A formal total synthesis of aplysiatoxin

Article abstract of DOI:10.1016/S0040-4039(00)93449-X

A total synthesis of aplysiatoxin was achieved formally by construction of Kishi's intermediate 13 which carried all the stereochemistry required for the synthesis of aplysiatoxin, from four fragments described in the preceding communication.

Full text of DOI:10.1016/S0040-4039(00)93449-X

Ten'ahedron Letters, Voi.32, No.38, pp 5141-5142, 1991
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A FORMAL T O T A L SYNTHESIS OF APLYSIATOXIN
Hiroaki Okamura, Satoru Kuroda, Satoru Ikegami, Yoshio Ito, Tsutomu Katsuki,* and Masaru Yamaguchi
Department of Chemistry, Faculty of Science, Kyushu University 33,
Hakozaki, Higashi-ku, Fukuoka 812, Japan
Summary: A total synthesis of aplysiatoxin was achieved formally by construction of Kishi's intermediate 13
which carded all the stereochemislry required for the synthesis of aplysiatoxin, from four fragments described in
the preceding communication.
Since the four optically active fragments corresponding to each parts (i-iv) in aplysiatoxin (1) as shown
below, was elaborated by using asymmetric epoxidation and [2,3] Wittig rearrangement as reported in the
preceding communication, l) construction of the four fragments to 1 in a convergent manner was attempted.
III
OH
Iv OH
2: R = H Debromoaplysiatoxin
The synthesis started with the coupling of fragments 3 and 4 which corresponded to i and ii,
respectively, as described in Scheme 1. Thus, treatment of epoxy alcohol 4 with Grignard reagent 3 in the
presence of CuI provided 1,3-diol 52) and a small amount of undesired stereoisomer. 3) This mixture was used
for the next step without separation. The resulting hydroxymethyl group in 5 was converted into methyl group
by mesylation and subsequent LAH reduction. In the latter process, the cleavage of the TBDMS ether occurred
simultaneously to give 1,4-diol 6. Conversion of 6 into epoxide 7 was effected by the sequence; i) acetyladon of
hydroxy groups, ii) acid hydrolysis of THP ether,4) iii) mesylation of the resulting hydroxy group, and iv)
alkaline hydrolysis of acetates accompanying epoxide ring formation. The minor undesired diastereomer
produced at the coupling of 3 and 4 (vide supra), could be removed by column chromatography (SiO2) at this
stage. Protection of hydroxy group of 7 as a MPM ether5) gave compound 8, which set the stage for the
coupling with fragment 9 corresponding to iii.
Coupling of them was accomplished by treatment of 8 with lithioanion derived from 9. Condensation of
the resulting alcohol 10 and carboxylic acid 11 was accomplished by using Yamaguchi method6) to give ester
12 which contained all the asymmetric centers to construct 1. After the acid hydrolysis of the acetonide,
treatment of 12 with lead tetraacetate7) gave aldehyde 13 which was a key intermediate in Kishi's synthesis.8)
For the structure confirrnation, 13 was further converted into another Kishi's intermediate 14. Both 13 and 14
gave identical 1H NMR spectra in every respects with those of the ctm'e~ponding authentic samples.
Since 13 has been reported to be convertible to I in 7 steps,8) our accomplishment constitutes a formal
total synthesis of optically active aplysiatoxin in an enantiospecific manner.
5141

5142
OMe
MoO
71% ~,~
HO OTHP
MoO
HO OTHP
MgBr
+
H O . , ~ % , . . X ~ .OTBDMS
~
:
-
:
~Ofl=
62%
OBOM
OBOM
OBOM
3
4
5
6
s
9
6--/-.
~
o
~ ~Mo .o r~
o-'~
.
i
~
b
d2,4e%,f,g ~ , ~ , ~ , ~ . 0:
87%
64%
OBOM
7
OBOM
8
OBOM
1 0
OMPM
H O O C v ~ /
11 o. o.
°
s
s
R
j
k,I
70°/0
88°/°" C JY v T T"° o-.
o . o .
1
2
OBOM
f 1 3 :
R
=
CHO
OBOM
mr',-14: R = CH20H
a) CuI; b) MsCI, Et3N; c) LAH; d) Ac20, DMAP; e) PPTS, MeOH; f) MsC1, DMAP; g) KOH, MeOH; h) MPMCI, Nail;
i) 9, nBuLi, TMEDA; j) 11, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP; k) PPTS, MeOH; 1) Pb(OAc)4, AcOK;
In) LiAIH(OtBu)3
Scheme 1
The authors thank Professor Y. Kishi of Harvard University for his kind providing 1H NMR spectra of
intermediates and aplysiatoxins. Financial support from Grand-in-Aid (No 63303003 and 62214010) from the
Ministry of Education, Science, and Culture, Japan and Ono pharmaceutical company were also greatly
acknowledged.
References and Notes
1) H. Okamura, S. Kuroda, K. Tomita, S. Ikegami, Y. Sugimoto, S. Sakaguchi. T. Katsuld, and M.
Yamaguchi, Tetrahedron Lett., the preceding communication.
2) Satisfactory 1H NMR (90 MI-Iz or 400 MHz) data were obtained for all compounds.
3) The coupling product was consisted of 5 and its diastereomer in a ratio of 9:1 because 4 of 71% ee
( reference 1) was coupled with 3 of 96%ee.
4) M. Miyashita, A. Yoshikoshi, and P. A. Grieco, J. Org. Chem., 42, 3772 (1977).
5) Y. Oikawa, T. Yoshioka, and O.Yonemitsu, Tetrahedron Lett., 23, 885 (1982).
6) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, and M., Yamaguchi, Bull. Chem. Soc. Jpn., 52, 1989 (1979).
7) E. J. Corey, L. O. Weige, A. R. Chamberlin, and B. Lipshutz, J. Am. Chem. Soc., 102, 1439 (1980).
8) P. Park, C. A. Broka, B. F. Jhonson, and Y, Kishi, J. Am. Chem. Soc., 109, 6205 (1987).
(Received in Japan 20 May 1991)