Total synthesis of brevenal

Article abstract of DOI:10.1021/ol900769d

A total synthesis of brevenal is described. The pentacyclic ether core was constructed by the intramolecular allylation of α-acetoxy ether and subsequent ring - closing metathesis. Both of the diene side chains were introduced by Wittig olefination and a

Full text of DOI:10.1021/ol900769d

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2531-2534
Total Synthesis of Brevenal
Hiroyoshi Takamura,† Shigetoshi Kikuchi,‡ Yuichi Nakamura,† Yuji Yamagami,†
Takayuki Kishi,† Isao Kadota,*,† and Yoshinori Yamamoto‡
Department of Chemistry, Graduate School of Natural Science and Technology,
Okayama UniVersity, 3-1-1 Tushimanaka, Okayama 700-8530, Japan, and Department
of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
kadota-i@cc.okayama-u.ac.jp
Received April 9, 2009
ABSTRACT
A total synthesis of brevenal is described. The pentacyclic ether core was constructed by the intramolecular allylation of r-acetoxy ether and
subsequent ring-closing metathesis. Both of the diene side chains were introduced by Wittig olefination and a Horner-Wadsworth-Emmons
reaction, respectively, in a highly stereoselective manner.
Brevenal (1), a new family of marine polycyclic ethers, was
isolated from Karenia breVis in 2004.1 This compound
Scheme 1. Retrosynthetic Analysis of Brevenal (1)
inhibits the binding of tritiated dihydrobrevetoxin-B to
voltage-sensitive sodium channels in a concentration de-
pendent manner and acts as a nontoxic brevetoxin antago-
nist.1,2 Moreover, a significant improvement of tracheal
mucus velocity was observed in an animal model of asthma.3
As well as the novel biological activities, the unique
structural features have attracted attention of synthetic
chemists. In 2006, the first total synthesis and structure
revision of 1 were reported by Sasaki and co-workers.4 In
this paper, we wish to report the recent results of our efforts
on the total synthesis of brevenal (1).
† Okayama University.
‡ Tohoku University.
(1) (a) Bourdelais, A. J.; Campbell, S.; Jacocks, H.; Naar, J.; Wright,
J. L. C.; Carsi, J.; Baden, D. G. Cell. Mol. Neurobiol. 2004, 24, 553–563.
(b) Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M.,
Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2–6.
(2) The antagonistic effect of brevenal on brevetoxin-induced DNA
damage is reported, see: Sayer, A.; Hu, Q.; Bourdelais, A. J.; Baden, D. G.;
Gibson, J. E. Arch. Toxicol. 2005, 79, 683–688
.
(3) Abraham, W. M.; Bourdelais, A. J.; Sabater, J. R.; Ahmed, A.; Lee,
T. A.; Serebriakov, I.; Baden, D. G. Am. J. Respir. Crit. Care Med 2005,
171, 26–34.
(4) (a) Fuwa, H.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc. 2006, 128,
9648–9650. (b) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki,
M. J. Am. Chem. Soc. 2006, 128, 16989–16999. (c) Ebine, M.; Fuwa, H.;
Sasaki, M. Org. Lett. 2008, 10, 2275–2278.
10.1021/ol900769d CCC: $40.75
Published on Web 05/14/2009
 2009 American Chemical Society

Scheme 2
Scheme 1 illustrates our retrosynthetic analysis of 1. Both
desired product from 12 directly, stereoinversion at C11
position was carried out. TPAP oxidation of 13 followed by
treatment of the resulting ketone with DBU in toluene at
110 °C provided 14 as a single stereoisomer. Deprotection
of the PMB group of 14 using DDQ furnished the alcohol
15 in 89% yield over 4 steps. Treatment of 15 with EtSH/
Zn(OTf)2 gave the mixed thioacetal 16 in 89% yield.4
Installation of the C12 angular methyl group was initially
examined by a reported procedure. Thus, oxidation of 16
with mCPBA followed by treatment with AlMe3 provided
17 as a single steroisomer in 69% yield.4,11 However, the
yield was not reproducible, and significant amounts of
unidentified byproduct, presumably generated from the
unstable sulfoxide intermediate, were formed in large-scale
experiment. After several examinations, we found that the
reaction of 16 with Me2Zn/Zn(OTf)2 furnished 17, directly,
in quantitative yield. The MOM ether at C14 position was
of the side chains would be constructed by Wittig-type
olefination at a later stage. The pentacyclic ether core would
be synthesized from 2 via the intramolecular allylation
followed by ring-closing metathesis.5 The cyclization precur-
sor 2 was retrosynthetically broken down into the ABC ring
segment 3 and the E ring precursor 4. The tricycle 3 would
be prepared from 5 and 6.
The synthesis of the ABC ring segment 3 is described in
Scheme 2. TBS protection of the known compound 76
followed by reductive cleavage of the benzylidene acetal with
DIBALH gave the corresponding primary alcohol, which was
protected with BnBr/KH to furnish the bis-benzyl ether 8 in
72% yield. Ozonolysis of the olefin 8 followed by Brown’s
asymmetric allylboration provided 9 as a single stereoisomer
in 95% yield.7 MOM protection of the alcohol 9 followed
by hydroboration-oxidation afforded the corresponding al-
cohol, which was subjected to stepwise oxidation leading to
the carboxylic acid 10. Removal of the TBS group with
TBAF and the Yamaguchi lactonization provided 6 in 64%
yield over 6 steps.8 Treatment of the lactone 6 with
(PhO)2POCl/KHMDS provided the enol phosphate 11. The
Suzuki-Miyaura coupling of 11 and an alkyl borate, prepared
from the iodide 54c by known procedure,9 was carried out
with PdCl2(dppf) to furnish the enol ether 12 in 81% yield
over 2 steps.10 Hydroboration of 12 with BH3 followed by
oxidative workup gave the undesired stereoisomer 13 as the
sole product. Since several attempts failed to obtain the
(5) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 124, 3562–3566
.
(6) (a) Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K.
Tetrahedron 1990, 46, 4517–4552. (b) Kadota, I.; Kadowaki, C.; Park, C.-
H.; Takamura, H.; Sato, K.; Chan, P. W. H.; Thorand, S.; Yamamoto, Y.
Tetrahedron 2002, 58, 1799–1816
(7) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401–404
(8) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993
(9) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885–7892
.
.
.
.
(10) Sasaki and co-workers have reported the same C-C bond formation
with this alkyl borate: see ref 4.
(11) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.;
Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321–5330
.
2532
Org. Lett., Vol. 11, No. 12, 2009

Scheme 3
totally inert under the reaction conditions. Debenzylation of
2.14,15 Intramolecular allylation of 2 was carried out with
MgBr2·OEt2 to give 25 as a single stereoisomer in 52% yield
over 2 steps.16 Ring-closing metathesis of the diene 25 was
carried out with the Grubbs’ catalyst 26 leading to the
pentacyclic ether 27 in 69% yield.17,18 At this stage, the trans
relationship between H22 and H23 was confirmed by the
coupling constant, JH22-H23 ) 9.0 Hz. Having synthesized
the pentacyclic ether core, we next examined the construction
of the right-hand side chain. However, deprotection of the
TCBn group was very slow under the standard hydrogenation
conditions such as H2 and Pd catalysts, and decomposition
of the substrate was observed when a prolonged reaction time
was employed.19 Finally, this problem was solved by the
Sajiki’s dechlorination procedure. Thus, the reaction of 27
with H2/Pd-C in the presence of Et3N proceeded smoothly
17 with H2/Pd(OH)2-C, protection of the resulting diol with
TESCl/imidazole, and selective cleavage of the primary TES
ether under acidic conditions afforded 18 in 89% yield over
3 steps. TPAP oxidation of the alcohol 18 followed by Wittig
reaction with Ph3PdCHCO2Me gave the corresponding
unsaturated ester (96% by 2 steps) which was subjected to
hydrogenation and saponification leading to the ABC ring
segment 3.
Scheme 3 describes the key segment coupling. Thus,
esterification of the carboxylic acid 3 and the known alcohol
412 under the Yamaguchi conditions gave the ester 19.8
Selective removal of the TES protective group was performed
with CSA to provide 20 in 74% yield over 4 steps.
Acetalization of 20 with γ-methoxyallylstannane 21 in the
presence of CSA provided the acetal 22 as a mixture of
diastereoisomers in 88% yield. Treatment of 22 with TMSI/
HMDS gave allylic stannane 23 in 91% yield.13 Since the
MOM protection was cleaved under the reaction conditions,
the resulting hydroxyl group of 23 was protected as a TBS
ether to furnish 24 in 95% yield. Modified Rychnovsky
acetylation of the ester 24 provided the R-chloroacetoxy ether
(14) Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.;
Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 46–47
.
(15) 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
.
(16) None of the other stereoisomers were detected. Although the
reaction conditions were optimized, partial decompsition of the substrate 2
was observed in this reaction.
(17) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039–2041. (b) Schwab, P.; Grubbs, R. H.;
(12) (a) Fujiwara, K.; Sato, D.; Watanabe, M.; Morishita, H.; Murai,
A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 5243–5246. (b)
Kadota, I.; Abe, T.; Ishitsuka, Y.; Touchy, A. S.; Nagata, R.; Yamamoto,
Y. Heterocycles 2007, 74, 617–627.
Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100–110
.
(18) The reaction of 25 required 3 equiv of 26 for the completion, and
the formation of unidentified by-products was observed.
(19) For successful examples of the deprotection of TCBn group in
similar cases, see ref 12.
(13) Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron Lett. 1996,
37, 3195–3198.
Org. Lett., Vol. 11, No. 12, 2009
2533

of the TBDPS group was carried out with TBAF/AcOH to
give the alcohol 32 in 94% yield. As well as the synthesis
of the pentacyclic ether framework, the stereoselective
construction of the left-hand side chain, highly substituted
(E,E)-diene moiety, was of the challenging problems inherent
in the total synthesis of brevenal. We chose the Horner-
Wadsworth-Emmons reaction as a possible route to the diene
system. Thus, after oxidation of 32, the resulting aldehyde
was treated with an anion generated from the phosphonate
33 and n-BuLi to provide 34 as a single steroisomer in 88%
yield over 2 steps.23 Reduction of the ester 34 with DIBALH
followed by desilylation with TBAF afforded the triol 35 in
98% yield. Finally, selective oxidation of the allylic alcohol
35 with MnO2 furnished brevenal (1) in quantitative yield.
The synthetic 1 exhibited physical and spectroscopic data
identical with those reported previously.
Scheme 4
In conclusion, we have achieved a total synthesis of
brevenal (1) via the intramolecular allylation of an R-chlo-
roacetoxy ether and ring-closing metathesis. The longest
linear sequence leading to 1 was 57 steps with 0.84% overall
yield. Novel methods for the direct methylation of O,S-acetal
(Scheme 2) and the stereoselective synthesis of the left-hand
(E,E)-diene system (Scheme 4) are also deserving of atten-
tion.
Acknowledgment. This work was financially supported
by the Nagase Science and Technology Foundation, the
Wesco Scientific Promotion Foundation, the Naito Founda-
tion, the Sumitomo Foundation, and the Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Supporting Information Available: Experimental details
1
and full spectral data. Copies of H and 13C NMR spectra
for selected compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
to give the corresponding benzyl ether in quantitative yield.20
Hydrogenation of the E ring olefin with diimide afforded
28, a synthetic intermediate of Sasaki’s total synthesis,4a,b,21
in 84% yield over 2 steps. Debenzylation of 28 was carried
out with H2/Pd(OH)2-C leading to 29 in 89% yield.
Construction of the right-hand (Z)-diene moiety was
carried out according to Nicolaou’s procedure (Scheme 4).22
Thus, oxidation of 29 with SO3·py/DMSO followed by Wittig
reaction using a ylide generated from 30 and NaHMDS, and
subsequent oxidation with H2O2 provided 31 as a single
stereoisomer in 90% yield over 3 steps. Selective removal
OL900769D
(20) Sajiki, H.; Kume, A.; Hattori, K.; Hirota, K. Tetrahedron Lett. 2002,
43, 7247–7250.
(21) 1H and 13C NMR spectra of 28 were identical with those reported
previously.
(22) (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.
(23) For the preparation of the phosphonate 33, see Supporting Informa-
tion.
2534
Org. Lett., Vol. 11, No. 12, 2009