Total synthesis of amphidinolide f

Article abstract of DOI:10.1002/anie.201301700

Orchestrated yet nonconsonant: The challenge posed by the "umpoled" 1,4-dioxygenation pattern characteristic for the polyketide frame of amphidinolide F was mastered by a late-stage ring-closing alkyne metathesis followed by a directed transannular hydration under the aegis of a carbophilic π-acid catalyst. This concordant strategy enabled a concise total synthesis of this enticing marine natural product. Copyright

Full text of DOI:10.1002/anie.201301700

Angewandte
Chemie
DOI: 10.1002/anie.201301700
Natural Products
Total Synthesis of Amphidinolide F**
Gaꢀlle Valot, Christopher S. Regens, Daniel P. OꢁMalley, Edouard Godineau, Hiroshi Takikawa,
and Alois Fꢂrstner*
Dedicated to the Bayer company on the occasion of its 150th anniversary
noma KB cell lines (IC50 of 5.8 and 4.6 ngmLꢀ1, respectively),
Marine dinoflagellates of the Amphidinium genus are
a remarkably prolific source of bioactive secondary metab-
olites. More than thirty macrolides have been isolated from
different strains, which are collectively called amphidinolides
but can actually be clustered into various subfamilies.[1,2] One
such panel comprises amphidinolide C, C2, C3, and F, which
exhibit different side chains but share the same odd-num-
its close relatives 1,[4] 3,[5] and 4[6] are up to three orders of
magnitude less potent. It remains to be seen, however, if this
striking bio-profile extends to a larger panel of tumor cell
lines. Because of the low isolation yields, the material supply
is a serious concern and may be one of the reasons why 1–4
attracted considerable attention from the synthetic commun-
ity.[7] Despite this, more than 20 years passed after the initial
isolation report before amphidinolide F (1) as the first and,
until now, only member of this subfamily succumbed to total
synthesis in 2012.[8]
As part of our long-term commitment to the amphidino-
lide family,[9–12] we now present another successful approach
to amphidinolide F (1) that is radically different in its
conception and considerably shorter in its implementation.
In an attempt to reflect the peculiarities of this target in the
synthesis blueprint, our plan evolved around the conspicuous
1,4-diketone moiety located at the C15 and C18 atoms
(Scheme 2). Such a nonconsonant (“umpoled”) pattern is
very unusual for a polyketide skeleton and its biosynthesis is
certainly not obvious. We envisaged that a directed trans-
annular alkyne hydration would provide access to this
bered frame consisting of
a 25-membered macrocycle
adorned with 11 (12) stereogenic centers, two 1,3-diene
units, and two trans-disposed tetrahydrofuran rings
(Scheme 1).
Scheme 1. Structures of the amphidinolides C and F.
Despite the obvious structural homology, these com-
pounds exhibit surprisingly different biological activities:
whereas amphidinolide C (2)[3] is highly cytotoxic for the
murine lymphoma L1210 and the human epidermoid carci-
[*] Dr. G. Valot, Dr. C. S. Regens, Dr. D. P. O’Malley, Dr. E. Godineau,
Dr. H. Takikawa, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
[**] Generous financial support by the MPG, the Alexander-von-
Humboldt Foundation (fellowship to D. P. O’M.), JSPS (fellowship
to H.T.) and the Fonds der Chemischen Industrie is gratefully
acknowledged. We thank the analytical departments of our Institute
for excellent support.
Scheme 2. Retrosynthetic analysis of 1 based on a directed trans-
annular alkyne hydration to be catalyzed by a carbophilic Lewis acid;
the dotted blue line in B indicates the quasi linear array that the
reacting sites must be able to reach.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301700.
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peculiar motif. Amongst the different conceivable incarna-
tions of this strategy, we opted for a hydroxy group (rather
than a ketone)[13] at C15 as the steering substituent and set the
ꢀ
alkyne site at the C17 C18 position. Activation of a substrate
of type B by a carbophilic noble-metal catalyst should trigger
a 5-endo-dig cyclization with formation of a dihydrofuran A,
which unveils the signature 1,4-oxygenation pattern upon
hydrolysis. This transformation is supposed to be highly
regioselective, as a 4-exo-dig pathway is unlikely to compete.
Although research into p-acid catalysis in general has gained
considerable momentum,[14] late-stage implementations in the
total synthesis of highly complex targets are rare.[15,16] By
subjecting an elaborate compound of type B to a carbophilic
catalyst, we thought to express our confidence in this
methodology that has grown considerably since our first
forays.[17] This plan is contingent upon the ability to forge the
necessary cycloalkyne from an adequate precursor C by ring-
closing alkyne metathesis (RCAM),[18,19] as well as on the
Scheme 3. a) TBSCl, Et3N, CH2Cl2, 08C!RT, 86%; b) TEMPO
(10 mol%), KBr, NaOCl, pH 8.6 buffer, CH2Cl2, 08C, 86%; c) 7, Pd-
(OAc)2 (5 mol%), PPh3 (5 mol%), Et2Zn, THF, ꢀ788C!ꢀ208C, 87%;
d) HCl (1%, v/v) in EtOH, 91%; e) TESOTf, 2,6-lutidine, CH2Cl2, 08C,
quant.; f) PPTS (10 mol%), MeOH, CH2Cl2, ꢀ508C, 80%;
ꢀ
proper choice of protecting groups, thus allowing the C15
OH function to be revealed in due time.
Mechanistically speaking, the projected hydration step is
thought to proceed through an outer-sphere attack of the
oxygen atom onto the activated alkyne, trans to the inducing
noble metal template; to this end, the partners must be able to
reach a quasi linear array (Scheme 2).[14,15] Handheld models
suggested that an R-configured secondary alcohol at C15 in B
might be better predisposed to meet this geometric precon-
dition than the 15S-isomer. It was planned to access the
required building block D by garnering its hidden symmetry
through a two-directional approach based on the powerful
anti-propargylation methodology developed by Marshall.[20]
To this end, aldehyde 6 was subjected to a zinc-mediated,
palladium-catalyzed reaction with mesylate 7 (98% ee) to
give product 8 (d.r. = 90:10) in high yield on a multigram scale
(Scheme 3).[21] The compound was then elaborated into
aldehyde 9, posed for a second Marshall propargylation.
After some experimentation it was found that the indium
variant worked better in this particular case,[22] for which the
uncapped mesylate 10 was used to ensure proper differ-
entiation of the alkyne termini in the resulting product 11.
Gratifyingly, careful flash chromatography allowed the other
diastereomers present at this stage to be largely removed.
After TBS protection of the free OH to ascertain the critical
orthogonality to the C15 TES ether, the terminal alkyne was
subjected to a silylcupration followed by a methyl iodide
quench.[23] Under optimized conditions the reaction worked
admirably well, affording compound 12 as a single isomer.
Basic methanol allowed for removal of the alkynyl TMS
group without affecting the three other silyl residues. C-
Methylation followed by iodine-for-silicon exchange gave
alkenyl iodide 14 as surrogate of synthon D. However, this
product turned out to be rather light sensitive and was
therefore released from its immediate precursor 13 only on
demand.
g) SO3·pyridine, iPr2NEt, DMSO, CH2Cl2, ꢀ308C, 93%; h) 10, InI,
[PdCl2(dppf)] (5 mol%), THF/HMPA, 73%; i) TBSOTf, 2,6-lutidine,
CH2Cl2, 08C, 91%; j) PhMe2SiLi, CuCN, MeI, THF, 08C, 90%;
k) K2CO3, MeOH, 408C, 88%; l) nBuLi, MeI, THF, ꢀ788C ! RT, 97%;
m) NIS, MeCN, benzene, 08C, 88%; dppf=1,1’-bis(diphenylphosphi-
no)ferrocene; Ms=methanesulfonyl; NIS=N-iodosuccinimide;
PPTS=pyridinium p-toluenesulfonate; TBS=tert-butyl-dimethylsilyl;
TES=triethylsilyl; TEMPO=2,2,6,6-tetramethyl-1-piperinyloxy radical;
Tf =trifluoromethansulfonyl; TMS=trimethylsilyl.
Scheme 4. a) Propyne, nBuLi, BF3·Et2O, THF, ꢀ788C, 87%;
b) (nmp)2Co (10 mol%), tBuOOH (10 mol%), O2 (1 atm), iPrOH,
558C, 84%; c) SO3·pyridine, iPr2NEt, DMSO, CH2Cl2, 08C, 86%;
d) i) 20, tBuLi, Et2O, ꢀ788C, then ZnBr2, Et2O, ꢀ358C!08C; ii) (ꢀ)-N-
methylephedrine/nBuLi, toluene, 08C; iii) 18, Et2O, ꢀ208C, 85%.
different in that the aerobic cobalt-catalyzed etherification
step was conducted with substrate 16, containing two different
p-bonds that might, a priori, be amenable to oxidation.
Gratifyingly, the transformation was strictly chemoselective,
in that the olefinic site of 16 reacted cleanly, whereas the
alkyne entity survived uncompromised. We acknowledge,
however, that the “second generation” Pagenkopf catalyst
carrying nmp ligands (Scheme 4)[7e] afforded consistently
better yields than other cobalt species previously used in
the literature.[24] Oxidation of the resulting trans-disubstituted
tetrahydrofuran derivative 17 to the corresponding aldehyde
An oxidative Mukaiyama cyclization reaction[24] opened
an expeditious entry into the tetrahydrofuran segment F
(Scheme 4). While this work was in progress, the group of
Pagenkopf reported a model study directed towards amphi-
dinolide C (2) following a similar logic.[7e,l] Our approach is
2
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18 followed by a chelate-controlled N-methylephedrine-
assisted addition[25] of the dienylzinc reagent derived from
bromide 20[26] also proceeded smoothly. Thus, the required
building block 19 was accessible in appreciable overall yield
and good diastereoselectivity (d.r. ꢁ 95:5) in only four oper-
ations.
Whereas a Yamaguchi esterification of 19 and 31 gave
product 32 without incident,[32] the subsequent Stille coupling
proved to be rather challenging (Scheme 6). Only under the
very mild conditions, which we had optimized during
a previous amphidinolide project,[11,33] could the isomeriza-
tion-prone 1,3-diene unit of 33 be assembled in a workable
56% yield, although a high catalyst loading was required.
With this considerable hurdle overcome, the stage was set for
macrocyclization by RCAM, to be followed by transannular
alkyne hydration. Two possible scenarios were conceived and
explored: the more conservative approach engaged the fully
protected diyne into ring closure, followed by selective
deprotection of the TES ether at C15; alternatively, one
may inverse the order and perform the RCAM step with
a substrate already exhibiting the free OH group.
Fragment E was prepared from the known alcohol 24,[3c]
which in turn was obtained from the commercially available
furanone 21 in six readily scalable steps (Scheme 5).[27,28]
A
We are pleased to report that either way was ultimately
successful. Specifically, diyne 33 was cyclized in good yield
with the aid of complex 39, activated in situ with CH2Cl2, as
previously described by our group,[34] whereas complex 40[35]
carrying somewhat bulkier silanolate ligands gave an acyclic
dimer as a by-product.[36] Gratifyingly though, catalyst 40
excelled after reducing the bulk about one of the alkyne units
in the cyclization precursor by cleavage of the flanking TES
group: the relieved compound 35 was cleanly transformed
into product 36 upon warming. This result is remarkable as
acidic protons were hardly manageable by earlier generations
of alkyne metathesis catalysts; moreover, one has to note that
alkylidyne 40 owes its excellent application profile to the
silanolate ligands, which might partly exchange with sub-
strates containing free OH groups. Although the compati-
bility of 40 with protic substituents needs further scrutiny, this
encouraging example illustrates the exquisite tolerance of the
latest generation of alkyne metathesis catalysts.[35]
The NMR spectra of the cycloalkynes 34 and, in
particular, 36 feature massive line broadening in the entire
temperature range that was surveyed, with (at least) two
slowly equilibrating conformers being detectable at ꢀ208C.
This conformational intricacy, however, did not obstruct
transannular alkyne hydration from occurring. Excellent
results were obtained under platinum catalysis:[37,38] treatment
of compound 36 with only 0.2 mol% of [{(C2H4)2PtCl2}2] in
Et2O afforded hydroxyketone 37 (in equilibrium with the
corresponding hemiketals) within minutes in essentially
quantitative yield after a brief hydrolytic work-up.[39] As
expected, the regioisomeric ketone derived from a 4-exo-dig
pathway could not be detected and both 1,3-diene subunits
remained untouched, illustrating the exquisite “alkynophilic-
ity” of the catalyst.[14] Subsequent oxidation of 37 with
TPAP[40] furnished diketone 38 that was identical in all
regards with the material previously prepared by a different
route.[8] Amongst the conceivable conditions for the final
deprotection, the use of HF·NEt3 at slightly elevated temper-
ature gave the best result. The analytical and spectral data of
amphidinolide F (1) thus formed were in excellent agreement
with those described in the literature.[4,8]
Scheme 5. a) TrCl, pyridine, 91%; b) (i) LDA, MeI, THF, ꢀ788C!
ꢀ308C; (ii) LDA, THF, ꢀ788C, aq. work up, 93% (over both steps);
=
c) Dibal-H, CH2Cl2, ꢀ788C; d) Ph3P CHCOOEt, toluene, 808C, 85%
(over both steps); e) TBAF·3H2O, THF, 08C, 87%; f) TFA, EtOH,
CH2Cl2, 08C, 86%; g) SO3·pyridine, iPr2NEt, DMSO, CH2Cl2, 08C;
h) 26, l-proline (50 mol%), DMF, 66% (over both steps); i) TBSOTf,
pyridine, CH2Cl2, 08C!RT, 91%; j) KHMDS, PhNTf2, THF, ꢀ788C,
73%; k) [Pd2(dba)3] (15 mol%), P(2-furyl)3 (60 mol%), Me6Sn2, LiCl,
THF, 81%; l) KOH, THF, EtOH, H2O, 458C, 98%; dba=dibenzylide-
neacetone; Dibal-H=di-isobutylaluminum hydride; KHMDS=potas-
sium hexamethyldisilazide; LDA=lithium di-isopropylamide; TBAF=
tetra-n-butylammonium fluoride; TFA=trifluoroacetic acid; Tr=trityl.
proline-catalyzed aldol reaction of the derived aldehyde 25
with 26 as the prenucleophile[29] furnished the required anti-
aldol derivative 27 in acceptable yield; its stereostructure was
confirmed by Mosher-ester analysis and by NOE studies on
the derived isopropylidene acetal. For preparative purposes,
however, bis-TBS protection of the diol was preferred, as the
isopropylidene acetal turned out to be rather labile. Com-
pound 28 behaved well in the subsequent alkenyl triflate
formation, even though it contains two potentially enolizable
sites. The kinetic and thermodynamic acidity of the methyl
ketone is obviously sufficiently higher than that of the ester
group, thus allowing us to secure appreciable amounts of
product 29. For its conversion into stannane 30, the combi-
nation of [Pd2(dba)3] and tris-2-furylphosphine[30] fared con-
siderably better than the more commonly used [Pd(PPh3)4]
catalyst.[31] Saponification of the ester finally delivered
building block 31 and opened the assembly phase of this
total synthesis project.
Our total synthesis of this exigent marine natural product
comprises a longest linear sequence of no more than 21 steps
and therefore compares favorably with the only other
completed approach known in the literature.[8] A late-stage
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Scheme 6. a) 2,4,6-Trichlorobenzoyl chloride, Et3N, DMAP, toluene, 80%; b) 14, [Pd(PPh3)4] (30 mol%), Ph2PO2NBu4, CuTC, DMF, 56%; c) 39
(30 mol%), toluene, CH2Cl2, 608C, 73%; d) PPTS (30 mol%), MeOH, CH2Cl2, 08C, 87% (36), 95% (35); e) 40 (20 mol%), toluene, 1008C, 70%;
f) [{(C2H4)PtCl2}2] (0.2 mol%), Et2O, 97%; g) PPTS, benzene, 98%; h) TPAP, CH2Cl2, 70%; i) HF·NEt3, Et3N, MeCN, 408C, 60%; CuTC=copper
thiophene-2-carboxylate; DMAP=4-dimethylaminopyridine; TPAP=tetra-n-propylammonium perruthenate
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interplay of RCAM and p-acid catalysis nicely solved the
selectivity issue arising from the unusual 1,4-dioxygenation
pattern decorating the targetꢀs polyfunctional backbone.[41]
The success of this strategy showcases the maturity of these
methods and augurs well for future applications.
Received: February 27, 2013
Published online: && &&, &&&&
Keywords: alkyne metathesis · molybdenum · natural products ·
.
platinum · total synthesis
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Fꢁrstner, Angew. Chem. 2012, 124, 12207 – 12212; Angew. Chem.
Int. Ed. 2012, 51, 12041 – 12046.
[37] B. Liu, J. K. De Brabander, Org. Lett. 2006, 8, 4907 – 4910.
[38] Exploratory studies with PdII, AuI, AuIII; or HgII were less
promising, despite a relevant literature precedent, see: G. Jalce,
X. Franck, B. Seon-Meniel, R. Hocquemiller, B. Figadꢄre,
Tetrahedron Lett. 2006, 47, 5905 – 5908.
[20] J. A. Marshall, J. Org. Chem. 2007, 72, 8153 – 8166.
[21] J. A. Marshall, N. D. Adams, J. Org. Chem. 1999, 64, 5201 – 5204.
[22] a) J. A. Marshall, C. M. Grant, J. Org. Chem. 1999, 64, 696 – 697;
b) B. A. Johns, C. M. Grant, J. A. Marshall, Org. Synth. 2002, 79,
59 – 71.
¯
[39] K. Bannai, T. Toru, T. Oba, T. Tanaka, N. Okamura, K.
Watanabe, A. Hazato, S. Kurozumi, Tetrahedron 1986, 42,
6735 – 6746.
[40] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
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[24] a) S. Inoki, T. Mukaiyama, Chem. Lett. 1990, 67 – 70; b) see also:
B. Menꢃndez Pꢃrez, D. Schuch, J. Hartung, Org. Biomol. Chem.
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at ꢀ788C and must be freshly prepared prior to use.
[41] For previous total syntheses based on RCAM in concert with p-
acid catalysis from our group, see: a) S. Benson, M.-P. Collin, A.
Arlt, B. Gabor, R. Goddard, A. Fꢁrstner, Angew. Chem. 2011,
123, 8898 – 8903; Angew. Chem. Int. Ed. 2011, 50, 8739 – 8744;
b) W. Chaładaj, M. Corbet, A. Fꢁrstner, Angew. Chem. 2012,
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c) L. Brewitz, J. Llaveria, A. Yada, A. Fꢁrstner, Chem. Eur. J.
2013, 19, 4532 – 4537.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Natural Products
G. Valot, C. S. Regens, D. P. O’Malley,
E. Godineau, H. Takikawa,
A. Fꢁrstner*
&&&& — &&&&
Total Synthesis of Amphidinolide F
Orchestrated yet nonconsonant: The
challenge posed by the “umpoled” 1,4-
dioxygenation pattern characteristic for
the polyketide frame of amphidinolide F
was mastered by a late-stage ring-closing
alkyne metathesis followed by a directed
transannular hydration under the aegis of
a carbophilic p-acid catalyst. This con-
cordant strategy enabled a concise total
synthesis of this enticing marine natural
product.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!