Formal total synthesis of hemibrevetoxin B by a convergent strategy

Article abstract of DOI:10.1016/j.tetlet.2004.05.020

Concise construction of the trans-fused 7/7/6/6 tetracyclic ether part of hemibrevetoxin B (1) was achieved by a convergent strategy based on coupling reaction of an acyl anion equivalent, reductive cyclization of an α,ε-dihydroxyketone, and introduction

Full text of DOI:10.1016/j.tetlet.2004.05.020

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5243–5246
Formal total synthesis of hemibrevetoxin B by a convergent strategy
Kenshu Fujiwara,* Daisuke Sato, Manabu Watanabe, Hiroshi Morishita,
Akio Murai,ꢀ Hidetoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 21April 2004; revised 29 April 2004; accepted 6 May 2004
Abstract—Concise construction of the trans-fused 7/7/6/6 tetracyclic ether part of hemibrevetoxin B (1) was achieved by a con-
vergent strategy based on coupling reaction of an acyl anion equivalent, reductive cyclization of an a,e-dihydroxyketone, and
introduction of a methyl group at the central ring junction by the Nicolaou method. The resultant tetracyclic ether was transformed
into the known intermediate, which was already converted to 1 by the Yamamoto group, thereby completing the formal total
synthesis of 1.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Hemibrevetoxin B (1), isolated as a congener of breve-
toxins from dinoflagellate Gymnodinium breve by Prasad
and Shimizu in 1989,1 has a trans-fused 7/7/6/6 tetracy-
clic ether structure. So far, many research groups have
finished the total synthesis of 1.2 Notably, all of them,
except the Holton group,2k adopted a linear synthetic
strategy, though a convergent strategy would have
comparable efficiency even in the synthesis of such small
polyether. In this context, synthesis of 1 through a
convergent strategy, which would allow the large-scale
preparation of 1, was planned. Here, a concise formal
total synthesis of 1 from the A- and D-ring segments (5
and 4, respectively) is described.
Our synthetic plan, illustrated in Scheme 1, focuses on a
short-step construction of the central BC-ring part of 1.
We envisioned the synthesis of tetracyclic ether 2, which
was already converted to 1 by the Yamamoto group,2d
Cyclic S,O-acetal formation and
C11-methyl introduction
OTIPS
OBn
OH
Me
OTCBn
H
O
H
H
NAPO
OH
Me
H
H
TIPSO
HO
H
BnO
O
O
H
11
O
O
C
A
B
4
1
25
19
D
O
O
O
CHO
O
H
O
H
O
H
H
H
Me
OH
Me
Me
OH
OTBS
OTBS
3
2
α,ε-Dihydroxyketone
formation
Hemibrevetoxin B (1)
Reductive cyclization
TCBn: 2,4,6-trichlorobenzyl
NAP: 2-naphthylmethyl
OBn
AcO
AcO
H
CHO
O
OBn
NAPO
OBn
O
O
A
D
+
AcO
O
MeS
MeS
OTBS
O
TCBnO
TCBnO
Me
Me
OH
OTBS
O
7
6
4
5
8
Scheme 1.
Keywords: Polyether; Hemibrevetoxin B; Natural product synthesis; Acyl anion equivalent; Convergent synthesis.
* Corresponding author. Tel.: +81-11-706-2701; fax: +81-11-706-4924; e-mail addresses: fjwkn@sci.hokudaiac.jp; amurai@rmail.plala.or.jp
ꢀ
Present address: Asabu-cho 6-14-44, Kita-ku, Sapporo 001-0045, Japan.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.020

5244
K. Fujiwara et al. / Tetrahedron Letters 45 (2004) 5243–5246
19
through reductive cyclization of a,e-dihydroxy ketone
33;4b;c followed by S,O-acetal formation and introduc-
tion of a methyl group at C11 according to the Nicolaou
procedure.5 The intermediate 3 would be constructed by
a coupling reaction of the A-ring 5 having a di-
methyldithioacetal mono-S-oxide group as an acyl an-
ion equivalent with the D-ring 4, and the subsequent
deprotection.4;6 The D-ring 4 could be synthesized from
c-butyrolactone 7 via 6 and the A-ring 5 could be pre-
OH
O
a, b
c, d
7
N
TCBnO Me
TCBnO Me
OMe
17
16
e
19
19
OH
OH
i, j
+
6
18
TCBnO Me
TCBnO Me
O
18
(–)-17
pared from tri-O-acetyl
D-glucal 8.
f, g, h
Synthesis of 5 is shown in Scheme 2. Transformation of
8 into methyl acetal 9 under the Yadav conditions7
followed by allylation gave 10 as a single stereoisomer in
63% yield for two steps. The triacetate 10 was subjected
to methanolysis and the subsequent selective protection
of the 1,3-diol part to produce 11 in 70% overall yield, in
which the free a-hydroxy group was inverted through
Swern oxidation8 followed by reduction with K-Select-
ride to afford 12 in 95% yield for two steps. Conversion
of 12 to a diol by hydroboration/oxidation and protec-
tion of the resulting diol part provided 13 in 55% overall
yield. The benzylidene acetal part of 13 was removed to
give a diol, which was selectively protected with a TBS
group at a primary hydroxy group and with a 2-naphthyl-
methyl (NAP) group9 at a secondary hydroxy group to
Scheme 3. Reagents and conditions: (a) HNMe(OMe)ÆHCl, AlMe3,
CH2Cl2, 0 ꢁC, 3 h; (b) NaH, DMF, 2,4,6-trichlorobenzyl bromide,
0 fi 23 ꢁC, 4 h, 84%; (c) isopropenyl magnesium bromide, THF, )78 fi
)20 ꢁC, 4 h, 98%; (d) NaBH4, CeCl3Æ7H2O, MeOH, 22 ꢁC, 1h, 98%; (e)
())-DIPT, Ti(OiPr)4, TBHP, CH2Cl2, )25 ꢁC, 12 h, ())-17: 47% (97%
ee), 18: 44% (88% ee); (f) PhCO2H, DEAD, Ph3P, THF, 23 ꢁC, 6.5 h,
77% (92% ee); (g) DIBAH, CH2Cl2, )78 ꢁC, 30 min, 98%; (h)
VO(acac)2, TBHP, PhH, 23 ꢁC, 6.5 h, 80%; (i) NaH, BnBr, Bu4NI,
THF, 0 fi 23 ꢁC, 17 h, 100%; (j) Sn(CH@CH2)4, BuLi, THF, )78 ꢁC,
1h, then CuCN, )78 ꢁC, 10 min, then BF3ÆOEt2, )78 ꢁC, 10 min, then
benzyl ether of 18, )78 fi 0 ꢁC, 80 min, 99%.
afford 14 in 93% yield for three steps. The TBS group of
14 was removed and the resulting alcohol was treated
with Tf2O to give 15 (99%), which was converted to 5
by a substitution reaction with lithiated methyl meth-
ylthiomethyl sulfoxide in 96% yield. Thus, the A-ring
segment 5 was obtained in 14 steps in 20% overall yield
from 8.
OAc
OAc
AcO
AcO
AcO
AcO
a
b
8
O
O
OMe
In the preparation of 6, depicted in Scheme 3, we em-
ployed Sharpless asymmetric epoxidation for kinetic
resolution of 17 in order to construct the stereocenters at
C18 and C19 of 6.10 The allyl alcohol 17 was provided
by a four-step process from 7 [Weinreb amidation,11
2,4,6-trichlorobenzyl (TCBn) protection, addition of
isopropenyl magnesium bromide, and Luche reduc-
tion]12 in 81% overall yield. When 17 was treated with
())-diisopropyl tartrate and tert-butyl hydroperoxide in
the presence of Ti(OiPr)4 at )25 ꢁC, the desired epoxide
18 was obtained in 88% ee (44% yield) along with
recovered ())-17 as an optically active form in 97% ee
(47% yield).13 The antipodal ())-17 was also convertible
to 18 through a three-step process including Mitsunobu
reaction,14 benzoyl deprotection, and diastereoselective
epoxidation15 (92% ee and 60% overall yield).13;16 The
optically active 1817 was protected as a benzyl ether and
treated with a higher-order divinylcyanocuprate in the
9
10
c, d
OBn
O
OH
OH
Ph
g, h
O
Ph
e, f
O
Ph
O
O
O
O
O
O
BnO
13
12
11
i, j, k
OBn
OBn
NAPO
NAPO
l, m
n
5
O
O
TfO BnO
TBSO BnO
14
15
18
presence of BF3ÆOEt2 to give 6 in 99% yield for two
steps.
Scheme 2. Reagents and conditions: (a) MeOH, NaI, CeCl3Æ7H2O,
MeCN, reflux, 3.5 h, 66%; (b) allyltrimethylsilane, TMSOTf, MeCN,
0 fi 23 ꢁC, 1.5 h, 96%; (c) NaOMe, MeOH, 0 fi 23 ꢁC, 3 h, 88%; (d)
PhCHO, TsOHÆH2O (cat.), PhH–DMF (3:1), reflux, 7 h, 79%; (e)
(COCl)2, DMSO, CH2Cl2, )78 ꢁC, 15 min, then Et3N, )78 fi 0 ꢁC,
30 min, 100%; (f) K-Selectride, THF, )78 ꢁC, 1h, 95%; (g) 9-BBN,
THF, 23 ꢁC, 1h, then TBHP, 3 M NaOH, 0 fi 23 ꢁC, 40 min; (h) BnBr,
tBuOK, Bu4NI, THF, 23 ꢁC, 4 h, 55% from 12; (i) 6 M HCl–THF (1:1),
23 ꢁC, 10 h, 94%; (j) TBSCl, Et3N, DMAP, CH2Cl2, 23 ꢁC, 160 min,
99%; (k) NAPBr, NaH, Bu4NI, THF, 0 fi 25 ꢁC, 14 h, 100%; (l) TBAF,
THF, 25 ꢁC, 2 h, 99%; (m) Tf2O, 2,6-lutidine, CH2Cl2, )78 ꢁC, 30 min,
100%; (n) MeSCH2S(O)Me, BuLi, THF, )78 ꢁC, 20 min, then 15,
)78 fi )20 ꢁC, 30 min, 96%.
Construction of the D-ring 4 from 6 is shown in Scheme
4. Transformation of 6 into 19 (87% overall yield)
through a three-step process [protection of the tertiary
alcohol with a TBS group, removal of the benzyl group,
and formation of an acryloyl ester] followed by a ring-
closing olefin metathesis reaction using the second-gen-
eration Grubbs’ catalyst19 produced a,b-unsaturated
lactone 20 (89% from 19), which was reduced to 21 in
quantitative yield. The lactone 21 was converted to
cyclic vinyl triflate 22, which was treated in situ with a

K. Fujiwara et al. / Tetrahedron Letters 45 (2004) 5243–5246
TCBnO
5245
OTCBn
TCBnO
NAPO
OH
OBn
H
O
a
O
O
+
4
5
O
O
a, b, c
d
O
6
MeS
MeS
H
BnO
Me
Me
Me
OTBS
OTBS
O
TBSO
TBSO
19
20
25
e
b
EEO
TCBnO
TCBnO
TCBnO
OTCBn
OTCBn
NAPO
OH
NAPO
OH
OBn
OBn
O
OTf
O
H
O
H
O
O
O
O
c
f
O
O
18
O
Me
Me
Me
H
H
H
H
Me
Me
OH
BnO
BnO
TBSO
TBSO
TBSO
OTBS
OTBS
23
22
21
26
3
g, h
d
OTCBn
OTCBn
EEO
NAPO
O
OBn
O
OBn
O
HO
TCBnO
H
O
H
O
O
e
10
15
19
O
i, j
14
O
O
H
H
H
BnO
H
4
H
H
Me
Me
Me
15
BnO
OTBS
OTBS
Me
OTBS
28
27
TBSO
f
24
OTCBn
OBn
R
Scheme 4. Reagents and conditions: (a) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 fi 23 ꢁC, 9 h, 99%; (b) DDQ, CH2Cl2–H2O (10:1), 23 ꢁC,
14.5 h, 93%; (c) acryloyl chloride, iPr2NEt, CH2Cl2, 0 fi 25 ꢁC, 4 h,
94%; (d) [(MesNCH2)2C](Cy3P)Cl2Ru@CHPh (cat.), (CH2Cl)2, reflux,
14 h, 89%; (e) H2, 5% Pt/C, EtOAc, 23 ꢁC, 5 h, 100%; (f) KHMDS,
HMPA, THF, )78 ꢁC, 2 h, then PhNTf2, )78 ꢁC, 1h, then EE-
OCH2CH2CH2MgBr, CuI, Me2S, )78 fi )40 ꢁC, 13.5 h; (g) thexyl-
borane, THF, 0 ꢁC, 13.5 h, then 3 M NaOH, TBHP, 0 fi 23 ꢁC, 1.5 h,
65% from 21; (h) TBSOTf, 2,6-lutidine, CH2Cl2, 0 fi 23 ꢁC, 6 h, 100%;
(i) PPTS (cat.), MeOH, 23 ꢁC, 8 h, 87%; (j) (COCl)2, DMSO, CH2Cl2,
)78 ꢁC, 15 min, then Et3N, )78 fi 0 ꢁC, 30 min, 100%.
H
H
H
O
O
ref. 2d
h, i, j
11
1
2
O
O
H
H
BnO
29: R = SEt
30: R = Me
OTBS
g
Scheme 5. Reagents and conditions: (a) 5, LDA (1equiv), THF,
)78 ꢁC, 15 min, then 4 (0.37 equiv), )78 ꢁC, 15 min, 86%; (b) TFA–
THF–H2O (1:5:5), 0 fi 23 ꢁC, 7.5 h, 71%; (c) TMSOTf, Et3SiH, MS4A,
CH2Cl2, )20 ꢁC, 10 min, 65%; (d) DMPI, CH2Cl2, 25 ꢁC, 1h, 100%; (e)
DDQ, CH2Cl2–MeOH–H2O (40:10:1), 0 fi 25 ꢁC, 1h, 93%; (f) EtSH,
Zn(OTf)2, CH2Cl2, 0 fi 23 ꢁC, 6.5 h, 85% (after three cycles); (g)
mCPBA, CH2Cl2, 0 ꢁC, 30 min, then AlMe3, 0 ꢁC, 1h, 92%; (h) DDQ,
CH2Cl2–H2O (10:1), 25 ꢁC, 5 h, 65%; (i) TIPSOTf, 2,6-lutidine, DMF,
70 ꢁC, 5 h; (j) H2, 10% Pd/C, EtOH, 25 ꢁC, 2 h, 83% (two steps).
Grignard reagent, prepared from protected 3-bromo-
propanol, in the presence of copper iodide to afford
cyclic vinyl ether 23.20 Hydroboration of 23 with thex-
ylborane and the subsequent oxidation provided 24
stereoselectively in 65% overall yield from 21. Depro-
tection followed by Swern oxidation8 gave 4 in 87%
yield for two steps.17 The D-ring 4 was, thus, synthesized
in 20 steps including the stereochemical inversion pro-
cess in 20% overall yield from 7.
Reaction of 28 with EtSH and Zn(OTf)2 in CH2Cl2 did
not complete even after 27 h and gave cyclic S,O-acetal
29 in 56% yield along with recovered 28 (42%); there-
fore, the process was repeated twice in order to obtain a
reasonable amount of 29 (85% yield after three cycles).23
Introduction of an angular methyl group at C11 was
performed by oxidation of 29 with mCPBA followed by
in situ treatment with AlMe3 according to the Nicolaou
Assembly of the ABCD-ring part is outlined in Scheme
5. Deprotonation of 5 with LDA followed by the reac-
tion with 4 (0.37 equiv) produced 25 as a mixture of
diastereomers (86% yield from 4, 57% recovery of 5).
The TBS and methylthio methysulfinyl acetal groups of
25 were removed under less acidic conditions to give 3
(71% yield), which was cyclized by short-time (within
10 min) treatment with Et3SiH in the presence of
TMSOTf at )20 ꢁC to produce 26 as a mixture of two
diastereomers in 65% yield.3;4;17;21 The alcohol 26 was
oxidized with Dess–Martin periodinane22 to give the
desired 27 as a single stereoisomer (100% yield), the
stereochemistry of which was confirmed by the presence
of NOE between H10 and H15. The NAP group of 27
was removed with DDQ to afford 28 in 93% yield.9
procedure to produce 30 in 92% yield.5 The tetracyclic
25
D
30 was converted to 2 {½aꢀ +23.6 (CHCl3, c 0.29)} in
54% total yield through a three-step process including
selective debenzylation, TIPS protection, and TCBn
deprotection. The spectral data (1H and 13C NMR as
well as IR) and optical rotation of the resulting 2 agreed
well with those of the literature.2d;h Thus, the A- and D-
ring segments (5 and 4) were convergently assembled
into the ABCD-ring part 2 (16% overall yield for 10
steps from 4), which was already converted to 1 by the
Yamamoto group,2d thereby completing the formal total
synthesis of 1.

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K. Fujiwara et al. / Tetrahedron Letters 45 (2004) 5243–5246
(c) Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.;
Murai, A. Synlett 2002, 1835–1838.
5. Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.;
Duggan, M. E.; Veale, C. A. J. Am. Chem. Soc. 1989,
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6. (a) Ogura, K.; Tsuchihashi, G. Tetrahedron Lett. 1972, 13,
2681–2684; (b) Herrmann, J. L.; Richman, J. E.; Wepplo,
P. J.; Schlessinger, R. H. Tetrahedron Lett. 1973, 14, 4707–
4710.
In conclusion, the concise construction of the trans-
fused 7/7/6/6 tetracyclic ether (ABCD-ring) part 2 of
hemibrevetoxin B (1) from the A- and D-ring segments
(5 and 4) was achieved by a convergent process includ-
ing coupling reaction of the acyl anion equivalent 5 with
4, reductive cyclization of a,e-dihydroxyketone 3, and
introduction of a methyl group at the central ring
junction of 29 by the Nicolaou method.
7. Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Satyanara-
yana, M. Tetrahedron Lett. 2002, 43, 7009–7012.
8. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2048.
Acknowledgements
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We are grateful to Prof. Yoshinori Yamamoto and Prof.
Isao Kadota (Tohoku University) for kindly providing
1H NMR, 13C NMR, and IR spectra of compound 2.
We also thank Mr. Kenji Watanabe and Dr. Eri
Fukushi (GC–MS & NMR Laboratory, Graduate
School of Agriculture, Hokkaido University) for the
measurements of mass spectra. This work was supported
by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science, and
Technology of Japanese Government.
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13. Enantiomeric purity of 17 and 18 was determined by
HPLC analysis using chiral columns (CHIRALCEL AD
[DAICEL] for 18, CHIRALCEL OD-H [DAICEL] for
benzoate ester of 17).
14. Mitsunobu, O. Synthesis 1981, 1–28.
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16. Slight lowering of the enantiomeric purity was observed in
the Mitsunobu reaction step.
17. Since epoxide 18 was used as it stood (88–92% ee), the
optical purity of 4 was same as that of 18. Although the
minor enantiomer of 4 produced small amounts of
undesired diastereomers, which were inseparable from
25, in the connection reaction with 5, these were facilely
separated from 26 at the C-ring cyclization step.
18. Alexakis, A.; Jachiet, D.; Normant, J. F. Tetrahedron
1986, 42, 5607–5619.
19. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
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20. (a) Tsushima, K.; Araki, K.; Murai, A. Chem. Lett. 1989,
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21. Prolonged reaction time resulted in elimination of the
TBSO group at C18 of 26 to produce a significant amount
of the corresponding C18-exomethylene derivative.
22. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155;
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23. The cyclic S,O-acetal formation reaction of 28 usually
stopped at about 50% conversion after 6 h. Several
attempts to improve the yield (changing solvent to MeCN
or MeNO2, heating, or changing concentration of 28 and
reagents) showed no effect.