Total synthesis of Brevetoxin-B

Article abstract of DOI:10.1021/ja0449269

Brevetoxin-B (BTX-B), produced by the red tide organism, Gymnodium breve Davis, is the first member of marine polycyclic ethers to be structurally elucidated and one of the most potent neurotoxins. The structural feature is a trans-fused polycyclic ether

Full text of DOI:10.1021/ja0449269

Published on Web 10/19/2004
Total Synthesis of Brevetoxin-B
Goh Matsuo, Koji Kawamura, Nobuyuki Hori, Hiroko Matsukura, and Tadashi Nakata*
RIKEN (The Institute of Physical and Chemical Research), Wako, Saitama 351-0198, Japan
Received August 23, 2004; E-mail: nakata@rs.kagu.tus.ac.jp
Brevetoxin-B (BTX-B, 1), produced by the red tide organism,
cyclization. After hydrolysis of the acetal 10 followed by oxidation,
treatment of the resultant bis(lactone) with MeLi underwent double
methylation to give bis(methyl ketone) 11. Treatment of 11 with
ethyl propiolate6 effected double hetero-Michael reaction to give
bis(â-alkoxy acrylate) 12. As expected, reaction of 12 with SmI2
induced double cyclization with complete stereoselection to give
trans-fused ester-lactone 13,7 corresponding to the CDE-ring, after
treatment with p-TsOH.8 For construction of the B- and F-rings, a
subtle difference in the reactivity between similar functional groups
at the left and right sides was successfully used. Protection of 13
as a TMS ether followed by DIBAH reduction afforded aldehyde-
lactol 14, which was efficiently converted into R,â-unsaturated
ketone-ester 15 by one-pot Wittig reaction. Thus, the first Wittig
reagent, Ph3PdC(Me)CO2Et, smoothly and predominantly reacted
with the lactol at 0 °C-rt, and the second Wittig reagent, Ph3Pd
CHCOMe, reacted with the aldehyde at 100 °C to give ketone-
ester 15, after TMS protection. The CBS asymmetric reduction9 of
the ketone 15 gave the desired â-alcohol 16,10 which is the matched
isomer for the subsequent Sharpless asymmetric epoxidation (AE)11
to give the desired R-epoxide. After DIBAH reduction of the ester
16, the stereoselective epoxidation of the resultant bis(allylic
alcohol) 17 was performed by consecutive Sharpless AE; i.e.,
treatment with TBHP/(-)-DIPT and then TBHP/(+)-DIPT effected
epoxidation at the right and left sides, respectively, to afford bis-
(R-epoxide) 18. The first epoxidation gave only R-epoxide, and
the stereoselectivity of the second one was ca. 8:1 in favor of
R-epoxide. Double oxidation of the diol 18 followed by double
Wittig olefination and removal of two TMS groups efficiently
afforded bis(vinyl epoxide) 19. Treatment of 19 with PPTS12 at 0
°C effected 6-endo-cyclization13 at the right side to give 20, after
TBS protection. Then, PPTS treatment of 20 at room temperature
induced 6-endo-cyclization at the left side to give the BCDEF-
ring 21.14 Differentiation of the left and right sides was completely
performed at this stage. After O-allylation of 21, ring-closing olefin
metathesis of the resultant 22 with Grubbs reagent15 smoothly
proceeded at room temperature to give 23.2d After removal of the
TBS group, Wacker oxidation of 23 took place at the exo-methylene
position16 to give aldehyde, which was subjected to the Wittig
reaction to give R,â-unsaturated ester 24. TBS protection of 24,
DIBAH reduction, and MCPBA epoxidation afforded â-epoxide
25 as a single product.2e,17 Removal of the TBS group followed by
PPTS treatment effected 6-endo-cyclization2e,18 to give 26,7 which
was successfully converted into phosphonium salt 2,2c corresponding
to the ABCDEFG-ring.
Gymnodium breVe Davis, is the first member of marine polycyclic
ethers to be structurally elucidated and one of the most potent
neurotoxins.1 The structural feature of 1 is a trans-fused polycyclic
ether ring system with 23 stereocenters, which contains six-, seven-,
and eight-membered ether rings, three carbon-carbon double bonds,
one hydroxyl group, and two carbonyl groups. Its unique, complex
structure and potent biological activity have attracted the attention
of numerous synthetic organic chemists.2 To date, Nicolaou and
co-workers reported the first and only total synthesis of 1 based
on a convergent strategy by the coupling of 2 and 3a.2a-c Herein,
we report the stereoselective total synthesis of BTX-B (1) via the
coupling of 2 and 3b, each ether ring of which was stereoselectively
and efficiently constructed on the basis of SmI2-induced intramo-
lecular cyclization, 6-endo-cyclization of hydroxy epoxide, ring-
closing olefin metathesis, and SmI2-induced intramolecular Refor-
matsky-type reaction. Several kinds of double reactions at the left
and right sides were efficiently used through the synthesis.
Scheme 1. Retrosynthetic Plan for BTX-B
A feature of our synthesis of the left segment 2 is a two-
directional strategy starting from the D-ring. Commercially available
tri-O-acetyl-D-glucal (4) was converted into R,â-unsaturated ester
6 via alcohol 5. The first task was stereoselective construction of
an R-methyl group on the D-ring. After several attempts to introduce
the methyl group into 6, we found that Kuwajima’s conditions3
smoothly effected the Michael addition: upon treatment with
MeMgBr and TMSCl in the presence of Cu(N-i-Pr-Sal)2 catalyst
7, the addition reaction efficiently took place only from the R-side
to give the desired adduct 8.4 Construction of the D-ring was then
carried out by our protocol using SmI2-induced intramolecular
cyclization.5 After conversion of 8 into the requisite aldehyde 9,
treatment with SmI2 in the presence of MeOH in THF effected
radical-induced reductive cyclization with concomitant lactonization
to give oxepane 10 with complete stereoselection. Here, we
expected that the C- and E-rings would be simultaneously con-
structed by the two-directional strategy with SmI2-induced double
Synthesis of the IJK-ring system 3b started with the construction
of the I-ring. Aldehyde 28 was prepared from commercially
available 2-deoxy-D-ribose (27) by thioacetalization,19 benzylidation,
hetero-Michael reaction, and deprotection of thioacetal. SmI2-
induced cyclization of 28 gave the desired trans-29 with complete
stereoselection. DIBAH reduction of 29, Wittig reaction, TBS
protection, and DIBAH reduction afforded allylic alcohol 30. The
Sharpless AE of 30 using (-)-DET stereoselectively produced the
* Present address: Department of Chemistry, Faculty of Science, Tokyo
University of Science, 1-3, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan.
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10.1021/ja0449269 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of the ABCDEFG-Ringa
a Reagents and conditions: (a) montmorillonite K-10, MeOH-CH2Cl2, 40 °C; (b) H2, 10% Pd/C, MeOH, rt; (c) K2CO3, MeOH, rt, 95% (three steps); (d)
TBSCl, imidazole, DMF, 50 °C, 100%; (e) CSA, MeOH-CH2Cl2, 0 °C, 97%; (f) (COCl)2, DMSO, CH2Cl2, -78 °C, i-Pr2NEt, -78 °C f rt, then
Ph3PdCHCO2Et, 0 °C f rt, 95%; (g) MeMgBr, TMSCl, 7, THF, -45 °C, 99%; (h) LiAlH4, Et2O, 0 °C; (i) TBAF, THF, rt, 97% (two steps); (j) TBSCl,
pyridine, CH2Cl2, rt, 81%; (k) ethyl propiolate, N-methylmorpholine, CH2Cl2, rt; (l) p-TsOH, EtOH, rt, 97% (two steps); (m) TEMPO, PhI(OAc)2, CH2Cl2,
rt; (n) SmI2, MeOH, THF, rt, 83% (two steps); (o) AcOH-H2O, 80 °C; (p) TEMPO, PhI(OAc)2, CH2Cl2, rt, 66% (two steps); (q) MeLi, THF, -78 °C, 95%;
(r) ethyl propiolate, N-methylmorpholine, CH2Cl2, rt, 95%; (s) SmI2, MeOH, THF, rt; (t) p-TsOH, toluene, 80 °C, 79% (two steps); (u) TMSOTf, 2,6-
lutidine, CH2Cl2, -78 °C, 100%; (v) DIBAH, toluene, -78 °C; (w) Ph3PdC(Me)CO2Et, toluene, 0 °C f rt, then Ph3PdCHCOMe, 100 °C, 67%, (two
steps); (x) TMSOTf, pyridine, CH2Cl2, -78 °C, 98%; (y) (R)-2-methyl-CBS-oxazaborolidine, cathecholborane, toluene, -78 °C; (z) DIBAH, toluene, -78
°C, 98% (two steps); (aa) TBHP, (-)-DIPT, Ti(Oi-Pr)4, 4 Å MS, CH2Cl2, -30 °C, 92%; (bb) TBHP, (+)-DIPT, Ti(Oi-Pr)4, 4 Å MS, CH2Cl2, -30 °C, 96%;
(cc) SO3‚pyridine, Et3N, DMSO-CH2Cl2, rt; (dd) Ph3P+MeBr-, NaHMDS, THF, rt; (ee) TBAF, THF, 0 °C, 96% (three steps); (ff) PPTS, CH2Cl2, 0 °C;
(gg) TBSOTf, pyridine, CH2Cl2, -20 f 0 °C, 62% (two steps); (hh) PPTS, CH2Cl2, rt, 78%; (ii) allylbromide, NaH, THF, rt; (jj) (PCy3)2Cl2RudCHPh,
CH2Cl2, rt, 96% (two steps); (kk) TBAF, THF, rt; (ll) PdCl2, CuCl, O2, DMF-H2O, rt f 60 °C; (mm) Ph3PdC(Me)CO2Et, toluene, 100 °C, 93% (three
steps); (nn) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C; (oo) DIBAH, toluene, -78 °C; (pp) MCPBA, CH2Cl2, -20 °C, 87% (three steps); (qq) TBAF, THF, rt;
(rr) PPTS, CH2Cl2, 0 °C f rt, 79% (two steps); (ss) Tf2O, 2,6-lutidine, CH2Cl2, -78 °C, then TBSOTf, -78 f 0 °C; (tt) NaCN, 4 Å MS, DMSO, 80 °C;
(uu) DIBAH, CH2Cl2, -78 °C, 69% (three steps); (vv) NaBH4, EtOH, 0 °C; (ww) I2, Ph3P, imidazole, THF-MeCN, rt, 91% (two steps); (xx) CSA,
CH2Cl2-MeOH, 70 °C; (yy) TMS-imidazole, CH2Cl2, rt, 91% (two steps); (zz) Ph3P, MeCN, 80 °C, 91%.
Scheme 3. Synthesis of the IJK-Ringa
a Reagents and conditions: (a) 1,3-propanedithiol, 6N HCl, CHCl3, rt, 90%;19 (b) PhCH(OMe)2, CSA, EtOAc, rt; (c) ethyl propiolate, N-methylmorpholine,
CH2Cl2, rt, 84% (two steps); (d) MeI, NaHCO3, MeCN-H2O, rt, 98%; (e) SmI2, MeOH, THF, 0 °C, 95%; (f) DIBAH, CH2Cl2, -78 °C; (g) Ph3PdC(Me)CO2Et,
toluene, 100 °C, 88% (two steps); (h) TBSCl, imidazole, DMF, rt; (i) DIBAH, toluene, -78 °C, 85% (two steps); (j) TBHP, (-)-DET, Ti(Oi-Pr)4, 4 Å MS,
CH2Cl2, -20 °C, 98%; (k) TPAP, NMO, 4 Å MS, CH2Cl2, rt; (l) Ph3P+MeBr-, NaHMDS, THF, 0 °C, 85% (two steps); (m) TBAF, THF, rt; (n) PPTS,
CH2Cl2, rt, 87% (two steps); (o) BrCH2COBr, pyridine, CH2Cl2, 0 °C, 97%; (p) O3, CH2Cl2, -78 °C, then Me2S, -78 °C f rt; (q) SmI2, THF, 0 °C, 71%
(two steps); (r) TBSOTf, pyridine, CH2Cl2, rt, 71%; (s) DIBAH, CH2Cl2, -78 °C; (t) Ac2O, pyridine, rt, 96% (two steps); (u) H2, Pd(OH)2/C, EtOAc, rt;
(v) PivCl, pyridine, rt; (w) CH2dC(CH2OAc)CH2TMS, TMSOTf, MeCN, -20 °C; (x) TBSOTf, pyridine, CH2Cl2, rt, 89% (four steps); (y) K2CO3, MeOH,
-5 °C; (z) TBDPSCl, imidazole, DMF, rt; (aa) LiAlH4, Et2O, 0 °C, 88% (three steps); (bb) TBSCl, imidazole, DMF, rt; (cc) TPAP, NMO, 4 Å MS, CH2Cl2,
rt, 90% (two steps); (dd) EtSH, Zn(OTf)2, CH2Cl2, rt, then CSA, MeOH, rt, 90%; (ee) SO3‚pyridine, Et3N, DMSO-CH2Cl2, 0 °C, 98%.
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C O M M U N I C A T I O N S
Scheme 4. Completion of the Total Synthesisa
in 59 steps as the longest linear sequence (tri-O-acetyl-D-glucal (4)
f BTX-B (1)) and in total 90 steps with an average of 93% yield
for each step.
Acknowledgment. This work was financially supported in part
by Special Project Funding for Basic Science (Chemical Biology)
from RIKEN. We thank Dr. H. Koshino for the NMR spectral
measurements and Ms. K. Harata for the mass spectral measure-
ments. We thank Prof. K. Nakanishi (Columbia University) for
providing an NMR chart of BTX-B.
Supporting Information Available: Experimental procedures and
spectral data for new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) 2, n-BuLi, HMPA, THF, -78 °C, then
3b, -78 °C f rt; (b) PPTS, CH2Cl2-MeOH, rt, 68% (two steps); (c)
AgClO4, NaHCO3, SiO2, 4 Å MS, MeNO2, rt; (d) Ph3SnH, AIBN, toluene,
110 °C; (e) TBAF, THF, rt, 71% (three steps); (f) PCC, benzene, 80 °C,
51% (75%22 based on oxidation of 41) for 40, 38% for 41; (g) HF‚pyridine,
CH2Cl2, 0 °C, 72%.
References
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E. A.; Tiebes, J.; Sato, M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117,
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Theodorakis, E. A.; Tiebes, J.; Sato, M.; Untersteller, E. J. Am. Chem.
Soc. 1995, 117, 10252. For synthetic approaches toward 1, see: (d)
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41, 7673. (e) Matsuo, G.; Hori, N.; Matsukura, H.; Nakata, T. Tetrahedron
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(7) Stereostructures of 13, 26, 34, and 36 were confirmed by the NMR analysis
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cyclization.
(9) For a review, see: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998,
37, 1986.
(10) Diastereoselectivity of this reduction was ca. 9:1.
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(22) Oxidation of 41 under the same reaction conditions gave 40 in 63% yield
(86% based on the consumed 41).
R-epoxide, which was converted into the vinyl epoxide 31. After
removal of the TBS group, treatment of 31 with PPTS effected
6-endo-cyclization to give 32, corresponding to the IJ-ring. The
remaining construction of the K-ring system was accomplished by
the SmI2-induced intramolecular Reformatsky-type reaction20 and
direct introduction of the side chain.2f,21 Acylation of 32 with BrCH2-
COBr followed by ozonolysis gave the required aldehyde 33, which
was treated with SmI2 in THF to give the â-hydroxy δ-lactone 347
as a single product. After conversion of 34 into acetate 35, the
carbon four unit as the side chain was stereoselectively introduced
by treatment with CH2dC(CH2OAc)CH2TMS in the presence of
TMSOTf to give 36.7 Methanolysis of the acetate in 36, TBDPS
protection, LiAlH4 reduction, selective TBS protection, and oxida-
tion afforded ketone 37, which was subjected to thioacetalization,
selective removal of the TBS group, and oxidation with SO3‚
pyridine to give aldehyde 3b, corresponding to the IJK-ring.
With both segments 2 and 3b in hand, our effort turned toward
completion of the total synthesis of 1 through their coupling
following Nicolaou’s procedure.2c Treatment of 2 with n-BuLi
followed by addition of 3b effected the coupling to give (Z)-olefin.
Removal of the TMS group followed by AgClO4 treatment induced
ring closure to monothioacetal 38, which was reduced with Ph3-
SnH in the presence of AIBN to give 39, corresponding to the
ABCDEFGHIJK-ring. After removal of the TBDPS group in 39,
treatment with PCC effected double oxidation of alcohol and A-ring
methylene at the right and left sides to give lactone-aldehyde 40,
accompanied by monooxidized 41.22 Final removal of the TBS
group of 40 furnished BTX-B (1). The spectral data of synthetic 1
were identical with those reported.1,2c Thus, the total synthesis of
BTX-B (1) has been efficiently achieved with high stereoselectivity
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