Total synthesis of antillatoxin, an ichthyotoxic cyclic lipopeptide, having the proposed structure. What is the real structure of antillatoxin?

Full text of DOI:10.1021/jo981744m

8638
J . Org. Chem. 1998, 63, 8638-8639
Sch em e 1
Tota l Syn th esis of An tilla toxin , a n
Ich th yotoxic Cyclic Lip op ep tid e, Ha vin g th e
P r op osed Str u ctu r e. Wh a t Is th e Rea l
Str u ctu r e of An tilla toxin ?
Fumiaki Yokokawa* and Takayuki Shioiri*
Faculty of Pharmaceutical Sciences, Nagoya City University,
Tanabe-dori, Mizuho-ku, Nagoya 467-8603, J apan
Received August 26, 1998
Antillatoxin (1) is an ichthyotoxic metabolite from the
marine cyanobacterium Lyngbya majuscula collected in
Curac¸ao.1 Goldfish toxicity measurements with antillatoxin
shows it to be among the most ichthyotoxic metabolites
isolated to date from a marine plant (LD50 ) 0.05 µg/mL).
Antillatoxin is a structurally novel lipopeptide with a high
degree of methylation. Especially, it has a conjugated diene
that contains a tert-butyl group and the isolated terminal
olefin. Therefore, antillatoxin is a structurally and biologi-
cally attractive marine natural product. We now wish to
report the total synthesis of antillatoxin having the reported
structure 1.2 In our convergent strategy, antillatoxin is
disconnected into the tripeptide unit 2 and the diene
fragment 3. Segment condensation of these fragments and
macrolactamization gives the desired macrocycle (Scheme
1).
Sch em e 2
Preparation of the tripepetide unit was achieved in a
stepwise manner from glycine ethyl ester as shown in
Scheme 2.3 Coupling of (S)-Boc-N-methylvaline with the
glycine ethyl ester was carried out using diethyl phosphoro-
cyanidate (DEPC, (EtO)2P(O)CN)4 to give the dipeptide 4,
(TES) derivative and reduction of the methyl ester with
diisobutylaluminum hydride (DIBAL) provided the primary
[R]26 -117.7° (c 1.0, CHCl3), in 86% yield. After removal
alcohol 11, [R]25 +1.9° (c 1.1 MeOH), in 98% yield.12
D
D
of the Boc group from 4 with trifluoroacetic acid (TFA),
coupling with (S)-Alloc-alanine using bis(2-oxo-3-oxazoli-
dinyl)phosphinic chloride (BopCl)5 afforded the tripeptide 5,
(9) The conjugated diene 8 was also prepared in a stepwise manner using
the Horner-Emmons protocol.
[R]26 -139.7° (c 1.1, CHCl3), in 50% yield. Alkaline
D
saponification of 5 gave the tripeptide unit 2, which was
directly used in the next step after an aqueous workup.
The synthesis of the diene fragment started from 4,4-
dimethyl-2-pentyne (6)6 as shown in Scheme 3.3 After
hydroboration of the alkyne 6 with catecholborane, the
resulting vinyl borane was coupled with the vinyl iodide 77
under Suzuki-coupling conditions8 to give the conjugated
diene 8 in 53% yield.9 Oxidation of the allylic alcohol 8 using
chemical manganese dioxide (CMD)10 followed by selective
formation of the stereocenters at both C(4) and C(5) by the
methodology of Evans et al.11 produced the alcohol 9, [R]26
D
-21.3° (c 1.0, CHCl3), in 93% yield. Removal of the chiral
auxiliary from 9 with alkaline hydrogen peroxide and
methylation of the resulting carboxylic acid gave the methyl
ester 10, [R]24D +8.7° (c 1.1 CHCl3), in 60% yield. Protection
of the secondary hydroxy group of 10 as the triethylsilyl
(10) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai, M.;
Ando, A.; Shioiri, T. Synlett 1998, 35-36.
(11) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 77-91.
(12) The stereochemistry of the alcohol 11 was confirmed using the
known compound 17 (ref 7) as follows.
(1) Orjala, J .; Nagle, D. G.; Hsu, V. L.; Gerwick, W. H. J . Am. Chem.
Soc. 1995, 117, 8281-8282.
(2) For other synthetic studies, see: Loh, T.-P.; Cao, G.-Q.; Pei, J .
Tetrahedron Lett. 1998, 39, 1453-1456 and 1457-1460.
(3) Satisfactory spectroscopic data (1H and 13C NMR, IR, HRMS, or
elemental analysis) were obtained for all new compounds.
(4) Takuma, S.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1982, 30,
3147-3153 and references therein.
(5) Tung, R. D.; Rich, D. H. J . Am. Chem. Soc. 1985, 107, 4342-4343.
(6) Bock, H.; Rittmeyer, P.; Stein, V. Chem. Ber. 1986, 119, 3766-3781.
(7) Baker, R.; Castro, J . L. J . Chem. Soc., Perkin Trans. 1 1990, 47-65.
(8) Suzuki, A. Pure Appl. Chem. 1991, 63, 419-422 and references
therein.
10.1021/jo981744m CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/05/1998

Communications
J . Org. Chem., Vol. 63, No. 24, 1998 8639
Sch em e 3
Catalytic oxidation of the alcohol 11 with tetra-n-propyl-
ammonium perruthenate (TPAP)13 followed by the Still-
Horner olefination14 afforded the (Z)-ester 12, [R]26D +86.0°
(c 1.2, CHCl3), in 74% yield. Cleavage of the secondary TES
ether of the (Z)-R,â-unsaturated ester 12 and acid-catalyzed
lactonization simultaneously occurred by treatment with
Although the synthetic antillatoxin showed reasonable 1H
and 13C NMR spectra and HRMS (EI, obsd M+ m/z 503.3362,
0.5 ppm error for C28H45N3O5), its NMR spectra showed
significant differences from those of the natural product.
Furthermore, the specific rotation of the synthetic sample
([R]25 -55.2° (c 0.24, MeOH)) was also different from that
D
trifluoroacetic acid (TFA) to give the lactone 13, [R]25
D
of the natural product ([R]D -140° (c 0.13, MeOH)).1 These
differences led us to the conclusion that the formula 1 does
not accurately reflect the stereostructure for antillatoxin. On
the basis of the assumption that the stereochemistries of
the amino acids are secure, the stereochemistry at C(4) and
C(5) would be doubtful. Further clarification of the relative
and absolute configurations at C(4) and C(5) of 1 will be
gained by the total synthesis of additional stereoisomers,
which are currently underway in our laboratory.
+357.6° (c 0.3, CHCl3), in 66% yield. Stereoselective intro-
duction of the phenylselenomethyl group as a precursor for
the isolated terminal olefin to the R,â-unsaturated lactone
13 was accomplished using PhSeCH2Li in the presence of
HMPA15 to provide the selenolactone 14, mp 80-82 °C, [R]24
D
+32.8° (c 0.6, CHCl3), in 73% yield as a single isomer.16
Saponification of the lactone ring 14, protection of the
resulting carboxylic acid as the allyl ester, and segment
condensation with a tripeptide unit 2 using 1-[3-(dimethyl-
amino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI‚
HCl) gave the ester 15, [R]24 -79.8° (c 0.7, CHCl3), in 78%
D
Ack n ow led gm en t. We thank Professor W. Gerwick
(Oregon State University) for providing the spectroscopic
data of the natural product and for the helpful cor-
respondence. This work was financially supported in part
by Grants-in-Aid from the Ministry of Education, Science,
Sports and Culture, J apan.
yield. Oxidative elimination of the phenylselenyl group
using NaIO4 afforded the terminal olefin 16, [R]25 -77.3°
D
(c 0.7, CHCl3), in 93% yield, which is the protected precursor
for macrolactamization. Treatment of 16 with Pd(Ph3P)4 in
the presence of morpholine caused simultaneous removal of
the C-terminal allyl group and the N-terminal allyloxycar-
bonyl group, and then the macrolactamization under condi-
tions of high dilution using diphenyl phosphorazidate (DPPA,
(PhO)2P(O)N3)17 and sodium hydrogen carbonate afforded
antillatoxin (1) in 45% yield.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and characterization data for all new compounds along with
copies of 1H and 13C NMR spectra and HRMS spectra of 1 (17
pages).
(13) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639-666.
J O981744M
(14) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(15) (a) Krief, A. Tetrahedron 1980, 36, 2531-2640. (b) Willson, T.;
Kocienski, P.; Faller, A.; Campbell, S. J . Chem. Soc., Chem. Commun. 1987,
106-108.
(17) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203-6205. (b) Shioiri, T.; Imaeda, T.; Hamada, Y. Heterocycles 1997,
46, 421-442.
(16) The stereochemistry of 14 was tentatively assigned by ref 15b.