Total synthesis of (+)-intricarene using a biogenetically patterned pathway from (-)-bipinnatin J, involving a novel transannular [5+2] (1,3-dipolar) cycloaddition

Article abstract of DOI:10.1039/b910572g

An asymmetric synthesis of the furanobutenolide-based macrocyclic diterpene (-)-bipinnatin J (4a) isolated from the gorgonian octocoral Pseudopterogorgonia bipinnata is described. The synthesis is based on elaboration of the chiral lactone-substituted vin

Full text of DOI:10.1039/b910572g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Total synthesis of (+)-intricarene using a biogenetically patterned
pathway from (-)-bipinnatin J, involving a novel transannular
[5+2] (1,3-dipolar) cycloaddition†
Bencan Tang, Christopher D. Bray and Gerald Pattenden*
Received 29th May 2009, Accepted 20th July 2009
First published as an Advance Article on the web 26th August 2009
DOI: 10.1039/b910572g
An asymmetric synthesis of the furanobutenolide-based macrocyclic diterpene (-)-bipinnatin J (4a)
isolated from the gorgonian octocoral Pseudopterogorgonia bipinnata is described. The synthesis is
based on elaboration of the chiral lactone-substituted vinyl iodide 26b from (+)-glycidol, followed by an
intermolecular Stille coupling reaction with the stannylfurfural 27, leading to 28a, and then an
intramolecular Nozaki–Hiyama–Kishi allylation reaction, 28b → 4a. Treatment of (-)-bipinnatin J (4a)
with VO(acac)2–tBuO2H followed by acetylation of the tautomeric hydroxypyranone product 7/8, next
gave the acetoxypyrone 30. When the acetoxypyranone 30 was heated in acetonitrile in the presence of
DBU, it gave (+)-intricarene 1, which is found in P. kallos, via a novel transannular [5+2] (or
1,3-dipolar) cycloaddition involving the butenolide-oxidopyrylium ion intermediate 31. We believe that
this total synthesis of (+)-intricarene 1 mimics its most likely origin in nature via oxidation of
(-)-bipinnatin J (4a), presumably involving photochemically generated singlet oxygen or possibly a
P450 monooxygenase enzyme system.
Introduction
Intricarene 1 is a novel polycyclic diterpene isolated from the
Caribbean gorgonian octocoral Pseudopterogorgia kallos.1 The
equally unusual diterpene bielschowskysin 2 co-occurs with
intricarene in P. kallos,2 together with providencin 3,3 another
cyclobutane ring-containing diterpene. Apart from their unusual
and interesting structures, the natural products 1–3 show some
useful and promising biological activities. Thus, bielschowskysin
2 displays significant cytotoxicity against lung and renal cancer
cell lines, in addition to strong antimalarial activity. Providencin
3 exhibits modest anti-cancer activity against human breast, lung
and CNS cancer cell lines. Intricarene 1 shows mild cytotoxicity,
but the dearth of natural product has not yet permitted a thorough
analysis of its biological properties.
It seems likely that intricarene 1 and bielschowskysin 2 are
related biogenetically as products of oxidation and transannu-
lar ring-forming processes from more simple furanobutenolide-
containing macrocyclic diterpenes, e.g. 4a and 4b, which have also
been isolated from Caribbean gorgonian corals in recent years.
Thus, we4 and others5,6 have surmised that the most plausible
biogenetic precursor to intricarene 1 is the furanobutenolide-
give the enedione 7 which would exist in tautomeric equilibrium
based natural product bipinnatin J (4a), found in P. bipinnata.7
We envisage that oxidation of the furan ring in 4a in the
marine milieu would most likely involve [4+2] cycloaddition of
photochemically generated singlet oxygen, leading to the labile
peroxide intermediate 5 (Scheme 1). Hydrolysis of 5 would next
with the hydroxypyranone 8. The same hydroxypyranone 8 could
also originate from the spiroepoxide intermediate 6 produced from
bipinnatin J via a monooxygenase. Whatever happens, elimination
of water from the hydroxypyranone 8 would next lead to the
oxidopyrylium ion species 9, which we envisage would then
undergo a transannular [5+2] (or 1,3-dipolar) cycloaddition8–10
with the butenolide alkene bond, leading to intricarene 1. In
this paper we first describe a total synthesis of (-)-bipinnatin J
(4a), and then its conversion into (+)-intricarene 1 based on the
aforementioned biosynthesis speculation.4 In contemporaneous
studies Trauner and Roethle,5 and Rawal and Huang6 reported
School of Chemistry, The University of Nottingham, University Park,
Nottingham, NG7 2RD, UK
† Electronic supplementary information (ESI) available: Experimental
procedures and data for compounds 15b, 16, 18, 10, 20, 21a and 21b;
copies of 1H and 13C NMR spectra for compounds 28a, 28b, 4a and 1. See
DOI: 10.1039/b910572g
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features in bipinnatin J suggested a Stille coupling17 involving a
Z-iodoalkene and a stannylfuran to elaborate the Z-vinylfuran
unit, and either an NHK reaction18 or an Evans alkylation
sequence using a furfural and an appropriate allylic species to
introduce the chiral furanmethanol functionality in 4a. Further-
more, both of these synthetic approaches could be executed in
both inter- and intramolecular fashion, thereby adding a further
level of flexibility to the overall synthetic strategy.
Scheme 1 Proposal for the origin of intricarene 1 from bipinnatin J (4a)
in vivo.
syntheses of racemic bipinnatin J and later, Trauner et al11
developed an alternative synthesis of (-)-bipinnatin J and also
described its biomimetic conversion into (+)-intricarene.
In our first synthetic approach to bipinnatin J, we examined
syntheses of the lactone substituted iodoalkene 10 and the chiral
allylic alcohol 11, with the intention of coupling these two
fragments via an alkylation reaction of the carbanion derived
from 10 with 11, leading to 12a. The vinyl iodide stannylfuran
12b would then be converted into 4a via an intramolecular
Stille reaction. This overall strategy had already been used by
us in an earlier synthesis of bis-deoxylophotoxin 13.13a Thus, the
lactone substituted iodoalkene 10 was prepared starting with the
known alkyne diol 14b19 produced in two steps from glycidol
(Scheme 2). The alkyne diol 14b was next treated with Cp2ZrCl2–
Me3Al, and then with iodine, following the conditions developed
by Negishi and Ma,20 leading to the Z-iodoalkene 15a. The
1,2-diol functionality in 15a was converted into the corresponding
epoxide 16. The epoxide 16 was now treated with the lithium salt of
ethoxyacetylene leading to 17, which was immediately hydrolysed
with PTSA producing the lactone 18. Finally, deprotonation
of 18 using LiHMDS at -78 ◦C, followed by quenching of
the resulting carbanion with phenylselenium bromide gave the
substituted lactone 10. The E-alkene isomer corresponding to 10
Total synthesis of (-)-bipinnatin J (4a)
A
wide variety of synthetic approaches towards the
furanobutenolide-based family of cembranoids, exemplified by
3 and 4a, have been described. These approaches differ largely
according to whether the precursors already contain a substituted
furan or butenolide prior to a macrocyclisation event, or whether
the furan and/or butenolide units are elaborated from macrocyclic
precursors.12 In addition, a significant number of protocols
have been developed to achieve macrocyclisations of precursors
to the cembranoids. These have included intramolecular Stille
coupling13 and Nozaki–Hiyama–Kishi reactions; intramolecular
Wadsworth–Emmons olefinations and metathesis reactions;14 in-
tramolecular 2,3-Wittig rearrangements;15 intramolecular alkyla-
tion reactions involving b-keto esters and propargylic iodides; and
intramolecular radical cyclisations.16
The bipinnatin J structure, i.e. 4a, accommodates a vinyl-
furan unit associated with a Z-trisubstituted alkene bond, to-
gether with a chiral furanmethanol unit, where the alcohol
group is also part of a homoallylic alcohol. These structural
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to find that the synthesis of the key homoallylic alcohol 20 was
not amenable to large scale operation, due to competing retro-
aldolisation and other features, and we were not able therefore to
take this sequence further.
We therefore changed our approach, and decided to synthesise
the butenolide 26c which was substituted at C5 with a terminal
Z-iodoalkene, and also at C3 with a terminal allyl bromide unit.
These functionalities would then be reacted, in sequence, with
the stannane-substituted furfural 27, to elaborate bipinnatin J
using sequential Stille cross coupling and NHK reactions. Thus,
the a-phenylselanyl ester 23 was first prepared from the known
allyl alcohol 22a,23 following protection as the TBS ether 22b and
phenylselanylation24 of the carbanion derived from 22b. Further
deprotonation of 23, using NaHMDS at -78 ◦C, followed by
quenching the resulting carbanion with the epoxide 16 in the
presence of BF3·OEt2 next gave the adduct 24a as a mixture
of diastereoisomers in 72% yield (Scheme 4). Hydrolysis of the
methyl ester group in 24a was followed by lactonisation, leading
to the phenylselanyl-substituted lactone 25. Oxidation of 25 and
in situ elimination of the elements of phenylseleninic acid then
gave the substituted butenolide 26a. Deprotection of the TBS
group in 26a finally gave the enantiomerically pure alcohol 26b.25
In contemporaneous studies Trauner and Roethle5 described a
synthetic route to the racemic alcohol 26b, and Rawal and Huang6
Scheme 2 Reagents and conditions: (i) TMS-acetylene, nBuLi, BF3·Et2O,
-78 to -30 ◦C, 2 h, then -30 ◦C, 19 h, 98%; (ii) K2CO3, MeOH/THF
(10:1), r.t., 14 h, 62–92%; (iii) a, Cp2ZrCl2, AlMe3, (CH2Cl)2, r.t. 19 h, then
reflux for 3 days; b, I2, THF, -30 ◦C to r.t., 2 h; (iv) TsCl, Py, 4 ◦C, 28 h, 48%
over two steps; (v) K2CO3, MeOH, r.t. 1.5 h, 73%; (vi) 1-ethoxyacetylene,
nBuLi, BF3·Et2O, -78 ◦C, 2 h; (vii) PTSA, EtOH, r.t., 2 h, then CHCl3,
reflux, 16 h, 81% for two steps; (viii) LiHMDS, THF, -78 ◦C, 15 min,
TMSCl, -78 ◦C, 30 min, PhSeBr, -78 ◦C to r.t., 1 h, 83%.
was known from our earlier studies and was used in a synthesis of
bis-deoxylophotoxin 13.13a
We next examined a synthesis of the substituted alkyl iodide 11
in readiness for the proposed alkylation reaction with the phenylse-
lanyl lactone 10, leading to 12a. Thus, deprotonation of the known
Evans’ chiral oxazolidinone 1921 derived from 3-methylbut-2-enoic
acid, using Bu2BOTf–Et3N at -78 ◦C, followed by addition of
3-methylfurfural22 resulted in deconjugative alkylation with the
formation of a single diastereoisomer of the homoallylic alcohol
20 (Scheme 3), whose absolute stereochemistry was confirmed by
X-ray crystallography.13a Reduction of the amide 20, using LiBH4–
MeOH, next led to the alcohol 21a which was then converted into
the corresponding tosylate 21b. Our next plan was to convert the
tosylate 21b into the homologous iodide 11, and then couple this
iodide to the phenylselanyl lactone 10. However, we were frustrated
Scheme 4 Reagents and conditions: (i) TBSCl, Imidazole, DMF, 0 ◦C,
10 min, 90%; (ii) a, LDA, THF, -78 ◦C, 45 min; b, TMSCl, -78 ◦C,
30 min; c, PhSeBr, THF, -78 ◦C to r.t., 1 h, 73%; (iii) NaHMDS, THF,
-78 ◦C, 0.5 h, then 16, BF3·Et2O, -78 ◦C to r.t. overnight, 72%; (iv) PTSA
(0.1 eq), DCM, r.t., 3 h; (v) H2O2, THF, 0 ◦C to r.t., 2 h; (vi) PPTS
(0.2 eq), DCM/MeOH (1:1), r.t., 24 h, 62% for 3 steps.
Scheme 3 Reagents and conditions: (i) Bu2BOTf, DCM, -78 ◦C, 5 min,
then Et3N, -78 ◦C, 1 h, 0 ◦C, 15 min, then 3-methylfurfural, -78 ◦C,
1 h, 0 ◦C, 1 h, 61%; (ii) LiBH4, MeOH, THF, 0 ◦C–r.t. overnight, 42%;
(iii) Et3N, DMAP, TsCl, DCM, r.t. 27 h, 49%.
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presented an alternative route to the MOM ether 26d of racemic
26b. Furthermore, both Trauner and Rawal and their respective
collaborators converted their racemic butenolides 26b and 26d into
( )-bipinnatin J, using essentially the same synthetic steps that we
have used in converting our enantiomerically pure (+)-alcohol 26b
into chiral (-)-bipinnatin J (4a).
and Roethle5 used CrCl2–NiCl2 and recorded a diastereoselectivity
of approx. 90%. The high diastereoselectivity found in the NHK
reaction 28b → 4a no doubt reflects the important role that
the Z-double bond in the precursor plays, allowing a favourable
chair transition state, i.e. 29, in the cyclisation. The relative
stereochemistry of the two new chiral centres resulting from the
NHK reaction, is no doubt determined by the remote asymmetric
centre on the butenolide ring in the starting material. The synthetic
A Stille coupling reaction between the enantiomerically pure
vinyl iodide 26b and 5-trimethylstannylfurfural 27,5,26 using
Pd(PPh3)4 and CuI in the presence of CsF at room temperature
gave the Z-vinylfuran 28a in an excellent 90% yield (Scheme 5).
Bromination of the alcohol 28a, using NBS and PPh3, next gave
the corresponding allyl bromide 28b which underwent a smooth
diastereoselective intramolecular NHK reaction in the presence
of CrCl2, leading to (-)-bipinnatin J (4a), obtained as colourless
crystals, mp 144–7 ◦C, in 70% yield. We found that the conditions
1
(-)-bipinnatin J displayed H and 13C NMR spectroscopic data
(Table 1) that were superimposable on those recorded for the
natural product isolated from P. bipinnata.7
Biomimetic synthesis of (+)-intricarene 1 from
(-)-bipinnatin J (4a)
6
˚
used by Rawal and Huang (i.e. CrCl2 in the presence of 4 A
Following the successful synthesis of (-)-bipinnatin J (4a), we now
proceeded to examine its conversion into the polycyclic diterpene
intricarene 1 via the proposed transannular [5 + 2] cycloaddition
molecular sieves) in the aforementioned NHK cyclisation led to a
diastereoselectivity >80%. For the same NHK reaction, Trauner
Scheme 5 Reagents and conditions: (i) Pd(PPh3)4, CuI, CsF, DMF, r.t., 20 min, 90%; (ii) Ph3P, NBS, DCM, -5 ◦C to 0 ◦C, 20 min, 80%; (iii) CrCl2, 4 A
˚
MS, THF, r.t., 16 h, 70%.
Table 1 NMR spectroscopic data for synthetic and natural (-)-bipinnatin J
Synthetic (-)-bipinnatin J
Natural (-)-bipinnatin J7
Position
1H, NMR
13C, NMR
1H, NMR
13C, NMR
1
2
3
4
5
6
7
8
9a
9b
10
11
12
13a
13b
14a
14b
15
16a
16b
17
18
19
20
OH
2.46–2.35, m
4.51, dd (2.9, 10.9)
51.3, d
65.1, d
149.3, s
121.2, s
114.0, d
151.1, s
117.5, d
129.2, s
39.8, t
2.35, dd (10.8, 10.8)
4.49, br d (10.8)
51.1, d
65.0, d
149.3, s
121.0, s
113.8, d
151.0, s
117.3, d
128.9, s
39.7, t
6.04, s
6.02, s
6.12, br s
6.09, br s
2.74, dd (4.4, 11.8)
3.21, t (11.8)
5.02–4.99, m
6.86, t (1.6)
2.71, dd (4.5, 12.0)
3.18, dd (11.7, 12.0))
4.96, m
78.8, d
152.4, d
132.7, s
19.8, t
78.6, d
152.2, d
132.6, s
19.6, t
6.83, br s
2.13–2.07, m
2.46–2.35, m
0.91, dt (3.8, 13.8)
1.68, tdd (3.3, 11.1, 13.8)
2.07, m
2.38, ddd (3.0, 14.2, 14.2)
0.88, ddd (3.3, 13.8, 13.8)
1.68, dddd (3.3, 3.3, 10.8, 13.8)
30.2, t
30.1, t
142.2, s
118.9, t
142.2, s
118.4, t
5.07, s
5.03, br s
5.14, br s
1.78, br s
2.03, s
5.18, br s
1.81, br s
2.06, s
17.6, q
9.6, q
26.0, q
174.4, s
17.6, q
9.4, q
25.7, q
174.2, s
2.01, br s
1.98, br s
1.86, d (2.9)
1.92, br s
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Table 2 NMR spectroscopic data for synthetic and natural (+)-intricarene
Synthetic (+)-intricarene
Natural (+)-intricarene1
1H NMR
Position
1H NMR
13C NMR
13C NMR
1
2
3
4
5
6
7
8
9a
9b
10
11
12
13a
13b
14a
14b
15
16a
16b
17
18
19
20
3.39, dd (5.8, 11.9)
46.3, d
102.8, s
193.0, s
137.2, s
147.3, d
84.6, s
128.0, d
135.2, s
35.6, t
3.38, dd (5.7, 11.9)
46.4, d
102.8, s
193.0, s
137.2, s
147.3, d
84.6, s
128.1, d
135.2, s
35.7, t
6.28, q (1.6)
6.43–6.41, m
6.27, q (1.6)
6.41, q (1.6)
2.84, dd (8.6, 18.6)
2.42, br d (18.6)
4.78, ddd (2.6, 5.3, 8.6)
2.55, d (5.3)
2.82, dd (8.6, 18.6)
2.41, br d (18.6)
4.77, ddd (2.6, 5.3, 8.6)
2.54, d (5.3)
70.7, d
58.0, d
64.1, s
29.3, t
70.7, d
58.0, d
64.2, s
29.3, t
2.03–1.98, m
1.97–1.90, m
2.14–2.09, m
1.97–1.90, m
2.01, m
1.92, m
2.11, m
1.91, m
28.5, t
28.5, t
141.7, s
113.3, t
141.8, s
113.3, t
4.93, q (1.3)
4.88, br s
1.76, br s
1.77, d (1.6)
1.85, t (1.4)
4.92, q (1.3)
4.86, br s
1.75, br s
1.76, d (1.6)
1.84, t (1.2)
23.2, q
14.4, q
23.1, q
178.0, s
23.1, q
14.4, q
23.0, q
177.9, s
from the oxidopyrylium ion intermediate 9, described earlier
(Scheme 1).
Thus, oxidation of the furan ring in (-)-bipinnatin J (4a), using
VO(acac)2 and tBuO2H, followed by in situ rearrangement and
tautomerisation, led to a mixture of isomers of presumably the ene-
dione 7 and the hydroxypyranone 8 (Scheme 6). Unfortunately the
hydroxypyranone 8 could not be easily purified and properly char-
acterised. It was therefore acetylated, using Ac2O–Et3N, leading
to the corresponding acetoxypyranone 30 which was obtained as
a relatively stable oil. When a solution of the acetoxypyranone
30 in acetonitrile was heated under reflux in the presence of
diazobicycloundecane it underwent the anticipated transannular
[5 + 2] cycloaddition, via the presumed oxidopyrylium ion 31
(cf 9), leading to (+)-intricarene 1 in an unoptimised yield
1
of 10%. The synthetic intricarene displayed H and 13C NMR
spectroscopic data that were superimposable on those recorded
for the natural product isolated from P. kallos1 (Table 2).
In contemporaneous studies Trauner et al.11 also converted their
synthetic bipinnatin J into intricarene using similar conditions to
our own. However, with a more plentiful amount of bipinnatin J
than we had been able to amass at the time, Trauner et al.
were able to achieve upwards of 26% yield in the conversion
of the acetoxypyrone 30 into intricarene under the optimum
conditions of heating 30 in DMSO at 150 ◦C in the presence
of tetramethylpiperidine.
The transannular cyclisation of 30 leading to the pentacyclic
system in intricarene occurred with endo selectivity. It is likely
that the crowded nature of this endo transition state, viz 31, and
the strain inherent in the pentacycle 1 could conspire to allow
competing dimerisations of the oxidopyrylium ion intermediate
31 to take place, thus accounting for the disappointing yield in
the overall conversion of 30 into 1. Unfortunately, the dearth of
materials did not allow us to characterise any “dimers” unam-
Scheme 6 Reagents and conditions: (i) VO(acac)2, tBuOOH, DCM,
-20 ◦C, 4 h; (ii) Ac2O, Et3N, DMAP (cat.), DCM, 0 ◦C– r.t., 2.5 h, 30%
over two steps; (iii) DBU, CH3CN, reflux, 1.2 h, 10%.
biguously. However, it is significant that Hendrickson and Farina27
established many years ago that when simple oxidopyrylium ions
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are produced in the absence of a dipolarophile they are indeed
prone to undergo dimerisation, viz 32 → 33.
Experimental
General details
All melting points were determined using a Kofler hot-stage or
Bibby Stuart Scientific SMP3 apparatus, and are uncorrected.
Infrared spectra were obtained on a Perkin-Elmer 1600 series
FTIR instrument as liquid films or as dilute solutions in spec-
troscopic grade chloroform. The abbreviation ‘br’ refers to a
broad absorption. Optical rotations were recorded on a JASCO
DIP 370 polarimeter. Proton NMR spectra were recorded on
a Bruker DPX360 (360 MHz), Bruker AM 400 (400 MHz) or
Bruker DRX 500 (500 MHz) spectrometer as dilute solutions
in deuteriochloroform at ambient temperature, unless stated
otherwise. The chemical shifts are quoted in parts per million
(ppm) relative to residual solvent peaks, and the multiplicity of
each signal is designated by the following abbreviations: s (singlet),
d (doublet), t (triplet), q (quartet), br (broad), m (multiplet)
and app (apparent). All coupling constants are quoted in Hertz.
Assignments were made on the basis of chemical shift, COSY and
HMQC experiments recorded on a Bruker AM 400 (400 MHz)
instrument and standard Bruker software with no modifications.
Carbon-13 NMR spectra were recorded using a Bruker DPX360
(90 MHz), Bruker AM 400 (101 MHz) or Bruker DRX500
(126 MHz) instrument as dilute solutions in deuteriochloroform,
unless stated otherwise. Chemical shifts are quoted in parts
per million (ppm) downfield of tetramethylsilane, spectra being
referenced to residual protonated solvent (dH = 77.0 p.p.m. for
CDCl3). Assignments were made on the basis of chemical shift
using the DEPT sequence. Abbreviations used in the description
of resonances are: s (singlet, quaternary), d (doublet, CH), t
(triplet, CH2), q (quartet CH3). Mass spectra were recorded on
either a VG Autospec, an MM-701CF, a VG Micromass 7070E
or a Micromass LCT spectrometer, using electron ionisation (EI),
electrospray (ESI) or fast atom bombardment (FAB) techniques.
High-resolution mass spectrometry data are calculated from the
molecular formula corresponding to the observed signal using the
most abundant isotopes of each element, to four decimal places.
Microanalytical data were obtained on a Perkin-Elmer 240B
elemental analyser. Flash chromatography was performed using
Merck silica gel 60 (230–400 mesh ASTM) as the stationary phase,
and the solvents employed were of analytical grade; the “petrol”
used in chromatography refers to light petroleum, bp 40–60 ◦C. All
reactions were monitored by thin layer chromatography (TLC) us-
ing aluminium plates precoated with Merck silica gel 60 F254, which
were visualised with ultraviolet light (lmax = 254 nm), and then
with either acidic alcoholic vanillin solution, phosphomolybdic
acid solution, basic potassium permanganate solution, or acidic
anisaldehyde solution. Unless stated otherwise, reactions requiring
anhydrous conditions were conducted in an inert atmosphere of
nitrogen in flame-dried or oven-dried apparatus. Molecular sieves
were stored in a hot oven before use. Dry organic solvents were
routinely stored under a nitrogen atmosphere and/or dried over
sodium wire. Dichloromethane, triethylamine and pyridine were
distilled from calcium hydride. Dry tetrahydrofuran and benzene
were distilled from sodium and benzophenone. Methanol and
ethanol were distilled from magnesium methoxide and magne-
sium ethoxide respectively. Anhydrous dimethylformamide and
dimethyl sulfoxide were obtained from Aldrich. Solvents were
Following the publication of our synthesis of intricarene 1
from bipinnatin J (4a) via the intermediate 8, Rodr´ıguez and his
colleagues28 reported the presence of the hydroxypyranones 34
and 35 in Pseudopterogorgia kallos. The structural relationship
between the hydroxypyrananes 34 (“bipinnatin N”) and 8 is
uncanny and provides considerable credence to our speculated
biosynthetic route to intricarene in P. kallos, i.e. 4a → 8 →
1. In passing, it may be significant that bipinnatin N (34) is
the oxy analogue of the hydroxypyranone 8, but where the
epoxide is derived from a D7,8 double bond precursor with the
E-configuration; cf the Z-configured D7,8 double bond in 8.
Conclusions
In summary, a total synthesis of the novel pentacyclic diterpene in-
tricarene has been achieved, based on biomimetic speculation that
the natural product is derived in vivo from the furanobutenolide-
based natural product bipinnatin J (4a), involving oxidation to 8,
followed by an unprecedented transannular dipolar cycloaddition,
viz 31 → 1. Following publication of our work in preliminary
form,4 Wang and Tantillo29 examined the dipolar cycloaddition
reaction 31 → 1 using quantum chemical calculations. These
authors concluded that although an enzyme is probably needed
to generate and organise the oxidopyrylium species 31, the
subsequent transannular cycloaddition reaction leading to 1 has a
sufficiently low activation barrier, i.e. approximately 20 kcal/mol,
that an enzyme is unlikely to be involved in this part of the
conversion. It is probable that other polycyclic diterpenes found
in gorgonian octocals, e.g. bielschowskysin 2, also have their
origin in related furanobutenolide-based macrocyclic diterpenes,
and involve related oxidative transformations and intramolecular
pericyclic and other cyclisations in their biosynthesis. Investiga-
tions are in progress in our laboratory to probe some of these
related biogenetic interconnections, through synthesis, and will be
described in due course.
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removed in vacuo at approx. 20 mm Hg using a Bu¨chi rotary
evaporator.
25.9 (t), 18.4 (s), 13.4 (q), -5.3 (2 ¥ q); HRMS (ESI) 465.1335
(M + Na+, C21H34O3SeSiNa requires 465.1340).
The NMR spectroscopic data for compounds 1, 4a and 28,
are assigned using the conventional numbering pattern for the
cembranes and their relatives shown on structure 4.
Acetic acid (E)-6-(tert-butyl-dimethyl-silanyloxy)-1-((Z)-(S)-2-
hydroxy-5-iodo-4-methyl-pent-4-enyl)-5-methyl-1-phenylselanyl-
hex-4-enyl ester 24a. A solution of NaHMDS (2.0 M) in THF
(1.50 ml, 3.0 mmol) was added dropwise via a syringe over 5 mins
to a stirred solution of the selan◦yl ester 23 (1.30 g, 2.94 mmol) in
anhydrous THF (20 ml) at -78 C under a nitrogen atmosphere.
The mixture was stirred at -78 ◦C for 0.5 hr, and then a solution
of the oxirane 16 (453 mg, 2.02 mmol) in anhydrous THF (10 ml)
was added dropwise via a cannula over 3 mins, followed by the
addition of BF3·OEt2 (287 mg, 2.02 mmol) dropwise via a syringe
over 5 mins. The stirred mixture was allowed to warm to room
temperature overnight and then it was quenched with a saturated
solution of aqueous NH4Cl (15 ml). The resulting solution was
diluted with water (30 ml) and Et2O (100 ml) and the separated
aqueous layer was then extracted with Et2O (3 ¥ 30 ml). The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. The residue was purified by chromatography on silica,
eluting with light petroleum-diethyl ether (5:1), to give a mixture of
diastereoisomer of the b-hydroxy ester (964 mg, 72%) as a yellow
oil, which was used in the next step.
(E)-7-(tert-Butyl-dimethyl-silanyloxy)-6-methyl-hept-5-enoic
acid methyl ester 22b. t-Butyldimethylsilyl chloride (576 mg,
3.84 mmol) and imidazole (285 mg, 4.19 mmol) were added in
one portion to a stirred solution of the alcohol 22a23 (600 mg,
3.49 mmol) in DMF (1.8 ml) at 0 ◦C. The mixture was stirred at
◦
0 C for 10 mins and then diluted with ether. The ether solution
mixture was washed with water (10 ml) and brine (5 ml), then dried
(Na2SO4) and concentrated in vacuo. The residue was purified
by chromatography on silica, eluting with light petroleum-diethyl
ether (30: 1), to give the silyl ether (897 mg, 90%) as colourless oil.
(Found: C, 62.9; H, 10.6. C15H30O3Si requires C, 62.9; H, 10.5%);
nmax (film)/cm-1 1741; dH (360 MHz; CDCl3) 5.39–5.35 (1 H, m,
=
CH), 4.01 (2 H, br s, TBSOCH2), 3.68 (3 H, s, CH3O), 2.32 (2
=
=
H, t, J 7.5, O CCH2), 2.07 (2 H, app. q, J 7.5, CH2CH ), 1.70
=
=
(2 H, p, J 7.5, CH2CH2CH ), 1.59 (3 H, s, CCH3), 0.91 (9 H, s,
TBS), 0.07 (6 H, s, TBS); dC (90 MHz, CDCl3) 174.1 (s), 135.4 (s),
123.2 (d), 68.4 (t), 51.4 (q), 33.5 (t), 26.8 (t), 25.9 (3 ¥ q), 24.7 (t),
18.4 (s), 13.4 (q), -5.3 (2 ¥ q). HRMS (ESI) 309.1851 (M + Na+,
C15H30O3SiNa requires 309.1862).
For characterization purposes, the diastereoisomers were sep-
arated by flash chromatography on silica, eluting with light
petroleum-diethyl ether (10:1), to give: i) a less polar diastereoiso-
mer (Found: C, 49.1; H, 6.5. C27H43IO4SeSi requires C, 48.7; H,
(E)-7-(tert-Butyl-dimethyl-silanyloxy)-6-methyl-2-phenylsel-
anyl-hept-5-enoic acid methyl ester 23. A solution of nBuLi
(2.5 M) in hexane (8.0 ml, 20 mmol) was added dropwise over
5 mins to a stirred solution of diisopropylamine (2.02 g, 2.8 ml,
6.5%): [a]D -12.4 (c 1.0, CHCl3); nmax (film)/cm-1 3509, 1724,
25
837; dH (400 MHz; CDCl3) 7.60–7.58 (2 H, m, PhH), 7.41–7.38 (1
◦
=
20 mmol) in anhydrous THF (9.19 ml) at◦0 C under a nitrogen
H, m, PhH), 7.33–7.27 (2 H, m, PhH), 6.02 (1 H, br s, ICH ),
=
atmosphere. The mixture was stirred at 0 C for 0.5 hr and then
kept at 0 ◦C to use in the next step as a 1.0 M solution of LDA in
THF.
5.31 (1 H, t, J 6.7, CH2CH ), 4.39–4.38 (1 H, m, CHOH), 3.98
(2 H, br s, CH2OTBS), 3.65 (3 H, s, OCH3), 2.71 (1 H, d, J
=
4.1, OH), 2.47 (1 H, dd, J 8.1 and 13.3, C(CH3)CHHCHOH),
As described by Chu et al.,24 a solution of freshly prepared
LDA (14.4 ml, 14.4 mmol, 1.0 M) in THF was added dropwise
over 5 mins to a stirred solution of the ester 22b (3.74 g, 13.1 mmol)
in anhydrous THF (52 ml) at -78 ◦C under a nitrogen atmosphere.
2.36 (1 H, dd, J 5.1 and 13.3, C(CH3)CHHCHOH), 2.31–2.22
=
=
=
(1 H, m, CHCHHCH2), 2.17–2.07 (2 H, m, CHCHHCH2
and CH(OH)CHH), 1.99–1.98 (3 H, m, ICH C(CH3)), 1.90–
1.80 (3 H, m, CH(OH)CHH and CHCH2CH2), 1.60 (3 H, s,
C(CH3)), 0.91 (9 H, s, TBS), 0.06 (6 H, s, TBS); dC (100 MHZ;
=
=
◦
=
The mixture was stirred at -78 C for 45 mins and then TMSCl
(1.56 g, 1.8 ml, 14.4 mmol) was added dropwise over 1 min. The
mixture was stirred at -78 ◦C for 0.5 hr, and then a solution
of PhSeBr (3.39 g, 14.4 mmol) in anhydrous THF (21 ml) was
added dropwise over 10 mins. The mixture was stirred at -78 ◦C
for 0.5 hr, and then allowed to warm to room temperature over
0.5 hr. The mixture was quenched with a saturated solution of
aqueous NH4Cl (130 ml), then diluted with water (150 ml) and
Et2O (300 ml). The separated aqueous layer was extracted with
Et2O (3 ¥ 80 ml) and the combined organic extracts were then dried
(MgSO4), and concentrated in vacuo. The residue was purified
by chromatography on silica, eluting with light petroleum-diethyl
ether (30:1), to give the a-selanyl ester (4.20 g, 73%) as a yellow
oil (Found: C, 57.5; H, 7.8. C21H34O3SeSi requires C, 57.1; H,
7.7%); nmax (film)/cm-1 1732; dH (400 MHz; CDCl3) 7.61–7.58 (2
CDCl3) 174.3 (s), 144.8 (s), 138.0 (2 ¥ d), 135.3 (s), 129.3 (d),
128.8 (2 ¥ d), 126.6 (s), 122.7 (d), 76.8 (d), 68.3 (t), 68.2 (d), 55.9
(s), 52.2 (q), 46.7 (t), 42.8 (t), 36.6 (t), 25.9 (3 ¥ q), 24.8 (q), 23.8
(t), 18.4 (s), 13.5 (q), -5.3 (2 ¥ q); HRMS (ESI) 689.1024 (M +
Na+, C27H43IO4SeSiNa requires 689.1038), and ii) a more polar
diastereoisomer (Found: C, 49.3; H, 6.4. C27H43IO4SeSi requires
C, 48.7; H, 6.5%). [a]D -3.76 (c 1.22, CHCl3); nmax (film)/cm-1
22
3492, 1723, 837; dH (400 MHz; CDCl3) 7.59–7.57 (2 H, m, PhH),
7.42–7.38 (1 H, m, PhH), 7.34–7.30 (2 H, m, PhH), 6.01 (1 H, br s,
=
=
ICH ), 5.36 (1 H, t, J 6.9, CH2CH ), 4.10–4.04 (1 H, m, CHOH),
4.00 (2 H, br s, CH2OTBS), 3.63 (3 H, s, OCH3), 2.45–2.33 (3 H,
=
=
m, C(CH3)CH2CHOH and CHCHHCH2), 2.29–2.22 (1 H,
=
m, CH(OH)CHH), 2.19–2.07 (2 H, m, CHCHHCH2 and OH),
=
2.04–1.86 (3 H, m, CH(OH)CHH and CHCH2CH2), 1.95 (3 H,
=
=
=
H, m, PhH), 7.32–7.29 (3 H, m, PhH), 5.33 (1 H, m, CH), 3.99
(2 H, s, TBSOCH2), 3.64 (3 H, s, CH3O), 3.67–3.61 (1 H, m,
br s, ICH C(CH3)), 1.63 (3 H, s, C(CH3)), 0.92 (9 H, s, TBS),
0.07 (6 H, s, TBS); dC (100 MHz; CDCl3) 174.8 (s), 144.6 (s), 137.9
(2 ¥ d), 135.2 (s), 129.4 (d), 128.8 (2 ¥ d), 126.6 (s), 123.0 (d),
76.9 (d), 68.4 (t), 68.0 (d), 54.4 (s), 52.2 (q), 47.2 (t), 41.6 (t), 33.3
(t), 25.9 (3 ¥ q), 24.8 (q), 23.5 (t), 18.4 (s), 13.6 (q), -5.3 (2 ¥
q); HRMS (ESI) 689.0999 (M + Na+, C27H43IO4SeSiNa requires
689.1038).
=
(PhSe)CH), 2.18–2.10 (2 H, m, CH2CH2C ), 2.05–1.94 (1 H,
m, (PhSe)CHCHH), 1.86–1.77 (1 H, m, (PhSe)CHCHH), 1.57 (3
=
H, s, CCH3), 0.91 (9 H, s, TBS), 0.06 (6 H, s, TBS); dC (90 MHz;
CDCl3) 173.4 (s), 136.0 (s), 135.6 (2 ¥ d), 129.0 (2 ¥ d), 128.5 (d),
127.7 (s), 122.2 (d), 68.3 (t), 52.0 (q), 42.8 (d), 31.5 (t), 25.9 (3 ¥ q),
4454 | Org. Biomol. Chem., 2009, 7, 4448–4457
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(S)-3-[(E)-5-(tert-Butyl-dimethyl-silanyloxy)-4-methyl-pent-3-
enyl]-5-((Z)-3-iodo-2-methyl-allyl)-3-phenylselanyl-dihydro-furan-
2-one 25. p-Toluenesulfonic acid monohydrate (92.7 mg,
0.487 mmol) was added in one portion to a stirred solution of
a mixture of diastereoisomers of the b-hydroxyester 24a (3.24 g,
4.87 mmol) in DCM (487 ml) at room temperature. The mixture
was stirred at room temperature for 3 hrs, and then quenched with
a saturated solution of aqueous NaHCO3 (30 ml). The resulting
solution was diluted with water (30 ml) and DCM (100 ml), and the
separated aqueous layer was then extracted with DCM (3 ¥ 30 ml).
The combined organic extracts were dried (MgSO4), filtered and
concentrated in vacuo to leave a mixture of diastereoisomers of the
g -lactone (3.09 g, 95%) as a yellow oil which was used in the next
step without further purification.
(d), 68.2 (t), 42.3 (t), 25.2 (t), 25.0 (t), 24.6 (q), 13.6 (q); HRMS
(ESI) 385.0274 (M + Na+, C14H19IO3Na requires 385.0276).
5-{(Z)-3-[(S)-4-((E)-5-Hydroxy-4-methyl-pent-3-enyl)-5-oxo-
2,5-dihydro-furan-2-yl]-2-methyl-propenyl}-3-methyl-furan-2-car-
baldehyde 28a. Solutions of the (+)-vinyl iodide 26b (500 mg,
1.38 mmol) in DMF (5 ml), and the furanylstannane 275,26 (489 mg,
1.79 mmol) in DMF (4 ml) were degassed separately for 0.5 hr
with argon before they were added successively via cannula to a
stirred mixture of Pd(PPh3)4 (64 mg, 0.06 mmol), CuI (21 mg,
0.11 mmol) and CsF (419 mg, 2.8 mmol) at room temperature.
The resulting yellow mixture was stirred at room temperature for
20 mins, whereupon the colour of the mixture changed to brown,
first, then black. The mixture was poured into a mixture of a
saturated solution of aqueous NH4Cl (30 ml) and Et2O (30 ml)
and the separated aqueous layer was then extracted with Et2O (1 ¥
30 ml). The combined organic extracts were washed with brine
(20 ml), then dried (Na2SO4), and concentrated in vacuo. The
residue was purified by flash chromatography on silica, eluting
with light petroleum (bp 40–60 ◦C)-ethyl acetate (1:1), to give
(S)-3-[(E)-5-(tert-Butyl-dimethyl-silanyloxy)-4-methyl-pent-3-
enyl]-5-((Z)-3-iodo-2-methyl-allyl)-5H-furan-2-one 26a. Aque-
ous H2O2 (30% w/w in water, 1.49 ml, 14.6 mmol) was added
dropwise over 5 mins to a stirred solution of the selanyl g-lactone
25 (3.1 g, 4.9 mmol) in THF (70 ml) at 0 ◦C. The mixture was
stirred at 0 ◦C for 5 mins and then at room temperature for
2 hrs. The reaction was quenched with a saturated solution of
aqueous NaHCO3 (15 ml) and then diluted with Et2O (100 ml).
The separated organic extract was washed with H2O (2 ¥ 10 ml)
and brine (5 ml), then dried (MgSO4) and concentrated in vacuo
to leave the furanone (2.25 g, 97%) as yellow oil, which was used
without further purification. (Found: C, 50.3; H, 7.0. C20H33IO3Si
25
the furanobutenolide (427 mg, 90%) as a yellow viscous oil. [a]D
+56.4 (c 1.0, CHCl3); nmax (sol CHCl3)/cm-1 3478, 1746, 1658; dH
(360 MHz; CDCl3) 9.60 (1 H, s, H-2), 7.32 (1 H, br s, H-11),
6.18 (1 H, s, H-5), 6.17 (1 H, br s, H-7), 5.41–5.38 (1 H, m,
H-1), 5.13–5.08 (1 H, m, H-10), 3.99 (2 H, s, H-16), 3.21 (1 H,
d, J 13.0, H-9a), 2.48–2.28 (5 H, m, H-9b, H-13 and H-14),
2.34 (3 H, s, Me-18), 2.18 (1 H, br s, OH), 2.05 (3 H, d, J 1.3,
Me-19), 1.64 (3 H, s, Me-17); dC (100 MHZ; CDCl3) 175.5 (s),
173.8 (d), 156.9 (s), 149.1 (d), 147.4 (s), 141.9 (s), 136.5 (2 ¥ s),
133.4 (s), 123.8 (d), 115.3 (d), 113.9 (d), 81.5 (d), 68.4 (t), 38.2 (t),
26.7 (q), 25.3 (t), 24.8 (t), 13.7 (q), 10.0 (q); HRMS (ESI) 367.1516
25
requires C, 50.4; H, 7.0%). [a]D +29.0 (c 1.20, CHCl3); nmax
(film)/cm-1 1759; dH (400 MHz; CDCl3) 7.09 (1 H, br s, CHCH ),
6.12 (1 H, br s, ICH ), 5.40–5.37 (1 H, m, CHCH2), 5.06–
=
=
=
=
5.02 (1 H, m, CHCH ), 4.01 (2 H, s, CH2OTBS), 2.67 (1 H,
dd, J 5.9 and 13.7, ICH C(CH3)CHH), 2.53 (1 H, dd, J 7.6
and 13.7, ICH C(CH3)CHH), 2.38–2.31 (4 H, m, CHCH2 and
CHCH2CH2), 2.00 (3 H, d, J 1.3, ICH C(CH3)), 1.61 (3 H, s,
=
1
(M + Na+, C20H24O5Na requires 367.1521). The IR, H NMR,
=
=
13C NMR and HRMS data were identical with those presented
contemporaneously in the literature for racemic material.5
=
=
=
C(CH3)), 0.91 (9 H, s, TBS), 0.06 (6 H, s, TBS); dC (100 MHz;
CDCl3) 173.3 (s), 147.6 (d), 142.4 (s), 135.9 (s), 134.1 (s), 122.4
(d), 79.4 (d), 78.4 (d), 68.2 (t), 42.5 (t), 25.9 (3 ¥ q), 25.2 (t), 25.2
(t), 24.8 (q), 18.4 (s), 13.5 (q), -5.3 (2 ¥ q); HRMS (ESI) 499.1141
(M + Na+, C20H33IO3SiNa requires 499.1141).
5-{(Z)-3-[(S)-4-((E)-5-Bromo-4-methyl-pent-3-enyl)-5-oxo-2,5-
dihydro-furan-2-yl]-2-methyl-propenyl}-3-methyl-furan-2-car-
baldehyde 28b. Triphenylphosphine (419 mg, 1.59 mmol) and
N-bromosuccinimide (284 mg, 1.59 mmol) were added to a stirred
solution of the (+)-alcohol 28a (427 mg, 1.24 mmol) in DCM
(30 ml) at -5 ◦C. The mixture was stirred at 0 ◦C for 20 mins,
and then poured into water (10 ml). The separated aqueous layer
was extracted with DCM (2 ¥ 30 ml), and the combined organic
extracts were then dried (Na2SO4) and concentrated in vacuo. The
residue was purified by flash chromatography on silica, eluting
with light petroleum (bp 40–60 ◦C)-ethyl acetate (4:1), to give
(S)-3-((E)-5-Hydroxy-4-methyl-pent-3-enyl)-5-((Z)-3-iodo-2-
methyl-allyl)-5H-furan-2-one 26b. Pyridinium p-toluenesul-
fonate (245 mg, 0.95 mmol) was added in one portion to a
solution of the TBS ether 26a (2.25 g, 4.72 mmol) in DCM
(140 ml) and MeOH (140 ml) and the mixture was stirred at
room temperature for 24 hrs and then concentrated in vacuo.
The residue was purified by chromatography on silica, eluting
with light petroleum (bp 40–60 ◦C)-ethyl acetate (1:2), to give
the alcohol (1.10 g, 62% over 3 steps) as an almost colourless
viscous oil (Found: C, 46.8; H, 5.3. C14H19IO3 requires C, 46.4; H,
27
the allyl bromide (400 mg, 80%) as a pale yellow oil. [a]D +59.8
(c 1.01, CHCl3); nmax (sol CHCl3)/cm-1 1754, 1660; dH (360 MHz;
CDCl3) 9.65 (1 H, s, H-2), 7.26 (1 H, br s, H-11), 6.19 (1 H, s,
H-5), 6.18 (1 H, br s, H-7), 5.55 (1 H, t, J 6.5, H-1), 5.15–5.11 (1
H, m, H-10), 3.93 (2 H, s, H-16), 3.17 (1 H, dd, J 3.8 and 13.4,
H-9a), 2.55 (1 H, dd, J 8.5 and 13.4, H-9b), 2.38–2.35 (2 H, m,
H-13a,b), 2.35 (3 H, s, Me-18), 2.31–2.28 (2 H, m, H-14a,b), 2.04
(3 H, d, J 1.3, Me-19), 1.74 (3 H, s, Me-17); dC (90 MHz; CDCl3)
175.5 (s), 173.3 (d), 156.5 (s), 148.9 (d), 147.3 (s), 140.8 (s), 135.7
(s), 133.3 (s), 132.9 (s), 129.2 (d), 115.5 (d), 113.9 (d), 81.0 (d), 41.0
(t), 38.0 (t), 26.5 (t), 25.8 (t), 24.4 (q), 14.5 (q), 10.0 (q); HRMS
(ESI) 429.0672 (M + Na+, C20H23BrO4Na requires 429.0676).
23
5.3%); [a]D +43.7 (c 1.27, CHCl3); nmax (film)/cm-1 3416, 1746;
=
dH (360 MHz; CDCl3) 7.12 (1 H, q, J 1.5, CHCH ), 6.13 (1 H,
q, J 1.5, ICH ), 5.44–5.40 (1 H, m, CHCH2), 5.07 (1 H, ddd, J
=
=
=
1.5, 6.0 and 7.4, CHCH ), 4.02 (2 H, d, J 6.1, CH2OH), 2.68 (1
H, dd, J 6.0 and 13.6, ICH C(CH3)CHH), 2.56 (1 H, dd, J 7.4
=
=
=
and 13.6, ICH C(CH3)CHH), 2.43–2.33 (4 H, m, CHCH2 and
=
=
CHCH2CH2), 2.00 (3 H, d, J 1.5, ICH C(CH3)), 1.68 (3 H, s,
=
C(CH3)), 1.34 (1 H, t, J 6.1, OH); dC (90 MHz; CDCl3) 173.3
(s), 147.7 (d), 142.2 (s), 136.1 (s), 133.7 (s), 123.5 (d), 79.3 (d), 78.4
This journal is
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©

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(-)-Bipinnatin J (4a). A solution of the (+)-allylbromo-
aldehyde 28b (220 mg, 0.54 mmol) in anhydrous THF (377 ml)
was degassed with nitrogen for 1 hr at room temperature, and
1710, 1677, 1613; dH (360 MHz; CDCl3) 7.16 (1 H, br, H-11), 6.42
(1 H, s, H-5), 6.31 (1 H, s, H-7), 5.80 (1 H, br s, H-2), 5.30 (1 H, d,
J 10, H-10), 4.92–4.88 (1 H, m, H-16a), 4.65 (1 H, br s, H-16b),
3.76 (1 H, d, J 14.6, H-9a), 3.23 (1 H, d, J 14.6, H-9b), 2.11 (3
H, s, OAc), 2.11 (3 H, s, Me-19), 2.01 (3 H, s, Me-18), 1.68 (3
H, s, Me-17); HRMS (ESI) 387.1802 (M + H+, C22H27O6 requires
387.1808), 409.1622 (M + Na+, C22H26O6Na requires 409.1627).
˚
then it was added via a cannula to a mixture of 4 A MS (activated
powder, 2.51 g) and anhydrous CrCl2 (1.37 g, 11.1 mmol) at room
temperature under an argon atmosphere. The resulting green-
coloured mixture was stirred at 25 ◦C for 16 hrs and then filtered
through celite. The filtrate was concentrated in vacuo and the
residue was diluted with Et2O (150 ml) and then washed with
water (2 ¥ 20 ml) and brine (10 ml). The separated organic extract
was dried (Na2SO4) and concentrated in vacuo to leave a residue
which was purified by chromatography on silica, eluting with light
petroleum-ethyl acetate (6:1), to give (-)-bipinnatin J (124 mg,
70%) as a colourless solid. mp 144–147 ◦C (EtOAc-petroleum),
(+)-Intricarene 1. A solution of DBU (8.67 mg, 0.057 mmol)
in degassed anhydrous CH3CN (60 ml) was added to the
6-acetoxypyranone 30 (20 mg, 0.052 mmol) at room temperature
under an atmosphere of argon. The mixture was stirred and
heated under reflux for 1.2 hrs under an argon atmosphere, then
cooled to room temperature and concentrated in vacuo. The
residue was purified by chromatography on silica, eluting with
light petroleum-diethyl ether (1:1), to give (+)-intricarene (1.7 mg,
10%) as colourless crystals. A satisfactory melting point could
Lit. mp 141–142 ◦C; [a]D27–129.9 (c 1.77, CHCl3), Lit [a]D -125.4
24
(c 1.65, CHCl3);7 nmax (sol CHCl3)/cm-1 3541, 1746; dH (360 MHz;
CDCl3) 6.86 (1 H, t, J 1.6, H-11), 6.12 (1 H, br s, H-7), 6.04 (1
H, s, H-5), 5.18 (1 H, br s, H-16b), 5.07 (1 H, s, H-16a), 5.02–4.99
(1 H, m, H-10), 4.51 (1 H, dd, J 2.9 and 10.9, H-2), 3.21 (1 H,
t, J 11.8, H-9b), 2.74 (1 H, dd, J 4.4, 11.8, H-9a), 2.46–2.35 (2
H, m, H-13b and H-1), 2.13–2.07 (1 H, m, H-13a), 2.06 (3 H, s,
Me-18), 2.01 (3 H, br s, Me-19), 1.86 (1 H, d, J 2.9, OH), 1.81
(3 H, br s, Me-17), 1.68 (1 H, tdd, J 3.3, 11.1 and 13.8, H-14b),
0.91 (1 H, dt, J 3.8, 13.8, H-14a); dC (90 MHz; CDCl3) 174.4
(s, C-20), 152.4 (d, C-11), 151.1 (s, C-6), 149.3 (s, C-3), 142.2
(s, C-15), 132.7 (s, C-12), 129.2 (s, C-8), 121.2 (s, C-4), 118.9 (t,
C-16), 117.5 (d, C-7), 114.0 (d, C-5), 78.8 (d, C-10), 65.1 (d, C-2),
51.3 (d, C-1), 39.8 (t, C-9), 30.2 (t, C-14), 26.0 (q, C-19), 19.8 (t,
C-13), 17.6 (q, C-17), 9.6 (q, C-18); HRMS (ESI) 351.1578 (M +
24
not be obtained as the crystals sublimed during heating. [a]D
+52.9 (c 0.14 CHCl3), Lit.1 [a]D +50.0 (c 0.7, CHCl3); nmax (sol
20
CHCl3)/cm-1 1769, 1702; dH (500 MHz; CDCl3) 6.43–6.41 (1 H,
m, H-7), 6.28 (1 H, q, J 1.6, H-5), 4.93 (1 H, q, J 1.3, H-16a),
4.88 (1 H, br s, H-16b), 4.78 (1 H, ddd, J 2.6, 5.3 and 8.6, H-10),
3.39 (1 H, dd, J 5.8 and 11.9, H-1), 2.84 (1 H, dd, J 8.6 and 18.6,
H-9a), 2.55 (1 H, d, J 5.3, H-11), 2.42 (1 H, br d, J 18.6, H-9b),
2.14–2.09 (1 H, m, H-14a), 2.03–1.98 (1 H, m, H-13a), 1.97–1.90
(2 H, m, H-13b and H-14b), 1.85 (3 H, t, J 1.4, Me-19), 1.77 (3 H,
d, J 1.6, Me-18), 1.76 (3 H, br s, Me-17); dC (125 MHZ; CDCl3)
193.0 (s), 178.0 (s), 147.3 (d), 141.7 (s), 137.2 (s), 135.2 (s), 128.0
(d), 113.3 (t), 102.8 (s), 84.6 (s), 70.7 (d), 64.1 (s), 58.0 (d), 46.3 (d),
35.6 (t), 29.3 (t), 28.5 (t), 23.2 (q), 23.1 (q), 14.4 (q); HRMS (ESI)
349.1410 (M + Na+, C20H22O4Na requires 349.1416). The IR, 1H
NMR, 13C NMR and HRMS were identical to those presented in
the literature for natural intricarene. Two additional compounds
(0.6 mg and 1.0 mg respectively) were also isolated but neither was
characterised. The HRMS (ESI) for the minor (0.6 mg) unknown
product showed: 387.1795 (M + H+, C22H27O6 requires 387.1808),
409.1610 (M + Na+, C22H26O6Na requires 409.1627), 404.2062
(M + NH4+ requires 404.2073); and the HRMS (ESI) for the major
(1 mg) unknown product: 387.1792 (M + H+, C22H27O6 requires
387.1808), 409.1610 (M + Na+, C22H26O6Na requires 409.1627),
Na+, C20H24O4Na requires 351.1572). The [a]D, IR, 1H NMR, 13
C
NMR and HRMS data were identical with those presented in the
literature for naturally-derived material.7
The 6-acetoxypyranone 30. Vanadyl(acetylacetate) (0.74 mg,
0.27 mmol) was added to a solution of synthetic (-)-bipinnatin J
(4a) (56 mg, 0.17 mmol) in anhydrous DCM (8 ml) at -20 ◦C
under a nitrogen atmosphere, followed by the addition of tBuOOH
(77.5 ml, 0.43 mmol, 5.5 M in decane). The mixture was stirred at
-20 ◦C for 4 hrs, and then poured into a mixture of DCM (20 ml)
and H2O (5 ml) at 0 ◦C. The two phase mixture was stirred at 0 ◦C
for 5 mins and the separated aqueous layer was then extracted
with DCM (pre-cooled to 5–10 ◦C, 2 ¥ 15 ml). The combined
organic extracts were washed with H2O (2 ¥ 4 ml) and brine (2 ¥
4 ml), then dried (Na2SO4), and concentrated in vacuo to leave a
yellow residue. The oil, which we believe consisted of a mixture of
tautomers of the cyclic hemiketal 8 was used immediately without
further purification. nmax (sol CHCl3)/cm-1 3534, 1754, 1671, 1626;
HRMS (ESI) 345.1697 (M + H+, C20H25O5 requires 345.1702),
367.1516 (M + Na+, C20H24O5Na requires 367.1521).
Triethylamine (172 mg, 236 ml, 1.7 mmol), acetic anhydride
(70 mg, 64 ml, 0.7 mmol) and DMAP (8.3 mg, 0.07 mmol) were
added to a solution of the crude cyclic hemiketal in anhydrous
DCM (8 ml) at 0 ◦C. The mixture was allowed to warm to room
temperature and stirred over 2.5 hrs, and then diluted with DCM
(50 ml). The solution was washed with H2O (3 ¥ 5 ml) and brine
(2 ¥ 3 ml), then dried (Na2SO4), and concentrated in vacuo. The
residue was purified by chromatography on silica, eluting with light
petroleum-ethyl acetate (5:1) to give 6-acetoxypyranone (20 mg,
30% over two steps) as a yellow oil. nmax (sol CHCl3)/cm-1 1754,
+
404.2051 (M + NH4 requires 404.2073).
Acknowledgements
We thank the University of Nottingham for a Dorothy Hodgkin
Postgraduate-Hutchinson Whampoa Award (to B.T), and for a
Post-doctoral Fellowship (to C.D. Bray).
References
1 J. Marrero, A. D. Rodriguez and C. L. Barnes, Org. Lett., 2005, 7,
1877–1880.
2 J. Marrero, A. D. Rodriguez, P. Baran, R. G. Raptis, J. A. Sanchez, E.
Ortega Barria and T. L. Capson, Org. Lett., 2004, 6, 1661–1664.
3 J. Marrero, A. D. Rodriguez, P. Baran and R. G. Raptis, Org. Lett.,
2003, 5, 2551–2554.
4 Preliminary communication: B. Tang, C. D. Bray and G. Pattenden,
Tetrahedron Lett., 2006, 47, 6401–6404.
5 P. A. Roethle and D. Trauner, Org. Lett., 2006, 8, 345–347.
6 Q. Huang and V. H. Rawal, Org. Lett., 2006, 8, 543–545.
7 A. D. Rodriguez and J.-G. Shi, J. Org. Chem., 1998, 63, 420–421.
4456 | Org. Biomol. Chem., 2009, 7, 4448–4457
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
8 J. B. Hendrickson and J. S. Farina, J. Org. Chem., 1980, 45, 3359–3361;
P. G. Sammes and L. J. Street, J. Chem. Soc., Perkin Trans. 1, 1983,
1261–1265.
17 See for example: G. Pattenden and D. J. Sinclair, J. Organomet. Chem.,
2002, 653, 261–268; H. W. Lam and G. Pattenden, Angew. Chem., 2002,
114, 526–29; N. K. Garg, S. Hiebert and L. E. Overman, Angew. Chem.,
2006, 118, 2978–2981; K. C. Nicolaou, D. Y.-K. Chen, Y. Li, N. Uesaka,
G. Petrovic, T. V. Koftis, F. Bernal, M. O. Frederick, M. Govindasamy,
T. Ling, P. M. Pihko, W. Tang and S. Vyskocil, J. Am. Chem. Soc.,
2006, 128, 2258–2267; P. Va and W. R. Roush, J. Am. Chem. Soc., 2006,
128, 15960–15961; N. K. Garg, S. Hiebert and L. E. Overman, Angew.
Chem., Int. Ed., 2006, 45, 2912–2915; K. C. Nicolaou, Y.-P. Sun, R.
Guduru, B. Banerji and D. Y.-K. Chen, J. Am. Chem. Soc., 2008, 130,
3633–3644; M. Tortosa, N. A. Yakelis and W. Roush, J. Am. Chem.
Soc., 2008, 130, 2722–2723.
9 For examples of the scope for intramolecular oxidopyrylium–alkene
[5 + 2] cycloadditions in synthesis see: S. M. Bromidge, P. G. Sammes
and L. J. Street, J. Chem. Soc., Perkin Trans., 1985, 1, 1725–1730; P. A.
Wender, K. D. Rice and M. E. Schnute, J. Am. Chem. Soc., 1997, 119,
7897–7898; W. Bauta, J. Booth, M. E. Bos, M. DeLuca, L. Diorazio,
T. Donohoe, N. Magnus, P. Magnus, J. Mendoza, P. Pye, J. Tarrant, S.
Thom and F. Ujjainwalla, Tetrahedron Lett., 1995, 36, 5327–5330.
10 For a recent review of the use of oxidopyrylium ions in synthesis see: V.
Singh, U. M. Krishna, Vikrant and G. K. Trivedi, Tetrahedron, 2008,
64, 3405–3428.
18 A. Fu¨rstner, Chem. Rev., 1999, 99, 991–1046.
11 P. A. Roethle, P. T. Hernandez and D. Trauner, Org. Lett., 2006, 8,
19 C. H. Heathcock, M. McLaughlin, J. Medina, J. L. Hubbs, G. A.
Wallace, R. Scott, M. M. Claffey, C. J. Hayes and G. R. Ott, J. Am.
Chem. Soc., 2003, 125, 12844–12849; K. C. Nicolaou, J.-K. Jung, W. H.
Yoon, Y. He, Y.-L. Zhong and P. S. Baran, Angew. Chem., Int. Ed.,
2000, 39, 1829–1832.
20 S Ma and E.-i. Negishi, J. Org. Chem., 1997, 62, 784–785.
21 P Galatsis, S. D. Millan and G. Ferguson, J. Org. Chem., 1997, 62,
5048–5056.
22 L. L. Klein, J. Org. Chem., 1985, 50, 1770–1773.
23 S Phoenix, E. Bourque and P. Deslongchamps, Org. Lett., 2000, 2,
4149–4152.
24 C. K. Chu, J. R. Babu, J. W. Beach, S. K. Ahn, H. Huang, L. S. Jeong
and S. J. Lee, J. Org. Chem., 1990, 55, 1418–1420.
25 For an alternative synthesis of the TBDPS ether of the (-)-alcohol 26b
see: M. Tsubuki, K. Takahashi, K. Sakata and T. Honda, Heterocycles,
2005, 65, 531–540.
5901–5904.
12 For a recent review covering aspects of these synthetic studies see:
P. A. Roethle and D. Trauner, Nat. Prod. Rep., 2008, 25, 298–317, and
references cited therein. For total syntheses see: C. M. Rayner, P. C.
Astles and L. A. Paquette, J. Am. Chem. Soc., 1992, 114, 3926–3936;
L. A. Paquette and P. C. Astles, J. Org. Chem., 1993, 58, 165–169;
J. A. Marshall and C. A. Sehon, J. Org. Chem., 1997, 62, 4313–4320;
J. A. Marshall and J. Liao, J. Org. Chem., 1998, 63, 5962–5970; J. A.
Marshall and E. A. Van Devender, J. Org. Chem., 2001, 66, 8037–8041;
T. J. Donohoe, A. Ironmonger and N. M. Kershaw, Angew. Chem., Int.
Ed., 2008, 47, 7314–7316, and references 5, 6 and 13a.
13 (a) M. Cases, F. Gonzalez-Lopez de Turiso and G. Pattenden, Synlett,
2001, 1869–1872; M. Cases, F. Gonzalez-Lopez de Turiso, M. S.
Hadjisoteriou and G. Pattenden, Org. Biomol. Chem., 2005, 3, 2786–
2804; (b) see also: I. Paterson, R. E. Brown and C. J. Urch, Tetrahedron
Lett., 1999, 40, 5807–5810.
26 F Roschangar, J. C. Brown, B. E. Cooley, M. J. Sharp and R. T.
Matsuoka, Tetrahedron, 2002, 58, 1657–1666.
14 T. Gaich, H. Weinstable and J. Mulzer, Synlett, 2009, 1357–1366.
15 J. A. Marshall and J. Liao, J. Org. Chem., 1998, 63, 5962–5970; M.
Tsubuki, K. Takahashi and T. Honda, J. Org. Chem., 2003, 68, 10183–
10186.
27 J. B. Hendrickson and J. S. Farina, J. Org. Chem., 1980, 45, 3361–3363.
28 J Marrero, J. Ben´ıtez, A. D. Rodr´ıguez, H. Zhao and R. G. Raptis,
J. Nat. Prod., 2008, 71, 381–389.
16 M. P. Astley and G. Pattenden, Synthesis, 1992, 101–105.
29 S. C. Wang and D. J. Tantillo, J. Org. Chem., 2008, 73, 1516–1523.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 4448–4457 | 4457
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