The first enantioselective synthesis of palinurin

Article abstract of DOI:10.1039/b822679b

The first enantioselective synthesis of palinurin has been accomplished starting from commercially available furaldehyde and (R)-methyl-3-hydroxy-2- methylpropionate; the key steps of the synthesis include the use of a chiral pyrrolidine to create the chiral tetronic moiety, and Horner-Wadsworth-Emmons, Wittig and Wittig-Horner reactions to construct the alkene units.

Full text of DOI:10.1039/b822679b

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The first enantioselective synthesis of palinurinw
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Manuel Perez, Daniel I. Perez,z Ana Martınez,z Ana Castro, Generosa Gomez*
and Yagamare Fall*a
Received (in Cambridge, UK) 18th December 2008, Accepted 6th April 2009
First published as an Advance Article on the web 5th May 2009
DOI: 10.1039/b822679b
The first enantioselective synthesis of palinurin has been
accomplished starting from commercially available furaldehyde
and (R)-methyl-3-hydroxy-2-methylpropionate; the key steps of
the synthesis include the use of a chiral pyrrolidine to create the
chiral tetronic moiety, and Horner–Wadsworth–Emmons,
Wittig and Wittig–Horner reactions to construct the alkene units.
Alzheimer’s disease (AD) is characterized by intracellular
disorganization (neurofibrillary tangles, NFTs) and extracellular
anomalies (amyloid plaques) in the hippocampus and neocortex.1
Amyloid plaques are composed of b amyloid [Ab] peptides
generated by cleavage of amyloid precursor protein (APP).
NFTs are formed of paired helical filaments (PHFs) generated
by aggregation of microtubule-associated tau protein in an
abnormally hyperphosphorylated state. Several studies have
implicated molecular and cell signaling cascades involving the
serine-threonine kinase glycogen synthase kinase 3b (GSK-3b)
in the formation of both kinds of lesion.2 One of the strategies
being pursued in the search for pharmacological therapies for
AD is blockade of tau hyperphosphorylation by selective
inhibitors of GSK-3b. Palinurin (1, Scheme 1), a linear
furanosesterterpene originally found in the Mediterranean
sponge Ircinia variabilis and later re-isolated from the Red
Scheme 1 Retrosynthetic analysis.
Sea sponge Ircinia echinata, is a compound with anti-
inflammatory and antibacterial properties.3a,b Related furano-
sesterterpenes with some cytotoxicity are known.3c,d Palinurin
has also emerged as a non-ATP-competitive inhibitor of GSK-
3b.4 To the best of our knowledge, no synthesis of this
compound has been published. Here we report the first
enantioselective synthesis of palinurin, which was based on
the retrosynthetic analysis indicated in Scheme 1: Wittig–
Horner coupling of a phosphine oxide containing the furan
ring (4, obtainable from commercially available furaldehyde 2)
to an aldehyde containing the tetronic moiety (7, obtainable
from (R)-methyl-3-hydroxy-2-methylpropionate (5).
Phosphine oxide 4 was prepared as shown in Scheme 2
(see also ESIw). Wittig reaction of 2, followed by reduction
with LiAlH4 and catalytic hydrogenation, afforded alcohol 10
in excellent yield (92% from 2). Alcohol 10 was easily
converted into iodide 11 in 99% yield, and treatment of 11
Scheme 2 Synthesis of phosphine oxide 4.
a
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Departamento de Quımica Organica, Facultad de Quımica,
Universidad de Vigo, 36200 Vigo, Spain.
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with sodium cyanide gave nitrile 12, likewise in 99% yield.
Reaction of 12 with methyllithium then afforded an 80%
yield of ketone 3, which was subjected to a Horner–
Wadsworth–Emmons reaction5 with phosphonate 13 to obtain
the a,b-unsaturated ester 14 in 99% yield. Finally, reduction of
14 with DIBALH gave allylic alcohol 15, which was unevent-
fully converted into phosphine oxide 4 in 85% yield.6
E-mail: yagamare@uvigo.es, ggomez@uvigo.es;
Fax: +34 986 81 22 62; Tel: +34 986 81 23 20
b NOSCIRA, S.A., Avda. de la Industria 52, 28760 Madrid, Spain
w Electronic supplementary information (ESI) available: Characteri-
zation data and experimental procedures for all new compounds, and
copies of NMR spectra. See DOI: 10.1039/b822679b
z Present address: Instituto de Quı
mica Medica (CSIC), Juan de la
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Cierva 3, 28006 Madrid, Spain.
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Scheme 3 Synthesis of allylic bromide 6.
The tetronic intermediate 7 was prepared via allylic bromide
6, which was obtained from commercially available
hydroxyester 5 as shown in Scheme 3. Silylation of 5 with
TBDPSCl and subsequent reduction of the methyl ester group
provided an excellent yield of alcohol 17, which was easily
converted into iodide 18 in 90% yield. Reaction of 18 with
dimethyl malonate anion afforded diester 19 in 91% yield, and
Krapcho decarboxylation7 of 19, followed by DIBALH
reduction, gave a mixture of diol 20 (16%) and the desired
alcohol 21 (74%) (see ESIw). TPAP oxidation of alcohol 21
and Wittig reaction of the resulting aldehyde then afforded
a,b-unsaturated ester 22, which upon reduction with DIBALH
provided allylic alcohol 23 (96%). Finally, reaction of 23
with PPh3 and CBr4 gave allylic bromide 6 in nearly
quantitative yield.
With allylic bromide 6 in hand, we turned our attention to
the tetronic moiety 7 (see Scheme 4). First, tetronic acid
derivative 26 was obtained by protection of glycolic acid with
cyclohexanone8 in 73% yield, followed by reaction of the
resulting lactone, 25, with methyl propanoate anion.9
(see ESIw). Reaction of 26 with commercially available
pyrrolidine 27 then gave an 80% yield of the chiral enamino-
furanone 28,10 coupling of which with compound 6 afforded,
as expected,11 the chiral furanone 29 (75%). Removal of the
silyl protecting group of 29 with TBAF provided an 89% yield
of alcohol 30; removal of the chiral auxiliary from 30 with
10% aqueous HCl in THF12a gave a 90% yield of diol 31; and
reaction of 31 with methanol under Mitsunobu conditions12
supplied a 90% yield of alcohol 32, which contains the desired
methyl tetronate moiety. Finally, Swern oxidation of alcohol
32 gave the target aldehyde 7 in nearly quantitative yield.
The synthesis of compound 1 was completed according to
plan by Wittig–Horner reaction13 of aldehyde 7 with phos-
phine oxide 4 (Scheme 5): reaction of 4 with n-Buli in THF
at ꢁ78 1C afforded a deep red anion that was coupled to
aldehyde 7, providing compound 33 in 40% yield with an
8:1 E/Z ratio at the newly formed double bond. Finally,
demethylation of 33 with n-C3H7SLi in HMPA14 (r.t., 2 h)
Scheme 4 Synthesis of aldehyde 7.
afforded 1 in 90% yield. The spectroscopic data of 1 were in
good agreement with those reported for natural palinurin.3a
The difference in the aD value measured by us at room
temperature (+28.8 degrees) and the published value
measured at 0 1C (+45.3 degrees) might be explained by the
instability of palinurin at room temperature.
In conclusion, we have achieved the first enantioselective
total synthesis of palinurin from commercially available
starting material. The key steps of the synthesis include the
use of a chiral pyrrolidine to create the chiral tetronic moiety,
and Horner–Wadsworth–Emmons, Wittig and Wittig–Horner
reactions to construct the alkene units. Biological evaluations
of the final target as well as all the intermediate compounds are
currently being carried out and will offer a platform from
which to design a QSAR model in the search for inhibitors of
glycogen synthase kinase 3b (GSK-3b). This is a highly
convergent and flexible synthetic strategy which may be used
to prepare palinurin analogues and other structures predicted
by the QSAR studies.
This work was financially supported by NeuroPharma S.A.
(now NOSCIRA, S.A.), the Spanish Ministry of Education
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Scheme 5 Completion of the synthesis of palinurin.
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This journal is The Royal Society of Chemistry 2009
3254 | Chem. Commun., 2009, 3252–3254