Synthesis of (-)-(Z)-deoxypukalide

Article abstract of DOI:10.1002/anie.200802703

(Chemical Equation Presented) Closing the deal: A ring-closing metathesis (RCM)/aromatization protocol, followed by a regioselective Negishi cross-coupling reaction and macrolactonization, with subsequent RCM mediate the synthesis of (-)-(Z)-deoxypukalide in 12 linear steps and 15% overall yield (see retrosynthesis; TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl).

Full text of DOI:10.1002/anie.200802703

Communications
DOI: 10.1002/anie.200802703
Natural Product Synthesis
Synthesis of (À)-(Z)-Deoxypukalide**
Timothy J. Donohoe,* Alan Ironmonger, and Neil M. Kershaw
The furan cembranolides are an intriguing class of macro-
cyclic marine natural products, which have been isolated from
several soft corals found at various locations around the
world.[1] Members of this family exhibit a wide range of
biological activities, from neurotoxicity through to anti-
inflammatory and anti-feedant properties (Scheme 1).[2] It
has been suggested that their biosynthetic origin involves the
macrocyclization of geranylgeranyl diphosphate to form a 14-
passes this test then an exceptionally short and efficient
synthesis of the natural product will be achieved.
Natural product (+)-1 was recently isolated from the
Pacific Octocoral Leptogorgia sp.[1i] The structure of (+)-1
was easily confirmed because its spectroscopic data was
identical to that of a sample prepared independently by
Marshall and Devender (through a 28-step synthesis), whose
studies were complete before (Z)-deoxypukalide was recog-
nized as a natural product.[5e]
The retrosynthesis of this molecule involves a late-stage
construction of the butenolide by means of ring-closing
metathesis (RCM) of a macrocyclic lactone (Scheme 2). The
lactone precursor would be prepared from a hydroxy acid that
would itself come from a Negishi coupling of functionalized
(and protected) vinyl iodide 4 with disubstituted furan 5. The
key test of our furan-forming RCM methodology would come
from the design of a short and efficient route to compound 5
that would allow the preparation of this precursor and enable
completion of the synthesis.
Scheme 1. Furan cembranolide natural products.
membered carbocycle, which is then subjected to an
oxidation cascade leading to the natural products.[3]
Interestingly, it has also been proposed that the oxida-
tion level of the C18 carbon may be correlated to the
genus of Octocoral that produces a particular product.[1i]
Several research groups have reported key synthetic
studies and elegant biomimetic investigations which
have culminated in the syntheses of members of this
class of natural product;[4,5] however, it has been
acknowledged that cembranolides are deceptively
demanding targets.[5f] Intrigued by its 14-membered
carbon macrocycle containing a trisubstituted furan
moiety, our interest was drawn to (Z)-deoxypukalide
(1) as a worthwhile synthetic target. More specifically,
we wanted to test a powerful new methodology that was
developed by our research group for the synthesis of
furans and which uses ring-closing metathesis as the key
step.[6] Our approach allows for some new and unusual
disconnections on the furan nucleus, and if the method
Scheme 2. Retrosynthetic analysis of( Z)-deoxypukalide. TBS=tert-butyl-
dimethylsilyl, TIPS=triisopropylsilyl.
Our synthesis began with (S)-perillyl alcohol, which is
commercially available and is inexpensive (Scheme 3). The
sequence shown will result in the formation of the enantiomer
of the natural product. (R)-Perillyl alcohol is commercially
available but reasonably expensive; however, it can be
obtained by the enzymatic oxidation of (+)-limonene.[7]
Silyl protection of the primary hydroxy group and then
selective ozonolysis of the trisubstituted alkene ensued.
Success for the regioselective ozonolysis (the trisubstituted
alkene reacts faster than a 1,1-disubstituted alkene) was only
achieved in the presence of a stoichiometric amount of
[*] Prof. T. J. Donohoe, Dr. A. Ironmonger, Dr. N. M. Kershaw
Department ofChemistry, University ofOxof rd
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
Fax: (+44)1865-275-708
E-mail: timothy.donohoe@chem.ox.ac.uk
[**] We thank the EPSRC for supporting this project, Merck for
unrestricted funding, and Dr. F. Churruca for some preliminary
experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802703.
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workers (Scheme 4).[10] The final carboalumination step is
noteworthy as the Z stereochemistry results from an equili-
bration process of the vinylalane, which is induced by the
higher temperatures and the presence of the homoallylic
alcohol.[11] By conducting this reaction at room temperature,
we could prepare the E isomer of 15 in 67% yield.
Scheme 4. Formation of( Z)-vinyl iodide for the cross-coupling reac-
tion. Cp=cyclopentadienyl, Trisyl=2,4,6-triisopropylbenzenesulfonyl.
Allylic alcohol 16 was formed from 15 by using a
regioselective sulfonylation of a primary alcohol with a
hindered sulfur electrophile, as developed by Hicks and
Fraser-Reid.[12] This transformation was followed by opening
of the epoxide and olefin formation using trimethylsulfonium
iodide and strong base, as reported by Alcarez et al.[13] Finally,
silyl protection of the free alcohol gave (Z)-vinyl iodide 4.
Completion of this sequence required joining of the two
fragments by using a Negishi cross-coupling reaction as shown
in Scheme 5.[14,5i] Double deprotonation of 5 with LDA and
then in situ transmetalation with zinc bromide was followed
by palladium-catalyzed coupling with 4; after removal of the
TBSgroup with TBAF, this sequence provided trisubstituted
furan 13 in 78% yield over two steps.
Scheme 3. RCM route to the furan segment. DIBAL-H=diisobutylalu-
minum hydride, HMPA=hexamethyl phosphoramide, imid=imida-
zole, PPTS=pyridinium p-toluenesulfonate, py=pyridine, TBAF=
tetra-n-butylammonium fluoride, TEMPO=2,2,6,6-tetramethyl-1-
piperidinyloxy, free radical.
pyridine and excess isoprene, both of which attenuated the
amount of over-oxidation of the 1,1-disubstituted alkene. The
use of pyridine to reduce the reactivity of ozone has been
reported by Slomp and Johnson.[8] In addition, we added
isoprene to act as a buffer that would be cleaved in preference
to the 1,1-disubstituted alkene in the substrate; to the best of
our knowledge, this is the first time that such a tactic has been
used in this context.
The resulting aldehyde 8 proved to be relatively unreac-
tive under Baylis–Hillman reaction conditions. Therefore it
was treated with a vinylalane, itself derived by addition of
DIBAL-H to methylpropiolate.[9] This sequence, which is a
useful alternative to the Baylis–Hillman reaction, resulted in
the formation of allylic alcohol 9 as an inconsequential (1:1)
mixture of diastereoisomers.
The pivotal furan-forming reaction sequence was then
examined, starting with the formation of the mixed acetal 10,
by exchange with commercially available acrolein diethyl
acetal. Subsequent ring-closing metathesis with the second-
generation Grubbs catalyst formed cyclic olefin 11, which was
immediately aromatized in situ with mild acid[6] to produce
disubstituted furan 12 in 85% overall yield (over two steps
from 9). This protocol was followed by a three-step functional
group manipulation to prepare furan 5, which was now ready
for the cross-coupling reaction.
To enable the proposed Negishi cross-coupling reaction,
we prepared (Z)-vinyl iodide 15 starting from (S)-glycidol
using a four-step sequence reported by Pattenden and co-
Scheme 5. Completion ofthe synthesis. DMAP =4-dimethylamino-
pyridine, dppf=1,1’-bis(diphenylphosphanyl)ferrocene,LDA=lithium
diisopropylamide, MNBA=2-methyl-6-nitrobenzoic anhydride.
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The final sequence required the implementation of the
macrolactonization procedure developed by Shiina et al. to
give lactone 14 in 73% yield (Scheme 5).[15] This remarkable
set of reaction conditions gave a much higher yield than the
macrolactonization protocol of Yamaguchi and co-workers,[16]
which failed to give more than about 5% of 14. Finally,
formation of the butenolide unit was completed by using
RCM with the second-generation Grubbs catalyst[17] in
toluene at reflux which proceeded smoothly in 72% yield
(with the remaining mass recovered as starting material). The
(À)-(Z)-deoxypukolide (1) that was synthesized by this
sequence had spectroscopic data identical to that reported
for the natural product.
In conclusion, we have completed the synthesis of (À)-
(Z)-deoxypukalide (1) by a sequence that is noteworthy for its
brevity and efficiency: just 12 linear steps and an overall yield
of 15%. The key features in the synthesis were the successful
RCM/aromatization protocol used to prepare a disubstituted
furan, and a regioselective Negishi cross-coupling reaction to
construct the fully substituted aromatic core of the target.
Finally, macrolactonization and subsequent RCM enabled us
to complete the synthesis.
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Received: June 9, 2008
Published online: August 8, 2008
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Keywords: furans · natural products · ring-closing metathesis ·
total synthesis
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