Synthesis of epiantillatoxin, a stereoisomer of the potent-ichthyotoxin from Lyngbya majuscula [10]

Full text of DOI:10.1021/ja983334l

1106
J. Am. Chem. Soc. 1999, 121, 1106-1107
Scheme 1a
Synthesis of Epiantillatoxin, a Stereoisomer of the
Potent Ichthyotoxin from Lyngbya majuscula
James D. White,* Roger Hanselmann, and Duncan J. Wardrop
Department of Chemistry, Oregon State UniVersity,
CorVallis, Oregon 97331-4003
ReceiVed September 18, 1998
Cyanobacteria (blue-green algae) have proven to be a rich
source of novel marine metabolites.1 A collection of Lyngbya
majuscula near Curac¸ao furnished, in addition to the novel tubulin-
binding agent curacin A,2 a small amount of a powerful
ichthyotoxic substance named antillatoxin (LD50 ) 0.005 mg/
mL). Structure 1, including the (4S,5R) configuration, was
a (i) Cp2ZrClH, THF; (ii) N-iodosuccinimide; (iii) MeCtCMgBr,
Pd(PPh3)4 (2.5 mol %), THF, 68% from 5; (iv) Bu3Sn(Bu)CuCNLi2, THF,
-50 °C; (v) MeOH, -50 °C f -10 °C, overnight; (vi) I2, Et2O, 0 °C,
52% from 7.
Scheme 2a
1
attributed to antillatoxin by Gerwick et al. on the basis of H
NMR spectroscopy, analysis of its CD spectrum, and molecular
modeling.3 Herein, we report a synthesis of 1 which establishes
that this assignment to antillatoxin is incorrect.4
Our synthetic approach follows a convergent strategy which
assembles 1 from the tripeptide 2, an aldehyde 3, and 1,3,5,5-
tetramethylhexa-1,3-dienyllithium (4). After the C5-C6 bond is
a (i) Me3SiCH2MgCl, CeCl3, THF; (ii) SiO2, CH2Cl2, 99%; (iii) 12,
CH3NO2, 0 °C; (iv) BF3‚OEt2, 0 °C, 70%; (v) IBX (1 M in DMSO),
THF, 70%.
The C1-C5 subunit 3 of 1 was constructed from methyl (R)-
3-hydroxy-2-methylpropionate via a sequence which conveniently
differentiated the two aldehyde termini of this segment. Addition
of excess (trimethylsilyl)methylmagnesium chloride to 10 in the
presence of cerium trichloride gave a tertiary carbinol which, upon
exposure to silica, underwent Peterson elimination to furnish
allylsilane 11.10 Electrophilic substitution of 11 with 1,3-dithie-
nium fluoroborate (12)11 in nitromethane produced a mixture of
alcohol 13 and its TBS ether (ca. 1:1); the mixture was converted
directly to 13 upon treatment with boron trifluoride etherate (see
Scheme 2). Oxidation of 13 with o-iodoxybenzoic acid (IBX)12
furnished the unstable aldehyde 3 which was reacted immediately
with the lithiated diene 4, obtained from 9 by treatment with tert-
butyllithium at low temperature, to yield an 8:1 mixture of two
stereoisomeric alcohols. After chromatographic purification, the
major alcohol 14 was acetylated, and the acetate 15 was converted
to carboxylic acid 16 by mild cleavage of the dithiane13 followed
by oxidation of the resultant aldehyde with buffered sodium
chlorite. The relative configuration of 16 was established by its
transformation to δ-lactone 17 in which the cis relationship of
hydrogens at C4 and C5 was confirmed by their coupling constant
of 3.0 Hz and a NOE of 7%. This result established the
configuration of the major alcohol from the reaction of 3 with 9
as (5R), corresponding to the Felkin mode of addition (see Scheme
3).
established, the coupled product is connected to the carboxyl
terminus of 2 prior to final lactamization.5
Synthesis of the diene side chain 4 of antillatoxin began from
4,4-dimethylpent-2-yne (5), which was subjected to hydrozir-
conation with Schwartz’ reagent6 and the resultant vinylzir-
conocene species was reacted with N-iodosuccinimide to yield
iodoalkene 6.7 The latter was coupled with propynylmagnesium
bromide in the presence of a palladium(0) catalyst8 to give 7.
Stannylcupration of enyne 7 at low temperature, followed by
methanolysis, led to 8, accompanied by ca. 10% of the inseparable
regioisomeric dienylstannane.9 Iodination of the mixture furnished
pure iododiene 9 after flash chromatography (see Scheme 1).
(1) Moore, R. E. J. Ind. Microbiol. 1996, 17, 134.
(2) (a) Nagle, D. G.; Geralds, R. S.; Yoo, H.-D.; Gerwick, W. H.; Kim,
T.-S.; Nambu, M.; White, J. D. Tetrahedron Lett. 1995, 36, 1189. (b) White,
J. D.; Kim, T.-S.; Nambu, M. J. Am. Chem. Soc. 1995, 117, 5612. (c) White,
J. D.; Kim, T.-S.; Nambu, M. J. Am. Chem. Soc. 1997, 119, 103.
(3) Orjala, J.; Nagle, D. G.; Hsu, V. L.; Gerwick, W. H. J. Am. Chem.
Soc. 1995, 117, 8281.
The tripeptide unit of antillatoxin was prepared from Cbz-
protected N-methylvaline (18)14 by bromotris(dimethylamino)-
phosphonium hexafluorophosphate(BroP)-mediated coupling with
methyl glycinate to give dipeptide 19. The Cbz group of 19 was
(4) The same conclusion was reached independently by Yokokawa and
Shioiri (Yokokawa, F.; Shioiri, T. J. Org. Chem. 1998, 63, 8638).
(5) An unsuccessful approach to 1 along different lines has been reported
(Loh, T.-P.; Cao, G.-Q.; Pei, J. Tetrahedron Lett. 1998, 39, 1453, 1457).
(6) Takahashi, T.; Suzuki, N. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L., Ed.; Wiley: Chichester, U.K., 1995; Vol. 2, pp 1082-
1087.
(7) Negishi, E.; Takahashi, T. Synthesis 1988, 1.
(8) Dang, H. P.; Linstrumelle, G. Tetrahedron Lett. 1978, 191.
(9) Aksela, R.; Oehlschlager, A. C. Tetrahedron 1991, 47, 1163.
(10) Lee, T. V.; Channon, J. A.; Cregg, C.; Porter, J. R.; Roden, F. S.;
Yeoh, H. T.-L. Tetrahedron 1989, 45, 5877.
(11) Westerlund, C. Tetrahedron Lett. 1982, 23, 4835.
(12) De Munari, S.; Frigerio, M.; Santagostino, M. J. Org. Chem. 1996,
61, 9272.
(13) Takano, S.; Hatakeyama, S.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1977, 68.
(14) McDermott, J. R.; Benoiton, N. L. Can J. Chem. 1973, 51, 1915.
10.1021/ja983334l CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/22/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 5, 1999 1107
Scheme 3a
Scheme 5a
a (i) t-BuLi, THF, -78 °C, 20 min, then 3, 60%; (ii) Ac2O, py, 20 h,
100%; (iii) MeI, CaCO3, MeCN-H2O, 16 h; (iv) NaClO2, NaH2PO4,
MeCHdCMe2, t-BuOH-H2O, 91%; (v) K2CO3, MeOH; (vi) CSA,
CH2Cl2, 43%.
a (i) 21, EDC, DMAP, CH2Cl2; (ii) MeI, CaCO3, MeCN-H2O; (iii)
NaClO2, NaH2PO4, MeCHdCMe2, t-BuOH-H2O, 75% from 14; (iv) Zn,
KH2PO4, THF; (v) HATU, (i-Pr)2 NEt, DMF, 60% from 23.
Scheme 4a
consistent with a stereoisomeric relationship, conspicuous dif-
ferences are the chemical shift of H4 (δ 2.71 in 1, δ 2.17 in
antillatoxin) and the coupling constant between H4 and H5. The
observed value of this coupling in 1 (J ≈ 0 Hz) is indicative of
a cis orientation of hydrogens, whereas the reported value (J )
11 Hz) for antillatoxin clearly is not. Cis configuration at C4,C5
in the natural product was assigned by Gerwick on the basis of
a NOE between protons attached to these carbons,3 but reexami-
nation of the NOE experiment has found that this result is
spurious.16 NMR evidence therefore points strongly toward a 4,5-
trans configuration for antillatoxin. At this time, we are unable
to distinguish between the (4R,5R) and (4S,5S) stereochemical
assignments for the natural product.
a (i) Gly‚OMe, BroP, (i-Pr)2 NEt, CH2Cl2, 93%; (ii) H2, Pd/C, MeOH;
(iii)Troc‚ala OH, HATU, (i-Pr)2NEt, CH2Cl2, 74%; (iv) LiOH, THF,
100%.
removed by hydrogenolysis, and the amine was condensed, using
(O-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexaflu-
orophosphate (HATU) as the coupling agent, with 1,1,1-trichlo-
roethoxycarbonyl (Troc)-protected alanine.15 The resultant tri-
peptide 20 was saponified to furnish carboxylic acid 21 (see
Scheme 4). Esterification of 14 with 21 was carried out in the
presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC)
and afforded 22 in good yield. After removal of the dithiane, the
derived aldehyde was oxidized to carboxylic acid 23. The Troc-
protecting group was cleaved, and final macrolactamization of
the liberated amino acid using HATU produced 1 (see Scheme
5). The latter was not identical in spectral properties, optical
rotation, or chromatographic behavior with a sample of natural
antillatoxin, and it is therefore concluded that the structure
assigned3 to antillatoxin must be revised.
Acknowledgment. We thank Professor William H. Gerwick, College
of Pharmacy, Oregon State University, for NMR spectra of natural
antillatoxin and for comparison of our synthetic 1 with a natural sample.
Financial support was provided by the National Institutes of Health
(GM50574), by the Marine-Freshwater Biomedical Sciences Center of
Oregon State University (ES03850), and by Dupont Pharmaceutical
Company.
Supporting Information Available: Experimental procedures, char-
acterization data, and NMR spectra (1H and 13C) for synthetic intermedi-
ates (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
Although most features of the 1H and 13C NMR spectra of our
synthetic 1 are similar to those of natural antillatoxin and are
JA983334L
(15) Carson, J. F. Synthesis 1981, 268.
(16) Private communication from Professor William H. Gerwick.