1H, obscured m), 3.75
(3H, s), 3.56 (1H, m), 3.36 (3H, s), 2.63 (1H, m), 2.48 (1H, dd,
J 13.3 and 11.1), 2.20 (1H, dd, J 13.3 and 7.4), 2.09 (1H, m),
m), 1.77–1.59 (3H, complex m); δC 204.3 (C᎐O), 159.0 (C),
᎐
143.8 (C), 136.1 (CH), 129.9 (C), 128.8 (CH), 113.6 (CH), 108.6
(C), 80.3 (CH), 72.7 (CH), 71.7 (CH2), 55.1 (CH3), 49.7 (CH3),
39.0 (CH), 38.0 (CH2), 27.3 (CH2), 23.6 (CH2), 20.3 (CH2);
1.72–1.57 (3H, complex m); δC 173.0 (C᎐O), 159.0 (C), 138.6
᎐
(C), 130.1 (C), 129.0 (CH), 122.5 (CH), 113.6 (CH), 109.3 (C),
79.6 (CH), 75.2 (CH), 71.3 (CH2), 55.2 (CH3), 51.8 (CH3),
50.1 (CH3), 40.5 (CH), 38.9 (CH), 31.4 (CH2), 22.1 (CH2),
ϩ
ϩ
ؒ
m/z 344 (M , 1%), 121 (p-CH3OC6H4CH2 , 100). Found
ϩ
ϩ
ϩ
ؒ
ؒ
ؒ
(HRMS): M , 344.1624. C20H24O5 requires M , 344.1624.
18.9 (CH2); m/z 374 (M , <1%), 253 (2), 193 (7), 133 (5), 121
ϩ
ϩ
ؒ
(p-CH3OC6H4CH2 , 100). Found (HRMS): M , 374.1730.
ϩ
ؒ
(2R,9S,9aR,10R)-4-Diazo-2,3,4,5,7,8,9,9a-octahydro-2-
methoxy-10-[(4Ј-methoxyphenyl)methoxy]-2,9-methano-1-
benzoxepin-5-one (23)
C21H26O6 requires M , 374.1729.
Concentration of fraction B afforded the title compound 4
(9 mg, 25%) as a clear, colourless oil, νmax/cmϪ1 2947, 1734,
1612, 1514, 1247, 1127, 1033; δH 7.23 (2H, d, J 8.7), 6.87 (2H, d,
J 8.7), 5.82 (1H, m), 4.50 (2H, ABq, J 11.7), 4.42 (1H, m), 3.80
(3H, s), 3.74 (3H, s), 3.72 (1H, m), 3.39 (3H, s), 3.04 (1H, d,
J 7.8), 2.83 (1H, d, J 13.7), 2.67 (1H, m), 2.26 (1H, dd, J 13.7
and 7.8), 2.07 (1H, m), 1.76–1.62 (3H, complex m); δC 174.4
(C), 159.1 (C), 138.7 (C), 130.2 (C), 128.9 (CH), 125.9 (CH),
113.7 (CH), 109.5 (C), 82.2 (CH), 75.9 (CH), 71.6 (CH2), 55.2
(CH3), 52.3 (CH3), 50.6 (CH3), 42.6 (CH), 38.3 (CH), 30.8
A solution of ketone 22 (60 mg, 0.17 mmol) in THF (1 mL)
was added, dropwise, to a magnetically stirred suspension of
NaH (36 mg, ca. 60% dispersion in mineral oil, 0.87 mmol) in
THF (1 mL) maintained at 0 ЊC under an atmosphere of nitro-
gen. After 30 min, ethyl formate (0.28 mL, 3.48 mmol) was
added, dropwise. The resulting mixture was allowed to warm to
18 ЊC over 1.5 h, and was then treated with HCl (2 mL of a 1 M
aqueous solution). The resulting mixture was extracted with
diethyl ether (3 × 10 mL) and the combined organic phases
were washed with brine (1 × 15 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
afford a pale yellow oil. This material was immediately dis-
solved in CH2Cl2 (3 mL) and the resulting solution cooled to
0 ЊC then treated with triethylamine (49 µL, 0.35 mmol) and
p-nitrobenzenesulfonyl azide (45 mg, 0.21 mmol) while being
maintained under an atmosphere of nitrogen. After 45 min, the
reaction mixture was partitioned between diethyl ether (10 mL)
and water (5 mL). The separated aqueous layer was extracted
with diethyl ether (3 × 10 mL) and the combined organic
phases were washed with brine (1 × 20 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
ϩ
ؒ
(CH2), 22.4 (CH2), 19.1 (CH2); m/z 374 (M , 4%), 253 [(M Ϫ
ϩ
ϩ
ؒ
ؒ
C8H9O ) , 44], 193 (100). Found (HRMS): M , 374.1724.
ϩ
ؒ
C21H26O6 requires M , 374.1729.
X-Ray crystallographic analysis of compound 19
Crystal data: C25H34O9, M = 478.54, T = 193(1) K, monoclinic
space group P21, a = 9.968(2), b = 10.083(2), c = 12.633(1) Å,
β = 105.15(1)Њ, U = 1225.6(4) Å3, Dc (Z = 2) = 1.297 g cmϪ3,
F(000) = 512.0, µ(Cu-Kα) = 8.19 cmϪ1, analytical absorption
correction; 1948 unique data (2θmax = 120Њ), 1909 with I > 2σ(I );
R = 0.053, wR = 0.044, GOF = 2.94. CCDC reference number
166070. See http://www.rsc.org/suppdata/p1/b1/b105376k/ for
crystallographic files in .cif or other electronic format.
2202
J. Chem. Soc., Perkin Trans. 1, 2001, 2194–2203

View Article Online
2000, 65, 490; (r) H. M. L. Davies, R. L. Calvo, R. J. Townsend,
Acknowledgements
P. Ren and R. M. Churchill, J. Org. Chem., 2000, 65, 4261; (s) M. M.
Bio and J. L. Leighton, Org. Lett., 2000, 2, 2905; (t) D. L. J. Clive,
S. Sun, V. Gagliardini and M. K. Sano, Tetrahedron Lett., 2000, 41,
6259; (u) T. Yoshimitsu, S. Yanagisawa and H. Nagaoka, Org. Lett.,
2000, 2, 3751; (v) H. M. L. Davies and P. Ren, Tetrahedron Lett.,
2000, 41, 9021; for useful reviews on synthetic approaches to the
“CP-compounds”, see U. Deiderichsen, Nachr. Chem. Tech. Lab.,
1999, 47, 1423; D. Hepworth, Chem. Ind. (London), 2000, 59;
J. T. Starr and E. M. Carreira, Angew. Chem., Int. Ed., 2000, 39,
1415.
Financial support from the Institute of Advanced Studies
(ANU) and the Department of Industry, Science and Tourism
(in the form of a Bilateral Science and Technology Program
Grant) is gratefully acknowledged. Dr Gregg Whited
(Genencor International Inc., Palo Alto, CA) is thanked for
providing expert advice and access to bioreactor facilities
which allowed us to produce compound 3, while the Australian
Research Council is thanked for provision of an Australian
Postgraduate Award to KJM.
5 G. A. Sulikowski, F. Agnelli and R. M. Corbett, J. Org. Chem., 2000,
65, 337.
6 (a) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, H.-S. Choi,
W. H. Yoon, Y. He and K. C. Fong, Angew. Chem., Int. Ed., 1999, 38,
1669; (b) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, K. C. Fong,
Y. He, W. H. Yoon and H.-S. Choi, Angew. Chem., Int. Ed., 1999,
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J. Am. Chem. Soc., 2000, 122, 7424; (d ) Q. Tan and S. J. Danishefsky,
Angew. Chem., Int. Ed., 2000, 39, 4509; (e) N. Waizumi, T. Itoh and
T. Fukuyama, J. Am. Chem. Soc., 2000, 122, 7825.
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