A concise, convergent total synthesis of monocerin

Article abstract of DOI:10.1039/b612256f

A concise and convergent eight-step synthesis of the antifungal metabolite monocerin 1 is reported. The key step involves an allylsilane metathesis/aldehyde condensation sequence to establish the core 2,3,5-trisubstituted tetrahydrofuran. End-game approac

Full text of DOI:10.1039/b612256f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A concise, convergent total synthesis of monocerin
John H. Cassidy,a Christopher N. Farthing,a Stephen P. Marsden,*b Anders Pedersen,b Mark Slaterb and
Geoffrey Stempc
Received 25th August 2006, Accepted 19th September 2006
First published as an Advance Article on the web 3rd October 2006
DOI: 10.1039/b612256f
A concise and convergent eight-step synthesis of the antifungal metabolite monocerin 1 is reported. The
key step involves an allylsilane metathesis/aldehyde condensation sequence to establish the core
2,3,5-trisubstituted tetrahydrofuran. End-game approaches based around intramolecular Heck
chemistry revealed an interesting example of formal 6-endo cyclisation, the origin of which was probed
using model substrates. The synthesis was ultimately completed by a strategy involving stepwise
oxidative cleavage of the C3-ethenyl substituent.
furan assembly would lend itself well to the further synthesis
Introduction
of analogues13 as potential antifungals. Herein we describe the
Monocerin (1) is an anti-fungal and insecticidal natural product
successful completion of the target synthesis.
that has been isolated from several fungal sources.1–4 A 15-step
total synthesis of racemic monocerin was reported in 1989 by
Results and discussion
Mori, alongside a 19-step asymmetric variant.5 Biosynthetically,
monocerin has been found to be of heptaketide origin, and
13C labelling studies suggest the tetrahydrofuran ring arises
by intramolecular nucleophilic trapping of a quinonemethide
intermediate by a pendant alcohol.2,6 This thesis was explored
in an elegant and successful biomimetic synthesis of monocerin
by Simpson in 1992,7 in which radical benzylic bromination was
used to initiate quinonemethide formation and cyclisation.
The requisite coupling partners for the assembly of the target
tetrahydrofuran were the allylsiloxane 3 (synthesised from known
4-hydroxyhept-1-ene 2 in two steps by our standard methodol-
ogy) and the known aldehyde 4,14 prepared by bromination of
commercial trimethoxybenzaldehyde (Scheme 1).
We have developed a stereoselective method for the conver-
gent assembly of tetrahydrofurans based upon the Lewis acid-
mediated condensation of cyclic allylsiloxanes (derived by ring-
closing metathesis) with aldehydes.8–12 Using this method, we
have prepared 2,3,5-8 and 2,3,4-trisubstituted10 as well as 2,3,4,5-
tetrasubstituted tetrohydrofurans11 with various stereochemical
motifs in a controlled manner, and have applied them in the
synthesis of the diaryllignan virgatusin11 and the octahydroisoben-
zofuran core of the eunicellins.12 With regard to monocerin, we
noted that the all-cis stereochemistry observed in the formation
of 2,3,5-trisubstituted tetrahydrofurans8 mirrors that observed in
the natural product. If we were able to employ the pendant 3-
vinyl substituent of such a tetrahydrofuran as a precursor to
the oxygen functionality at C3 of monocerin, with retention
of stereochemistry, this would allow a concise approach to the
total synthesis; further, the convergent nature of the tetrahydro-
Scheme 1 Reagents and conditions: (i) (allyl)Me2SiCl, Et3N, CH2Cl2,
0 ◦C (82%); (ii) 1% (PCy3)2RuCl2 CHPh, CH2Cl2, rt (95%); (iii) 4, 1 eq.
=
BF3·OEt2, CH2Cl2, −78 ◦C (86%).
Condensation of 3 and 4 under the previously identified condi-
tions (exposure to boron trifluoride etherate at −78 ◦C followed by
slow warming to room temperature) yielded the desired tetrahy-
drofuran 5 in 86% yield as a 9 : 1 mixture of diastereoisomers. The
all-cis relative stereochemistry of the major diastereomer shown
was the previously observed stereochemical outcome for 2,3,5-
trisubstituted tetrahydrofurans. We have, however, observed in
tetrahydrofurans with alternative substitution patterns that the use
of boron trifluoride in conjunction with electron-rich aldehydes
can lead to predominant formation of 2,3-trans isomers by C2-
epimerisation of an initially formed cis-adduct via a stabilised
benzylic cation,10,11 and hence sought confirmation of the assigned
stereochemistry. Comparison of diagnostic chemical shift data for
both the benzylic proton and the internal vinylic proton for the
aDepartment of Chemistry, Imperial College, London, SW7 2AY, UK
bSchool of Chemistry, University of Leeds, Leeds, LS2 9JT, UK. E-mail:
s.p.marsden@leeds.ac.uk; Fax: +44 113 343 6565; Tel: +44 113 343 6425
cNew Frontiers Science Park, GlaxoSmithKline, Third Avenue, Harlow,
Essex, CM19 5AW, UK
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cis and trans isomers in each series supports the assignment of
5 as having the stereochemistry shown.† This assignment was
eventually confirmed by the successful total synthesis.
the aryl bromide was at least partly responsible, and we therefore
examined the behaviour of the simplified model 9, readily prepared
from siloxane 10 (Scheme 3). Upon exposure to the same standard
Heck conditions which had given the 6-endo adduct with 5, we
instead found that 9 underwent a clean and high-yielding (84%)
cyclisation to give the 5-exo isomer 11. This result confirmed
that the highly electron-rich arene was playing some part in the
formation of the 6-endo product, and we therefore prepared the
acyclic substrate 12 in two steps from aldehyde 4. Treatment
of 12 with palladium(II) acetate and triphenylphosphine (with
potassium carbonate as base) gave an 80% yield of the 5-exo
adduct 13, which confirmed that the highly hindered nature of
the tricyclic carbopalladation adduct(s) formed from 5 was also
responsible for the anomalous regiochemical outcome.
Our initial approach to installation of the tricyclic lactone
present in monocerin focused on the formation of ketone 6,
which would be accessed by oxidative cleavage of alkene 7, the
product of a 5-exo Heck cyclisation of 5 (Fig. 1). We planned
that stereoselective insertion of an oxygen between C3 of the
tetrahydrofuran and the carbonyl would be possible, either directly
by Baeyer–Villiger oxidation, or more likely in a stepwise protocol
via an enol derivative of 6. We therefore commenced studies into
the Heck reaction.
Fig. 1 Proposed approach to monocerin 1 via stereoselective oxygen
insertion to ketone 6.
Upon exposure of 5 to standard Heck coupling conditions
(palladium(II) acetate, triphenylphosphine and triethylamine), we
were surprised to observe that the only identifiable product of
the reaction was the undesired 6-endo isomer 8, formed in 67%
yield (Scheme 2). Intramolecular Heck reactions of electroni-
cally unbiased olefins leading to 6-endo products are extremely
rare,15–17 and are usually indicative of some rearrangement of an
initially formed 5-exo adduct.15,16 We therefore hoped that the
regiochemical outcome might be altered by tuning the reaction
conditions. The use of electron-rich alkylphosphines led either to
debromination of 5 or simply returned starting material. However,
the use of the bidentate ligand bis(diphenylphosphinyl)ferrocene
gave an 85% yield of the desired 5-exo adduct 7.
Scheme 3 Reagents and conditions: (i) (o-Br)PhCHO, BF3·OEt2, CH2Cl2,
−78 ◦C to rt (81%); (ii) 3% Pd(OAc)2, PPh3, Et3N, MeCN, heat (84%);
(iii) allylMgBr, Et2O, −15 ◦C to rt (93%); (iv) NaH, MeI, THF, 0 ◦C to rt
(89%); (v) 10% Pd(OAc)2, PPh3, K2CO3, MeCN, heat (80%).
A possible explanation for the observed behaviour is that all
of the substrates undergo an initial 5-exo cyclisation, which for
substrates 5/9 generates tricyclic intermediates of type 14/15
(Fig. 2). If b-hydride elimination to the exo-methylene products
7/11 is slow in these highly hindered intermediates, the op-
portunity for the intervention of the electron-rich arene arises.
1
This would presumably be triggered by p,g complexation of
the arene to the palladium, following dissociation of one of the
phosphine ligands, in a complex such as 16. Complexes of the
type 16 have previously been observed and characterised by X-ray
crystallography.18 The precise mechanism for the conversion of 16
to the 6-endo adduct 8 is not known, but a potential pathway is
indicated. Nucleophilic substitution at palladium by electron-rich
p-systems is well documented,19,20 and would in this case lead to a
palladacyclobutane. Reductive elimination of palladium generates
a phenonium ion, which could then undergo fragmentation and
loss of a proton to generate 8. Skeletal migrations of aryl groups
in formal E1 processes, likely proceeding via phenonium ions, are
known.21 Regardless of the actual mechanism for the formation
of 8, the intermediacy of complex 16 en route to the 6-endo
product does, however, help to explain the experimental observa-
tions. Using substrate 9, the less electron-rich phenyl substituent
would be less likely to form a complex of type 16 and would
therefore undergo slow b-hydride elimination to the observed 5-
exo product 11. Likewise, although substrate 12 contains the same
highly electron-rich arene as 5, the reduced steric constraints in
the initially formed 5-exo carbopalladation product means that
Scheme 2 Reagents and conditions: (i) 3% Pd(OAc)2, PPh3, Et3N, MeCN,
heat (67%, 8); (ii) 3% Pd(OAc)2, dppf, Et3N, MeCN, heat (85%, 7).
We were intrigued by this unusual regiochemical outcome
and undertook some model studies to clarify the origin of the
selectivity. We suspected that the highly electron-rich nature of
† We have previously observed in the 2,3,4-trisubstituted series that the
benzylic tetrahydrofuran proton in the 2,3-cis diastereomer appears be-
tween 5.18 and 5.08 ppm (cf. 4.64–4.52 ppm for the trans-diastereomer),10
a trend mirrored in previously synthesised 2,3,5-trisubstituted tetrahy-
drofurans (5.20–5.01 ppm for cis-diastereomer).8 The benzylic proton
of 5 appears at 5.20 ppm. Additionally, for 2-aryl-2,3,5-trisubstituted
tetrahydrofurans, the internal vinylic proton for the major cis-diastereomer
routinely occurs at ca. 5.2 ppm (cf. 5.7–6.0 ppm for the minor trans-
isomer):8 the signals for this proton in 5 occur at 5.18 and 5.94 ppm for
major and minor isomers respectively.
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Fig. 2 Diversion of 5-exo pathway to formal 6-endo product for substrate 5. (5, 14, 7: R = Pr, X = OMe; 9, 15, 11: R = Cy, X = H).
b-hydride elimination will be too fast to compete with formation
of a p,g complex, and again the 5-exo product is observed.
using either oxygen or benzoquinone as co-oxidant. Ultimately we
were able to direct the regiochemistry by performing sequential
oxymercuration/palladium-catalysed oxidation,23 although high
catalyst loadings of palladium and superstoichiometric copper(II)
chloride were required to attain high conversions. Under these
conditions, a 70% yield of the ketone 18 was obtained, along
with 7% of aldehyde 19 (Scheme 5). Disappointingly, however,
the ketone 18 proved stubbornly resistant to Baeyer–Villiger
oxidation: the use of mCPBA returned starting material, whereas
peracetic or pertrifluoroacetic acid led to decomposition of the
ketone to unidentified by-products.
1
Finally, the observation that the 5-exo product 7 is observed
when bidentate phosphines are used as ligands is also explained
by this model: the reluctance of the bidentate phosphine to
undergo decomplexation due to the chelate effect would disfavour
formation of complex 16, and hence the ‘normal’ product 7 is
observed.
With the alkene 7 in hand, oxidative cleavage to ketone 6 was
easily achieved using osmium tetroxide followed by periodate
(Scheme 4).
Scheme
4
Reagents and conditions: (i) OsO4, NMO, tBuOH–
acetone–H2O, then KIO4 (67%); (ii) mCPBA, NaHCO3, CH2Cl2, 0 ◦C
Scheme 5 Reagents and conditions: (i) 10% PdCl2, O2, DMF–H2O (73%,
18 : 19 = 1 : 1); (ii) 10% PdCl2, benzoquinone, perchloric acid, MeCN–H2O
(80%, 18 : 19 = 3 : 2); (iii) Hg(OAc)2, THF–H2O, then 65 mol% PdCl2,
CuCl2 (77%, 18 : 19 = 10 : 1).
(76%).
Attempts to install the C3 oxygen directly by Baeyer–Villiger
oxidation were unsuccessful, with the sole product of the reaction
being the isomeric lactone 17 formed by migration of the electron-
rich aryl substituent in preference to the inductively-destabilised
secondary alkyl group. Although the migratory tendencies of
aryl and secondary alkyl groups are similar,22 the electronic
imbalances caused by the substituents in this case bias the
migration exclusively in the undesired direction. We therefore
attempted to form silyl enol ethers of ketone 6 as a prelude
to oxidative olefin cleavage, but were unable to effect enolate
formation using lithium amide bases, with starting material being
returned in most cases. We therefore elected to return to the
monocyclic series and attempt to effect installation of the C3-
oxygenation at this stage.
Our first attempts focused again on Baeyer–Villiger oxidation,
this time on ketone 18 – here the reluctance of methyl groups
to undergo migration ought to bias the regiochemistry in the
desired sense.22 Initial attempts to form 18 by Wacker oxida-
tion of the ethenyl substituent of 5 were complicated by the
competing formation of the regioisomeric aldehyde product 19,
Our final approach to monocerin 1 was therefore to install
the C3-oxygenation by olefin migration and oxidative cleavage
to yield a ketone, which ought to be subject to stereoselective
hydride addition from the less hindered face to deliver the desired
C3-stereochemistry. Attempts to isomerise the vinyl group to
the exocyclic trisubstituted olefin under rhodium catalysis were
unsuccessful, but application of Sharpless’ allylic chlorination
technology using phenylselenenyl chloride gave a 50% yield of
allylic chloride 20 as a 5 : 1 mixture of olefin isomers (Scheme 6).24
Ozonolytic cleavage of the olefin gave ketone 21 in 48% yield.
Finally, stereoselective reduction of the ketone with sodium
borohydride afforded 22 as a single diastereoisomer in 88% yield.
The final ring closure to the tetrahydrofuro[3,2-c][2]benzo-
pyran-5-one ring system was achieved by sequential treatment
of the alcohol with one equivalent each of lithium hexamethyl-
disilazide then butyllithium, quenching the resulting dianion with
methyl chloroformate. This gave an 80% yield of the known mono-
cerin methyl ether 23, which exhibited identical spectroscopic data
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Scheme 6 Reagents and conditions: (i) PhSeCl, H2O2, pyridine, CCl4, −30 ◦C (50%); (ii) O3, CH2Cl2, −78 ◦C, then PPh3, −78 to 0 ◦C (48%); (iii) NaBH4,
MeOH, 0 ◦C (88%); (iv) LiHMDS, THF, −40 ◦C, then BuLi, −60 ◦C, then MeO2CCl, −60 ◦C to rt (80%); (v) BBr3, CH2Cl2, −30 ◦C (57%).
to that reported in the literature.5 Application of Mori’s conditions
for regioselective demethylation of monocerin methyl ether gave
lion (d) relative to tetramethylsilane, and are referenced to (residual
protic) solvent; coupling constants (J) are expressed in Hertz.
Infrared spectra were recorded on a Perkin Elmer 683 Infrared
Spectrometer. Mass spectra were recorded on a VG Autospec Q
or Micromass Platform II spectrometer under chemical ionisation
(CI) with ammonia, or under electrospray ionisation (ES) on a
Bruker micrOTOF instrument. Melting points were measured
using a Gallenkamp melting point apparatus and are uncorrected.
Tetrahydrofuran and dichloromethane for use as reaction
solvents were dried by prolonged heating under reflux over,
and distillation from, sodium/benzophenone ketyl and calcium
hydride respectively.
1
a 57% yield of monocerin 1, whose H NMR data was also in
agreement with the reported values.5
Conclusions
We have completed a concise, 8-step synthesis of monocerin 1 from
known alcohol 2 in 6.5% overall yield. The core trisubstituted
tetrahydrofuran 5 was assembled using our previously disclosed
allylsiloxane/aldehyde condensation chemistry. In the course of
attempts to construct the tricyclic ring system by Heck annulation,
an unusual dependence of regiochemical outcome upon ligand
type was observed. Model experiments show that the observation
of formal 6-endo products is due to a combination of the hindered
nature of the tricyclic system and the highly electron-rich character
of the aryl bromide, and suggest possible pathways proceeding via
initial 5-exo ring-closure followed by rearrangement to the 6-endo
product mediated by the electron-rich arene. Successful conclusion
of the total synthesis was instead achieved by oxidative removal of
the ethenyl side-chain of 5, followed by stereoselective reduction
of the resulting ketone and cyclocarbonylation of the hydroxy
aryl bromide. The current work provides further evidence of the
synthetic utility of allylsiloxane/aldehyde condensation chemistry
for the rapid elaboration of tetrahydrofuran-containing natural
products.25
4-Allyldimethylsilyloxy-1-pentene
To a solution of allylchlorodimethylsilane (1.46 ml, 10.0 mmol),
in DCM (60 ml) at 0 ◦C was added dropwise via cannula a
solution of triethylamine (1.54 ml, 11.0 mmol) and alcohol 2
(1.26 g, 11.0 mmol) in DCM (40 ml). The mixture was stirred
at 0 ◦C for 90 min and the reaction then quenched by the addition
of a saturated solution of NaHCO3 (50 ml). The mixture was
separated and the aqueous layer washed with DCM (3 × 15 ml).
The combined organic extracts were washed with brine (50 ml),
water (50 ml), dried (MgSO4), filtered and the solvent removed
in vacuo. The residue was purified by chromatography on basic
alumina (eluent petrol) to yield the title compound as a clear oil
(1.73 g, 82%): mmax/cm−1 3015, 1632, 1255, 1158, 1027, 1042, 837.
1
=
H NMR (CDCl3; 250 MHz) d 5.77 (2H, m, 2 × CH CH2),
=
Experimental
5.01 (4H, m, 2 × CH CH2), 3.69 (1H, app. p, J 5.7, OCH),
=
2.20 (2H, app. t, J 6.6, CH2–C C), 1.62 (2H, d, J 7.9, Si–CH2),
All dry glassware was oven-dried at 150 ◦C overnight or flame-
dried prior to use. All reactions in anhydrous solvent were
carried out under a dry nitrogen atmosphere. Analytical thin layer
chromatography was performed on pre-coated glass-backed plates
(Merck Kieselgel 60 F254). Visualisation was accomplished with
UV light (254 nm), acidic ammonium molybdate(IV) or potassium
permanganate. Flash column chromatography was performed on
Merck Kieselgel 60 (200–300 mesh) under gentle pressure from
hand bellows.
1.46–1.26 (4H, m, -(CH2)2), 0.93 (3H, t, J 6.8, Me), 0.11 (6H, s,
SiMe2). 13C NMR (CDCl3, 62.5 MHz) d 135.3, 134.3, 116.7, 113.5,
72.2, 42.1, 39.2, 25.2, 18.8, 14.1, −1.8. m/z (CI+/NH3) 230 (M +
NH4), 188, 171, 116, 74. HRMS (CI+/NH3) calc. for [M + NH4]+:
C12H28NOSi = 230.1940. Found 230.1952.
2,2-Dimethyl-7-propyl-1-oxa-2-sila-4-cycloheptene 3
To a thoroughly degassed solution of the above siloxane (300 mg,
1H and 13C NMR spectra were recorded on Bruker ARX250,
JEOL-GSL270, Bruker DRX300 and DPX300 and Bruker Avance
500 spectrometers. Chemical shifts are expressed in part per mil-
l.4 mmol) in DCM (70 ml) was added [Cl2(PCy3)2Ru CHPh]
=
(11 mg, 1 mol%) in one portion. The mixture was stirred at
room temperature for 4 h, then evaporated in vacuo and purified
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through a short pad of silica (eluent 15% EtOAc–hexane) to yield
3 as a clear oil (295 mg, 95%). Found C 65.06, H 10.97; calc.
for Cl0H20OSi C 65.21, H 11.00%. mmax/cm−1 3021, 2959, 1641,
8 (20 mg, 67%) as a yellow oil. mmax/cm−1 2957, 2932, 1643, 1569,
1108, 832. 1H NMR (CDCl3, 250 MHz) d 6.97 (1H, s, Ar-H), 6.26
=
=
(1H, d, J 9.5, Ar–CH C), 5.50 (1H, dd, J 5.6, 9.5, CH CAr),
5.31 (1H, d, J 7.8, Ar–CHO), 4.06–3.98 (1H, m, C3H7CHO), 3.85
1
1455, 1421, 1266, 1081, 1040, 896, 838 cm−1. H NMR (CDCl3,
=
250 MHz) d 5.77 (1H, dt, J 10.4, 6.8, C CH), 5.54 (1H, dt, J 10.4,
(3H, s, OMe), 3.81 (3H, s, OMe), 3.79 (3H, s, OMe), 3.55–3.46
ꢀ
=
=
=
6.3, C CH), 4.85 (1H, app. p, J 7.5, OCH), 2.26–2.24 (2H, m,
=
(1H, m, CH–C C), 2.38 (1H, ddd, 11.2, 5.9, 4.3, CHH CC C),
ꢀ
=
C CCH2), 1.52 (2H, d, J 7.0 SiCH2), 1.51–1.26 (4H, m, -(CH2)2),
1.52–1.12 (5H, m, CHH CC C and -(CH2)2), 1.04–0.99 (3H, t,
0.89 (3H, t, J 6.9, Me), 0.11 (3H, s, SiMe), 0.10 (3H, s, SiMe). 13
C
J 7.1, Me). 13C NMR (CDCl3, 62.5 MHz) d 132.5, 130.5, 130.1,
128.2, 126.9, 126.0, 125.0, 107.0, 82.3, 79.1, 61.0, 60.9, 56.1, 45.9,
38.9, 39.0, 37.6, 19.5. m/z (CI+/NH3) 305 (M + H), 291, 233.
HRMS (CI+/NH3): m/z calc. for [M + H]+: C18H25O4 requires
305.1753. Found 305.1755.
NMR (CDCl3, 62.5 MHz) d 127.6, 124.2, 72.4, 40.4, 37.0, 19.1,
18.8, 14.1, −1.6, −1.8. m/z (CI+/NH3) 202 (M + NH4), 185 (M +
H), 137, 92,81, 74. HRMS (CI+/NH3): m/z calc. for [M + H]+:
Cl0H21OSi = 185.1361. Found 185.1360.
(2SR,3SR,5SR)-2-(2-Bromo-3,4,5-trimethoxyphenyl)-3-ethenyl-5-
propyltetrahydrofuran 5
(2SR,3aSR,8bSR)-4,5,6-Trimethoxy-4-methylene-2-propyl-
3,3a,4,8b-tetrahydro-2H-indene[1,2-b]furan 7
To a solution of siloxane 3 (1.50 g, 8.2 mmol) in dry DCM (41 ml)
at −78 ◦C, was added BF3·OEt2 (1.01 ml, 8.2 mmol) and the
solution stirred for 5 min prior to the addition of aldehyde 4
(2.24 g, 8.2 mmol). The mixture was stirred at −78 ◦C for 2 h
and then allowed to warm to room temperature over 18 h. The
reaction was quenched by the addition of brine (50 ml) and the
mixture extracted with EtOAc (3 × 30 ml). The combined organic
layers were washed with water (50 ml), dried (MgSO4), filtered
and the solvent removed in vacuo. The residue was purified by
chromatography on silica gel (eluent 10% ether–petrol) to yield 5
as an inseparable 90 : 10 mixture of diastereomers (2.71 g, 86%).
Anal. calc. for C18H25BrO4: C 55.93, H 6.48%. Found: C 56.14,
H 6.49. mmax/cm−1 2959, 2936, 1569, 1484, 1427, 1328, 1108, 852.
1H NMR (CDCl3, 250 MHz) (major diastereomer) d 6.91 (1H, s,
To a solution of olefin 5 (l50 mg, 0.38 mmol) in acetonitrile (8 ml)
was added dppf (399 mg, 0.72 mmol), triethylamine (0.10 ml,
0.72 mmol) and palladium acetate (2.5 mg, 3 mol%). The resulting
dark solution was heated under reflux for 16 h, allowed to cool
to room temperature and quenched by the addition of a saturated
NaHCO3 solution (5 ml). This solution was extracted with EtOAc
(5 × 10 ml) and the combined organic extracts were washed with
brine (15 ml), water (15 ml), dried (MgSO4), filtered and the solvent
removed in vacuo. The residue was purified by chromatography
over silica gel (eluent 10% ether–petrol) to yield 7 (95 mg, 85%) as
a yellow oil. mmax/cm−1 2959, 2934, 1636, 1596, 1471, 1418, 1338,
1132, 1029, 743. 1H NMR (CDCl3, 250 MHz) d 6.80 (1H, s, Ar-H),
ꢀ
=
5.80 (1H, d, J 1.2, Ar–C CHH ), 5.21 (1H, d, J 7.4, ArCHO),
ꢀ
=
5.06 (1H, d, J 1.2, Ar–C CHH ), 3.91–3.86 (1H, m, C3H7CHO),
3.92 (3H, s, OMe), 3.88 (3H, s, OMe), 3.86 (3H, s, OMe), 3.57–
Ar-H), 5.20 (1H, d, J 7.5, Ar–CHO), 5.19–5.15 (1H, ddd, J 17.0,
ꢀ
ꢀ
=
=
=
=
10.0, 9.2, CH CH2), 4.88 (1H, app. dt, J 17.0, 0.9, CH CHH ),
3.50 (1H, m, CHC C), 2.43 (1H, m, CHH CC C) 1.49–1.38 (5H,
ꢀ
ꢀ
4.67 (1H, app. dt, J 10.0, 0.9, CH CHH ), 3.99–3.92 (1H, m,
m, CHH CC C and -(CH2)2), 0.91–0.87 (3H, t, J 7.2, Me). 13C
=
=
C3H7CHO), 3.85 (6H, app. s, 2 × OMe), 3.86 (3H, s, OMe),
NMR (CDCl3, 62.5 MHz) d 150.4, 128.5, 128.3, 126.3; 126.0,
125.0, 122.9, 106.8, 84.1, 81.7, 62.0, 60.1, 56.0, 49.2, 48.6, 39.5,
37.2, 19.6. m/z 305 (M + H), 205, 196, 77. HRMS m/z calc. for
[M + H]+: C18H25O4 requires 305.1753. Found 305.1761.
=
3.25 (1H, app. p, J 8.1, CH–C C), 2.29 (1H, dt, J 12.7, 6.3,
ꢀ
ꢀ
=
=
CHH –CC C ), 1.79 (1H, ddd, J 12.7, 9.4, 6.8, CHH –CC C),
1.76–1.40 (4H, m, -(CH2)2), 0.99 (3H, t, J 7.3, Me); signals for
the minor diastereomer are visible at: 5.94 (1H, app. dt, J 16.8,
=
10.0, 1.0, CH CH2), 4.05 (1H, m, C3H7CHO), 1.93 (1H, ddd,
(2SR,3SR,5RS)-2-(2ꢀ-Bromophenyl)-5-cyclohexyl-3-ethenyltetra-
hydrofuran 9
ꢀ
J 12.1, 6.6, 5.4, CHH CC C). 13C NMR (CDCl3, 62.5 MHz)
=
d (major diastereomer) 141.8, 138.4, 138.1, 137.2, 136.0, 135.2,
115.2, 107.0, 84.0, 78.9, 61.0, 56.0, 51.6, 46.3, 45.9, 38.5, 37.4,
19.5. mlz (CI+/NH3) 404/402 (M + NH4, 81Br/79Br), 386/384,
(M + H, 81Br/79Br), 305, 276, 274, 233. HRMS (CI+/NH3): m/z
calc. for [M + H]+: C18H2681BrO4 387.0994. Found 387.0999.
To a solution of siloxane 10 (45 mg, 0.20 mmol), in dry DCM (1 ml)
at −78 ◦C, was added BF3·OEt2 (20 ll, 0.20 mmol) and the solution
stirred for 5 min prior to the addition of 2-bromobenzaldehyde
◦
(25 mg, 0.20 mmol). The mixture was stirred at −78 C for 2 h
and then allowed to warm to room temperature over 18 h. The
reaction was quenched by the addition of brine (10 ml) and the
mixture extracted with EtOAc (3 × 10 ml). The combined organic
layers were washed with water (10 ml), dried (MgSO4), filtered
and the solvent evaporated in vacuo. The residue was purified by
chromatography on silica gel (eluent 5% ether–petrol) to yield 9
as an inseparable 96 : 4 mixture of diastereomers (54 mg, 81%).
(2aSR,3aSR,9SR)-6,7,8-Trimethoxy-2-propyl-2,3,3a,9b-
tetrahydronaptho[1,2-b]furan 8
To a solution of olefin 5 (39 mg, 0.10 mmol) in acetonitrile (2 ml)
was added triphenylphosphine (52 mg, 0.20 mmol), triethylamine
(50 ll, 0.36 mmol) and palladium acetate (0.7 mg, 3 mol%). The
resulting dark solution was heated under reflux for 16 h, allowed
to cool to room temperature and quenched by the addition of a
saturated NaHCO3 solution (5 ml). This solution was extracted
with EtOAc (5 × 5 ml), and the combined organic extracts were
washed with brine (5 ml), water (5 ml), dried (MgSO4), filtered
and the solvent removed in vacuo. The residue was purified by
chromatography over silica gel (eluent 10% ether–petrol) to yield
1
mmax/cm−1 2924, 1612, 1069, 1022, 993, 843. H NMR (CDCl3,
250 MHz) (major diastereomer) d 7.50 (1H, dd, J 7.6, 1.7, Ar-H),
7.47 (1H, dd, J 7.9, 1.1, Ar-H), 7.29 (1H, td, J 7.5, 1.2, Ar-H),
7.12 (1H, td, J 7.9, 1.7. Ar-H), 5.21 (1H, d, J 7.4, OCHAr),
=
5.26–5.19 (1H, m, CH CH2), 4.91 (1H, ddd, J 17.0, 2.0, 0.8,
ꢀ
ꢀ
=
=
CH CHH ), 4.68 (1H, ddd, J 10.1, 2.0, 0.8, CH CHH ), 3.69
(1H, ddd, J 9.4, 7.4, 6.2, CyCHO), 3.33 (1H, app. q, J 7.9,
4122 | Org. Biomol. Chem., 2006, 4, 4118–4126
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ꢀ
=
=
CHC C), 2.24 (1H, ddd, J 12.5, 8.3, 6.2, CHH C C), 2.05 (1H,
calc. for [M + Na]+: C13H1779BrNaO4 requires 339.0202. Found
339.0191.
ꢀ
=
m, CH of Cy), 1.91–1.60 (7H, m, 3 × (CH2) and CHH CC C),
1.49–1.20 (4H, m, 2 × CH2); signals for minor diastereomer visible
ꢀ
=
=
at 6.03 (1H, m, CH CH2), 5.02 (1H, m, CH CHH ), 3.86 (1H,
m, CyCHO) : 13C NMR (CDCl3, 62.5 MHz) (major diastereomer)
d 139.6, 138.5, 132.1, 128.3, 126.9, 121.9, 114.5, 83.4, 81.9, 46.1,
43.0, 30.0, 29.2, 26.6, 26.1, 25.9; m/z (CI+/NH3) 354/352 (M +
NH4, 81Br/79Br), 337/335 (M + H, 81Br/79Br), 317, 239, 150, 108.
HRMS (CI+/NH3): m/z calc. for [M + H]+: C18H2479BrO requires
335.1012. Found 335.1011.
2-Bromo-3,4,5-trimethoxy-1-(1-methoxybut-3-enyl)benzene 12
To a solution of the above alcohol (997 mg, 3.15 mmol) in THF
(32 ml) at 0 ◦C was added sodium hydride (60% dispersion in
mineral oil, 631 mg, 15.77 mmol) and iodomethane (0.98 ml,
◦
15.77 mmol) and the resulting solution stirred for 5 min at 0 C
and a further 18 h at room temperature. The reaction mixture was
cooled to 0 ◦C and H2O (15 ml) added dropwise. Et2O (35 ml)
was added and the biphasic solution partitioned. The aqueous
layer was washed with Et2O (3 × 40 ml) and the combined organic
extracts dried (MgSO4), filtered and the solvent removed in vacuo.
The residue was purified by chromatography over silica gel (eluent
25% ether–petrol) to yield the title compound as a colourless oil
(928 mg, 89%): mmax/cm−1 2978, 2936, 2825, 1568, 1480, 1426, 1394,
1350, 1323, 1235, 1195, 1163, 1105, 1010, 921. 1H NMR (CDCl3,
300 MHz,) d 6.83 (1H, s, Ar H), 5.88 (1H, ddt, J = 17.1, 10.3,
(2SR,3aSR,8bSR)-2-Cyclohexyl-4-methylene-3,3a,4,8b-tetra-
hydro-2H-indeno[1,2-b]furan 11
To a solution of 9 (50 mg, 0.15 mmol) in acetonitrile (1.5 ml)
was added triphenylphosphine (79 mg, 0.30 mmol), triethylamine
(0.04 ml, 0.30 mmol) and palladium acetate (l mg, 3 mol%). The
resulting dark solution was refluxed for 16 h, allowed to cool to
room temperature and the reaction quenched with a saturated
solution of NaHCO3 (5 ml). This solution was extracted with
EtOAc (5 × 5 ml) and the combined organic extracts washed with
brine (15 ml), water (l5 ml), dried (MgSO4), filtered and the solvent
removed in vacuo. The residue was purified by chromatography
over silica gel (eluent 1% ether–petrol) to yield 11 (32 mg, 84%)
=
=
6.8 Hz, CH CH2), 5.13–5.05 (2H, m, CH2 CH), 4.65 (1H, dd,
J = 8.3, 4.0 Hz, CHO), 3.90, 3.89, 3.87, 3.27 (4 × 3H, s, CH3O),
2.49–2.44 (1H, m, 1H of CH2CHO), 2.39–2.33 (1H, m, 1H of
CH2CHO). 13C NMR (CDCl3, 75 MHz) d 153.2, 150.5, 142.2,
136.5, 134.6, 117.0, 109.1, 105.6, 81.9, 61.1, 61.0, 57.2, 56.2, 41.1.
HRMS (ES): m/z calc. for [M + Na]+: C14H1979BrNaO4 requires
353.0359. Found 353.0362.
as a clear oil. mmax/cm−1 2962, 1642, 1266, 1071, 740. H NMR
(CDCl3, 250 MHz) d 7.51–7.45 (2H, m, ArH), 7.35–7.21 (2H,
m, ArH), 5.52 (1H, d, J 1.9, Ar–C CHH ), 5.05 (1H, d, J 7.6,
ArCHO), 5.05 (1H, d, J 1.9, Ar–C CHH ), 3.68 (1H, ddd, J 10.1,
7.8, 5.0, CH–C C), 3.60 (1H, app. p, J 7.6, CyCHO), 2.36 (1H,
ddd, J 12.4, 9.4, 5.0, CHH CCC C), 1.94–1.89 (1H, m, CH of
1
ꢀ
=
1,4,5,6-Tetramethoxy-3-(methylene)indan 13
ꢀ
=
To a solution of 12 (60 mg, 0.18 mmol) in MeCN (2.2 ml) was
added potassium carbonate (150 mg, 1.09 mmol), triphenylphos-
phine (19.0 mg, 40 mol%) and palladium acetate (4.1 mg, 10
mol%). The resulting dark solution was heated under reflux for
27 h, allowed to cool to room temperature and the reaction
quenched with a saturated solution of NaHCO3 (6 ml). This
solution was extracted with Et2O (3 × 6 ml) and the combined
organic extracts washed with brine (15 ml), water (15 ml), dried
(MgSO4), filtered and the solvent removed in vacuo. The residue
was purified by chromatography over silica gel (eluent 20% ether–
petrol) to yield the title compound as a colourless oil (36 mg, 80%):
mmax/cm−1 2936, 2823, 1599, 1470, 1417, 1354, 1328, 1109, 1064,
=
ꢀ
=
ꢀ
=
Cy), 1.67–1.40 (7H, m, 3 × CH2 and CHH CC C), 1.41–1.21
(4H, m, 2 × CH2). 13C NMR (CDCl3, 62.5 MHz) d 141.2, 138.6,
129.0, 128.7, 127.3, 126.1, 122.5, 104.3, 87.0, 84.1, 42.5, 37.4, 30.3,
29.1, 26.5, 25.9. m/z (CI+/NH3) 272 (M + NH4), 255 (M + H), 237,
171, 143, 129. HRMS (CI+/NH3): m/z calc. for [MH]+: C18H23O
requires 255.1749. Found 255.1759.
1-(2-Bromo-3,4,5-trimethoxyphenyl)but-3-en-1-ol
To a solution of 2-bromo-3,4,5-trimethoxybenzaldehyde (935 mg,
3.40 mmol) in Et2O (35 ml) at −15 ◦C was added a 1.0 M solution
of allylmagnesium bromide in Et2O (5.10 ml, 5.10 mmol) slowly.
The reaction was allowed to warm to room temperature and
stirred for 3 h. The reaction was cooled to 0 ◦C, a saturated
solution of NH4Cl (22 ml) slowly added and the flask warmed
to room temperature. This solution was extracted with Et2O (2 ×
60 ml) and the combined organic extracts dried (MgSO4), filtered
and the solvent removed in vacuo. The residue was purified by
chromatography over silica gel (eluent 40% EtOAc–petrol) to yield
the title compound as a colourless oil (997 mg, 93%): mmax/cm−1
3435, 2938, 1569, 1481, 1426, 1394, 1324, 1195, 1162, 1105, 1009.
1H NMR (CDCl3, 500 MHz,) d 6.97 (1H, s, Ar H), 5.95–5.86
1
1029. H NMR (CDCl3, 500 MHz,) d 6.76 (1H, s, Ar H), 5.75
=
(1H, app. q, J = 2.0 Hz, 1H of CH2 C), 5.11 (1H, app. q, J =
=
1.5 Hz, 1H of CH2 C), 4.81 (1H, dd, J = 6.9, 3.6 Hz, CHO), 3.92,
3.89, 3.87, 3.40 (4 × 3H, s, CH3O), 3.02 (1H, ddt, J = 16.4, 6.9,
1.9 Hz, 1H of CH2CHO), 2.72 (1H, ddt, J = 16.4, 3.6 and 1.9 Hz,
1H of CH2CHO). 13C NMR (CDCl3, 75 MHz) d 153.4, 149.2,
143.4, 141.6, 140.3, 124.9, 105.3, 102.6, 80.2, 59.9, 58.9, 55.0, 54.9,
38.3. HRMS (ES): m/z calc. for [M + Na]+: C14H18NaO4 requires
273.1097. Found 273.1085.
(2SR,3aSR,8bSR)-4,5,6-Trimethoxy-2-propyl-3,3a,4,8b-tetra-
hydro-2H-indeno[1,2-b]furan-4-one 6
=
(1H, ddt, J = 17.1, 10.3, 6.8 Hz, CH CH2), 5.24–5.19 (2H, m,
To a solution of the olefin 7 (91 mg, 0.3 mmol) in acetone–
water (8:5, 3 ml) was added N-methylmorpholine-N-oxide (39 mg,
0.33 mmol) and a 5% solution of OsO4 in t-BuOH (0.05 ml). The
resulting solution was stirred for 16 h at room temperature until
no more starting material was visible by TLC. At this point KIO4
(76 mg, 0.33 mol) was added and the solution was stirred for
=
CH2 CH), 5.10 (1H, dt, J = 8.6, 3.0 Hz, CHO), 3.89 (6H, s, 2 ×
CH3O), 3.88 (3H, s, CH3O), 2.66–2.62 (1H, m, 1H of CH2CHO),
2.34–2.27 (1H, m, 1H of CH2CHO), 2.19 (1H, d, J = 3.0 Hz, OH).
13C NMR (CDCl3, 75 MHz) d 153.0, 150.4, 142.1, 138.5, 134.5,
118.9, 107.8, 105.8, 71.8, 61.1, 61.0, 56.1, 42.2. HRMS (ES): m/z
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another 40 min. The reaction was then quenched by the addition of
a saturated sodium thiosulfate solution (10 ml) and extracted with
EtOAc (4 × 10 ml). The combined organic extracts were washed
with brine (20 ml), water (20 ml), dried (MgSO4) and the solvent
removed in vacuo. The residue was purified by chromatography
on silica gel (eluent 50% ether–hexane) to yield 6 as a yellow
oil (68 mg, 67%). mmax/cm−1 2916, 2815, 1714, 1596, 1294, 1204,
1006, 840. H NMR (CDCl3, 250 MHz) d 6.89 (1H, s, Ar-H),
5.30, (1H, d, J 6.6, ArCHO), 4.09–4.03 (1H, m, C3H7CHO), 4.01
(3H, s, OMe), 3.96 (3H, s, OMe), 3.92 (3H, s, OMe), 3.39 (1H,
petrol) to yield 18 as a white crystalline solid (160 mg, 70%).
Mp 89 ◦C. mmax/cm−1 2958, 2361, 1713, 1569, 1483, 1165, 930.
1H NMR (CDCl3, 250 MHz) d 6.99 (1H, s, Ar-H), 5.38 (1H,
d, J 4.3, ArCHCO), 4.11–4.01 (1H, m, C3H7CHO), 3.88 (3H, s,
OMe), 3.87 (3H, s, OMe), 3.86 (3H, s, OMe), 3.12 (1H, ddd, J
9.8, 4.3, 2.5, CHCOMe), 2.26 (3H, s, COMe), 2.10 (1H, ddd, J
ꢀ
=
15.0, 5.3, 2.5, CHH CC O), 1.82–1.73 (1H, ddd, J 15.2, 9.6, 3.0,
1
ꢀ
=
CHH CC O), 1.62–1.20 (4H, m, -(CH2)2), 0.99 (3H, t, 7.3, Me).
13C NMR (CDCl3, 62.5 MHz) d 208.0, 152.8, 150.2, 142.2, 137.6,
l08.0, 106.4, 81.2, 79.2, 77.6, 76.6, 60.9, 55.9, 54.4, 36.7, 35.1, 30.7,
19.4. m/z (CI+/NH3) 420/418 (M + NH4, 81Br/79Br), 402/400
(MH, 81Br/79Br), 343/341, 195, 172, 155. HRMS (CI+/NH3): m/z
calc. for [M + NH4]+: C18H2981BrNO5 requires 420.1208. Found
420.1183. Further elution gave 19 as a white solid (11 mg, 7%).
Mp 67 ◦C. mmax/cm−1 3128, 3067, 1735, 1600, 1584, 1548, 1010.
1H NMR (CDCl3, 250 MHz) d 9.04 (1H, dd, J 4.2, 5.6 CHO),
6.84 (1H, s, Ar-H), 5.26 (1H, d, J 6.7, ArCHCO), 3.92–3.86 (1H,
m, C3H7CHO), 3.88 (3H, s, OMe), 3.87 (6H, app. s, OMe), 3.26
=
app. dt, J 10.4, 6.7, -CHC O), 2.41 (1H, ddd, J 10.4, 7.6, 5.3,
ꢀ
ꢀ
=
=
CHH CC O), 1.83–1.38 (5H, m, CHH CC C and -(CH2)2), 0.98
(3H, t, J 7.1, Me). 13C NMR (CDCl3, 62.5 MHz) d 200.4, 163.4,
150.0, 141.2, 139.6, 130.1, 128.1, 104.1, 83.9, 79.6, 61.4, 56.1, 52.9,
37.3, 36.4, 34.5, 19.4. mlz (CI+/NH3) 307 (M + H), 235, 61. HRMS
(CI+/NH3): m/z calc. for [M + H]+: C17H23O5 requires 307.1545.
Found 307.1551.
(1H, ddd, J 12.3, 6.3, 4.0, CHHꢀCO), 3.14 (1H, ddd, J 12.3, 7.2,
4.6, CHH CO), 2.53 (1H, m, CHCC O), 2.15 (1H, ddd, J 14.8,
8.4, 5.3, CHH CCC O), 1.87–1.32 (5H, m, CHH CCC O and
-(CH2)2), 0.96 (3H, t, J 6.9, Me). m/z (CI+/NH3) 420/418 (M +
NH4, 81Br and 79Br), 402/400 (M + H, 81Br and 79Br), 343/341,
300, 172, 155. HRMS (CI+/NH3): m/z calc. for [M + NH4]+:
C18H2981BrNO5 requires 420.1208. Found 420.1198.
(2SR,3aRS,9bRS)-6,7,8-Trimethoxy-2-propyl-2,3,3a,9b-tetra-
hydro-4H-furo[3,2-c]-1-benzopyranone 17
ꢀ
=
ꢀ
ꢀ
=
=
To ketone 6 (20 mg, 0.065 mmol) in DCM (6 ml) at 0 ◦C was
added NaHCO3 (11 mg, 0.13 mmol) and meta-chloroperbenzoic
acid (87 mg, 0.13 mmol). The solution was stirred at 0 ◦C for
4 h before being allowed to warm to room temperature overnight.
Brine (5 ml) was added and the mixture extracted with DCM (5 ×
5 ml). The combined organic fractions were washed with brine
(10 ml), water (10 ml), dried (MgSO4) and the solvent removed
in vacuo. The residue was purified by chromatography over silica
gel (eluent 40% ether–petrol) to yield 17 as a white solid (16 mg,
(2SR,3E,5SR)- and (2SR,3Z,5SR)-2-(2-Bromo-3,4,5-trimethoxy-
phenyl)-2-chloroethylidene-5-propyltetrahydrofuran 20
A solution of 5 in CCl4 (8 ml) was cooled to 0 ◦C, and a
solution of phenylselenenyl chloride (240 mg, 1.25 mmol) in
CCl4 (2 ml) added dropwise over 10 min. The reaction mixture
was allowed to stir at 0 ◦C for 30 min, and then cooled to
◦
76%). Mp 82 C. mmax/cm−1 2957, 1761, 1651, 1593, 1470, 1143,
754. 1H NMR (CDCl3, 250 MHz) d 6.70 (1H, s, Ar-H), 4.78, (1H,
d, J 6.1, ArCHO), 4.06–3.98 (1H, m, C3H7CHO), 3.95 (3H, s,
◦
OMe), 3.90 (3H, s, OMe), 3.85 (3H, s, OMe), 3.28 (1H, ddd, J 9.2,
−30 C. Pyridine (100 ll, 1.32 mmol) was then added, followed
ꢀ
=
=
6.1, 4.7, -CHC O), 2.59 (1H, ddd, J 13.0, 7.7, 9.0, CHH CC O),
by aqueous hydrogen peroxide (27.5%, 1.00 ml). The reaction was
stirred vigorously for 2 h while being allowed to warm to room
temperature. Water (30 ml) was then added, and the solution
extracted with DCM (2 × 30 ml). The combined organic extracts
were evaporated in vacuo, and purified by flash chromatography
over silica gel (eluent ether–petrol 1 : 7) to afford 3 products
of elimination of the intermediate chloroselenide. First to be
eluted was (2SR,3SR,5SR)-2-(2-bromo-3,4,5-trimethoxyphenyl)-
3-(1-chloroethylidene)-5-propyltetrahydrofuran (119 mg, 24%).
mmax/cm−1 2960, 2938, 2873, 1569, 1482, 1395, 1363, 1330, 1237,
1198, 1107, 1011. 1H NMR (CDCl3, 250 MHz) d 6.72 (1H, s, Ar-
H), 5.81 (1H, dd, J 13.2, 0.5, CHCl), 5.24 (1H, dd, J 13.2, 10.1,
ꢀ
=
2.58 (1H, ddd, J 13.0, 7.4, 4.7, CHH CC O), 1.61–1.18 (4H, m,
-(CH2)2), 0.93 (3H, t, J 7.2, Me). 13C NMR (CDCl3, 62.5 MHz)
d 175.8, 159.4, 158.6, 155.6, 152.0, 148.9, 149.8, 75.2, 74.3, 61.3,
55.6, 52.9, 41.3, 35.2, 23.5, 22.4, 14.0. m/z (CI+/NH3) 323 (M +
H), 219, 203, 139, 105. HRMS (CI+/NH3): m/z calc. for [M +
H]+: C17H23O6 requires 323.1495. Found 323.1496.
(2SR,3RS,5SR)-2-(2-Bromo-3,4,5-trimethoxy)phenyl-3-(1-oxo-
ethyl)-5-propyltetrahydrofuran 18 and (2SR,3SR,5SR)-2-(2-
bromo-3,4,5-trimethoxy)phenyl-3-(2-oxoethyl)-5-propyltetra-
hydrofuran 19
=
CH CCl), 5.13 (1H, d, J 7.6, ArCHO), 3.88 (1H, m, C3H7CHO),
=
To a solution of 5 (152 mg, 0.4 mmol) in THF–water (3 : 1,
3.4 ml) was added mercury(II) acetate (128 mg, 0.4 mmol) in
a single portion. The resulting yellow suspension was stirred
for 48 h at room temperature until no more starting material
was visible by TLC. A mixture of palladium acetate (30 mg,
0.26 mmol) and copper(II) chloride (204 mg, 1.20 mmol) was
added and the mixture stirred for a further 12 h. The reaction
was quenched by the addition of a saturated solution of NaHCO3
(10 ml) and extracted with EtOAc (4 × 10 ml). The combined
organic extracts were washed with brine (10 ml), water (10 ml),
dried (MgSO4) and the solvent removed in vacuo. The residue
was purified by chromatography on silica gel (eluent 12% EtOAc–
3.87 (3H, s, OMe), 3.82 (6H, s, OMe), 3.37 (1H, m, CHC C),
ꢀ
=
2.27 (1H, ddd, J 14.3, 8.3, 6.0, CHH CCC C), 1.31–1.69 (5H,
m, CHH CCC C and -(CH2)2), 0.96 (3H, t, J 7.2, Me). 13C
ꢀ
=
NMR (62.9 MHz; CDCl3) d 152.6, 150.6, 142.1, 134.5, 133.4,
107.9, 117.2, 106.7, 81.7, 78.8, 61.1, 56.1, 43.9, 38.6, 37.5, 19.4,
14.2 (two MeO signals overlapped). m/z (CI+/NH3) 438/436
(M[35Cl81/79Br] + NH4), 421/419 (M[35Cl81/79Br] + H), 276/274.
HRMS m/z (CI+/NH3) calc. for [M + NH4]+: C18H28NO435Cl81Br
requires 438.0870. Found 438.0867. Further elution afforded E-20
(206 mg, 42%) mmax/cm−1 2952, 2938, 2860, 1685, 1587, 1568, 1483,
1392, 1338, 1239, 1196, 1165, 1106. 1H NMR (CDCl3, 250 MHz) d
=
6.74 (1H, s, ArH), 5.65 (1H, br s, ArCHO), 5.35 (1H, m, C CH),
4124 | Org. Biomol. Chem., 2006, 4, 4118–4126
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4.06 (1H, m, C3H7CHO), 4.02 (2H, br d, J 7.9, CH2Cl), 3.89
(3H, s, OMe), 3.88 (3H, s, OMe), 3.83 (3H, s, OMe), 2.87 (1H, br
(CDCl3, 250 MHz) d 7.05 (1H, s, Ar CH), 4.97 (1H, d, J 3.7,
CHAr), 4.71 (1H, ddt, J 2.5, 6.8, 3.7, CHOH), 4.00 (1H, app. p,
J 6.8, CHPr), 3.88 (3H, s, OMe), 3.87 (3H, s, OMe), 3.86 (3H, s,
OMe), 2.48 (1H, app. p, J 7.0, ring CHH), 1.34–1.81 (5H, m,
ring CHH + CH2CH2), 1.21 (1H, d, J 3.7, OH), 0.97 (3H, t, J
7.2, CH2CH3). 13C NMR (CDCl3, 62.5 MHz) 152.8, 150.5, 142.4,
132.1, 107.4, 108.2, 71.8, 77.7, 84.3, 61.0, 56.0, 40.5, 38.3, 19.4,
14.2 (two aliphatic carbon signals overlapped). m/z (CI+/NH3)
392/394 (M + NH4), 374/376 (M + H), 277, 275, 168. HRMS
(CI+/NH3): m/z calc. for [M + NH4]+: C16H27NO579Br requires
392.1073. Found 392.1082.
ꢀ
ꢀ
=
=
dd, J 5.8, 16.1, CHH C C), 2.36 (1H, m, CHH C C), 1.45–1.78
(4H, m, -(CH2)2), 0.98 (3H, t, J 7.2, Me). 13C NMR (62.5 MHz;
CDCl3) d 153.0, 150.5, 148.1, 142.9, 135.4, 118.0, 109.8, 107.6,
81.9, 77.7, 61.0, 56.0, 42.0, 37.3, 35.5, 19.1, 14.2 (two MeO
signals overlapped). m/z (CI+/NH3) 438/436 (M[35Cl81/79Br] +
NH4), 421/419 (M[35Cl81/79Br] + H), 385/383, 340, 305. HRMS
(CI+/NH3): m/z calc. for [M + H]+: C18H25O435Cl81Br requires
421.0604. Found 421.0604. Eluting last was Z-20 (36 mg, 8%).
mmax/cm−1 2962, 2933, 2869, 1679, 1569, 1481, 1459, 1450, 1427,
1394, 1332, 1240, 1195, 1164, 1106, 1012, 975, 925, 842, 738.
1H NMR (CDCl3, 250 MHz) d 6.69 (1H, s, Ar-H), 5.80 (1H,
(2SR,3aRS,9bRS)-6,7,8-Trimethoxy-2-propyl-2,3,3a,9b-tetra-
hydro-5H-furo[3,2-c]benzopyran-5-one (monocerin methyl
ether, 23)
=
br s, CHAr), 5.45 (1H, app. tq, J 7.9, 2.4, C CH), 4.37 (1H, m,
C3H7CHO), 4.06 (2H, br d, J 7.9, CH2Cl), 3.83 (3H, s, OMe),
3.87 (3H, s, OMe), 3.89 (3H, s, OMe), 2.93 (1H, ddt, J 16.2,
A solution of 22 (4.1 mg, 10.9 mmol) in THF (1 ml) was cooled to
−40 ◦C. A solution of LiHMDS (1 N in THF, 30 ll, 0.030 mmol)
was then added dropwise, and the solution allowed to warm
to −30 ◦C over 10 min, before being cooled to −60 ◦C. n-
Butyllithium (20 ll of a 2 N solution in pentane, 0.040 mmol)
was then added dropwise, and the solution allowed to stir for
20 min. Methyl chloroformate (50 ll, 60 mg, 0.650 mmol) was
then added dropwise, and the solution allowed to warm to room
temperature. After 3 h, the reaction was quenched by the addition
of water (5 ml) and the solution extracted with DCM (2 × 10 ml).
The combined organic extracts were then evaporated and purified
by flash chromatography over silica gel (eluent ether–petrol 3 :
1) to afford 23 (2.8 mg, 80%), whose NMR data matched that
reported in the literature.5
ꢀ
ꢀ
=
=
7.0, 1.6, CHH C), 2.45 (1H, br d, J 17.8, CHH C), 1.35–1.75
(4H, m, -(CH2)2), 0.96 (3H, t, J 7.1, Me). m/z (CI+/NH3) 438/436
(M[35Cl81/79Br] + NH4), 421/419 (M[35Cl81/79Br] + H+), 402. HRMS
m/z (CI+/NH3) calc. for [M + NH4]+: C18H28NO435Cl81Br requires
438.0870. Found: 438.0864.
(2RS,5SR)-2-(2-Bromo-3,4,5-trimethoxyphenyl)-5-propyltetra-
hydrofuran-3-one 21
A solution of 20 (305 mg, 0.73 mmol) in DCM (20 ml) was
◦
cooled to −78 C, and ozone bubbled through until a pale blue
colour was clearly visible. The ozoniser was then turned off
and oxygen allowed to bubble through the solution for 10 min.
Triphenylphosphine (200 mg, 0.76 mmol) was added in a single
portion and the solution allowed to warm to room temperature
and stir for 16 h. The reaction mixture was then evaporated
in vacuo, and purified by flash chromatography over silica gel
(eluent 25% ether–petrol) to afford 21 (129 mg, 48%) as a
colourless oil. mmax/cm−1 2958, 2935, 2871, 1760, 1587, 1569, 1483,
1452, 1394, 1351, 1238, 1197, 1145, 1108, 1008, 975, 831. 1H
NMR (CDCl3, 250 MHz) d 6.68 (1H, s, Ar-H), 5.15 (1H, br s,
ArCHO), 4.33 (1H, app. sextet, J 5.7, C3H7CHO), 3.89 (3H, s,
OMe), 3.86 (3H, s, OMe), 3.84 (3H, s, OMe), 2.67 (1H, dd, J 18.1,
5.6, CHHꢀCO), 2.38 (1H, dd, J 18.1, 10.6, CHHꢀCO), 2.01–1.70 &
1.54–1.39 (2 × 2H, m, CH2CH2), 1.01 (3H, t, J 7.3, Me). 13C NMR
(CDCl3, 62.5 MHz) d 212.1, 152.9, 151.2, 143.4, 130.7, 110.4,
108.1, 83.3, 75.6, 61.0, 56.1, 42.9, 37.5, 18.7, 14.1 (two aliphatic
carbon signals overlapped). m/z (CI+/NH3) 390/392 (M + NH4),
372/374 (M + H), 262/264, 210. HRMS (CI+/NH3): m/z calc. for
[M + NH4]+: C16H25NO581Br requires 392.0896. Found. 392.0897.
( )-Monocerin 15
A solution of 23 (2.4 mg, 7.4 lmol) was dissolved in DCM (1 ml)
and cooled to −30 ◦C. Boron tribromide (80 ll of a 0.92 M
solution in DCM, 7.4 lmol) was then added and the solution
allowed to warm to −20 ◦C. After 90 min, TLC indicated complete
consumption of starting material, and the reaction was quenched
by the addition of a saturated solution of NaHCO3 (2 ml). Water
(2 ml) was then added and the mixture extracted with DCM
(2 × 10 ml). The combined organic extracts were combined and
evaporated, and the residue purified by flash chromatography over
silica gel (eluent EtOAc–petrol 1 : 3) to afford ( )-monocerin 1
(1.3 mg, 57%) as a film, whose NMR data matched that reported
in the literature.5
Acknowledgements
(2RS,3RS,5SR)-2-(2-Bromo-3,4,5-trimethoxyphenyl)-3-hydroxy-
5-propyltetrahydrofuran 22
We are grateful to Professor Ron Grigg (University of Leeds) for
helpful discussions regarding the Heck chemistry. We thank the
EPSRC/GlaxoSmithKline (CASE award to JHC), EPSRC (DTA
to MS) and Leverhulme Trust (CNF) for financial support and
Pfizer and Merck for generous unrestricted assistance. We also
thank the EPSRC for grant EP/C010973/1, which established the
new high resolution mass spectrometry facilities at Leeds.
To a solution of 21 (52 mg, 0.14 mmol) in methanol (2 ml) at
◦
0 C was added sodium borohydride (10 mg, 0.26 mmol). After
stirring at 0 ◦C for 30 min, the reaction was quenched by the
addition of water (5 ml). The solution was then extracted with
DCM (2 × 10 ml), and the combined organic extracts evaporated
in vacuo. The crude product was purified by flash chromatography
over silica gel (eluent ether–petrol 1 : 2) to afford 22 (46 mg, 88%)
as a colourless oil. mmax/cm−1 3480, 2956, 2869, 1569, 1483, 1465,
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