Total synthesis, structure revision, and absolute configuration of (-)-brevenal

Article abstract of DOI:10.1021/ja066772y

Total synthesis of structure 1 originally proposed for brevenal, a nontoxic polycyclic ether natural product isolated from the Florida red tide dinoflagellate, Karenia brevis, was accomplished. The key features of the synthesis involved (i) convergent ass

Full text of DOI:10.1021/ja066772y

Published on Web 12/07/2006
Total Synthesis, Structure Revision, and Absolute
Configuration of (-)-Brevenal
Haruhiko Fuwa,† Makoto Ebine,† Andrea J. Bourdelais,‡ Daniel G. Baden,‡ and
Makoto Sasaki†,*
Contribution from the Laboratory of Biostructural Chemistry, Graduate School of Life Sciences,
Tohoku UniVersity, Aoba-ku, Sendai 981-8555, Japan, and Wilmington Center for Marine
Science, UniVersity of North Carolina, 5600 MarVin K. Moss Lane, Wilmington, North Carolina
28409
Received September 20, 2006; E-mail: masasaki@bios.tohoku.ac.jp
Abstract: Total synthesis of structure 1 originally proposed for brevenal, a nontoxic polycyclic ether natural
product isolated from the Florida red tide dinoflagellate, Karenia brevis, was accomplished. The key features
of the synthesis involved (i) convergent assembly of the pentacyclic polyether skeleton based on our
developed Suzuki-Miyaura coupling chemistry and (ii) stereoselective construction of the multi-substituted
(E,E)-dienal side chain by using copper(I) thiophen-2-carboxylate (CuTC)-promoted modified Stille coupling.
The disparity of NMR spectra between the synthetic material and the natural product required a revision
of the proposed structure. Detailed spectroscopic comparison of synthetic 1 with natural brevenal, coupled
with the postulated biosynthetic pathway for marine polyether natural products, suggested that the natural
product was most likely represented by 2, the C26 epimer of the proposed structure 1. The revised structure
was finally validated by completing the first total synthesis of (-)-2, which also unambiguously established
the absolute configuration of the natural product.
Introduction
with massive fish kills and marine mammal poisoning, and they
are thought to be responsible for adverse human health effects,
Marine polycyclic ether natural products continue to fascinate
chemists and biologists because of their unique and highly
complex molecular architecture coupled with diverse and
extremely potent biological activities.1,2 Among these, bre-
vetoxin-B, produced by the Florida red tide dinoflagellate,
Karenia breVis (formerly known as Gymnodinium breVe and
Ptychodiscus breVis), is the first member of this class of natural
products to be structurally elucidated by spectroscopic and X-ray
crystallographic analysis by Nakanishi and co-workers in 1981
(Figure 1).3 Ever since, a number of congeners, including
brevetoxin-A,4 have been isolated and structurally characterized.
These toxic metabolites are known to exhibit their potent
neurotoxicity by binding with a receptor site 5 on voltage-
sensitive sodium channels (VSSC) in excitable membranes,
thereby causing the channels to open at normal resting potentials
with an increase in mean channel open time and inhibiting
channel inactivation.5 Blooms of K. breVis have been associated
such as respiratory irritation and airway constriction observed
in beach-goers during a red tide. In addition, the consumption
of shellfish contaminated with brevetoxins results in neurotoxic
shellfish poisoning (NSP) in humans, which is characterized
by sensory abnormalities, cranial nerve dysfunction, gastrointes-
tinal symptoms, and sometimes respiratory failure.6 Hemibre-
vetoxin-B, another polycyclic ether compound, was isolated by
Prasad and Shimizu from the same organism, and the molecular
size is about one-half of that of brevetoxins.7 Hemibrevetoxin-B
was reported to cause the same characteristic rounding of
cultured mouse neuroblastoma cells as brevetoxins and show
cytotoxicity at a concentration of 5 µM.
Brevenal, isolated recently by Baden, Bourdelais, and co-
workers from the laboratory cultures of K. breVis along with
brevetoxins, represents the newest member of polycyclic ethers.8
The gross structure of brevenal, including the relative stereo-
chemistry, was disclosed in 2004 as structure 1 on the basis of
extensive 2D NMR studies; however, the absolute stereochem-
istry remained to be established. Although the size of the
molecule is relatively compact compared with brevetoxins, the
† Tohoku University.
‡ University of North Carolina.
(1) For reviews on marine polycyclic ethers, see: (a) Yasumoto, T.; Murata,
M. Chem. ReV. 1993, 93, 1897-1909. (b) Murata, M.; Yasumoto, T. Nat.
Prod. Rep. 2000, 293-314. (c) Yasumoto, T. Chem. Rec. 2001, 3, 228-
242.
(6) For recent reviews, see: (a) Baden, D. G.; Bourdelais, A. J.; Jacocks, H.;
Michelliza, S.; Naar, J. EnViron. Health Perspect. 2005, 113, 621-625.
(b) Kirkpatrick, B.; Fleming, L. E.; Squicciarini, D.; Backer, L. C.; Clark,
R.; Abraham, W.; Bentson, J.; Cheng, Y. S.; Johnson, D.; Pierce, R.; Zais,
J.; Bossart, G. D.; Baden, D. G. Harmful Algae 2004, 3, 99-115.
(7) Prasad, A. V. K.; Shimizu, Y. J. Am. Chem. Soc. 1989, 111, 6476-6477.
(8) (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) For recent comprehensive reviews on total synthesis of polycyclic ethers,
see: (1) Nakata, T. Chem. ReV. 2005, 105, 4314-4347. (b) Inoue, M. Chem.
ReV. 2005, 105, 4379-4405.
(3) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golik, J.;
James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773-6775.
(4) Shimizu, Y.; Chou, H.-N.; Bando, H.; Van Duyne, G.; Clardy, J. C. J. Am.
Chem. Soc. 1986, 108, 514-515.
(5) Poli, M. A.; Mende, T. J.; Baden, D. G. Mol. Pharmacol. 1986, 30, 129-
135.
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J. AM. CHEM. SOC. 2006, 128, 16989-16999
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A R T I C L E S
Fuwa et al.
Figure 1. Structures of brevetoxin-A, brevetoxin-B, hemibrevetoxin-B, and brevenal (proposed structure 1 and revised structure 2).
Scheme 1. Retrosynthetic Analysis
pentacyclic polyether core arranged with four methyl and two
hydroxy groups and, especially, the characteristic heavily
substituted left-hand (E,E)-dienal side chain make it a syntheti-
cally challenging target molecule. In addition, the biological
profile of brevenal is particularly unique and intriguing in that
it competitively displaces tritiated dihydrobrevetoxin-B ([3H]-
PbTx-3) from VSSC in rat brain synaptosomes in a dose-
dependent manner and antagonizes the toxic effects of bre-
vetoxins in vivo.8,9 More importantly, picomolar concentrations
of brevenal increased tracheal mucus velocity to the same degree
as that observed with millimolar concentrations of a sodium
channel blocker, amiloride, which is used in the treatment of
cystic fibrosis.10 Thus, brevenal represents a potential lead for
the development of novel therapeutic agents for the treatment
of mucociliary dysfunction associated with cystic fibrosis and
other lung disorders.
The remarkable structural and biological aspects of this
natural product led us to embark on its total synthesis. We have
recently reported the first total synthesis of structure 1 originally
proposed for brevenal by means of our developed Suzuki-
Miyaura coupling-based convergent strategy.11 However, the 1H
Results and Discussion
and 13C NMR spectra for the synthetic material were not
Synthesis Plan. Our total synthesis of structure 1 originally
proposed for brevenal was based on a retrosynthetic analysis
as depicted in Scheme 1. The characteristic unsaturated side
chains at both ends of the molecule were to be constructed at
a late stage of the total synthesis. The right-hand (Z)-diene is
the same as that found in the hemibrevetoxin-B structure, and
thus this could be prepared by the precedented procedure,
namely, selenyl-Wittig reaction using the ylide generated from
phosphonium salt 4 followed by syn elimination of the sele-
noxide.12 On the other hand, the left-hand side chain that
contains a multi-substituted (E,E)-dienal moiety was planned
to be constructed in a stereoselective manner by the Stille
identical to those reported for the natural product, suggesting
that it is necessary to revise the initial structural assignment.
Herein, we describe the details of our total synthesis of the
proposed brevenal structure 1 and non-identity to the natural
product. On the basis of the NMR distinctions, a revised
structure 2, the C26-epimer of 1, was proposed and finally
confirmed by the total synthesis of (-)-2, which has also led
to unambiguous determination of the absolute configuration of
the natural product.
(9) Sayer, A.; Hu, Q.; Bourdelais, A. J.; Baden, D. G.; Gilson, J. E. Arch.
Toxicol. 2005, 79, 683-688.
(10) 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.
(12) (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.
(11) For a preliminary communication, see: Fuwa, H.; Ebine, M.; Sasaki, M.
J. Am. Chem. Soc. 2006, 128, 9648-9650.
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Total Synthesis of (−)-Brevenal
A R T I C L E S
Scheme 2. Synthesis of the AB Ring Fragmenta
a Reagents and conditions: (a) n-Bu2BOTf, Et3N, CH2Cl2, -78 f 0 °C; (b) NaBH4, THF/H2O, rt, 90% (two steps); (c) p-MeOC6H4CH(OMe)2, PPTS,
CH2Cl2, rt; (d) DIBALH, CH2Cl2, -78 f -40 °C, 94% (two steps); (e) MsCl, Et3N, CH2Cl2, 0 °C; (f) NaCN, DMSO, 60 °C, 96% (two steps); (g)
DIBALH, CH2Cl2, -78 °C, 90%; (h) Ph3PdC(Me)CO2Et, toluene, 100 °C, 97%; (i) DIBALH, CH2Cl2, -78 °C, quant.; (j) (+)-DET, Ti(Oi-Pr)4, t-BuOOH,
CH2Cl2, -40 °C, 88%; (k) SO3‚pyridine, Et3N, DMSO/CH2Cl2 (1:1), 0 °C; (l) Ph3P+CH3Br-, NaHMDS, THF, 0 °C, 90% (two steps); (m) DDQ, CH2Cl2/
H2O (20:1), rt; (n) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 89% (two steps); (o) (Sia)2BH, THF, 0 °C; then aq NaHCO3, 30% H2O2, rt, 92%; (p) SO3‚pyridine,
Et3N, DMSO/CH2Cl2 (1:1), 0 °C; (q) Ph3PdCHCO2Bn, toluene, 60 °C, 86% (two steps); (r) 1 M HCl, THF, rt, 95%; (s) H2, 20% Pd(OH)2/C, THF/MeOH
(2:1), rt, 90%; (t) 2,4,6-Cl3C6H2COCl, Et3N, THF, 0 °C f rt; then DMAP, toluene, 110 °C, 98%; (u) KHMDS, (PhO)2P(O)Cl, HMPA, THF, -78 °C, 96%.
coupling of (E)-vinyl iodide 3 and (E)-vinyl stannane 5.13 In
turn, the pentacyclic polyether core in 3 was envisaged to be
available from the AB ring enol phosphate 6 and the DE ring
exocyclic enol ether 7 by means of our Suzuki-Miyaura
coupling-based chemistry.14-16
Oxidation of 15 followed by Wittig olefination provided vinyl
epoxide 16 in 90% yield for the two steps. Upon exposure of
16 to DDQ (CH2Cl2/H2O (20:1), room temperature), deprotec-
tion of the PMB group with concomitant 6-endo cyclization
took place20 to furnish the A ring pyran 17, which was then
protected as the TES ether 18 (89% yield for the two steps).
The relative stereochemistry of 17 was established by NOE
experiments as shown. Hydroboration of 18 with disiamylborane
gave an alcohol (92% yield), which was then subjected to
oxidation and Wittig reaction to afford R,â-unsaturated ester
19 in 86% yield for the two steps. Removal of the TES group
under mild acidic conditions provided alcohol 20. Hydrogenation
of 20 with concomitant hydrogenolysis of the benzyl ester,
followed by Yamaguchi lactonization,21 generated seven-
membered lactone 21 (88% overall yield), which was then
transformed to the requisite AB ring enol phosphate 6 by the
usual method.22
Synthesis of the AB Ring Fragment 6. The synthesis of
the AB ring fragment 6 started with Evans aldol reaction of
aldehyde 8 and oxazolidinone 9, which provided the desired
syn-aldol adduct (Scheme 2).17 The chiral auxiliary was reduc-
tively removed with NaBH418 to provide 1,3-diol 10 as a single
stereoisomer in 90% overall yield. The resultant diol 10 was
protected as the p-methoxybenzylidene acetal, which was then
reduced with DIBALH in a regioselective manner to afford
primary alcohol 11 in 94% yield for the two steps.19 Mesylation
of 11 followed by displacement with sodium cyanide gave nitrile
12 in 96% yield (two steps). DIBALH reduction of the nitrile
and subsequent Wittig reaction of the resulting aldehyde
provided R,â-unsaturated ester 13 in 87% yield for the two steps.
After reduction with DIBALH, Sharpless asymmetric epoxida-
tion of the resultant allylic alcohol 14 under the stoichiometric
conditions gave epoxy alcohol 15 in 88% yield. In contrast,
under the catalytic conditions, the yield of 15 was moderate
(ca. 50%) and several unidentified byproducts were formed.
Synthesis of the DE Ring Fragment 7. For the synthesis of
the DE ring fragment 7, the known seven-membered ether 22,23
corresponding to the D ring, was selected as a starting material
(Scheme 3). Benzylation of 22 followed by ozonolysis and
reductive workup with NaBH4 gave alcohol 23 in 96% yield
for the two steps. The primary alcohol of 23 was protected as
the benzyl ether and the benzylidene acetal was removed under
acidic conditions to afford diol 24 in a quantitative yield for
the two steps. Selective triflation of the primary alcohol followed
by TBS protection of the residual secondary alcohol was carried
out in one-pot following the method of Mori.24 The resulting
primary triflate was immediately subjected to nucleophilic
displacement with allylmagnesium bromide in the presence of
CuBr25 to afford elongated olefin 25 in 85% overall yield. The
terminal olefin of 25 was oxidatively cleaved (OsO4, 4-meth-
(13) For recent reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4442-4489. (b) Espinet, P.; Echavarren,
A. E. Angew. Chem., Int. Ed. 2004, 43, 4704-4734. (c) Mitchell, T. C. In
Metal-catalyzed Cross-coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; pp 125-162. (d) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652.
(14) For reviews on Suzuki-Miyaura coupling, see: (a) Suzuki, A.; Miyaura,
N. Chem. ReV. 1995, 95, 2457-2483. (b) Chemler, S. R.; Trauner, D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544-4568.
(15) (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron Lett. 1998,
39, 9027-9030. (b) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana, K.
Org. Lett. 1999, 1, 1075-1077. (c) Sasaki, M.; Ishikawa, M.; Fuwa, H.;
Tachibana, K. Tetrahedron 2002, 58, 1889-1911. (d) Sasaki, M.; Fuwa,
H. Synlett 2004, 1851-1874.
(16) (a) Fuwa, H.; Sasaki, M.; Satake, M.; Tachibana, K. Org. Lett. 2002, 4,
2981-2984. (b) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am.
Chem. Soc. 2002, 124, 14983-14992. (c) Tsukano, C.; Sasaki, M. J. Am.
Chem. Soc. 2003, 125, 14294-14295. (d) Tsukano, C.; Ebine, M.; Sasaki,
M. J. Am. Chem. Soc. 2005, 127, 4326-4335.
(17) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-
2129.
(20) Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.; Le
Brazidec, J.-M.; Hirama, M. Tetrahedron 2002, 58, 6493-6512.
(21) Yamaguchi, M.; Inanaga, J.; Hirata, K.; Sasaki, H.; Katsuki, T. Bull. Chem.
Soc. Jpn. 1979, 52, 1989-1993.
(22) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Ga¨rtner, P.; Yang, Z. J. Am.
Chem. Soc. 1997, 119, 5467-5468.
(23) Kadota, I.; Ohno, A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett.
1998, 39, 6373-6776.
(18) Prashad, M.; Har, P.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998, 39,
7067-7070.
(19) (a) Johansson, R.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1984,
201-202. (b) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans.
1 1984, 2371-2374.
(24) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996, 118, 8158-
8159.
(25) Kotsuki, H.; Kadota, I.; Masamitsu, O. Tetrahedron Lett. 1990, 31, 4609-
4612.
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A R T I C L E S
Fuwa et al.
Scheme 3. Synthesis of Ketone 29a
a Reagents and conditions: (a) KOt-Bu, BnBr, n-Bu4NI, THF, rt; (b) O3, CH2Cl2/MeOH (1:1), -78 °C; then NaBH4, 0 °C, 96% (two steps); (c) NaH,
BnBr, THF/DMF (1:1), rt; (d) CSA, MeOH/CH2Cl2 (10:1), rt, quant. (two steps); (e) Tf2O, 2,6-lutidine, CH2Cl2, -78 °C; then TBSOTf, 0 °C; (f) allylMgBr,
CuBr, Et2O, 0 °C, 85% (two steps); (g) OsO4, NMO, THF/H2O (7:1), rt; then NaIO4, rt; (h) HS(CH2)3SH, BF3‚OEt2, CH2Cl2, -78 f 0 °C; (i) TBAF, THF,
rt, 88% (three steps); (j) methyl propiolate, NMM, CH2Cl2, rt; (k) MeI, NaHCO3, MeCN/H2O (4:1), rt, 99% (two steps); (l) SmI2, MeOH, THF, rt; then
p-TsOH‚H2O, toluene, 80 °C, 84% (two steps); (m) DIBALH, CH2Cl2, -78 °C; (n) Ph3P+CH3Br-, NaHMDS, THF, 0 °C f rt, 94% (two steps); (o) TPAP,
NMO, 4 Å molecular sieves, CH2Cl2, rt, 97%.
Table 1. Stereoselective Methylation of Ketone 29
Scheme 5. Synthesis of R-Hydroxy Ketone 37a
entry
reagents and conditions
30a:30b
% yielda
1
2
3
4
5
Me3Al (10 equiv), CH2Cl2, -78 °C f rt
MeMgBr (10 equiv), THF, -78 °C
MeMgBr (1.5 equiv), THF, -78 °C f rt
MeMgBr (1.5 equiv), toluene, -78 °C f rt
MeLi (1.2 equiv), THF, -78 °C f rt
1.3:1
2.5:1
2.3:1
1:1.3
10:1
78 (20)b
36 (52)b
99
quant.
97
a Isolated yields. b Yields in parentheses are recovered 29.
Scheme 4. Synthesis of the DE Ring Fragment 7a
a Reagents and conditions: (a) 7, 9-BBN, THF, rt; aq Cs2CO3, 6,
Pd(PPh3)4, DMF, 50 °C; (b) BH3‚SMe2, THF, rt; then aq NaHCO3, 30%
H2O2, rt, 84% (two steps); (c) TPAP, NMO, 4 Å molecular sieves, CH2Cl2,
0 °C, 98%; (d) LiHMDS, TMSCl, Et3N, THF, -78 °C; (e) OsO4, NMO,
THF/H2O (4:1), rt, 87% (two steps).
a Reagents and conditions: (a) TBSOTf, Et3N, CH2Cl2, rt, quant.; (b)
9-BBN, THF, rt; then aq NaHCO3, 30% H2O2, rt; (c) H2, 20% Pd(OH)2/C,
MeOH, rt; (d) p-MeOC6H4CH(OMe)2, PPTS, CH2Cl2, rt, 70% (three steps);
(e) KOt-Bu, BnBr, n-Bu4NI, THF, rt; (f) DIBALH, CH2Cl2, -78 f 0 °C,
87% (two steps); (g) I2, PPh3, imidazole, benzene, rt; (h) KOt-Bu, THF, 0
°C, 92% (two steps).
yield for the two steps as a single stereoisomer. DIBALH
reduction of the γ-lactone and Wittig reaction of the resulting
hemiacetal, followed by oxidation of the derived secondary
alcohol with tetra-n-propylammonium perruthenate (TPAP)/
NMO,27 led to ketone 29 in 91% yield for the three steps. At
this stage, the stereochemistry at the C27 position28 was
confirmed by NOE experiment as shown.
We next investigated stereoselective methylation of ketone
29 using several nucleophiles under various conditions, and the
results are summarized in Table 1. Treatment of 29 with excess
ylmorpholine N-oxide (NMO); then NaIO4) to give the corre-
sponding aldehyde, which was treated with 1,3-propanedithiol
in the presence of boron trifluoride etherate to provide alcohol
26 after deprotection of the silyl group (88% yield for the four
steps). Hetero-Michael reaction of 26 with methyl propiolate
and 4-methylmorpholine (NMM) followed by hydrolysis of the
dithioacetal (MeI, NaHCO3, aq MeCN) afforded â-alkoxyacry-
late 27 in 99% yield for the two steps. Exposure of 27 to SmI2
in the presence of methanol (THF, room temperature) effected
reductive cyclization to form the seven-membered ether,26 and
after acidic treatment, tricyclic lactone 28 was obtained in 84%
(26) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 1999,
40, 2811-2814. (b) Hori, N.; Matsukura, H.; Nakata, T. Org. Lett. 1999,
1, 1099-1101. (c) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron Lett. 1999,
40, 8859-8862. (d) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T.
Tetrahedron 2002, 58, 1853-1864.
(27) Ley, S. V.; Normann, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639-666.
(28) The carbon numbering of all compounds in this paper corresponds to that
of brevenal.
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Total Synthesis of (−)-Brevenal
A R T I C L E S
Scheme 6. Synthesis of the Pentacyclic Polyether Corea
provided 30a,b in 99% combined yield (ca. 2.3:1 dr, entry 3).
The use of toluene as the solvent led to less favorable ratio (ca.
1:1.3 dr) of products (entry 4). Finally, it was found that addition
of methyllithium (1.2 equiv) to 29 in THF at -78 °C followed
by gradual warming to room temperature furnished a 10:1
mixture of 30a and 30b in 97% yield (entry 5). The undesired
minor isomer 30b could be easily separated by flash chroma-
tography. Stereochemistry at the C26 tertiary stereocenter of
30a was unequivocally established by NOE between 26-Me
and 27-H. The corresponding NOE was not observed for the
isomer 30b.
Conversion of tertiary alcohol 30a to the DE ring fragment
7 was carried out as illustrated in Scheme 4. Thus, 30a was
protected with TBSOTf and triethylamine to give the TBS ether
31. Hydroboration of the terminal olefin and removal of the
benzyl groups under hydrogenolysis, followed by p-methoxy-
benzylidene acetal formation, led to primary alcohol 32 in 80%
yield for the three steps. Benzylation followed by reductive
cleavage of the acetal with DIBALH provided alcohol 33 (85%
yield, two steps). Finally, iodination and subsequent base
treatment furnished the DE ring exo-olefin fragment 7 in 99%
yield for the two steps.
Construction of the Pentacyclic Polyether Core. With the
requisite fragments in hand, we set out to assemble the
pentacyclic polyether core as summarized in Schemes 5 and 6.
Hydroboration of the DE ring exocyclic enol ether 7 with 9-BBN
produced the corresponding alkylborane, which was in situ
reacted with the AB ring enol phosphate 6 in the presence of
aqueous Cs2CO3 and Pd(PPh3)4 in DMF at 50 °C to furnish the
desired coupling product 34 as a single stereoisomer (Scheme
5). The endocyclic enol ether within 34 was then hydroborated
with BH3‚SMe2 to give alcohol 35 (84% overall yield from 7),
which was oxidized with TPAP/NMO to afford ketone 36 in
98% yield. At this stage, the newly generated stereocenters at
C16 and C18 were unambiguously confirmed by NOE experi-
ments as shown. Subsequent stereoselective introduction of the
C14 hydroxy group was successfully achieved by the previously
described method.16c,d,29 Thus, treatment of ketone 36 with
LiHMDS in the presence of TMSCl and triethylamine gave the
corresponding silyl enol ether, which was then treated with
OsO4/NMO to provide R-hydroxy ketone 37 as the sole product
(87% for the two steps).
a Reagents and conditions: (a) DIBALH, THF, -78 °C, 76% (+
diastereomer, 7%; recovered 37, 12%); (b) TESOTf, Et3N, CH2Cl2, 0 °C;
(c) DDQ, CH2Cl2/pH 7 phosphate buffer, rt; (d) TPAP, NMO, 4 Å molecular
sieves, CH2Cl2, rt, 88% (three steps); (e) EtSH, Zn(OTf)2, THF, rt, 79%;
(f) TBSOTf, Et3N, CH2Cl2, 0 °C, 97%; (g) mCPBA, CH2Cl2, -78 °C; then
Me3Al (excess), -78 f 0 °C, 92%.
Figure 2. Stereochemical confirmation of cis-diol 38.
Subsequent reduction of hydroxy ketone 37 with DIBALH
in THF at -78 °C provided an approximately 10:1 mixture of
cis-diol 38 and its trans-isomer in 83% combined yield, along
with a 12% yield of recovered 37 (Scheme 6). The desired
isomer 38 could be easily separated by flash chromatography.
The newly generated stereocenters at the C14 and C15 positions
were established by derivatization to the cyclopentylidene acetal
39 and NOE experiments (Figure 2). It is noteworthy that
DIBALH reduction of the TES-protected derivative of 37 led
exclusively to the corresponding R-alcohol, suggesting the
importance of the free hydroxy group. The outcome of this
stereoselective reduction of 37 can be explained as follows.
Initially, the C14 hydroxy group reacts with DIBALH to form
the corresponding aluminum alkoxide, which coordinates to the
adjacent C15 carbonyl group to form a five-membered chelate
structure, thereby blocking the â-side of the molecule and
Figure 3. Stereochemical confirmation of pentacyclic polyether 43.
trimethylaluminum in CH2Cl2 produced an approximately 1.3:1
mixture of tertiary alcohols 30a and 30b along with recovered
starting material 29 (entry 1). Exposure of 29 to excess
methylmagnesium bromide in THF at -78 °C gave a mixture
of 30a and 30b with slightly improved diastereoselectivity (ca.
2.5:1 dr), but a significant amount of ketone 29 was recovered
(entry 2). Increasing the reaction temperature dramatically
improved the conversion yield without affecting the diastereo-
selectivity. Thus, treatment of 29 with 1.5 equiv of methyl-
magnesium bromide in THF at -78 °C to room temperature
(29) Sasaki, M.; Ebine, M.; Takagi, H.; Takakura, H.; Shida, T.; Satake, M.;
Oshima, Y.; Igarashi, T.; Yasumoto, T. Org. Lett. 2004, 6, 1501-1504.
9
J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006 16993

A R T I C L E S
Fuwa et al.
Table 2. Stille Coupling of Vinyl Stannane 5 and Vinyl Iodide 44
entry
vinyl stannane
reagents and conditions
% yield
(E,E):(E,Z)
1
5a
5b
5b
5b
5b
5b
5a
5a
PdCl2(MeCN)2, DMF, rt f 45 °C
trace
57
54
48
66
84
40
69
nda
ca. 3.5:1
ca. 5:1
1:1
1:1
ca. 10:1
1:0
2b
3b
4b
5b
6b
7c
8c
Pd2(dba)3, (2-furyl)3P, CuI, DMSO/THF, rt
Pd2(dba)3, Ph3As, CuI, DMSO/THF, rt
Pd2(dba)3, (2-furyl)3P, CuI, DMSO/THF, 60 °C
Pd2(dba)3, Ph3As, CuI, DMSO/THF, 60 °C
Pd2(dba)3, Ph3As, CuTC, DMSO/THF, rt
Pd2(dba)3, Ph3As, CuI, DMSO/THF, rt
Pd2(dba)3, Ph3As, CuTC, DMSO/THF, rt
1:0
a nd ) not determined. b Isolated as a mixture of (E,E)- and (E,Z)-isomers. Ratio was estimated by 1H NMR (600 MHz). c Isolated as an inseparable
1
mixture of 45a and homocoupling product 47. Yield was estimated based on H NMR analysis (600 MHz) of a purified mixture of 45a and 47.
forcing the second equivalent of the reductant to approach from
the less hindered R-side.
suggested the difficulty of constructing such a heavily substituted
diene system by means of palladium(0)-catalyzed cross-coupling
reactions,13 we planned to utilize Stille coupling for connecting
the C3-C4 bond. We first set out on model experiments in
order to explore optimal conditions. (E)-Vinyl stannane 5 and
(E)-vinyl iodide 44 (E:Z ) ca. 4:1) were chosen as model
substrates (Table 2). Stille coupling of 5a and 44 under the
conventional conditions led to only a trace amount of the desired
diene 45a, and significant amounts of the starting materials were
recovered (entry 1). We assumed that this disappointing result
was attributable to the low reactivity of 5a and 44 arising from
steric hindrance. We reasoned that use of a soft ligand such as
(2-furyl)3P or Ph3As, which accelerates the transmetallation step
of the catalytic cycle of Stille coupling,31 and copper(I) salt as
a co-catalyst, which promotes transmetallation of vinyl stannane
5 to a more reactive copper species,32 would be favorable in
the present case. In the event, under the influence of the Pd2-
(dba)3/(2-furyl)3P/CuI or Pd2(dba)3/Ph3As/CuI catalyst system,
Stille coupling of a sterically less encumbered vinyl stannane
5b and 44 proved to be very effective, giving diene 45b in
acceptable yields (entries 2 and 3). However, increasing the
reaction temperature to 60 °C caused significant isomerization
of the diene configuration (entries 4 and 5). The structure of
the isomerized byproduct, (E,Z)-diene 46, was confirmed by
NOE experiments. Gratifyingly, it was found that the use of
copper(I) thiophene-2-carboxylate (CuTC)33 instead of CuI
realized further improvement of the yield of 45b (84% yield,
entry 6). When the TBDPS-protected 5a was again used as a
coupling partner, homocoupling product 47 was formed as a
byproduct and hence the yield of the desired 45a was sligtly
lowered (entries 7 and 8).
After protection of 38 as the bis-TES ether, oxidative removal
of the PMB group with DDQ, followed by oxidation of the
resulting secondary alcohol with TPAP/NMO, led to ketone 40
in 88% yield for the three steps. To complete the C ring with
an angular methyl group at C19, ketone 40 was treated with
ethanethiol in the presence of zinc triflate in THF at room
temperature to effect deprotection of the TES groups with
concomitant formation of a mixed thioacetal to generate 41 in
79% yield.30 After protection of the secondary hydroxy group
as the TBS ether (97%), introduction of the C19 axial methyl
group was next investigated. Although we initially attempted
oxidation of the sulfur within 42 with mCPBA to the corre-
sponding sulfone under various conditions, it became evident
that the mixed sulfonyl acetal derived from 42 was so prone to
undergo hydrolysis that we could only obtain the corresponding
hemiacetal derivative. Therefore, we decided to avoid isolation
of the unstable intermediate and carry out the oxidation-
methylation in a one-pot manner.30a Thus, after oxidation of 42
with mCPBA at -78 °C, excess amount of trimethylaluminum
(3 × 4 equiv + 2 equiv) was added and the resulting mixture
was allowed to warm to 0 °C. Gratifyingly, this one-pot
procedure ensured the desired pentacyclic polyether core 43 in
92% yield as a single isomer. The addition of trimethylaluminum
in several portions was crucial for the success of the present
process. The newly generated stereocenters were unambiguously
established on the basis of NOE studies and 3JH,H data (Figure 3).
Model Experiments for the Synthesis of the Multi-
Substituted (E,E)-Diene Side Chain. Having constructed the
pentacyclic polyether skeleton, we next turned our attention to
construction of the left-hand side chain. The multi-substituted
(E,E)-dienal side chain is one of the characteristic structural
features of brevenal. Although a survey of the literature
Total Synthesis of the Proposed Structure of Brevenal.
Having secured the reliable reaction conditions for constructing
(31) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595.
(32) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org.
Chem. 1994, 59, 5905-5911.
(33) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-
2749.
(30) (a) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.; Veale,
C. A. J. Am. Chem. Soc. 1989, 111, 5321-5330. (b) Fuwa, H.; Sasaki,
M.; Tachibana, K. Tetrahedron Lett. 2000, 41, 8371-8375. (c) Fuwa, H.;
Sasaki, M.; Tachibana, K. Tetrahedron 2001, 57, 3019-3033.
9
16994 J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006

Total Synthesis of (−)-Brevenal
A R T I C L E S
Scheme 7. Total Synthesis of the Proposed Structure 1 for Brevenala
a Reagents and conditions: (a) LiDBB, THF, -78 °C, 99%; (b) TBSOTf, Et3N, CH2Cl2, 0 °C, 98%; (c) TBAF, AcOH, THF, rt, 78% after three recycles;
(d) Dess-Martin periodinane, CH2Cl2, rt; (e) Bestmann reagent, K2CO3, MeOH, rt; (f) n-BuLi, THF/HMPA (10:1), -78 °C; then MeI, rt, 99% (three steps);
(g) HF‚pyridine, THF, rt, 96%; (h) TESOTf, Et3N, CH2Cl2, 0 °C, 99%; (i) (Me2PhSi)2Cu(CN)Li2, THF, -78 f 0 °C, regioselectivity ) ca. 9:1; (j) NIS,
MeCN/THF (3:1), rt, 99% (two steps), E:Z ) 6:1; (k) 5b, Pd2(dba)3, Ph3As, CuTC, DMSO/THF (1:1), rt, 63%; (l) TBDPSCl, imidazole, DMF, 0 °C, 99%;
(m) PPTS, CH2Cl2/MeOH (4:1), 0 °C, 75%; (n) SO3‚pyridine, Et3N, CH2Cl2/DMSO (3:1), 0 °C; (o) 4, n-BuLi, HMPA, THF, -78 °C f rt, 97% (two steps);
(p) 30% H2O2, NaHCO3, THF, rt, 77%; (q) TAS-F, THF/DMF (1:1), rt, 79%; (r) MnO2, CH2Cl2, rt, quant.
the left-hand side chain, the final stage of the total synthesis of
1 was executed as shown in Scheme 7. Reductive removal of
the benzyl group from 43 with LiDBB34 was followed by
reprotection as the TBS group to give silyl ether 48. Selective
removal of the primary TBDPS group from 48 in the presence
of the three TBS groups was successfully carried out according
to the procedure of Nakata and co-workers,35 leading to primary
alcohol 49 in 73% yield after three recycles.36 Oxidation of 49
with Dess-Martin periodinane37 followed by treatment of the
resulting aldehyde with the Ohira-Bestmann reagent (K2CO3,
MeOH)38 produced an alkyne, which was then methylated with
(34) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924-
1930. (b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854-
860.
Figure 4. Partial 1H NMR spectra (600 MHz, C6D6) of the natural brevenal
(panel A) and synthetic 1 (panel B).
(35) Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shirahama, H.;
Nakata, M. Synlett 2000, 1306-1308.
(36) The reaction mixture was stirred at room temperature overnight (ca. 13 h).
Since, at this point, ca. 50% of the starting material 48 remained unreacted
and a small amount of diol S8 was observed by TLC analysis, the reaction
was quenched. After separation of 48, 49, S8, and S7 by flash chroma-
tography, recycling of the recovered 48 (three times) provided 49 (78%),
S8 (8%) and S7 (12%).
Figure 5. Selected key NOE data for synthetic 1.
n-butyllithium/methyl iodide to provide alkyne 50 in excellent
overall yield. At this stage, the robust TBS protecting groups
(38) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) Mu¨ller, S.; Liepold,
(37) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-522.
9
J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006 16995

A R T I C L E S
Fuwa et al.
Table 3. 1H NMR Chemical Shifts of Natural Product and Synthetic 1a
natural
brevenalb
natural
brevenalb
no.
synthetic 1
∆δ
no.
synthetic 1
∆δ
1
2
3
4
5
6
10.09
6.14
-
10.09
6.15
-
0.00
-0.01
-
21
1.77
2.16
3.35
3.17
1.77
1.90
1.52
1.54
-
3.16
1.44
1.57
2.35
2.35
5.45
6.07
6.77
5.05
5.16
1.80
1.55
0.97
1.18
1.13
0.98
1.74
2.13
3.23
3.22
1.50
1.92
1.52
1.69
-
2.92
1.39
1.71
2.31
2.31
5.39
6.10
6.78
5.08
5.18
1.78
1.55
0.96
1.19
1.14
0.87
0.03
0.03
0.12
-0.05
0.27
22
23
24
-
-
-
5.81
2.01
2.13
1.09
1.47
3.28
1.46
1.75
1.75
4.00
-
5.81
2.01
2.14
1.08
1.49
3.28
1.44
1.75
1.75
4.04
-
0.00
0.00
-0.01
0.01
-0.02
0.00
0.02
0.00
0.00
-0.02
0.00
25
7
-0.15
26
27
28
-
8
9
10
0.24
0.05
-0.14
0.04
0.04
0.06
-0.03
-0.01
-0.03
-0.02
0.02
0.00
0.01
-0.01
-0.01
0.11
29
11
12
13
-0.04
-
30
31
32
33
2.23
2.32
4.08
3.45
3.71
1.85
2.24
2.94
-
2.23
2.35
4.10
3.47
3.75
1.86
2.27
2.92
-
0.00
-0.03
-0.02
-0.02
-0.04
-0.01
-0.03
0.02
-
-0.01
0.08
14
15
16
17
3-Me
4-Me
9-Me
12-Me
19-Me
26-Me
18
19
20
1.68
1.77
1.69
1.69
a C6HD5 was adjusted to 7.15 ppm. b Chemical shift values were adjusted because in the original report (ref 8b) internal residual benzene was referenced
to 7.16 ppm.
Table 4. 13C NMR Chemical Shifts of Natural Product and Synthetic 1a
natural
natural
no.
brevenalb
synthetic 1
∆δ
0.3
no.
brevenalb
synthetic 1
∆δ
0.2
0.7
0.9
0.0
1.4
-0.4
-1.1
0.7
0.5
0.1
-0.1
0.1
-0.3
0.2
0.0
0.1
0.2
0.4
-2.2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
191.0
126.0
156.7
135.8
134.6
26.4
32.7
70.9
33.4
35.3
76.5
77.2
48.0
69.9
75.0
73.7
34.5
82.0
76.7
37.8
190.7
126.0
156.1
135.8
134.6
26.4
32.6
70.7
33.4
35.2
76.4
77.2
47.8
69.9
75.0
73.6
34.4
82.1
76.7
37.5
21
22
23
24
25
26
27
28
29
30
31
32
29.8
86.3
84.8
29.4
38.8
73.9
87.4
30.6
25.3
133.0
130.1
132.7
117.0
14.0
13.7
12.9
19.5
16.2
23.5
29.6
85.6
83.9
29.4
37.4
74.3
88.5
29.9
24.8
132.9
130.2
132.6
117.3
13.8
13.7
12.8
19.3
15.8
25.7
0.0
0.6
0.0
0.0
0.0
0.1
0.2
0.0
0.1
0.1
0.0
0.2
0.0
0.0
0.1
0.1
-0.1
0.0
0.3
33
3-Me
4-Me
9-Me
12-Me
19-Me
26-Me
a 13C6D6 was adjusted to 128.0 ppm. b Chemical shift values were adjusted because in the original report (ref 8b) internal residual benzene was referenced
to 128.4 ppm.
were replaced with the easily removable TES ethers. Thus,
alkyne 50 was treated with HF‚pyridine, and the resulting triol
was reprotected with TESOTf and triethylamine to give tris-
TES ether 51. Regioselective silylcupration of 51 with (Me2-
exposure to N-iodosuccinimide (NIS) in MeCN/THF (4:1) at
room temperature.40 Under these reaction conditions, isomer-
ization of the olefin stereochemistry partially occurred and ca.
6:1 mixture of (E)-vinyl iodide 3 and its (Z)-isomer, along with
small amounts of regioisomers, were produced in 99% combined
yield from 51. The (E)-geometry of 3 was tentatively assigned
because it is well-known that the iododesilylation generally
proceeds with retention of configuration,40 and this was later
confirmed by characterization of the cross-coupled product 53
(vide infra). Without separation of these isomers, the crucial
39
PhSi)2Cu(CN)Li2 delivered the desired vinylsilane 52 in an
approximately 9:1 regioselectivity. The regiochemistry of 52
was confirmed by the characteristic pattern of the olefinic proton
(dd, J ) 7.0, 7.0 Hz). Conversion of 52 to vinyl iodide 3,
required for the projected Stille coupling, was performed on
(39) (a) Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc. Perkin Trans 1
1981, 2527-2532. (b) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem.
Soc. 2003, 125, 7822-7824.
(40) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8647-
8650.
9
16996 J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006

Total Synthesis of (−)-Brevenal
A R T I C L E S
Figure 6. Proposed biosynthetic pathway for marine polycyclic ether natural products.
Scheme 8. Synthesis of the 26-epi-DE Ring Fragment 57a
a Reagents and conditions: (a) Cu(OAc)2, PdCl2, O2, DMA/H2O (7:1), rt, 92%; (b) TBAF, THF, rt; (c) methyl propiolate, NMM, CH2Cl2, rt, 96% (two
steps); (d) SmI2, MeOH, THF, rt, 57% for 60, 37% for 61; (e) LiAlH4, THF, 0 °C, quant. from 60, quant. from 61; (f) TBSOTf, Et3N, CH2Cl2, rt; (g) CSA,
MeOH/CH2Cl2 (1:1), 0 °C, 90% (two steps); (h) SO3‚pyridine, Et3N, DMSO/CH2Cl2 (1:1), 0 °C; (i) Ph3P+CH3Br-, NaHMDS, THF, 0 °C, 94% (two steps);
(j) 9-BBN, THF, rt; then aq NaHCO3, 30% H2O2, rt; (k) H2, 20% Pd(OH)2/C, MeOH, rt; (l) p-MeOC6H4CH(OMe)2, PPTS, CH2Cl2, rt, 80% (three steps);
(m) BnBr, KOt-Bu, n-Bu4NI, THF, rt; (n) DIBALH, CH2Cl2, -78 f 0 °C, 85% (two steps); (o) I2, PPh3, imidazole, benzene, rt; (p) KOt-Bu, THF, 0 °C,
98% (two steps).
Stille coupling was carried out under the established conditions.
Thus, cross-coupling of 3 with vinyl stannane 5b in the presence
of the Pd2(dba)3/Ph3As/CuTC catalyst system in THF/DMSO
(1:1) at room temperature proceeded smoothly to furnish (E,E)-
diene 53 in 63% yield as a single stereoisomer, after purification
by flash chromatography.41 The stereochemistry of the diene
system was unequivocally established by NOE experiments as
shown.
of the C1 alcohol by MnO2 completed the synthesis of the
proposed structure 1 for brevenal in a quantitative yield.
Revised Structure of Brevenal. Unfortunately, however, the
1H and 13C NMR spectra of synthetic 1 were not identical with
those of the authentic sample, suggesting that revision of the
originally proposed structure of brevenal is necessary (Figure
1
4). For detailed comparison with the natural product, the H
and 13C NMR data of synthetic 1 were carefully assigned on
After protection of the allylic alcohol of 53 as the TBDPS
ether, the primary TES ether was selectively removed with PPTS
to give alcohol 54 in 74% yield for the two steps. Introduction
of the right-hand (Z)-diene side chain was performed without
incident according to the procedure of Nicolaou et al.12 Thus,
oxidation of 54 with SO3‚pyridine/DMSO followed by Wittig
olefination using the ylide, derived from phosphonium salt 4,
and subsequent hydrogen peroxide treatment led to conjugated
(Z)-diene 55 in 75% overall yield from 54. Global deprotection
of the silyl protecting groups from 55 by the action of TAS-F42
provided triol 56 in 79% yield. Finally, chemoselective oxidation
the basis of extensive 2D NMR experiments, and the results
are summarized in Tables 3 and 4 and Figure 5. The H and
1
13C NMR chemical shifts in the left-hand region of synthetic 1
matched very closely those reported for the natural brevenal.
In contrast, there were subtly distinct discrepancies of the
chemical shifts in the DE ring region. Particularly, the observed
chemical shifts around the C26 tertiary alcohol of 1 significantly
deviated from those for the natural product, suggesting that an
error(s) may exist somewhere around the E ring. COSY, HSQC,
and HMBC correlations of the synthetic sample completely
(42) (a) Noyori, R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem. Soc.
1980, 102, 1223-1225. (b) Sheidt, K. A.; Chen, H.; Follows, B. C.;
Chemler, S. R.; Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436-
6437.
(41) We initially attempted the Stille coupling of TBDPS-protected vinyl
stannane 5a with vinyl iodide 3; however, the desired cross-coupled product
was obtained in only poor yield (22%).
9
J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006 16997

A R T I C L E S
Fuwa et al.
Scheme 9. Total Synthesis of the Revised Structure 2 for Brevenala
a Reagents and conditions: (a) 57, 9-BBN, THF, rt; then 3 M aq Cs2CO3, 6, Pd(PPh3)4, DMF, 50 °C; (b) BH3‚SMe2, THF, rt; then aq NaHCO3, 30%
H2O2, rt, 81% (two steps); (c) TPAP, NMO, 4 Å molecular sieves, CH2Cl2, 0 °C, 98%; (d) LiHMDS, TMSCl, Et3N, THF, -78 °C; (e) OsO4, NMO,
THF/H2O (4:1), rt, 83% (two steps); (f) DIBALH, THF, -78 °C, 85% (+ diastereomer, 8%; recovered 69, 3%); (g) TESOTf, Et3N, CH2Cl2, 0 °C; (h) DDQ,
CH2Cl2/pH 7 phosphate buffer (10:1), rt; (i) TPAP, NMO, 4 Å molecular sieves, CH2Cl2, rt, 88% (three steps); (j) EtSH, Zn(OTf)2, CH2Cl2, rt, 51%; (k)
TBSOTf, Et3N, CH2Cl2, 0 °C f rt, 86%; (l) mCPBA, CH2Cl2, -78 °C; then Me3Al (excess), -78 f 0 °C, 94%; (m) LiDBB, THF, -78 °C, 95%; (n)
TBSOTf, Et3N, CH2Cl2, 0 °C, 99%; (o) TBAF, AcOH, THF, rt, 79% after two recycles; (p) SO3‚pyridine, Et3N, CH2Cl2/DMSO (3:1), 0 °C; (q) Bestmann
reagent, K2CO3, MeOH, rt; (r) n-BuLi, THF/HMPA (10:1), -78 °C; then MeI, rt, 78% (three steps); (s) HF‚pyridine, THF, rt, 97%; (t) TESOTf, Et3N,
CH2Cl2, 0 °C, 89%; (u) (Me2PhSi)2Cu(CN)Li2, THF, -78 f 0 °C, regioselectivity ) ca. 8.5:1; (v) NIS, MeCN/THF (3:1), rt, 88% (two steps), E:Z ) ca.
6:1; (w) 5b, Pd2(dba)3, Ph3As, CuTC, DMSO/THF (1:1), rt, 60%; (x) TBDPSCl, imidazole, DMF, 0 °C, 87%; (y) PPTS, CH2Cl2/MeOH (4:1), 0 °C, 70%;
(z) SO3‚pyridine, Et3N, CH2Cl2/DMSO (4:1), 0 °C; (aa) 4, n-BuLi, HMPA, THF, -78 °C f rt, 99% (two steps); (bb) 30% H2O2, NaHCO3, THF, rt, 78%;
(cc) TAS-F, THF/DMF (1:1), rt, quant.; (dd) MnO2, CH2Cl2, rt, 76%.
reproduced those of the authentic sample. However, a series of
intense cross-peaks were observed between 26-Me/27-H and
26-Me/28-H2 in the NOESY spectrum of synthetic 1 (Figure
5), whereas no such NOESY correlations have been reported
for naturally occurring brevenal.8b These NMR variations
prompted us to propose the stereochemical inversion of the C26
tertiary alcohol within 1, giving the revised structure 2 for
brevenal.
The revised structure 2 is also supported by the postulated
biosynthetic pathway for ladder-shaped polycyclic ether marine
natural products (i.e., a cascade of polyepoxide cyclization)
proposed by Shimizu and Nakanishi, independently (Figure
6).7,43,44 The stereochemistry at C26 of brevenal would be
epimeric to the proposed structure 1, provided that a similar
biosynthetic route is applicable to brevenal (Figure 6).
(43) (a) Nakanishi, K. Toxicon 1985, 23, 473-479. (b) Shimizu, Y. In Natural
Toxins: Animal, Plant and Microbial; Harris, J. B., Ed.; Clarendon Press:
Oxford, 1986; pp 115-125. (c) Lee, M. S.; Repeta, D. J.; Nakanishi, K. J.
Am. Chem. Soc. 1986, 108, 7855-7856. (d) Chou, H.-N.; Shimizu, Y. J.
Am. Chem. Soc. 1987, 109, 2184-2185. Lee, M. S.; Qin, G.; Nakanishi,
K.; Zagorski, M. G. J. Am. Chem. Soc. 1989, 111, 6234-6241. (e)
Townsend, C. A.; Basak, A. Tetrahedron 1991, 47, 2591-2602. (f)
Gallimore, A. R.; Spencer, J. B. Angew. Chem., Int. Ed. 2006, 45, 4406-
4413.
(44) For recent reviews on biomimetic synthesis of polycyclic ethers, see: (a)
Fujiwara, K.; Murai, A. Bull. Chem. Soc. Jpn. 2004, 77, 2129-2146. (b)
Valentine, J. C.; McDonald, F. E. Synlett 2006, 1816-1828.
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16998 J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006

Total Synthesis of (−)-Brevenal
A R T I C L E S
Conclusion
Total Synthesis of Revised Structure and the Absolute
Configuration of Brevenal. To confirm our postulated idea,
we turned to the synthesis of the C26 epimer 2 of the originally
proposed structure 1. Starting with an intermediate 25 in the
synthesis of 7 (see Scheme 3), the requisite DE ring fragment
57 (26-epi-7) was prepared as summarized in Scheme 8.
Wacker-Tsuji reaction45 of the terminal olefin within 25 using
the PdCl2/Cu(OAc)2 system46 provided methyl ketone 58 in 92%
yield. Removal of the TBS group from 58 followed by
incorporation of a â-alkoxyacrylate unit to the resulting second-
ary alcohol produced 59 in high overall yield. Reductive
cyclization of 59 with SmI2 (MeOH/THF, room temperature)
proceeded smoothly to form the seven-membered ether ring with
the desired stereochemistry at C26, providing a mixture of
γ-lactone 60 and hydroxy ester 61 in 57% and 37% yield,
respectively.26 The C26 and C27 stereochemistries of 60 were
confirmed by NOE experiments as shown. Each of these
compounds was cleanly reduced with lithium aluminum hydride
(THF, 0 °C) to yield the same diol 62 in high yield. After
protection as the bis-TBS ether, selective cleavage of the primary
TBS ether under acidic conditions provided alcohol 63 in 90%
yield for the two steps. Oxidation with SO3‚pyridine/DMSO
followed by Wittig methylenation of the resulting aldehyde led
to 64 (94% yield, two steps), which was subsequently trans-
formed to the DE ring fragment 57 following a similar sequence
described for the conversion of 31 to 7 (see, Scheme 4).
We accomplished the first total synthesis of the proposed
structure 1 of brevenal. The key features of our synthesis include
a convergent assembly of the pentacyclic polyether skeleton by
using the Suzuki-Miyaura coupling-based strategy and a
stereoselective construction of the left-hand multi-substituted
(E,E)-diene system by the CuTC-promoted modified Stille
coupling. The H and 13C NMR spectra of synthetic 1 did not
1
match those for the natural product. Detailed NMR comparison
of the synthetic material with the natural substance and the
proposed biosynthesis of ladder-shaped polycyclic ether natural
products led us to propose a revised structure 2, the C26-epimer
of 1. In the event, the revised structure was validated through
total synthesis, which also led to determination of the absolute
configuration. This study demonstrates the important role of
stereoselective total synthesis in structure determination of
complex natural products.47 Moreover, the highly convergent
nature of the present synthesis will allow divergent total
synthesis of structural analogues for more detailed structure-
activity relationship studies of this intriguing natural product.
Further studies along this line are currently underway and will
be reported in due course.
Acknowledgment. We thank Mr. Ryuichi Watanabe (Tohoku
University) for NMR measurements, and Dr. Thomas Schuster
and Dr. Sophie Michelliza (UNCW) for their technical expertise.
This work was financially supported in part by the Naito
Foundation and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan (MEXT) and the Japan Society for the Promotion of
Science (JSPS). A postdoctoral fellowship for H.F. and a
research fellowship for M.E. from JSPS are acknowledged.
Convergent union of the DE ring fragment 57 and the AB
ring enol phosphate 6 and subsequent elaboration of the resulting
cross-coupled product 67 could be performed in much the same
way as that used to reach 1 and proceeded in similar yields,
thus completing the total synthesis of the revised structure 2
for brevenal (Scheme 9). To our delight, the 1H and 13C NMR
spectra and high-resolution mass spectrum of synthetic 2 were
completely identical with those of the natural product, culminat-
ing in a conclusion that the C26 epimer of the originally
proposed structure is the correct structure of brevenal. In
Supporting Information Available: Full experimental details
and spectroscopic data for all new compounds, comparison of
1H and 13C NMR spectra for natural brevenal and synthetic 2,
and copies of 1H and 13C NMR spectra for all new compounds
(pdf). This material is available free of charge via the Internet
at http://pubs.acs.org.
27
addition, synthetic brevenal 2 exhibited specific rotation, [R]D
-33.5 (c 0.27, benzene), which matched the value [R]D27 -32.3
(c 0.27, benzene) for the natural product; thus, the absolute
configuration of brevenal was unequivocally determined to be
shown as structure 2.
JA066772Y
(45) For a review, see: Tsuji, J. Synthesis 1984, 369-384.
(46) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett. 1998, 39,
8765-8768.
(47) For recent reviews, see: (a) Weinreb, S. M. Acc. Chem. Res. 2003, 36,
59-65. (b) Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005,
44, 1012-1044.
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