Total synthesis of brevetoxin B

Article abstract of DOI:10.1021/ja051171c

The convergent total synthesis of brevetoxin B (1) has been achieved. The intramolecular allylation of the O,S-acetal 20, prepared from the α-chlorosulfide 17 and the alcohol 5, was carried out using AgOTf as a Lewis acid to give the diene 21, predominant

Full text of DOI:10.1021/ja051171c

Published on Web 06/01/2005
Total Synthesis of Brevetoxin B
Isao Kadota,*,† Hiroyoshi Takamura,‡ Hiroki Nishii,‡ and Yoshinori Yamamoto‡
Contribution from the Research and Analytical Center for Giant Molecules and Department of
Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received February 23, 2005; E-mail: ikadota@mail.tains.tohoku.ac.jp; yoshi@yamamoto1.chem.tohoku.ac.jp
Abstract: The convergent total synthesis of brevetoxin B (1) has been achieved. The intramolecular allylation
of the O,S-acetal 20, prepared from the R-chlorosulfide 17 and the alcohol 5, was carried out using AgOTf
as a Lewis acid to give the diene 21, predominantly. Ring-closing metathesis of 21 with the Grubbs catalyst
23 afforded the hexacyclic ether 25 which was converted to the A-G ring segment 2 through several
steps. The intramolecular allylation of the R-acetoxy ether 42, prepared from 2 and the J-K ring segment
3, followed by ring-closing metathesis provided the polycyclic ether framework 44. A series of reactions of
44, including oxidation of the A ring, deprotection of the silyl ethers, and selective oxidation of the resulting
allylic alcohol, furnished 1.
Introduction
Brevetoxin B (1), a potent neurotoxin, was isolated from the
red tide organism Gymnodinium breVe Davis in 1981 as the
first example of marine polycyclic ethers (Figure 1).1 The unique
structural features and biological activity of this molecule have
attracted significant attention from synthetic chemists. To date,
two total syntheses of 1 have been accomplished using a
hydroxy dithioacetal cyclization for the key segment connec-
tion.2 In this paper, we wish to report a convergent total synthesis
of 1 based on our own methodology.
Figure 1. Structure of Brevetoxin B (1).
afforded the enol ether 9 in 80% overall yield.5,6 Hydroboration
of the olefin and simultaneous reduction of the ester group gave
the corresponding diol, which was converted to the primary
alcohol 10 in 66% overall yield via protection and selective
deprotection. Stepwise oxidation of 10 afforded the B-C ring
segment 4 in 96% overall yield.
Coupling of Segments 4 and 5. The next task of the total
synthesis was the convergent construction of the A-G ring
framework. The carboxylic acid 4 and the alcohol 54 were
connected by Yamaguchi conditions to give the ester 11 in
quantitative yield (Scheme 3).7 Treatment of 11 with TBAF/
AcOH gave the alcohol 12 in 88% yield. Acid-catalyzed acetal
formation with the γ-methoxyallylstannane 13 followed by
acetal cleavage with TMSI/HMDS furnished the allylic stannane
14 in 72% overall yield.8 The ester 14 was then subjected to
the Rychnovsky acetylation. Thus, partial reduction of 14 with
DIBAL-H followed by treatment of the resulting aluminum
hemiacetal with Ac2O/DMAP/pyridine afforded the R-acetoxy
ether 15.9 However, the yield was only 15%, and significant
amounts of over-reduced products were obtained.10 Presumably,
the steric repulsion between the diisobutylaluminum moiety and
Results and Discussion
Retrosynthetic Analysis. A brief retrosynthetic analysis of
1 is illustrated in Scheme 1. We have developed a convergent
method for the synthesis of polycyclic ether frameworks via
the intramolecular allylation of R-acetoxy ethers and subsequent
ring-closing metathesis.3 On the basis of this methodology, the
polycyclic ether framework of 1 was retrosynthetically broken
down into the A-G ring segment 2 and the J-K fragment 3.
The heptacycle 2 would be prepared from 4 and 5 via the same
methodology.
Synthesis of the B-C Ring Segment 4. Scheme 2 describes
the synthesis of the B-C ring segment 4. Conversion of the
lactone 64 into the corresponding ketene acetal triflate 7 via
the standard conditions followed by treatment with the chiral
zinc homoenolate 8 in the presence of a palladium catalyst
† Research and Analytical Center for Giant Molecules.
‡ Department of Chemistry.
(1) 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.
(2) (a) Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.;
Sato, M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173-1174. (b)
Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.; Sato,
M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 10252-10263. (c)
Matsuo, G.; Kawamura, K.; Hori, N.; Matsukura, H.; Nakata, T. J. Am.
Chem. Soc. 2004, 126, 14374-14376.
(5) Kadota, I.; Takamura, H.; Sato, K.; Yamamoto, Y. J. Org. Chem. 2002,
67, 3494-3498.
(6) For the palladium-catalyzed coupling of alkylzinc reagents, see: Negishi,
E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821-1823.
(7) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989-1993.
(3) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002,
124, 3562-3566.
(4) For the preparation of compounds 5 and 6, see Supporting Information.
(8) Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron Lett. 1996, 37, 3195-
3198.
9
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J. AM. CHEM. SOC. 2005, 127, 9246-9250
10.1021/ja051171c CCC: $30.25 © 2005 American Chemical Society

Total Synthesis of Brevetoxin B
A R T I C L E S
Scheme 1. Retrosynthetic Analysis of Brevetoxin B (1)
Scheme 2. Synthesis of the B-C Ring Segment 4a
Scheme 3. Coupling of Segments 4 and 5a
a Reagents and conditions: (a) KHMDS, PhNTf2, DMPU, THF, -78
°C, 94%; (b) 8, PdCl2(o-Tol3P)2, benzene, 40 °C, 85%; (c) (i) BH3‚SMe2,
THF, 0 °C to room temperature, then NaOH, H2O2, 0 °C to room
temperature; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 76%; (d) AcOH, H2O-
THF (1:1), 0 °C to room temperature, 87%; (e) (i) SO3‚py, DMSO, Et3N,
CH2Cl2, 0 °C, 100%; (ii) NaClO2, NaH2PO4, 2-methyl-2-butene, THF-t-
BuOH-H2O, 0 °C, 96%.
the methyl group on the side chain would destabilize the
hemiacetal intermediate. Since several attempts for improving
the yield of 15 resulted in failure, we next examined an
alternative approach.
a Reagents and conditions: (a) DCC, DMAP, CSA, CH2Cl2, reflux,
100%; (b) TBAF, AcOH, THF, 50 °C, 88%; (c) 13, CSA, CH2Cl2, rt, 93%;
(d) TMSI, HMDS, CH2Cl2, -20 °C, 77%; (e) DIBAL-H, -90 °C, CH2Cl2,
then Ac2O, pyridine, DMAP, -90 °C to room temperature, 15%.
Intramolecular Allylation of O,S-Acetal. Recently, Hirama,
Inoue, and co-workers reported the radical cyclization of O,S-
acetals for the synthesis of polycyclic ethers.11 It was thought
that the use of the O,S-acetal as an electrophile for the
intramolecular allylation would provide an efficient method for
the convergent assembly of cyclic ethers. Scheme 4 describes
a new approach for the coupling of the B-C and F-G ring
segments. Treatment of 10 with (PhS)2/Bu3P gave the sulfide
16 in 90% yield.12 Chlorination of 16 with NCS afforded the
R-chlorosulfide 17,13 which was immediately coupled with the
(9) (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.
(10) The acetates A and B were obtained in 51 and 79% yields, respectively.
(11) (a) Inoue, M.; Wang, G.-X.; Wang, J.; Hirama, M. Org. Lett. 2002, 4,
3439-3442. (b) Inoue, M.; Miyazaki, K.; Uehara, H.; Maruyama, M.;
Hirama, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12013-12018.
(12) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 1409-1412.
(13) Mukaiyama, T.; Sugaya, T.; Marui, S.; Nakatsuka, T. Chem. Lett. 1982,
1555-1558.
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A R T I C L E S
Kadota et al.
Scheme 4. Alternative Approacha
Scheme 6. Synthesis of the A-G Ring Segment 2a
a Reagents and conditions: (a) (PhS)2, n-Bu3P, DMF, rt, 90%; (b) NCS,
CCl4, rt; (c) 5, AgOTf, DTBMP, MS4A, CH2Cl2, -78 to -10 °C, 81%
based on 5; (d) TBAF, THF, rt; (e) 13, CSA, CH2Cl2, rt, 81% (2 steps); (f)
TMSI, HMDS, CH2Cl2, 0 °C, 84%; (g) AgOTf, MS4A, CH2Cl2, -78 °C
to room temperature, 84% (21:22 ) 78:22).
Scheme 5. Ring-Closing Metathesis of 21 and 22
a Reagents and conditions: (a) (i) CSA, CH2Cl2-MeOH, rt; (ii) TBSOTf,
2,6-lutidine, CH2Cl2, 0 °C to room temperature; (iii) H2, Pd-C, Et3N,
EtOAc, rt; (iv) CSA, CH2Cl2-MeOH, 0 °C, 80%; (b) (i) TPAP, NMO,
MS4A, CH2Cl2, rt; (ii) MeMgI, THF, 0 °C; (iii) TPAP, NMO, MS4A,
CH2Cl2, rt, 91%; (c) (i) Ph3PCH3+Br-, NaHMDS, THF, 0 °C to room
temperature; (ii) TBAF, THF, 40 °C; (iii) allyl bromide, KH, THF, 0 °C to
room temperature, 90%; (d) 23, CH2Cl2, rt, 98%; (e) (i) Li, liquid NH3,
THF, -78 °C; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, rt; (iii) CSA, CH2Cl2-
MeOH, 0 °C, 90%; (f) (i) TPAP, NMO, MS4A, CH2Cl2, rt; (ii) Ph3PCH3+Br-,
NaHMDS, THF, 0 °C to room temperature; (iii) TBAF, THF, 60 °C, 83%.
of 22 was performed by using the second-generation Grubbs
catalyst to afford 26 in quantitative yield.17 The stereochemistries
of 25 and 26 were determined on the basis of 1H NMR analysis
and NOE experiments, as shown in Scheme 5.
F-G ring segment 5 in the presence of AgOTf/DTBMP to
provide the O,S-acetal 18 in 81% yield.14,15 A series of reactions,
including desilylation with TBAF, acid-catalyzed acetal forma-
tion with 13, and selective cleavage of the methyl acetal with
TMSI/HMDS, furnished the allylic stannane 20 in 68% overall
yield. The reaction conditions employed did not affect the O,S-
acetal moiety. After several attempts, we found that the
intramolecular allylation of the O,S-acetal 20 proceeded smoothly
in the presence of AgOTf to give a 78:22 mixture of the desired
product 21 and its stereoisomer 22 in 84% yield.
Scheme 6 describes the preparation of the A-G ring segment
2. Removal of the benzylidene acetal of 25, protection of the
resulting diol using TBSOTf/2,6-lutidine, hydrogenation of the
olefin with H2/Pd-C/Et3N, and selective desilylation of the
primary silyl ether afforded the alcohol 27 in 80% overall yield.
Oxidation of 27 with TPAP/NMO followed by treatment with
MeMgI and subsequent TPAP oxidation of the resulting
secondary alcohol gave the methyl ketone 28 in 91% overall
yield. Wittig reaction of 28 gave the corresponding exo-
methylene derivative. The TBS ether was deprotected and
The diene 21 obtained was subjected to ring-closing meta-
thesis using the Grubbs catalyst 23, leading to 25 in 72% yield
(Scheme 5).16 On the other hand, the ring-closing metathesis
(16) (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.; Ziller,
J. W. J. Am. Chem. Soc. 1996, 118, 100-110.
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-
956.
(14) MacAuliffe, J. C.; Hindsgaul, O. Synlett 1998, 307-309.
(15) The yield is based on the alcohol 5.
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Total Synthesis of Brevetoxin B
A R T I C L E S
Scheme 7. Synthesis of the J-K Ring Segment 3a
Scheme 8. Coupling of Segments 2 and 3a
a Reagents and conditions: (a) (i) O3, MeOH, -78 °C, then Me2S; (ii)
allylbromide, Zn powder, saturated NH4Cl, THF, 0 °C, 93% (S:R ) 2:1);
(b) O3, CH2Cl2, -78 °C, then PPh3; (ii) Ac2O, pyridine, DMAP, CH2Cl2,
rt, 98%; (c) (i) H2, Pd(OH)2-C, MeOH, rt; (ii) PvCl, pyridine, DMAP,
CH2Cl2, reflux, 86%; (d) CH2dC(CH2OAc)CH2TMS, TMSOTf, CH3CN,
-20 °C, 93%; (e) (i) K2CO3, MeOH, 0 °C; (ii) TBDPSCl, imidazole, DMF,
rt, 85%; (f) (i) K2CO3, MeOH, 40 °C; (ii) p-MeOC6H4CH(OMe)2, CSA,
MS4A, CH2Cl2, 0 °C; (iii) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 82%; (g) (i)
PPTS, MeOH, rt; (ii) I2, PPh3, imidazole, Et2O-benzene, rt; (iii) NaCN,
DMSO, 50 °C; (iv) TESCl, 2,6-lutidine, CH2Cl2, 0 °C, 86%; (h) DIBAL-
H, CH2Cl2, -78 °C, 94%; (i) NaClO2, NaH2PO4, 2-methyl-2-butene, THF-
t-BuOH-H2O, 0 °C, 82%.
a Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N,
THF, 40 °C, then 2, DMAP, toluene, rt, 94%; (b) (i) TBAF, THF, 0 °C;
(ii) 13, CSA, CH2Cl2, rt; (iii) HMDS, TMSI, CH2Cl2, 0 °C, 71%; (c)
DIBAL-H, CH2Cl2, -78 °C, then (CH2ClCO)2O, DMAP, pyridine, CH2Cl2,
-78 °C, 68%; (d) MgBr2‚OEt2, CH3CN, 40 °C, 82%.
TMSOTf gave 36 as the sole product in 93% yield.24 Selective
removal of the primary acetyl group was carried out with
K2CO3 in MeOH at 0 °C, and the resulting alcohol was protected
with TBDPSCl/imidazole to afford 37 in 85% overall yield.
Saponification of 37 with K2CO3 in MeOH at 40 °C gave the
corresponding triol. Acetalization of the 1,3-diol moiety with
p-MeOC6H4CH(OMe)2/CSA followed by the TBS protection
of the remaining secondary alcohol gave 38 in 82% overall yield.
Selective hydrolysis of the acetal protection of 38 was carried
out with PPTS in MeOH. Selective iodination of the primary
alcohol, substitution of the iodide with cyanide, and protection
of the remaining secondary alcohol with TESCl/2,6-lutidine
furnished the nitrile 39 in 86% overall yield. DIBAL-H reduction
of 39 followed by oxidation of the resulting aldehyde gave the
carboxylic acid 3 in 77% overall yield.
converted to the allyl ether 29 in 90% overall yield by the
standard conditions. Ring-closing metathesis of 29 with 23
provided the known compound 302a,b in 98% yield.18 Debenzyl-
ation of 30 under the Birch conditions, TBS protection of the
resulting diol, and selective cleavage of the primary silyl ether
afforded the primary alcohol 31 in 90% overall yield. TPAP
oxidation of 31 followed by Wittig reaction and desilylation
with TBAF gave the A-F ring segment 2 in 83% overall yield.
Synthesis of the J-K Ring Segment. We next examined
the synthesis of the J-K ring segment 3 (Scheme 7).19
Ozonolysis of the known olefin 3220 afforded the corresponding
aldehyde, which was subjected to the Barbier-type allylation
using allyl bromide and Zn powder in the presence of saturated
NH4Cl to give a 2:1 mixture of the desired homoallylic alcohol
33 and its stereoisomer in 93% combined yield.21,22 Ozonolysis
of 33 followed by acetylation of the resulting hemiacetal gave
34 in 98% yield. Removal of the benzylidene acetal of 34 with
H2/Pd(OH)2-C followed by protection of the resulting diol with
PvCl/pyridine/DMAP afforded 35 in 86% overall yield.23
Treatment of 35 with 2-(acetoxymethyl)allyltrimethylsilane and
Coupling of Segments 2 and 3. Esterification of the A-G
ring segment 2 and the J-K segment 3 under the Yamaguchi
conditions afforded the ester 40 in 94% yield (Scheme 8).
Selective removal of the TES group of 40 was carried out using
TBAF to give the corresponding alcohol, which was converted
to the allylic stannane 41 via the standard procedure in 71%
overall yield. Modified Rychnovsky acetylation of 41 via
DIBAL-H reduction followed by treatment with (CH2ClCO)2O/
DMAP/pyridine gave the R-chloroacetoxy ether 42 in 68%
(18) Construction of the A ring moiety via ring-closing metathesis has been
reported by Nakata; see ref 2c.
(19) For the preliminary study on the synthesis and coupling of the JK ring
fragment, see: Kadota, I.; Nishina, N.; Nishii, H.; Kikuchi, S.; Yamamoto,
Y. Tetrahedron Lett. 2003, 44, 7929-7932.
(20) Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K. Tetrahedron
1990, 46, 4517-4552.
(21) Pe´trier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910-912.
(22) The Grignard reaction of the hydroxy aldehyde gave poor results.
(23) The benzylidene acetal of 34 was unstable under the reaction conditions
which were used in the next C-glycosidation.
(24) The direct introduction of the C4 unit has been reported by Nakata:
Matsukura, H.; Hori, N.; Matsuo, G.; Nakata, T. Tetrahedron Lett. 2000,
41, 7681-7684.
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A R T I C L E S
Kadota et al.
Scheme 9. Completion of the Total Synthesis of Brevetoxin B (1)a
selective oxidation of the resulting allylic alcohol with MnO2
provided brevetoxin B (1) in 84% overall yield. The synthetic
1 exhibited physical and spectroscopic data identical to those
reported previously.1,2
Conclusions
The total synthesis of brevetoxin B (1) has been accomplished
in a highly convergent manner via the assembly of three
fragments. The key steps for the synthesis of 1 are the
intramolecular allylation and subsequent ring-closing metathesis.
Although an attempt to couple segments 4 and 5 via the
R-acetoxy ether 15 resulted in failure (Scheme 3), a new
coupling method via the O,S-acetal 20 proceeded smoothly
(Scheme 4). The longest linear sequence leading to 1 was 63
steps with 0.28% overall yield, and the number of the total steps
was 108. Further investigation on the convergent synthesis of
other marine polycyclic ethers based on the present methodology
is in progress.
Acknowledgment. We thank Professor K. Nakanishi (Co-
lumbia University) for providing an analytical sample of natural
brevetoxin B, and Professor M. Inoue (Tohoku University) for
his helpful discussions on the preparation of O,S-acetals. This
work was financially supported by the Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
a Reagents and conditions: (a) 23, benzene, 40 °C; (b) PCC, benzene,
80 °C, 81% (2 steps); (c) (i) HF‚py, CH2Cl2, 0 °C; (ii) MnO2, Et2O, rt,
84%.
yield.25 Intramolecular allylation of 42 with MgBr2‚OEt2 in
CH3CN gave the desired product 43 as a single stereoisomer in
82% yield.
Supporting Information Available: Schemes for the prepara-
tion of compounds 5 and 6. Experimental procedures and
characterization data for all new compounds. Copies of 1H NMR
spectra for selected compounds (62 pages, print/PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
The Final Stage. Completion of the total synthesis is
described in Scheme 9. Ring-closing metathesis of 43 with 23
provided the A-K ring skeleton 44. Oxidation of the A ring
moiety of 44 with PCC gave the lactone 45 in 81% overall yield.
After removal of the silyl protective groups with HF‚py,
(25) Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto,
Y. J. Am. Chem. Soc. 2003, 125, 11893-11899.
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