SYNTHESIS OF APLYSIATOXIN: STEREOSELECTIVE SYNTHESIS OF KEY FRAGMENTS

Article abstract of DOI:10.1016/S0040-4039(00)93448-8

Stereoselective synthesis of key fragments for the synthesis of aplysiatoxin has been achieved.All the stereogenic carbons contained in fragments B-E were elaborated on the basis of <2,3> Wittig rearrangement and titanium-mediated asymmetric epoxidation.

Full text of DOI:10.1016/S0040-4039(00)93448-8

Tetrahedron Letters, Vol.32, No.38, pp 5137-5140, 1991
Printed in Great Britain
0040-4039/91 $3.00 +.00
Pcrgamon Press plc
SYNTHESIS OF APLYSIATOXIN:
STEREOSELECTIVE SYNTHESIS OF KEY FRAGMENTS
Hiroaki Okamura, Satoru Kuroda, Kenji Tomita, Satoru Ikegami,
Yu-ichi Sugimoto, Shin-ich Sakaguchi, Tsutomu Katsuki,* and Masaru Yamaguchi
Department of Chemistry, Faculty of Science, Kyushu University 33,
Hakozaki, Higashi-ku, Fukuoka 812, Japan
Summary: Stereoselective synthesis of key fragments for the synthesis of aplysiatoxin has been achieved. All
the stereogenic carbons contained in fragments B~E were elaborated on the basis of [2,3] Wittig rearrangement
and titanium-mediated asymmetric epoxidation.
Aplysiatoxin (1) and debromoaplysiatoxin (2) isolated from the digestive grand of sea hare Stylocheilus
longicauda, have received much attentions as attractive targets for total synthesis due to their unique molecular
architecture together with peculiar biological activities such as strong cancer promotion.1) Several synthetic
approaches to this class of compounds have appeared in literatures,2) but only one total synthesis of 1 and 2 has
been reported to date.3) Recently we developed an efficient methodology for the construction of polypropionate
segment.4) As an extension of the study, synthesis of I was examined.
o1~
o "~"
OH
0
oP2
Op3
ROMe
O ~
,===0
" ~ _ "OH
OH
OH
OP1
A
B
1: R = Br Aplysiatoxin
2: R = H I)ebromoaplysiatoxin
ol~
Op~
C
D
E
S c h e m e
1
Our synthetic strategy is based on the retrosynthetic analysis shown in Scheme 1. Dissociation of two
estor linkage in I gives fragments A and B. Further division of fragment A gives three fragments C, D, and E,
in which C and E are considered to be combined with D by nucleophilic opening of two different epoxides in
D. The terminal epoxide in D is masked as a protected diol until an appropriate stage. It seems to be possible to
synthesize fragments B, C, and E by using titanium-mediated asymmetric epoxidation5) (hereafter referred to as
A.E.) as a key step and to introduce the stereochemistry of fragment D by [2,3] Wittig rearrangement we
reported. 4d) In this and following communications, we describe preparations of optically active fragments and
synthesis of 1, respectively.
Synthesis of fragment B started with crotyl alcohol (3) as shown in Scheme 2. A.E. of 3 gave epoxy
alcohol 46) of 90% ee. Treatment of 4 with phenyl isocyanate gave carbamate 5, which was recrystallized to
5137

5138
optical purity. Acid treatment of 5 followed by hydroxy protection gave carbonate 6, which was further
converted into epoxide 7 by the sequence: i) alcoholysis of carbonate, ii) protection of the resulting primary
hydroxy group as a pivalate, iii) mesylation of secondary hydroxy group, iv) reductive removal of pivaloyl
group, and v) epoxide formation. One carbon elongation to 8 was achieved by the treatment of 7 with 2-1ithio-
1,3-dithiane. Transformation of 8 into the desired carboxylic acid 9 corresponding to fragment B was achieved
in three steps: i) protection of hydroxy group as a MPM ether,7) ii) hydrolysis of dithioacetal, and iii) oxidation
of the resulting aldehyde.
a
.
0
b
0
0
c,d
.jO..BvO.M.~0 e,f,g,h
"
f.L--oX..ph
22% from 3
12%
0-'~0
56%
3
4
9 0 % e e
5
l O0%ee
6
OBOM
OBOM
j,k,I
OBOM
J
'
-
<
'
o
,
.
-
7
8
9
a) Ti(Oipr)4, (-)-DET, TBI-IP, MS 4.t.; b) phenyl isocymm~, Et3N then recryst~izaticm from AcOEt; c) I--ICIO4;
d) BOMCI, EtN/Pr2; e) K2CO3, MeOH; f) (CH3)3CCOCI, Et3N then MsCI; g) DIBAL; h) tBuOK; i) 2-1i~io-l,3-di~iane;
j) MPMCI, Nail; k) MeI, CaCO3; 1) NaCIO2, 2-me~yl-2-butene
Scheme 2
,.CO=H a,b,c ~ { ~ / ~ / ~ O H
~
~
.
J
73% from 11
71%
OH
OBOM
11
OBOM
OBOM
1 3
1 2 9 6 % e e
1 0
35:1
o~
o~
-
Br
.
I~Br
73%
OBOM
1 4
OBOM
1 5
a)EtOH, H2SO4; b) BOMCI, EtNiPr2; c) DIBAL; d) Ti(OiPr)4, (-)-DIPT, TBHP, MS 4A; e) Red-M; f) TsCl, Et3N;
g) MeI, Nail; h) NaBr; i) Mg
Scheme 3
For fragment C, m-hydroxycinnamic acid (10) was employed as a starting material (Scheme 3).
Conversion of 10 to allylic alcohol I1 was carried out in a conventional manner. A.E. of 11 gave epoxy alcohol
12 with high enantioselectivity (96% ee). Red-al reduction8) of 12 proceeded with high regioselectivity (1,3- :
1,2-diol = 35 : 1) to give diol 13.9) Conversion of 13 to 14 was achieved by the sequence: i) tosylation of
primary hydroxy group, ii) methylation of secondary hydroxy group, and iii) replacement of the tosylate with
bromide. Treatmentof 14 with magnesium gave 15 to be used for the coupling with fragment D.
Synthesis of fragment D started with (2R,3E)-1-benzyloxy-3-buten-2-ol (16) of 71% ee,10) which was
obtained by kinetic resolution of dl-164c) (Scheme 4). Compound 16 was converted into ester 17 according to

5139
the reported procedure.11) Titanium-mediated [2,3] Wittig rearrangement of 17 afforded to-benzyloxylated
hydroxy ester 18 with quantitative chirality transfer together with high syn selectivity.12) After alkaline
hydrolysis, 18 was subjected to iodolactonization.13) Lactone 19 was converted into hydroxy epoxide 20 in
three steps; i) protection of hydroxy group as a THP ether,14) ii) methanolysis of lactone along with epoxide
formation, and iii) LAH reduction of the resulting methyl ester. Hydroxy protection as a TBDMS ether followed
by hydrogenolysis afforded epoxy alcohol 21 which was a synthetic equivalent of fragment D.
""-~"'~"~.OBn
a,b
~
O
B
n
c
OH
d,e
00_.~0
f,g,h
:
~
"
OH
76% "
OvCO~r 72% " B n O " " ' ~ , : C 6O2%~ r ~ B n O ~ O H
;
~
75%
16 71%ee
17 18 19
0
OTHP
i,j
84%
0
OTHP
B n O ~ , ~ , ~ " - O "
.
H o ~ O T B D M S
20
21
a) BrCH2CO2H, Nail; b) iprI, Na2CO3; c) LDA then Cp.2TiCI2; d) KOH, MeOH-H20; e) 12; f) DHP, PPTS;
g) K2CO3, MeOH; h) LAH: i) TBDMSCI, Et3N, DMAP; j) 1-12, Pd/C
S
c h e m e 4
O H C . ~ a,b,c,d,e THPO~. , . ~.. AOH
49%
f
T
H
P
O
~
oH
g , h
69%
2 2
2 3
2 4 95%ee
t
O ~ o T r~
ij
--
k,l,m,n
,
26 6----~0 65%
T H P O . , ~ _ .OTr THPO
-
H O ~ o
f...s
..fi
OH
25
/26% from 24
2 7
2.7:1
a) NaBI-I4; b) DHP, PPTS; c) OsO4, NalO4; d) (EtO)2P(O)CH2CO2Et, Nail; e) DIBAL;
f) Ti(OiPr)4, (+)-DET, TBHP, MS 4A; g) TrCI, Et3N, DMAP; h) MeMgBr, CuI; i) CSA, MeOH;
j) COIm2 then chromatographic separation; k) Swem oxdn.; 1) 1,3-propanedithiol, BF3.OEt2; m) K2CO3, MeOH;
n) 2,2-dimethoxypropane, PPTS
Scheme 5
Fragment E was derived from easily available olefin 22.15) As shown in Scheme 5, 22 was First
converted into allylic alcohol 23 by the sequence: i) reduction of aldehyde, ii) protection of the resulting hydroxy
group as a THP ether, 14) iii) oxidative cleavage of olefin, iv) two carbon elongation by Wittig-Honer
olefination,16) and v) DIBAL reduction. A.E. of 23 gave epoxide 24 of 95% ee. After hydroxy protection as a
trityl ether, 24 was exposed to methylmagnesium bromide in the presence of CuI giving a mixture of 25 and its
regioisomer in a ratio of 2.7 : 1.9,17) After acid hydrolysis, compound 25 and its regioisomer were treated with
carbonyldiimidazole and the resulted regioisomeric carbonates were separated by column chromatography (SiO2)
to give 26. Dithioacetal 27 to be used as fragment E, was elaborated from 26 in four steps; i) Swern oxidation,

5140
ii) dithioacetalization of the resulting aldehyde, iii) alcoholysis of carbonate, and iv) protection of the resulting
diol as an acetonide.
With fragments B, C, D, and E in hand, the stage was set for the construction of 1, which will be
described in the following communication.
Financial supports from a Grand-in-Aid for Scientific Research (No. 63303003 and No. 62214010)
from the Ministry of Education, Science, and Culture, Japan and Ono pharmaceutical company were greatly
acknowledged.
References and Notes
1) a) Y. Kato and P. J. Sheuer, J. Am. Chem. Soc., 96, 2245 (1974). b) Idem, Pure & Appl. Chem., 41, 1
(1975). c) Idem, ibid., 48, 29 (1976). d) R. E. Moore, A. J. Blackman, C. E. Cheuk, J. S. Mynderse, G.
K. Matsumoto, J. Clardy, R. W. Woodard, and J. C. Craig, J. Org. Chem., 49, 2484 (1984).
2) a) R. E. Ireland, S. Thaisrivongs, and P. H. Dussault, J. Am. Chem. Soc., 110, 5768 (1988). b) H.
Toshima, S.Yoshida, T. Suzuki, S. Nishiyama, and S. Yamamura, Tetrahedron Lett., 30, 6721 (1989). c)
H. Toshima, T. Suzuki, S. Nishiyama, and S. Yamamura, ibid., 30, 6725 (1989). d) R. D. Walkup, R. R.
Kane, P. D. Boatman, Jr., and R. T. Cunningham, ibid., 31, 7587 (1990).
3) P. Park, C. A. Broka, B. F. Jhonson, and Y. Kishi, J. Am. Chem. Soc., 109, 6205 (1987).
4) a) T. Hanamoto, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 28, 6191 (1987). b) ldem, ibid., 28,
6195 (1987). c) S. Kuroda, S. Sakaguchi, S. Ikegami, T. Hanarnoto, T. Katsuki, and M. Yarnaguchi,.ibid.,
29, 4763 (1988). d) S. Ikegami, T. Katsuki, and M. Yamaguchi, ibid., 29, 5285 (1988). e) T. Hanamoto,
T. Katsuki, and M. Yamaguchi, Bull. Chem. Soc. Jpn., 63, 1039 (1990).
5) a) T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 102, 5974 (1980). b) Y. Gao, R. M. Hanson, J.
M. Klunder, S. Y. Ko, H. Masamune, and K. B. Sharpless, ibid., 109, 5765 (1987).
6) Satisfactory spectroscopic data were obtained for all compounds.
7) Y. Oikawa, T. Yoshioka, and O. Yonemitsu, Tetrahedron Lett., 23, 885 (1982).
8) a) J. M. Finan and Y. Kishi, Tetrahedron Lett., 23, 2719 (1982). b) S. M. Viti, Tetrahedron Lett., 23, 4541
(1982).
9) The isomers ratio was determined by 1H NMR (400MHz, CDCI3) analysis after the acetylation of hydroxy
group.
10) Kinetic resolution of dl-16 by a Ti(Oipr4), (-)-DIPT, TBHP system (reference 5b) was not so effective. At
the stage of 64% conversion of starting material, remained (R)-I6 showed 71% ee. This sample was used in
the next reaction.
11) T. Nakai, K. Mikami, S. Taya, Y. Kimura, and T. Mimura, Tetrahedron Lett., 22, 69 (1981).
12) The preliminary result about the rearrangement of 17 was reported in reference 4c.
13) P. A. Bartlett and J. Myerson, J. Am. Chem. Soc., 100, 3950 (1978).
14) M. Miyashita, A. Yoshikoshi, and P. A. Grieco, J. Org. Chem., 42, 3772 (1977).
15) K. C. Brannock, J. Am. Chem. Soc., 81, 3379 (1959).
16) H. Nagaoka and Y.Kishi, Tetrahedron, 37, 3873 (1981).
17) H. Uchiyama, Y. Kobayashi, and F. Sato, Chem. Lett., 467 (1985).
(Received in Japan 20 May 1991)