First total synthesis of (-)-caulerpenynol

Article abstract of DOI:10.1039/b818243d

The first diastereoselective synthesis of the antimicrobial and cytotoxic agent (-)-caulerpenynol 2 has been achieved in relatively few steps from the commercially available (S)-malic acid. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b818243d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
First total synthesis of (-)-caulerpenynol†
Laurent Commeiras,* Je´roˆme Thibonnet and Jean-Luc Parrain*
Received 15th October 2008, Accepted 21st November 2008
First published as an Advance Article on the web 28th November 2008
DOI: 10.1039/b818243d
The first diastereoselective synthesis of the antimicrobial and
cytotoxic agent (-)-caulerpenynol 2 has been achieved in
relatively few steps from the commercially available (S)-malic
acid.
(epoxidation) from 1 to caulerpenynol 2 have been reported in the
literature6,7 but no total synthesis of 2 has been realized.
Results and discussion
The main structural features of
2 are a terminal 1,4-
Introduction
diacetoxybutadiene moiety, an en-yn-ene moiety, two chiral cen-
ters and a 1,3-anti-diol moiety in which one alcohol function is
protected as acetate. As outlined in Scheme 1, our strategy for
synthesizing 2 called for the initial preparation of three fragments
referred to as west, central and east. We considered that the
assembly of three fragments could be obtained through two C–C
coupling reactions. The first coupling was realized between
alkynyl lithium 3 (west fragment obtained from Fritsh-Buttenberg-
Wiechell rearrangement) and lactone 4 (central fragment). The
carbon skeleton was achieved through a second coupling be-
tween vinyllithium 5 (east fragment obtained from a tin-lithium
exchange) and the corresponding west-central fragment.
Some metabolites from tropical algae have been described as
implicated in chemical defence against grazing fishes and inver-
tebrates in herbivore-rich tropical waters1 and has been proposed
as an explanation for the unhindered proliferation of Caulerpa
taxifolia, a tropical green seaweed, accidentally introduced in the
Mediterranean. Compared to other Caulerpa species in the tropics,
Caulerpa taxifolia contains large amount of caulerpenyne 1, a
sesquiterpene isolated from 10 different species of Caulerpa and
was first identified from Caulerpa prolifera.2 Among its biological
activities, which are attributed to the diacetoxybutadiene moiety,
caulerpenyne 1 inhibits the proliferation of the fibroblastic cell line
BHK 21/C13 from baby hamster kidneys and the division of sea
urchin eggs.3 The cytotoxicity was also demonstrated in various
tumor cell lines4 and recently it was shown that caulerpenyne 1 has
antiproliferative activity against the tumor cell line SK-N-SH and
modifies the microtubule network.5 In addition, several secondary
metabolites were identified and could contribute to the toxicity
of C. taxifolia from the Mediterranean (Fig. 1). Among these
metabolites, caulerpenynol 2 was isolated and identified in 1993 by
Guerriero et al.6 The antibacterial and cytotoxic activities of 2 were
evaluated against prokaryotic marine bacteria, and unicellular
eukaryotes ciliate protists, and 2 proved to be the most active
of the terpenes of C. taxifolia with the exception of two bacteria.6
Scheme 1 Retrosynthetic scheme of caulerpenynol 2.
Synthesis of the key central fragment (Scheme 2) started from
the commercially available (S)-malic acid, which was transformed
in three steps, in high yield and multigram scale, into the known
lactone 6.8 First, (S)-malic acid was protected as an acetonide
(2,2-dimethoxypropane, p-TsOH), the carboxylic acid was then
reduced to the alcohol using BH3-THF. This unstable product
immediately rearranged to (S)-3-hydroxybutyrolactone 6 in the
presenceof p-TsOH. Lastly, the alcohol function of 6 was protected
as the triethylsilyl ether to give the central fragment 7 (71% yield
over four steps).
Fig. 1
Inspired by the pronounced biological activities of 2 and
to provide material for a more extensive biological evaluation,
we have undertaken the total synthesis of caulerpenynol 2. To
the best of our knowledge, only few synthetic transformations
Synthesis of the western fragment was performed via the
Corey-Fuchs alkynylation reaction.9 Commercially available 3,3-
dimethylacrolein was first converted quantitatively into the known
corresponding gem-dibromide, which by treatment with 2 eq.
of n-BuLi generated alkynyl lithium 3 by a Fritsch-Buttenberg-
Wiechell rearrangement.
Aix-Marseille Universite´, Institut des Sciences Mole´culaires de Mar-
seille iSm2, UMR 6263, e´quipe STeRe´O, Campus Scientifique de
Saint Je´roˆme, service 532, 13397, Marseille cedex 20, France.
E-mail: laurent.commeiras@univ-cezanne.fr, jl.parrain@univ-cezanne.fr;
Fax: +33 4 91 28 91 87; Tel: +33 4 91 28 91 26
† Electronic supplementary information (ESI) available: Synthesis pro-
cedures, 1H and 13C NMR spectra for new compounds. See DOI:
10.1039/b818243d
The remaining east fragment 10 was prepared in two
steps from the commercially available but-2-yn-1,4-diol via a
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Scheme 2 Synthesis of caulerpenynol 2.
palladium-catalyzed hydrostannation reaction, giving quantita-
tively the known (E)-vinyltin reagent.10 Subsequent selective pro-
tection of the less hindered primary alcohol as a triethylsilyl ether
furnished 10 in 53% overall yield for the two-step transformation.
Construction of the carbon skeleton of (-)-caulerpenynol 2
started by a coupling reaction between the central fragment 7
and the alkynyllithium 3 to furnish the corresponding alcohol
8, which was then oxidized using Dess-Martin periodinane to
afford aldehyde 9. The carbon skeleton of caulerpenynol was
achieved through a second coupling reaction between 9 and a
vinyl lithium reagent generated by tin-lithium exchange reaction
reported for the naturally derived caulerpenynol,6,15 confirming
our prediction of the relative and absolute configuration of anti-
diastereomer 11.
Conclusion
In summary, the first diastereoselective total synthesis of the
metabolite (-)-caulerpenynol 2 has been reported in relatively few
steps.
Acknowledgements
on 10, giving diol 11 in 43% yield as a 7/3 mixture (based on 13
C
LC thanks Roselyne Rosas for NMR studies and Nicolas Van-
thuyne for HPLC separations.
NMR) of separable diastereomers in favour of anti diastereomer.11
The mixture of isomers were separated and purified by flash
chromatography.12
Notes and references
At this stage, both hydroxy groups of the major anti isomer
11 were protected as the acetates to give bis-acetate 12 which
was subjected to olefination reaction using standard conditions
to afford 13. Selective cleavage of the primary allylic triethylsilyl
ether in the presence of the secondary allylic triethylsilyl ether was
performed with a 2/1/10 mixture of AcOH/H2O/THF at 40 ◦C,
furnishing the desired primary alcohol 14,13 which was further
oxidized with Dess-Martin periodinane into aldehyde 15. To
generate the diacetoxybutadiene moiety, we employed conditions
developed in our group (NEt3, DMAP, Ac2O at 80 ◦C) and applied
for the synthesis of other natural products.14 The TES-protected
caulerpenynol 16 was obtained in a 53/47 E/Z diastereomeric
mixture. Finally, a 3/2/1 mixture of AcOH/H2O/THF at 45 ◦C
was used to remove the triethylsilyl protecting group, cleanly
affording a 52/48 diastereomeric mixture of caulerpenynol 2 and
iso-caulerpenynol iso-2 separable by HPLC. The physical and
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1
spectroscopic data (mass, H NMR, 13C NMR, optical rotation)
of our synthetic material are in complete agreement with those
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11 The stereochemistry of anti diol 11 was confirmed by our previously
unpublished work on the synthesis of caulerpenynol. 1H and 13C NMR
spectra of 13 exactly matched those of the TBS analog 17 (excepting the
alkyl silyl chain). Stereochemistry of the TBS analog 17 was deduced
by NOESY experiments of the corresponding p-methoxybenzylidene
acetal 18..
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15 See supporting information for a NMR comparison between natural
and synthetic caulerpenynol 2.
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