A conjugate addition-radical cyclisation approach to sesquiterpene-phenol natural products

Article abstract of DOI:10.1039/b005617k

A conjugate addition-radical cyclization approach to sesquiterpenephenol natural products was discussed. The first step involved the conjugate addition of an organocopper species to a chromone-3-carboxylate which resulted in 2,2-disubstituted chroman-4-ones. The second step was the generation of a β-ketoester radical. The last step involved a stereoselective manganese(III) acetate-mediated radical cyclization reaction.

Full text of DOI:10.1039/b005617k

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A conjugate addition–radical cyclisation approach to sesquiterpene-
phenol natural products
Barry S. Crombie,a Colin Smith,b Christalla Z. Varnavasa and Timothy W. Wallace*a
1
a Department of Chemistry and Applied Chemistry, University of Salford, Salford,
UK M5 4WT. E-mail: T.W.Wallace@salford.ac.uk
b Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, UK SG1 2NY
Received (in Cambridge, UK) 12th July 2000, Accepted 4th September 2000
First published as an Advance Article on the web 2nd January 2001
The polycyclic ring system which forms the nucleus of a series of sesquiterpene-phenol natural products, including
the antimalarial 15-oxopuupehenol, can be constructed in racemic form in four efficient steps, the last of these being
a stereoselective manganese() acetate-mediated radical cyclisation reaction.
materials and might ultimately provide access to biologically
Introduction
active analogues of potential therapeutic use.
A series of biologically active natural products, many of
Most of the existing approaches to this type of compound
marine origin,1 is based on a fusion of sesquiterpene and
are based on a strategy involving the initial formation of a
phenolic moieties. The series includes the sponge metabolite
suitably functionalised bicyclic (terpenoid) unit, with the pyran
puupehenone 1,2 its congeners 15-cyanopuupehenol 2,3 15-
ring being generated late in the sequence. This strategy has pro-
oxopuupehenol 34 and related dimers,5 8-epichromazonarol 4,6
vided siccanin 6,11 puupehenone 1,12 and the methylenedioxy
and ring-opened systems such as hyatellaquinone 5.7 The anti-
derivative of 3.13 More recently a biomimetic cyclisation
fungal agent siccanin 6,8 which was isolated from the culture
broth of a parasitic rye-grass fungus, also belongs in this
approach was used to construct chromazonarol (8-epi-4).14
In seeking a more flexible route to the tetracyclic nucleus of
category although its carbon skeleton, which incorporates a
this type of compound, we devised a convergent strategy based
cis/syn/cis fusion of three saturated rings, is unusual.
on the sequence shown in Scheme 1. The first step is the con-
jugate addition of an organocopper species to a chromone-3-
carboxylate, a mild and flexible route to 2,2-disubstituted
chroman-4-ones.15 The second step is the generation of a β-
ketoester radical, a convenient and relatively clean process
under whose oxidative conditions any subsequent cyclisation
involving a suitably located olefinic bond can give rise to a func-
tionalised product. This principle has been widely recognised
and exploited in a variety of contexts, most notably by Snider
and his group.16 The results of our investigation of the sequence
outlined in Scheme 1 are herein described in detail.17
Results and discussion
Synthesis of chromanones
In the first approach to a radical cyclisation precursor, the
ketoester 11 was prepared via alkylation of the dianion of
methyl acetoacetate with the bromide 10,18 and condensed
with 2-fluorobenzoyl chloride19 to obtain the 4-oxochromene-
3-carboxylate 12 (Scheme 2). Treatment of the latter with lith-
ium dimethylcuprate gave, via conjugate addition at C-2,
the anticipated15 mixture of cis-keto, trans-keto and enol
forms of the chromanone 13. It was later established that
an alternative route to 11, via the methoxycarbonylation of
dihydro-β-ionone 14,20 readily provided large quantities of the
We have been seeking a synthetic route to compounds of
this type, our interest being focused on 2, which has antiviral
properties3 and activity against tuberculosis,9 and 3, which is
active against Plasmodium falciparum malaria at the micro-
molar level.4 Of the world’s infectious diseases tuberculosis
and malaria are leading killers, accounting for millions of
deaths each year, and drug-resistant strains of both continue to
emerge.10 A flexible route to sesquiterpene phenols such as 2
and 3 would offer an alternative source of these interesting
chromanone ester 13.
The flexibility of the two routes to the ester 13 was briefly
investigated. The alkylation route using 10 was used to prepare
the tert-butyl ester 15 but gave only a modest yield, and a
subsequent attempt to convert this into the corresponding
chromone 16 using the standard procedure19 was unsuccess-
ful, presumably due to adverse steric interactions during the
cyclisation process. The alkoxycarbonylation route from 14
is compromised by the limited availability of suitably reactive
206
J. Chem. Soc., Perkin Trans. 1, 2001, 206–215
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b005617k

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carbonates, but the allyl ester 17 proved accessible by this
method. The latter was also prepared in reasonable yield via
the transesterification of 11 using allyl alcohol and a tin-based
solid acid catalyst.21 An attempt to prepare the tert-butyl ester
15 by this method was unsuccessful, delivering only the decarb-
alkoxylation product 14 (57%).
The conversion of the allyl ester 17 into the corresponding
chromone 18 was fairly efficient. The ester 18 possesses two
sites with potential reactivity towards organocopper reagents,
viz. the activated enone and allylic ester moieties, and provided
an interesting opportunity to probe the chemoselectivity which
might be displayed by such substrates. For example, treating
18 with lithium dimethylcuprate gave rise to a substantial yield
of the carboxylic acid 19, which presumably arose via an allylic
displacement (SN2Ј) process.22 By contrast, the major reaction
pathway observed on subjecting the ester 18 to a copper()-
catalysed methyl Grignard addition23 in the presence of tri-
methylsilyl chloride24 was conjugate addition to the enone unit,
which gave rise to the ester 20 in fair yield. These and other
chemoselective reactions of allyl enoates are the subject of
further investigation and will be described in due course.
The isomeric chromanone ester 29 was prepared using the
sequence shown in Scheme 3. The aldehyde 21, prepared in
three steps from 2,2-dimethylcyclohexanone,25 was reduced with
sodium borohydride and the resultant alcohol 22 transformed
into the ester 23 via a Claisen rearrangement.26 Reduction then
provided ( )-γ-cyclohomogeraniol 2427 which was converted
via a standard sequence28 into the iodide 26. The latter served
as the precursor to the mixed thienylcyanocuprate 27,29 which
underwent conjugate addition to methyl 2-methyl-4-oxo-
chromene-3-carboxylate 2819 to give the chromanone ester
29 as a mixture of diastereoisomers in 66% yield. The same
mixture was also produced, less efficiently, using reagents
derived from copper() iodide and lithium imidazol-1-
idocyanocuprate.
Oxidative cyclisations
Oxidation of the isomeric mixture of 13 with manganese()
acetate was attempted under a variety of conditions using
copper() acetate as a co-oxidant.30 There was no discernible
reaction at 20 ЊC during one week, but heating at 55–60 ЊC
brought about a reaction in a few hours (higher temperatures
tended to lead to a more complex mixture of products so
as to make isolation difficult). A reaction was indicated by a
colour change, the initial solution of manganese() and
copper() acetates being a dark blue–green, becoming much
paler in colour as the reaction proceeded, ending with a
Scheme 1 (E = CO2Me, X = OAc).
Scheme 2 Reagents and conditions: i, O3, MeOH, Ϫ30 ЊC, then Zn, HOAc; ii, NaBH4, EtOH, PriOH, 20 ЊC, 1 h; iii, PBr3, hexane, Et2O, Ϫ30 to
ϩ20 ЊC, 15 h; iv, MeCOCH2CO2Me, NaH, BuLi, THF, 0 ЊC, then 10, 0 to 20 ЊC, 0.5 h; v, NaH, toluene, 50 ЊC, 1 h, then 2-FC6H4COCl, 110 ЊC, 3 d;
vi, Me2CuLi, Et2O, THF; vii, Bu3SnH, AIBN, 80 ЊC, 15 h, then SiO2; viii, NaH, (MeO)2CO, dioxane, 100 ЊC, 3.5 h; ix, allyl alcohol, catalyst, toluene,
110 ЊC; x, TMSCl, cat. CuI, MeMgCl, THF, Ϫ10 ЊC, 5 h, then HOAc, 20 ЊC.
J. Chem. Soc., Perkin Trans. 1, 2001, 206–215
207

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Scheme 3 Reagents and conditions: i, NaBH4, EtOH, 0 to 10 ЊC, 2 h;
ii, MeC(OEt)3, cat. EtCO2H, 150 ЊC, 5 h; iii, LAH, THF, 20 ЊC, 12 h;
iv, MsCl, Et3N, DCM; v, NaI, acetone, reflux, 4 h; vi, t-BuLi, Et2O–
pentane, Ϫ30 ЊC, 15 min, then 2-thienylCu(CN)Li, THF, Ϫ50 to
Ϫ20 ЊC; then chromone 28, Et2O, Ϫ50 ЊC, 1 h.
Scheme 4 (E = CO2Me). Reagents and conditions: i, Mn(OAc)3, Cu-
(OAc)2ؒH2O, HOAc, 58 ЊC, 5 h; ii, Mn(OAc)3, HOAc, 80 ЊC, 12 h.
turquoise solution. Aqueous work up followed by chromato-
graphy over silica gel gave as a major product the lactone
30, a colourless crystalline solid, in 25–30% yield. Analysis by
1H NMR spectroscopy and TLC indicated that the balance
included starting material and several minor products; none
of these was fully characterised. The efficiency of the reaction
depended to some extent on the quality of the solvent and the
substrates. Initially manganese() acetate dihydrate (Aldrich)
was used, but it was found that the reaction proceeded more
cleanly with the anhydrous material31 and with dry and
degassed acetic acid.
The structure of the lactone 30 was initially deduced by
spectroscopic means, especially a 1H–13C heteronuclear shift
correlation NMR experiment, which indicated the presence
of a new oxygenated quaternary carbon adjacent to the gem-
dimethyl centre. The relative stereochemistry was confirmed by
X-ray crystallography17 as that found in the natural products
1–4, and is presumed to arise via an initial 6-endo-trig cyclis-
ation of the β-ketoester radical 31 derived from 13, leading to
32 which undergoes further oxidation to a cation 33, followed
by lactonisation (Scheme 4).32 On the basis that the second
oxidation step, from 32 to 33, should be within the scope of
manganese() alone,16 the reaction was repeated in the absence
of copper() acetate and after some optimisation afforded the
lactone 30 in 58% yield.
The chromanone 29 was more easily oxidised than 13, and
gave rise to a large number of products when run at different
temperatures, or in the presence or absence of copper()
acetate. Analysis of the reaction was rendered more complex
by the initial presence of up to four diastereoisomers of 29.
Typically, an acetic acid solution of the mixed isomers 29 was
treated with dried33 manganese() acetate at 65 ЊC; the solu-
tion became noticeably lighter in colour after 30 min and was
worked up after three hours. Chromatography of the product
mixture over silica gel yielded as a major product the crystalline
hemiacetal 34 (31%) whose structure was established by X-ray
crystallography.17 This product is seen as arising from the
7-endo-trig cyclisation of the initially-formed ketoester radical
35, giving 36 which undergoes further oxidation to the cation
37. The latter is ultimately intercepted by water to give 38 and
Scheme 5 (E = CO2Me). Reagents and conditions: i, Mn(OAc)3, HOAc,
65 ЊC, 3 h.
hence 34 (Scheme 5).34 Given that the isolated product can only
arise from the (rel-2S,1ЉR) radical 35, the overall sequence is
a fairly efficient one.
A study of the chemistry of the lactone 30 has been initiated
with experiments involving reducing agents. A small-scale
208
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chemical ionisation method; most fragment ions with a relative
intensity of less than 20% of the base peak have been omitted.
UV spectra were measured for ethanolic solutions using a
Hewlett Packard 8452A Diode Array spectrophotometer.
Ozone was generated using a Wallace & Tiernan ozonator
(type BA.023).
Reactions were usually carried out under a slight overpres-
sure of either argon or nitrogen. Starting materials and solvents
were routinely purified by conventional techniques.36 Acetic
acid was dried with acetic anhydride and degassed before use.
Organic solutions were dried using anhydrous magnesium
sulfate and concentrated by rotary evaporation. Analytical
thin layer chromatography (TLC) was carried out on Camlab
Polygram SIL G/UV254 plates. Spots were visualised with
ethanolic phosphomolybdic acid or acidic vanillin reagents37
unless otherwise indicated. Preparative (column) chromato-
graphy was carried out using silica gel (Merck 9385 and the
flash technique38) or on Florisil (Aldrich 28,870-5). Com-
positions of solvent mixtures are quoted as ratios of volume.
‘Petroleum’ refers to a light petroleum fraction, bp 40–60 ЊC,
unless otherwise stated. ‘Ether’ refers to diethyl ether.
Fig. 1 X-Ray structure of the lactone 30.
reaction of 30 with DIBAL-H (3 mol. equiv.) gave as a major
product a compound whose UV and IR spectra indicated
that aromatic carbonyl function had been reduced (loss of
absorptions at 256, 316 nm and 1683 cmϪ1). Comparing models
of the starting material 30 and the related ketone 40, whose
reduction with LAH occurs exclusively from the Si face of
the aromatic carbonyl group,35 leads us to conclude that the
product obtained is the alcohol 39 which would result from
reduction of the more open face (Fig. 1, arrowed) of the corre-
sponding carbonyl group in 30. Treating the lactone 30 with
a larger excess of DIBAL-H produced a mixture thought to
consist mainly of a lactol 41 and a second product which was
partially characterised as the ether-bridged 42. The reduction
of 30 with LAH (2 mol. equiv.) afforded the lactol 41 cleanly
but in low yield.
2,6,6-Trimethylcyclohex-1-ene-1-carbaldehyde 8.39 A solution
of β-ionone† 7 (7.68 g, 0.04 mol) in methanol (70 ml) was
cooled to Ϫ30 ЊC. With vigorous stirring, a stream of oxygen–
ozone was passed into the solution at a rate of about 50 l hϪ1
(corresponding to 0.052 mol of ozone per hour). After 6 h
the reaction was complete by TLC and the solution was flushed
with N2 for 5 min. Zinc (4 g) was then added to the cooled
solution and, with further cooling, 50% acetic acid (30 ml)
was added dropwise. The reduction was noticeably exothermic
(Ϫ5 to ϩ25 ЊC) and took 30 min. After stirring for a further
1 h, the reaction mixture was poured into cold water (400 ml)
and extracted with DCM (3 × 75 ml). The organic phase was
neutralised by washing with saturated aqueous sodium hydro-
gen carbonate, dried over anhydrous sodium sulfate and con-
centrated in vacuo. The crude product was fractionally distilled
under reduced pressure to obtain the aldehyde 8 (3.95 g,
65%), bp 70–74 ЊC at 1 mmHg (lit.,39 bp 50–51 ЊC at 0.35
mmHg); νmax (neat)/cmϪ1 1715; δH (300 MHz) 1.14 (6 H, s,
6-Me2), 1.34–1.41 (2 H, m, 5-H2), 1.53–1.61 (2 H, m, 4-H2), 2.04
(3 H, s, 1-Me), 2.14 (2 H, t, J 6 Hz, 3-H2), 10.07 (1 H, s, CHO);
m/z 170 (M ϩ NH4ϩ, 100%), 153 (M ϩ Hϩ, 35), 65 (25).
2,6,6-Trimethylcyclohex-1-ene-1-methanol 9.40 A solution of
β-cyclocitral 8 (4 g, 26 mmol) in propan-2-ol (7 ml) was added
dropwise to an ice-cooled suspension of sodium borohydride
(1.47 g, 39 mmol) in ethanol–propan-2-ol (1:1, 10 ml) with
stirring. When addition was complete, the mixture was allowed
to warm up to ambient temperature and stirring was main-
tained for 1 h. The reaction mixture was then poured into water
(20 ml) and the excess borohydride allowed to decompose.
The aqueous phase was saturated with sodium chloride
and extracted with ether (3 × 10 ml). The organic extracts
were combined, washed with water (10 ml) and brine (10 ml),
dried and concentrated in vacuo. The resulting viscous, colour-
less oil was purified via column chromatography (petroleum
ether–ethyl acetate 4:1) to give the alcohol 9 (3.4 g, 85%)
as a colourless waxy solid, mp 32–34 ЊC (lit.,40 40–42 ЊC);
νmax (Nujol)/cmϪ1 3345, 1654; δH (300 MHz) 1.01 (6 H, s,
6-Me2), 1.35–1.45 and 1.50–1.60 (both 2 H, m, 4-H2 and 5-H2),
1.72 (3 H, s, 1-Me), 1.94 (2 H, t, J 6 Hz, 3-H2), 4.10 (1 H,
s, CH2O).
The transformation of 13 into 30 generates the tetracyclic
nucleus and four contiguous stereogenic centres of the natural
products 1–4, and thus offers an efficient and potentially
flexible route to polycycles of this type in four steps from
commercially available materials. Enantioselective versions of
the synthetic sequence, together with further transformations
of the lactone 30 (in particular the nett reductive removal of
the lactone bridge) are currently under investigation and will be
described in due course.
Experimental
All compounds are racemic. Melting points were recorded
using an Electrothermal apparatus and are uncorrected. Unless
stated otherwise, IR spectra were recorded as neat films on
sodium chloride plates on Perkin-Elmer 1710FT or Nicolet
5SXC FTIR spectrometers. NMR spectra were measured for
solutions in deuteriochloroform with tetramethylsilane as
the internal reference using Bruker 250, 300 or 400 MHz
instruments. Unless otherwise indicated, mass spectra were
measured on Finnegan 4500 (low resolution) or Kratos
Concept S1 (high resolution) instruments using the ammonia
2-Bromomethyl-1,3,3-trimethylcyclohex-1-ene 10.41 Phos-
phorus tribromide (1.3 g, 4.8 mmol) in hexane–ether (1:1,
† The IUPAC name for β-ionone is 4-(2,6,6-trimethylcyclohex-1-en-1-
yl)but-3-en-2-one.
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209

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10 ml) was added dropwise to a solution of the alcohol 9
(2.0 g, 13 mmol) in hexane–ether (1:1, 25 ml) over 1 h at
Ϫ30 ЊC under an inert atmosphere. The reaction mixture
was stirred for an additional 2 h at this temperature and
then was allowed to warm up to room temperature and stirred
for another 12 h. When the reaction was complete saturated
aqueous sodium hydrogen carbonate was added dropwise
until effervescence was no longer apparent. The solution was
extracted with ether (3 × 10 ml) and the combined extracts
washed with water (10 ml) and brine (10 ml), dried and con-
centrated under reduced pressure to obtain the title compound
10 (2.75 g, 98%) as a pale brown liquid which was used without
further purification; νmax (CHBr3)/cmϪ1 1638, 515; δH (250
MHz) 1.10 (6 H, s, 3-Me2), 1.40–1.65 (4 H, m, 4-H2, 5-H2), 1.74
(3 H, s, 2-Me), 2.02 (2 H, t, J 5.5 Hz, 6-H2), 4.08 (2 H, s,
CH2Br).
The reaction was then heated under reflux for 72 h. After
cooling the reaction was poured into water (200 ml) and
extracted with ether (3 × 100 ml). The combined organics were
washed with water (50 ml), brine (50 ml), and dried over sodium
sulfate. Concentration gave an orange oil which was purified
by flash chromatography, eluting with petroleum–ethyl acetate
(2:1), yielding the title compound 12 (7.356 g, 89%) as a
viscous yellow oil (M ϩ Hϩ, 355.1913. C22H27O4 requires
355.1909); νmax (neat)/cmϪ1 1736, 1652, 1622, 1575; δH (300
MHz) 1.02 (6 H, s, 6Љ-Me2), 1.4–1.6 (4 H, m, 4Љ-H2, 5Љ-H2),
1.66 (3 H, s, 2Љ-Me), 1.92 (2 H, t, J 6 Hz, 3Љ-H2), 2.4–2.5 (2 H,
m, 2Ј-H2), 2.7–2.8 (2 H, m, 1Ј-H2), 3.90 (3 H, s, OMe), 7.35–
7.45 (2 H, m, 6-H, 8-H), 7.66 (1 H, ddd, J 1.5, 7, 7.5 Hz, 7-H),
8.19 (1 H, dd, J 1.5, 7.5 Hz, 5-H); m/z (CI, MeCN/NH3) 355
(M ϩ Hϩ, 100%); Rf 0.55 (petroleum–ethyl acetate 2:1, UV
active).
Methyl 3-oxo-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pentano-
ate 11. Method 1.18 A suspension of sodium hydride (60%
dispersion in mineral oil, 0.48 g, 12 mmol) in anhydrous THF
(20 ml) under an inert atmosphere was stirred with ice-cooling
as methyl acetoacetate (1.28 g, 11 mmol) was added dropwise.
The reaction mixture was stirred for 10 min and then n-
butyllithium (1.22 M, 9.4 ml, 11.5 mmol) was added carefully.
After a further 10 minutes stirring, the bromide 10 (2.29 g,
10.5 mmol) was added in one portion and the mixture was
stirred at room temperature for 30 min. Hydrochloric acid
(4 M, 6 ml) was added carefully and the resulting solution
diluted with ether (15 ml). The aqueous layer was back-washed
with ether (2 × 10 ml) and the combined organic extracts
were washed with water (2 × 20 ml) and brine (20 ml), dried
over anhydrous sodium sulfate and concentrated in vacuo. The
resulting yellow oil was purified by chromatography, eluting
with petroleum–ethyl acetate (5:1), which gave the title com-
pound 11 (1.66 g, 60%) as an off-white waxy solid, mp 35–37 ЊC
(lit.,18 bp 118–125 ЊC at 0.3 mmHg); νmax (CHBr3)/cmϪ1 1741,
1712; δH (300 MHz) 0.96 (6 H, s, 6Ј-Me2), 1.37–1.60 (4 H, m,
4Ј-H2, 5Ј-H2), 1.57 (3 H, s, 2Ј-Me), 1.87 (2 H, t, J 6 Hz, 3Ј-H2),
Methyl 2,3-dihydro-2-methyl-2-[2-(2,6,6-trimethylcyclohex-1-
en-1-yl)ethyl]-4-oxo-4H-1-benzopyran-3-carboxylate 13. To a
suspension of copper() iodide (6.094 g, 0.032 mol) in dry ether
(100 ml) under Ar at Ϫ10 ЊC was added methyllithium in ether
(1.5 M, 42.7 ml, 0.064 mol). On addition of a second equivalent
of methyllithium, the reaction mixture turned from a yellow
suspension to a colourless solution. A solution of 12 (7.356 g,
0.021 mol) in anhydrous THF (100 ml) was added directly to
the above solution. The reaction mixture was then cooled down
to Ϫ42 ЊC (MeCN–CO2 slush) and stirred for 1 h. The reaction
was quenched by stirring with saturated aqueous ammonium
chloride (100 ml) for 15 min. The mixture was then extracted
with ether (3 × 100 ml) and the combined organics washed
with 2 M hydrochloric acid (100 ml), water (100 ml), brine
(100 ml) and dried. On concentration, a crude dark orange
oil was obtained which was purified by flash chromatography
(petroleum–ethyl acetate 2:1) to give the title compound 13
(5.960 g, 74%) as an orange oil (M ϩ Hϩ, 371.2214. C23H31O4
requires 371.2222); νmax (neat)/cmϪ1 1747, 1695, 1609, 1464,
764; δH (300 MHz) 0.72 (minor), 0.85 (major), 0.90 (minor)
and 0.95 (major) (total 6 H, 4 × s, 6Љ-Me2 of diastereo-
isomers), 1.32 (minor) and 1.45 (major) (total 3 H, 2 × s, 2-Me
of diastereoisomers), 1.52 (6 H, br s, 2Љ-Me of major and minor
diastereoisomers), 1.3–1.4 (2 H, m, 5Љ-H2), 1.45–1.6, 1.65–1.9
and 2.0–2.3 (total 8 H, m, 1Ј-H2, 2Ј-H2, 3Љ-H2, 4Љ-H2), 3.74
and 3.75 (total 3 H, 2 × s, OMe of diastereoisomers), 3.80 and
3.83 (total 1 H, 2 × s, 3-H of diastereoisomers), 6.9–7.0 (2 H,
m, 6-H and 8-H), 7.48 (1 H, br t, J 7 Hz, 7-H), 7.84 (1 H, dd,
J 1, 7 Hz, 5-H); m/z (peaks > 10%) 388 (M ϩ NH4ϩ, 100%), 371
(M ϩ Hϩ, 77), 219 (36); Rf 0.63 (petroleum–ethyl acetate 2:1,
UV active). The presence of an enol tautomer was indicated
by characteristic peaks in the NMR spectrum, e.g. δ 13.0 ppm
(s, enolic OH).
2.22–2.30 (2 H, m, 4-H2), 2.55–2.63 (2 H, m, 5-H2), 3.42 (2 H, s,
ϩ
2-H2), 3.71 (3 H, s, OMe); m/z (peaks > 10%) 270 (M ϩ NH4
,
100%), 253 (M ϩ Hϩ, 50), 193 (12); Rf 0.45 (DCM, UV active,
orange with vanillin). The presence of an enol tautomer was
indicated by characteristic peaks in the NMR spectrum at
δH 4.97 (s, vinyl) and 11.97 (s, enolic OH).
Method 2.20 Dimethyl carbonate (7.055 g, 6.6 ml, 0.078 mol)
and sodium hydride (60% oil dispersion, 3.12 g, 0.078 mol) in
dry dioxane (70 ml) under Ar were stirred and heated under
reflux. A solution of dihydro-β-ionone‡ 1420 (7.59 g, 0.039 mol)
in dry dioxane (10 ml) was then added dropwise over 1.5 h. The
reaction was heated under reflux for a further 2 h. Upon cooling
the reaction mixture was neutralised with 4 M hydrochloric
acid. After vigorous stirring the organic layer was separated,
the aqueous layer was extracted with ether, and the combined
organics were dried and evaporated. The residue was purified
by flash chromatography, eluting with petroleum–ethyl acetate
(3:1), to obtain the title compound 11 (8.646 g, 88%) as a
yellow oil, identical (NMR, TLC) with material prepared by
method 1.
tert-Butyl
3-oxo-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-
anoate 15. A suspension of sodium hydride (60% dispersion in
mineral oil, 0.073 g, 1.83 mmol) in dry THF (5 ml) under Ar
was stirred with ice cooling as tert-butyl acetoacetate (0.290 g,
1.83 mmol) was added. The reaction mixture was stirred for
15 min at 0 ЊC and then BuLi (1.21 ml, 1.83 mmol, 1.51 M)
was added. After a further 15 min of stirring the bromide 10
(0.346 g, 1.59 mmol) in dry THF (3 ml) was added at 0 ЊC. The
reaction was then allowed to reach room temperature over-
night. Dilute acetic acid was added until a clear solution
resulted. The aqueous layer was separated and extracted with
ether (2 × 10 ml). All the organic layers were recombined,
washed with water (5 ml), brine (5 ml), dried over sodium
sulfate and then evaporated under reduced pressure. Purifi-
cation by chromatography, eluting with petroleum–ethyl acetate
(4:1), gave the title compound 15 (0.197 g, 42%) as a pale yellow
oil (M ϩ Hϩ, 295.2276. C18H31O3 requires 295.2273); δH (300
MHz) 0.95 (6 H, s, 6Ј-Me2), 1.35–1.45 (4 H, m, 4Ј-H2, 5Ј-H2),
1.45 (9 H, s, t-Bu), 1.54 (3 H, s, 2Ј-Me), 1.87 (2 H, t, J 6 Hz,
Methyl 2-[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]-4-oxo-
4H-1-benzopyran-3-carboxylate 12. A solution of ester 11
(5.90 g, 0.023 mol) in anhydrous toluene (60 ml) was added
to a suspension of sodium hydride (60% oil dispersion, 1.40 g,
0.035 mol) in anhydrous toluene (60 ml) under Ar at room
temperature. This was then stirred for 1 h at 50 ЊC. To this
yellow suspension was added dropwise a solution of 2-fluoro-
benzoyl chloride (2.75 ml, 0.023 mol) in dry toluene (60 ml).
‡ The IUPAC name for dihydro-β-ionone is 4-(2,6,6-trimethylcyclohex-
1-en-1-yl)butan-2-one.
210
J. Chem. Soc., Perkin Trans. 1, 2001, 206–215

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3Ј-H2), 2.2–2.3 (2 H, m, 4-H2), 2.55–2.65 (2 H, m, 5-H2), 3.32
(2 H, s, 2-H2); m/z (peaks > 10%) 312 (M ϩ NH4ϩ, 30%), 295
(M ϩ Hϩ, 28), 256 (100), 239 (61), 136 (30).
Prop-2-en-1-yl 2-[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]-
4-oxo-4H-1-benzopyran-3-carboxylate 18. To a solution of
sodium hydride (60% dispersion in mineral oil, 0.152 g,
3.8 mmol) in dry toluene (5 ml) was added the ester 17
(0.660 g, 2.37 mmol) in dry toluene (5 ml). Effervescence was
observed. The resulting yellow solution was stirred at room
temperature for 20 min and then 2-fluorobenzoyl chloride
(0.372 g, 2.35 mmol) was added followed by a further addition
of dry toluene (10 ml). The reaction was heated under reflux for
24 h and then the cooled suspension was poured into cold water
(20 ml). The aqueous layer was extracted with ether (3 × 10 ml)
and the combined organics were dried over sodium sulfate and
evaporated under reduced pressure. The residual orange oil
was purified by chromatography, eluting with DCM, to obtain
the title compound 18 (0.489 g, 55%) as a yellow oil (M ϩ Hϩ,
381.2061. C24H29O4 requires 381.2066); νmax (neat)/cmϪ1 1732,
1651, 1575, 1218, 1127, 1037, 763; δH (300 MHz) 1.02 (6 H, s,
6Љ-Me2), 1.4–1.6 (4 H, m, 4Љ-H2, 5Љ-H2), 1.66 (3 H, s, 2Љ-Me),
1.92 (2 H, t, J 6 Hz, 3Љ-H2), 2.4–2.5 (2 H, m, 2Ј-H2), 2.75–2.8
(2 H, m, 1Ј-H2), 4.82 (2 H, dd, J ca. 1, 6 Hz, 1ٞ-H2), 5.28 (1 H,
dd, J ca. 1, 10.5 Hz, 3ٞ-H), 5.45 (1 H, dd, J ca. 1, 17 Hz, 3ٞ-H),
6.00 (1 H, tdd, J 6, 10.5, 17 Hz, 2ٞ-H), 7.39 (1 H, t, J ca. 8 Hz,
6-H), 7.44 (1 H, br d, J 8.5 Hz, 8-H), 7.66 (1 H, ddd, J 1.5,
7.5, 8.5 Hz, 7-H), 8.19 (1 H, dd, J 1.5, 8 Hz, 5-H); m/z
(peaks > 10%) 381 (100%); Rf 0.20 (DCM, UV active).
Attempted preparation of the ester 15 by transesterification. A
mixture of the ketoester 11 (40 mg, 0.16 mmol), tert-butanol
(tert-butyl alcohol) (0.1 ml, 77.5 mg, 1.05 mmol) and ‘sulfated
SnO2’ catalyst21 (33 mg) in toluene (5 ml) was heated to 110 ЊC
in a round-bottomed flask fitted with a condenser. The reaction
was monitored by TLC (silica, DCM), and after 18 h a new
product was visible (Rf 0.52), together with some starting
material (Rf 0.45). The mixture was cooled and evaporated
under reduced pressure. Chromatography of the residue,
eluting with DCM–petroleum (4:1), afforded the ketone 14
(17.8 mg, 57%) as a colourless oil, identical (TLC, NMR) with
an authentic sample.20
Attempted preparation of the ester 16. A solution of 15
(0.160 g, 0.54 mmol) in dry toluene (2 ml) was added drop-
wise to a suspension of sodium hydride (60% dispersion in
mineral oil, 0.025 g, 0.62 mmol) in dry toluene (3 ml) under N2.
Effervescence was observed. The reaction mixture was stirred
at room temperature for 10 min and then a solution of 2-
fluorobenzoyl chloride (0.086 g, 0.54 mmol) in toluene (2 ml)
was added. The resulting yellow solution was heated under
reflux for 48 h and then quenched by the addition of water
(20 ml). This was then extracted with ether (2 × 10 ml) and the
organic phases were combined and dried over sodium sulfate.
Evaporation under reduced pressure gave an orange oil whose
1H NMR spectrum over the aromatic region indicated that the
reaction had not proceeded (absence of characteristic signal at
δ > 8.0 ppm expected for 5-H of chromone).
2-[2-(2,6,6-Trimethylcyclohex-1-en-1-yl)ethyl]-4-oxo-4H-1-
benzopyran-3-carboxylic acid 19. A solution of lithium di-
methylcuprate was prepared by treating a stirred suspension
of copper() iodide (0.131 g, 0.069 mmol) in ether (3 ml)
with methyllithium in ether (1.6 M, 0.87 ml, 1.39 mmol) at
Ϫ10 ЊC until the yellow solution turned colourless. The ester
18 (0.175 g, 0.460 mmol) in dry THF (5 ml) was then added
dropwise at 0 ЊC. After 30 min the reaction was quenched by
stirring vigorously with saturated aqueous ammonium chloride
(3 ml) and the resulting solution extracted into ethyl acetate
(3 × 5 ml), dried and evaporated to give a yellow oil. Flash
chromatography, eluting with DCM, gave the title compound 19
(0.07 g, 45%) which formed colourless needles, mp 110–112 ЊC
(EtOH) (M ϩ Hϩ, 341.1757. C21H25O4 requires 341.1753);
νmax (film)/cmϪ1 1734, 1610 br, 1573, 1543, 1493, 1460, 1429,
1389, 1137, 1038, 772; δH (300 MHz) 1.07 (6 H, s, 6Љ-Me2), 1.42–
1.46 (2 H, m, 5Љ-H2), 1.55–1.60 (2 H, m, 4Љ-H2), 1.74 (3 H, s,
2Љ-Me), 1.93 (2 H, t, J 6 Hz, 3Љ-H2), 2.45–2.51 (2 H, m, 2Ј-H2),
3.47–3.53 (2 H, m, 1Ј-H2), 7.5–7.6 (2 H, m, 6-H, 8-H), 7.82 (1 H,
dt, J ca. 1.5, 8 Hz, 7-H), 8.27 (1 H, dd, J 1.5, 8 Hz, 5-H);
δC (CDCl3, 75 MHz) 14.17, 19.49, 19.81, 26.42, 28.54, 33.02,
35.25, 40.05, 117.97, 121.95, 126.40, 126.66, 129.75, 135.45,
135.58, 155.34, 164.43, 180.49, 181.06; m/z 341 (M ϩ Hϩ,
90%), 300 (29), 279 (53), 205 (45), 156 (100), 137 (20); Rf 0.40
(DCM, UV).
Prop-2-en-1-yl 3-oxo-5-(2,6,6-trimethylcyclohex-1-en-1-yl)-
pentanoate 17. Method 1. A solution of the ketone 1420 (0.50 g,
2.57 mmol) and diallyl carbonate (1.10 g, 7.7 mmol) in dry
toluene (5 ml) was added to a suspension of sodium hydride
(60% dispersion in mineral oil, 0.206 g, 5.14 mmol) in dry
toluene (5 ml) under Ar, and the mixture then heated at 110 ЊC
for 3 h. Upon cooling a mixture of ether (9 ml), conc. hydro-
chloric acid (1.5 ml) and water (3 ml) was carefully added. After
vigorous stirring the organic layer formed was separated and
combined with a subsequent ether extract of the aqueous layer.
This was then dried, evaporated and chromatographed, eluting
with DCM, to give the title compound 17 (0.255 g, 35%) as a
colourless oil (M ϩ Hϩ, 279.1966. C17H27O3 requires 279.1960);
νmax (neat)/cmϪ1 2928, 2866, 1748, 1718, 1649, 1625, 1474, 1457,
1411, 1363, 1316, 1226, 1170, 989, 932; δH (300 MHz) 0.95 (6 H,
s, 6Ј-Me2), 1.35–1.40 (2 H, m, 5Ј-H2), 1.53 (3 H, s, 2Ј-Me), 1.50–
1.60 (2 H, m, 4Ј-H2), 1.87 (2 H, t, J 6 Hz, 3Ј-H2), 2.20–2.30 (2 H,
m, 4-H2), 2.55–2.65 (2 H, m, 5-H2), 3.45 (2 H, s, 2-H2), 4.62
(2 H, dd, J 1.5, 6 Hz, 1Љ-H2), 5.24 (1 H, dd, J 1.5, 10.5 Hz, 3Љ-H),
5.32 (1 H, dd, J 1.5, 16 Hz, 3Љ-H), 5.90 (1 H, tdd, J 6, 10.5,
16 Hz, 2Љ-H); δC (CDCl3, 75 MHz) 19.34, 19.61, 21.91, 28.32
(6Ј-Me2), 32.66, 34.93, 39.66, 43.71, 49.02, 65.80 (C-1Љ), 118.74
(C-3Љ), 128.06 (C-2Ј), 131.53 (C-2Љ), 135.57 (C-6Ј), 166.77 (C-1),
202.38 (C-3); m/z (peaks > 10%) 296 (M ϩ NH4ϩ, 80%), 279
(M ϩ Hϩ, 100), 261 (10), 136 (11); Rf 0.54 (DCM, orange with
vanillin).
Method 2. A mixture of the ketoester 11 (203 mg, 0.80
mmol), allyl alcohol (0.1 ml, 85 mg, 1.46 mmol) and ‘sulfated
SnO2’ catalyst21 (40 mg) in toluene (10 ml) was heated to 110 ЊC
in a round-bottomed flask fitted with a condenser. The reaction
was monitored by TLC (silica, DCM), and after 24 h the ester
17 was visible (Rf 0.54), together with some starting material 11
(Rf 0.45). The mixture was cooled, the catalyst was removed
by filtration, the filtrate was evaporated and the residual oil
was chromatographed, eluting with DCM–petroleum (4:1), to
obtain the ester 17 (130 mg, 58%) as a colourless oil, identical
(NMR, TLC) with material obtained by method 1.
Prop-2-en-1-yl
2,3-dihydro-2-methyl-2-[2-(2,6,6-trimethyl-
cyclohex-1-en-1-yl)ethyl]-4-oxo-4H-1-benzopyran-3-carboxylate
20. A solution of the chromone ester 18 (0.40 g, 1.05 mmol)
in dry THF (5 ml) was cooled to Ϫ10 ЊC. To this solution was
added chlorotrimethylsilane (1 M in THF, 4.2 ml, 4.2 mmol) to
give a yellow suspension. Copper() iodide (60 mg, 0.3 mmol)
was then added followed by methylmagnesium chloride (3 M
in THF, 0.77 ml, 2.3 mmol) which resulted in the yellow suspen-
sion changing to a yellow solution. After completion of the
reaction (ca. 5 h, monitored by TLC), cold glacial acetic acid
(2 ml) was added and the reaction was allowed to warm up
to room temperature overnight. The mixture was extracted
with ether (3 × 10 ml), washed with saturated aqueous sodium
hydrogen carbonate and dried over sodium sulfate. Evaporation
under reduced pressure gave a yellow oil which was purified
by chromatography, eluting with DCM, to obtain the title
compound 20 (0.260 g, 62%) as a yellow oil (M ϩ Hϩ, 397.2382.
C25H33O4 requires 397.2379); δH (300 MHz) 0.73 (minor),
J. Chem. Soc., Perkin Trans. 1, 2001, 206–215
211

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0.85 (major), 0.90 (minor) and 0.94 (major) (total 6H, 4 × s,
6Љ-Me2 of diastereoisomers), 1.31 (minor) and 1.44 (major)
(total 3 H, 2 × s, 2-Me of diastereoisomers), 1.53 (6 H, br s,
2Љ-Me of major and minor diastereoisomers), 1.3–1.4 (2 H, m,
5Љ-H2), 1.45–1.55, 1.6–1.9 and 2.0–2.3 (total 8 H, m, 1Ј-H2,
2Ј-H2, 3Љ-H2, 4Љ-H2), 3.82 (minor) and 3.84 (major) (total 1 H,
2 × s, 3-H of keto isomers), 4.55–4.75 (2 H, m, 1ٞ-H2), 5.19–
5.32 (2 H, m, 3ٞ-H2), 5.80–5.95 (1 H, m, 2ٞ-H), 6.91–7.00 (2 H,
m, 6-H, 8-H), 7.41–7.52 (1 H, m, 7-H), 7.80–7.86 (1 H, m,
5-H); m/z (peaks > 10%) 415 (14%), 414 (M ϩ NH4ϩ, 100), 397
(M ϩ Hϩ, 35), 245 (32).
3.4–3.6 (2 H, m, 1-H ), 4.56 (1 H, d, J 1.5 Hz, C᎐CH), 4.71 (1 H,
᎐
2
J 1.5 Hz, C᎐CH); m/z (CI, MeCN/NH ) 169 (M ϩ Hϩ, 20%),
᎐
3
151 (70), 106 (25), 41 (55).
2-(6,6-Dimethyl-2-methylenecyclohexyl)ethyl
methanesulf-
onate 25.28 To a solution of freshly distilled triethylamine
(1.82 g, 18 mmol) in anhydrous DCM (35 ml) under Ar at
Ϫ10 ЊC was added dropwise the alcohol 24 (2.0 g, 12 mmol).
After stirring for 10 min methanesulfonyl chloride (1.60 g,
14 mmol) was added. The reaction mixture was stirred for a
further 20 min and then washed with saturated aqueous sodium
hydrogen carbonate (20 ml), water (20 ml) and brine (10 ml),
dried and concentrated in vacuo. The crude mesylate was
chromatographed, eluting with petroleum–ethyl acetate (10:1),
to obtain the title compound 25 (2.68 g, 90%) as an off-white
waxy solid, mp 30–32 ЊC (M ϩ NH4ϩ, 264.1636. C12H26NO3S
requires 264.1633); νmax (neat)/cmϪ1 1626, 1390; δH (300 MHz)
0.83 (3 H, s, 6Ј-Me), 0.91 (3 H, s, 6Ј-Me), 1.2–2.0 (7 H, m, 1Ј-H,
4Ј-H2, 5Ј-H2, 2-H2), 2.02 (2 H, t, J 6 Hz, 3Ј-H2), 2.96 (3 H,
1-Hydroxymethyl-3,3-dimethylcyclohex-1-ene 22. To a stirred
solution of sodium borohydride (0.753 g, 20 mmol) in ethanol
(10 ml) at 0 ЊC was added dropwise over 0.5 h a solution of 3,3-
dimethylcyclohex-1-ene-1-carbaldehyde 2125 (2 g, 14.5 mmol)
in ethanol (15 ml). The reaction mixture was then warmed
to 10 ЊC, stirred for a further 2 h and then poured into water
(15 ml). When the effervescence had ceased the aqueous solu-
tion was extracted with ether (3 × 10 ml). The combined
organic extract was washed with water (10 ml) and brine
(10 ml), dried over anhydrous sodium sulfate and concentrated
in vacuo. The residue was distilled under reduced pressure,
yielding the title compound 22 (1.43 g, 70%) as a colourless
viscous oil, bp 76–78 ЊC at 2 mmHg (lit.,25 78–80 ЊC at 2 mmHg);
νmax (neat)/cmϪ1 3342, 2930, 2864, 1467, 1454, 1360, 1123, 1066,
1031, 1000, 909, 735; δH (300 MHz) 0.91 (6 H, s, 2 × 3-Me), 1.35
(2 H, m, 4-H2), 1.54–1.63 (2 H, m, 5-H2), 1.88 (2 H, t, J 6 Hz,
6-H2), 2.28 (1 H, s, OH), 3.89 (2 H, s, CH2OH), 5.32 (1 H, s,
2-H); m/z (CI, MeCN/NH3) 141 (M ϩ Hϩ, 30%), 123 (100), 109
(65), 107 (25), 79 (45), 40 (50).
s, SO Me), 3.95–4.21 (2 H, m, 1-H ), 4.58 (1 H, s, C᎐CH), 4.80
᎐
2
2
(1 H, s, C᎐CH); m/z (CI, NH ) 264 (M ϩ NH ϩ, 100%).
᎐
3
4
2-(2-Iodoethyl)-3,3-dimethyl-1-methylenecyclohexane
26.28
To a solution of sodium iodide (0.525 g, 3.5 mmol) in hot
anhydrous acetone (30 ml) under Ar was added dropwise
a solution of the mesylate 25 (0.5 g, 2 mmol) in anhydrous
acetone (25 ml), and the resulting mixture was heated under
reflux for 4 h. The acetone was then removed in vacuo and the
residue dissolved in ether. Water was added to dissolve the
remaining sodium iodide and the organic layer was separated,
washed with water (50 ml) and brine (50 ml), dried and con-
centrated in vacuo. The residue was chromatographed, eluting
with pentane, yielding the title compound 26 (0.396 g, 71%) as
a pale brown oil (Mϩ, 278.0536. C11H19I requires 278.0533);
δH (300 MHz) 0.81 (3 H, s, 3-Me), 0.91 (3 H, s, 3-Me), 1.20–1.53
(4 H, m, 4-H2, 5-H2), 1.85–2.03 (5 H, m, 2-H, 6-H2, 1Ј-H2),
Ethyl 2-(6,6-dimethyl-2-methylenecyclohexyl)ethanoate 23.
To a mixture of the alcohol 22 (2 g, 14.2 mmol) and freshly
distilled triethyl orthoacetate (16.3 g, 100 mmol) was added
a catalytic amount of propanoic acid (0.1 g, 1.34 mmol). The
mixture was heated to 150 ЊC and the ethanol formed during
the reaction was allowed to distil off.26 After 1 h of reaction a
further portion of propanoic acid (0.1 g, 1.34 mmol) was added
and the addition was repeated each hour until the reaction was
complete (total 5 h). The triethyl orthoacetate was then distilled
off at atmospheric pressure and the brown oily residue was
chromatographed, eluting with pentane, to obtain the title com-
pound 23 (2.12 g, 71%) as a colourless oil (M ϩ Hϩ, 211.1695.
C13H23O2 requires 211.1698); νmax (neat)/cmϪ1 2933, 1735, 1646,
1157, 912, 734; δH (300 MHz) 0.76 (3 H, s, 6Ј-Me), 0.98 (3 H,
s, 6Ј-Me), 1.18 (3 H, t, J 6 Hz, OCH2CH3), 1.38–1.63 (4 H, m,
4Ј-H2, 5Ј-H2), 2.16–2.23 (3 H, m, 1Ј-H, 3Ј-H), 2.32–2.41 (2 H,
2.87–3.21 (2 H, m, 2Ј-H ), 4.59 (1 H, s, C᎐CH), 4.81 (1 H, s,
᎐
2
C᎐CH); ν
᎐
(neat)/cmϪ1 2931, 2866, 1645, 1449, 1366, 1230,
max
1165, 891; m/z 296 (M ϩ NH4ϩ, 34%), 279 (M ϩ Hϩ, 71), 278
(40), 265 (38), 173 (52), 156 (32), 151 (59), 129 (22), 123 (52),
109 (70), 95 (100), 81 (40), 69 (54).
Methyl 2-methyl-4-oxo-4H-1-benzopyran-3-carboxylate 28.
This was prepared from methyl acetoacetate and 2-fluoro-
benzoyl chloride as described.19 The product had mp 116–
117 ЊC (lit.,19 115–116 ЊC); νmax (CHBr3)/cmϪ1 1725, 1646, 1620;
δH (CDCl3) 2.52 (3 H, s, 2-Me), 3.97 (3 H, s, OMe), 7.36–7.44
(2 H, m, 6-H, 8-H), 7.67 (1 H, dt, J6,7 8, J7,8 8, J5,7 1 Hz, 7-H),
8.21 (1 H, dd, J5,6 7.5, J5,7 1 Hz, 5-H).
m, 2-H ), 4.07 (2 H, q, J 6 Hz, OCH CH ), 4.51 (1 H, s, C᎐CH),
᎐
2
2
3
4.76 (1 H, s, C᎐CH); m/z 228 (M ϩ NH ϩ, 12%), 211 (M ϩ Hϩ,
᎐
4
100), 197 (18).
Methyl 2,3-dihydro-2-methyl-2-[2-(2,2-dimethyl-6-methylene-
cyclohexyl)ethyl]-4-oxo-4H-1-benzopyran-3-carboxylate
29.
2-(6,6-Dimethyl-2-methylenecyclohexyl)ethanol 24. To an
ice-cooled, stirred suspension of lithium aluminium hydride
(364 mg, 9.5 mmol) in anhydrous THF (5 ml) under N2 was
added dropwise over 0.5 h a solution of the ester 23 (2.0 g,
9.5 mmol) in anhydrous THF (15 ml). The mixture was allowed
to warm to room temperature and then stirred for 12 h, after
which time the reaction was judged by TLC to be complete.
The excess lithium aluminium hydride was destroyed by adding
10% sodium hydroxide dropwise to the cooled reaction mixture,
and the precipitated lithium hydroxide was filtered off. The
organic solution was washed with water (10 ml) and brine
(10 ml), dried and concentrated in vacuo. The residue was puri-
fied by chromatography, eluting with pentane–ethyl acetate
(10:1), which gave the alcohol 24 (1.28 g, 80%) as a colourless
oil; νmax (neat)/cmϪ1 3325, 2931, 1645, 1464, 1451, 1053, 889
(lit.,26 3337, 2929, 1644, 1453, 1052, 889); δH (300 MHz) 0.79
(3 H, s, 6Ј-Me), 0.86 (3 H, s, 6Ј-H), 1.1–1.7 (6 H, m, 2-H2, 4Ј-H2,
5Ј-H2), 1.8–2.1 (3 H, m, 1Ј-H, 3Ј-H2), 2.15 (1 H, br s, OH),
Method 1. To a solution of the iodide 26 (250 mg, 0.9 mmol) in
anhydrous ether (15 ml) was added tert-butyllithium in pentane
(1.7 M, 0.53 ml, 0.9 mmol) dropwise under Ar at Ϫ35 ЊC. After
stirring for 15 min the pale yellow solution was added to a
suspension of copper() iodide (96 mg, 0.5 mmol) in anhydrous
ether (10 ml) at Ϫ50 ЊC via a cannula. The reaction mixture was
stirred for another 15 min at Ϫ50 ЊC and the chromone ester
28 (109 mg, 0.5 mmol) in anhydrous ether (10 ml) was then
added dropwise. Stirring at Ϫ50 ЊC was continued for a further
1 h, and saturated aqueous ammonium chloride (15 ml) then
added. The slurry was stirred for 5 min and the organic layer
then separated. The aqueous phase was back-washed with ethyl
acetate (2 × 20 ml) and the combined organic extracts were
washed with 10% hydrochloric acid (20 ml), water (20 ml)
and brine (20 ml), dried and concentrated in vacuo. The crude
product was chromatographed, eluting with petroleum–ethyl
acetate (15:1), to obtain the title compound 29 (77 mg, 46%;
mixture of diastereoisomers) as a pale yellow oil (M ϩ NH4
ϩ
,
212
J. Chem. Soc., Perkin Trans. 1, 2001, 206–215

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388.2480; C23H34NO4 requires 388.2488); νmax (neat)/cmϪ1 2951,
1742, 1695, 1643, 1609, 1464, 1272, 1241, 763; δH (300 MHz)
0.79, 0.83, 0.87, 0.90 (total 6 H, 4 × s, 2Љ-Me2 of diastereo-
isomers), 1.15–2.05 (total 11 H, m, 1Ј-H2, 2Ј-H2, 1Љ-H, 3Љ-H2,
4Љ-H2, 5Љ-H2), 1.48, 1.49 (total 3 H, 2 × s, 2-Me of diastereo-
isomers), 3.74 (3 H, s, OMe), 3.6–3.85 (1 H, m, 3-H), 4.4–4.8
3-H2), 1.95 (1 H, ddd, J5ꢁ,6ꢁ 8 Hz, J5ꢀ,6ꢁ 12 Hz, J6ꢀ,6ꢁ 15 Hz,
6β-H), 2.04 (1 H, dd, J5ꢁ,6ꢁ 8 Hz, J5ꢀ,5ꢁ 14 Hz, 5β-H), 2.22 (1 H,
ddd, J5ꢀ,6ꢀ 7 Hz, J5ꢀ,6ꢁ 12 Hz, J5ꢀ,5ꢁ 14 Hz, 5α-H), 2.36 (1 H,
dd, J5ꢀ,6ꢀ 7 Hz, J6ꢀ,6ꢁ 15 Hz, 6α-H), 6.90 (1 H, d, J8,9 8 Hz, 8-H),
7.02 (1 H, t, J9,10 8 Hz, J10,11 8.5 Hz, 10-H), 7.48 (1 H, apparent
dt, J8,9 8 Hz, J9,10 8 Hz, J9,11 1 Hz, 9-H), 7.92 (1 H, dd, J9,11 1 Hz,
J10,11 8.5 Hz, 11-H); δC (100 MHz, CDCl3) 17.13 (2-C), 17.87
(12b-Me), 21.94 (3-C), 23.36 (6a-Me), 23.82 (4-Me), 26.3
(4-Me), 32.86 (1-C), 32.94 (6-C), 35.93 (5-C), 36.04 (4-C), 47.52
(12b-C), 67.30 (12a-C), 78.88 (6a-C), 89.65 (4a-C), 118.07
(8-C), 121.39 (10-C), 121.91 (11a-C), 126.97 (11-C), 136.18
(9-C), 159.38 (7a-C), 171.46 (13-C), 186.51 (12-C); m/z (FAB)
355 (M ϩ Hϩ, 76%), 327 (81), 303 (30), 300 (100), 283 (65); Rf
0.45 (DCM, UV).
(total 2 H, 2 × br s, 2 × d, J ca. 2 Hz, C᎐CH of diastereo-
᎐
2
isomers), 6.9–7.0 (2 H, m, 6-H, 8-H), 7.48 (1 H, apparent dt,
J7,8 7, J6,7 8, J5,7 1.5 Hz, 7-H), 7.83 (1 H, dd, J5,6 7, J5,7 1.5 Hz,
5-H); m/z 388 (M ϩ NH4ϩ, 100%), 371 (M ϩ Hϩ, 30), 322 (25),
219 (30). The presence of enol tautomers was suggested by
peaks in the NMR spectrum at δH 6.8 (d, J 8 Hz, 6-H), 7.6
(d, J 8 Hz, 6-H) and 12.9 (s, enolic OH).
Method 2. To a solution of the iodide 26 (250 mg, 0.9 mmol)
in anhydrous ether (10 ml) was added tert-butyllithium in
pentane (1.7 M, 0.53 ml, 0.9 mmol) dropwise under Ar at
Ϫ30 ЊC. The solution was stirred for 15 min and then lithium
2-thienylcyanocuprate in THF (0.25 M, 4.0 ml, 1.0 mmol)
was added dropwise at Ϫ50 ЊC to give a dark brown suspension.
The solution was allowed to warm up to Ϫ20 ЊC and stirred
until all the brown solid had dissolved. At this point the
reaction mixture was cooled back to Ϫ50 ЊC and a solution of
the chromone ester 28 in ether (218 mg, 1 mmol) was added
slowly. The resulting deep-red solution was stirred at Ϫ50 ЊC
for 1 h and then quenched with saturated aqueous ammonium
chloride (25 ml). The ethereal layer was separated, the aqueous
phase was back-washed with ethyl acetate (2 × 25 ml), and the
combined organic extracts were washed with 10% hydrochloric
acid (25 ml), water (25 ml) and brine (25 ml). The extracts were
then dried and concentrated in vacuo. The residual green oil was
chromatographed, eluting with petroleum ether–ethyl acetate
(15:1), to obtain the title compound 29 (220 mg, 66%; mixture
of diastereoisomers) as a pale yellow oil.
Method 3. The procedure described Method 2 was repeated,
except that the lithium 2-thienylcyanocuprate was replaced with
lithium N-imidazol-1-idocyanocuprate. This was made by treat-
ing a solution of imidazole (102 mg, 1.5 mmol) in anhydrous
THF (6 ml) with n-butyllithium in hexanes (1.5 M, 1.0 ml,
1.5 mmol) under Ar at Ϫ10 ЊC to obtain N-lithioimidazole.
This solution was added to copper() cyanide (134 mg,
1.5 mmol), producing the desired cuprate reagent as a pale
green solution. This was added to the lithiated iodide (see
Method 2) instead of its 2-thienyl analogue. The yield of 29 was
173 mg (52%).
Method 2. A solution of anhydrous manganese() acetate
(387 mg, 1.67 mmol) in acetic acid (dried with acetic anhydride
and degassed; 50 ml) was heated to 80 ЊC under Ar and treated
dropwise with a solution of 13 (309 mg, 0.834 mmol) in dry
degassed acetic acid (20 ml). The reaction mixture was stirred
at 80 ЊC for 12 h, during which the colour of the solution
changed from red–brown to yellow, and then quenched with
water (40 ml). The aqueous phase was extracted with DCM
(3 × 25 ml) and the organic extracts were washed with saturated
aqueous sodium hydrogen carbonate (3 × 25 ml), water (25 ml)
and brine (25 ml), dried and concentrated. The resulting yellow
oil was chromatographed, eluting with petroleum–ethyl acetate
(3:1), which gave the lactone 30 (170 mg, 0.48 mmol, 58%) as a
colourless solid, identical to the previously characterised sample.
( )-Methyl (5aꢀ,7aꢁ,11aꢁ,12aꢀ,13ꢁ)-5a,6,7,7a,8,9,10,11,12a,
13-decahydro-13-hydroxy-5a,8,8-trimethyl-12H-11a,13-epoxy-
benzo[4,5]cyclohepta[1,2-b]chromene-12a-carboxylate 34. To a
degassed and dried33 solution of manganese() acetate hydrate
(75 mg, 0.28 mmol) in acetic acid (10 ml) at 65 ЊC under Ar
was added a solution of the isomeric chromanones 29 (50 mg,
0.14 mmol) in acetic acid (5 ml). The solution was stirred
at 65 ЊC for 3 h and then quenched by the addition of water
(10 ml). The aqueous phase was extracted with DCM (3 ×
10 ml) and the combined extract washed with saturated
aqueous sodium hydrogen carbonate (3 × 10 ml), water (10 ml)
and brine (10 ml), and dried. The solvent was removed
under reduced pressure and the residual mixture was chrom-
atographed, eluting with petroleum–ethyl acetate (12:1).
The major product, a white solid, was identified as the title
compound 34 (16 mg, 31%), which formed colourless crystals,
mp 158–159 ЊC (petroleum 60–80 ЊC) (Found: C, 71.40; H,
7.75. C23H30O5 requires C, 71.46; H, 7.83%); δH (300 MHz) 0.87
(3 H, s, 8-Me), 0.89 (3 H, s, 8-Me), 1.2–1.6 (7 H, m, 7-H2, 7a-H,
9-H2, 10-H2), 1.46 (3 H, s, 5a-Me), 1.7–1.9 (2 H, m, 6-H, 11-H),
2.12 (1 H, dd, J 2, 13.5 Hz, 6-H or 11-H), 2.27 (1 H, d, J 13.5
Hz, 12-H), 2.34 (1 H, d, J 12.5 Hz, 6-H or 11-H), 2.44 (1 H, d,
J 13.5 Hz, 12-H), 2.88 (1 H, s, exchanges with D2O, OH), 3.66
(3 H, s, OMe), 6.79 (1 H, dd, J2,4 1 Hz, J3,4 8 Hz, 4-H), 6.96 (1 H,
apparent dt, J2,4 1 Hz, J2,3 8.5 Hz, J1,2 8.5 Hz, 2-H), 7.20 (1 H,
apparent dt, J1,3 1.5 Hz, J3,4 8.5 Hz, J2,3 8.5 Hz, 3-H), 7.56
(1 H, dd, J1,3 1.5 Hz, J1,2 8.5 Hz, 1-H); δC (CDCl3, 100 MHz)
19.57 (10-C), 21.17 (9-C), 21.18 (8-Me), 23.62 (8-Me), 31.74
(5a-Me), 34.85 (8-C), 35.54, 36.66, 41.59, 43.09 (6-C, 7-C, 11-C,
12-C), 50.00 (OMe), 52.08 (7a-C), 63.59 (12a-C), 80.39 (5a-C),
86.54 (11a-C), 97.45 (13-C), 116.86 (4-C), 121.24 (2-C), 124.04
(13a-C), 125.91 (1-C), 129.91 (3-C), 151.62 (4a-C), 172.08
(C᎐O); ν (CHCl3)/cmϪ1 3488, 1728, 1614, 1587, 1486, 1459,
( )-(4aꢀ,6aꢀ,12aꢀ,12bꢁ)-1,3,4,6,6a,12b-Hexahydro-4,4,6a,
12b-tetramethyl-2H,5H-4a,12a-(epoxymethano)benzo[a]-
xanthene-12,13-dione 30. Method 1. A solution of anhydrous
manganese() acetate31 (35 mg, 0.15 mmol) and copper()
acetate monohydrate (299 mg, 0.15 mmol) in dry degassed acetic
acid (10 ml) was heated to 58 ЊC under an inert atmosphere and
treated dropwise with a solution of 13 (50 mg, 0.14 mmol)
in dry degassed acetic acid (5 ml). The reaction mixture was
stirred at this temperature for a further 5 h, during which
the colour of the solution changed from dark blue–green to
turquoise, and was then quenched with water (10 ml). The
mixture was transferred to a separating funnel and the aqueous
phase was extracted with DCM (3 × 10 ml). The organic
extracts were washed with saturated aqueous sodium hydrogen
carbonate (3 × 10 ml), water (10 ml) and brine (10 ml), dried
and concentrated. The resulting clear gum was chromato-
graphed, eluting with cyclohexane–ethyl acetate (10:1), which
gave several fractions. A major product was crystallised from
cold ethyl acetate to give the title compound 30 (12 mg, 25%) as
colourless crystals, mp 227–228 ЊC (EtOH) (Found: C, 74.29;
H, 7.48. C22H26O4 requires C, 74.55; H, 7.39%); λmax (EtOH)/
nm 256, 316 (end absorption at 217); νmax (Nujol)/cmϪ1 1784,
1683, 1605, 1462, 1320, 1302, 1226, 1157, 1032, 926, 756;
δH (400 MHz) 1.02 (3 H, s, 4-Me), 1.08 (3 H, s, 4-Me), 1.27 (3 H,
s, 12b-Me), 1.42 (3 H, s, 6a-Me), 1.2–1.75 (6 H, m, 1-H2, 2-H2,
᎐
max
1308, 1262, 1244, 1098, 1060, 1042, 1027, 1006, 757; m/z
(CI, NH3) 404 (M ϩ NH4ϩ, 2%), 386 (M Ϫ H2O ϩ NH4ϩ, 2),
369 (M Ϫ H2O ϩ Hϩ, 100).
( )-(4aꢀ,6aꢀ,12aꢀ,12bꢁ)-1,3,4,6,6a,12b-Hexahydro-4,4,6a,
12b-tetramethyl-13-oxo-2H,5H,12H-4a,12a-(epoxymethano)-
benzo[a]xanthen-12-ol 39. To a solution of lactone 30 (65.5 mg,
0.185 mmol) in dry toluene (2 ml) at Ϫ78 ЊC under Ar
J. Chem. Soc., Perkin Trans. 1, 2001, 206–215
213

View Article Online
was added dropwise DIBAL-H in toluene (1 M, 0.56 ml,
0.56 mmol). The reaction was held at Ϫ78 ЊC for 1 h and then
allowed to warm up to room temperature overnight. Water
(4 ml) was added and the reaction mixture was extracted with
ether (3 × 5 ml). The organics were washed with water (5 ml)
and brine (5 ml), dried and concentrated, yielding the title com-
pound 39 (14.6 mg, 23%) as a colourless solid, mp 185–190 ЊC
(M ϩ Hϩ, 357.2065. C22H28O4 requires 357.2066); λmax (EtOH)
end absorption at 217 nm only; νmax (Nujol)/cmϪ1 3495, 1749,
1606, 1583, 1295, 1269, 1228, 1152, 1126, 1067, 1047, 1005, 941,
912, 755; δH (300 MHz) 0.95 (3 H, s, 4-Me), 1.03 (3 H, s, 4-Me),
1.18 (3 H, s, 12b-Me), 1.25 (3 H, s, 6a-Me), 1.2–1.75 (6 H, m,
1-H2, 2-H2, 3-H2), 1.80–1.95 (2 H, m, 5β-H, 6β-H), 2.00–2.20
(2 H, m, 5α-H, 6α-H), 2.84 (1 H, br s, OH), 5.59 (1 H, br s,
12-H), 6.71 (1 H, d, J 8 Hz, 8-H), 6.95 (1 H, apparent t, J 7.5
Hz, 10-H), 7.16 (1 H, apparent t, J 7.5 Hz, 9-H), 7.57 (1 H,
d, J 7.5 Hz, 11-H); δC (CDCl3, 75 MHz) 17.43, 18.31, 21.75,
24.08, 24.82, 27.00, 34.05, 35.50, 36.01 (quaternary), 36.34,
48.99 (quaternary), 57.60 (C-6a), 66.80 (C-12), 91.35 (C-4a),
116.03 (C-8), 120.93 (C-10), 123.59 (C-11a), 126.42, 128.76,
153.00 (C-7a), 176.95 (C-13) (one peak hidden; assignments
tentative); m/z (peaks > 10%) 374 (M ϩ NH4ϩ, 100%); Rf 0.30
(DCM, UV active, no colour with vanillin).
6-H2), 0.88 (3 H, s, 4-Me), 0.93 (3 H, s, 4-Me), 1.17 (3 H, s,
12b-Me), 1.24 (3 H, s, 6a-Me), 1.62 (1 H, d, J 9.5 Hz, disappears
on D2O shake, 12-OH), 3.64 (1 H, d, J 9 Hz, 13-H), 4.26 (1 H, d,
J 9 Hz, 13-H), 4.96 (1 H, d, J 9.5 Hz, becomes s on D2O shake,
12-H), 6.70 (1 H, d, J 7.5 Hz, 8-H), 6.92 (1 H, apparent t,
J 7.5 Hz, 10-H), 7.16 (1 H, apparent t, J 7.5 Hz, 9-H), 7.48 (1 H,
d, J 7.5 Hz, 11-H).
Acknowledgements
We are grateful to the EPSRC and Glaxo Wellcome for a
CASE studentship. We warmly thank Mrs Laurie Cunliffe
and Mrs Ruth Howard for mass spectra, and Dr Mike Stuckey
(Salford), Dr Steve Simpson (Salford) and Mr Sean Lynn
(Glaxo Wellcome) for their assistance with NMR measure-
ments. We also acknowledge the use of the EPSRC’s Chemical
Database Service at Daresbury.
References
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( )-(4aꢀ,6aꢀ,12aꢀ,12bꢁ)-1,3,4,6,6a,12b-Hexahydro-4,4,6a,
12b-tetramethyl-2H,5H,12H-4a,12a-(epoxymethano)benzo[a]-
xanthene-12,13-diol
41
( )-(4aꢀ,6aꢀ,12aꢀ,12bꢁ)-1,3,4,6,
6a,12b-hexahydro-4,4,6a,12b-tetramethyl-2H,5H,12H-4a,12a-
(epoxymethano)benzo[a]xanthen-12-ol 42. Method 1. To a
solution of lactone 30 (11.1 mg, 0.031 mmol) in dry THF
(3 ml) at 0 ЊC under Ar was added LAH in ether (1 M,
0.06 ml, 0.06 mmol, 2 mol. equiv.). This was stirred at 0 ЊC
for 3 h and then at room temperature for two days. The
reaction was quenched with dilute sulfuric acid (2 M, 5 ml)
and extracted with ether (3 × 5 ml). The extract was washed
with water (10 ml), and brine (10 ml), dried and concen-
trated to obtain a crude white solid which by TLC appeared to
be a two-component mixture. Flash chromatography, eluting
with petroleum–ethyl acetate (3:1), gave the title compound
41 (2.8 mg, 25%) as a colourless solid, mp 210–215 ЊC (Mϩ,
358.2127. C22H30O4 requires 358.2144) (M Ϫ H2O ϩ Hϩ,
341.2112. C22H29O3 requires 341.2117); νmax (Nujol)/cmϪ1 3351
(br), 1584, 1226, 1129, 1099, 967, 909, 754; δH (300 MHz)
0.8–1.75 (6 H, m, 1-H2, 2-H2, 3-H2), 0.91 (3 H, s, 4-Me), 0.96
(3 H, s, 4-Me), 1.18 (3 H, s, 12b-Me), 1.27 (3 H, s, 6a-Me),
1.85–2.0 (3 H, m, 5-H2, 6α-Heq*), 2.63 (1 H, ddd, J 4, 13, 13 Hz,
6β-Hax*), 3.45 (1 H, d, J 2 Hz, 12-OH), 3.59 (1 H, br s, 13-OH),
5.31 (1 H, d, J 3.5 Hz, 13-H), 5.36 (1 H, br s, 12-H), 6.69 (1 H,
d, J 7.5 Hz, 8-H), 6.94 (1 H, apparent t, J 7.5 Hz, 10-H), 7.15
(1 H, apparent t, J 7.5 Hz, 9-H), 7.57 (1 H, d, J 7.5 Hz, 11-H)
[(*) denotes tentative assignment]; m/z (CI) 358 (Mϩ, 5%), 341
(M Ϫ H2O ϩ Hϩ, 100), 323 (46), 219 (50); Rf 0.15 (DCM,
vanillin).
15 S. T. Saengchantara and T. W. Wallace, Tetrahedron, 1990, 46,
3029.
Method 2. To a solution of lactone 30 (32.2 mg, 0.091 mmol)
in dry toluene (2 ml) at Ϫ78 ЊC under Ar was added dropwise
DIBAL-H in toluene (1 M, 1.10 ml, 1.10 mmol, 12 mol. equiv.).
The reaction was held at Ϫ78 ЊC for 1 h and then allowed to
warm up to room temperature overnight. Water (4 ml) was
added and the reaction mixture was extracted with ether (3 ×
5 ml). The organics were washed with water (5 ml), brine (5 ml),
dried and concentrated, yielding a mixture consisting of the
diol 41 and a second compound which was tentatively identified
as the alcohol 42 (total 12.8 mg, ca. 40%) in which 42 was
16 B. B. Snider, Chem. Rev., 1996, 96, 339 and references cited
therein.
17 Preliminary account and X-ray data: B. S. Crombie, A. D.
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1
slightly predominant. The H NMR spectrum of 41 appears
as described above, with changes in hydroxy signals as follows:
δH 3.43 (1 H, d, J 2 Hz, disappears on D2O shake, 12-OH), 3.39
(1 H, d, J 3.5 Hz, disappears on D2O shake, 13-OH), 5.30 (1 H,
d, J 3.5 Hz, becomes s on D2O shake, 13-H), 5.36 (1 H, br
s, sharpens on D2O shake, 12-H). Signals attributed to 42
(mixture with 41): δH 0.8–2.05 (10 H, m, 1-H2, 2-H2, 3-H2, 5-H2,
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214
J. Chem. Soc., Perkin Trans. 1, 2001, 206–215

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J. Chem. Soc., Perkin Trans. 1, 2001, 206–215
215