28 ヘミブレベトキシンBの全合成(口頭発表の部)
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The brevetoxins, represented by brevetoxin A and B, are potent neurotoxins produced by the red tide organism Gymnodium breve and constitute an important class of marine polycyclic ethers. Hemibrevetoxin B (1), whose molecular size is about half that of brevetoxins, was isolated from the cultured cells of Gymnodinium breve by Shimizu in 1989. The characteristic structural features of 1 include trans-fused 6, 6, 7, 7-tetracyclic ether rings (ABCD-ring system) having 10 chiral centers, an α-vinyl aldehyde and a (Z)-diene moieties. The unique complex structure and potent biological activity have attracted the attention of numerous synthetic organic chemists, and the total syntheses of 1 have recently been accomplished by the Nicolaou and Yamamoto groups. We have also reported several studies directed toward developing an efficient method for the synthesis of the cyclic ethers and toward the total synthesis of this class of marine polyethers. We now report the stereoselective total synthesis of hemibrevetoxin B (1), which features a novel double rearrangement-ring expansion of the bicyclic ether for the CD-ring formation, an exclusive 6-endo cyclization of the hydroxy styrylepoxide for the B-ring formation, and a direct insertion of a C-4 unit as the side chain on the A-ring. The allyl alcohol 16, prepared from geraniol, was converted into 6,6-membered bicyclic ether 22 via the Sharpless asymmetric epoxidation (AE). Upon treatment of bis(chloromethanesulfonate) 23 with Zn(OAc)2 in aq AcOH at 60-80℃, the expected double rearrangement-ring expansion took place effectively giving the 7,7,-membered bicyclic ether, which was hydrolyzed with K_2CO_3 to give 24 corresponding to the CD-ring system. The bicyclic ether 24 was converted into styrylepoxide 29, which was treated with CSA to give the desired 6-memberd ether 30 corresponding to the B-ring system. Ozonolysis of the double bond in 31 followed by reaction with allylmagnesium chloride stereoselectively produced 613-alcohol 32 along with the 6a-isomer. Ozonolysis of 32 followed by treatment with Dowex in MeOH effected acetalization of the resulting lactol and simultaneous deprotection of the acetonide, giving the diol which was oxidized with NaIO_4 to give aldehyde 33 having the ABCD-ring system. The Wittig reaction of 33 using PhSeCH_2CH_2CH=PPh_3 followed by H_2O_2 treatment gave (Z)-diene 34, which was treated with CH_2=CH(CH_2OAc)CH_2TMS in the presence of TMSOTf in MeCN to give exclusively 4β-substituted compounds 35 and 36. The TBS ether 35 was converted into the alcohol 36 by treatment with TMSOTf in MeCN. Alkaline hydrolysis of the acetate 36 gave alllyl alcohol 37, which was finally oxidized with MnO_2 in ether to give α,β-unsaturated aldehyde 1. The ^1H and ^<13>C NMR spectra of the synthetic 1 were identical with those of natural hemibrevetoxin B (1).
- 天然有機化合物討論会の論文
- 1996-09-02
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