Total synthesis of neurymenolide-A Based on a gold-catalyzed synthesis of 4-hydroxy-2-pyrones

Article abstract of DOI:10.1002/anie.201203180

Treat me gently: For a selective synthesis of the unusually sensitive cyclophanic α-pyrone neurymenolide A, the chosen catalysts must be able to distinguish between six different sites of unsaturation, without scrambling any of the skipped π systems. This challenge was met with a new gold-catalyzed pyrone synthesis in combination with a molybdenum-catalyzed ring-closing alkyne metathesis. Copyright

Full text of DOI:10.1002/anie.201203180

Angewandte
Chemie
DOI: 10.1002/anie.201203180
Natural Product Synthesis
Total Synthesis of Neurymenolide A Based on a Gold-Catalyzed
Synthesis of 4-Hydroxy-2-pyrones**
Wojciech Chaładaj, Matthieu Corbet, and Alois Fꢀrstner*
Bioassay-guided fractionations of the extracts of the red alga
Neurymenia fraxinifolia harvested off Fiji island afforded two
polyunsaturated a-pyrone derivatives, dubbed neurymenoli-
de A (1) and B (3).[1] These metabolites exhibit appreciable
activity against methicillin-resistant Staphylococcus aureus
(MRSA) and vancomycin-resistant Enterococcus faecium
(VREF), and show moderate cytotoxicity against 12 human
cancer cell lines.[1] What makes them really unique, however,
is their unusual carbon skeleton, which is thought to derive
from eicosapentaenoic acid by diketide chain extension
followed by macrocyclization/pyrone formation as the key
steps (Scheme 1).[2–5] The resulting cyclophane framework of
the narrower sibling 1 carries a chiral center of as yet
unknown absolute configuration and shows an element of
planar chirality as well. Therefore, the two atropisomers are
diastereomeric to each other. After acetylation of the
4-hydroxy group on the pyrone ring, the individual isomers
of 2 are stable enough to be separated by HPLC, even though
they equilibrate in solution on a time scale of hours.[1,6]
The skipped array of the four double bonds in 1, two of
which may also migrate into conjugation with the pyrone ring,
renders neurymenolide A exceptionally labile. Whereas an
attempted purification of 1 on normal-phase silica led to rapid
isomerization,[1] the derived acetate 2 seems somewhat more
manageable. The fragile character transpiring from these data
imposes serious constraints upon any synthetic approach. As
outlined below, however, we were able to meet this challenge
with the aid of new methodologies developed in this
laboratory, which capitalize on the ability of transition
metal catalysts to rigorously distinguish between alkynes
and alkenes under exceptionally mild conditions.[7,8]
To this end, it seemed necessary to revisit the method-
ology for the formation of 4-hydroxy-2-pyrones. Although
many procedures for the preparation of this heterocyclic
motif are known in the literature,[9] the biomimetic cyclization
of tricarbonyl precursors (see compound 5) is still most widely
practiced. However, previous experiences led us to doubt that
this particular transformation qualifies for the very demand-
ing neurymenolide A case.[10] Yet, we anticipated that sub-
strates of type 6 might be an attractive alternative, since
alkynes are carbonyl equivalents that can be activated under
exceptionally mild conditions with the aid of carbophilic
catalysts.[11,12]
In fact, the readily available substrate 6a (R1 = H, R2 =
Et)[13] was transformed into the corresponding pyrone deriv-
ative 7a in excellent yield on treatment with 1 mol% of
[(SPhos)AuNTf2] (8; Tf = trifluoromethanesulfonate)[14] at
ambient temperature (Scheme 2). Although the cyclization
proceeded well in a variety of solvents, the use of either
nitromethane or acetic acid resulted in the highest reaction
rates.[15] A series of control experiments showed that neither
HOAc alone nor in combination with HNTf2 effected this
transformation well. AgNTf2 exhibits some activity, even
though it is much less effective than gold complex 8.[16]
The examples compiled in Scheme 2 indicate a substantial
scope for this convenient new entry into 4-hydroxy-2-pyrones,
which also scales well (see the Supporting Information).
Various substituents at the 3- and the 6-position are well
tolerated. Even substrates 6d,e (R1 = Br, F), which carry
labile bromide or fluoride substituents on their b-keto ester
subunit, reacted cleanly to the corresponding 2-halogenated
pyrones 7d,e. Only the silylated derivative 7 f was formed in
modest yield, which echoes previous experiences with sily-
lated alkynes in gold catalysis.[17] The current synthesis of
pseudopyronine A (7g), an antibiotic interfering with micro-
bial fatty acid biosynthesis, also favorably compares to an
Scheme 1. Neurymenolide A (1, R=H), an atropisomeric cyclophane
of marine origin, and its ring-expanded homologue neurymenolide B
(3). Proposed biosynthetic pathway toward 1 by cyclization of an
eicosapentaenoic acid-derived precursor.[1,3] Enz=enzyme.
[*] Dr. W. Chaładaj, Dr. M. Corbet, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
[**] Generous financial support by the MPG and the Fonds der
Chemischen Industrie is gratefully acknowledged. We thank D.
Laurich for assistance and our analytical departments for excellent
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203180.
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Scheme 4. Documented example of a highly favorable diauration of
a b-alkoxy-alkenylgold intermediate.[20]
this side track could explain why HOAc is a particularly
favorable (co)solvent for this transformation.
In line with the proposed mechanism, the formal replace-
ment of the tert-butyl groups in 6 by other ester functions
should allow this methodology to be diverted to the prepa-
ration of isomeric g-pyrone derivatives. This notion is
corroborated by the clean conversion of benzyl ester 9 into
the stable benzyl derivative 10 shown in Scheme 5.
These encouraging results notwithstanding, the total
synthesis of neurymenolide A as the biologically more
Scheme 2. Gold-catalyzed synthesis of 4-hydroxy-2-pyrones. [a] In
HOAc. [b] In MeNO2. Cy=cyclohexyl, Tf=trifluoromethanesulfonate.
earlier approach.[18] Product 7h, representing a protected
form of hispidine, which is the first pyrone derivative isolated
from natural sources,[19] suggests that the new method leaves
pre-existing alkenes uncompromised and may hence qualify
for the projected total synthesis of neurymenolide A.
Scheme 5. Extension to the preparation of g-pyrone derivatives.
A plausible catalytic cycle is depicted in Scheme 3. As this
mechanism suggests, the ready cleavage of the tert-butyl
group off of putative intermediate B is critical for the release
of the a-pyrone ring. Previous studies from this laboratory,
however, showed that alkenylgold species carrying oxygen
substituents at the b-position are biased to react with a second
gold atom to give gem-diaurated intermediates, which are
surprisingly stable (Scheme 4).[20] This pathway may seriously
compete with proto-deauration and hence retard the catalytic
turnover. It is of note that the proposed intermediate C
contains this characteristic structural element (Scheme 3,
color coded in red).[21] Although it yet remains to be seen
whether gem-diauration interferes in the pyrone series or not,
relevant and synthetically more challenging of the two sister
compounds presents a much more rigorous test for the
performance of the new methodology. As shown in Scheme 6,
freshly distilled (Z)-3-hexenal (11) served as our entry
point,[22] which reacted with lithio trimethylsilylacetylide to
give propargyl alcohol 13 after standard proto-desilylation. A
palladium-catalyzed hydrostannylation then provided 14,
which was cross-coupled with the known alkenyl iodide
15.[23] This Stille-type reaction was best promoted by copper
thiophene-2-carboxylate (CuTC) in the absence of palla-
dium;[24] under these conditions, compound 16 was secured in
excellent yield after acetylation of the primary product. This
ester was then subjected to a remarkably high yielding,
deconjugative Ireland–Claisen rearrangement[25,26] to set
three of the four skipped unsaturated sites with the correct
Z,E,Z-pattern, as contained within the neurymenolide tether.
After conversion of acid 17 into the corresponding tert-
butyl ester 18, the yet missing unsaturation was installed by
cleavage of the primary tert-butyldimethylsilyl group and
conversion of the resulting alcohol into the Z-configured
allylic bromide 19. Gratifyingly, a copper-catalyzed reaction
with propynylmagnesium bromide in THF/HMPA (HMPA =
hexamethylphosphoramide) allowed the required alkyne
moiety to be introduced without any noticeable scrambling
of the allylic double bond or competing SN2’ substitution.[27]
The success of this route stands out against the failure of the
slightly more elaborate compound 22 to undergo an analo-
gous Ireland–Claisen rearrangement in preparatively mean-
ingful yields.
Next, compound 20 was deprotonated at low temperature
and the resulting lithium enolate condensed with methyl
dodeca-2,10-diynoate[28] to give product 21 in respectable
yield (Scheme 7). With this highly sensitive material in hand,
Scheme 3. Proposed catalytic cycle.
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Scheme 7. a) LDA, THF, then methyl dodeca-2,10-diynoate, ꢁ788C!08C,
76%; b) (i) 22 (5 mol%), MeNO2/HOAc (4:1, 0.04m); (ii) Ac2O, Et3N,
CH2Cl2, 08C, 73%; c) 24 (5 mol%), toluene, 5 ꢁ molecular sieves, 88%;
d) H2 (1 atm), Lindlar catalyst, quinoline (cat.), EtOAc/1-hexene, 84%;
e) K2CO3, MeOH, 08C, see text for details. Cy=cyclohexyl, LDA=lithium
diisopropylamide.
ꢀ
Scheme 6. a) Me3SiC CH, nBuLi, THF, ꢁ788C!RT, 84%; b) K2CO3,
MeOH, 98%; c) Bu3SnH, [PdCl2(PPh3)2] (2 mol%), THF, 08C, 59%; d)
1. CuTC, NMP, 08C; 2. Ac2O, Et3N, DMAP (5 mol%), CH2Cl2, 08C,
93%; e) 1. LDA, TBSCl, THF/HMPA, ꢁ788C!RT; 2. K2CO3, MeOH,
08C, 93%; f) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP (cat.), tolu-
ene, then tBuOH, 73%; g) TBAF, THF, 95%; h) CBr4, PPh3, CH2Cl2,
08C, 92%; i) propynylmagnesium bromide, CuI (20 mol%), THF,
ꢁ108C, 98%; j) 1. CuTC, NMP, 08C; 2. Ac2O, Et3N, DMAP (cat.),
CH2Cl2, 08C, 74%. CuTC=copper thiophene-2-carboxylate, DMAP=
4-dimethylaminopyridine, HMPA=hexamethylphosphoramide, LDA=
lithium diisopropylamide, NMP=N-methyl-2-pyrrolidinone, TBAF=
tetra-n-butylammonium fluoride, TBS=tert-butyldimethylsilyl.
tion. After considerable experimentation it was found that
recourse to gold complex 22, which contains the even more
bulky Xphos ligand,[30] allowed the desired product 23 to be
isolated in modest 26% yield from a still quite complex
mixture, together with unreacted starting material (37%).
Gratifyingly though, the addition of HOAc as cosolvent,
meant to accelerate the presumably critical protodeauration
step within the catalytic cycle, resulted in a much cleaner
transformation. Under these conditions, pyrone 23 was
isolated in 73% yield after acetylation of the crude material.
This in situ protection was mandatory to suppress fast
isomerization of the lateral alkenes.[31] It is believed that the
selective activation of the least electron-rich acetylene group
in 21, which leads to pyrone formation, is kinetic in origin and
the ensuing reaction is irreversible due to the gain of
aromaticity.
The subsequent macrocyclization of this very delicate
compound was effected with remarkable efficiency using the
molybdenum alkylidyne ate-complex 24 as the arguably most
active and selective catalyst for ring closing alkyne metathesis
(RCAM)[8,32] known to date. Specifically, the desired cyclo-
phane 25 was obtained in 88% yield (as a 1:1 mixture of two
atropisomers) within less than 30 min upon exposure of
substrate 23 to catalytic amounts of 24 (5 mol%)[33,34] in
toluene at ambient temperature in the presence of molecular
sieves to sequester the released 2-butyne. The fragile array of
skipped olefins was not damaged at all, which proves that
alkyne metathesis is strictly orthogonal in chemical terms to
alkene metathesis;[35] this feature is instrumental, since an
analogous closure of the neurymenolide frame by conven-
tional RCM seems inconceivable with any of the catalysts
known to date[36] in view of the four double bonds of E- and Z-
configuration, each of which is disubstituted and needs to pass
uncompromised.[37,38]
which contains six different non-conjugated sites of unsatura-
tion (not counting the partial enol form of the b-ketoester
visible in the NMR spectra), the critical phase of the total
synthesis was reached, in which the heterocyclic ring and the
cyclophanic frame had to be forged. From a conceptual
viewpoint, it seemed reasonable to perform the gold chemis-
try prior to the macrocyclization, as the resulting pyrone
might impart some stability onto the very fragile polyunsa-
turated material. To this end, however, it is mandatory that
the catalyst is able to rigorously distinguish between the
different p systems of 21. However, since the acetylene in
conjugation to the keto group is the least electron rich of the
three alkynes and may therefore have the lowest affinity to an
electrophilic gold fragment, it was by no means clear if this
transformation would be successful, even if the alkenes do not
get scrambled by the catalyst, which is also non-obvious. On
top of this, one of the alkynes in 21 is perfectly set up for
a gold-catalyzed 6-exo-dig Conia-ene cyclization,[29] which has
to be outperformed by the pyrone cyclization too.
Our initial attempts to close the required 4-hydroxy-2-
pyrone 23 seemed to reflect these difficulties. Specifically,
treatment of 21 under aprotic conditions with catalytic
amounts of 8 in nitromethane resulted in rapid decomposi-
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degraded upon contact with silica and neutral alumina alike.
In summary, the first total synthesis of neurymenolide A,
a highly unusual a-pyrone of eicosanoid origin, was accom-
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occurring cyclophane constituted a stringent test for the
efficiency and tolerance of the methodology developed in our
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and selective manner in either step—with the aid of an early
as well as with a late transition metal catalyst—which is at the
heart of this success.
[13] Prepared in 91% yield by Claisen condensation of commercial
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Received: April 25, 2012
Published online: && &&, &&&&
Keywords: alkynes · gold · molybdenum · natural products ·
.
total synthesis
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Communications
Natural Product Synthesis
Treat me gently: For a selective synthesis
of the unusually sensitive cyclophanic a-
pyrone neurymenolide A, the chosen cat-
alysts must be able to distinguish
between six different sites of unsatura-
tion, without scrambling any of the
skipped p systems. This challenge was
met with a new gold-catalyzed pyrone
synthesis in combination with a molyb-
denum-catalyzed ring-closing alkyne
metathesis.
W. Chaładaj, M. Corbet,
A. Fꢁrstner*
&&&& — &&&&
Total Synthesis of Neurymenolide A
Based on a Gold-Catalyzed Synthesis of 4-
Hydroxy-2-pyrones
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!