Total Synthesis of Limaol

Article abstract of DOI:10.1021/jacs.0c12948

A nonthermodynamic array of four skipped methylene substituents on the hydrophobic tail renders limaol, a C40-polyketide of marine origin, unique in structural terms. This conspicuous segment was assembled by a two-directional approach and finally coupled to the polyether domain by an allyl/alkenyl Stille reaction under neutral conditions. The core region itself was prepared via a 3,3′-dibromo-BINOL-catalyzed asymmetric propargylation, a gold-catalyzed spirocyclization, and introduction of the southern sector via substrate-controlled allylation as the key steps.

Full text of DOI:10.1021/jacs.0c12948

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Total Synthesis of Limaol
̈
Stephan N. Hess, Xiaobin Mo, Conny Wirtz, and Alois Furstner*
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ABSTRACT: A nonthermodynamic array of four skipped methylene substituents on the hydrophobic tail renders limaol, a C40-
polyketide of marine origin, unique in structural terms. This conspicuous segment was assembled by a two-directional approach and
finally coupled to the polyether domain by an allyl/alkenyl Stille reaction under neutral conditions. The core region itself was
prepared via a 3,3′-dibromo-BINOL-catalyzed asymmetric propargylation, a gold-catalyzed spirocyclization, and introduction of the
southern sector via substrate-controlled allylation as the key steps.
ike many other marine dinoflagellates of the genus
Prorocentrum, P. lima species are toxigenic.1,2 They were
circumstantially associated with cases of diarrheic shellfish
poisoning, likely caused by ocadaic acid (3) and analogues
(Scheme 1). These intriguing polyether toxins produced by the
unique in structural terms: four of the five “exo”-methylene
groups decorating the 40-carbon backbone are clustered in a
skipped array; the resulting 1,3,5,7-tetra(methylene)heptane
substructure is without precedent.7 Although the isolation
team did not mention any particular stability issues, it seemed
prudent to bear the nonthermodynamic character of this
peculiar motif in mind during retrosynthetic planning (Scheme
2). A late-stage attachment of the polyunsaturated side chain
to the core region seemed advisible,8−10 preferably by cross-
coupling of an alkenyl nucleophile with an allylic electrophile
under essentially neutral conditions to minimize the risk of
deleterious rearrangement into a partly or fully conjugated
tetraene. For the same reasons, it was planned to use only silyl
L
Scheme 1. Natural Products Derived from P. lima
Scheme 2. Retrosynthetic Analysis
benthic dinoflagellate occasionally accumulate in mussels,
scallops, and sponges, and thus can reach the human food
chain and cause severe ailment.3 This discovery sparked
considerable interest in the mode of action. Most importantly,
3 was recognized to be a highly potent and specific inhibitor of
the Ser/Thr-protein phosphatases PP1 and PP2A; as such, it
became an indispensable tool for the study of processes as
fundamental as cell cycle control, apoptosis, and tumor
promotion, to mention but a few.3
The disproportionally large genome of many Prorocentrum
species encodes numerous additional secondary metabolites of
remarkable structural complexity, even though their biological
role or physiological properties are often less clear.4,5 A recent
addition to this list is limaol (1) isolated from a P. lima strain
collected in Korea.6 1 showed moderate cytotoxicity, but no
further biological profiling beyond this standard assay was
reported. This is all the more regrettable since 1 is arguably
Received: December 14, 2020
Published: February 3, 2021
© 2021 The Authors. Published by
American Chemical Society
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protecting groups to avoid (strongly) acidic, basic, oxidative, or
reductive conditions during global deprotection.
resulting enoate 10 failed despite close literature precedent,20
whereas the derived thiolester21 11 was compliant: on
treatment with MeMgBr in the presence of CuI (2 mol %)
and ligand 19 (2.4 mol %), adduct 12 was obtained in high
yield and excellent diastereoselectivity (>3 g scale).22 The
thioester group then streamlined the reduction to the
corresponding aldehyde 13,23 which was chain-extended to
give alkyne 14. Addition of 9-I-9-BBN followed by protolytic
cleavage of the C−B bond furnished alkenyl iodide 15
quantitatively.24,25 The derived organozinc reagent was
coupled to allylic chloride 7 with the aid of catalytic
Pd(0);26,27 the resulting lipophilic compound was deprotected
to render the purification more facile. This rewarding outcome
together with the fact that product 16 and the derived allylic
acetate 17 could be kept in a freezer for weeks made us
confident that a similar allyl/alkenyl cross-coupling reaction
would enable the projected late-stage fragment coupling.
For the synthesis of the central fragment, cheap 20 was
subjected to C-glycosylation with allyltrimethylsilane on
multigram scale8 and the resulting primary product was
elaborated into aldehyde 22 by standard protecting group
and oxidation state management (Scheme 4). When reacted
with allenylboronate 33 in the presence of catalytic (R)-3,3′-
dibromo-BINOL (32), the desired homopropargyl alcohol 23
was obtained as a single diastereomer (96%, 1 mmol
scale).28−30 Adjustment of the protecting groups then set the
stage for chain extension to be followed by the critical
spirocyclization event.
The spirotricyclic core of 1 resembles that of prorocentin
(2), yet another secondary metabolite derived from P. lima, of
which only the relative configuration is known;11 a closer look,
however, also reveals subtle but important stereochemical
differences. We recognized an opportunity to craft this
substructure, which features a double anomeric effect, via π-
acid catalysis.12,13 This allows the masked C18-carbonyl group
to be encoded as a triple bond, which, in turn, should facilitate
the build-up of the carbon skeleton from smaller subunits. The
homoallylic alcohol at C27 was deemed another privileged
assembly point, given the huge repertoire of known
asymmetric allylation reactions.14 This analysis traces 1 back
to three building blocks A−C of similar size and complexity
and leaves a certain flexibility with regard to the exact
implementation of the actual fragment coupling events.
In the forward sense, we were particularly keen on testing
the access to and stability of the side chain segment bearing the
unusual skipped array of methylene substituents. A two-
directional approach was chosen that builds upon the latent
symmetry of this sector (Scheme 3).15 Specifically, a Baylis−
a
Scheme 3
Of the different modules considered for this purpose,31
ketone 31 proved most adequate; it was readily prepared from
epichlorohydrin by copper-catalyzed ring opening with 35 and
relocation of the epoxide.32 Compound 29 was subjected to
iododesilylation,33 and the resulting oxirane 30 reacted with
lithiated ethyl vinyl ether34 and BF3·OEt2 as promotor to give
31 after acidic workup. Sonogashira coupling with 24 furnished
25.35 Exposure of this compound to the gold catalyst 34 and
cocatalytic PPTS entailed a remarkably clean spirocyclization
to give 26 as a single isomer in 65−78% yield (1.7 mmol
scale).36 On account of the carbophilic complex, ketal
formation occurred exclusively at the triple bond while leaving
the peripheral ketone untouched; as expected, the reaction was
accompanied by rearrangement of the exo-methylene group to
the endocyclic position.37 Selective cleavage of the terminal
olefin furnished keto-aldehyde 27 in readiness for fragment
coupling.
The third building block was derived from glucal 36, which
was transformed into the 2-deoxyglycoside 37 (Scheme 5).38
Upon activation with TMSOTf, 37 reacted with allyltrime-
thylsilane to give 38 with >10:1 selectivity in favor of the
required 2,6-trans-disubstitution. This favorable outcome is
thought to reflect a Curtin−Hammett situation, whereby
“inside attack” of the nucleophile to a 4H3 half-chair
oxocarbenium intermediate as shown in J is selectivity-
determining.39 After replacement of the acetyl groups by
TBS-ethers, compound 39 was subjected to cross-metathesis
with 3-buten-1-ol. Since both partners are “type I” olefins, this
transformation was far from trivial.19,40 Gratifyingly though,
the crossed product 40 could be obtained in 75% yield when
the tailored complex 4741 was used as catalyst and the
conversion was driven with excess 3-buten-1-ol.
a
Reagents and conditions: (a) (i) H2CCHCOOMe, DABCO; (ii)
Dibal-H, THF, 57%; (b) TBSCl, NaH, THF, 0 °C → rt, 87%; (c)
MsCl, Et3N, THF, 88%; (d) LiCl, THF, 40 °C, 98%; (e) H2C
CHMgBr, CuI (17 mol %), THF, −78 °C → 0 °C; (f) TBDPSCl,
imidazole, CH2Cl2, 81%; (g) Grubbs II, H2CCHCOOMe, CH2Cl2,
reflux, 86%; (h) TMS-SEt, AlCl3, THF, reflux, 86%; (i) MeMgBr,
CuBr·SMe2 (2 mol %), 19 (2.4 mol %), tBuOMe, −78 °C, 90% (dr
>20:1); (j) Et3SiH, Pd/C (5 mol %), CH2Cl2, 85%; (k) 18, K2CO3,
MeOH, 94%; (l) 9-I-9-BBN, hexane, then HOAc, quant.; (m) (i) Zn,
LiCl, THF, reflux; (ii) 17, Pd(PPh3)4 (5 mol %), THF; (iii) TBAF,
THF, 0 °C, 76% (over both steps); (n) Ac2O, pyridine, DMAP (10
mol %), 96%.
Hillman reaction of bromomethacrylate 4 with excess methyl
acrylate16 followed by instant reduction of 5 and mono-
silylation of the resulting diol paved the way to allylic chloride
7 in readiness for a first chain extension. The nucleophilic
partner was prepared by copper-catalyzed opening of
commercial 8 with vinylmagnesium bromide,17 protection of
the resulting alcohol, and cross metathesis of 918 with methyl
acrylate.19 The projected asymmetric 1,4-addition to the
While the elaboration of 41 into tosylate 46 was
straightforward, all attempts at reacting this product with
appropriate C-nucleophiles essentially met with failure. This
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Communication
a
a
Scheme 4
Scheme 5
a
Reagents and conditions: (a) CeCl3·7H2O, NaI, MeOH, MeCN,
reflux, 52%; (b) TMSOTf, allyltrimethylsilane, MeCN, 57% (dr
>10:1); (c) K2CO3, MeOH; (d) TBSOTf, 2,6-lutidine, CH2Cl2, 95%
(over two steps); (e) 47 (10 mol %), 1-buten-3-ol (excess), CH2Cl2,
reflux, 75% (+7% of Z-isomer); (f) TBDPSCl, imidazole, CH2Cl2,
quant.; (g) CSA (cat.), MeOH, CH2Cl2, −20 °C, 77%; (h)
Pb(OAc)4, THF, 61%; (i) SnCl4, CH2Cl2, −78 °C, 83% (dr =
5:1); (j) Bu3SnLi, THF, −78 °C, 91%; (k) TsCl, DMAP cat.,
pyridine, CH2Cl2, 69%.
a
Reagents and conditions: (a) allyltrimethylsilane, BF3·OEt2, MeCN,
80 °C, 56%; (b) NaOMe, MeOH; (c) MeOC6H4CH(OMe)2, p-
TsOH cat., DMF, 79% (over two steps); (d) TBSOTf, 2,6-lutidine,
CH2Cl2, −40 °C, 86%; (e) Dibal-H, CH2Cl2, −78 °C, quant.; (f)
(COCl)2, DMSO, Et3N, CH2Cl2, −78 °C → rt, 87%; (g) 33, 32 (10
mol %), toluene, 96%; (h) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C,
quant.; (i) DDQ, aq. CH2Cl2, 0 °C → rt, 99%; (j) 31, Pd2(dba)3 (5
mol %), PPh3 (20 mol %), CuI (15 mol %), HN(iPr)2, 93%; (k) 34
(10 mol %), PPTS (10 mol %), CH2Cl2, 65−78%; (l) OsO4 (10 mol
%), NaIO4, 2,6-lutidine, 1,4-dioxane, H2O, 87−93%; (m) 35, CuCN
(10 mol %), THF, −50 °C → −20 °C, quant.; (n) NaOH, Et2O,
quant.; (o) (i) ICl, CH2Cl2, −78 °C, (ii) TBAF, THF/Et2O, 0 °C,
79%; (p) (i) tBuLi, ethyl vinyl ether, BF3·OEt2, THF, −78 °C; (ii) aq.
HCl, THF/H2O, 63%.
6).44,45 This expectation ultimately proved incorrect, but the
mistake was recognized only after 48 had been elaborated into
what was thought to be limaol. To this end, the ketone was
transformed into alkenylstannane 49 via kinetic enolization
with tritylpotassium as the base,46 quenching with PhNTf2, and
instant reaction of the resulting alkenyl triflate with
(Bu3Sn)2CuCNLi2 at low temperature.47 Stille coupling of
49 with 17 under conditions previously developed in our
laboratory for exigent cases allowed the sensitive side chain to
be attached without any scrambling of the olefins (which was
inevitable under more conventional conditions).48−50 This
gratifying outcome is best assessed by comparison with the
challenges encountered in the deprotection of product 50: only
HF·pyridine in THF/pyridine allowed the silyl groups to be
cleaved without affecting the integrity of the compound.31 Yet,
the spectra of the resulting product did not match those of
limaol;6 the deviations were clustered about the C27-
position,31 suggesting that the substrate-controlled asymmetric
allylation had given the wrong diastereomer and the formed
product epi-1 hence represents the C27-isomer of limaol.
The bias inherent to this addition is so pronounced that
various attempts to overturn it by means of reagent- or
catalyst-controlled allylation reactions basically met with
failure.31 Additional control experiments showed that the
outcome is not caused by any peculiarities of the chiral
allylstannane 45 either: thus, Lewis acid mediated addition of
simple 51a (X = H) or 51b (X = CH2Cl) followed the same
stereochemical course to give (27R)-configured products of
type 52 exclusively.30 Lewis acids other than MgBr2 led to
product mixtures in low yields.31,51 Further investigations are
necessary to clarify the origin of this peculiar steric preference.
inertia is ascribed to the ring-flip enforced by the bulky
−OTBS groups of 46:42 for an SN2 reaction with an external
nucleophile to take place, the tosylate would have to reside
under the ring, where it clashes into one of the axially disposed
protecting groups. Gratifyingly, this problem could be
bypassed: treatment of 41 with Pb(OAc)4 gave the “anomeric”
acetate 42 by excising the C-atom carrying the primary
alcohol.43 On activation with SnCl4, 42 reacted with the
functionalized allylsilane 43 to give allyl chloride 44 with
appreciable selectivity. Either this compound itself or the
derived allylstannane 45, formed on treatment of 44 with
Bu3SnLi, was deemed adequate to serve the projected coupling
of this “southern” fragment to the core unit.
Indeed, addition of 45 to 27 mediated by MgBr2·OEt2
furnished a single isomer in 88% yield; exclusive attack at the
aldehyde was observed, whereas the ketone was a mere
bystander. For the chelating Lewis acid promotor and the rigid
trans-decaline-type scaffold, the Cram-chelate product should
be formed, as necessary for the total synthesis of 1 (Scheme
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a
to limaol was analogous to that pursued toward epi-1. Once
again, kinetic enolization/stannylation of 53 followed by
palladium catalyzed fragment coupling of 54 with 17 under
notably mild conditions installed the tail region with the four
skipped “exo”-methylene groups; equally critical were the
conditions for the final deprotection of 55 thus formed. The
analytical and spectral data of synthetic 1 matched those of
natural limaol in all respects.6,31 The acquired material can
hence serve further biological profiling. The results of these
studies and further investigations into the fascinating estate of
dinoflagellate-derived metabolites will be reported in due
course.
Scheme 6
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12948.
Experimental Section including characterization data
and NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Alois Furstner − Max-Planck-Institut für Kohlenforschung,
̈
45470 Mülheim/Ruhr, Germany; orcid.org/0000-0003-
0098-3417; Email: fuerstner@kofo.mpg.de
a
Reagents and conditions: (a) MgBr2·OEt2, CH2Cl2, −78 °C, 88%;
(b) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 64%; (c) Ph3CK,
PhNTf2, THF, −78 °C; (d) (Bu3Sn)2CuCNLi2, THF, −55 °C, 77%
(isomer ratio ≈ 4:1); (e) 17, Pd(PPh3)4 (20 mol %), CuTC,
[Bu4N][Ph2P(O)O], NMP, 77% (pure isomer); HF·pyridine,
THF/pyridine, 37%.
Authors
Stephan N. Hess − Max-Planck-Institut für Kohlenforschung,
45470 Mülheim/Ruhr, Germany
Xiaobin Mo − Max-Planck-Institut für Kohlenforschung,
45470 Mülheim/Ruhr, Germany
Conny Wirtz − Max-Planck-Institut für Kohlenforschung,
45470 Mülheim/Ruhr, Germany
Since all attempts to form the correct isomer directly failed,
we resorted to an inversion of the secondary alcohol in 48
under Mitsunobu conditions (Scheme 7).52 Thereon, the route
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12948
a
Scheme 7
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the Max-Planck-Gesellschaft is
gratefully acknowledged. We thank Dr. G. Garivet for
exploratory studies, Dr. M. Leutzsch for an independent
confirmation of the assignment of the C27-stereochemistry,
and the Analytical Departments of our Institute for excellent
support.
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́
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