Total synthesis of (-)-colombiasin A and (-)-elisapterosin B

Article abstract of DOI:10.1002/anie.200462268

Intramolecular cycloaddition reactions are central in the total syntheses of colombiasin A (1) and elisapterosin B (2) described, which use (-)-dihydrocarvone as the starting material. A Moore rearrangement of a vinylcyclobutene is used to initiate the cycloaddition.

Full text of DOI:10.1002/anie.200462268

Angewandte
Chemie
Natural Product Synthesis
Total Synthesis of (À)-Colombiasin A and
(À)-Elisapterosin B**
David C. Harrowven,* David D. Pascoe,
Daniela Demurtas, and Heather O. Bourne
Colombiasin A (1) and elisapterosin B (2) are recent addi-
tions to the family of diterpenes from the gorgonian octacoral
Pseudopterogorgia elisabethae.[1,2] Discovered by Rodriguez
et al., their unusual molecular architecture soon attracted
attention from the natural products community.[3] Initially,
colombiasin A proved the more popular target,[4] with total
syntheses being reported firstly by Nicolaou et al.[5] and then
by Kim and Rychnovsky.[6] The latter report also describes the
first total synthesis of (À)-elisapterosin B, a compound that
exhibits strong antiplasmodial activity against Plasmodium
falciparum, the parasite responsible for the most severe forms
of malaria.[3] A synthesis of (+)-elisapterosin B by Rawal
et al. followed soon after.[7] Herein we describe total synthe-
ses of both (À)-colombiasin A (1) and (À)-elisapterosin B (2)
Scheme 1. Synthesis of intermediate 14; ipc=2,6,6-trimethylbicy-
clo[3.1.1]hept-3-yl, NaHMDS=sodium hexamethyldisilazane, Ts=p-tol-
uenesulfonyl, DIBAL-H=diisobutylaluminum hydride.
in which a Moore rearrangement[8] of vinylcyclobutene 14 is
used to set up intramolecular [4+2][4–6] and [5+2][7,9] cyclo-
addition reactions leading to the target compounds.
Z and E dienones 11 was equilibrated to (E)-11 in near
quantitative yield with catalytic iodine.
The next step, a Shapiro reaction between dienone (E)-11
and squarate 12,[13] proved troublesome.[14] Though the
tosylhydrazone of (E)-11 was readily formed and isolated, it
gave triene 13 as the major product on treatment with
butyllithium and addition of squarate 12. By contrast, all
attempts to prepare and isolate the corresponding trisylhy-
drazone (trisyl = triisopropylbenzenesulfonyl), either directly
or indirectly,[15] met with failure. Monitoring the reaction by
NMR spectroscopy showed that the formation of the
trisylhydrazone was facile at room temperature in CDCl3,
and that it subsequently decomposed on prolonged standing.
Consequently, an in situ variant of the Shapiro reaction was
developed (Scheme 1). Trisylhydrazine and (E)-11 in THF
were first stirred at ambient temperature for 2 h before the
reaction mixture was cooled to À788C. Four equivalents of
nBuLi were then added and the temperature raised to À208C.
At this juncture squarate 12 was added, giving vinylcyclobu-
tene 14 in 36% yield.
Our synthesis of 14 (Scheme 1) began with (À)-dihydro-
carvone (3), which was reduced to alcohol 4 using LiAlH4.
Hydroboration with ((À)-ipc)2BH,[10] followed by oxidative
work-up gave diols 5 as a 5:2 mixture of diastereomers. These
were separated by a combination of column chromatography
and fractional crystallization. Sequential monotosylation to 6,
cyanide displacement to nitrile 7, and DIBAL-H reduction to
aldehyde 8 then allowed us to introduce the diene function by
means of a Julia reaction with 9.[11] Higher yields were
obtained using the Kocienski modification,[12] these condi-
tions giving 10 as a 3:1 mixture of Z and E isomers in 79%
yield. Swern oxidation followed, and the resulting mixture of
[*] Dr. D. C. Harrowven, D. D. Pascoe, D. Demurtas, Dr. H. O. Bourne
School of Chemistry
University of Southampton
Highfield, Southampton, SO171BJ (UK)
Fax: (+44)2380-596-805
The stage was now set for a Moore rearrangement of 14 to
hydroquinone 16,[8] a reaction that proceeded smoothly at
1108C in THF under microwave irradiation (Scheme 2).
After cooling to ambient temperature and stirring in air,
quinone 18 was isolated in a satisfying 80% yield. Heating a
toluene solution of 18 in the dark at 1508C, either conven-
E-mail: dch2@soton.ac.uk
[**] Financial support from EPSRC, Pfizer, and the University of
Southampton is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 1221 –1222
DOI: 10.1002/anie.200462268
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1221

Communications
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Scheme 2. Total syntheses of (À)-colombiasin A (1) and (À)-elisapter-
osin B (2) starting with 14.
tionally or in the microwave oven, induced an intramolecular
Diels–Alder cycloaddition to (À)-colombiasin A tert-butyl
ether 17.[4–6] Attempts to effect removal of the protective
group with TiCl4 succeeded in that task,[16] but also led to
À
Markovnikov addition of HCl across the sensitive C10 C11
double bond.[5] Deprotection with diethyl ether–trifluorobor-
ane however, proceeded cleanly to complete a total synthesis
of (À)-colombiasin A (1). Notably, exposing quinone 18 to
diethyl ether–trifluoroborane induced both deprotection of
the tert-butyl ether and an intramolecular [5+2] cycloaddition
to give (À)-elisapterosin B (2);[6] our synthetic samples of 1
and 2 exhibit physical and spectral characteristics identical to
those reported for the natural products.[1,2]
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In conclusion, stereocontrolled syntheses of (À)-colom-
biasin A (1) and (À)-elisapterosin B (2) have been achieved,
in twelve and eleven steps respectively from (À)-dihydrocar-
vone (3). The problematic C7 stereocenter was established by
hydroboration with ((À)-ipc)2BH, and the use of a tert-butyl
protective group ensured that deprotection could be accom-
[17] G. Zanoni, M. Franzini, Angew. Chem. 2004, 116, 4942 – 4946;
Angew. Chem. Int. Ed. 2004, 43, 4837 – 4841
À
plished in high yield without disruption of the sensitive C10
C11 double bond.[5] A distinctive feature of our approach is
the use of a Moore rearrangement to set up intramolecular
[4+2] and [5+2] cycloaddition reactions, leading to (À)-
colombiasin A (1) and (À)-elisapterosin B (2) respectively.
Studies are underway to further develop and improve the
in situ Shapiro reaction and to apply the “reagent-free”
rearrangement sequence in syntheses of related natural
products such as elisapterosins A and D.[2,3,17]
Received: October 11, 2004
Keywords: cycloaddition · diterpenes · marine natural products ·
.
rearrangement · total synthesis
[1] A. D. Rodrꢀguez, C. Ramꢀrez, Org. Lett. 2000, 2, 507 – 510.
[2] A. D. Rodrꢀguez, C. Ramꢀrez, I. I. Rodrꢀguez, C. L. Barnes, J.
Org. Chem. 2000, 65, 1390 – 1398.
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