Regiocontrolled synthesis of the macrocyclic polyamine alkaloid (±)-lunarine, a time-dependent inhibitor of trypanothione reductase

Article abstract of DOI:10.1039/b110149h

A regiocontrolled synthesis of the macrocyclic polyamine alkaloid (±)-lunarine is described. The key steps involve the preparation of the differentially functionalised cis-3-oxo-8-bromo-9b-cyano-1,2,3,4,4a,9b-hexahydrobenzofuranyl tricyclic scaffold 14 wh

Full text of DOI:10.1039/b110149h

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Regiocontrolled synthesis of the macrocyclic polyamine alkaloid
( )-lunarine, a time-dependent inhibitor of trypanothione reductase
Chris J. Hamilton,a Alan H. Fairlambb and Ian M. Eggleston*a
1
a Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences,
Carnelley Building, University of Dundee, Dundee, UK DD1 4HN
b Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences,
Wellcome Trust Biocentre, University of Dundee, Dundee, UK DD1 5EH
Received (in Cambridge, UK) 9th November 2001, Accepted 26th February 2002
First published as an Advance Article on the web 3rd April 2002
A regiocontrolled synthesis of the macrocyclic polyamine alkaloid ( )-lunarine is described. The key steps involve the
preparation of the differentially functionalised cis-3-oxo-8-bromo-9b-cyano-1,2,3,4,4a,9b-hexahydrobenzofuranyl
tricyclic scaffold 14 which, following further elaboration, is coupled to the selectively protected
acrylamidospermidine† 5 via a Heck coupling reaction to give the pre-cyclised lunarine derivative 23.
Introduction
The parasitic protozoa Trypanosoma and Leishmania cause a
number of severely infectious diseases in man and domestic
livestock in tropical countries. These include the often-fatal
South American Chagas’ disease and African sleeping sick-
ness (caused by Trypanosoma cruzi and Trypanosoma brucei
respectively), and kala-azar, oriental sore and espundia (caused
by Leishmania spp.). The parasites are transmitted by blood-
sucking insects and currently there are no vaccines against
the resulting diseases, while existing drug treatments are either
ineffective or rather toxic.
A potential means of controlling trypanosomes and leish-
mania has become apparent through the identification of
a unique feature in their metabolism. They both possess
the metabolite trypanothione (N 1,N 8-bis(glutathionyl)sperm-
idine), which performs many of the protective and anti-oxidant
roles which are associated with glutathione in mammalian cells
(Fig. 1a).1 Furthermore, the parasites do not contain gluta-
thione reductase but instead use the analogous enzyme trypano-
thione reductase (TryR) to maintain trypanothione in the
reduced form which plays a major role in the defence against
reactive oxygen species generated by host cells. Disabling the
function of TryR in Leishmania2 and T. brucei3 has been shown
to markedly increase the parasites’ sensitivity to oxidative
stress.
For some time a variety of molecules have been known to be
inhibitors of TryR, most notably polyamine derivatives4a–c such
as the naturally occurring bis(tetrahydrocinnamoyl)spermine,
kukoamine A.4a More recently, the availability of the X-ray
structure of TryR has allowed the structure-based identification
and development of several interesting small molecule
inhibitors.4d–g In the course of one such study the macrocyclic
polyamine alkaloid lunarine 1 was predicted to be a potential
lead inhibitor (Fig. 1b).5 This was subsequently confirmed
using a sample of naturally occurring lunarine 1, but surpris-
ingly this proved not to be a simple competitive inhibitor,
instead showing time-dependent inhibition kinetics. It was
proposed that the origin of this time-dependent inhibition
stemmed from the covalent modification of TryR through the
Michael addition of an active site of cysteine onto either
C-10 or C-25 of the lunarine macrocycle.5 In view of this, it
† The IUPAC name for spermidine is N-(3-aminopropyl)butane-1,4-
diamine.
Fig. 1
DOI: 10.1039/b110149h
J. Chem. Soc., Perkin Trans. 1, 2002, 1115–1123
1115
This journal is © The Royal Society of Chemistry 2002

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was essential to obtain adequate supplies of lunarine for
more detailed enzyme inhibition studies. Reported herein is a
regioselective synthesis of ( )-lunarine 1 that allows access to
various other Lunaria alkaloids and their analogues.
Results and discussion
The biosynthesis of lunarine has recently attracted some atten-
tion with respect to the formation of the tricyclic “Pummerer
ketone” moiety. Zenk and co-workers6 have demonstrated that
in vitro lunarine is formed by the stereoselective phenolic
oxidative coupling of N 1,N 10-bis(p-coumaryl)spermidine, but
although such a synthetic strategy is conceptually attractive, it
has not so far been successfully realised.7 Similarly, although
oxidative phenolic coupling has been employed in the prepar-
ation of a key intermediate towards the Pummerer ketone unit
in earlier, non-regioselective, syntheses of lunarine 1 and its
regioisomer 2,7,8 in our hands such an approach proved to be
highly inefficient. As these syntheses also did not allow differen-
tial elaboration of the two side-chains at C-8 and C-9b (desir-
able for the preparation of simplified acyclic analogues), we
were prompted to examine other routes which would, inter alia,
permit the regiocontrolled synthesis of lunarine and derivatives.
Our retrosynthetic approach is outlined in Scheme 1a. We aimed
to achieve the regioselective synthesis of lunarine via an intra-
molecular macrolactamisation of a “pre-cyclised” adduct such
as 3. This, in turn, could be prepared from the Heck coupling of
an aryl bromide precursor 4 and the N 1-acrylamidospermidine
derivative 5. The differentially functionalised tricyclic scaffold 4
should also then allow access to a range of valuable analogues
(eg. dihydrolunarine derivatives with selective saturation of one
of the α,β-unsaturated amide moieties found in lunarine).
The key step in the preparation of 4 is an intramolecular
Michael addition upon an α,β-unsaturated ketone, elaborated
via Diels–Alder addition upon a suitable phenolic dienophile
partner. The former step has some precedent in a recent syn-
thesis of the prototypical tricyclic Pummerer ketone scaffold 7
(Scheme 1b)9 that was first described in 1925.10
The pre-cyclisation adduct 13 was prepared as outlined
in Scheme 2. 5-Bromo-2-methoxyacetophenone 9 was quanti-
tatively converted to cyano phosphate 10 by treatment with
diethyl cyanophosphonate in the presence of a catalytic amount
of LDA.11 As significant product loss occurred during chrom-
atographic purification (60% isolated yield), crude 10 (following
work-up) was treated directly with boron trifluoride–diethyl
etherate to give the acrylonitrile adduct 11 in 52% overall
yield.11b The dienophile 11 readily underwent Diels–Alder
cycloaddition with Danishefsky’s diene,12 to give the Diels–
Alder adduct 12 which when treated with catalytic trimethylsilyl
triflate ‡ (TMSOTf )13 gave the desired cyclohexenone 13.
Catalytic TMSOTf was used in lieu of dilute acid hydrolysis to
avoid the predominant formation of the β-methoxy ketone
by-product, which was encountered when 12 was treated with
1 mM aqueous HCl.
Scheme 1
Whilst the methyl ether proved to be an excellent protecting
group in the preceding series of reactions, its removal from 13
prior to intramolecular cyclisation to produce 14 proved to be
very problematic. Treatment of 13 with trimethylsilyl iodide,
under the same reaction conditions used for 6,9 failed to remove
the methyl group. Other deprotection procedures, using lithium
salts14 or various boron trihalides,15 were also tried without
success. Deprotection methods were limited to electrophilic
reagents as nucleophilic reagents, such as cyanide or thiolate
anions, would preferentially react with the enone moiety.
Allyl protection was now chosen as an alternative as this has
been used in similar intramolecular cyclisation procedures to
produce the tricyclic scaffold of the Amaryllidaceae alkaloid
Scheme 2 (i) K2CO3, MeI, acetone, reflux, 3 h; (ii) LDA (cat.),
(EtO)2P(O)CN, THF, Ϫ10 ЊC, 2.5 h; (iii) BF3OEt2, CH2Cl2, 15 min; (iv)
1-methoxy-3-(trimethylsilyloxy)buta-1,3-diene, PhMe–CH2Cl2, reflux,
5 h; (v) TMSOTf, collidine, acetone, Ϫ78 ЊC, 10 min.
‡ The IUPAC name for triflate is trifluoromethanesulfonate.
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J. Chem. Soc., Perkin Trans. 1, 2002, 1115–1123

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lycoramine.16 The new dienophile 16 was prepared from the
o-allyloxy acetophenone 15 in 59% yield without isolation of
the cyano phosphate intermediate (Scheme 3).11 The o-allyloxy
although the reaction had to be maintained at reflux for 21
hours in order to drive it to completion.
Treatment of 17 with either rhodium trichloride,16 palladium/
carbon in the presence of toluene-p-sulfonic acid17 or potas-
sium tert-butoxide followed by acidic work-up18 failed to effect
the clean removal of the allyl ether group. However, on reaction
of 17 with a catalytic amount of tetrakis(triphenylphosphine)-
palladium() in the presence of an excess of morpholine at
room temperature19 the allyl ether was cleanly removed fol-
lowed by intramolecular cyclisation to give the racemic fused
tricyclic product 14 in 74% yield. An original concern with this
procedure was that under these Heck-type reaction conditions
the palladium catalyst would be inactivated by preferential
complexation with the aryl bromide functionality of 17. How-
ever, at room temperature the palladium catalysed isomeris-
ation of the allyl ether proved to be a more favourable reaction.
Compound 14 was recrystallised from dichloromethane and
an X-ray structure was obtained in order to verify the relative
stereochemistry across the fused ring junction (Fig. 2). As
Fig. 2 Molecular structure of 14 showing 50% probability ellipsoids
Scheme 3 (i) NaH, allyl bromide, DMF, 0–20 ЊC, 12 h; (ii) LDA (cat.),
(EtO)2P(O)CN, THF, Ϫ10 ЊC, 2 days; (iii) BF3OEt2, CH2Cl2, 10 min;
(iv) 1-methoxy-3-(trimethylsilyloxy)buta-1,3-diene, CH2Cl2–PhMe
reflux, 6.5 h, then TMSOTf, collidine, acetone, Ϫ78 ЊC, 20 min; (v)
(PPh3)4Pd(), morpholine, THF, 30 min; (vi) (TMSOCH2)2, TMSOTf,
CH2Cl2, Ϫ78 to 0 ЊC, 4.5 h; (vii) DIBAL-H, CH2Cl2, Ϫ10 ЊC, 20 min;
(viii) NaH, triethyl phosphonoacetate, THF, 2 h.
anticipated, the crystal structure of 14 shows the desired cis
stereochemistry of the nitrile and H-4a at the fused ring junc-
tion. It is interesting to note that the cyclohexanone component
sits in a skew-boat conformation20 comparable to that of lun-
arine 1;21 a factor which we believe plays an important part in
determining the effectiveness of some other Lunaria alkaloid
derivatives as time-dependent inhibitors of TryR. It should be
noted that during scale-up preparations it was possible to com-
plete the 4-step preparation of compound 17, from 8, on a
multi-gram scale without the need for intermediate purification
(other than standard work-up procedures). In this manner the
overall yield of 17 was increased to 58% (compared to 14%
when purification was carried out at each step).
Standard acid catalysed preparation of the 1,3-dioxolane 18
using ethylene glycol under Dean–Stark conditions gave very
poor yields, but the trimethylsilyl triflate catalysed reaction
of 14 with 1,2-bis(trimethylsilyloxy)ethane22 proved to be
extremely effective giving 18 in 94% yield. Conversion of nitrile
18 to the aldehyde 19 was effected in modest but accept-
able yield (32%) using DIBAL-H. This step, which was not
optimised, was followed by Wadsworth–Emmons reaction with
triethyl phosphonoacetate23 to give the α,β-unsaturated ethyl
ester 20, in 72% yield. As outlined above, compound 20, with its
readily differentiable aryl bromide and carboxy functions, is not
only a key intermediate for the present synthesis of lunarine 1,
but also for the preparation of various cyclic and acyclic lunar-
ine analogues where the acrylamido ‘side chains’ of the tricyclic
core have been selectively modified. The synthesis of such
compounds and their use as mechanistic probes to determine
the nature of TryR inhibition by lunarine 1 will be reported
elsewhere.27
substituent in 15 appeared to significantly retard the rate of
reaction with diethyl cyanophosphonate to give the intermed-
iate cyano phosphate derivative. This reaction took 2 days to
reach completion when using 1.5 equivalents of diethyl cyano-
phosphonate compared with the 2.5 hours that were required
for the preparation of the o-methoxy derivative 10. Larger
excesses of diethyl cyanophosphonate have been used to
accelerate such sluggish reactions11 and in this example the
reaction time was reduced to 5 hours by increasing the diethyl
cyanophosphonate quantity to just 2.5 equivalents. At room
temperature, compound 16 gradually degraded over several
days to give an insoluble resin, and since storage at Ϫ20 ЊC
failed to retard this process, 16 was promptly converted after
purification to the more stable cyclohexenone 17.12,13 For this
reaction, the dienophile 16 proved to be soluble in dichloro-
methane but insoluble in higher boiling point solvents like
toluene. The low boiling point of dichloromethane made it an
unsuitable solvent for this thermally driven reaction, so a co-
solvent mixture of dichloromethane and toluene was initially
used. The low yield (27%) obtained at this stage was therefore
due to the difficulty in achieving an appropriate balance
between reagent solubility and reaction temperature. Because
16 was also soluble in the higher boiling point solvent chloro-
form, this was used in the scale-up preparations (see below)
J. Chem. Soc., Perkin Trans. 1, 2002, 1115–1123
1117

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The selectively protected spermidine precursor 21 was pre-
pared according to the method of Humora and Quick (Scheme
4).24 These authors used lithium aluminium hydride to reduce
Scheme 4 (i) Raney nickel (cat.), NaOH, EtOH, H2 (40 psi), 24 h;
(ii) acryloyl chloride, DMAP, Et3N, CH2Cl2, 16 h.
the nitrile 21 to the primary amine 22, but in our hands this
method gave very poor results. Hydrogenation of 21 in the
presence of Raney nickel under basic conditions was much
more satisfactory and gave excellent recovery of essentially
pure product 22 following a simple work-up.25 Reaction of
22 with acryloyl chloride in dichloromethane then gave the
fully protected acrylamidospermidine 5 in 50% overall yield
from 21.
Scheme 5 (i) Pd(OAc)2, 5, Et3N, (o-Tol)3P, DMF, 60 ЊC, 11 h; (ii)
LiOH, EtOH (aq), 8 h; (iii) C6F5OH, EDC, DMAP (cat.), CH2Cl2, 15 h;
(iv) 4 M HCl in dioxane; (v) DIPEA, CH2Cl2, 21 h.
In conclusion, the first regiocontrolled synthesis of racemic
lunarine 1 has been achieved. The strategy employed is now
being used for the preparation of a range of lunarine deriv-
atives and may also be employed for the asymmetric synthesis
of such compounds. Racemic lunarine 1 and the dioxolane 26
are now being evaluated against TryR as part of our ongoing
studies on the anti-trypanosomal properties of the Lunaria
alkaloids. These results will be reported elsewhere.27
The final functionalisation of the tricyclic scaffold 20 via a
Heck coupling with the acrylamidospermidine fragment 5 pro-
ceeded smoothly within three hours at 60 ЊC to give 23 in 70%
yield (Scheme 5). In this reaction, tri-o-tolylphosphine was used
as a palladium ligand to minimise the occurrence of unwanted
side-reactions that are sometimes encountered when electron-
rich para-substituted aryl bromides are employed in Heck
coupling procedures.26 Saponification of 23 then gave the free
acid 24 in 88% yield which was the desired “precyclised” lunar-
ine intermediate. The dioxolane group was retained until this
stage to prevent the β-phenoxyketone functionality from
undergoing a base-induced retro-Michael reaction, followed by
1,4-addition of the resultant phenoxide anion onto the α,β-
unsaturated ester moiety in 23.8 Macrolactamisation of 24 was
achieved by first reacting the free acid with pentafluorophenol
in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodi-
imide hydrochloride (EDC) to give the activated penta-
fluorophenyl ester. Following work-up, and without further
purification, the N-Boc protecting groups were removed using
4 M HCl in anhydrous dioxane. Excess HCl was removed from
theresultingaminesaltbyrepeatedcoevaporationwithdichloro-
methane followed by drying of the solid under high vacuum for
several hours. Intramolecular cyclisation was then induced by
treating this salt with a large excess of N,N-diisopropylethyl-
amine (DIPEA) in dichloromethane under high dilution con-
ditions (concentration of the pre-cyclised product was 0.9 mM).
Within 16 hours the cyclisation was deemed complete (by TLC)
and following purification, by chromatography, racemic lunar-
ine 1 was isolated in 28% yield. A small quantity of the 1,3-
dioxolane derivative 25 was also recovered (9%). The relative
ease of formation of this 20-membered macrocycle is presum-
ably due to the rigidity of the tricyclic scaffold which helps
maintain a pre-cyclised conformation which is amenable to
Experimental
General
Melting points were recorded on an Electrothermal IA9000
series digital melting point apparatus, using open capillaries,
1
and are quoted uncorrected. NMR Spectra: H-NMR spectra
were recorded on a Bruker Avance DPX 300 FT-spectrometer
at 300 MHz, 13C-NMR were recorded on the same spectro-
meter at 75 MHz. All NMR spectra were taken at 300 K, except
where specified. Chemical shifts (δ) are expressed in ppm and
coupling constants (J) are given in Hz. Mass spectra were
recorded on a VC 70-S double focusing mass spectrometer
in fast atom bombardment (FAB) and electron impact (EI)
modes. Electrospray mass spectra were carried out on a
VG Quattro triple quadrupole mass spectrometer. Elemental
analyses were carried out by Medac Ltd, Brunel Science
Centre, Surrey, UK. Flash Chromatography was performed on
columns of silica gel (Fluorochem, Silica Gel 60; 40–63 µ).
Petroleum ether(bp 40–60 ЊC, referred to as petrol) was distilled
through a Vigreux column prior to use. Anhydrous acetone was
prepared by stirring over B2O3 for 12 h prior to distillation and
storage under nitrogen. Collidine was distilled from CaH2 and
stored over 3 Å molecular sieves at Ϫ18 ЊC. Triethylamine
was distilled from CaH2 and stored under nitrogen at room
temperature. All other solvents were dried using standard
procedures.
macrolactamisation. Lunarine 1 was indistinguishable (1H, 13
NMR) from an authentic sample of natural (ϩ)-lunarine.
C
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N-(3-acrylamidopropyl)-N,N-bis(tert-butoxycarbonyl)butane-
1,4-diamine (5)
(C-6), 133.93 (C-4), 134.30 (᎐CH ), 156.65 (C-2); [Found:
᎐
2
(EI) 236.97760, C10H8BrNO requires 236.97893] m/z 237 (38%,
Mϩ), 222 (20, M Ϫ CH3), 211 (9, M Ϫ CN), 143 (100, M Ϫ
CH3 Ϫ Br).
A solution of 22 (570 mg, 1.65 mmol), triethylamine (1.8 cm3,
12.91 mmol) and DMAP (2 mg, 0.017 mmol) in anhydrous
dichloromethane (8 cm3), at 0 ЊC, was treated with a solution of
acryloyl chloride (0.15 cm3, 1.85 mmol) in dichloromethane
(2 cm3), added dropwise. The reaction mixture was slowly
allowed to warm to room temperature whilst stirring overnight.
It was then washed with 5% aqueous citric acid and brine, dried
(Na2SO4) and the solvent was evaporated to give an oil. This
was purified by chromatography (petrol–EtOAc (2 : 8) eluent)
to give 5 as a viscous colourless oil (367 mg, 56%). νmax(NaCl)/
cmϪ1 3480–3200 (NH), 3075 (CH᎐CH ), 1724–1625 (C᎐O), 989
4-(2-Methoxy-5-bromophenyl)-4-cyanocyclohex-2-en-1-one (13)
A mixture of 11 (859 mg, 3.61 mmol) and 1-methoxy-3-
(trimethylsilyloxy)buta-1,3-diene (1.05 cm3, 4.69 mmol) in a
co-solvent mixture of anhydrous toluene (13 cm3) and dichloro-
methane (10 cm3) was heated to reflux under argon for 5 h. The
reaction was cooled to Ϫ78 ЊC and anhydrous acetone (1.3 cm3,
18.05 mmol) was added. A solution of TMSOTf (100 µl,
0.55mmol)andanhydrouscollidine(9µl,0.07mmol)indichloro-
methane (1.4 cm3) was then added via a cannula to give a deep
red solution, which was stirred at Ϫ78 ЊC for 10 min. The reac-
tion mixture was quenched with brine and was extracted with
dichloromethane. The combined organics were dried (MgSO4)
and the solvents evaporated to give a brown oily solid. The
crude product was purified by chromatography (CH2Cl2 eluent)
to give 13 as a white solid (663 mg, 60%). δH (300 MHz, CDCl3)
2.45–2.85 (4H, m, 2 × CH2), 3.91 (3H, s, OCH3), 6.28 (1H, d,
᎐
᎐
2
(CH ᎐CH, def ); δ (300 MHz, CDCl3) 1.44 (9H, s, 3 × CH3),
᎐
2
H
1.46 (9H, s, 3 × CH3), 1.49–1.62 (2H, m, CH2), 1.64–1.80 (4H,
br, 2 × CH2), 3.09–3.22 (4H, br, 2 × CH2), 3.22–3.40 (4H, br, 2 ×
CH ), 4.58 (1H, br, N8–H), 5.62 (1H, d, J 10.2, ᎐CHHtrans), 6.14
᎐
2
(1H, dd, J 16.8, 10.2, ᎐CHH ), 6.28 (1H, d, J 16.8, CH᎐CH ),
᎐
᎐
cis
2
7.05 (1H, br, N1–H); δC (75 MHz, CDCl3) 25.45 (C-6), 27.16,
27.40 (C-7) and (C-2), 28.17 (CH3), 35.56 (C-1), 39.80 (C-8),
43.24 (C-3), 46.42 (C-5), 78.73 (C), 79.48 (C), 125.40 (᎐CH ),
᎐
2
131.21 (CH᎐CH ), 155.91, 156.16 (2 × carbamate C᎐O), 165.50
᎐
᎐
2
J 10.0, ᎐CH-2), 6.89 (1H, d, J 8.7, H-3Ј), 6.95 (1H, dd, J 10.0,
᎐
(amide C᎐O); m/z (FAB) 400 (27%, Mϩ), 300 (37, M ϩ H Ϫ
᎐
0.9, ᎐CH-3), 7.47 (1H, d, J 2.4, H-6Ј), 7.51 (1H, dd, J 8.7, 2.4,
᎐
tBuOCO), 244 (53, M Ϫ (tBuOCO ϩ CH2CH2CO).
H-4Ј); δC (75 MHz, CDCl3) 33.22 (C-5), 35.18 (C-6), 40.52
(C-4), 56.34 (OCH3), 113.70 (C-Br), 114.42 (C-3Ј), 119.17 (CN),
126.79 (C-1Ј), 130.93 (C-2), 131.39 (C-4Ј), 133.72 (C-6Ј), 146.02
5-Bromo-2-methoxyacetophenone (9)
(C-3), 156.46 (C-2Ј), 196.74 (C᎐O); [Found: (EI) 305.0046,
᎐
A mixture of 5-bromo-2-hydroxyacetophenone (6.06 g, 28.0
mmol), potassium carbonate (6.94 g, 70.0 mmol) and methyl
iodide (7 cm3, 113 mmol) in acetone (100 cm3, pre-dried over 4
Å molecular sieves) was heated under reflux for 3 h. The reac-
tion mixture was filtered and the solvents were evaporated to
give an oil. This was re-dissolved in ether and then washed with
water, 0.1 M NaOH and then water once more. The organics
were dried (MgSO4), the solvents evaporated and the crude
material purified by chromatography (petrol–EtOAc eluent
9 : 1) to give 9 as an off-white solid (5.54 g, 86%). δH (300 MHz,
CDCl3) 2.59 (3H, s, CH3), 3.90 (3H, s, CH3O), 6.86 (1H, d, J
8.8, H-3), 7.53 (1H, dd, J 8.8, 2.6, H-4), 7.82 (1H, d, J 2.6, H-6);
δC (75 MHz, CDCl3) 32.11 (CH3), 56.23 (CH3O), 113.50 (C-5),
113.95 (C-3), 130.03 (C-1), 133.33 (C-6), 136.47 (C-4), 158.33
C14H12BrNO2 requires 305.0051] m/z 305 (75%, Mϩ), 198 (95),
127 (100).
cis-3-Oxo-8-bromo-9b-cyano-1,2,3,4,4a,9b-hexahydrodibenzo-
[b,d]furan (14)
Tetrakis(triphenylphosphine)palladium() (2.30 g, 1.99 mmol)
was added, in one portion, to a solution of 17 (9.97 g, 30.01
mmol) and anhydrous morpholine (23 cm3, 263.7 mmol) in
anhydrous THF (250 cm3) under argon. The reaction mixture
was stirred at room temperature for 30 min. Most of the solvent
was then removed and the residue was diluted in ethyl acetate
(100 cm3). The organics were washed with 0.1 M HCl (× 2),
followed by water, dried (MgSO4) and the solvent was evapor-
ated to give a brown oily solid (ca. 15 g). The crude product was
first passed through a thin bed of silica (CH2Cl2 eluent) to give
approximately 10 g of a brown solid, which was further purified
by chromatography (CH2Cl2 eluent). Mixed fractions were
purified by an additional chromatographic step to give 14 as
an off-white solid (6.48 g, 74%). Mp (CH2Cl2) 163–164 ЊC;
νmax(CDCl3)/cmϪ1 2255 (CN), 1732 (C᎐O); δ (300 MHz,
(C-2), 198.62 (C᎐O); [Found: (EI) 227.97873, C H BrO
᎐
9
9
2
requires 227.97859] m/z 227 (30%, Mϩ), 213 (100, M Ϫ CH3).
2-(5-Bromo-2-methoxyphenyl)acrylonitrile (11)
A solution of freshly made LDA (0.351 mmol) in THF (4 cm3)
at Ϫ15 ЊC was added dropwise to a solution of 9 (1.61 g, 7.03
mmol) in THF (10 cm3), pre-cooled to Ϫ15 ЊC, to give a
pale yellow solution. This was stirred at Ϫ15 ЊC for 15 min
before the dropwise addition of neat diethyl cyanophosphonate
(1.38 g, 8.43 mmol) which was then stirred at Ϫ15 to 0 ЊC for
2.5 h. The reaction mixture was quenched (H2O) and then
extracted with ethyl acetate. The combined organics were dried
(MgSO4) and the solvent was evaporated to give the cyano
phosphate intermediate 10 as a light brown oil (2.98 g, quanti-
tative yield). This was dissolved in dichloromethane (20 cm3)
and boron trifluoride–diethyl etherate (2.99 g, 21.06 mmol)
was added dropwise and the reaction was stirred at room
temperature for 15 min. The reaction mixture was diluted with
dichloromethane (30 cm3) and then washed with saturated
aqueous NaHCO3 followed by water. The organics were dried
(Na2SO4), the solvents evaporated and the crude product puri-
fied by chromatography (CH2Cl2 eluent) to give 11 as a pale
yellow oil (872 mg, 52%) that slowly solidified. Mp (CH2Cl2)
163–164 ЊC; δH (300 MHz, CDCl3) 3.91 (3H, s, OCH3), 6.26
᎐
H
CDCl3) 1.95–2.67 (4H, m, 2 × CH2), 2.92 (1H, dd, J 17.3, 3.4,
cis-H-4), 3.03 (1H, dd, J 17.3, 3.4, trans-H-4), 5.43 (1H, t, J 3.4,
H-4a), 6.75 (1H, d, J 8.6, H-6), 7.41 (1H, dd, J 8.6, 2.1, H-7),
7.52 (1H, d, J 2.0, H-9); δC (75 MHz, CDCl3) 32.39 (C-1), 34.78
(C-2), 40.99 (C-4), 43.04 (C-9b), 85.00 (C-4a), 112.79 (C-6),
114.65 (C-Br), 120.53 (CN), 127.65 (C-9), 127.81 (C-9a), 134.72
(C-7), 158.19 (C-5a), 204.78 (C᎐O); [Found: (EI) 290.98595,
᎐
C13H10BrNO2 requires 291.00949] m/z 291 (100%, Mϩ), 265 (27,
M Ϫ CN), 221 (45, M Ϫ C4H6O).
5-Bromo-2-allyloxyacetophenone (15)
A solution of 5-bromo-2-hydroxyacetophenone (8.78 g, 40.83
mmol) in DMF (10 cm3) was added dropwise to a stirred
suspension of sodium hydride (2.12 g, 53.1 mmol of a 60%
dispersion in mineral oil, pre-washed with petrol) in anhydrous
DMF (70 cm3), cooled to 0 ЊC. This was stirred at room tem-
perature for 2 h to give a yellow–brown solution. After cooling
to 0 ЊC allyl bromide (9.79 g, 80.98 mmol, freshly distilled from
K2CO3) was added dropwise and the reaction was left to stir
at room temperature overnight. The reaction mixture was
quenched (H2O, 100 cm3) and was extracted with diethyl ether
(1H, s, ᎐CHH ), 6.41 (1H, s, ᎐CHH ), 6.85 (1H, d, J 8.8,
᎐
᎐
trans
cis
H-3), 7.48 (1H, dd, J 8.7, 2.5, H-4), 7.53 (1H, d, J 2.5, H-5);
δC (75 MHz, CDCl3) 56.36 (OCH3), 113.33 (C-5), 113.56
(C-3), 118.12 (CN), 119.65 (C᎐CH ), 124.46 (C-1), 132.54
᎐
2
J. Chem. Soc., Perkin Trans. 1, 2002, 1115–1123
1119

View Article Online
(2 × 100 cm3). The organics were then washed with 0.1 M
NaOH (3 × 60 cm3), followed by water (2 × 30 cm3), dried
(MgSO4) and the solvent was evaporated. The crude material
was recrystallised from a minimum amount of hot petrol to give
15 as a white solid (8.94 g, 86%). Mp (petrol) 55–57 ЊC
(lit.,28 58 ЊC); νmax(CDCl3)/cmϪ1 1677 (C᎐O), 1598 (C᎐C);
m/z = 331. The dominant fragment was the [M Ϫ OH]ϩ ion at
m/z = 314 whose formula was confirmed by accurate mass
analysis. Although accurate mass analysis of the molecular ion
was not possible, the empirical formula was confirmed by satis-
factory elemental analysis. (Found: C, 57.82; H, 4.25; N, 4.21.
C16H14NO2Br requires C, 57.85; H, 4.28; N, 4.14%)
νmax(CDCl3)/cmϪ1 2260 (CN), 1697 (C᎐O); δ (300 MHz,
᎐
᎐
δH (300 MHz, CDCl3) 2.65 (3H, s, CH3), 4.63 (2H, d, J 5.2,
OCH ), 5.34 (1H, dd, J 10.5, 1.0, CH᎐CHH ), 5.43 (1H, dd,
᎐
H
CDCl3) 2.40–2.83 (4H, 2 × CH2), 4.62 (2H, dd, J 4.2, 0.9,
᎐
2
cis
J 17.3, 1.0, CH᎐CHH ), 6.00–6.13 (1H, m, CH᎐CH ), 6.84
OCH ), 5.31 (1H, dd, J 10.5, 0.8, CH᎐CHH ), 5.41 (1H, dd,
᎐
2 cis
᎐
᎐
trans
2
(1H, d, J 8.8, H-3), 7.52 (1H, dd, J 8.7, 2.6, H-4), 7.84 (1H, d,
J 2.6, H-6); δC (75 MHz, CDCl3) 32.29 (CH3), 70.12 (OCH2),
J 17.3, 1.1, CH᎐CHH ), 5.95–6.10 (1H, m, CH᎐CH ), 6.25
᎐ ᎐
trans 2
(1H, d, J 10.0, H-2Ј), 6.87 (1H, d, J 9.4, H-3), 6.95 (1H, d,
J 10.0, H-3Ј), 7.42–7.49 (2H, m, H-4, H-6); δC (75 MHz, CDCl3)
33.16 (C-5Ј), 35.16 (C-6Ј), 40.54 (C-4Ј), 70.28 (OCH2), 113.76
113.72 (C-Br), 115.12 (C-3), 119.05 (᎐CH ), 130.38 (C-1),
᎐
2
132.53 (CH᎐CH ), 133.42 (C-6), 136.38 (C-4), 157.30 (C-2),
᎐
2
198.73 (C᎐O); [Found: (EI) 253.99568, C H BrO requires
(C-Br), 115.45 (C-3), 119.03 (᎐CH ), 119.21 (CN), 126.83 (C-1),
᎐
᎐
11 11
2
2
253.99424] m/z 254 (35%, Mϩ), 199 (100, M Ϫ 55), 132 (28,
M Ϫ CH3CO Ϫ Br).
131.00, 131.46, 132.24, 133.63 (C-2Ј, C-4, C-6, CH᎐CH ),
᎐
2
146.05 (C-3Ј), 155.41 (C-2), 196.65 (C᎐O); [Found: (EI)
᎐
314.01825, C16H13BrNO requires 314.01798] m/z 314 (100%,
2-(5-Bromo-2-allyloxyphenyl)acrylonitrile (16)
[M Ϫ OH]ϩ), 304 (29, M Ϫ HCN), 290 (22, M Ϫ CH ᎐CHCH ).
᎐
2
2
A solution of 15 (7.02 g, 27.52 mmol) in THF (10 cm3), pre-
cooled to Ϫ15 ЊC, was added dropwise to a solution of freshly
prepared LDA (1.38 mmol) in THF (40 cm3) at Ϫ15 ЊC to give a
pale yellow solution. After stirring at Ϫ15 ЊC for 20 min, neat
diethyl cyanophosphonate (5.8 cm3, 38.23 mmol) was added.
The mixture was left at 0 ЊC for 1 h and then at room temper-
ature for 2 days after which most of the starting material had
been consumed. The reaction mixture was quenched (H2O) and
then extracted with ethyl acetate. The combined organics were
dried (MgSO4) and the solvent evaporated to give a light brown
oil (11.44 g). This was dissolved in dichloromethane (80 cm3)
and boron trifluoride–diethyl etherate (10 cm3, 81.62 mmol)
was added dropwise producing a dark red–brown solution
which was stirred for 10 min at room temperature. The reaction
mixture was diluted with dichloromethane (100 cm3) and then
washed with water. The organics were dried (MgSO4), the sol-
vents evaporated and the crude oil purified by chromatography
(CH2Cl2 eluent) to give 16 as a pale yellow oil (4.28 g, 59%).
Once purified, 16 started to degrade into an insoluble resin
within 24 h when stored at Ϫ20 ЊC. Due to its instability, it was
promptly used following purification. δH (300 MHz, CDCl3)
Scale-up preparation of 4-(2-allyloxy-5-bromophenyl)-4-
cyanocyclohex-2-ene-1-one (17)
To a stirred suspension of sodium hydride (2.40 g, 60 mmol of
a 60% dispersion in mineral oil, pre-washed with petrol) in
anhydrous DMF (70 cm3), cooled to 0 ЊC, was added a solution
of 5-bromo-2-hydroxyacetophenone (9.73 g, 45.25 mmol) in
DMF (10 cm3). This was stirred at room temperature for 2 h to
give a yellow–brown solution. After cooling to 0 ЊC, allyl brom-
ide (7.8 cm3, 90.50 mmol, freshly distilled from K2CO3) was
added dropwise and then left to stir at room temperature for 16
h. The reaction mixture was quenched with water (100 cm3) and
extracted with diethyl ether (2 × 100 cm3). The organics were
washed with 0.1 M NaOH (3 × 60 cm3), followed by water (2 ×
30 cm3), dried (MgSO4) and the solvents evaporated to give
crude 15 as a a pale yellow solid (10.89 g). An additional 2.39 g
of previously made 15 was added to this prior to the subsequent
chemical steps.
A solution of crude 15 (13.28 g, 52.06 mmol) in THF
(20 cm3), pre-cooled to Ϫ15 ЊC, was added dropwise to a sol-
ution of freshly made LDA (2.56 mmol) in THF (40 cm3) at
Ϫ15 ЊC to give a brown solution. This was stirred at Ϫ15 ЊC for
10 min before the dropwise addition of neat diethyl cyanophos-
phonate (20.0 cm3, 131.2 mmol) which was stirred at 0 ЊC for
5 h. The reaction mixture was quenched (H2O) and then
extracted with ethyl acetate. The combined organics were dried
(MgSO4) and the solvent was evaporated to give a brown oil
(28.3 g). This was dissolved in dichloromethane (100 cm3)
and boron trifluoride–diethyl etherate (18 cm3, 147.9 mmol)
was added dropwise producing a dark brown solution that was
stirred for 5 min at room temperature. The reaction mixture was
diluted with dichloromethane (100 cm3), an excess of saturated
NaHCO3 was added and the mixture was stirred vigorously
until the effervescence had stopped. The organic layer was
separated, washed (saturated NaHCO3 followed by water), dried
(MgSO4) and the solvents were evaporated to give crude 16 as
an oil (15.75 g).
A mixture of 16 (52.1 mmol) and 1-methoxy-3-(trimethyl-
silyloxy)buta-1,3-diene (14 cm3, 69.6 mmol) in anhydrous
chloroform (60 cm3) was heated to reflux under argon for 21 h.
The reaction was cooled to Ϫ78 ЊC and anhydrous acetone
(18.0 cm3, 245.1 mmol) was added. A solution of TMSOTf
(2.01 cm3, 11.05 mmol) and anhydrous collidine (0.43 cm3, 3.45
mmol) in dichloromethane (15 cm3) was then added, via a can-
nula, to give a deep purple solution, which was stirred at Ϫ78 ЊC
for 20 min. The reaction mixture was quenched with water and
extracted with dichloromethane. The combined organics were
dried (MgSO4) and the solvent was evaporated to give a brown
oily solid. The crude product was purified by chromatography
(petrol–EtOAc (8 : 2) eluent) to give 17 as a white solid (10.09 g,
58% overall yield from 5-bromo-2-hydroxyacetophenone).
4.60–4.63 (2H, m, OCH ), 5.33 (1H, dd, J 10.6, 1.3, CH᎐
᎐
2
CHH ), 5.45 (1H, dd, J 17.3, 1.4, CH᎐CHHtrans), 6.00–6.13
᎐
cis
(1H, m, CH᎐CH ), 6.24 (1H, s, ᎐CHHtrans), 6.40 (1H, s,
᎐
᎐
2
᎐CHH ), 6.82 (1H, d, J 8.8, H-3), 7.43 (1H, dd, J 8.8, 2.4, H-4),
᎐
cis
7.51 (1H, d, J 2.4, H-6); δC (75 MHz, CDCl3) 70.17 (CH2),
113.50 (CBr), 114.78 (C-3), 118.14 (CN), 118.86 (CH᎐CH ),
᎐
2
119.70 (C), 124.77 (C-1), 132.48, 132.62 (C-4 and C-6), 133.86
(CH᎐CH ), 134.39 (᎐CH ), 155.57 (C-2); [Found: (EI)
᎐
᎐
2
2
262.99483, C12H10BrNO requires 262.99458] m/z 263 (16%,
Mϩ), 222 (62, M Ϫ CH CH᎐CH ), 143 (100, M Ϫ CH CH᎐CH
᎐
᎐
2
2
2
2
Ϫ Br).
4-(2-Allyloxy-5-bromophenyl)-4-cyanocyclohex-2-ene-1-one (17)
A mixture of 16 (273 mg, 1.034 mmol) and 1-methoxy-3-
(trimethylsilyloxy)buta-1,3-diene (0.3 cm3, 1.49 mmol) in a 1 : 1
co-solvent mixture of anhydrous dichloromethane–toluene
(4 cm3) was heated to reflux under argon for 6.5 h. The solution
was transferred to another round bottomed flask via a syringe
to separate undissolved and unconsumed starting material.
This was cooled to Ϫ78 ЊC and anhydrous acetone (0.37 cm3,
5.04 mmol) was added. A solution of TMSOTf (30 µl, 0.166
mmol) and 0.1 M anhydrous collidine in dichloromethane
(0.5 cm3) were then added, via a cannula, to give a dark red–
brown solution, which was stirred at Ϫ78 ЊC for 20 min. The
reaction mixture was quenched with water and extracted with
dichloromethane. The combined organics were dried (MgSO4)
and the solvent was evaporated to give a purple–brown oil. The
crude product was purified by chromatography (CH2Cl2 eluent)
to give 17 as a white solid (93 mg, 27%). The EI mass spectrum
of this compound did not show the expected molecular ion at
1120
J. Chem. Soc., Perkin Trans. 1, 2002, 1115–1123

View Article Online
cis-3,3-(Ethylenedioxy)-8-bromo-9b-cyano-1,2,3,4,4a,9b-hexa-
hydrodibenzo[b,d]furan (18)
6.77 (1H, d, J 8.4, H-6), 7.09 (1H, d, J 15.9, ᎐CH-10), 7.14 (1H,
d, J 1.9, H-9), 7.28 (1H, dd, J 8.5, 2.0, H-7); δC (75 MHz,
CDCl3) 14.62 (CH3), 29.40 (C-1), 30.67 (C-2), 36.46 (C-4),
50.23 (C-9b), 61.11 (OCH2), 64.57, 65.10 (OCH2CH2O), 87.77
᎐
A solution of 17 (6.20 g, 21.22 mmol) in dichloromethane
(80 cm3), was pre-cooled to Ϫ78 ЊC and added via a cannula to
a solution of trimethylsilyl triflate (0.280 cm3, 1.55 mmol) and
1,2-bis(trimethylsilyloxy)ethane (6.46 cm3, 26.36 mmol) in
dichloromethane (20 cm3), cooled to Ϫ78 ЊC. This was allowed
to slowly warm to room temperature, whilst stirring over 8 h.
The reaction mixture was quenched with pyridine (1 cm3),
poured into saturated NaHCO3 and extracted with dichloro-
methane. The combined organics were washed with brine, dried
(MgSO4), and the solvent evaporated to give a yellow solid.
This was purified by chromatography (petrol–EtOAc (3 : 1)
eluent) to give 18 as a white solid (6.96 g, 94%). Mp (EtOAc)
126–130 ЊC; δH (300 MHz, CDCl3) 1.67–2.35 (6H, m, 3 × CH2),
3.90–4.06 (4H, m, OCH2CH2O), 4.98 (1H, t, J 4.4, H-4a), 6.81
(1H, d, J 8.5, H-6), 7.36 (1H, dd, J 8.6, 2.2, H-7), 7.45 (1H, d,
J 2.1, H-9); δC (75 MHz, CDCl3) 30.69 (C-1), 31.93 (C-2), 35.37
(C-4), 43.23 (C-9b), 64.67, 65.35 (2 × OCH2CH2O), 86.01
(C-4a), 106.43 (C-3), 113.54 (C-6), 114.14 (C-Br), 120.24 (CN),
126.72 (C-9), 130.87 (C-9a), 133.67 (C-7), 157.56 (C-5a);
[Found: (EI) 335.01816, C15H14BrNO3 requires 335.01571] m/z
335, 337 (27%, 1 : 1, Mϩ), 236, 238 (8, 1 : 1, M Ϫ 99), 99 (100,
M Ϫ 236).
(C-4a), 107.61 (C-3), 113.12 (C-6), 113.41 (C-Br), 122.09 (᎐CH-
᎐
11), 126.97 (C-9), 132.31 (C-7), 134.82 (C-9a), 150.09 (᎐CH-10),
᎐
158.21 (C-5a), 166.56 (C᎐O); [Found: (EI) 426.0916,
᎐
C19H25BrNO5 requires 426.09161] m/z 431 (100%, M ϩ Naϩ),
426 (30, M ϩ NH4ϩ).
N-(3-aminopropyl)-N,N’-bis(tert-butoxycarbonyl)butane-
1,4-diamine (22)
A mixture of 21 (957 mg, 2.80 mmol) and Raney nickel (250
mg) in 10 M ethanolic sodium hydroxide (10 cm3) were stirred
at room temperature under a hydrogen atmosphere (40 psi) for
24 h. The nickel residues were filtered off and most of the eth-
anol was removed from the filtrate before diluting with water
and extracting with dichloromethane. The organics were dried
(MgSO4) and the solvent evaporated to give 22 (872 mg, 90%)
as a colourless oil. δH (300 MHz, CDCl3) 1.40 (9H, s, 3 × CH3),
1.41 (9H, s, 3 × CH3), 142–1.58 (4H, m, 2 × CH2), 160–1.69
(2H, m, CH2), 230–2.61 (2H, br, NH2), 2.67 (2H, t, J 6.6,
CH2NH2), 3.00–3.31 (6H, m, 3 × CH2), 4.57–4.81 (1H, br,
amide-NH); δC (75 MHz, CDCl3) 25.49 (C-6), 27.15 (C-7),
28.16 (CH3), 28.20 (CH3), 30.88 (C-2), 38.55 (C-1), 39.95 (C-8),
43.63 (C-3), 46.32 (C-5), 78.91 (C), 79.31 (C), 156.03 (C᎐O); m/z
᎐
cis-3,3-(Ethylenedioxy)-8-bromo-9b-formyl-1,2,3,4,4a,9b-hexa-
hydrodibenzo[b,d]furan (19)
(ESI) 346 (100%, M ϩ Hϩ).
cis-3,3-(ethylenedioxy)-8-((E )-2-{3-[N-(tert-butoxycarbonyl)-
N-(4-tert-butoxycarbonylaminobutyl)amino]propylcarbamoyl}-
vinyl)-9b-[(E )-ethoxycarbonylvinyl]hexahydrodibenzo[b,d]furan
23
A solution of 18 (6.93 g, 20.61 mmol) in anhydrous dichloro-
methane (200 cm3) was cooled to Ϫ10 ЊC and a 1.5 M solution
of DIBAL-H in toluene (24 cm3, 36 mmol) was added dropwise
to give a pale yellow solution which was stirred at Ϫ10 ЊC for
20 min. The reaction mixture was quenched by the slow addi-
tion of water (200 cm3) whilst stirring vigorously. The aqueous
layer was extracted with dichloromethane, the combined
organics dried (MgSO4) and the solvent evaporated to give a
sticky white foam. This was purified by chromatography
(CH2Cl2 eluent) to give 19 as a pale yellow oil (2.25 g, 32%
yield). νmax(NaCl)/cmϪ1 1724 (C᎐O); δ (300 MHz, CDCl3)
1.62–2.30 (6H, 3 × CH2), 3.86–4.02 (4H, m, –OCH2CH2O–),
5.22 (1H, t, J 6.7, H-4a), 6.78 (1H, d, J 8.5, H-6), 7.22 (1H, d,
J 2.0, H-6), 7.33 (1H, dd, J 8.5, 2.1, H-7), 9.57 (1H, s, CHO); δC
(75 MHz, CDCl3) 24.93 (C-1), 30.58 (C-2), 36.70 (C-4), 59.53
(C-9b), 64.66, 65.01, (OCH2CH2O), 82.85 (C-4a), 107.47 (C-3),
113.12 (C-6), 113.54 (C-Br), 127.33 (C-9), 129.45 (C-9a), 133.28
A solution of 20 (800 mg, 1.906 mmol), 5 (870 mg, 2.178
mmol), palladium acetate (44 mg, 0.192 mmol), tri-o-tolyl-
phosphine (170 mg, 0.559 mmol) and triethylamine (0.5 cm3,
3.578 mmol) in DMF (6 cm3) was stirred at 60 ЊC under argon
overnight. The reaction mixture was then quenched with water
and extracted four times with diethyl ether. The combined
organics were dried (Na2SO4) and the solvent was evaporated to
give a brown gum. Purification by chromatography [petrol–
EtOAc (2 : 8) eluent] failed to separate the product from the
unconsumed starting material 5 so product fractions were
re-chromatographed on a finer grade of silica (Merck silica gel
60, Merck No. 1.07729) (CH2Cl2–MeOH (98 : 2) eluent) to give
23 as a foamy white solid (975 mg, 70%). νmax(CH2Cl2)/cmϪ1
᎐
H
(C-7), 158.88 (C-5a), 197.52 (C᎐O); [Found: (EI) 338.01730,
᎐
3500–3200 (br, NH), 1713, 1699, 1694 C᎐O, overlapping);
᎐
C15H15BrO4 requires 338.01537] m/z 338 (23%, Mϩ), 309
(68, M Ϫ CHO), 115 (100, cyclic ethylene ketal fragmentation
C5H6O3ϩ).
δH (300 MHz, CDCl3) 1.22 (3H, t, J 7.1, CH3), 1.37 (9H, s, 3 ×
CH3), 140 (9H, s, 3 × CH3), 1.24–1.70 (8H, m, 4 × CH2), 1.93–
2.12 (4H, m, 2 × CH2), 2.94–3.38 (8H, m, 4 × CH2), 3.80–3.96
(4H, m, –OCH2CH2O–), 4.13 (2H, q, J 7.1, CH2), 4.71 (1H, t,
J 5.5, H-4a), 4.80–4.90 (1H, br, carbamate NH), 5.74 (1H, d,
cis-3,3-(Ethylenedioxy)-8-bromo-9b-[(E )-2-ethoxycarbonyl-
vinyl]-1,2,3,4,4a,9b-hexahydrodibenzo[b,d]furan (20)
J 15.9, ᎐CH-11), 6.30 (1H, d, J 15.6, ᎐CH-14), 6.79 (1H, d,
᎐
᎐
J 8.3, H-6), 6.99 (1H, d, J 15.9, ᎐CH-10), 7.03–7.12 (1H, br,
amide NH), 7.18, (1H, s, H-9), 7.27 (1H, d, J 8.3, H-7), 7.49
᎐
A suspension of sodium hydride (21.50 mmol) in THF
(25 cm3), was treated with triethyl phosphonoacetate (4.3 cm3,
21.67 mmol), added dropwise. This was stirred under argon at
room temperature for 60 min until hydrogen gas evolution had
ceased. A solution of 19 (2.19 g, 6.47 mmol) in THF (15 cm3)
was then added dropwise and the mixture was left to stir at
room temperature. The reaction was complete after 2 h (as
determined by 1H NMR of a reaction sample following a mini
work-up). The reaction mixture was quenched with water and
extracted with ether. The combined organics were dried
(MgSO4) and the solvent evaporated to give an oil. This was
purified by chromatography [eluting with CH2Cl2 and then
CH2Cl2–EtOAc (19 : 1)] to give the 20 as a colourless gum
(2.08 g, 81%). νmax(NaCl)/cmϪ1 1720 (C᎐O), 1649 (C᎐C); δ (300
(1H, d, J 15.6, ᎐CH-13); δ (75 MHz, CDCl3) 13.98 (CH3),
᎐
C
25.48, 27.19, 27.53 (3 × CH2), 28.19 (CH3), 28.74 (C-1), 30.06
(C-2), 35.60 (CH2), 35.91 (C-4), 39.81, 43.16, 46.42 (3 × CH2),
49.24 (C-9b), 60.40 (CO2CH2), 63.90, 64.40 (OCH2CH2O),
78.81 (C), 79.53 (C), 87.09 (C-4a), 107.02 (C-3), 111.00 (C-6),
118.88 (C-14), 121.23 (C-11), 122.22 (C-9), 128.53 (C-8), 129.93
(C-7), 132.58 (C-9a), 139.74 (C-13), 149.92 (C-10), 155.88 (C᎐
᎐
O), 156.28 (C-5a), 159.75 (C᎐O), 166.00 (C᎐O); m/z (ESI) 729
᎐
᎐
t
(45%, M ϩ Hϩ), 629 (40, M Ϫ BuOCO), 529 (80, M Ϫ
2tBuOCO), 383 (100, M Ϫ NH(CH2)3N(Boc)(CH2)4NH(Boc)).
cis-3,3-(ethylenedioxy)-8-((E )-2-{3-[N-(tert-butoxycarbonyl)-
N-(4-tert-butoxycarbonylaminobutyl)amino]propylcarbamoyl}-
vinyl)-9b-[(E )-carboxyvinyl]hexahydrodibenzo[b,d]furan (24)
᎐
᎐
H
MHz, CDCl3) 1.30 (3H, t, J 7.2, CH3), 1.55–2.10 (6H, m, 3 ×
CH2), 3.83–4.01 (4H, m, –OCH2CH2O–), 4.20 (2H, q, J 7.2,
OCH ), 4.74 (1H, t, J 5.5, H-4a), 5.80 (1H, d, J 15.9, ᎐CH-11),
A solution of 23 (304 mg, 0.418 mmol) and lithium hydroxide
᎐
2
J. Chem. Soc., Perkin Trans. 1, 2002, 1115–1123
1121

View Article Online
(400 mg, 9.13 mmol) in 60% aqueous ethanol (10 cm3) was
stirred for 8 h at room temperature. 5% Aqueous citric acid was
then added dropwise until a milky emulsion formed at pH 7.
The emulsion was extracted with ethyl acetate and the com-
bined extracts were washed with H2O, dried (MgSO4) and the
solvent was evaporated to give 24 as a white foamy solid (257
mg, 88%). δH (300 MHz, CDCl3, 323 K) 1.43 (9H, s, 3 × CH3),
146 (9H, s, 3 × CH3), 1.48–2.18 (12H, m, 6 × CH2), 3.04–3.42
(8H, m, 4 × CH2), 3.81–4.02 (4H, m, OCH2CH2O), 4.76 (1H, t,
NH); δC (75 MHz, d6-DMSO) 26.59, 27.14, 28.21 (C-1, C-15,
C-16), 30.55, 30.73 (C-2, C-20), 34.84 (C-4), 38.47, 41.40 (C-14,
C-21), 48.84 (C-9b), 50.66 (C-17, C-19 overlapping), 63.66,
64.38 (OCH2CH2O), 89.42 (C-4a), 107.06 (C-3), 110.23 (C-6),
119.93 (C-9), 120.68 (C-24), 126.67 (C-11), 128.30 (C-8), 131.87
(C-7), 136.84 (C-9a), 138.27 (C-25), 142.07 (C-10), 159.87
(C-5a), 164.31 (C᎐O), 164.83 (C᎐O); m/z (ESI) 482 (100%,
᎐
᎐
M ϩ Hϩ).
Crystal data§ for cis-3-oxo-8-bromo-9b-cyano-1,2,3,4,4a,9b-
hexahydrodibenzo[b,d]furan (14)
J 5.3, H-4a), 5.81 (1H, d, J 15.9, ᎐CH-11), 6.31 (1H, d, J 15.6,
᎐
᎐CH-14), 6.82 (1H, d, J 8.3, H-6), 7.09 (1H, d, J 15.9, ᎐CH-10),
᎐
᎐
7.21 (1H, s, H-9), 7.32 (1H, d, J 7.3, H-7), 7.54 (1H, d, J 15.6,
Crystals of 14 were grown from dichloromethane. C13H10-
BrNO2, M = 292.13. Triclinic, a = 7.5226(15), b = 9.1659(18),
᎐CH-13); δ (75 MHz, CDCl3) 25.61, 27.28, 27.62 (3 × CH2),
᎐
C
t
28.33 (CH3, Bu), 28.96 (C-1), 30.20 (C-2), 35.79 (C-4), 35.91
c = 9.3917(19) Å, α = 84.65(3), β = 74.43(3), γ = 66.85(3)Њ, V =
(CH2), 39.99, 43.42, 46.60 (3 × CH2), 49.41 (C-9b), 64.04, 64.59
(OCH2CH2O), 79.18 (C), 79.87 (C), 87.24 (C-4a), 107.22 (C-3),
111.16 (C-6), 118.74 (C-14), 121.34 (C-11), 122.55 (C-9), 128.65
(C-8), 130.04 (C-7), 132.73 (C-9a), 140.31 (C-13), 151.13 (C-
3
¯
573.5(2) Å , T = 150(2) K, space group P1, Z = 2, Dx = 1.692 g
cmϪ3 µ = 3.57 mmϪ1, 6708 reflections collected, 3033 independ-
ent reflections, R1 = .0452 [I > 2σ(I )], wR2 (F 2) = 0.1231. Data
processing was carried out using the DENZO,29 COLLECT,30
and SORTAV31 and SHELX32 software packages. Fig. 2 was
produced using PLATON solution and refinement software.33
The cyclohexanone ring C-1,2,3,4,4a,9b is in a skew boat con-
formation. Taking the plane C2,3,4a,9b the average deviation
of those atoms from the plane is 0.13 Å; C-1, C-4 and the CN
group on C-9b are all on one side of the plane, at Ϫ0.62, Ϫ0.53
and Ϫ1.84 (N-9b) Å respectively. C-9b and O-5 are at 0.002 Å
from the plane of the benzene ring. C-4a is Ϫ0.330 Å from that
plane. H-4a and the CN group are both axial.
10), 156.09 (C᎐O), 156.49 (C᎐O), 159.94 (C-5a), 166.59 (C᎐O),
᎐
᎐
᎐
169.07 (C᎐O); m/z (ESI) 722 (52%, M ϩ Naϩ), 700 (50, M ϩ
᎐
Hϩ), 600 (100, M ϩ H Ϫ tBuOCO).
( )-Lunarine (1) and ( )-3,3-(ethylenedioxy)lunarine (25)
A solution of 24 (200 mg, 0.286 mmol), in dichloromethane
(8 cm3) was cooled to 0 ЊC and then treated with a solution of
EDC (63 mg, 0.329 mmol), DMAP (2 mg, 0.016 mmol) and
pentafluorophenol (63 mg, 0.343 mmol) in dichloromethane
(1 cm3). This was left to stir at room temperature overnight. The
reaction mixture was then washed with three portions of satur-
ated aqueous NaHCO3, followed by brine, dried (MgSO4) and
the solvent was evaporated to give the crude pentafluorophenol
ester as a pale brown solid. The tert-butoxycarbonyl groups
were then removed by dissolving the pentafluorophenol ester in
a 4 M solution of HCl in anhydrous dioxane (10 cm3), which
was left to stir at room temperature for 20 min. The solvent was
then evaporated off and the residue co-evaporated several times
with dichloromethane to give a pale yellow–brown foam. This
was re-dissolved in dichloromethane (10 cm3) before slowly
being added dropwise, over 20 min, to a solution of DIPEA
(1.5 cm3, 8.61 mmol) in dichloromethane (300 cm3) and the
mixture was left to stir at room temperature overnight. The
reaction mixture was then concentrated to 50 cm3, washed with
two portions of saturated aqueous NaHCO3 followed by brine,
dried (Na2SO4) and the solvent was then evaporated to give
a solid. This was purified by chromatography (eluting with a 5–
12% gradient of ethanol (saturated with ammonia) in chloro-
form) to give 1 as a white solid (35 mg, 28%). Some of the
uncleaved dioxolane 25 was also isolated as a white solid
(15 mg, 11%). 1: δH (300 MHz, d6-DMSO) 1.42–1.71 (7H, m),
2.04–2.15 (1H, m), 2.28–2.53 (5H, m), 2.70–2.82 (2H, m), 3.03–
3.23 (3H, m), 3.44–3.55 (2H, m), 5.25 (1H, d, J 2.9, H-4a), 6.23
Acknowledgements
We would like to thank Dr C. Poupat (Institute de Chemie des
Substances Naturelles, CNRS, Gif-sur-Yvette, France) for the
generous gift of an authentic sample of (ϩ)-lunarine, Dr
J. C. Barnes (School of Life Sciences, University of Dundee)
for assistance with the crystallographic studies, Professor
M. Hursthouse for data collection at the EPSRC X-Ray
Crystallographic Service, University of Southampton and
the UNDP/WORLD BANK/WHO (Special Programme for
Research and Training in Tropical Diseases) for financial
support for C. J. H.
§ CCDC reference number 174011. See http://www.rsc.org/suppdata/
p1/b1/b110149h/ for crystallographic files in .cif or other electronic
format.
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᎐
᎐
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᎐
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᎐
8.08 (1H, br, NH), 8.47–8.55 (1H, br, NH), 9.09–9.16 (1H, br,
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J. Chem. Soc., Perkin Trans. 1, 2002, 1115–1123

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