A convergent approach to the formal total synthesis of hemibrevetoxin B

Article abstract of DOI:10.1016/j.tetlet.2006.11.058

A convergent synthesis of the key synthetic intermediate of hemibrevetoxin B was achieved via the intramolecular allylation of an α-chloroacetoxy ether and subsequent ring-closing metathesis.

Full text of DOI:10.1016/j.tetlet.2006.11.058

Tetrahedron Letters 48 (2007) 219–221
A convergent approach to the formal total
synthesis of hemibrevetoxin B
Isao Kadota,a,* Takashi Abe,b Yukako Ishitsuka,b Abeda S. Touchy,b
Ryoko Nagatab and Yoshinori Yamamotob
aDepartment of Chemistry, Graduate School of Natural Science and Technology, Okayama University,
3-1-1 Tsushima-naka, Okayama 700-8530, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 3 October 2006; revised 31 October 2006; accepted 9 November 2006
Abstract—A convergent synthesis of the key synthetic intermediate of hemibrevetoxin B was achieved via the intramolecular allyl-
ation of an a-chloroacetoxy ether and subsequent ring-closing metathesis.
Ó 2006 Elsevier Ltd. All rights reserved.
Hemibrevetoxin B (1), which has a 6,6,7,7-tetracyclic
ether skeleton including 10 stereocenters, was isolated
from the cultured cells of the red tide organism Gym-
nodinium breve by Shimizu and Prasad in 1989.1 The
unique structural features have attracted the attention
of synthetic chemists, and a number of strategies have
been investigated. To date, seven total syntheses, includ-
ing three formal syntheses, have been reported.2 In this
letter, we report a convergent formal total synthesis
of 1.
Scheme 1 describes our retrosynthetic analysis of 1. We
focused on the convergent construction of the key inter-
mediate 2, which was converted to 1 in our previous syn-
thesis,2c,e via the intramolecular allylation of a-acetoxy
ether 3 followed by ring-closing metathesis.3 The
Me
Me
OH
OTBS
H
H
H
H
H
H
H
H
O
O
OHC
O
A
O
D
OH
B
O
C
O
H
O
H
H
H
TIPSO
O
Me
Me
HO
TIPSO
2
Hemibrevetoxin B (1)
Bu3Sn
Me
OTBS
H
O
H
Me
H
H
H
O
OTBS
O
OTES
CO2H
RO
A
B
O
+
OTCBn
OTCBn
TIPSO
O
O
TIPSO
HO
H
H
Me
H
Me
TIPSO
TIPSO
5
R = CH2ClCO
3
4
Scheme 1. Retrosynthetic analysis of hemibrevetoxin B (1).
Keywords: Hemibrevetoxin B; Polycyclic ethers; Convergent synthesis.
*
Corresponding author. Tel./fax: +81 86 251 7836; e-mail: kadota-i@cc.okayama-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.058

220
I. Kadota et al. / Tetrahedron Letters 48 (2007) 219–221
H
H
H
H
O
OH
O
OTES
CO2Me
a
BnO
O
CO2Me
BnO
O
H
Me
H
Me
BnO
BnO
7
6
b
H
H
H
H
H
H
O
OTES
CO2Me
O
OTES
CO2Me
c
TIPSO
O
HO
O
Me
Me
TIPSO
HO
9
8
d
H
H
H
H
H
H
O
OTES
O
OTES
CO2H
e
OH
TIPSO
O
TIPSO
O
Me
Me
TIPSO
TIPSO
10
4
Scheme 2. Reagents and conditions: (a) TESOTf, 2,6-lutidine, CH2Cl2, rt, quant; (b) H2, Pd(OH)2–C, EtOAc, rt; (c) TIPSOTf, 2,6-lutidine, DMF,
rt–70 °C, 71% (two steps); (d) LiAlH4, ether, 0 °C and (e) (i) SO3Æpy, DMSO, Et3N, CH2Cl2, 0 °C; (ii) NaClO2, 2-methyl-2-butene, NaH2PO4, THF–
H2O, 0 °C.
cyclization precursor 3 would be prepared from carb-
oxylic acid 4 and alcohol 5.
tion of the resulting tertiary alcohol with TBSOTf/2,6-
lutidine followed by removal of the MPM protection
provided the alcohol 5 in 61% yield.
Synthesis of the AB ring segment 4 is illustrated in
Scheme 2. The alcohol 6, prepared by a known
procedure,2c,e was converted to TES ether 7 in quantita-
tive yield. Hydrogenation and debenzylation of 7 were
performed with H2/Pd(OH)2–C to give 8. The resulting
diol was protected with TIPSOTf/2,6-lutidine to give 9
in 71% overall yield. Reduction of the ester 9 with
LiAlH4 afforded alcohol 10 which was subjected to
stepwise oxidation to furnish the carboxylic acid 4.4
Coupling of the prepared segments is described in
Scheme 4. Esterification of the carboxylic acid 4 and
the alcohol 5 under Yamaguchi conditions gave ester
14 in 81% overall yield.6 Selective removal of the
TES protective group was performed using catalytic
CSA in MeOH to afford 15 in 94% yield. Acetalization
of 15 with c-methoxyallylstannane 16 in the presence
of CSA afforded mixed acetal 17 in 81% yield. Treat-
ment of 17 with TMSI/HMDS gave allylic stannane
18 in 91% yield.7 Modified Rychnovsky acetylation of
the ester 18 provided a-acetoxy ether 3 in 65% yield.8,9
Intramolecular allylation of 3 was carried out with
MgBr2ÆOEt2 to give 19 as a single stereoisomer in
79% yield. Ring-closing metathesis of the diene 19 with
the second generation Grubbs’ catalyst 20 furnished 21
in 76% yield.10 The stereochemistry of the 7,7-system
The D ring precursor 5 was prepared from the known
epoxide 11 (Scheme 3). Protection of 112j with
MPMCl/NaH gave 12 in 70% yield. Treatment of the
epoxide 12 with dimethylsulfonium methylide generated
in situ afforded allylic alcohol 13 in 77% yield.5 Protec-
O
O
was confirmed by 1H NMR analysis (JHaÀHb
=
Me
Me
a
9.3 Hz). Finally, hydrogenation of the D ring olefin
and deprotection of the 2,4,6-trichlorobenzyl (TCBn)
group were performed with H2/Pd–C to give the target
compound 2 in 68% yield. The physical and spectro-
scopic data of 2 were identical with those reported
previously.2e
OTCBn
OTCBn
HO
MPMO
11
12
b
Me
OTBS
Me
OH
In conclusion, we have achieved a convergent formal
total synthesis of hemibrevetoxin B 1 via the intramole-
cular allylation of an a-chloroacetoxy ether and ring-
closing metathesis. The longest linear sequence leading
to the key synthetic intermediate 2 from mannose was
37 steps, while our previous synthesis based on a linear
synthetic strategy required 49 steps.2c,e,11 Application of
the present strategy to the synthesis of other marine
natural products is in progress.
c
OTCBn
OTCBn
HO
MPMO
5
13
Scheme 3. Reagents and conditions: (a) MPMCl, NaH, TBAI, THF,
reflux, 70%; (b) Me3S+IÀ, n-BuLi, THF, À10 °C to rt, 77% and (c) (i)
TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C–rt, 87%; (ii) DDQ, CH2Cl2, aq
NaHCO3, 35 °C, 70%.

I. Kadota et al. / Tetrahedron Letters 48 (2007) 219–221
221
Me
OTBS
H
H
H
Me
OTBS
H
H
H
O
OH
O
OTES
O
O
b
a
OTCBn
4
OTCBn
TIPSO
O
O
TIPSO
O
O
H
Me
H
Me
TIPSO
TIPSO
15
c
14
Bu3Sn
Bu3Sn
OMe
O
Me
Me
OTBS
H
O
H
H
O
H
OTBS
O
O
d
O
OTCBn
OTCBn
TIPSO
O
O
TIPSO
O
O
H
H
H
Me
H
Me
TIPSO
TIPSO
17
18
e
Bu3Sn
Me
OTBS
H
Me
OTBS
H
O
H
H
H
O
O
O
f
RO
OTCBn
O
H
OTCBn
H
TIPSO
O
O
TIPSO
O
H
H
Me
H
Me
TIPSO
TIPSO
19
3
g
Bu3Sn
R = CH2ClCO
OMe
Me
OTBS
Me
OTBS
16
Ha
O
H
H
H
H
H
H
H
O
O
O
h
OH
OTCBn
N Mes
Ph
Mes
Cl
Cl
N
O
H
O
H
H
Hb
TIPSO
O
TIPSO
O
Ru
Me
Me
TIPSO
TIPSO
JHa-Hb = 9.3 Hz
PCy3
2
21
20
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then 5, DMAP, toluene, rt, 81% (four steps); (b) CSA,
MeOH, 0 °C, 94%; (c) 16, CSA, CH2Cl2, rt, 81%; (d) HMDS, TMSI, CH2Cl2, 0 °C, 91%; (e) DIBAL–H, À78 °C, CH2Cl2, then (CH2ClCO)2O,
˚
DMAP, pyridine, À78 °C, 65%; (f) MgBr2ÆOEt2, 4 A MS, CH2Cl2, 0 °C, 79%; (g) 20, benzene, 80 °C, 76% and (h) H2, 10% Pd–C, EtOAc, rt, 68%.
119, 4557–4558; (h) Mori, Y.; Yaegashi, K.; Furukawa, H.
J. Org. Chem. 1998, 63, 6200–6209; (i) Rainier, J. D.;
Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66, 1380–
1386; (j) Fujiwara, K.; Sato, D.; Watanabe, M.; Morishita,
H.; Murai, A.; Kawai, H.; Suzaki, T. Tetrahedron Lett.
2004, 45, 5243–5246.
Acknowledgements
This work was financially supported by the Novartis
Foundation for the Promotion of Science, the Kurata
Memorial Hitachi Science and Technology Foundation,
the Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan.
3. Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2002, 124, 3562–3566.
4. Attempts at the direct saponification of 9 gave poor
results.
5. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.;
Le Gall, T.; Shin, D.-S.; Falck, J. R. Tetrahedron Lett.
1994, 35, 5449–5452.
References and notes
6. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yama-
guchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
7. Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron
Lett. 1996, 37, 3195–3198.
8. Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda,
K.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 46–
47.
9. For the original conditions, see: (a) Dahanukar, V. H.;
Rychnovsky, S. D. J. Org. Chem. 1996, 61, 8317–8320; (b)
Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000,
65, 191–198; (c) Kopecky, D. J.; Rychnovsky, S. D. Org.
Synth. 2003, 80, 177–183.
1. Prasad, A. V. K.; Shimizu, Y. J. Am. Chem. Soc. 1989,
111, 6476–6477.
2. For total syntheses of hemibrevetoxin B, see: (a) Nicolaou,
K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y.
J. Am. Chem. Soc. 1992, 114, 7935–7936; (b) Nicolaou, K.
C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y.;
Hwang, C.-K. J. Am. Chem. Soc. 1993, 115, 3558–3575; (c)
Kadota, I.; Park, J.-Y.; Koumura, N.; Pollaud, G.;
Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett. 1995, 36,
5777–5780; (d) Morimoto, M.; Matsukura, H.; Nakata, T.
Tetrahedron Lett. 1996, 37, 6365–6368; (e) Kadota, I.;
Yamamoto, Y. J. Org. Chem. 1998, 63, 6597–6606; (f)
Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc.
2003, 125, 7822–7824; For formal syntheses, see: (g) Mori,
Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1997,
10. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956.
11. Seven steps are required to complete the total synthesis of
1 from 2.