Synthetic studies on brevetoxin-B. Part 1: Stereoselective synthesis of the ABC-ring system

Article abstract of DOI:10.1016/S0040-4039(00)01341-1

The ABC-ring system of brevetoxin-B was stereoselectively synthesized based on the 6-endo-cyclization of a hydroxy methylepoxide, ring-closing olefin metathesis and SmI₂-induced reductive intramolecular cyclization. (C) 2000 Elsevier Science Lt

Full text of DOI:10.1016/S0040-4039(00)01341-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7673–7676
Synthetic studies on brevetoxin-B. Part 1: Stereoselective
synthesis of the ABC-ring system
Goh Matsuo, Hiroko Matsukura, Nobuyuki Hori and Tadashi Nakata*
RIKEN (The Institute of Physical and Chemical Research), Wako, Saitama 351-0198, Japan
Received 13 July 2000; revised 3 August 2000; accepted 4 August 2000
Abstract
The ABC-ring system of brevetoxin-B was stereoselectively synthesized based on the 6-endo-cyclization
of a hydroxy methylepoxide, ring-closing olefin metathesis and SmI2-induced reductive intramolecular
cyclization. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: brevetoxin-B; endo-cyclization; olefin metathesis; radical cyclization; samarium diiodide.
Brevetoxin-B (BTX-B) (1),1 a potent neurotoxin produced by the red tide organism Gymnodium
breve Davis, has a trans-fused polycyclic ether ring system which contains six-, seven- and
eight-membered ether rings, 23 stereocenters, three carbonꢀcarbon double bonds and two carbonyl
groups. Its unique complex structure and potent biological activity have attracted the attention
of synthetic organic chemists, and the first total synthesis of 1 was accomplished by the Nicolaou
group.2 We have recently been investigating the total synthesis of 1 based on our developed
synthetic methods. Our synthetic strategy toward BTX-B (1) mainly includes four efficient methods
for the stereoselective synthesis of trans-cyclic ethers: (a) the Zn(OAc)2-induced ring-expansion
reaction of cyclic ethers ii having a chloromethanesulfonate (monochlate) as the leaving group,3
(b) the 6-endo-cyclization of styrylepoxide iv with CSA, PPTS, or NaH,4 (c) the SmI2-induced
reductive intramolecular cyclization of cyclic ethers vi having a b-alkoxyacrylate and a carbonyl
group,5 and (d) the 6-endo-cyclization of the methylepoxide viii. In addition to our recently
developed methods (a–c), we included (d) the 6-endo-cyclization of viii as an efficient method
for the stereoselective synthesis of trans-cyclic ethers. The cyclization of the methylepoxide
* Corresponding author. Fax: +81 48 462 4666; e-mail: nakata@postman.riken.go.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01341-1

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of this type would proceed in the 6-endo-mode at the methyl position without any activation.6
This method might also be useful for the synthesis of the B-, G-, and J-ring systems.
We now report the stereoselective synthesis of the ABC-ring system of BTX-B (1) in this
paper, and the synthesis of the EFG- and IJK-ring systems in subsequent papers. Our
stereoselective synthesis of the ABC-ring system features the 6-endo-cyclization of a methylepox-
ide,6 ring-closing olefin metathesis,7 and SmI2-induced reductive intramolecular cyclization,5 for
the construction of the B-, A-, and C-ring systems, respectively.
The epoxy alcohol 2,8 prepared from 2-deoxy-
-ribose, was chosen as the starting material for
D
the synthesis of the ABC-ring system. Deprotection of the TBS group of 2 followed by the
treatment of the resulting hydroxy methylepoxide with PPTS9 at 0°C effected the 6-endo-cycliza-
tion to give the 2,3-trans-tetrahydropyran 3, corresponding to the B-ring of 1, in 93% yield.
Thus, the 6-endo-cyclization took place at the desired methyl position of the epoxide without
any activation; the cyclization using this type of methylepoxide apparently does not need
activation by a vinyl10 or a styryl group4 next to the epoxide. To construct the dihydropyran ring
as an ideal precursor for the A-ring lactone,2 a ring-closing olefin metathesis7 would be an
efficient protocol. The diol 3 was thus converted into the diene 7 as the substrate for the olefin
metathesis via the allyl ether 5. The acetonide formation of the diol 3 followed by hydrogenoly-
sis of the benzylidene with a catalytic amount of Pd(OH)2 gave the diol 4, which was then
converted into the allyl ether 5 in three steps: (1) selective protection of the primary alcohol as
the TBS ether, (2) allylation of the secondary alcohol and (3) deprotection of the TBS group.
The oxidation of 5 with TPAP11 and NMO followed by the Grignard reaction using MeMgBr
gave the alcohol 6, which was subjected to TPAP oxidation and the Wittig reaction using
Ph3PꢁCH2 to give the required diene 7. Upon treatment of 7 (20 mM in CH2Cl2) with 0.02
equiv. of Grubbs’ reagent,7 the ring-closing olefin metathesis smoothly proceeded at room
temperature for 3 h to give exclusively the desired dihydropyran 8 in 98% yield. The oxidation
of 8 with PCC in benzene at reflux afforded the a,b-unsaturated d-lactone 9, corresponding to
the AB-ring system of 1 (Scheme 1).
We then examined the stereoselective construction of the C-ring system based on the
SmI2-induced reductive intramolecular cyclization5 (Scheme 2). The removal of the acetonide in
8 with CSA in MeOH and subsequent treatment with triflic anhydride followed by TBSOTf in
12
the presence of 2,6-lutidine in CH2Cl2 gave the triflate 10, which was treated with NaCN to
give the nitrile 11. After reduction of 11 with DIBAH, the treatment of the resulting aldehyde

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Scheme 1. (a) TBAF, THF, rt; (b) PPTS, CH2Cl2, 0°C (93% from 2); (c) Me2C(OMe)2, CSA, DMF, rt (94%); (d) H2,
Pd(OH)2, EtOAc, rt (99%); (e) TBSCl, pyridine, rt (93%); (f) allyl bromide, NaH, benzene, reflux (96%); (g) TBAF,
THF, rt (95%); (h) TPAP, NMO, MS-4A, CH2Cl2, rt (86%); (i) MeMgBr, THF, rt (90%); (j) TPAP, NMO, MS-4A,
CH2Cl2, rt (88%); (k) Ph3P+MeBr−, NaHMDS, THF, 0°C (96%); (l) (PCy3)2Cl2RuꢁCHPh, CH2Cl2, rt (98%); (m)
PCC, benzene, reflux (53%)
with 1,3-propanedithiol in the presence of BF3·Et2O in CH2Cl2 simultaneously allowed the
thioacetalization and desilylation to give the thioacetal 12. The hetero-Michael addition of 12
with ethyl propiolate in the presence of N-methylmorpholine followed by dethioacetalization
with MeI13 gave the aldehyde 13. Upon treatment of 13 with 2.2 equiv. of SmI2 in the presence
of 2.2 equiv. of MeOH in THF, a radical-mediated reductive cyclization smoothly proceeded at
0°C for 1 h to exclusively give trans-fused tricyclic tetrahydropyran 14 in 91% yield, correspond-
ing to the ABC-ring system of 1. The stereostructure of 14 was confirmed by the NMR analysis
(NOE and HMBC).
Scheme 2. (a) CSA, MeOH, rt (92%); (b) Tf2O, 2,6-lutidine, CH2Cl2, −78°C, then TBSOTf, −78ꢀ0°C (98%); (c)
NaCN, MS-4A, DMSO, 80°C (61%); (d) DIBAH, CH2Cl2, −78°C; (e) BF3·Et2O, HS(CH2)3SH, CH2Cl2, −78ꢀ0°C;
(f) TBAF, THF, rt (63% from 11); (g) ethyl propiolate, N-methylmorpholine, CH2Cl2, rt (70%); (h) MeI, aq. MeCN,
rt (100%); (i) 2.2 equiv. of SmI2, 2.2 equiv. of MeOH, THF, 0°C (91%)

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In summary, the ABC-ring system of BTX-B (1) was efficiently synthesized with complete
stereoselection based on the 6-endo-cyclization of the methylepoxide, the ring-closing olefin
metathesis, and the SmI2-induced cyclization.
Acknowledgements
This work was supported in part by Special Project Funding for Basic Science (Multibio-
probe) from RIKEN. The authors thank Dr. H. Koshino for the NMR spectral measurements
and Ms. K. Harata for the mass spectral measurements.
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