A new and efficient method for o-quinone methide intermediate generation: Application to the biomimetic synthesis of the benzopyran derived natural products (±)-lucidene and (±)-alboatrin

Article abstract of DOI:10.1039/b508972g

Lucidene and alboatrin are complex benzopyran derived natural products. A key step in their biogenesis may involve a hetero Diels-Alder cycloaddition between an o-quinone methide intermediate with a simple, or activated tri-substituted olefin. Experimental evidence is provided to support this hypothesis, with the biomimetic synthesis of both (±)-lucidene and (±)-alboatrin successfully achieved using a new and efficient method for o-quinone methide generation. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b508972g

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A R T I C L E
A new and efficient method for o-quinone methide intermediate
generation: application to the biomimetic synthesis of the benzopyran
derived natural products ( )-lucidene and ( )-alboatrin
Raphae¨l Rodriguez,a John E. Moses,b Robert M. Adlingtona and Jack E. Baldwin*a
a The Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford,
UK OX1 3TA. E-mail: jack.baldwin@chem.ox.ac.uk
b The School of Pharmacy, University of London, 29-39 Brunswick Square, London,
UK WC1N 1AX
Received 28th June 2005, Accepted 25th July 2005
First published as an Advance Article on the web 7th September 2005
Lucidene and alboatrin are complex benzopyran derived natural products. A key step in their biogenesis may involve
a hetero Diels–Alder cycloaddition between an o-quinone methide intermediate with a simple, or activated
tri-substituted olefin. Experimental evidence is provided to support this hypothesis, with the biomimetic synthesis of
both ( )-lucidene and ( )-alboatrin successfully achieved using a new and efficient method for o-quinone methide
generation.
o-Quinone methides are highly reactive transient species,
Introduction
which have been applied as intermediates in the synthesis of
In recent years many structurally novel benzopyran derived
several natural products.6,7 Such compounds are known to
natural products have been isolated from organisms as di-
verse as plants, animals, insects and fungi (Scheme 1). Many
react with nucleophiles in 1,4-Michael addition type fashion,
or with a range of dienophiles to perform [4 + 2] cycloaddition
of these compounds display interesting biological properties
to provide benzopyran type structures. Many strategies have
including activity against Plasmodium falciparum,1 phytotoxic
been established in order to generate o-quinone methides in
properties,2 erythropoietin gene expression,3 and acetylcholine
situ. However, problems with such protocols often include
esterase inhibition.4 As part of our continuing efforts directed
undesirable high temperatures,7,8 long reaction times,4,7,8 the
towards the biomimetic synthesis of natural products, we be-
need for catalysis,7,9 and/or acidic7 or basic conditions,7,10a
came interested in studying these class of benzopyranic natural
which can induce problematic side reactions. In addition, the
products which include ( )-lucidene 1,5 (+)-alboatrin 2,2 (+)-
o-quinone methide precursors necessary for use with existing
pughiinin A 3,1 and (+)-epolone A 43 (Scheme 1), and in
methodologies are often unstable and relatively inaccessible.7
developing methodology that would allow ready access to the
Thus, we chose to investigate alternative methodologies for the
common benzopyran core structure. We have recently reported
a biomimetic synthesis of ( )-alboatrin 2, which involved a
generation of o-quinone methides for the application towards
natural product synthesis.
novel hetero Diels–Alder cycloaddition of an o-quinone methide
intermediate and a readily accessible dienophile.6a We now wish
Results and discussion
to report a complete account of these studies which include a new
method for the generation of o-quinone methide intermediates,
and their application towards the biomimetic synthesis of
complex natural products.
We have previously reported the generation of o-quinone me-
thide by the thermal driven dehydration of an o-hydroxybenzyl
alcohol precursor 5.6c Although this method proved syntheti-
cally useful, the reaction temperatures necessary to facilitate de-
hydration were undesirable and potentially disruptive to delicate
structures. However, we were keen to build upon this methodol-
ogy and uncover a more attractive o-quinone methide precursor.
We envisaged a solution to the problem might involve activation
of the benzyl alcohol moiety of the o-quinone methide precursor,
thus facilitating dehydration through a more attractive acetyl
leaving group. To investigate our hypothesis, we prepared the
o-quinone methide precursors 6a and 6b (Scheme 2), since
benzopyran sub units are common structural features of several
natural products (Scheme 1). Although o-acetoxymethylphenols
(including 6b) have been described in the literature, members
of this class of compounds have been reported as being labile
structures which “can be conserved for several days in dilute
solution but polymerise rapidly as soon as they are pure”.10a
Their reported synthesis is likewise unattractive; for example
Loubinoux has reported the need for a six-step synthesis of o-
acetoxymethylphenol (6b) from salicylaldehyde.10b Perhaps as
a consequence, reports of potential o-acetoxymethylphenols
to serve as o-quinone methide synthons are limited to base
promoted chemistry, followed by in situ nucleophilic Michael
addition.10a We have been unable to find reports of their use for
o-quinone methide generation under purely thermal conditions.
Scheme 1
3 4 8 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 8 8 – 3 4 9 5
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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To investigate the potential of compounds 6a and 6b
as o-quinone methide precursors, several readily available
dienophiles were exposed to both compounds under a range
of reaction conditions. The results from these studies are sum-
marised in Table 1. Generally, the reaction times, temperatures
required and yields obtained compare favourably with those
described for other methods,4,7,8,14 and the reaction could be
performed on very hindered dienophiles such as a-pinene.
To further demonstrate the usefulness of this new method
for o-quinone methide generation, we decided to investigate
its potential towards the biomimetic synthesis of benzopyran
containing natural products. With this in mind, we focused our
initial efforts towards the synthesis of alboatrin ( )-2.
(+)-Alboatrin2 2 is a phytotoxic benzopyran natural product
reported in 1988 by Ichihara et al., and later structurally
corrected by Murphy et al.15 The biosynthesis of (+)-alboatrin
2 may be proposed to proceed through a hetero Diels–Alder
cycloaddition of an orcinol-derived o-quinone methide 16, and
(R)-4,5-dihydro-2,4 dimethylfuran 9 (Fig. 2). Indeed, Wilson
et al. have made a similar connection and demonstrated in a
recent study its feasibility as a major pathway to the structurally
related natural product (−)-xyloketal A 17 and (−)-xyloketal D
184 (Fig. 3). In order to provide further biosynthetic details
regarding the origin of (+)-2, and to further evaluate our
methodology towards natural product synthesis, dienophile ( )-
4,5-dihydro-2,4-dimethylfuran 9 was prepared according to the
procedure of Wilson et al.4 Thereafter, simple heating of 6a
in the presence of ( )-9 afforded ( )-acetylalboatrin 10 as the
major isolated product (63% yield), ( )-acetyl-epi-alboatrin16
(5% yield), and an inseparable mixture [3 : 2] of diastereoisomers
( )-19 (25% yield). De-acylation of ( )-10 gave target ( )-
alboatrin, for which spectral data were identical to the natural
material [1H, 13C].2 The structure of ( )-2 was also confirmed
by X-ray analysis and was found to be in agreement with
Murphy’s proposal15 (Fig. 4).13 With the successful application
Scheme 2 Reagents and conditions: (a) BH3–MS (1 equiv.), THF, 0 ◦C,
to rt, 1 h, 84%; (b) ( )-4,5-dihydro-2,4-dimethylfuran 9 (1equiv.), ben-
zene, reflux, 36 h, 93% overall; (c) K2CO3 (3 equiv.), DCM–MeOH–H2O
(12 : 7 : 1), rt, 6 h, 97%.
In order to avoid the lengthy reported synthesis of 6b,10b we chose
to investigate conditions that would allow selective acylation
of the primary alcohol moiety of commercially available o-
hydroxybenzyl alcohol 5. Subsequently, it was discovered that
this selectivity could indeed be achieved by careful control of
the reaction temperature and rate of addition of the acylating
reagent, leading to the synthesis of 6b in an impressive 89%
yield. In order to prepare 6a, we considered that a related
selective acylation of the corresponding hydroxymethyl-orcinol
derivative 7 could also be used. However, upon reduction of the
corresponding aldehydic precursor, compound 7 was found to be
unstable and rapidly decomposed under the reaction conditions.
To address this problem, it was reasoned that suitable protection
of the phenolic position may prevent premature decomposition.
To this end, diacetate 811 was prepared, which we reasoned
could be reduced to the corresponding alcohol, and that such
a compound may facilitate o-quinone methide formation under
thermal conditions from an o-acetoxymethylphenol 6a, itself
generated via a transesterification mechanism. In practice, the
transfer of the phenolic acetate to the adjacent benzyl alcohol
group occurred during the reduction of 8 with borane–DMS
complex, thus giving the stable compound 6a12 (Fig. 1)13 with a
gratifying 84% yield. The proton NMR of 6a displayed a sharp
signal at 8.23 ppm, characteristic of a hydrogen bond between
the phenolic OH and the benzylic acetate. This was encouraging
since it was envisaged that such a hydrogen bond may facilitate
the elimination of acetic acid through a six-membered ring
transition state, furnishing the desired o-quinone methide under
relatively mild conditions.
Fig. 2 Biomimetic analysis of alboatrin (+)-2.
Fig. 3
Fig. 1 X-Ray structure of 6a.
Fig. 4 X-Ray structure of ( )-2.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 8 8 – 3 4 9 5
3 4 8 9

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3 4 9 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 8 8 – 3 4 9 5

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of this methodology towards the synthesis of ( )-2, we next
decided to re-investigate the biomimetic synthesis of ( )-
lucidene, employing this newly developed approach.
the temperatures employed in the cycloaddition reaction were
excessive.
To probe for further biosynthetic details, we applied our new
method of o-quinone methide generation toward the synthesis
of ( )-lucidene 1, as a comparison with our previous method
which employed an unactivated o-quinone methide precursor
5.6c In the former case the reaction was carried out in ◦toluene at
( )-Lucidene is a bis(benzopyranyl) sesquiterpene isolated
from the root bark of Uvaria lucida ssp. lucida5 in racemic
form. The co-isolation of a-humulene 20 from the same species
led to speculation that lucidene is the product of two con-
secutive inverse demand hetero Diels–Alder cycloadditions of
20, with two equivalents of o-quinone methide 21 (Fig. 5).5
This hypothesis is attractive on the grounds that FMO theory
supports the regiochemical and syn-stereochemical aspects17 of
such inverse electron demand hetero Diels–Alder processes,
since electronic factors would favour addition to the more
electron rich tri-substituted double bonds at the expense of
the more sterically hindered di-substituted double bond. It
has also been reported that (E) double bonds in medium
sized rings show a higher reactivity than otherwise expected
on account of steric strain.18 We have previously provided
convincing evidence to support this biosynthetic proposal, where
thermolysis of o-hydroxybenzyl alcohol 5 was used to generate
the o-quinone methide intermediate (Scheme 3).19 A summary
of our previous study is provided in Table 2.6c The experimental
results demonstrated that the naturally occurring diastereomer
( )-lucidene 1, is the favoured bis-adduct of a-humulene 20
with unsubstituted o-quinone methide 21 at high temperature.
The isolation of monoadduct ( )-22 en route to lucidene, offers
positive evidence that a similar pathway may occur in the
biosynthesis of ( )-lucidene 1. However, it was appreciated that
◦
130–140 C, as opposed to heating in xylene at 170 C. When
a-humulene was heated in the presence of 2.05 equivalents of
compound 6b, monoadduct ( )-2220 was obtained in 52% yield,
along with a mixture of bis-adducts ( )-1/( )-23 in 38% yield,
which favoured the natural product ( )-lucidene 1 [2.5 : 0.7].
The same reaction using 4.10 equivalents of precursor 6b gave an
inseparable mixture of compound ( )-1/( )-23 in the same ratio
as above, with an encouraging 71% yield. In this case, no trace of
mono-adduct or tris-adduct compounds were detected. In order
to investigate the effect of temperature on the diastereoselectivity
of the second cycloaddition process, compound ( )-22 was ex-
posed to 2.0 equivalents of 6b in benzene at 90 ◦C for 36 hours. A
mixture of compounds ( )-1/( )-23 in 32% yield was obtained,
with a similar ratio in favour of compound 1 [2.5 : 0.6].
In the same manner, we synthesised compound ( )-25
(Fig. 6)13 by condensation of precursor 6a with a-humulene
(20) (53% yield) to provide adduct ( )-24 and subsequent de-
acetylation under basic conditions (82% yield) (Scheme 4). We
believe this building block constitutes a useful starting material
for the biomimetic synthesis of pughiinin A 3 and epolone A 4
in racemic form.
Fig. 5 Biomimetic analysis of lucidene.
Fig. 6 X-Ray structure of 25.
Scheme 4 Reagents and conditions: (a) neat humulene 20 (5 equiv.),
140 ◦C, 12 h, 53% overall; (c) K2CO3 (1.1 equiv.), DCM–MeOH–H2O
(12 : 7 : 1), rt, 6 h, 82%.
Conclusion
In conclusion, we have developed a new and efficient method for
Scheme 3
o-quinone methide generation from o-acetoxymethyl-phenols.
Table 2
o-Hydroxybenzyl
alcohol 5 (equiv.)
Yield of
Yield of mixture
( )-1/( )-23 (%) [ratio]
Humulene 20 (equiv.)
Solvent
Temp./◦C
(
)-22 (%)
1
1
1
1
2.05
2.05
2.05
6
Xylene
170
170
170
170
28
32
23
—
17 [2.5 : 1]
7
Acetonitrile–water 1 : 1
1,4-Dioxane
Xylene
4
45 (trace of tris-adduct)21
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 8 8 – 3 4 9 5
3 4 9 1

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The described methodology required no added acid,7 base7,10b
or catalyst7,9 for the formation of the Diels–Alder adducts. The
elimination of acetic acid was not found to be detrimental to
the reaction. The reaction times, temperatures required and
yields obtained compare favourably with those described for
traditional methods.4,7,8,14 The reaction can be performed on
very hindered dienophiles such as a-pinene and on complex
non-conjugated polyene such as a-humulene with high regio-,
chemo- and stereoselectivity. Our novel method has been
applied to a rapid biomimetic synthesis of the complex natural
products ( )-alboatrin 2 and ( )-lucidene 1. Application to the
biomimetic syntheses of ( )-pughiinin A 3 and ( )-epolone A-4
are objectives.
chloride (100 ml) and washed three times with a saturated
solution of copper sulfate (3 × 100 ml). The organic layer was
dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure to afford 6b as a colourless oil (6.0 g, 89%)
which was used without further purification. RF 0.3 [80 : 20 30–
40 petroleum ether (PE) : EtOAc]; mmax/cm−1 (film) 3369 (s), 1711
(s), 1490 (m), 1458 (m), 1383 (m), 1281 (s), 1244 (s), 909 (s), 734
(s); dH (200 MHz, CDCl3) 2.12 (3H, s), 5.13 (2H, s), 6.88–7.00
(2H, m), 7.22–7.35 (2H, m), 7.81 (1H, s); dC (100 MHz, CDCl3)
21.0, 63.4, 117.9, 120.6, 121.7, 131.3, 132.3, 155.6, 173.9; m/z
(ES−) 165.14 ([M − H]−). 6b was stable for over three months
at 0 ◦C.
2-Phenylchroman (15)14
Experimental
In a sealed tube was stirred 2-acetoxymethylphenol 6b (200 mg,
1.2 mmol) in styrene (1.4 ml, 12.2 mmol) at 100 ◦C, under
argon for 12 hours. After evaporation of excess of styrene under
reduced pressure, the yellow oil was purified by flash silica gel
chromatography (98 : 2 30–40 PE : EtOAc) to give 15 as a white
solid (200 mg, 79%). Mp = 40–41 ◦C; RF 0.6 (95 : 5 30–40 PE :
EtOAc); mmax/cm−1 (film) 3063 (m), 3029 (m), 2927 (m), 2846
(m), 1582 (s), 1488 (s), 1455 (s), 1235 (s), 754 (s); dH (200 MHz,
CDCl3) 2.02–2.32 (2H, m), 2.77–2.89 (1H, ddd, J 16.5, 5.0,
3.5 Hz), 2.96–3.13 (1H, m), 5.10 (1H, dd, J 9.5, 3.0 Hz), 6.89–
6.99 (2H, m), 7.12–7.25 (2H, m), 7.32–7.51 (5H, m); dC (50 MHz,
CDCl3) 25.1, 30.0, 77.8, 117.0, 120.4, 121.9, 126.0 (2C), 127.4,
127.9, 128.6 (2C), 129.6, 141.8, 155.2.
All solvents and reagents were purified by standard techniques,22
or used as supplied from commercial sources as appropriate.
Solvents were removed under reduced pressure using a Buchi
R110 or R114 Rotavapor fitted with a water condenser. Final
traces of solvent were removed from samples using an Edwards
E2M5 high vacuum pump with pressures below 2 mmHg. All
experiments were carried out under inert atmosphere unless
1
otherwise stated. H NMR spectra were recorded at 200, 400
and 500 MHz using, Bruker DPX200, DQX400 and Bruker
AMX500 instruments. For 1H spectra recorded in CDCl3,
CD3OD, C6D6, chemical shifts are quoted in parts per million
(ppm) and are referenced to the residual solvent peak. The
following abbreviations are used: s, singlet; d, doublet; t, triplet;
m, multiplet; br, broad. Proton assignments and stereochemistry
2,4-Dihydroxy-6-methylbenzaldehyde11
are supported by H–1H COSY and NOESY where necessary.
1
Phosphorous oxychloride (5.6 ml, 60.5 mmol) was added
◦
Data are reported in the following manner: chemical shift
(integration, multiplicity, coupling constant if appropriate).
Coupling constants (J) are reported in Hertz to the nearest
0.5 Hz. 13C NMR spectra were recorded at 50.2, 100.6 and
125.8 MHz using Bruker DPX200, Bruker DQX400, and
Bruker AMX500 instruments. Carbon spectra assignments are
supported by DEPT-135 spectra, 13C–1H (HMQC) correlations
where necessary. Chemical shifts are quoted in ppm and are
referenced to the appropriate residual solvent peak. Flash
column chromatography was carried out using SorbsilTM C60
(40–63 mm, 230–40 mesh) silica gel. Thin layer chromatography
was carried out on glass plates pre-coated with Merck silica gel
60 F254 which were visualised by quenching of UV fluorescence or
by staining with 10% w/v ammonium molybdate in 2 M sulfuric
acid or 1% w/v potassium permanganate in aqueous alkaline
solution followed by heat, as appropriate. Melting points were
recorded using a Cambridge Instruments GallenTM III Kofler
Block melting apparatus or a Buchi 510 capillary apparatus
and are uncorrected. Infrared spectra were recorded either as
a thin film between NaCl plates on a Perkin-Elmer Paragon
1000 Fourier Transform spectrometer with internal referencing.
Absorption maxima are reported in wavenumbers (cm−1) and
the following abbreviations are used: w, weak; m, medium; s,
strong; br, broad. Low resolution mass spectra were recorded
on V. G. Micromass ZAB 1 F and V. G. Masslab instruments
as appropriate with modes of ionisation being indicated as CI,
EI, ES or APCI with only molecular ions. High resolution mass
spectrometry was measured on a Waters 2790-Micromass LCT
electrospray ionisation mass spectrometer and on a VG autospec
chemical ionisation mass spectrometer.
dropwise over 10 minutes to stirring DMF (20 ml) at −10 C
under nitrogen, and the mixture stirred for a further 20 minutes.
Orcinol (7.5 g, 60.5 mmol) in DMF (25 ml) was then added
to the solution at −10 ◦C and the mixture allowed to warm to
room temperature over 2 hours. To the reaction was then added
ice and 10% aqueous NaOH until pH 9–10 was achieved, and a
precipitate formed. The mixture was then heated to boiling for
10 minutes then cooled to room temperature. The acidity was
then adjusted to pH 3, and the precipitate then formed was
filtered and washed with water until neutral, then dried in a vac-
uum desiccator to give the 2,4-dihydroxy-6-methylbenzaldehyde
as a yellow solid (3.5 g, 38%) which was used without further
purification. Mp = 178–180 ◦C; RF 0.2 (75 : 25 30–40 PE :
EtOAc); mmax/cm−1 (KBr) 3080 (m), 2926 (m), 1628 (s), 1482 (s),
1303 (s), 1233 (s), 1170 (s); dH (400 MHz, MeOD) 2.50 (3H, s),
6.11 (1H, d, J 2.0 Hz), 6.22 (1H, d, J 2.0 Hz), 10.02 (1H, s);
dC (100 MHz, MeOD) 17.3, 100.5, 110.8, 113.0, 145.3, 166.2,
166.5, 193.2; HRMS (APCI) Calculated for C8H9O3 ([M + H]+):
153.0552, Found: 153.0551.
2,4-Diacetoxy-6-methylbenzaldehyde (8)11
To a stirred solution of 2,4 dihydroxy-6-methylbenzaldehyde
(4.0 g, 26.3 mmol) in dry DCM (100 ml) was slowly added
at 0 ◦C pyridine (4.6 ml, 58.0 mmol) and acetyl chloride (2.0 ml,
29.0 mmol) under nitrogen. The reaction mixture was warmed
to room temperature, stirred two hours and then cooled to
0
◦C when another quantity of acetyl chloride was slowly
added (2.0 ml, 29.0 mmol). The reaction was stirred for a
further two hours then quenched with a saturated solution of
ammonium chloride (100 ml) and washed three times with a
saturated solution of copper sulfate (3 × 150 ml). The combined
organic layers were dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure to give a yellow oil which
was purified by flash silica gel chromatography (80 : 20 30–40
PE : EtOAc) to afford the desired product 8 as a colourless
oil (4.4 g, 71%). RF 0.5 (70 : 30 30–40 PE : EtOAc); mmax/cm−1
(film) 2930 (w), 1774 (s), 1692 (s), 1610 (s), 1369 (m), 1193 (s),
1126 (s); dH (200 MHz, CDCl3) 2.28 (3H, s), 2.34 (3H, s), 2.61
2-Acetoxymethylphenol (6b)6a
To a stirred solution of 2-hydroxybenzyl alcohol 5 (5.0 g,
40.2 mmol) in dry DCM (80 ml) was added slowly at 0 ◦C
pyridine (3.3 ml, 40.2 mmol) and acetyl chloride (2.9 ml,
40.2 mmol) under nitrogen. The reaction mixture was then
warmed to room temperature and stirred one hour. The reaction
mixture was quenched with a saturated solution of ammonium
3 4 9 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 8 8 – 3 4 9 5

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(3H, s), 6.85 (1H, d, J 2.0 Hz), 6.91 (1H, d, J 2.0 Hz), 10.30
(1H, s); dC (50 MHz, CDCl3) 20.6, 20.9, 21.2, 114.8, 122.5, 123.9,
144.0, 153.7, 154.3, 168.4, 169.1, 188.8; m/z (ES+) 254.19 ([M +
NH4]+).
121.8, 123.1, 127.2, 128.8, 136.5, 142.0, 154.0; HRMS (CI+)
Calculated for C22H31O ([M + H]+): 311.2375, Found: 311.2378.
( )-5a(R*),10a(S*),16a(R*),18a(S*)-(E)-5a,6,9,10,10a,16a,
17,18,18a,19-Decahydro-5a,9,9,16a-tetramethyl-11H-
cycloundeca[1,2-b:5,6-bꢀ]bisbenzopyran (lucidene) (1)5
2-Acetoxymethyl-3-methyl-5-acetoxyphenol (6a)6a
Mp = 208–211 ◦C; RF 0.6 (98 : 2 30–40 PE : EtOAc); mmax/cm−1
(film) 2921 (s), 1610 (w), 1585 (m), 1487 (s), 1454 (s), 1378 (m),
1304 (m), 1259 (s), 1220 (m), 753 (m); dH (500 MHz, CDCl3)
1.09 (1H, dd, J 14.0, 5.5 Hz), 1.09 (3H, s), 1.13 (3H, s), 1.27
(6H, s), 1.55 (1H, m), 1.71 (1H, m), 1.83 (2H, m), 1.97 (1H,
m) 2.06 (1H, br m), 2.22 (1H, m), 2.58 (1H, m,), 2.59 (2H, d, J
7.0 Hz), 2.67 (1H, br d, J 16.0 Hz), 2.81 (1H, dd, J 17.0, 5.5 Hz),
2.82 (1H, br m), 5.65 (1H, dt, J 16.0, 8.0 Hz), 5.79 (1H, d, J
16.0 Hz), 6.76 (1H, d, J 8.0 Hz), 6.77 (1H, d, J 8.0 Hz), 6.79
(1H, td, J 7.0, 1.0 Hz), 6.82 (1H, td, J 7.0, 1.0 Hz), 7.00 (1H,
d, J 7.0 Hz), 7.06 (1H, d, J 7.0 Hz), 7.07 (2H, t, J 7.0 Hz); dC
(125 MHz, CDCl3) 19.6, 21.3, 23.7, 26.7, 29.1, 29.6, 30.0, 31.8,
32.6, 35.7, 40.8, 46.0, 49.0, 79.4, 79.7, 116.7, 117.2, 119.3, 119.6,
121.7, 122.8, 124.5, 127.1, 127.3, 128.7, 129.1, 143.9 (2C), 153.5;
HRMS (CI+) Calculated for C29H37O2 ([M + H]+): 417.2794,
Found: 417.2782.
To a stirred solution of 2,4-diacetoxy-6-methylbenzaldehyde 8
(3.8 g, 16.1 mmol) in dry THF (90 ml) was slowly added a 2 M
THF solution of borane–DMS complex (8.0 ml, 16.0 mmol) at
◦
0 C under nitrogen. The reaction was stirred for one hour at
room temperature and was then quenched at 0 ◦C with water
(2 ml). The mixture was evaporated to dryness under reduced
pressure to give a crude product which was purified by flash
silica gel chromatography (70 : 30 30–40 PE : EtOAc). The title
compound was obtained as a white solid which was crystallised
from ether to afford 6a as white crystals (3.2 g, 84%). Mp =
◦
95–96 C; RF 0.3 (70 : 30 30–40 PE : EtOAc); mmax/cm−1 (film)
3413 (br), 1779 (s), 1735 (s), 1708 (s), 1599 (m), 1370 (m), 1209
(s), 1133 (s); dH (400 MHz, CDCl3) 2.10 (3H, s), 2.27 (3H, s),
2.38 (3H, s), 5.12 (2H, s), 6.53 (1H, s), 6.54 (1H, s) 8.23 (1H, s);
dC (100 MHz, CDCl3) 19.6, 21.0, 21.2, 59.6, 109.3, 115.8, 118.8,
141.2, 152.1, 157.3, 169.5, 174.3; HRMS (ES−) Calculated for
C12H13O5 ([M − H]−): 237.0763, Found: 237.0763. Crystal data
( )-5a(R*),10a(R*),16a(S*),18a(S*)-(E)-5a,6,9,10,10a,16a,
17,18,18a,19-Decahydro-5a,9,9,16a-tetramethyl-11H-
cycloundeca[1,2-b:5,6-bꢀ]bisbenzopyran (isolucidene) (23)
for 6a: C12H14O5, M = 238.24, monoclinic, a = 29.1890(14), b =
3
˚
˚
4.9244(3), c = 19.8157(11) A, U = 2363.5(2) A , T = 150 K,
space group C2/c, Z = 8, l(Mo-Ka) = 0.105 mm−1, 11482
reflections measured, 2983 unique (Rint = 0.045) which were
used in calculations. The final wR was 0.0599.13
Mp = 121 ◦C; RF 0.6 (98 : 2 30–40 PE : EtOAc); mmax/cm−1 (film)
2919 (s), 1610 (w), 1586 (s), 1499 (s), 1456 (s), 1377 (m), 1310
(m), 1254 (s), 1141 (m), 1102 (m), 1032 (m), 940 (w), 754 (s);
dH (500 MHz, CDCl3) 1.05 (1H, m), 1.05 (3H, s), 1.09 (3H, s),
1.15 (1H, br m), 1.20 (3H, s), 1.26 (3H, s), 1.55–1.68 (3H, m),
1.87–2.04 (3H, m), 2.41 (1H, dd, J 13.0, 7.5 Hz), 2.50–2.62 (3H,
m), 2.78 (1H, dd, J 16.5, 5.5 Hz), 2.83 (1H, dd, J 16.5, 5.5 Hz),
5.48 (1H, ddd, J 15.5, 7.0, 6.0 Hz), 5.55 (1H, d, J 15.5 Hz), 6.76
(1H, d, J 7.5 Hz), 6.78 (1H, d, J 7.5 Hz), 6.82 (2H, t, J 7.5 Hz),
7.03 (1H, d, J 7.5 Hz), 7.05 (1H, d, J 7.5 Hz), 7.09 (1H, t, J
7.5 Hz), 7.10 (1H, t, J 7.5 Hz); dC (125 MHz, CDCl3) 19.1, 20.9,
24.4, 29.6, 30.7, 30.8, 30.9, 32.6, 36.3, 38.3, 41.3, 47.6, 48.4, 79.6,
80.6, 116.7, 116.7, 119.3, 119.5, 121.6, 121.6, 122.5, 127.2, 127.3,
128.4, 128.8, 143.5, 153.4, 153.6; HRMS (CI+) Calculated for
C29H37O2 ([M + H]+): 417.2794, Found: 417.2784.
( )-5a(R*),14a(S*),(E)-(E)-5a,6,9,10,13,14,14a,15-Octahydro-
5a,9,9,12-tetramethylcycloundeca[1,2-b]benzopyran (22)
Procedure A. In a sealed tube was stirred 2-acetoxy-
methylphenol 6b (750 mg, 4.5 mmol) in dry toluene (6 ml) with
a-humulene (0.52 ml, 2.2 mmol) at 130 ◦C, under argon for
12 hours. After evaporation of toluene under reduced pressure,
the yellow oil was purified by flash silica gel chromatography (99 :
1 30–40 PE : EtOAc) to give the monoadduct ( )-22 as a white
solid (353 mg, 52%) and an inseparable mixture (346 mg, 38%),
[2.5 : 0.7] of diadduct ( )-lucidene 1 and ( )-isolucidene 23 as
a white solid.
Procedure C. In a sealed tube was stirred compound ( )-
22 (130 mg, 0.42 mmol) in dry benzene (0.5 ml◦) with 2-
acetoxymethylphenol 6b (140 mg, 0.84 mmol) at 90 C, under
argon during 36 hours. After evaporation of benzene under
reduced pressure, the yellow oil was purified by flash silica gel
chromatography (99 : 1 30–40 PE : EtOAc) to give a white
solid (56 mg, 32%) which was an inseparable mixture [2.5 : 0.6]
of ( )-lucidene 1 and ( )-isolucidene 23. The mixture of two
compounds was crystallized from hexane to afford selectively
white crystals of ( )-1.
Procedure B. In a sealed tube was stirred 2-acetoxy-
methylphenol 6b (1.5 g, 9.0 mmol) in dry toluene (6 ml) with
a-humulene (0.52 ml, 2.2 mmol) at 130 ◦C, under argon for
12 hours. After evaporation of toluene under reduced pressure,
the yellow oil was purified by flash silica gel chromatography
(99 : 1 30–40 PE : EtOAc) to give a white solid (641 mg, 71%)
which was an inseparable mixture [2.5 : 0.7] of diadduct ( )-
lucidene 1 and ( )-isolucidene 23. The compounds ( )-1 and
( )-23 were separated, for the purpose of characterisation by
preparative HPLC. A reverse phase Hypersil C18 (25 cm × 0.25
inch) column was found to achieve the required separation with
an aqueous acetonitrile solvent system (4 : 1 MeCN : H2O).
( )-3a(R*),9a(R*)-2,3,3a,9a-Tetrahydro-5,9a-dimethyl-7-
acetoxy-4H-furo[2,3-b]chroman (3-nor-methyl-acetyl-
alboatrin) (11)6a
Compound ( )-22. Mp = 118 ◦C; RF 0.7 (98 : 2 30–40 PE :
EtOAc); mmax/cm−1 (KBr) 3056 (w), 2986 (m), 2928 (s), 2852 (m),
1584 (m), 1492 (s), 1456 (s), 1250 (s), 1136 (m), 1040 (m), 982
(s), 757 (s); dH (500 MHz, CDCl3) 1.06 (3H, s), 1.10 (3H, s), 1.15
(3H, s), 1.17 (1H, m), 1.38 (1H, dd, J 13.0, 11.0 Hz), 1.68, (3H, s),
1.80 (1H, dd, J 12.5, 4.0 Hz), 1.88 (1H, dd, J 13.0, 11.0 Hz),
1.94 (1H, ddd, J 12.5, 9.0, 5.5 Hz), 2.16 (1H, dd, J 13.0, 7.5 Hz),
2.22 (1H, t, J 12.5 Hz), 2.35 (1H, dd, J 14.5, 10.0 Hz), 2.50 (1H,
dd, J 16.5, 12.5 Hz), 2.58 (1H, dt, J 14.5, 2.0 Hz), 2.96 (1H, dd,
J 16.5, 5.5 Hz), 5.06 (1H, br dd, J 12.5, 4.0 Hz), 5.16 (1H, dd,
J 16.0, 2.0 Hz), 5.24 (1H, ddd, J 16.0, 10.0, 2.0 Hz), 6.86 (1H,
d, J 7.5 Hz), 6.87 (1H, t, J 7.5 Hz), 7.10 (1H, d, J 7.5 Hz), 7.15
(1H, t, J 7.5 Hz); dC (125 MHz, CDCl3) 17.2, 20.2, 24.3, 29.5,
30.3, 30.4, 35.6, 37.8, 38.2, 41.4, 43.1, 80.2, 117.0, 119.2, 121.0,
In a sealed tube was stirred 2-acetoxymethyl-3-methyl-5-
acetoxyphenol 6a (203 mg, 0.85 mmol) in 4,5-dihydro-2-
methylfuran (1.0 ml, 10.9 mmol) at 100 ◦C, under argon for
12 hours. After evaporation under reduced pressure, the yellow
oil obtained was purified by flash silica gel chromatography (95 :
5 30–40 PE : EtOAc) to give ( )-11 as a white solid (175 mg,
◦
78%). Mp = 115–117 C; RF 0.2 (90 : 10 30–40 PE : EtOAc);
mmax/cm−1 (film) 3056 (w), 2982 (w), 1757 (s), 1597 (m), 1482 (w),
1368 (w), 1265 (w), 1213 (w), 1109 (w), 736 (s); dH (400 MHz,
CDCl3) 1.51 (3H, s), 1.75–1.85 (1H, m), 2.01–2.09 (1H, m), 2.21
(3H, s), 2.26 (3H, s), 2.43–2.49 (1H, m), 2.78 (1H, s), 2.79 (1H, s),
3.95 (1H, dd, J 16.5, 8.5 Hz), 4.03 (1H, td, J 8.5, 3.0 Hz), 6.43
(1H, br s), 6.50 (1H, br s); dC (100 MHz, CDCl3) 19.4, 21.2, 22.4,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 8 8 – 3 4 9 5
3 4 9 3

View Article Online
23.5, 29.0, 40.5, 66.7, 106.3, 108.2, 115.0, 115.3, 138.1, 149.5,
153.8, 169.7; HRMS (ES+) Calculated for C15H19O4 ([M + H]+):
263.1283, Found: 263.1289.
(1H, dd, J 8.5, 6.5 Hz), 4.21 (1H, dd, J 9.5, 8.5 Hz), 4.43–4.44
(1H, m); dC (100 MHz, C6D6) 13.6, 20.9, 37.8, 77.1, 101.4, 155.0.
( )-3(R*),3a(R*),9a(R*)-2,3,3a,9a-Tetrahydro-3,5,9a-
trimethyl-7-acetoxy-4H-furo[2,3-b]chroman (acetylalboatrin)
(10)6a
( )-4a(R*),10a(S*)-3,4,4a,10a-Tetrahydro-6-methyl-8-
acetoxy-2H,5H-pyrano[2,3-b]chroman (12)6a
In a sealed tube was stirred 2-acetoxymethyl-3-methyl-5-
acetoxyphenol 6a (203 mg, 0.85 mmol) in 3,4-dihydro-2H-pyran
(1.0 ml, 10.9 mmol) at 100 ◦C, under argon for 12 hours. After
evaporation under reduced pressure, the yellow oil obtained was
purified by flash silica gel chromatography (95 : 5 30–40 PE :
EtOAc) to give ( )-12 as a colourless oil (161 mg, 72%). RF
0.3 (90 : 10 30–40 PE : EtOAc); mmax/cm−1 (film) 3055 (m), 2934
(w), 1759 (s), 1598 (m), 1422 (m), 1265 (s), 1217 (s), 1093 (s),
897 (m), 739 (s); dH (400 MHz, CDCl3) 1.62–1.70 (5H, m), 2.18
(3H, s), 2.26 (3H, s), 2.50 (1H, dd, J 16.5, 4.5 Hz), 2.72 (1H,
dd, J 16.5, 6.5 Hz), 3.69–3.73 (1H, m), 3.98–4.04 (1H, m), 5.28
(1H, d, J 2.5 Hz), 6.49 (1H, s), 6.50 (1H, s); dC (100 MHz,
CDCl3) 19.4, 21.2, 23.6, 24.4, 26.5, 31.6, 62.7, 96.3, 107.8, 115.6,
116.4, 138.3, 149.4, 153.3, 169.7; HRMS (CI+) Calculated for
C15H19O4 ([M + H]+): 263.1283, Found: 263.1288.
In a sealed tube was stirred 2-acetoxymethyl-3-methyl-5-
acetoxyphenol 6a (200 mg, 0.84 mmol) with ( )-4,5-dihydro-
2,4-dimethylfuran 9 (82 mg, 0.84 mmol) in benzene (1 ml)
at 80 ◦C under argon for 36 hours. After evaporation under
reduced pressure, the colourless oil obtained was purified by
flash silica gel chromatography (98 : 2 30–40 PE : EtOAc) to
give the spiroacetal ( )-19 as a viscous colourless oil (57 mg,
1
25%, as an inseparable mixture [3 : 2 from H NMR] of two
diastereoisomers, RF 0.5 (90 : 10 30–40 PE : EtOAc)), and ( )-
acetylalboatrin 10 and ( )-acetyl-epi-alboatrin as a white solid
(158 mg, 68%, as a mixture [12.6 : 1 from 1H NMR], RF 0.3 (90 :
10 30–40 PE : EtOAc)).
Data for ( )-10. mmax/cm−1 (film) 3054 (s), 2987 (s), 1760
(m), 1603 (m), 1421 (s), 1262 (s), 1215 (m), 896 (s), 752 (s);
dH (200 MHz, CDCl3) 1.04 (3H, d, J 6.0 Hz), 1.50 (3H, s),
1.93 (1H, ddd, J 11.0, 4.5, 3.0 Hz), 2.12–2.17 (1H, m), 2.22
(3H, s), 2.26 (3H, s), 2.71–2.73 (2H, m), 3.52 (1H, t, J 8.0 Hz),
4.17 (1H, t, J 8.0 Hz), 6.42 (1H, d, J 2.0 Hz), 6.49 (1H, d,
J 2.0 Hz); dC (100 MHz, CDCl3) 15.9, 19.5, 21.2, 22.0, 22.8,
35.4, 47.9, 74.1, 107.1, 108.3, 114.9, 115.3, 138.1, 149.5, 153.6,
169.7; HRMS (ES+) Calculated for C16H21O4 ([M + H]+):
277.1440, Found: 277.1431. The 1H NMR spectra of the mixture
of acetylalboatrin and acetyl-epi-alboatrin displayed signals
which compare favourably with the structure of epi-alboatrin
described by Murphy et al. (ref. 15). e.g. for acetyl-epi-alboatrin
dH (200 MHz, CDCl3) 0.85 (3H, d, J 7.0 Hz); for epi-alboatrin dH
(200 MHz, CDCl3) 0.88–0.90 (3H, d, J 7.0 Hz). The two epimers
could be separated and characterised by GCMS, LRMS (CI+)
277 for each. The Dept 135 experiment of the mixture of two
spiroacetals ( )-19 displays two new CH2’s for each compound
and the disappearance of one CH and one CH3. The 1H NMR
spectra also confirms the disappearance of one CH3 for each
compound and the HRMS of the mixture of compounds is in
agreement with both proposed structures calculated for C6H21O4
([M + H]+): 277.1440, Found: 277.1431. Likewise the structure
of the spiroacetal compounds ( )-19 was in agreement with
quinone methide derived products described by Wilson et al.4 in
an analogous study.
(−)-1(S),3(R),4a(S),10a(R)-6,10a,11,11-Tetramethyl-8-
acetoxybicyclo[3.1.1]heptan[2,3-b]chroman (13)6a
In a sealed tube was stirred 2-acetoxymethyl-3-methyl-5-
acetoxyphenol 6a (203 mg, 0.85 mmol) in (1R)-(+)-a-pinene
◦
(1.0 ml, 6.3 mmol) at 140 C, under argon for 12 hours. After
evaporation under reduced pressure, the yellow oil obtained was
purified by flash silica gel chromatography (99 : 1 30–40 PE :
EtOAc) to give ( )-13 as a viscous colourless oil (81 mg, 30%).
[a]2D5 = − 2.9 (c = 1, CHCl3); RF 0.6 (98 : 2 30–40 PE : EtOAc);
mmax/cm−1 (film) 2922 (s), 1758 (s), 1559 (s), 1483 (m), 1369 (m),
1256 (s), 1216 (s), 1127 (s), 1015 (m), 739 (s); dH (500 MHz,
CDCl3) 1.04 (3H, s), 1.16 (1H, d, J 10.5 Hz), 1.28 (3H, s), 1.31
(3H, s), 1.32–1.35 (1H, m), 1.81–1.84 (1H, m), 2.04–2.15 (2H,
m), 2.17 (1H, t, J 5.5 Hz), 2.24 (3H, s), 2.25 (3H, s), 2.43 (1H, dd,
J 15.0, 5.0 Hz), 2.47–2.53 (1H, m), 2.73 (1H, dd, J 15.0, 6.0 Hz),
6.40 (1H, d, J 2.5 Hz), 6.49 (1H, d, J 2.5 Hz); dC (125 MHz,
CDCl3) 19.2, 21.2, 23.2, 26.8, 27.5, 28.0, 29.3, 34.2, 34.5, 40.2,
40.4, 54.9, 84.0, 108.3, 114.9, 121.3, 136.8, 149.3, 157.3, 169.7;
HRMS (ES+) Calculated for C20H27O3 ([M + H]+): 315.1960,
Found: 315.1963.
( )-4a(S*),9a(S*)-2,3,4,4a,9,9a-Hexahydro-4a,8-dimethyl-6-
acetoxy-1H-xanthene (14)6a
( )-3(R*),3a(R*),9a(R*)-2,3,3a,9a-Tetrahydro-3,5,9a-
trimethyl-7-hydroxy-4H-furo[2,3-b]chroman (alboatrin) (2)2
In a sealed tube was stirred 2-acetoxymethyl-3-methyl-5-
acetoxyphenol 6a (203 mg, 0.85 mmol) in 1-methylcyclohexene
◦
To a stirred solution of ( )-acetylalboatrin 10 and ( )-acetyl-
epi-alboatrin [12.6 : 1] (480 mg, 1.74 mmol) in 9 ml of DCM–
MeOH–H2O (12 : 7 : 1) was added potassium carbonate (721 mg,
5.21 mmol) at room temperature under nitrogen. The mixture
was stirred for 6 hours and was then extracted with ethyl
acetate (3 × 50 ml). The combined organic layers were washed
with a saturated solution of ammonium chloride (3 × 50 ml),
dried over magnesium sulfate and concentrated under reduced
pressure. The crude obtained was purified by flash silica gel
chromatography (98 : 2 30–40 PE : EtOAc) to give a white solid.
The solid was crystallised from ether to afford ( )-alboatrin 2
(368 mg, 97%) as white crystals.
(1.0 ml, 8.5 mmol) at 140 C, under argon for 12 hours. After
evaporation under reduced pressure, the yellow oil was purified
by flash silica gel chromatography (99 : 1 30–40 PE : EtOAc) to
give ( )-14 as a white solid (141 mg, 60%). Mp = 100–101 ◦C;
RF 0.6 (98 : 2 30–40 PE : EtOAc); mmax/cm−1 (film) 2933 (s), 1758
(s), 1596 (s), 1370 (m), 1265 (s), 1218 (s), 1125 (s), 737 (s); dH
(400 MHz, CDCl3) 1.17 (3H, s), 1.24–1.31 (2H, m), 1.36–1.44
(2H, m), 1.48–1.52 (1H, m), 1.57–1.75 (3H, m), 1.93 (1H, br d,
J 13.5 Hz), 2.18 (3H, s), 2.24 (1H, d, J 17.0 Hz), 2.25 (3H, s),
2.81 (1H, dd, J 17.0, 6.5 Hz), 6.40 (1H, d, J 2.0 Hz), 6.44 (1H,
d, J 2.0 Hz); dC (100 MHz, CDCl3) 19.4, 21.2, 21.7, 25.4, 25.6,
27.1, 28.8, 36.8, 38.3, 74.7, 108.0, 114.3, 116.4, 138.4, 149.1,
153.8, 169.8; HRMS (CI+) Calculated for C17H23O3 ([M + H]+):
275.1647, Found: 275.1644.
Mp = 148–149 ◦C; RF 0.1 (90 : 10 30–40 PE : EtOAc);
mmax/cm−1 (film) 3400 (s), 2958 (m), 1620 (s), 1599 (s), 1494 (m),
1462 (m), 1335 (m), 1204 (m), 1148 (s), 1117 (s), 986 (m), 845 (m);
dH (200 MHz, CDCl3) 1.04 (3H, d, J 6.5 Hz), 1.51 (3H, s), 1.93
(1H, ddd, J 11.0, 4.5, 3.5 Hz), 2.01–2.14 (1H, m), 2.19 (3H, s),
2.68 (2H, br s), 3.51 (1H, t, J 8.5 Hz), 4.17 (1H, t, J 8.5 Hz), 4.80
(1H, br s), 6.26 (1H, s), 6.29 (1H, s); dC (100 MHz, CDCl3) 16.0,
19.4, 21.5, 23.2, 35.5, 48.4, 74.0, 101.9, 107.5, 109.6, 110.0, 138.2,
( )-4,5-Dihydro-2,4-dimethylfuran (9), Prepared by the method
of Wilson et al.4
Bp = 100 ◦C at atmospheric pressure; dH (400 MHz, C6D6) 0.86
(3H, d, J 7.0 Hz), 1.67 (3H, d, J 2.0 Hz), 2.72–2.82 (1H, m), 3.70
3 4 9 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 8 8 – 3 4 9 5

View Article Online
153.7, 155.1; HRMS (ES−) Calculated for C14H17O3 ([M − H]−):
233.1178, Found: 233.1180. Crystal data for 2: C14H18O3, M =
C23H31O2 ([M − H]−): 339.2324, Found: 339.2331.Crystal data
for 25: C23H32O2, M = 240.51, monoclinic, a = 19.4765(3), b =
3
˚
˚
234.30, monoclinic, a = 8.8435(3), b = 13.4040(5), c = 10.6982(3)
9.6966(2), c = 21.0587(4) A, U = 3964.72(13) A , T = 150 K,
space group P21/c, Z = 8, l(Mo-Ka) = 0.071 mm−1, 32823
reflections measured, 9525 unique (Rint = 0.051) which were
used in calculations. The final wR was 0.0524.13
3
˚
˚
A, U = 1221.60(7) A , T = 150 K, space group P21/n, Z =
4, l(Mo-Ka) = 0.088 mm−1, 1990 reflections measured, 2890
unique (Rint = 0.024) which were used in calculations. The final
wR was 0.0498.13
Acknowledgements
( )-5a(R*),14a(S*),(E)-(E)-5a,6,9,10,13,14,14a,15-Octahydro-
5a,9,9,12,16-pentamethyl-18-acetoxycycloundeca[1,2-
b]benzopyran (24)
We thank Dr Andrew Cowley for crystallographic analysis, and
Dr Barbara ODell for NMR assistance. We thank the EPSRC
for funding JEM.
In a sealed tube was stirred 2-acetoxymethyl-3-methyl-5-
acetoxyphenol 6a (203 mg, 0.85 mmol) with a-humulene (1 ml,
4.35 mmol) at 140 ◦C, under argon for 12 hours. The yellow
mixture obtained was purified by flash silica gel chromatography
(pure 30–40 PE, then 99 : 1 30–40 PE : EtOAc) to give ( )-24
as a white solid (173 mg, 53%). Mp = 130–132 ◦C; RF 0.4 (90 :
10 30–40 PE : EtOAc); mmax/cm−1 (film) 2925 (s), 1761 (s), 1598
(s), 1452 (m), 1367 (m), 1211 (s), 1126 (s), 1046 (m), 911 (m);
dH (400 MHz, CDCl3) 1.02 (3H, s), 1.04 (3H, s), 1.05 (3H, s),
1.14 (1H, td, J 13.0, 8.0 Hz), 1.34 (1H, dd, J 13.0, 11.0 Hz),
1.62 (3H, s), 1.75 (1H, dd, J 12.5, 4.0 Hz), 1.79–1.88 (2H, m),
2.07–2.18 (3H, m), 2.21–2.30 (1H, m), 2.22 (3H, s), 2.26 (3H, s),
2.50 (1H, br d, J 14.5 Hz), 2.82 (1H, dd, J 16.5, 5.5 Hz), 5.00
(1H, dd, J 11.5, 4.0 Hz), 5.09 (1H, dd, J 16.0, 1.5 Hz), 5.16 (1H,
ddd, J 16.0, 10.0, 2.0 Hz), 6.42 (1H, d, J 2.5 Hz), 6.44 (1H, d, J
2.5 Hz); dC (100 MHz, CDCl3) 16.1, 18.1, 18.8, 19.9, 23.3, 26.1,
29.3, 29.5, 34.4, 36.8, 37.1, 40.3, 41.8, 78.7, 106.8, 112.9, 117.0,
119.7, 122.0, 135.2, 136.3, 140.9, 148.1, 153.3, 168.5; HRMS
(ES+) Calculated for C25H35O3 ([M + H]+): 383.2586, Found:
383.2581.
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Lett., 1989, 30, 1939; (b) B. Loubinoux, S. Tabbache, P. Gerardin
and J. Miazimbakana, Tetrahedron, 1988, 44, 6055.
11 E. M. Gruneiro and E. G. Gros, An. Asoc. Quim. Argent., 1971, 59,
259.
A repeated reaction using the same conditions with only one
equivalent of humulene in xylene gave the same product ( )-24
in 48% yield.
( )-5a(R*),14a(S*),(E)-(E)-5a,6,9,10,13,14,14a,15-Octahydro-
5a,9,9,12,16-pentamethyl-18-hydroxycycloundeca[1,2-
b]benzopyran (25)
12 Stable at room temperature for over four months.
13 CCDC reference numbers 2 239364, 6a 237660, 25 239363. See
http://dx.doi.org/10.1039/b508972g for crystallographic data in
CIF or other electronic format.
14 (a) M. Yato, T. Ohwada and K. Shudo, J. Am. Chem. Soc., 1990, 112,
5341; (b) S. Nakamura, M. Uchiyama and T. Ohwada, J. Am. Chem.
Soc., 2003, 125, 5282.
To a stirred solution of ( )-24 (820 mg, 2.14 mmol) in 20 ml of a
mixture (12 : 7 : 1) of DCM–MeOH–H2O was added potassium
carbonate (330 mg, 2.38 mmol) at room temperature under
nitrogen. The mixture was stirred for 6 hours and then extracted
with ethyl acetate (3 × 100 ml). The combined organic layers
were washed with a saturated solution of ammonium chloride
(3 × 100 ml), dried over magnesium sulfate and concentrated
under reduced pressure. The solid obtained was purified by flash
silica gel chromatography (98 : 2 30–40 PE : EtOAc) to give a
white solid which was crystallised from ether to afford ( )-25
(601 mg, 82%) as white crystals. Mp = 155–157 ◦C; RF 0.4 (90 : 10
30–40 PE : EtOAc); mmax/cm−1 (film) 3400 (s), 2925 (s), 2859 (m),
1616 (s), 1600 (s), 1461 (s), 1381 (m), 1324 (m), 1265 (m), 1145
(s), 1046 (m), 991 (m), 839 (m), 738 (s); dH (400 MHz, CDCl3)
1.03 (3H, s), 1.05 (3H, s), 1.06 (3H, s), 1.14 (1H, td, J 13.5,
8.5 Hz), 1.34 (1H, dd, J 13.5, 10.5 Hz), 1.63 (3H, s), 1.75 (1H,
dd, J 13.0, 4.5 Hz), 1.81–1.87 (2H, m), 2.04–2.17 (3H, m), 2.19
(3H, s), 2.28 (1H, dd, J 14.5, 10.0 Hz), 2.50 (1H, br d, J 14.5 Hz),
2.80 (1H, dd, J 16.5, 5.5 Hz), 4.72 (1H, br s), 5.02 (1H, d, J 12.0,
4.5 Hz), 5.11 (1H, dd, J 16.0, 1.5 Hz), 5.18 (1H, ddd, J 16.0,
10.0, 2.5 Hz), 6.20 (1H, d, J 2.5 Hz), 6.26 (1H, d, J 2.5 Hz); dC
(100 MHz, CDCl3) 17.3, 19.3, 19.9, 24.4, 27.0, 30.4, 30.7, 35.8,
38.0, 38.3, 41.5, 43.0, 79.9, 101.4, 108.6, 113.1, 121.0, 123.1,
136.7, 137.8, 142.0, 154.3, 154.7; HRMS (ES−) Calculated for
15 S. R. Graham, J. A. Murphy and A. R. Kennedy, J. Chem. Soc.,
Perkin Trans. 1, 1999, 3071.
16 Deacetylated to epi-alboatrin15.
17 A regiochemically controlled reaction of o-quinone methide 21 to
(−)-alloaromadendrene to provide (−)-tanzanene has been reported,
see: S. K. Paknikar, K. P. Fondekar and R. Mayer, Nat. Prod.
Lett., 1996, 8, 253. For related Diels–Alder approaches employing
functionalized o-quinone methides, see for example: L. O. Chapman,
M. R. Engel, J. P. Springer and J. C. Clardy, J. Am. Chem. Soc., 1971,
93, 6696; J. P. Marino and S. L. Dax, J. Org. Chem., 1984, 49, 3671;
Y. Genisson, P. C. Tyler and R. N. Young, J. Am. Chem. Soc., 1994,
116, 759.
18 K. Nakanishi, T. Goto, S. Ito, S. Natori and S. Nazoe, Natural
Product Chemistry, Academic Press, New York, 1974, vol. 1, p. 87.
19 This dehydration route to o-quinone methide 21 proved superior to
others, see: J. I. Cunneen, E. H. Farmer and H. P. Koch, J. Chem.
Soc., 1943, 472.
20 Structure was confirmed by single-crystal X-ray diffraction. See
reference 6c.
21 Mass spectrum: ([M + H]+): 523.
22 D. D. Perrin and W. L. F. Armarego, Purification of Laboratory
Chemicals, Pergamon Press, Oxford, 3rd edn, 1988.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 4 8 8 – 3 4 9 5
3 4 9 5