Synthetic studies on brevetoxin-B. Part 3: Stereoselective synthesis of the IJK-ring system

Article abstract of DOI:10.1016/S0040-4039(00)01339-3

The IJK-ring system of brevetoxin-B was stereoselectively synthesized based on the 6-endo-cyclizations of a hydroxy methylepoxide and a hydroxy styrylepoxide, and the direct introduction of the C-4 unit as the side chain. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01339-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7681–7684
Synthetic studies on brevetoxin-B. Part 3: Stereoselective
synthesis of the IJK-ring system
Hiroko Matsukura, Nobuyuki Hori, Goh Matsuo 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 IJK-ring system of brevetoxin-B was stereoselectively synthesized based on the 6-endo-cyclizations
of a hydroxy methylepoxide and a hydroxy styrylepoxide, and the direct introduction of the C-4 unit as
the side chain. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: brevetoxin-B; endo-cyclization; styrylepoxide; allyl C-glycosidation.
In the preceding two papers,1,2 we reported the stereoselective synthesis of the ABC- and
EFG-ring systems of brevetoxin-B (BTX-B) (1). We now report the stereoselective synthesis of
the IJK-ring system of BTX-B (1). Our synthesis of the IJK-ring system features 6-endo-cycliza-
tions of a hydroxy methylepoxide and styrylepoxide for the construction of the J- and I-ring
systems, respectively, and direct introduction of a C-4 unit as the side chain on the K-ring.
Since the structure of the J-ring is identical with that of the B-ring, the tetrahydropyran 2,1 the
key intermediate in the synthesis of the ABC-ring system, was chosen as the starting material for
* 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)01339-3

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the construction of the IJK-ring system. First, the construction of the I-ring system was
investigated using the 6-endo-cyclization of hydroxy styrylepoxide (Scheme 1).3 The treatment of
the diol 2 with triflic anhydride followed by TBSOTf4 gave the triflate 3. The reaction of 3 with
the methoxypropylidene (MOP) ether 4,5 prepared from propargyl alcohol, in the presence of
n-BuLi in THF–DMPU at −20°C6 and subsequent deprotection of the MOP group with PPTS7
afforded propargylic alcohol 5 in 76% yield from 2. The reduction of 5 with Red-Al® gave the
(E)-allylic alcohol, which was subjected to the Sharpless asymmetric epoxidation8 with
t-BuOOH in the presence of (+)-DET and Ti(Oi-Pr)4 in CH2Cl2 to give the b-epoxide 6. The
oxidation of the alcohol 6 with TPAP9 followed by the Wittig reaction using Ph3PꢀCHPh gave
the styrylepoxide 7. After deprotection of the TBS group with TBAF, the cyclization of 7 was
examined. The regio- and stereoselective 6-endo-cyclization of the resulting hydroxy styrylepox-
ide was performed by treatment with NaH in DMSO3 to give the six-membered ether 8,
corresponding to the IJ-ring, in 92% yield from 7. The cyclization with CSA, as an acidic
activator, in CH2Cl2 produced 8 in 62% yield. Thus, in this case, base conditions gave better
results for the 6-endo-cyclization.
Scheme 1. (a) Tf2O, 2,6-lutidine, CH2Cl2, −78°C, then TBSOTf, −78ꢀ0°C; (b) 4, n-BuLi, THF-DMPU (6:1), −20°C;
(c) PPTS, MeOH, 0°C, (76% from 2); (d) Red-Al®, Et2O, rt (88%); (e) t-BuOOH, (+)-DET, Ti(Oi-Pr)4, MS-4A,
CH2Cl2, −20°C (93%); (f) TPAP, NMO, MS-4A, CH2Cl2, rt; (g) Ph3P+CH2PhCl−, NaHMDS, THF, 0°C (64% from
6); (h) TBAF, THF, rt; (i) NaH, DMSO, 0°Cꢀrt (92% from 7)
The construction of the K-ring system and introduction of the C-4 unit as the side chain were
then investigated (Scheme 2). The alcohol 8 was converted into the alcohol 10 in five steps via
9: (1) protection of the hydroxyl group as the benzyl ether, (2) deprotection of the acetonide, (3)
acetylation of the primary alcohol, (4) silylation of the secondary alcohol and (5) methanolysis
of the acetate. The oxidation of 10 with TPAP9 followed by the Grignard reaction using
allylmagnesium chloride in THF at −78°C gave the desired b-alcohol 11a and its a isomer 11b
in 65 and 21% yields, respectively. Both isomers 11a and 11b were converted into the same diol
14, a precursor of the a,b-unsaturated aldehyde 15 corresponding to the IJK-ring, as shown in
Schemes 2 and 3, respectively.

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Scheme 2. (a) BnBr, n-Bu4NI, NaH, THF, 0°Cꢀrt (96%); (b) CSA, MeOH, rt (94%); (c) AcCl, 2,4,6-collidine,
CH2Cl2, −78°C; (d) TBSOTf, 2,6-lutidine, CH2Cl2, 0°C; (e) K2CO3, MeOH, rt (85% from 9); (f) TPAP, NMO,
MS-4A, CH2Cl2, rt; (g) allylMgCl, THF, −78°C (11a 65% and 11b 21% from 10); (h) TBAF, THF, rt (91%); (i) OsO4,
NMO, aq. t-BuOH (1:1), rt; (j) NaIO4, aq. THF, rt (91%, 2 steps); (k) Ac2O, pyridine, rt (99%); (l)
CH2ꢀC(CH2OAc)CH2TMS, TMSOTf, MeCN, 0°C (98%); (m) K2CO3, MeOH, rt (95%); (n) MnO2, Et2O, rt (81%)
Scheme 3. (a) TBAF, THF, rt (98%); (b) OsO4, NMO, aq. t-BuOH (1:1), rt; (c) NaIO4, aq. THF, rt (80%, two steps);
(d) Dowex® (50W-X2), MeOH, rt (75%); (e) CH2ꢀC(CH2OAc)CH2TMS, TMSOTf, MeCN, 0°C (82%); (f) PCC,
MS-4A, benzene, 80°C (80%); (g) L-Selectride®, THF, −78°C, then MeOH (85%); (n) MnO2, Et2O, rt (81%)
After deprotection of the TBS group in 11a with TBAF, dihydroxylation of the olefin with
OsO4–NMO followed by NaIO4 treatment produced a hemiacetal, which was acetylated to give
the diacetate 12 (Scheme 2). The direct introduction of a C-4 unit as the side chain of the K-ring
was then carried out. The reaction of 12 with CH2ꢀC(CH2OAc)CH2TMS in the presence of
TMSOTf in MeCN at 0°C exclusively produced the desired b-substituted compound 13 as a
1
single isomer in 98% yield.3b,10 The stereochemistry of 13 was determined by H NMR analysis
and an NOE experiment. Methanolysis of the diacetate 13 with K2CO3 gave the allyl alcohol 14,
which was oxidized with MnO2 in ether to give the a,b-unsaturated aldehyde 15 in 81% yield.
The product 15 corresponds to the IJK-ring system of BTX-B (1).
On the other hand, the isomeric a-alcohol 11b was also converted into the diol 14 via the
ketone 18 (Scheme 3).3b The a-alcohol 11b was converted into the acetal 16 in four steps: (1)
desilylation, (2) oxidation of the olefin to a diol, (3) oxidative cleavage of the diol to an

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aldehyde, and (4) hemiacetalization. The treatment of 16 with CH2ꢀCH(CH2OAc)CH2TMS in
the presence of TMSOTf also gave the b-substituted compound 17 in 82% yield as the single
product. After oxidation of 17 with PCC, reduction of the resulting ketone 18 with L-Selectride®
exclusively took place from the a-side to give the b-alcohol 14, accompanied by cleavage of the
acetate. The diol 14 was oxidized with MnO2 to the desired aldehyde 15, which was identical
with the aldehyde 15 from 11a.
In summary, the IJK-ring system 15 of BTX-B (1) was efficiently synthesized based on the
6-endo-cyclization of the methyl epoxide and styrylepoxide, and formation of the hemiacetal
followed by direct introduction of a C-4 unit as the side chain of the K-ring. We have
accomplished the stereoselective syntheses of the ABC-, EFG-, and IJK-ring systems of BTX-B
(1). Further studies toward the total synthesis of BTX-B are now in progress in our laboratory.
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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