Total synthesis of amphidinolide X

Article abstract of DOI:10.1021/ja044130+

A concise total synthesis of the cytotoxic marine natural product amphidinolide X (1) is described. A key step of the highly convergent route to this structurally rather unusual macrodiolide derivative consists of a newly developed, highly syn selective f

Full text of DOI:10.1021/ja044130+

Published on Web 11/19/2004
Total Synthesis of Amphidinolide X
Olivier Lepage, Egmont Kattnig, and Alois Fu¨rstner*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
Received September 27, 2004; E-mail: fuerstner@mpi-muelheim.mpg.de
Scheme 1
Marine dinoflagellates of the genus Amphidinium sp. living in
symbiosis with the Okinawan flatworm Amphiscolops spp. produce
a host of secondary metabolites endowed with potent cytotoxicity
against various cancer cell lines. Commonly called “amphidino-
lides”,1 these conspicuous marine natural products usually embed
a “conserved” set of structural elements into highly diverse
macrolactone backbones. Amphidinolide X (1), however, is a
significant exception to this rule.2 This compound has neither the
characteristic exo-methylene group, nor a vicinal one-carbon branch,
nor a 1,3-diene unit found in virtually all other members of this
series. Moreover, 1 is the only naturally occurring macrodiolide
known to date that consists of a diacid and a diol unit rather than
of two hydroxyacid entities.2
Scheme 2
These rather unique structural features together with the promis-
ing cytotoxicity of 1 against murine lymphoma and human
epidermoid carcinoma prompted us to pursue a total synthesis of
this scarce compound.3,4 While the ester linkages forming the
macrodiolide ring constitute obvious sites of disconnection, it was
envisaged to assemble the C7-C22 segment by metal-catalyzed
cross coupling at the C13-C14 bond (Scheme 1). Not only does
this strategy ensure high convergence and employs building blocks
A-C of similar size, but also allows us to address the critical
formation of the tetrasubstituted chiral center C19 residing at the
ether bridge in an early stage of the synthesis campaign.
Scheme 3 a
The chosen route to this key structural element hinges upon
methodology recently developed in our laboratory (Scheme 2).5
Specifically, it was planned to use a chiral allene as latent progenitor
of the tetrahydrofuran ring, which can be formed stereoselectively
by an iron-catalyzed reaction of a propargyl epoxide with a suitable
Grignard reagent. This sequence should efficiently transfer the
central chirality of a readily accessible epoxide to the tetrasubstituted
chiral sp3 center C19 via the axial chirality of an allene relay.
Toward this end, allylic alcohol 26 was epoxidized by the
Sharpless method to give product 3 in excellent yield and decent
optical purity (ee ) 83%) (Scheme 3).7 Swern oxidation followed
by treatment of the resulting aldehyde with the Ohira-Bestmann
reagent8 gave alkyne 4, which was end-capped on treatment with
LiHMDS and MeOTf. Gratifyingly, reaction of the resulting
propargyl epoxide 5 with PrMgCl in the presence of cheap and
benign Fe(acac)3 as the precatalyst furnished, in less than 5 min,
the desired allene 6 as a 8:1 mixture in favor of the required syn
isomer. This pronounced selectivity likely results from a directed
delivery of the nucleophile enforced by a precoordination of the
oxophilic catalyst and/or reagent to the epoxide ring (Scheme 2)
and nicely complements the anti selectivity of the standard copper-
based methods for allenol formation.5a
a Conditions: [a] Ti(OiPr)4 cat., L-(+)-DET, tBuOOH, MS 4 Å, CH2Cl2,
97% (ee ) 83%); [b] (i) oxalyl chloride, DMSO, Et3N, CH2Cl2; (ii)
(MeO)2P(O)C(N2)COMe, K2CO3, MeOH, 67%; [c] LiHMDS, MeOTf, THF,
95%; [d] PrMgCl, Fe(acac)3 cat., toluene, 62% (syn:anti ) 8:1); [e] AgNO3,
CaCO3, aqueous acetone, 90%; [f] NBS, DMF/H2O (15/1), 65%; [g] AIBN,
(TMS)3SiH, toluene; [h] NaHCO3, MeOH, 90% (over both steps); [i]
PMBOC(dNH)CCl3, PPTS, CH2Cl2/C6H12, 76%; [j] TBAF, THF, 97%;
[k] I2, PPh3, imidazole, MeCN/Et2O, 92%.
in the bromo-esterification of 7 with NBS in aqueous DMF.10 From
a practical perspective, this detour was even rewarding as the C19
isomers could be separated at that stage by flash chromatography.
Removal of the bromide in 8 using (Me3Si)3SiH and AIBN11
followed by standard protecting group manipulations furnished
product 10 as adequate surrogate of synthon A.
Because the allene isomers were not readily separable, the
mixture was treated with AgNO3/CaCO3 in aqueous acetone to
afford the corresponding dihydrofuran 7 with strict chirality
transfer.9 While we had originally envisaged to install the missing
-OH group at C17 via hydroboration/oxidation, this sequence
turned out to be low yielding. A satisfactory alternative was found
The second building block was accessed by the palladium-
catalyzed, Et2Zn-mediated addition of the enantiopure propargyl
mesylate 12 to aldehyde 11 (Scheme 4).12 The major anti isomer
13 (ee ) 93%) was protected as a PMB-ether prior to C-
methylation. Hydrozirconation/iodination13 of the alkyne group in
15 afforded vinyl iodide 16 in good overall yield. Cleavage of the
9
15970
J. AM. CHEM. SOC. 2004, 126, 15970-15971
10.1021/ja044130+ CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4 a
efficient alkyl-alkenyl cross coupling17 of segments 21 and 10.
Specifically, alkyl iodide 10 was treated with t-BuLi at -78 °C
followed by addition of excess 9-MeO-9-BBN to give the corre-
sponding borate 22, which transfers its functionalized alkyl group
to the organopalladium species derived from alkenyl iodide 21 and
(dppf)PdCl2/AsPh3, thus delivering product 23 in 74% isolated yield.
Selective cleavage of the methyl ester in diester 23 with LiI in
pyridine18 followed by successive removal of the remaining acetal
moiety and the PMB ether gave seco-acid 25. The final macro-
cyclization of this compound proceeded smoothly under Yamaguchi
conditions,19,20 affording amphidinolide X 1 in 62% yield, thereby
completing the first total synthesis of this bioactive marine natural
product. Its analytical data are in excellent agreement with those
reported in the literature.2
Acknowledgment. Generous support by the DFG (Leibniz
award), the Fonds der Chemischen Industrie, the Merck Research
Council, and the Deutsch-Israelische Projektkooperation (DIP) is
gratefully acknowledged. O.L. thanks the AvH Foundation and
FQRNT for a fellowship.
a Conditions: [a] Et2Zn, Pd(OAc)2 cat., PPh3 cat., THF, 65% (anti:syn
) 4.5:1); [b] PMBCl, NaH, TBAI, DMF, 94%; [c] LiHMDS, MeI, THF,
95%; [d] (i) Cp2ZrHCl, C6H6; (ii) I2, CH2Cl2, 61%; [e] DDQ, CH2Cl2, pH
7 buffer, 89%; [f] (EtO)2P(O)CH2COOMe, LiCl, DBU, MeCN, 94%; [g]
HF‚pyridine, MeCN, quant.; [h] (i) oxalyl chloride, DMSO, Et3N, CH2Cl2;
(ii) NaClO2, NaH2PO4, (CH3)2CdCHCH3, tBuOH, 92%.
Supporting Information Available: Experimental details and
characterization of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Scheme 5 a
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JA044130+
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