A biomimetic total synthesis of (+)-intricarene

Article abstract of DOI:10.1016/j.tetlet.2006.06.150

An asymmetric synthesis of the furanocembrane (-)-bipinnatin J (3a) found in gorgonian corals is described. Treatment of 3a with VO(acac)₂-^tBuOOH, followed by acetylation, gave acetoxypyranone 15. When 15 was heated in the presence o

Full text of DOI:10.1016/j.tetlet.2006.06.150

Tetrahedron Letters 47 (2006) 6401–6404
A biomimetic total synthesis of (+)-intricarene
Bencan Tang, Christopher D. Bray and Gerald Pattenden*
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, UK
Received 8 June 2006; accepted 27 June 2006
Abstract—An asymmetric synthesis of the furanocembrane (ꢀ)-bipinnatin J (3a) found in gorgonian corals is described. Treatment
of 3a with VO(acac)2-tBuOOH, followed by acetylation, gave acetoxypyranone 15. When 15 was heated in the presence of DBU, it
underwent a transannular oxidopyrylium-alkene [5+2] cycloaddition producing the polycyclic diterpene (+)-intricarene 1, isolated
from the coral Pseudopterogorgia kallos. The total synthesis of intricarene 1 mimics its most likely biosynthesis via oxidation of bi-
pinnatin J (3a) in vivo.
Ó 2006 Elsevier Ltd. All rights reserved.
Intricarene 1 and bielschowskysin 2 are two structurally
intriguing polycyclic diterpenes which have recently
O
been isolated from the coral Pseudopterogorgia kallos
O
by Rodriguez et al.1,2 Bielschowskysin 2 has been shown
H
to display specific in vivo cytotoxicity against cell lung
H
O
and renal cancer in the NCI antitumor screen; however,
due to the dearth of material, a detailed biological eval-
uation of intricarene 1 has not been possible at this time.
Diterpenes 1 and 2 are related as significantly rear-
ranged furanocembrane natural products, which we be-
lieve have their origins in the furanobutenolide structure
3.3 In the case of intricarene 1, the most plausible bioge-
netic precursor is 3a, which is a natural product, known
as bipinnatin J, found in P. bipinnata.4 Thus, oxidation
of 3a in vivo5 would be expected to lead to a precursor,
viz 4, to oxidopyrylium ion 5 which by way of transannu-
lar [5+2] cycloaddition6 with the butenolide double
bond should produce intricarene 1 (Scheme 1). In this
letter, we describe an asymmetric synthesis of (ꢀ)-bi-
pinnatin J (3a) followed by its conversion into (+)-intric-
arene 1 based on this biosynthesis speculation.
O
Intricarene 1
OH
H
HO
H
O
OH
H
O
O
H
H
O
OAc
Bielschowskysin 2
strategies described by Trauner and by Rawal, and uses
a similar combination of Pd(0)-mediated cross coupling
and Cr(II)-catalysed macrocyclisation protocols from
the central intermediate 13. Our synthesis of enantio-
merically pure 13 started from (+)-glycidol 6, however,
and was based on the chemistry we had earlier devel-
oped in our synthesis of the furanocembrane bis-
deoxylophotoxin.9
In contemporaneous investigations, Trauner and Rawal,
and their respective collaborators, have independently
drawn attention to the biosynthetic interrelationships
between furanobutenolide cembranes and the polycyclic
diterpenes 1 and 2, and both research groups have re-
cently reported a total synthesis of racemic bipinnatin
J (3a).7,8 Our asymmetric synthesis of (ꢀ)-bipinnatin J
(3a), presented here, has features in common with the
Thus, conversion of (+)-glycidol into the known alkyne-
diol 7,10 followed by carbometallation, isomerisation
and iodination, using the conditions described by Negi-
shi et al.11 first gave the Z-iodoalkene 8, which was next
transformed into the corresponding epoxide 9 in two
straightforward steps (Scheme 2). Epoxide 9 was now
added to a solution of the anion derived from the a-
selenylester 10 (NaHMDS, ꢀ78 °C),12 in the presence
of BF3ÆOEt2, which led to a 3:2 mixture of diastereoiso-
*
Corresponding author. Tel.: +44 115 951 3530; fax: +44 115 951
3535; e-mail: gerald.pattenden@nottingham.ac.uk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.150

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B. Tang et al. / Tetrahedron Letters 47 (2006) 6401–6404
O
H
HO
OH
OH
oxidation
O
O
O
O
R
O
O
O
O
O
O
3
4
H2O
O
a, R = H; b, R = OH
O
O
O
[5+2]cycloaddition
H
H
O
O
O
O
5
Intricarene
Scheme 1. Speculative biosynthetic route to intricarene 1 from bipinnatin J (3a).
OH
OH
O
O
i,ii
iii
iv,v
OH
OH
OH
vi
I
I
6
8
9
7
I
SePh
SePh
vii
OTBS
OTBS
MeO2C
OH CO2Me
11
10
OR
PhSe
I
I
OTBS
viii
x
O
O
O
O
a
b
c
, R = TBS
, R = H
, R = MOM
ix
13
12
R
CHO
OH
O
O
xii
O
O
O
O
3a
14
a
b
, R = OH
, R = Br
(−)-Bipinnatin J
xi
Scheme 2. Reagents and conditions: (i) TMS-acetylene, nBuLi, BF3ÆOEt2, ꢀ78 °C to ꢀ30 °C, 97%; (ii) K2CO3, MeOH/THF, rt, 92%; (iii) Cp2ZrCl2,
AlMe3, (CH2Cl)2 rt, then reflux three days, then I2, THF, ꢀ30 °C to 0 °C; (iv) TsCl, C5H5N, 0–3 °C, 48% over two steps; (v) K2CO3, MeOH, 73%;
(vi) NaHMDS, THF, ꢀ78 °C, then 9, BF3ÆOEt2, ꢀ78 °C to rt, 60%; (vii) p-TSA, CH2Cl2, rt; (viii) H2O2, THF, 0 °C to rt; (ix) PPTS (cat.), CH2Cl2/
MeOH, 62% over three steps; (x) 3-methyl-5-trimethylstannylfurfural, Pd(PPh3)4, CuI, CsF, DMF; (xi) Ph3P, NBS, 72% over two steps; (xii) CrCl2,
˚
4 A MS, THF, 70%.
mers of adduct 11 in 60% yield. Treatment of 11 with p-
TSA next gave c-lactone 12 which, following oxidative
elimination of PhSeOH, produced the corresponding
butenolide 13a.9 Deprotection of the TBS group in 13a
then gave the enantiomerically pure alcohol-vinyl iodide
intermediate 13b. Racemic alcohol 13b and its MOM
ether 13c were prepared by different routes by Trauner7
and Rawal8, respectively. These research groups con-
verted intermediate 13 into ( )-bipinnatin J using essen-
tially the same synthetic steps which we have followed
here. Thus, a Pd(0)-catalysed coupling reaction between
the vinyl iodide 13b and 3-methyl-5-trimethylstannyl-
furfural first gave the enantiomerically pure furanobuten-
olide 14a.7 Bromination of 14a using NBS/PPh3 next
led to bromide 14b, which then underwent a smooth dia-
stereoselective intramolecular cyclisation in the presence
of CrCl2 producing (ꢀ)-bipinnatin J (3a) in 70%
yield.13,14 The furanobutenolide 3a was obtained as

B. Tang et al. / Tetrahedron Letters 47 (2006) 6401–6404
6403
O
AcO
H
O
O
i,ii
iii
3a
O
5
H
H
O
O
O
O
15
(+)-Intricarene 1
t
Scheme 3. Reagents and conditions: (i), VO(acac)2, BuOOH, DCM, ꢀ20 °C; (ii), Ac2O, Et3N, DMAP(cat.), DCM, rt, 30% over two steps; (iii)
DBU, CH3CN, reflux, 1 h, 10%.
23
colourless crystals, mp 144–147 °C, ½aꢁD ꢀ103.3 (c 0.91,
References and notes
24
CHCl3); Lit mp 141–142 °C, ½aꢁD ꢀ125.4 (c 1.65,
CHCl3), and the H and 13C NMR spectra were super-
1
´
1. Marrero, J.; Rodrıguez, A. D.; Baran, P.; Raptis, R. G.;
´
Sanchez, J. A.; Ortega-Barria, E.; Capson, T. L. Org. Lett.
2004, 6, 1661–1664.
imposable on those reported for natural (ꢀ)-bipinnatin
J isolated from P. bipinnata.
´
2. Marrero, J.; Rodrıguez, A. D.; Barnes, C. L. Org. Lett.
2005, 7, 1877–1880.
We were now in the position to investigate the proposed
biogenetically patterned conversion of our (ꢀ)-bipinna-
tin J (3a) into intricarene 1, implicating a transannular
[5+2] cycloaddition reaction from the oxidopyrylium
ion-alkene species 5 (Scheme 1).6 Thus, treatment of
3. For some complementary studies with the methylenecy-
clobutanol-based furanbutenolide diterpene providencin,
which co-occurs with bielschowskysin and intricarene in
P. kollas, see: Bray, C. D.; Pattenden, G. Tetrahedron Lett.
2006, 47, 3937–3939.
t
´
(ꢀ)-bipinnatin J (3a) with VO(acac)2 and BuOOH re-
4. Rodrıguez, A. D.; Shi, J.-G. J. Org. Chem. 1998, 63, 420–
421.
sulted in oxidative ring expansion of the furan moiety
in 3a and the formation of a mixture of tautomers of
the presumed enedione-hydroxypyrone 4, which could
not be purified and adequately characterised. Instead,
the product from oxidation was acetylated, using
Ac2O–Et3N in DCM at room temperature leading to
6-acetoxypyranone 15 (Scheme 3) as a 5:1 mixture of
C-6 epimers. When a solution of acetoxypyranone 15
in acetonitrile was heated under reflux in the presence
of DBU, the anticipated transannular [5+2] cycloaddi-
tion involving the oxidopyrylium ion 5 took place giving
(+)-intricarene 1 in an unoptimised 10% yield.15 The
synthetic (+)-intricarene was obtained as colourless
5. This process is likely to involve photochemically generated
singlet oxygen, cf. Look, S. A.; Burch, M. T.; Fenical, W.;
Zheng, Q.; Clardy, J. J. Org. Chem. 1985, 50, 5741–5746.
6. For some earlier examples of the scope for oxidopyrylium-
alkene [5+2] cycloadditions in synthesis, see: (a) Hend-
rickson, J. B.; Farina, J. S. J. Org. Chem. 1980, 45, 3359–
3361; (b) Bromidge, S. M.; Sammes, P. G.; Street, L. J. J.
Chem. Soc., Perkin Trans. 1 1985, 1725–1730; (c) Wender,
P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997,
119, 7897–7898.
7. Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345–347.
8. Huang, Q.; Rawal, V. H. Org. Lett. 2006, 8, 543–545.
9. Cases, M.; Gonzalez-Lopez de Turiso, F.; Hadjisoteriou, M.
S.; Pattenden, G. Org. Biomol. Chem. 2005, 3, 2786–2804.
10. cf (a) Nicolaou, K. C.; Jung, J.-K.; Yoon, W. H.; He, Y.;
Zhong, Y.-L.; Baran, P. S. Angew. Chem. Int. Ed. 2000, 39,
1829–1832; (b) Heathcock, C. H.; McLaughlin, M.;
Medina, J.; Hubbs, J. L.; Wallace, G. A.; Scott, R.;
Claffey, M. M.; Hayes, C. J.; Ott, G. R. J. Am. Chem. Soc.
2003, 125, 12844–12849.
24
20
crystals, ½aꢁD +52.9 (c 0.136, CHCl3); Lit ½aꢁD +50.0 (c
0.7, CHCl3) whose infrared, and 1H and 13C NMR
spectra were superimposable on those recorded for the
natural product isolated from P. kallos.
In summary, we have achieved an asymmetric synthesis
of the furanobutenolide cembrane (ꢀ)-bipinnatin J (3a)
and demonstrated that it can be converted into the
intriguing pentacyclic natural product (+)-intricarene
1, following oxidation to 4 and transannular oxidopyry-
lium-alkene [5+2] cycloaddition involving species 5. We
believe that our synthesis of intricarene demonstrates a
clear biosynthetic relationship with bipinnatin J, and is
therefore biomimetic. Further biomimetic studies are
now in progress to probe links between other families
of structurally intriguing and biologically important nat-
ural products isolated recently from corals, including
bielschowskysin 2.
11. Ma, S.; Negishi, E.-i. J. Org. Chem. 1997, 62, 784–
785.
12. a-Selenylester 10 was prepared from the correspond-
ing, known, methyl E-7-hydroxy-6-methylhept-5-enoate
(Phoenix, S.; Bourque, E.; Deslongchamps, P. Org. Lett.
2000, 2, 4149–4152.) by (i) protection of the alcohol as its
TBS ether (TBSCl, imidazole, DMF, 0 °C, 90%), followed
by (ii) phenylselenylation using LDA, THF, TMSCl,
PhSeBr, ꢀ78 °C to 20 °C, 97%.
13. The diastereoselectivity in the formation of (ꢀ)-bipinnatin
J using the procedure of Rawal 8 was >80%, and the minor
diastereoisomers were eliminated by routine chromato-
graphy. Trauner7 used the Nozaki-Hiyama-Kishi condi-
tions, that is, CrCl2/NiCl2, and obtained a diastereo-
selectivity of approx. 90%.
14. (a) This CrCl2-mediated macrocyclisation protocol was
used earlier by Paquette et al. in their synthesis of the
furanobutenolide cembrane acerosolide (Paquette, L. A.;
Astles, P. C. J. Org. Chem. 1993, 58, 165–169.) and other
Acknowledgements
We thank the University of Nottingham for a Dorothy
Hodgkin Postgraduate-Hutchinson Whampoa Award
(to B.T.).
cembranes; For a recent review, see: (b) Furstner, A.
¨
Chem. Rev. 1999, 99, 991–1046.

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B. Tang et al. / Tetrahedron Letters 47 (2006) 6401–6404
15. The yield of intricarene 1 was not optimised due to the
relative dearth of (ꢀ)-bipinnatin J (3a) available. An
analysis of molecular models demonstrates a demanding
endo transition state for the transannular [5+2]
cycloaddition of 5. It is likely therefore that dimerisation
of the oxidopyrylium species 5, for example, com-
petes with the cycloaddition under unfavourable
reaction conditions, and this feature requires further
investigation.
Following the completion of this manuscript for publica-
tion, we were informed that Professor D. Trauner had
also completed the synthesis of intricarene from bipinn-
atin J, using similar chemistry and with a similar outcome;
private communication from Professor Trauner.