Enantioselective synthesis of the dimeric pyranonaphthoquinone core of the cardinalins using a late-stage homocoupling strategy

Article abstract of DOI:10.1039/b813605j

The enantioselective synthesis of a dimeric pyranonaphthoquinone closely related to the cardinalins is described. Whilst attempts to effect a double Hauser-Kraus annulation of enone 5 were unsuccessful using both bis-phthalide 4 and bis-sulfone 21, a sing

Full text of DOI:10.1039/b813605j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective synthesis of the dimeric pyranonaphthoquinone core of the
cardinalins using a late-stage homocoupling strategy†
Jonathan Sperry, Jennifer S. Gibson, Jimmy J. P. Sejberg and Margaret A. Brimble*
Received 5th August 2008, Accepted 1st September 2008
First published as an Advance Article on the web 10th October 2008
DOI: 10.1039/b813605j
The enantioselective synthesis of a dimeric pyranonaphthoquinone closely related to the cardinalins is
described. Whilst attempts to effect a double Hauser–Kraus annulation of enone 5 were unsuccessful
using both bis-phthalide 4 and bis-sulfone 21, a single annulation of cyanophthalide 28 with enone 5
furnished functionalised naphthalene 31. Suzuki–Miyaura homocoupling of the aryl triflate 29 derived
from 31 effected a late-stage construction of the biaryl bond and facilitated access to the biaryl 3.
Double stereoselective lactol reduction installed the 1,3-cis stereochemistry of the pyran rings and a
final double oxidative demethylation step furnished model dimer 1, completing the enantioselective
synthesis of a dimeric pyranonaphthoquinone bearing the core structure of cardinalin 3.
Introduction
Australasian toadstools belonging to the genus Dermocybe are a
rich source of bioactive secondary metabolites.1 For example, the
deep-red ethanolic extract of the fresh fruit bodies of the New
Zealand toadstool Dermocybe cardinalis was shown to exhibit
significant cytotoxic activity (IC50 of 0.47 mg mL-1) against a
P388 murine leukaemia cell line. Separation of this extract into its
individual components yielded cardinalins 1–6, a series of dimeric
pyranonaphthoquinones (Fig. 1).2a,3 Subsequently, cardinalins
8–12, unique pre-naphthoquinone dehydrodimers were isolated
from the same source.2b
The common structural feature of cardinalins 1–6 is the presence
of two cis-1,3-dimethylpyran rings fused to their respective
naphthoquinone (or hydroquinone) nuclei. In turn a C8–C8¢ biaryl
bond present in cardinalins 1–3 affords a bisquinonoid structure
that exists as their respective (aS)-atropisomers (Fig. 1).
Limited enantioselective syntheses of dimeric pyranonaph-
thoquinones exist in the literature. In 1987, a relay synthesis
of an enantiomer of actinorhodin from a monomeric degra-
dation product confirmed the position of the biaryl bond at
C8–C8¢.4 A successful total synthesis of (+)-BE-52440A, a dimeric
nanaomycin derivative bridged with sulfur at C4a was disclosed in
2007,5 and an elegant total synthesis of crisamicin A was recently
reported in 2008.6
Our longstanding interest in the synthesis of pyranonaphtho-
quinones3 combined with the challenging dimeric structure and
biological activity of the cardinalins prompted us to instigate a
program directed towards their synthesis. Thus, it was decided
to initially focus on the asymmetric synthesis of the biaryl core
of cardinalin 3, namely model dimeric pyranonaphthoquinone 1.
We therefore herein report the full details of our efficient enan-
tioselective synthesis of the dimeric pyranonaphthoquinone 1.7,8
Department of Chemistry, University of Auckland, 23 Symonds Street,
Auckland, New Zealand. E-mail: m.brimble@auckland.ac.nz
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures, NOE data and spectra of compounds 1, 3, 12, 28, 29,
30, 31, 32 and 33. See DOI: 10.1039/b813605j
Fig. 1 Cardinalins 1–6.
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Our initial retrosynthesis (Scheme 1) was based on our method-
ology for the stereoselective construction of cis-1,3-dimethylpyran
rings, which has recently been implemented in an enantioselective
synthesis of the topoisomerase II inhibitor eleutherin.9 Thus, in
the present work, model dimer 1 was envisioned to be accessible via
double stereoselective reduction10 of bis-lactol 2 that in turn would
be accessible by double intramolecular pyran ring formation.
Biaryl 3 was envisioned to be accessible via double Hauser–Kraus
annulation11,12 of bis-cyanophthalide 4 with two equivalents of
enone 5. Thus, our original thoughts were aimed at constructing
the key biaryl bond at an early stage of the synthesis with the
model dimer 1 being assembled in a tandem fashion. A similar
strategy was adopted by de Koning et al. for a racemic synthesis
of cardinalin 3.7d
lithium anion derived from 10 with dimethylformamide furnished
aldehyde 11, which underwent concomitant silyl group deprotec-
tion in situ. Smooth removal of the trimethylsilyl was achieved
using caesium fluoride in aqueous dimethylformamide at elevated
temperature affording phenol 12 that then underwent smooth
conversion to the triflate 13, the key homocoupling precursor.
Next, the key Suzuki–Miyaura homocoupling step was under-
taken. After careful optimization, it was found that microwave
irradiation (300 W, 150 ◦C) of a solution of triflate 13 in
dioxane with bis(pinacolato)diboron (0.5 eq.), freshly ground
dried potassium carbonate (3 eq.) with Cl2Pd(dppf) as catalyst
(10 mol%) for 30 min gratifyingly afforded in near quantitative
yield the homocoupled product 14 in a one-pot operation. Smooth
conversion to bis-cyanophthalide 4 was then effected upon
treatment with trimethysilylcyanide in the presence of catalytic
quantities of potassium cyanide followed by treatment with acetic
acid15 (Scheme 2).
Results and discussion
Unfortunately, the route depicted in Scheme 2 only allowed for
the preparation of milligram quantities of bis-phthalide 4. Given
the somewhat lengthy synthesis of 4, a more concise synthesis
was designed. By modifying a literature procedure,16 radical
ring-opening of 6-methoxyphthalide17 with N-bromosuccinimide
followed by hydrolysis under gentle reflux afforded acid 15. Facile
diethylamide formation gave 16,18 which surprisingly, resisted all
attempts to effect removal of the methoxy group under Lewis
acidic conditions, with extensive degradation occurring in all cases.
The synthesis of bis-cyanophthalide 4 was achieved as follows;
meta-anisic acid was converted to its diethylamide via the acid
chloride giving 6.13 Boron tribromide mediated methyl ether
cleavage gave phenol 7, which underwent smooth silylation with
hexamethyldisilazide furnishing the unstable silyl ether 8. Anion-
induced silyl group migration14 using tert-butyllithium furnished
trimethylsilyl aryl 9. Protection of the free phenol as tert-
butyldimethylsilyl ether 10 provided an ideal substrate for subse-
quent directed metalation. With this idea in mind, treatment of the
Scheme 1 Initial retrosynthesis of model dimer 1, early stage construction of the biaryl bond.
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Scheme 2 Synthesis of bis-phthalide 4.
Pleasingly, the use of thiophenol and potassium carbonate at
elevated temperature in N-methylpyrrolidone19 gave the desired
phenol 12 in 4 steps compared to the 7-step synthesis described
previously (Scheme 3).
Our next option was to effect oxidation of 17 to a bis-
naphthoquinone, a tactic previously employed by Hauser to fa-
cilitate isolation of a double Hauser–Kraus annulation product.20
To this end, it was hoped that bis-naphthoquinone 19 would
be stable enough to be isolated. Again, unfortunately only slow
degradation was observed upon subjecting the crude reaction
mixture to Fe´tizons reagent20 and further oxidants including CAN,
AgO, FeCl3, Fremy’s salt and molecular oxygen. Changing the
base to lithium tert-butoxide or LDA offered no improvement.
These disappointing results followed similar observations from
our laboratory during efforts towards the total synthesis of
crisamicin A, wherein double Hauser–Kraus annulation of a
bis-cyanophthalide with a carbohydrate-derived enone only pro-
ceeded in a poor 23% yield.21 To date only two double Hauser–
Kraus annulations that employ an excess of the electrophilic
annulation partner have been reported, including our own.21
Hauser reported a double annulation during a total synthesis
of ( )-biphyscion (36% yield),20 and a closely related annulation
involving the double toluate anion addition of a dimeric orsellinic
acid derivative to a lactone electrophile has been reported (9%
yield).22 The paucity of double annulations in the literature
combined with our own synthetic difficulties prompted us to
modify our initial synthetic route.
Scheme 3 Improved route to key phenol 12.
With sufficient quantities of bis-phthalide 4 in hand, the key
double Hauser–Kraus annulation could be conducted. Initially,
the conditions used for the successful Hauser–Kraus annula-
tion in the synthesis of the monomeric pyranonaphthoquinone
eleutherin9 were adopted. A bright-red solution was immedi-
ately obtained upon treatment of the bis-cyanophthalide 4 with
potassium tert-butoxide in THF–DMSO, highly indicative of
successful dianion formation. The red colour then disappeared
upon addition of two equivalents of the enone 5,9 suggesting
successful consumption of the dianion. At this stage, only one
product was detected by TLC. Attempts to purify the compound
only led to degradation of what was assumed to be the bis-
hydroquinone product 17. Further attempts to purify 17 on silica
gel, alumina and by crystallisation all met with failure (Scheme 4).
At this stage it was decided to trap the presumably unstable bis-
hydroquinone 17 as tetramethyl ether 3 or tetraacetate 18 in order
to facilitate purification. Unfortunately, no annulation products
were isolated despite subjecting the crude annulation product to a
range of reductive trapping conditions.
Modified double annulation
A variant of the Hauser–Kraus annulation involves the addition of
anions stabilised by adjacent sulfur groups to Michael acceptors.
Due to the acyclic nature of the Michael donor, phenolic products
are produced.11a Our attention therefore turned to use of this
reaction as it was envisioned the phenolic annulation products
would be stable enough to be purified without the need for trapping
of the initial annulation product. Thus, a bis-sulfoxide 20 or bis-
sulfone 21 were envisioned to be ideal targets to investigate for
a double annulation with enone 5. The resultant bis-naphthol 22
could then undergo a similar series of transformations outlined
in Scheme 1 to give the key dimer 1 (Scheme 5). Given that
only monomeric Hauser–Kraus-type annulations of sulfoxides
and sulfones with electrophiles exist in the literature, the use of
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Scheme 4 Failed double Hauser–Kraus annulation.
DBU gave bis-sulfide 27. Unfortunately, bis-sulfide 27 could not
be oxidised cleanly to the bis-sulfoxide 20, with only a mixture
oxidation products being obtained. However, oxidation of 27
with hydrogen peroxide with catalytic quantities of ammonium
molybdate26 did furnish bis-sulfone 21 in excellent yield. Due
to the difficulties obtaining bis-sulfoxide 20, bis-sulfone 21 was
decided upon as the annulation target. Thus, treatment of the
crude dibromide 26 with sodium salt of benzenesulfinic acid in
dimethylformamide gave the bis-sulfone 21 in good overall yield
in a convenient one-pot procedure obviating the need to proceed
via the corresponding sulfide (Scheme 6).
With sufficient quantities of bis-sulfone 21 in hand, the stage
was now set for the modified double annulation. Initial treatment
of 21 with both lithium and potassium tert-butoxide in DMSO and
THF led to formation of weakly coloured solutions. Addition of
two equivalents of electrophile 5 to these solutions only afforded
recovered starting material. However, treatment of 21 with two
equivalents of lithium diisopropylamide at -78 ◦C in THF did
lead to a bright orange–red solution that dissipated upon addition
of enone 5 with warming to room temperature. Unfortunately
however, only unreacted bis-sulfone 21 and enone 5 were isolated
from the reaction mixture with no double annulation product 22
being observed.
Scheme 5 Modified double annulation route.
a dimeric sulfone or sulfoxide presented an attractive novel route
to bis-naphthalene systems.
At this stage, it was concluded that our original plan to construct
the biaryl bond at an early stage of the synthesis followed by
effecting a double Hauser–Kraus (or closely related) annulation
had failed and a different synthetic strategy was sought.
Thus, following a closely related literature protocol,23 2-
methylfuran underwent an aluminium-trichloride-promoted re-
gioselective Diels–Alder reaction with methyl propiolate to pro-
vide phenol 2324 in moderate yield. Smooth conversion to triflate
24 proceeded under standard conditions. Unfortunately, the
Suzuki–Miyaura conditions used successfully for the synthesis
of biaryl 14 failed to afford satisfactory yields of the desired
homocoupled product 25 despite numerous attempts. However,
the use of a nickel-catalyzed protocol reported by Percec et al.25
gave the homocoupled product 25 in 79% yield.
Late-stage homocoupling
Our revised strategy focused on conducting the key homocoupling
step to forge the biaryl unit at an advanced stage of the synthesis.
Thus, a single Hauser–Kraus annulation of benzyl-protected
cyanophthalide 28 with enone 5 was envisioned as the crucial
step to construct an appropriately functionalised monomeric
naphthalene that could then be smoothly converted to aryl triflate
29 (Scheme 7). Homocoupling of triflate 29 would then provide the
biaryl 3 that would undergo a similar synthetic sequence to that
Double radical bromination was effected using N-
bromosuccinimide in carbon tetrachloride at reflux affording
crude dibromide 26 that upon treatment with thiophenol and
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Scheme 6 Synthesis of bis-sulfone 21.
Scheme 8 Synthesis of protected cyanophthalide 28.
The stage was now set for investigation of the key mono
Hauser–Kraus annulation. Thus, reaction of cyanophthalide 28
with enone 5 proceeded smoothly in the presence of potassium tert-
butoxide in dimethylsulfoxide. Immediate reductive methylation
of the crude annulation product using sodium dithionite, sodium
hydroxide and dimethylsulfate under phase-transfer conditions
gratifyingly furnished the functionalised naphthalene 31. Facile
debenzylation then afforded naphthol 32 that underwent smooth
triflate formation using standard conditions furnishing the key
aryl triflate homocoupling precursor 29 in excellent overall yield
(Scheme 9).
Next, the key homocoupling step was investigated. It was found
that use of several literature conditions, including two methods
previously used for the synthesis of biaryls 14 and 25, failed
to give satisfactory yields of the desired biaryl 3 (Scheme 10,
Table 1). Generally, palladium catalysis (entry 6) was more
promising compared to nickel catalysis (entries 1–3). After careful
optimization, it was discovered that the yield of the biaryl was
highly dependant on the addition of extra phosphine ligand
(dppf) to the palladium catalyst and on the concentration of
the reactants. Ultimately, it was found that microwave irradiation
(300 W, 150 ◦C) of a 0.26 M solution of triflate 29 in dioxane
containing bis(pinacolato)diboron (0.5 eq.), potassium carbonate
(3 eq.) with PdCl2(dppf) (10 mol%) as catalyst and additional
dppf ligand (10 mol%) for 1 h afforded the homocoupled product
in 51% yield (entry 7). This result mirrors similar observations
noted on our studies towards the dimeric pyranonaphthoquinone
Scheme 7 Revised strategy, late-stage homocoupling.
in Scheme 1, in which simultaneous construction of both pyran
rings would be executed.
Given the ready availability of chiral enone 59 attention turned
to the synthesis of benzyl-protected cyanophthalide 28 that
upon annulation with enone 5, could be easily converted to
the aryl triflate 29, the key substrate for the proposed late-
stage homocoupling. Thus, smooth benzylation of the previously
synthesised phenol 12 delivered the benzyl ether 30 (Scheme 8).
Ring closure using trimethylsilyl cyanide in the presence of
catalytic quantities of potassium cyanide and 18-crown-6 then
provided the cyanophthalide annulation precursor 28 (Scheme 8).
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concomitant in situ cyclisation. Due to the unstable nature of bis-
lactol 2 it was immediately reduced to bis-cis-1,3-dimethylpyran
33 with trifluoroacetic acid and triethylsilane. The formation of a
single symmetrical product was observed in the 1H NMR spectrum
that supported the formation of the all cis-diastereomer resulting
from pseudo-axial delivery of hydride during the reduction step.10
The 1,3-cis stereochemistry was unequivocally confirmed by the
NOE correlation between the axial protons at C1 and C3 on the
pyran ring (see ESI†) and by X-ray crystallographic analysis29
(Fig. 2). Finally, facile CAN-mediated oxidative demethylation
provided the model dimer 1, 7,7¢-demethoxy-9,9¢-deoxycardinalin
3 (Scheme 11).
In conclusion, an efficient synthesis of the dimeric core structure
of cardinalin 3 constitutes a novel enantioselective synthesis of
a dimeric pyranonaphthoquinone. Attempts to effect a double
Hauser–Kraus annulation to access the dimeric naphthoquinone
core failed. However, the combined use of a Hauser–Kraus
annulation to assemble a monomeric naphthoquinone followed
by a late-stage Suzuki–Miyaura homocoupling provided a flexible
synthetic strategy for the synthesis of the target dimer 1. Studies
towards the total synthesis of the cardinalins and related dimeric
pyranonaphthoquinones using this synthetic strategy are ongoing.
Scheme 9 Synthesis of aryl triflate 29.
Experimental
General
All reactions were carried out in oven-dried or flame-dried
glassware under a nitrogen atmosphere unless otherwise stated.
Analytical thin layer chromatography was performed using
0.2 mm Kieselgel F254 (Merck) silica plates and compounds
were visualised under 365 nm ultraviolet irradiation followed by
staining with either alkaline permanganate or ethanolic vanillin
solution. Infrared spectra were obtained using a Perkin-Elmer
spectrum One Fourier Transform Infrared spectrometer as thin
films between sodium chloride plates. Absorption maxima are
expressed in wavenumbers (cm-1). Optical rotations were measured
Scheme 10 Homocoupling of aryl triflate 29.
crisamicin A7c wherein it was observed that homocoupling of
highly oxygenated naphthalenes was challenging compared to
simpler aryl systems; a sentiment expressed by Yang et al. during
their recent total synthesis of crisamicin A.6 With a synthetic route
to biaryl 3 successfully established, double pyran ring formation
could next be attempted. Treatment of biaryl 3 with an excess
of tetrabutylammonium fluoride in tetrahydrofuran effected re-
moval of both tert-butyldiphenylsilyl ether protecting groups with
Fig. 2 X-Ray crystal structure of dimer 33.
Table 1 One-pot homocoupling of aryl triflate 29 to biaryl 3
Entry
Conditions
Yield of 3 (%)
1
2
3
4
5
6
7
NiCl2(PPh3)2, Zn, nBu4NI, THF, reflux, 1.5 h25
12
NiCl2(PPh3)2, Zn, nBu4NI, THF, 1.5 h, microwave 300 W, 100 ◦C, 15 min
NiCl2(dppe), Zn, KI, THF, reflux, 3 h27
16
—
—
—
20
51
Pd(OAc)2, nBu4NBr, Et3N, DMF, 115 ◦C, 5 h28
Pd(OAc)2, nBu4NBr, K2CO3, DMF–H2O, 115 ◦C, 5 h28
PdCl2(dppf), bis(pinacolato)diboron, K2CO3, dioxane, microwave, 300 W, 150 ◦C, 1 h
PdCl2(dppf), dppf, bis(pinacolato)diboron, K2CO3, dioxane, microwave, 300 W, 150 ◦C, 1 h
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130 ◦C for 2 h. After cooling to room temperature, sodium
hydroxide (1 M, 30 mL) was added and the aqueous layer washed
with dichloromethane (3 ¥ 30 mL). The basic aqueous layer was
acidified to pH = 2 with concentrated hydrochloric acid and the
resulting solution extracted with dichloromethane (3 ¥ 50 mL).
The combined organic layers were washed with brine (100 mL),
dried (MgSO4), filtered and concentrated in vacuo. Purification by
flash chromatography eluting with hexanes–ethyl acetate (1 : 3)
gave the title compound (2.26 g, 10.3 mmol, 77%) as a colourless
solid, spectroscopic data identical with that reported previously.
N,N-Diethyl 5-(benzyloxy)-2-formylbenzamide (30). To a so-
lution of N,N-diethyl 2-formyl-5-hydroxybenzamide 12 (502 mg,
2.3 mmol) in dry DMF (8 mL) was added potassium carbonate
(428 mg, 3.1 mmol) and benzyl bromide (0.32 mL, 461 mg,
2.7 mmol). The reaction mixture was stirred at r.t. for 16 h then
water (20 mL) was added. The aqueous layer was extracted with
ethyl acetate (20 mL ¥ 3). The combined organic extracts were
dried over anhydrous magnesium sulfate, filtered and concentrated
in vacuo. The resulting residue was purified by flash chromatogra-
phy eluting with hexanes–ethyl acetate (1:1) to afford the title
compound (676 mg, 2.2 mmol, 96%) as an off white oil; umax
(oil)/cm-1 3365, 3064, 3034, 2975, 2935, 2754, 1736, 1693, 1633,
1566, 1455, 1381, 1292; dH (300 MHz, CDCl3) 0.98 (3 H, t, 3JHH
7.1, NCH2CH3), 1.31 (3 H, t, 3JHH 7.1, NCH2CH3), 3.09 (2 H, q,
3JHH 7.1, NCH2CH3), 3.60 (2 H, br m, NCH2CH3), 5.17 (2 H, s,
CH2Ph), 6.89 (1 H, d, 4JHH 2.5, Ar-H), 7.08 (1 H, dd, 3JHH 8.7, 4JHH
2.5, Ar-H), 7.37–7.41 (5 H, m, Ar-H), 7.90 (1 H, d, 3JHH 8.7, Ar-H),
9.91 (1 H, s, CHO); dC (100 MHz, CDCl3) 12.6 (NCH2CH3), 13.8
(NCH2CH3), 39.1 (NCH2CH3), 42.9 (NCH2CH3), 70.5 (CH2Ph),
113.0 (CH), 115.4 (CH), 126.0 (C), 127.4 (2 ¥ CH), 128.4 (CH),
Scheme 11 Synthesis of dimer 1.
128.8 (2 ¥ CH), 132.4 (CH), 135.6 (C), 141.8 (C), 163.2 (C), 168.3
using a Perkin-Elmer 341 polarimeter at l = 598 nm and are
given in 10-1 deg cm2 g-1. Melting points were recorded on an
Electrothermal melting point apparatus and are uncorrected.
NMR spectra were recorded as indicated on either a Bruker DRX-
400 spectrometer operating at 400 MHz for 1H nuclei and 100 MHz
for 13C nuclei or on a Bruker Avance 300 spectrometer operating
at 300 MHz and 75 MHz for 1H and 13C nuclei, respectively.
Chemical shifts are reported in parts per million (ppm) relative
to the tetramethylsilane peak recorded as d 0.00 ppm in CDCl3–
TMS solvent, or the residual chloroform peak at d 7.25 ppm. The
13C NMR values were referenced to the residual chloroform peak
at d 77.0 ppm. 13C NMR values are reported as chemical shift d,
+
=
(C O), 189.0 (CHO); m/z (EI) 311 (4%, [M] ), 282 (55, [M -
CHO]+), 239 (2, [M - NEt2]+), 91 (100, [Bn]+); HRMS (EI, [M]+)
Found 311.1523 Calc. for C19H21NO3 311.1521.
5-(Benzyloxy)-3-oxo-1,3-dihydroisobenzofuran-1-carbonitrile (28).
N,N-Diethyl 5-(benzyloxy)-2-formylbenzamide 30 (270 mg,
0.87 mmol) was taken up in dry dichloromethane (5 mL)
and cooled to 0 ◦C. Trimethylsilyl cyanide (0.13 mL, 1.1 eq.,
0.95 mmol) was added followed by potassium cyanide (6 mg, 0.1
eq, 0.09 mmol) ◦and 18-crown-6 (10 mg). The reaction mixture
was stirred at 0 C for 1.5 h then at r.t. for 30 min. The reaction
mixture was concentrated in vacuo and the residue taken up in
acetic acid (5 mL) and stirred at r.t. for 16 h. A 1 M aqueous
solution of sodium hydroxide (10 mL) was added, followed by
ethyl acetate (20 mL). The layers were separated and the aqueous
layer extracted with ethyl acetate (20 mL ¥ 3). The combined
organic extracts were dried over anhydrous sodium sulfate, filtered
and concentrated in vacuo. The resulting residue was purified by
flash chromatography eluting with hexanes–ethyl acetate (3 : 1)
to afford the title compound (218 mg, 0.82 mmol, 94%) as an off-
white solid; m.p. 117–118 ◦C; umax (oil)/cm-1 2931, 1786, 1624,
1496, 1465, 1294, 1242, 1044; dH (300 MHz, CDCl3) 5.16 (2 H, s,
CH2Ph), 6.02 (1 H, s, CH), 7.39–7.45 (7 H, m, Ar-H), 7.57 (1 H,
ddd, J 7.7, 1.4, 0.7, Ar-H); dC (75 MHz, CDCl3) 65.6 (CHCN),
70.8 (CH2Ph), 109.6 (CH), 114.0 (CN), 123.7 (CH), 124.9 (CH),
1
multiplicity and assignment. H NMR shift values are reported
as chemical shift d, relative integral, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet), coupling constant (J in
Hz) and assignment. Assignments are made with the aid of DEPT
135, COSY, NOESY and HSQC experiments. High-resolution
mass spectra were recorded on a VG-70SE mass spectrometer
at a nominal accelerating voltage of 70 eV. For all microwave-
assisted reactions the CEM Discover system with a circular single
mode and focused waves was used, resulting in the formation of a
homogeneous field pattern surrounding the sample.
N,N-Diethyl-2-formyl-5-hydroxybenzamide (12). To a solu-
tion of N,N-diethyl-2-formyl-5-methoxybenzamide 1618 (3.13 g,
13.3 mmol) in N-methylpyrrolidone (12 mL) was added potassium
carbonate (20 mol%, 2.66 mmol, 367 mg) followed by thiophenol
(1.9 mL, 18.6 mmol) and the reaction mixture was heated to
126.1 (C), 127.6 (2 ¥ CH), 128.6 (CH), 128.9 (2 ¥ CH), 134.0 (C),
+
=
135.4 (C), 161.3 (C), 167.5 (C O); m/z (EI) 265 (6%, [M] ), 91
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(100, [Bn]+), 65 (10); HRMS (EI, [M]+) Found 265.0737 Calc. for
C16H11NO3 265.0738.
(c 5.0, CH2Cl2); umax (oil)/cm-1 3393 (OH), 3071, 2962, 2934, 2894,
1692, 1627, 1591, 1445, 1427, 1354, 1219, 1111; dH (300 MHz,
3
CDCl3) 0.98 (9 H, s, C(CH3)3), 0.99 (3 H, d, JHH 5.5, CHCH3),
(S)-1-(7-(Benzyloxy)-3-(2-(tert-butyldiphenylsilyloxy)propyl)-1,
4-dimethoxynaphthalen-2-yl)ethanone (31). To a solution of
potassium tert-butoxide (250 mg, 2.2 mmol) in freshly distilled
DMSO (5 mL) was added a solution of 5-(benzyloxy)-3-oxo-
1,3-dihydroisobenzofuran-1-carbonitrile 28 (478 mg, 1.8 mmol)
in DMSO (5 mL) followed by a solution of (S,E)-6-(tert-
butyldiphenylsilyloxy)hept-3-en-2-one 5 (600 mg, 1.6 mmol) in
DMSO (7.5 mL). The reaction mixture was stirred for 30 min then
diluted with diethyl ether (50 mL) and quenched by the addition of
saturated ammonium chloride (50 mL). The resulting mixture was
partitioned between diethyl ether and ammonium chloride and
the aqueous layer extracted with diethyl ether (80 mL ¥ 3). The
combined organic extracts were washed with water (50 mL ¥ 2),
dried over anhydrous magnesium sulfate, filtered and concentrated
in vacuo. The resulting residue was taken up in THF–H2O (5 : 2,
35 mL). Tetrabutylammonium bromide (59 mg, 0.18 mmol) was
added, followed by a solution of sodium dithionite (1.78 g,
10.2 mmol) in water (10 mL). The reaction mixture was stirred
for 2 h then a solution of sodium hydroxide (1.40 g, 35.0 mmol)
in water (15 mL) was added followed by dimethyl sulfate (3.2 mL,
4.27 g, 33.8 mmol). The reaction mixture was stirred at r.t. for
2 h. Water (25 mL) and ethyl acetate (100 mL) were added and
the layers separated. The aqueous layer was extracted with ethyl
acetate (80 mL ¥ 3). The combined organic extracts were dried over
anhydrous magnesium sulfate, filtered and concentrated in vacuo.
The resulting residue was purified by flash chromatography eluting
with hexanes–ethyl acetate (95 : 5) to afford the title compound (901
2
2.44 (3 H, s, C OCH3), 2.81 (1 H, dd, JHH 13.5, 3JHH 7.4, CHH),
=
3.03 (1 H, dd, 2JHH 13.5, 3JHH 6.7, CHH), 3.73 (3 H, s, OCH3), 3.78
(3 H, s, OCH3), 4.21 (1 H, ddq (app. sext.), 3JHH 7.4, 6.7, 5.5, CH),
5.98 (1 H, s, OH), 7.14 (1 H, dd, J 9.0, J 2.4, Ar-H), 7.24–7.37 (7
H, m, Ar-H), 7.51 (2 H, dd, J 7.9, J 1.0, Ar-H), 7.64 (2 H, dd, J 7.9,
J 1.0, Ar-H), 7.92 (1 H, d, J 9.0, Ar-H); dC (75 MHz, CDCl3) 19.1
=
(Si(C(CH3)3), 23.4 (CHCH3), 27.0 (Si(C(CH3)3), 32.8 (C OCH3),
36.8 (CH2), 61.7 (OCH3), 63.1 (OCH3), 69.7 (CH), 104.5 (CH),
118.9 (CH), 121.6 (C), 124.4 (C), 125.0 (CH), 127.4 (4 ¥ CH),
129.38 (2 ¥ CH), 129.41 (C), 134.32 (C), 134.35 (C), 134.7 (C),
135.8 (2 ¥ CH), 135.9 (2 ¥ CH), 147.7 (C), 151.8 (C), 154.4 (C),
+
t
+
=
206.0 (C O); m/z (EI) 542 (3%, [M] ), 485 (100, [M - Bu] ), 381
(22), 269 (84), 239 (42, [SiPh2 Bu]+), 199 (82), 135 (72); HRMS
(EI, [M]+) Found 542.2476 Calc. for C33H38O5Si 542.2488.
t
(S)-7-Acetyl-6-(2-(tert-butyldiphenylsilyloxy)propyl)-5,8-dime-
thoxynaphthalen-2-yl trifluoromethanesulfonate (29). (S)-1-(3-(2-
(tert-Butyldiphenylsilyloxy)propyl)-7-hydroxy-1,4-dimethoxyna-
phthalen-2-yl)ethanone 32 (463 mg, 0.85 mmol) was taken up
in dichloromethane (4 mL). 4-Dimethylaminopyridine (21 mg,
0.17 mmol) and N-phenyl-bis(trifluoromethanesulfonimide)
(458 mg, 1.28 mmol) were added followed by freshly distilled
triethylamine (0.24 mL, 174 mg, 1.7 mmol). The reaction mixture
was stirred at r.t. for 1 h then saturated ammonium chloride
(20 mL) was added. The mixture was extracted with ethyl acetate
(50 mL ¥ 3) and the combined organic extracts were dried over
anhydrous magnesium sulfate, filtered and concentrated in vacuo.
The resulting residue was purified by flash chromatography eluting
with hexanes–ethyl acetate (9 : 1) to yield the title compound
25
mg, 1.4 mmol, 87%) as a yellow foam; [a]D -1.0 (c 1.1, CH2Cl2);
umax (oil)/cm-1 3070, 3047, 2931, 2856, 1695, 1625, 1590, 1498,
1471, 1454, 1343, 1271, 1206, 1111; dH (300 MHz, CDCl3) 0.99
25
(546 mg, 0.81 mmol, 95%) as a yellow oil; [a]D +5.3 (c 0.9,
3
(3 H, d, JHH 5.8, CHCH3), 1.00 (9 H, s, Si(CH3)3), 2.44 (3 H, s,
CH2Cl2); umax (oil)/cm-1 3073, 2962, 2934, 2858, 1698, 1644,
1496, 1427, 1343. 1212, 1140, 1111; dH (300 MHz, CDCl3) 0.97
2
3
=
C OCH3), 2.83 (1 H, dd, JHH 13.5, JHH 7.5, CHH), 3.04 (1 H,
2
3
3
dd, JHH 13.5, JHH 6.7, CHH), 3.75 (6 H, s, 2 ¥ OCH3), 4.24 (1
H, ddq, (app. sext.), 3JHH 7.5, 6.7, 5.8, CH), 5.24 (2 H, s, CH2Ph),
7.23–7.56 (15 H, m, Ar-H), 7.66 (1 H, dd, J 7.0, J 1.5, Ar-H),
7.67 (1 H, d, J 9.2, Ar-H), 7.95 (1 H, d, J 9.0, Ar-H); dC (75
MHz, CDCl3) 19.1 (C-Si), 23.4 (CHCH3), 27.0 (C(CH3)3), 32.8
(9 H, s, SiC(CH3)3), 0.98 (3 H, d, JHH 6.0, CHCH3), 2.45 (3 H,
2
3
=
s, C OCH3), 2.86 (1 H, dd, JHH 13.5, JHH 6.9, CHH), 3.06
2
3
(1 H, dd JHH 13.5, JHH 7.1, CHH), 3.77 (3 H, s, OCH3), 3.82
(3 H, s, OCH3), 4.25 (1 H, ddq (app. sext.), JHH 7.1, 6.9, 6.0,
3
CH), 7.20–7.45 (7 H, m, Ar-H), 7.48 (2 H, dd, J 7.7, 1, Ar-H),
7.63 (2 H, dd, J 7.7, 1.4, Ar-H), 7.94 (1 H, d, J 2.4, Ar-H), 8.11
(1 H, d, J 9.2, Ar-H); dC (75 MHz, CDCl3) 19.1 (Si(C(CH3)3),
=
(C OCH3), 36.9 (CH2), 61.7 (OCH3), 63.1 (OCH3), 69.7 (CH),
70.2 (CH2Ph), 102.2 (CH), 120.0 (CH), 121.9 (C), 124.6 (C), 124.7
(CH), 127.4 (2 ¥ CH), 127.5 (2 ¥ CH), 127.7 (2 ¥ CH), 128.1 (CH),
128.7 (2 ¥ CH), 129.3 (CH), 129.4 (CH), 129.6 (C), 134.36 (C),
134.41 (C), 134.78 (C), 135.8 (2 ¥ CH), 135.9 (2 ¥ CH), 136.7 (C),
=
23.6 (CHCH3), 26.9 (Si(C(CH3)3), 32.7 (C OCH3), 37.1 (CH2),
61.9 (OCH3), 63.8 (OCH3), 69.5 (CH), 114.5 (CH), 120.7 (CH),
125.9 (CH), 126.4 (C), 127.37 (2 ¥ CH), 127.42 (2 ¥ CH), 127.9
(C), 128.1 (C), 129.4 (CH), 129.5 (CH), 134.2 (C), 134.5 (C), 135.6
(C), 135.7 (2 ¥ CH), 135.9 (2 ¥ CH), 147.8 (C), 148.8 (C), 151.6
=
147.9 (C), 151.7 (C), 157.2 (C), 205.5 (C O); m/z (EI) 632 (4%,
t
t
[M]+), 575 (100, [M - Bu]+), 484 (6, [M - Bn - Bu]+), 359 (38), 199,
(40), 135 (54), 91 (84, [Bn]+); HRMS (EI, [M]+) Found 632.2952
Calc. for C40H44O5Si 632.2958.
=
(C), 204.5 (C O), triflate carbon not observed; m/z (CI) 675 (11%,
[MH]+), 617 (18), 527 (4, [MH - OTf + H]+), 419 (46), 271 (25), 199
(44), 94 (60), 78 (100, [PhH]+); HRMS (CI, [M]+) Found 675.2072
Calc. for C34H38F3O7SSi 675.2059.
(S)-1-(3-(2-(tert-Butyldiphenylsilyloxy)propyl)-7-hydroxy-1,4-
dimethoxynaphthalen-2-yl)ethanone (32). (S)-1-(7-(Benzyloxy)-
3-(2-(tert-butyldiphenylsilyloxy)propyl)-1,4-dimethoxynaphtha-
len-2-yl)ethanone 31 (901 mg, 1.42 mmol) was taken up in freshly
distilled methanol (50 mL). 10% Palladium on carbon (20 mg) was
added and the reaction mixture was stirred under an atmosphere
of hydrogen for 18 h. The reaction mixture was filtered through
1,1¢-(6,6¢-bis((S)-2-(tert-Butyldiphenylsilyloxy)propyl)-5,5¢,8,8¢-
tetramethoxy-2,2¢-binaphthyl-7,7¢-diyl)diethanone
(3). (S)-7-
Acetyl-6-(2-(tert-butyldiphenylsilyloxy)propyl)-5,8-dimethoxy-
naphthalen-2-yl trifluoromethanesulfonate 29 (164 mg,
0.24 mmol) was taken up in freshly distilled dioxane (0.9 mL).
Potassium carbonate (101 mg, 0.73 mmol), bis(pinacolato)diboron
(31 mg, 0.12 mmol) and dppf (13 mg, 0.023 mmol) were added
and the resulting suspension degassed under a stream of argon
R
Celiteꢀ then concentrated in vacuo to yield the title compound
(746 mg, 1.37 mmol, 97%) as an unstable brown oil that was used
25
directly in the next step without further purification; [a]D +4.9
4268 | Org. Biomol. Chem., 2008, 6, 4261–4270
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for 15 min. PdCl2(dppf) (10 mol%, 20 mg, 0.024 mmol) was
added and the reaction mixture was further degassed under a
stream of argon for 5 min. The reaction mixture was heated under
microwave irradiation in a sealed tube (300 W, 150 ◦C) for 1 h.
After cooling to room temperature, the resulting suspension was
diluted with ethyl acetate (15 mL) and water was added (30 mL).
The layers were separated and the aqueous layer extracted with
ethyl acetate (10 mL ¥ 3). The combined organic extracts were
washed with brine (20 mL), dried over anhydrous magnesium
sulfate, filtered and concentrated in vacuo. The residue was
purified by flash chromatography eluting with hexanes–ethyl
acetate (9 : 1) to give the title compound (65 mg, 0.062 mmol, 51%)
(6 H, s, 2 ¥ OCH3), 3.95 (6 H, s, 2 ¥ OCH3), 5.26 (2 H, q, 3JHH 6.6,
2 ¥ CHCH3), 7.89 (2 H, dd, 3JHH 8.8, 4JHH 1.6, Ar-H), 8.18 (2 H,
3
4
d, JHH 8.8, Ar-H), 8.37 (2 H, d, JHH 1.6, Ar-H); dC (75 MHz,
CDCl3) 21.8 (2 ¥ CHCH3), 22.4 (2 ¥ CHCH3), 32.0 (2 ¥ CH2),
61.1 (2 ¥ OMe), 61.4 (2 ¥ OMe), 69.6 (2 ¥ CH), 71.3 (2 ¥ CH),
120.4 (2 ¥ CH), 122.8 (2 ¥ CH), 125.5 (2 ¥ C), 125.7 (2 ¥ CH),
126.6 (2 ¥ C), 127.7 (2 ¥ C), 129.9 (2 ¥ C), 138.3 (2 ¥ C), 148.8
(2 ¥ C), 149.0 (2 ¥ C); m/z (EI) 542 (100%, [M]+), 527 (39), 199
(22), 105 (32), 57 (40), 44 (72); HRMS (EI, [M]+) Found 542.2667
Calc. for C34H38O6 542.2668.
7,7¢-Demethoxy-9,9¢-deoxycardinalin
5,5¢,10,10¢-Tetramethoxy-1,1¢,3,3¢-tetramethyl-3,3¢,4,4¢-tetra-
hydro-1H,1¢H-8,8¢-dibenzo[g]isochromene 33 (24 mg,
(1). (1R,1¢R,3S,3¢S)-
as a colourless oil; [a]D -21.8 (c 2.5, CH2Cl2); umax (oil)/cm-1
25
3070, 3049, 2959, 2932, 2894, 1679, 1588, 1450, 1427, 1348, 1330,
0.044 mmol) was suspended in acetonitrile (1.5 mL) and a
solution of ammonium cerium(IV) nitrate (152 mg, 0.28 mmol) in
water (1.25 mL) was added. The reaction mixture was stirred at
r.t. for 45 min, then water (5 mL) was added and the whole was
extracted with ethyl acetate (10 mL ¥ 3). The combined organic
extracts were dried over anhydrous magnesium sulfate, filtered,
concentrated in vacuo, and the resulting residue was purified by
flash chromatography eluting with hexanes–ethyl acetate (4 : 1)
to afford the title compound (13.5 mg, 0.028 mmol, 63%) as a
1204, 1112; dH (400 MHz, CDCl3) 0.97 (18 H, s, 2 ¥ C(CH3)3),
0.98 (6 H, d, 3JHH 6.0, 2 ¥ CH3), 2.48 (6 H, s, 2 ¥ C OCH3), 2.90
=
(2 H, dd, 2JHH 13.4, 3JHH 7.5, 2 ¥ CHH), 3.11 (2 H, dd, 2JHH 13.4,
3JHH 6.7, 2 ¥ CHH), 3.81 (6 H, s, 2 ¥ OCH3), 3.90 (6 H, s, 2 ¥
3
OCH3), 4.27 (2 H, ddq (app. sext.), JHH 7.5, 6.7, 6.0, 2 ¥ CH),
7.27 (4 H, m, Ar-H), 7.38 (8 H, m, Ar-H), 7.54 (4 H, dd, J 8.1,
1.3, Ar-H), 7.66 (4 H, dd, J 8.1, 1.6, Ar-H), 7.93 (2 H, dd, J 8.8,
1.8, Ar-H), 8.15 (2 H, d, J 8.8, Ar-H), 8.36 (2 H, d, J 1.8, Ar-H);
dC (100 MHz, CDCl3) 19.1 (2 ¥ Si(C(CH3)3), 23.4 (2 ¥ CHCH3),
yellow solid; m.p. 239–240 ◦C; [a]D +356.1 (c 0.15, CH2Cl2);
23
=
27.0 (2 ¥ Si(C(CH3)3), 32.8 (2 ¥ C OCH3), 37.0 (2 ¥ CH2), 61.8 (2
umax (CH2Cl2)/cm-1 3432, 3025, 1663, 1265, 736, 705; dH (400
MHz, CDCl3) 1.40 (6 H, d, 3JHH 6.1, 2 ¥ CHCH3), 1.58 (6 H, d,
3JHH 6.5, 2 ¥ CHCH3), 2.31 (2 H, ddd, JHH 18.7, 10.2, 4.0, 2 ¥
CHaxH), 2.82 (2 H, dt, JHH 18.7, 2.5, 2 ¥ CHeqH), 3.64 (2 H, m, 2
¥ OCH3), 63.7 (2 ¥ OCH3), 69.6 (2 ¥ CH), 120.6 (2 ¥ CH), 123.7
(2 ¥ CH), 124.8 (2 ¥ C), 126.8 (2 ¥ CH), 127.4 (8 ¥ CH), 127.9 (2
¥ C), 128.3 (2 ¥ C), 129.40 (2 ¥ CH), 129.43 (2 ¥ CH), 134.27 (2 ¥
C), 134.31 (2 ¥ C), 134.7 (2 ¥ C), 135.8 (4 ¥ CH), 135.9 (4 ¥ CH),
3
¥ CHCH3), 4.89 (2 H, m, 2 ¥ CHCH3), 8.02 (2 H, dd, JHH 8.0,
=
138.6 (2 ¥ C), 149.3 (2 ¥ C), 151.6 (2 ¥ C), 205.3 (2 ¥ C O); m/z
3
4
4JHH 1.9, Ar-H), 8.20 (2 H, d, JHH 8.0, Ar-H), 8.35 (2 H, JHH
1.9, Ar-H); dC (100 MHz, CDCl3) 20.8 (2 ¥ CHCH3), 21.2 (2 ¥
CHCH3), 30.5 (2 ¥ CH2), 68.7 (2 ¥ CH), 70.0 (2 ¥ CH), 125.0 (2
¥ CH), 127.3 (2 ¥ CH), 131.4 (2 ¥ CH), 131.9 (2 ¥ C), 133.0 (2 ¥
(FAB) 1050 (4%, [M]+), 993 (6, [M - C(CH3)3]+), 795 (14), 397
(10), 197 (40), 135 (100); HRMS (FAB, [M]+) Found 1050.4921
Calc. for C66H74O8Si2 1050.4922.
=
C), 143.0 (2 ¥ C), 144.2 (2 ¥ C), 147.0 (2 ¥ C), 183.4 (2 ¥ C O),
183.7 (2 ¥ C O); m/z (EI) 482 (100%, [M] ), 467 (20), 237 (15),
(1R,1¢R,3S,3¢S)-5,5¢,10,10¢-Tetramethoxy-1,1¢,3,3¢-tetramethyl-
3,3¢,4,4¢-tetrahydro-1H,1¢H-8,8¢-dibenzo[g]isochromene (33). To
+
=
199 (20), 131 (21), 91 (99), 77 (25), 57 (37), 40 (85); HRMS (EI,
[M]+) Found 482.1720. Calc. for C30H26O6 482.1729.
a
solution of 1,1¢-(6,6¢-bis((S)-2-(tert-butyldiphenylsilyloxy)-
propyl)-5,5¢,8,8¢-tetramethoxy-2,2¢-binaphthyl-7,7¢-diyl)dietha-
none 3 (144 mg, 0.14 mmol) in THF (5 mL) was added a 1 M
solution of tetra-n-butylammonium fluoride (3.0 mL, 3.0 mmol).
The reaction mixture was stirred under nitrogen at r.t. for 3 d then
concentrated in vacuo. The resulting residue was flushed through
a pad of silica (hexanes–ethyl acetate 1 : 1–1 : 3). The filtrate
was concentrated in vacuo and the resulting crude bis-lactol 2
was dissolved in distilled dichloromethane (5 mL) and cooled
to -78 ◦C. Trifluoroacetic acid (0.065 mL, 98 mg, 0.86 mmol)
was added dropwise and reaction mixture was stirred for 15 min
before addition of triethylsilane (0.13 mL, 94 mg, 0.80 mmol).
The reaction mixture was then allowed to reach r.t. over 16 h.
Water (20 mL) was added and the mixture extracted with ethyl
acetate (20 mL ¥ 3). The combined organic extracts were dried
over anhydrous magnesium sulfate, filtered, concentrated in vacuo
and the resulting residue was purified by flash chromatography
eluting with hexanes–ethyl acetate (7 : 3) to give the title compound
(52 mg, 0.096 mmol, 70%) as a cream-coloured solid; m.p. 268–
Acknowledgements
The authors thank the Royal Society of New Zealand Marsden
fund for financial support.
References
1 M. Gill, Aust. J. Chem., 1995, 48, 1.
2 (a) M. Gill, M. S. Buchanan and J. Yu, J. Chem. Soc., Perkin Trans. 1,
1997, 919; (b) M. Gill, M. S. Buchanan and J. Yu, Aust. J. Chem., 1997,
50, 1081.
3 For reviews regarding isolation, structure and synthesis of pyranon-
aphthoquinone antibiotics see: (a) M. A. Brimble, L. J. Duncalf and
M. R. Nairn, Nat. Prod. Rep., 1999, 16, 267; (b) M. A. Brimble, M. R.
Nairn and H. Prabaharan, Tetrahedron, 2000, 56, 1937; (c) J. Sperry, P.
Bachu and M. A. Brimble, Nat. Prod. Rep., 2008, 25, 376.
4 H. Laatsch, Liebigs Ann. Chem., 1987, 297.
5 K. Tatsuta, Y. Suzuki, T. Toriumi, Y. Fuyura and S. Hosokawa,
Tetrahedron Lett., 2007, 48, 8018.
6 Z. Li, Y. Gao, Y. Tang, M. Dai, G. Wang, Z. Wang and Z. Yang, Org.
Lett., 2008, 10, 3017.
7 For racemic syntheses of dimeric pyranonaphthoquinones see: (a) M.
A. Brimble, L. J. Duncalf and D. Neville, J. Chem. Soc., Perkin Trans.
1, 1998, 4165; (b) M. A. Brimble and M. Y. H. Lai, Org. Biomol.
Chem., 2003, 1, 4227; (c) M. A. Brimble and M. Y. H. Lai, Org. Biomol.
◦
24
269 C; [a]D +36.2 (c 0.12, CH2Cl2); umax (CH2Cl2)/cm-1 3418,
3053, 2986, 1638, 1421, 1264, 733; dH (300 MHz, CDCl3) 1.44
(6 H, d, 3JHH 6.0, 2 ¥ CHCH3), 1.73 (6 H, d, 3JHH 6.6, 2 ¥ CHCH3),
2
3
2.66 (2 H, dd, JHH 16.2, JHH 11.0, 2 ¥ CHaxH), 3.11 (2 H, dd,
2JHH 16.2, 3JHH 1.5, 2 ¥ CHeqH), 3.74 (2 H, m, 2 ¥ CHCH3), 3.91
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4261–4270 | 4269
©

View Article Online
Chem., 2003, 1, 2084; (d) For a racemic synthesis of cardinalin 3 see: S.
Govender, E. M. Mmutlane, W. A. L. van Otterlo and C. B. de Koning,
Org. Biomol. Chem., 2007, 5, 2433.
18 R. J. Mill, N. J. Taylor and V. Snieckus, J. Org. Chem., 1989, 54, 4372.
19 M. K. Nayak and A. K. Chakraborti, Tetrahedron Lett., 1997, 38, 8749.
20 F. M. Hauser and P. J. F. Gauuan, Org. Lett., 1999, 1, 671.
21 O. Andrey, J. Sperry, U. S. Larsen and M. A. Brimble, Tetrahedron,
2008, 64, 3912. A noteworthy double annulation involving addition
of excess of a Michael donor to a bis-enone has been achieved in
good yields (61–70%) during the synthesis of dimeric analogues of the
anthracyclines.; P. Ge and R. Russel, Tetrahedron, 1997, 53, 17477.
22 S. E. Bode, D. Drochner and M. Mu¨ller, Angew. Chem., Int. Ed., 2007,
46, 5916.
8 For a preliminary communication of this work, see: M. A. Brimble, J.
S. Gibson, J. J. P. Sejberg and J. Sperry, Synlett, 2008, 867.
9 J. S. Gibson, O. Andrey and M. A. Brimble, Synthesis, 2007, 2611.
10 G. A. Kraus, M. T. Molina and J. A. Walling, J. Chem. Soc., Chem.
Commun., 1986, 1568.
11 (a) F. M. Hauser and R. P. Rhee, J. Org. Chem., 1978, 43, 178; (b) G.
A. Kraus and H. Sugimoto, Tetrahedron Lett., 1978, 19, 2263.
12 For recent reviews on the Hauser–Kraus annulation see: (a) K. Rathwell
and M. A. Brimble, Synthesis, 2007, 643; (b) D. Mal and P. Pahari,
Chem. Rev., 2007, 107, 1892.
23 A. W. McCulloch and A. G. McInnes, Can. J. Chem., 1971, 49,
3152.
24 A. G. Schultz, R. E. Harrington, M. Macielag, P. G. Mehta and A. G.
Taveras, J. Org. Chem., 1987, 52, 5482.
25 V. Percec, J.-Y. Bae, M. Zhao and D. H. Hill, J. Org. Chem., 1995, 60,
176.
13 P. Beak and R. A. Brown, J. Org. Chem., 1982, 47, 34.
14 R. J. Billedau, M. P. Sibi and V. Snieckus, Tetrahedron Lett., 1983, 24,
4515.
15 F. Kaiser, L. Schwink, J. Velder and H.-H. Schmalz, J. Org. Chem.,
26 D. J. Cundy, A. C. Donahue and T. M. McCarthy, J. Chem. Soc., Perkin
2002, 67, 9248, and references therein.
Trans. 1, 1999, 1, 559.
16 B. Denes and C. Szantay, Arch. Pharm., 1958, 342. For a similar example
employing molecular bromine, see:; V. T. Abaev, A. S. Dmitriev, A. V.
Gutnov, S. A. Podelyakin and A. V. Butin, J. Heterocycl. Chem., 2006,
43, 1195.
27 A. Jutand and A. Mosleh, J. Org. Chem., 1997, 62, 261.
28 V. Penalva, J. Hassan, L. Lavenot, C. Gozzi and M. Lemaire,
Tetrahedron Lett., 1998, 39, 2559.
29 J. J. P. Sejberg, J. Sperry, K. W. Choi, P. D. W. Boyd and M. A. Brimble,
Acta Crystallogr. Sect. E, 2008, 64, o758.
17 M. A. Brimble and C. V. Burgess, Synthesis, 2007, 754.
4270 | Org. Biomol. Chem., 2008, 6, 4261–4270
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The Royal Society of Chemistry 2008
©