Enantioselective synthesis of (-)-exiguolide by iterative stereoselective dioxinone-directed prins cyclizations

Article abstract of DOI:10.1002/anie.201102790

Three become one: The title compound can be prepared in 26 steps by employing a unified Prins cyclization strategy to construct both tetrahydropyran rings (see scheme). The route combines two similar dioxinone fragments and one aldehyde component to gener

Full text of DOI:10.1002/anie.201102790

Communications
DOI: 10.1002/anie.201102790
Total Synthesis
Enantioselective Synthesis of (ꢀ)-Exiguolide by Iterative
Stereoselective Dioxinone-Directed Prins Cyclizations**
Erika A. Crane, Thomas P. Zabawa, Rebecca L. Farmer, and Karl A. Scheidt*
Exiguolide (1, Scheme 1) is an unusual natural product
isolated in 2006 by Ohta, Ikegami, and co-workers from the
marine sponge Geodia exigua Thiele.[1] This molecule inhibits
the fertilization of sea urchin gametes (H. pulcherrimus) at a
concentration of 20 mm but does not affect the development of
the already fertilized eggs at higher concentrations (100 mm),
thus indicating that it might possess relevant anticancer
activity.[2] The similarity of compound 1 to the bryostatin
family of natural products, which are known antitumor
compounds, was proposed by Cossy[3] and also intrigued us.
In particular, the bispyran architecture and the exocyclic
enoate appended onto a tetrahydropyran ring are motifs
common to both exiguolide and the bryostatins.[4]
employing iterative and stereoselective dioxinone-based
Prins reactions.
Our synthetic plan, detailed in Scheme 1, involved 1) a
late-stage CuI-mediated cross-coupling to construct the triene
side chain, 2) an olefination with an enantiomerically
enriched Horner–Wadsworth–Emmons (HWE) reagent to
The first synthesis of exiguolide was reported by Lee and
co-workers, who established the absolute configuration of the
natural product.[5a] The current synthetic approaches to this
16-membered macrolide tend to rely on linear macrolactoni-
zation strategies by esterification to establish the primary ring
system.[5] While these polyketide/macrolide strategies are
effective, we sought a complimentary approach by focusing
on maximum convergency and flexibility for biological
studies. Indeed, this target seemed ideal to deploy a unified
strategy to construct the tetrahydropyran (THP) rings and the
macrocycle in an efficient manner.[6] Given the inherent
challenges involving macrocyclizations in many total syn-
thesis campaigns with only slight modifications of related
substrates,[7] this target also offered the opportunity to expand
our Prins-type cyclization strategy[8] to larger ring sizes
beyond those previously examined by us.[6c] Herein, we
report the enantioselective synthesis of (ꢀ)-exiguolide by
Scheme 1. Retrosynthetic strategy.
install the exocyclic unsaturated ester, and 3) an intramolec-
ular dioxinone Prins cyclization to simultaneously build the
16-membered macrocycle and generate one of the two THP
rings. The linear precursor (2) would be assembled by an
intermolecular Prins cyclization of a dioxinone (4b) and an
aldehyde (5) to create the 2,6-cis-tetrahydropyran ring. An
esterification to append a second dioxinone fragment (a
carboxylic acid derived from 4a) would install the entire
carbon framework without the triene side chain and the
exocyclic enoate. Notably, a key b-hydroxy dioxinone frag-
ment would be employed twice to construct aldehyde 2,
thereby streamlining the synthesis and improving the overall
efficiency.
Our synthesis commenced with a catalytic, asymmetric
acyl halide/aldehyde cyclocondensation developed by Nelson
et al.[9] of alkyne 6 and propionyl bromide 7 in the presence of
AlIII catalyst I to provide the cis-substituted b lactone 8
(Scheme 2). The lactone was converted to the Weinreb amide
9 (72% yield over two steps), which facilitated the assessment
of the diastereoselectivity (d.r. > 20:1) and enantioselectivity
(90% ee) of the cyclocondensation process. The resulting
[*] E. A. Crane, Dr. T. P. Zabawa, R. L. Farmer, Prof. Dr. K. A. Scheidt
Department of Chemistry
Center for Molecular Innovation and Drug Discovery
Chemistry of Life Processes Institute
Silverman Hall, Northwestern University
Evanston, IL 60208 (USA)
E-mail: scheidt@northwestern.edu
Homepage: http://chemgroups.northwestern.edu/scheidt/
[**] Financial support for this work was provided by the NCI (RO1
CA126827 and SPORE in Prostate Cancer P50 CA090386), the
American Cancer Society (Research Scholar Award to K.A.S.) and
Amgen. We are grateful to Boehringer-Ingelheim for the New
Investigator Award in Organic Chemistry supporting T.P.Z. R.L.F.
thanks the NIH for a predoctoral fellowship (F31CA138097). E.A.C.
and R.L.F. thank the Malkin Scholars Program for additional
support (Robert H. Lurie Comprehensive Cancer Center at North-
western University). We would like to thank Dr. Andrew Mazar, Keith
Macrenaris, Rich Ahn, and Elden Swindell (NU) for providing the
cancer cell lines and cell culture technical support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102790.
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Angew. Chem. Int. Ed. 2011, 50, 9112 –9115

Scheme 3. Dioxinone and vinyl iodide syntheses. a) TBSCl, imidazole,
DMF, 91% yield; b) PPTS, EtOH, 83% yield; c) PDC, DMF, 97% yield;
d) PPh3CH2I2, NaHMDS, HMPA, DMF, ꢀ788C; e) PPTS, MeOH, 61%
yield over two steps; f) DMP, CH2Cl2; g) NaClO2, NaH2PO4, 2-Me-2-
butene, tBuOH, H2O; h) TMSCHN2, MeOH, benzene, 50% yield over
3 steps. DMF=N,N-dimethylformamide, HMDS=hexamethyldisila-
zide, HMPA=hexamethylphosphoramide, PDC=pyridinium dichro-
mate, PG=protecting group, PPTS=pyridinium p-toluenesulfonate,
TBDPS=tert-butyldiphenylsilyl.
Scheme 2. Aldehyde fragment synthesis. a) iPr2NEt, 10 mol% I,
CH2Cl2, ꢀ508C; b) MeONHMe·HCl, iPr2NEt, CH2Cl2, 72% over
2 steps; c) TBSCl, imidazole, CH2Cl2, 89% yield; d) allylMgBr, diethyl
ether, 08C; e) iPr2NEt, 94% over 2 steps; f) (S)-CBS catalyst (12),
BH3·OMe2, THF, ꢀ158C, 70% yield; g) MeC(OMe3)2NMe2, xylenes,
1408C, 85% yield; h) LiNH2BH3, THF, 08C, 93% yield; i) DMP,
NaHCO3, CH2Cl2, 99% yield; j) HCl (aq), THF, 84% yield. Bn=benzyl,
DMP=Dess–Martin periodinane, (S)-CBS=(S)-(ꢀ)-2-methyl-CBS-oxa-
zaborolidine, TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl.
alcohol 9 was protected as the TBS ether, and an allyl
Grignard addition followed by an olefin isomerization, which
was catalyzed by Hꢀnigꢁs base, afforded a,b-unsaturated
ketone 10. A subsequent asymmetric reduction to the allylic
alcohol was performed using Corey–Bakshi–Shibata condi-
tions[10] and followed by heating with N,N-dimethylacetamide
dimethyl acetal in order to promote an Eschenmoser–Claisen
rearrangement[11] to deliver amide 11 in 85% yield. This
sequence efficiently and selectively installed the E olefin with
the necessary geometry and established the stereocenter that
bears the methyl group. The transformation to aldehyde 5
occurred by reduction of amide 11 with LiNH2BH3 to the
primary alcohol,[12] subsequent oxidation with Dess–Martin
periodinane to the aldehyde,[13] and removal of the TBS
protecting group under acidic conditions (77% yield over
three steps).
The related dioxinone fragments 4a and 4b were accessed
using a catalytic enantioselective vinylogous aldol reaction
reported by Scettri and co-workers (Scheme 3).[6c,14] Protect-
ing-group manipulations and oxidation of dioxinone 4a
afforded acid 13 in 73% yield over three steps. The requisite
vinyl iodide fragment 3 was constructed by a Wittig olefina-
tion of aldehyde 14[15] by using the Stork–Zhao protocol.[16] To
obtain the desired E/Z selectivity of the diene, it was essential
to use DMF as solvent with HMPA, and to maintain the
reaction temperature at ꢀ788C.[17] The removal of the TBS
group from the vinyl iodide product afforded alcohol 15,
which underwent sequential Dess–Martin and Pinnick[18]
oxidations and treatment with diazomethane to afford
coupling partner 3 (50% over three steps).
Scheme 4. Fragment-assembly Prins cyclization.
conditions. The most reproducible and highest yielding
reactions utilized BF3·OEt2 as the Lewis acid and calcium
sulfate as the drying agent. Overall, this intermolecular
dioxinone Prins coupling produced the desired pyranone
ring in 55% yield on a gram scale (combined yields of 16 and
17).
At this point, protecting-group manipulation of both 16
and 17 produced bicyclic dioxinone 18 (Scheme 5).[19] Sub-
sequent decarboxylation of cyclization product 18 by heating
in xylenes led to the cyclohexanone product. Removal of the
carbonyl group from the THP ring was then achieved
efficiently by reduction with sodium borohydride to form
the pyranol, iodination, and radical-mediated dehalogenation
to afford pyran 19. The acetate protecting group of 19 was
removed and the resulting secondary alcohol was esterified
with dioxinone acid 13.[20] A global deprotection and the
selective oxidation of the primary alcohol to the aldehyde was
achieved with a silica gel accelerated catalytic oxidation using
TEMPO and PhI(OAc)2.[21]
The key macrocyclization of linear precursor 2 proceeded
smoothly, forming both the THP ring and the macrocycle
concurrently. In contrast to the earlier intermolecular Prins
reaction, catalytic conditions using scandium(III) (50 mol%
of Sc(OTf)3) effectively promoted the cyclization of the 16-
membered macrocycle and the second pyran ring in 66%
yield. The decarboxylation of bicyclic dioxinone 20, a
Horner–Wadsworth–Emmons olefination with a phosphonate
derived from (S)-1,1’-bi-2-naphthol (II),[22] and deprotection
of the TMS group afforded terminal alkyne 21 with an enoate
With the appropriate fragments constructed, we explored
the first Prins cyclization for the union of aldehyde 5 and
dioxinone 4b (Scheme 4). Following an extensive survey of
reaction conditions and protecting groups (not shown), we
found that the desired cyclization proceeded only when we
used more robust Lewis acids, such as BF3·OEt2; however, we
observed variable loss of protecting groups under these
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Communications
Figure 1. Exiguolide and analogues that were evaluated against tumor
cell lines.
assay (Figure 1). From all of the cell lines examined,[26]
exiguolide demonstrated significant antiproliferative activity
against A549 lung cancer cells, inhibiting their growth by
(52 ꢁ 6)% at 10 mm and (26 ꢁ 6)% at 1 mm. Additionally, the
natural product also showed moderate growth inhibition
against other cell lines, inhibiting growth of PC3 prostate
cancer cells ((35 ꢁ 7)%), MDA-MB-231 breast cancer cells
((30 ꢁ 10)%), and BxPC3 pancreatic cancer cells ((33 ꢁ 9)%)
at 10 mm. The intriguing observation that exiguolide specifi-
cally inhibits A549 lung cancer cell growth with a higher
potency than it exhibits against the other cell lines tested was
first reported by Fuwa et al.[27] and subsequently confirmed by
us. This fact underscores that this natural product or related
congeners have potential as selective biological tools for
oncology research and as chemotherapeutic agents. Interest-
ingly, 28-(E)-exiguolide (22), macrocyclic alkene 23, and
macrocyclic alkyne 21 all demonstrated only minimal activity
against all of the cell lines, thus indicating that the triene side
chain and the Z-enoate geometry are both essential for the
biological activity. The fact that only the Z enoate is active in
our assays is particularly relevant, as this finding closely
mirrors the results of structure–activity-relationship studies
on the bryostatin family of natural products,[4b] and presents
new structure–activity-relationship (SAR) data when com-
pared to the recent report by Fuwa et al.[27] Further studies to
enhance and understand this selective activity are underway.
In summary, we have completed a convergent synthesis of
(ꢀ)-exiguolide in 26 steps (longest linear route) by employing
a unified Prins cyclization approach. This strategy employs
two highly diastereoselective dioxinone-directed Prins reac-
tions, which are integral in constructing both tetrahydropyran
rings of the molecule: the first to unify the highly function-
alized substrates in the construction of the linear precursor of
exiguolide, and the second in a 16-membered macrocycliza-
tion, which simultaneously installs the second THP ring. The
route described herein is highly modular and combines two
similar dioxinone fragments and one aldehyde component to
generate the core structure of the target. Preliminary
biological screening suggests that this natural product selec-
tively inhibits the growth of a number of cancer cell lines, and
that the triene side chain and Z-enoate geometry are required
for the observed growth inhibition. This flexible strategy,
which is driven by the Prins reaction, enables the coupling and
cyclization of complex substrates and should be applicable to
related targets to continue our chemical-biological investiga-
tions.
Scheme 5. Macrocyclization and completion of the synthesis.
a) Xylenes, H2O, 1308C, 81% yield; b) NaBH4, MeOH, ꢀ108C, 76%
yield; c) NIS, PPh3, imidazole, CH2Cl2, 82% yield; d) Bu3SnH, AIBN,
toluene, 808C, 91% yield; e) DIBAL-H, hexanes, ꢀ788C, 76% yield;
f) acid 13, C6Cl3H2COCl, NEt3, DMAP, THF, 91% yield; g) HF·pyridine,
THF, 85% yield; h) TEMPO, SiO2, C6H5I(OAc)2, CH2Cl2, 86% yield;
i) 50 mol% Sc(OTf)3, CaSO4, MeCN, 08C, 66% yield; j) DMSO, H2O,
1308C, 85% yield; k) phosphonate II, NaHMDS, THF, ꢀ788C!
ꢀ408C, 62% yield; l) nBu4NF, THF, 08C, 80% yield; m) 0.5 mol%
[Pd2(dba)3], 2 mol% Cy3PHBF4, 20 mol% iPr2NEt, HSnBu3, toluene,
ꢀ788C, 72% yield; n) vinyl iodide 3, CuTC III, NMP, 08C, 75% yield.
AIBN=azobisisobutyronitrile, Cy=cyclohexyl, dba=trans,trans-diben-
zylidenacetone, DIBAL-H=diisobutylaluminium hydride, DMAP=4-
dimethylaminopyridine, DMSO=dimethyl sulfoxide, NIS=N-iodosuc-
cinimide, NMP=N-methylpyrrolidinone, TC=thiophene carboxylate,
TEMPO=(tetramethylpiperidinyl)oxyl, Tf=trifluoromethanesulfonyl.
isomer ratio of Z/E = 7:1. The completion of the synthesis
necessitated appending the polyene side chain with control of
the sensitive E/Z/E triene. After significant development, a
selective hydrostannylation proceeded smoothly to afford
predominantly the E-vinyl stannane.[23] While a Pd0-catalyzed
Stille coupling afforded complex mixtures of products, a
Liebeskind CuI-mediated coupling[24] afforded (ꢀ)-exiguo-
lide, which gratifyingly possessed identical physical data to
the natural material.[25]
Subsequently, we evaluated the ability of exiguolide to
inhibit cancer cell growth. We suspected that exiguolide
would possess antiproliferative activity because of its struc-
tural similarities to the bryostatin natural products, as well as
its activity against sea urchin gamete formation. To test this
hypothesis, a variety of late-stage intermediates, including
exiguolide (1), 28-(E)-exiguolide (22), alkene 23, and alkyne
21 were screened against nine cancer cell lines in an MTS
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Angew. Chem. Int. Ed. 2011, 50, 9112 –9115

Received: April 21, 2011
Revised: July 4, 2011
Published online: August 17, 2011
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material: [a]D20 = ꢀ81.4 (CHCl3, c = 0.07), optical rotation for
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Supporting Information for details.
[26] Tested cell lines: A549 (lung), HT-29 (colorectal), RT4 (urinary
bladder), HT1080 (fibrosarcoma), FaDu (pharynyx), MDA-MB-
231 (breast), OVCAR-3 (ovarian), BxPC-3 (pancreatic), and
PC-3 (prostate). See the Supporting Information for details.
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[10] An Evans–Tishchenko reduction failed with deprotected 10.
Other reductions that did not produce the desired selectivity
include the use of sodium borohydride, zinc borohydride, as well
as l-Selectride and BINAL.
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