Total synthesis of antillatoxin

Article abstract of DOI:10.1039/b608193m

The total synthesis of natural (4R,5R)-antillatoxin and its analog (4S,5S)-antillatoxin has been achieved; the optically pure key intermediates were prepared from indium mediated allylation of either primary or secondary allylic bromide with aldehyde in a

Full text of DOI:10.1039/b608193m

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Total synthesis of antillatoxin{
Kiew-Ching Lee and Teck-Peng Loh*
Received (in Cambridge, UK) 8th June 2006, Accepted 7th August 2006
First published as an Advance Article on the web 24th August 2006
DOI: 10.1039/b608193m
reaction on our system. Especially noteworthy is the possibility of
avoiding protection–deprotection sequences such as the hydroxy
group in organic synthesis. This will reduce the number of required
synthetic steps. Furthermore, it also enables large scale production,
whereby the need to carry out the experiment under strictly
anhydrous conditions can be avoided.
The total synthesis of natural (4R,5R)-antillatoxin and its
analog (4S,5S)-antillatoxin has been achieved; the optically
pure key intermediates were prepared from indium mediated
allylation of either primary or secondary allylic bromide with
aldehyde in aquoues media, followed by highly selective
Luche’s reduction and chiral resolution.
Two strategies have been proposed as shown in Scheme 1. In
strategy 1, it is envisaged that the homoallylic alcohol 4 can be
obtained from the indium-mediated allylation reaction of aldehyde
7 and secondary allylic bromide 6 to generate the two new chiral
centers at C4 and C5. Strategy 2 proposed that fragment 4 could be
formed from the indium-mediated allylation reaction of aldehyde 7
and b-substituted bromide 8 followed by one-carbon elongation to
the proposed 4.
Antillatoxin (1) is a structurally novel lipopeptide with an
exceptionally high degree of methylation and without close parallel
to any known natural product. The molecule is also distinguished
by the multiple stereocenters of the highly functionalized 15-
membered ring with an unstable b,c-unsaturated amide moiety. It
also has very interesting biological activity, being one of the most
ichthyotoxic compounds extracted to date from marine sources
and it is exceeded in potency only by brevetoxins. More recently, it
has been shown to be neurotoxic in primary cultures of rat
cerebellar granule cells and also induced a concentration-
dependent cytotoxicity in cerebellar granule neurons.1
In our first approach, the advanced homoallylic alcohol 5 has
been successfully synthesized using indium-mediated allylation of
aldehyde 7 with allylic bromide 6 in water in good yield and
moderate syn selectivity (72 : 28)6 (Scheme 2).
However, antillatoxin was only isolated from marine organisms
in minute quantities (1.3 mg, 0.07% of extract1). Due to its scarcity
in nature, the total synthesis of antillatoxin was first undertaken to
obtain enough material for further biochemical studies.
Treatment of the homoallylic alcohol 5 with Dess–Martin
periodinane7 followed by Luche8 reduction in THF–water
cosolvent at 0 uC afforded the desired anti configuration of
homoallylic alcohol (¡)-11 in 77% yield. Remarkably, the desired
anti-isomer was obtained as the sole product. Chiral resolution of
(¡)-11 with S-(+)-a-acetoxyphenylacetic acid9 followed by LiOH
hydrolysis afforded both enantiomers of 11.
The isolation of antillatoxin (1b) was reported by Gerwick and
co-workers1 as having a 4S,5R configuration at C4 and C5 (see
Fig. 1). However, the structure was later revised to be a 4R,5R
configuration by Shioiri et al.2 and White et al.3
In our second approach, the homoallylic alcohol 5 was
synthesized from a simpler homoallylic alcohol with one carbon
less (Scheme 3). Chiral resolution of 178 followed by a series of
Our convergent synthetic strategy to (4R,5R)-antillatoxin (1b) is
outlined in Scheme 1. Retrosynthetic analysis traces back to
tripeptide unit 3 and homoallylic alcohol 4 as key intermediates.
The tripeptide acid 3 could be obtained by coupling of the
corresponding Fmoc-N-methyl-L-valine, glycine and alanine using
well-established peptide chemistry.4 Homoallylic alcohol 4 can be
synthesized using an indium-mediated allylation of allylic bromide
6 or 8 with aldehyde 7 in aqueous media.5
The many advantages of carrying out reactions in aqueous
media have encouraged us to investigate this transformation
Fig. 1 Revised structure of antillatoxin
Division of Chemistry and Biological Chemistry, Nanyang Technological
University, Singapore 637616. E-mail: teckpeng@ntu.edu.sg;
Fax: +65 6791 1961; Tel: +65 6316 8899
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b608193m
Scheme 1 Retrosynthetic analysis of antillatoxin.
Chem. Commun., 2006, 4209–4211 | 4209
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Scheme 2 Synthesis of homoallylic alcohol (¡)-11. Reagents and
conditions: a) In, La(OTf)3, THF–H2O (1 : 1), rt, 16 h; b) Dess–
Martin periodinane, CH2Cl2, 0 uC, 3 h; c) NaBH4, CeCl3?7H2O, THF–
H2O (10 : 1), 0 uC, 3 h; d) chiral resolution of 11 was carried out with
S-(+)-a-acetoxyphenylacetic acid followed by LiOH hydrolysis.
functional group manipulations and finally, a one-carbon elonga-
tion using indium-mediated allylation reaction afforded the
optically pure (R,R)-11b (Scheme 3). The absolute stereochemis-
tries of 17b and 17c were confirmed based on comparison with the
natural products, where 17b will correspond to (4R,5R)-antilla-
toxin and 17c to (4S,5S)-antillatoxin.
Subsequent coupling of the tripeptide acid
3 with the
enantiopure homoallylic alcohol 11b/11c using EDC and DMAP
afforded the desired 23b/23c in 90% and 88% isolated yield
respectively (Scheme 4). Deprotection of the silyl group with
TBAF followed by Dess–Martin and NaClO2 oxidations furnished
the corresponding acids 25b/25c in 71 and 73% yields respectively.
Treatment of 25b/25c with Pd(Ph3P)4 in the presence of morpho-
line followed by diphenyl phosphorazidate (DPPA)1–3 promoted
macrocyclization to provide (4R,5R)- and (4S,5S)-antillatoxin
Scheme 4 Reagents and conditions: a) EDC?HCl, DMAP, CH2Cl2, 0 uC
to rt, 16 h; b) TBAF, THF, rt, 0.5 h; c) Dess–Martin periodinane, CH2Cl2,
rt, 1 h; d) NaClO2, NaH2PO4, MeCHLCMe2, t-BuOH–H2O, rt, 1 h; e)
Pd(Ph3P)4, morpholine, THF, rt, 0.5 h; f) DPPA, NaHCO3, DMF, 0 uC,
3 days. [EDC?HCl = 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride; DMAP = 4-dimethyl amino pyridine; TBAF = tetra-
butylammonium floride; DPPA = diphenylphosphoryl azide].
(1b/1c) in 63 and 62% yields respectively. The product was
confirmed by comparing the spectroscopic data of our synthetic
sample with that of the natural product.
In conclusion, the total synthesis of antillatoxin has been
achieved in very short steps. A few notable features of this
synthesis include the indium-mediated allylation of either primary
or secondary allylic bromide with aldehyde in aqueous media, an
oxidation–reduction sequence to control the two chiral centres at
C4 and C5 followed by chiral resolution to afford the optically
pure homoallylic alcohol. Especially noteworthy are the con-
vergent nature of this synthetic strategy and the incorporation of
all the necessary functionalities in the early stages of the synthesis.
The procedure developed here may be used for the large scale
synthesis of other biologically interesting natural products. Our
strategy provides a practical and easy entry into antillatoxin
analogs as well as many interesting fragments. Screening of this
library of simpler fragments and analogs obtained during the
process of the total synthesis has resulted in the discovery of a
potent fragment which has similar biological activity to the parent
(4R,5R)-antillatoxin. More detailed biological screening is cur-
rently being studied.
Scheme 3 Reagents and conditions: a) In, La(OTf)3, sat. NH4Cl, rt, 16 h;
b) DIBAL, CH2Cl2, 0 uC, 3 h; c) TBDPSCl, imidazole, DMF, 0 uC, 1.5 h;
d) Dess–Martin periodinane, CH2Cl2, 0 uC, 3 h; e) NaBH4, CeCl3?7H2O,
THF–H2O (10 : 1), 0 uC, 3 h; f) TBAF, THF, rt; g) chiral resolution of 17
was carried out with S-(+)-a-acetoxyphenylacetic acid followed by LiOH
hydrolysis; h) EtOCOCl, DMAP, Et3N, CH2Cl2, 0 uC to rt, 3 h; i)
TBDPSCl, AgNO3, DMF, 0 uC to rt, 12 h; j) 1% K2CO3/MeOH, rt, 16 h;
k) NBS, PPh3, CH2Cl2, 278 uC to 0 uC, 3 h; l) HCHO, In, La(OTf)3,
THF–H2O (1 : 1), rt, 4 days; m) (i)TBAF, THF, rt; (ii) TBDPSCl,
imidazole, DMF, 0 uC, 1.5 h.
We are grateful to BMRC for their generous financial support.
Notes and references
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