Exploiting the Maitland-Japp reaction: A synthesis of (±)- centrolobine

Article abstract of DOI:10.1016/j.tet.2005.04.011

Application of our one-pot, three-component variation of the Maitland-Japp reaction has led to the formation of a tetrahydropyran-4-one, which was converted in three steps to the antiparasitic and antibiotic natural product (±) centrolobine.

Full text of DOI:10.1016/j.tet.2005.04.011

Tetrahedron 61 (2005) 5433–5438
Exploiting the Maitland–Japp reaction:
a synthesis of (G)-centrolobine*
*
Paul A. Clarke and William H. C. Martin
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Received 14 February 2005; revised 21 March 2005; accepted 7 April 2005
Abstract—Application of our one-pot, three-component variation of the Maitland–Japp reaction has led to the formation of a
tetrahydropyran-4-one, which was converted in three steps to the antiparasitic and antibiotic natural product (G) centrolobine.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
leishmanial compounds.3,4 Interestingly, (K)-centrolobine
1 had already been shown to be one of the active ingredients
in a herbal tea made from the wood of Centrolobum
robustum that is used by the native peoples of the Amazon
as a tonic cure for a variety of ailments.
(K)-Centrolobine 1 was isolated from the heartwood of
Centrolobium robustum and from the stem of Brosinum
potabile.1,2 Recently, (K)-centrolobine 1 and related
natural products, have been shown to be active against
Leishmania amazonensis promastigotes; a parasite associ-
ated with leishmaniasis, a major health problem in Brazil.3,4
(K)-Centrolobine 1 is a 2,6 cis-substituted tetrahydropyran
and its simple structure has made it a test-bed for pyran-
forming methodologies in recent years. The structure of 1
was proven with the synthesis of the racemic methyl ether
in 1964,1 but it was not until 2002, that the absolute
configuration was assigned by the asymmetric total
synthesis of 1 by Colobert and co-workers.5,6 Three further,
asymmetric syntheses followed from the groups of
Rychnovsky,7 Evans8 and Cossy.9
Leishmania is a parasitic disease transmitted by the sand fly,
and is related to Indian dum dum fever. Once in its human
host, the parasite attacks the spungiform organs of the body,
especially the liver and spleen, where the initial symptoms
include a high fever, meaning that the disease is often
mistaken for malaria. If the parasite attacks the skin, similar
symptoms to leprosy arise, again, often leading to the wrong
treatment being given to the patient. For the past 80 years,
the only available drug for this distressing disease has been
the pentavalent antimonials, which have been recently,
linked to cardiac and renal toxicity.3 It is for this reason that
Leon and co-workers, conducted a screen of traditional
remedies from the Amazon rainforest to find new anti-
The first, total synthesis by Colobert et al.5 featured the
reduction of a b-ketosulfoxide followed by an intra-
molecular cyclisation and yielded the natural product in
nine steps. The second synthesis by Rychnovsky7 utilised
a Prins cyclisation as the key step and furnished (K)-centro-
lobine in seven steps. A synthesis by Evans,8 formed the
tetrahydropyran ring by an intramolecular reductive ether-
ification strategy and provided the natural product in five
steps from aldehyde 5. Finally, Cossy reported a four step
synthesis of (K)-centrolobine in an overall yield of 7%.9
2. Results and discussion
* Taken in part from the Ph.D. thesis of William H. C. Martin, University of
Nottingham, 2005.
We were of the opinion that the existing syntheses of centro-
lobine were either unduely long or produced centrolobine in
an unacceptably low yield, and that our renaissance of the
Maitland–Japp reaction may provide a way to synthesise
centrolobine in a more expedient and higher yielding
Keywords: Multi-component; Tetrahydropyran; Maitland–Japp;
Centrolobine.
*
Corresponding author. Tel.: C44 115 9513566; fax: C44 115 9513564;
e-mail: paul.clarke@nottingham.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.011

5434
P. A. Clarke, W. H. C. Martin / Tetrahedron 61 (2005) 5433–5438
Scheme 1. Retrosynthetic analysis of centrolobine.
manner. Retrosynthetically, it was hypothesised that
centrolobine 1 could be obtained by reduction and
decarboxylation of the tetrahydropyran-4-one 2, which
would be the result of the Lewis acid mediated Maitland–
Japp reaction of Chan’s diene 3 and the two aldehydes 4
and 5 (Scheme 1).
investigated. Pyran formation appeared to be rapid by
TLC analysis but prolonged reaction times were necessary
to effect in situ TBS deprotection. This led to the isolation of
two diastereomeric tetrahydropyran-4-ones 2 and 7 in a
1.0:0.6 ratio and in a combined overall yield of 56% from
the aldehyde 5 (Scheme 2).
In an attempt to increase, the yield and the selectivity of
the Maitland–Japp cyclisation reaction, it was decided to
investigate introduction of the side chains in the reverse
order, to give pyranone 9. Therefore, aldol adduct 8 was
synthesised in an unoptimised 54% yield by reaction of
Chan’s diene 3 with anisaldehyde 4. The cyclisation reac-
tion between 8 and the aldehyde 5 was attempted under the
standard boron trifluoride diethyl etherate mediated con-
ditions,10 however, none of the desired product 9 was iso-
lated. In a further, experiment it was found that the d-hydroxy
b-ketoester 8 was unstable to the Lewis acidic reaction
conditions (Scheme 3), probably as the hydroxyl centre is
activated by the 4-methoxy group on the aromatic ring.
2.1. The two-pot construction of tetrahydropyran-4-one
2
Initially, construction of the tetrahydropyran-4-one 2 by our
original two-pot procedure was investigated.10 It was
decided to use aldehyde 5 as the aldol reaction coupling
partner, as it had been used previously as a starting point in
Evans’ synthesis of centrolobine.8 Aldehyde 5 was prepared
according to the procedure of Jones11 and was subjected to a
Mukaiyama aldol reaction with Chan’s diene 3, to give aldol
adduct 6, which was used without any further, purification.
With the d-hydroxy b-ketoester 6 in hand, the boron
trifluoride mediated pyran-forming reaction was
Scheme 2. Reagents and conditions: (i) 5, TiCl4, CH2Cl2, K78 8C; (ii) anisaldehyde, BF3$OEt2, CH2Cl2, room temperature, 24 h, 56% over two steps.
Scheme 3. Reagents and conditions: (i) anisaldehyde, TiCl4, CH2Cl2, K78 8C, 54%; (ii) 5, BF3$OEt2, CH2Cl2, room temperature.

P. A. Clarke, W. H. C. Martin / Tetrahedron 61 (2005) 5433–5438
5435
Scheme 4. Reagents and conditions: (i) Yb(OTf)3, 5, K78 8C, 1 h, then TFA, anisaldehyde, K78 8C to room temperature, 12 h, 92%.
2.2. The one-pot construction of tetrahydropyran-4-one
2
saponification of the methyl ester via nucleophilic attack at
the carboxyl group, rather than enolate formation, which led
to the competing retro-Michael reaction. For the purposes of
comparison and to establish that epimerisation at the C6
position had not taken place during the decarboxylation
process, the 2,6 trans-isomer 11 was formed by decarboxyl-
ation of the trans pyranone 7 using the same LiOH/H2O2
conditions employed for the cis-isomer 2. The two
The one-pot pyran-forming methodology12 was also applied
to the synthesis of tetrahydropyran-4-one 2.13 It had
previously been found that ytterbium (III) triflate favoured
the formation of the 2,6 cis-isomer over the 2,6 trans-
isomer, and using the optimised reaction conditions the 2,6
cis-isomer 2 was formed in a 2:1 ratio to the 2,6 trans-
isomer 7 and in an excellent 92% yield (Scheme 4). It was
possible to separate and then resubmit the trans-dia-
stereomer to the reaction conditions and hence, re-equili-
brate to a 2:1 mixture of 2:7, thus, increasing the isolated
yield of 2 to 82%.
1
compounds, 10 and 11, had markedly different H NMR
spectra with 10 having an ABX system with J3Z10.7,
3.4 Hz for H2 coupling to H3a and H3b, and J3Z10.7,
3.8 Hz for H6 coupling to H5a and H5b, indicating the 2,6
cis stereochemistry whereas 11 had J3Z5.7, 5.4 Hz for H6
coupling to H5a and H5b, consistent with a 2,6 trans
structure in rapid conformational equilibrium. The fact that
no epimerisation occurred during the decarboxylation of
either pyranone indicates that, under these conditions,
decarboxylation is more facile than the retro-Michael
reaction and that the decarboxylation of 7 must proceed
via tautomerisation of 7 to its keto-tautomer.
With a reasonably efficient route to the desired 2,6 cis-
isomer 2 in hand, the final stages of the synthesis were
investigated. Decarboxylation of the pyranone 2 was
attempted using LiOH, however, the product of a retro-
Michael reaction was formed exclusively, rather than that,
of decarboxylation. Decarboxylation was achieved by use of
LiOH and H2O2, which provided 10 in 60% yield. The
remaining mass balance of the reaction was an enone arising
from a retro-Michael reaction. We rationalised that the less
basic, more nucleophilic hydroperoxide anion favoured
The final synthetic challenge was to effect the reduction of
the carbonyl of 10 to a methylene group. The first method
investigated was the Wolff–Kischner reaction, but upon
work-up this was found to have returned only starting
Scheme 5. Reagents and conditions: (i) H2O2, LiOH, THF, H2O, room temperature, 5 h, then 70 8C, 30 min, then room temperature, 12 h, 60%;
(ii) HSCH2CH2SH, BF3$OEt2, CH2Cl2, room temperature, 100%; (iii) Raney nickel, H2, EtOH, 30 8C, 100%.

5436
P. A. Clarke, W. H. C. Martin / Tetrahedron 61 (2005) 5433–5438
material. Analysis by TLC suggested that the hydrazone
was formed readily, which implied that the base-mediated
elimination was the problematic step. The phenolic
hydroxyl group would have been deprotonated under the
reaction conditions giving an anionic species that would
perhaps be less susceptible to elimination of the hydrazone.
With the failure of the Wolff–Kischner reaction it was
decided to effect the carbonyl removal in two steps via
formation of the dithiane. To this end the carbonyl in 10 was
treated with ethane dithiol and boron trifluoride diethyl
etherate to give the dithiane 12 in quantitative yield. Raney
Nickel reduction of 12 proceeded under an atmosphere of
hydrogen at 70 8C to give (G)-centrolobine 1 quantitatively
(Scheme 5).
To a stirred mixture of 5-hydroxy-3-oxo-7-(4-tertbutyldi-
methlsilyloxyphenyl) heptanoic acid methyl ester 6 (1.00 g,
2.63 mmol) in CH2Cl2 (40 mL) at room temperature was
added anisaldehyde (383 mL, 3.16 mmol) followed by boron
trifluoride diethyletherate (333 mL, 2.63 mmol). The yellow
solution was stirred at room temperature for 48 h and was
then taken up in Et2O (60 mL) and washed with brine
(2!30 mL), dried (MgSO4), and concentrated in vacuo.
Purification by flash column chromatography (1:10 EtOAc–
petroleum ether) gave 2 and 7 in a ratio of 1.0:0.6 in favour
of 2 (566 mg, 56%).
Compound 2. Oil nmax (film) 3598, 2955, 2930, 1744
1
(C]O), 1714 (C]O), 1614, 1514, 1251, 1176 cmK1; H
NMR (400 MHz; CDCl3) d 7.32 (2H, d, JZ8.4 Hz), 7.00
(2H, d, JZ8.4 Hz), 6.89 (2H, d, JZ8.8 Hz), 6.74 (2H, d,
JZ8.4 Hz), 5.37 (1H, br s), 4.81 (1H, d, JZ10.7 Hz), 3.81
(3H, s), 3.81 (1H, dddd, JZ11.2, 7.4, 4.4, 2.4 Hz), 3.62 (1H,
d, JZ10.7 Hz), 3.60 (3H, s), 2.70–2.64 (2H, m), 2.56 (1H,
dd, JZ14.6, 2.4 Hz), 2.46 (1H, dd, JZ14.6, 11.2 Hz), 2.03
(1H, m), 1.85 (1H, m) ppm; 13C NMR (100 MHz; CDCl3) d
202.0, 168.0, 154.0, 133.0, 130.9, 129.4, 128.1, 115.3,
114.0, 80.4, 76.0, 55.2, 46.9, 37.8, 30.9, 30.2 ppm; m/z
(CIC) 384 (40%, MC), 325 (33%, MC–CO2Me), 107
(100%, MeOPhC); HRMS: found (MC), 384.1561.
C22H24O6 requires (MC) 384.1573.
3. Conclusions
We have applied our variation of a one-pot, three-
component Maitland–Japp reaction to the synthesis of
(G)-centrolobine. The synthesis was achieved in four steps
and in 50% yield from aldehyde 5, which compares
extremely favourably with those syntheses already reported.
4. Experimental
4.1. General
Compound 7. Oil nmax (film) 3354, 2924, 2853, 1714
(C]O), 1612, 1414, 1259, 1216, 1173, 1097, 1031 cmK1
;
1H NMR (400 MHz; CDCl3) d 12.29 (1H, s), 7.28 (2H, d,
JZ8.8 Hz), 6.93 (2H, d, JZ8.8 Hz), 6.68 (2H, d, JZ
8.8 Hz), 6.61 (2H, d, JZ8.3 Hz), 5.64 (1H, s), 3.88 (3H, s),
3.65 (3H, s), 3.52 (1H, m), 2.60 (1H, ddd, JZ13.7, 8.3,
4.9 Hz), 2.40–2.30 (2H, m), 2.22 (1H, dd, JZ18.1, 3.9 Hz),
1.81 (1H, dddd, JZ17.1, 14.1, 7.8, 4.9 Hz), 1.62 (1H, dddd,
JZ17.1, 11.7, 8.3, 3.4 Hz) ppm; 13C NMR (100 MHz;
CDCl3) d 171.2, 171.0, 159.2, 153.5, 133.1, 133.1, 129.8,
129.5, 115.0, 113.5, 99.0, 72.4, 64.7, 55.3, 51.6, 37.6, 34.8,
30.2 ppm; m/z (TOF ESC) 448 (69%, MCCNaCCH3CN),
407 (100%, MCCNa), 385 (36%, MCCH); HRMS: found
(MCCNa), 407.1459. C22H24O6 requires (MCCNa)
407.1471.
All melting points are uncorrected. Reaction progress was
monitored using glass-backed TLC plates pre-coated with
silica UV254 and visualised by using either UV radiation
(254 nm), ceric ammonium molybdate or anisaldehyde
stains. Column chromatography was performed using silica
gel 60 (220–240 mesh), with the solvent systems indicated
in the relevant experimental procedures. Dichloromethane
was distilled from calcium hydride, tetrahydrofuran and
diethyl ether were distilled from sodium/benzophenone
ketyl, dimethyl formamide was stirred with calcium hydride
and distilled prior to use. Benzene, DMSO and MeCN were
all distilled from calcium hydride prior to use. Hexane was
distilled prior to use. All other reagents were used as
received from commercial suppliers unless stated otherwise
in the appropriate text.
4.3. The one-pot procedure for the synthesis of
4-hydroxy-6-(2-(4-hydroxyphenyl)-ethane)-2-(4-
hydroxyphenyl)-2,3-dihydro-2H-pyran-3-carboxylic
acid methyl ester 2 and 6-(2-(4-hydroxyphenyl)-ethane)-
2-(4-hydroxyphenyl)tetrahydro-pyran-3-carboxylic acid
methyl ester 7
4.2. The two-pot procedure for the synthesis of
4-hydroxy-6-(2-(4-hydroxyphenyl)-ethane)-2-(4-hydroxy-
phenyl)-2,3-dihydro-2H-pyran-3-carboxylic acid methyl
ester 2 and6-(2-(4-hydroxyphenyl)-ethane)-2-(4-hydroxy-
phenyl)tetrahydro-pyran-3-carboxylicacidmethylester7
To a suspension of ytterbium (III) triflate (310 mg,
0.50 mmol) in CH2Cl2 (5 mL) at K78 8C was added
3-(4-tert-butyldimethlsilyloxyphenyl) propanal 6 (130 mg,
0.50 mmol) followed by Chan’s diene (285 mL, 1.00 mmol).
The white mixture was stirred at K78 8C for 180 min and
then trifluoroacetic acid (158 mL, 2 mmol) was added
followed by the anisaldehyde (75 mL, 0.60 mmol). The
mixture was warmed to room temperature over 5 min and
then stirred at room temperature for 5 h. The mixture was
then diluted with Et2O (40 mL) and washed with 5% aq,
NaHCO3 soln, (3!30 mL) and brine (2!30 mL), dried
(MgSO4), and concentrated in vacuo. Purification by flash
column chromatography (1:10 EtOAc–petroleum ether)
To a solution of 3-(4-tert-butyldimethlsilyloxyphenyl)
propanal 5 (264 mg, 1.00 mmol) in CH2Cl2 (10 mL) at
K78 8C was added titanium tetrachloride (111 mL,
1.00 mmol). The black solution was stirred for 2 min and
then Chan’s diene 3 (570 mL, 2.00 mmol) was added over a
1 min period. The black solution was stirred at K78 8C for
1 h and then 5% aq, NaHCO3 soln (20 mL) was added and
the reaction allowed to warm to room temperature. The
solution was taken up in Et2O (30 mL) and washed with 5%
aq, NaHCO3 soln (3!30 mL), and brine (2!30 mL), dried
(MgSO4), and concentrated in vacuo. The product 6 was
used without further purification in the next reaction.

P. A. Clarke, W. H. C. Martin / Tetrahedron 61 (2005) 5433–5438
5437
pyran products 2 (115 mg, 60%) and 7 (62 mg, 32%), which
were spectroscopically identical to those made via the
method above.
(CIC) 326 (83%, MC), 205 (10%, MC–CH2CH2C6H4OH)
134 (80%), 107 (30%, C6H4OMeC); HRMS: found (MC),
326.1509. C20H22O4 requires (MC) 326.1518.
4.3.1. 2,6-cis-6-(2-(4-Hydroxyphenyl)-ethane)-2-(4-
hydroxyphenyl)-4-oxo-tetrahydropyran 10. To a solution
of 6-(2-(4-hydroxyphenyl)-ethane)-2-(4-hydroxyphenyl)-
tetrahydro-pyran-3-carboxylic acid methyl ester 2 (70 mg,
0.18 mmol) in THF/H2O (4:1, 2 mL) at room temperature
was added hydrogen peroxide (90 mL, 0.72 mmol) followed
by lithium hydroxide (9 mg, 0.28 mmol). The solution was
stirred at 60 8C for 2 h and then taken up in Et2O (30 mL)
and washed with 5% aq, sodium metabisulfite soln, (3!
330 mL), and brine (2!20 mL), dried (MgSO4), filtered
and the solvent removed under reduced pressure. Purifi-
cation by flash column chromatography (1:10 EtOAc–
petroleum ether) gave the title compound 10 as an oil
(36 mg, 60%) nmax (film) 3414, 2856, 1714 (C]O), 1660,
1514, 1444, 1250, 1032 cmK1; 1H NMR (500 MHz; CDCl3)
d 7.31 (2H, d, JZ8.4 Hz), 7.03 (2H, d, JZ8.4 Hz), 6.93
(2H, d, JZ8.8 Hz), 6.74 (2H, d, JZ8.8 Hz), 4.92 (1H, s),
4.56 (1H, dd, JZ10.7, 3.8 Hz), 3.82 (3H, s), 3.71 (1H, dddd,
JZ10.7, 8.1, 4.3, 3.4 Hz), 2.77 (1H, ddd, JZ14.1, 9.5,
5.5 Hz), 2.71 (1H, ddd, JZ14.1, 8.5, 7.7 Hz), 2.61 (1H, ddd,
JZ14.5, 3.8, 1.3 Hz), 2.57 (1H, dd, JZ14.5, 10.7 Hz), 2.44
(1H, ddd, JZ14.1, 3.4, 1.3 Hz), 2.39 (1H, dd, JZ14.1,
10.7 Hz), 2.04 (1H, dddd, JZ13.6, 8.5, 8.1, 5.5 Hz), 1.84
(1H, dddd, JZ13.6, 9.4, 7.7, 4.3 Hz) ppm; 13C NMR
(125 MHz; CDCl3) d 207.2 (s), 159.3 (s), 153.8 (s), 133.5
(s), 133.0 (s), 129.5 (d), 127.0 (d), 115.2 (d), 114.0 (d),
112.7 (s), 78.2 (d), 76.1 (d), 55.3 (q), 49.3 (t), 47.7 (t), 38.1
(t) ppm; m/z (CIC) 326 (38%, MC), 107 (30%,
C6H4OMeC) 84 (100%); HRMS: found (MC), 326.1505.
C20H22O4 requires (MC) 326.1518.
4.3.3. 4-Dithiane-6-(2-(4-hydroxyphenyl)-ethane)-2-(4-
hydroxyphenyl)-tetrahydropyran 12. To a solution of
6-(2-(4-hydroxyphenyl)-ethane)-2-(4-hydroxyphenyl)-4-
oxo-tetrahydropyran 10 (20 mg, 0.061 mmol), in CH2Cl2
(1 mL), was added ethane dithiol (5.6 mL, 0.07 mmol),
followed by boron trifluoride etherate (8.5 mL, 0.06 mmol).
The solution was stirred at room temperature for 20 min
then taken up in Et2O (30 mL), washed with brine (20 mL),
dried over MgSO4, filtered and the solvent removed under
reduced pressure to yield the title compound as an oil
(25 mg, 100%). nmax (film) 3389, 2922, 2852, 1814, 1613,
1442, 1248, 1176, 1033 cmK1; 1H NMR (500 MHz; CDCl3)
d 7.31 (2H, d, JZ8.8 Hz), 7.03 (2H, d, JZ8.8 Hz), 6.89
(2H, d, JZ8.8 Hz), 6.73 (2H, d, JZ8.8 Hz), 4.52 (1H, dd,
JZ11.1, 2.0 Hz), 3.80 (3H, s), 3.67 (1H, dddd, JZ11.1, 6.7,
4.4, 2.0 Hz), 3.37–3.35 (4H, m), 2.77 (1H, ddd, JZ14.0,
9.9, 5.6 Hz), 2.67 (1H, ddd, JZ14.0, 9.6, 6.7 Hz), 2.31 (1H,
ddd, JZ13.5, 2.4, 2.4 Hz), 2.15 (1H, dd, JZ13.5, 11.1 Hz)
2.15 (1H, ddd, JZ13.5, 4.1, 2.0 Hz) ppm; 13C NMR
(125 MHz; CDCl3) d 159.0 (s), 153.7 (s), 134.3 (s), 134.2
(s), 129.5 (d), 127.3 (d), 115.2 (d), 113.8 (d), 78.1 (d), 76.4
(d), 65.8 (s), 55.4 (q), 49.7 (t), 47.4 (t), 39.3 (t), 37.9 (t), 37.8
(t), 30.8 (t) ppm; m/z (CIC) 402 (47%, MC), 309 (100%,
MC-PhOH), 135 (45%), 107 (91%, C6H4OMeC); HRMS:
found (MC), 402.1315. C22H26O3S2 requires (MC)
402.1323.
4.3.4. (G) Centrolobine 1. To a solution of 4-dithiane-6-(2-
(4-hydroxyphenyl)-ethane)-2-(4-hydroxyphenyl)-tetra-
hydropyran 12 (20 mg, 0.05 mmol) in EtOH (2 mL), was
added Raney nickel (150 mg, 50% slurry in H2O). The
heterogeneous mixture was heated at 35 8C for 18 h under
an atmosphere of H2 and then passed through celite. The
solvent was removed under reduced pressure to give (G)
centrolobine as a white solid (15 mg, 100%) The data were
in agreement with the literature values.5–8 Mp 87–89 8C
(lit.1,5,6 85–87 8C); nmax (film) 3348, 2924, 2851, 1613,
4.3.2. 2,6-trans-6-(2-(4-Hydroxyphenyl)-ethane)-2-(4-
hydroxyphenyl)-4-oxo-tetrahydropyran 11. To a solu-
tion of 4-hydroxy-6-(2-(4-hydroxyphenyl)-ethane)-2-(4-
hydroxyphenyl)-2,3-dihydro-2H-pyran-3-carboxylic acid
methyl ester 7 (40 mg, 0.10 mmol) in THF/H2O (1 mL,
4:1), was added hydrogen peroxide (75 mL, 0.416 mmol)
followed by lithium hydroxide (7 mg, 0.166 mmol). The
reaction was stirred at room temperature for 5 h. No change
was seen by TLC analysis so the temperature was raised to
70 8C for 3 h and the reaction was then stirred for a further,
15 h at room temperature. The reaction mixture was taken
up in ether (30 mL), and then washed with 5% aq sodium
metabisulfite soln, (3!20 mL), and brine (2!20 mL),
dried (MgSO4), and concentrated in vacuo. Purification by
flash column chromatography (1:10 EtOAc–petroleum
ether) gave the title compound 11 as an oil (21 mg, 65%)
nmax (film) 3598, 3019, 2929, 2856, 1714 (C]O), 1612,
1
1514, 1454, 1246, 1174, 1080, 1035, 827 cmK1; H NMR
(500 MHz; CDCl3) d 7.31 (2H, d, JZ8.5 Hz), 7.05 (2H, d,
JZ8.8 Hz), 6.88 (2H, d, JZ8.5 Hz), 6.74 (2H, d, JZ
8.8 Hz), 4.29 (1H, dd, JZ11.1, 2.0 Hz), 3.80 (3H, s), 3.44
(1H, dddd, JZ12.6, 6.4, 4.7, 1.8 Hz), 2.73 (1H, m), 2.65
(1H, m), 1.95–1.22 (8H, m) ppm; 13C NMR (125 MHz;
CDCl3) d 158.7, 153.5, 135.9, 134.7, 129.6, 127.2, 115.1,
113.7, 79.1, 77.2, 55.4, 38.4, 33.4, 31.3, 30.8, 24.1 ppm; m/z
(TOF ESC) 335 (50%, MC CNa), 233 (100%); HRMS:
found (MC CNa), 335.1623. C20H24O3 requires (MC
C
1
1514, 1181, 1034 cmK1; H NMR (500 MHz; CDCl3) d
Na) 335.1626.
7.29 (2H, d, JZ8.8 Hz), 6.94 (2H, JZ8.4 Hz), 6.89 (2H, d,
JZ8.8 Hz), 6.69 (2H, d, JZ8.4 Hz), 5.24 (1H, dd, JZ5.7,
5.4 Hz), 4.73 (1H, br s), 3.89 (1H, m), 3.82 (3H, s), 2.84
(1H, ddd, JZ14.9, 5.4, 1.1 Hz), 2.79 (1H, ddd, JZ14.9, 5.7,
1.1 Hz), 2.69 (1H, ddd, JZ14.1, 9.6, 5.0 Hz), 2.54–2.48
(2H, m), 2.35 (1H, ddd, JZ14.5, 7.6, 1.1 Hz), 1.96 (1H,
dddd, JZ18.4, 14.1, 9.2, 5.0 Hz), 1.67 (1H, dddd, JZ18.4,
14.2, 7.3, 4.2 Hz) ppm; 13C NMR (125 MHz; CDCl3) d
207.4, 159.4, 133.5, 132.1, 129.5, 128.4, 115.2, 114.0,
114.0, 73.4, 70.6, 55.3, 47.3, 45.9, 36.7, 30.6 ppm; m/z
Acknowledgements
We thank the EPSRC and the University of Nottingham for
DTA studentship funding (W.H.C.M.), AstraZeneca for an
unrestricted research award (P.A.C.) and the EPSRC
National Mass Spectrometry service, Swansea, for accurate
mass determination.

5438
P. A. Clarke, W. H. C. Martin / Tetrahedron 61 (2005) 5433–5438
6. Carreno, M. C.; Mazery, R. D.; Urbano, A.; Colobert, F.;
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