Synthetic Study of Marine Polycyclic Ethers: Total Synthesis of Hemibrevetoxin B Abstract: Two Efficient Methods for the Synthes
Total Page：16
File Type：pdf, Size：1020Kb
Synthetic Study of Marine Polycyclic Ethers: Total Synthesis of Hemibrevetoxin B Tadashi Nakata The Institute of Physical and Chemical Research (RIKEN) Abstract: Two efficient methods for the synthesis of the cyclic ethers, the important fundamental components of marine polycyclic ethers, were developed: (1) rearrangement-ring expansion reaction and (2) endo-cyclization of hydroxy styrylepoxide. Based on the newly developed methods, stereoselective total synthesis of hemibrevetoxin B (2) has been completed. 1. Introduction The brevetoxins, represented by brevetoxin B (1), are potent neurotoxins produced by the red tide organism Gymnodium breve and constitute an important class of marine polycyclic ethers. Their biological activities are exerted by activating sodium channels and causing repetitive firing in neurons. Since brevertoxin B (1) was isolated as a red tide toxin in 1981 (ref. 1), a number of marine polycyclic ethers has also been reported; hemibrevetoxin B (2), whose molecular size is about half that of brevetoxin B, was isolated as the smallest member (ref. 2) and, recently, maitotoxin (3) was reported as Brevetoxin B (1) Hemibrevetoxin B (2) Partial Structure of Maitotoxin (3) 940 ( 76 ) J. Synth. Org . Chem. , Jpn. the most toxic and largest natural product known to date except for biopolymers like proteins or polysaccharides (ref. 3). The most characteristic feature of this family includes trans-fused polycyclic ether ring systems, in which medium- and large-membered ethers are involved. The synthetically challenging structure combined with potent biological activity has attracted the attention of numerous synthetic organic chemists to studies directed toward developing an efficient method for the synthesis of the cyclic ethers (ref. 4) and toward the total synthesis of this class of marine polycyclic ethers (ref. 5). Recently, we have developed two efficient methods for the synthesis of the cyclic ethers (ref. 6,7) and have completed the stereoselective total synthesis of hemibrevetoxin B (2) based on the newly developed methods (ref. 8,9). Herein, I would like to present our recent synthetic studies on the marine polycyclic ethers which particularly focused on the total synthesis of hemibrevetoxin B (2). 2. Synthetic Methods of Cyclic Ether Ring Systems The development of an efficient method for the synthesis of 2,3-trans-cyclic ether 6, a fundamental component of marine polycyclic ethers, was the most important task towards the total synthesis. A simple and efficient method for the synthesis of 6 would be the cyclization of epoxy alcohol 5 in the endo-mode (Scheme 1). This cyclization, however, mostly proceeds in the exo-mode, as predicted by Baldwin's rule (ref. 10), to give the cyclic ether 7 having a hydroxy group on the side chain. Our first synthetic strategy is based on the rearrangement of the cyclic ether 7 having the leaving group on the side chain with ring expansion to give the desired cyclic ether 6 (ref. 6). Our second strategy involves a direct endo-cyclization of the epoxy alcohol 5, which was achieved using hydroxy styrylepoxide 5 (R2= CH=CHPh) (ref. 7). Scheme 1 4 5 6 2.1. Rearrangement-Ring Expansion Reaction The rearrangement of the five- and six-membered ethers 8a-10a having a mesylate as the leaving group at the C 1'-position on the side chain was examined (Scheme 2) (ref. 6). This type of rearrangement was first reported during the total synthesis of lasalocid A (ref. 11), in which the rearrangement of the tetrahydrofuran to a tetrahydropyran system was accomplished by treatment with Ag2CO3 in acetone-H2O. The rearrangement of 8a was first investigated under the original reaction conditions, i.e., upon treatment with Ag2CO3 in acetone-H2O at reflux for 24 h, the rearrangement took place giving the ring-expanded ether 11 in 46% yield along with the recovered starting material 8a (39%). After several attempts, we found that treatment of 8a with 4 equiv of zinc acetate in AcOH-H20 (1:1) at reflux for 6 h effectively gave the desired six-membered ether 11 in 75% yield after acetylation. We then examined the ring expansion of the six-membered ether to a seven-membered ether. The treatment of 9a with Ag2CO3 in EtCOMe-H20 at reflux for 38 h produced the seven-membered ether 12 Vol.56, No.11 (November 1998) ( 77 ) 941 in only 17% yield along with the recovered 9a (48%). The best result was again obtained by treatment of 9a with zinc acetate in Ac0H-1120 at reflux for 8 h to give the desired 12 in 95% yield. The rearrangement of tetrasubstituted ether 10a was completed within 2 h at reflux or almost proceeded even at 80 •Ž for 8 h to give 13 in 90% yield. The 1,3-diaxial repulsion by the substituent groups would cause an acceleration of this rearrangement (ref. 6). Scheme 2 11 8a 8b 12 9a 9b 13 10a 10b We have recently reported that the chloromethanesulfonate (monochlate) served as an extremely effective leaving group for the inversion of secondary alcohols (ref. 12). Thus, this new leaving group, monochlate, was applied to the present rearrangement-ring expansion reaction (ref. 13). When the monochlate was used instead of mesylate, the reaction smoothly proceeded under milder reaction conditions (Scheme 2). Upon treatment of 8b with zinc acetate in AcOH-H20, the expected rearrangement-ring expansion took place very smoothly even at 50 •Žfor 4 h, giving the ring-expanded ether 11 in 85% yield, while, under the same reaction conditions, the reaction of the corresponding mesylate 8a gave 11 in only 13% yield along with the recovered starting material 8a (67% yield). The reaction of six-membered ether 9b having a monochlate at 80 •Ž afforded the seven-membered ether 12 in 87% yield, while the corresponding mesylate 9a did not produce 12. The ring expansion of 10b proceeded even at room temperature or without zinc acetate at 50 •Ž, giving 13 in high yield. Further detailed investigation of the rearrangement-ring expansion using several stereoisomers suggested that the reaction would stereoselectively proceed via the oxonium ion, which should be formed through the antiperiplanar conformation (Scheme 3) (ref. 14). Thus, the antiperiplanar conformation of the C-0 bond in the ether ring and the mesyloxy group as the leaving group should be very important in this rearrangement-ring expansion reaction. 942 ( 78 ) J . Synth . Org . Chem . , Jpn Scheme 3 An efficient method for the stereoselective synthesis of six- and seven-membered ethers was now developed based on the rearrangement-ring expansion, which might be very effective for the synthesis of marine polyethers such as brevetoxins and maitotoxin. Then, the newly developed method was successfully applied to the synthesis of the C-ring system of hemibrevetoxin B (2), which should be a crucial step for the total synthesis. The tetrahydropyran 14 having appropriate substituents was treated with zinc acetate in Ac0H-H20 at reflux to give the oxepane 15, corresponding to the C-ring system, in 73% yield (Scheme 4) (ref. 8). Repeating the same reaction sequences would construct the D-ring system of 2, since 15 has the requisite functional groups. Scheme 4 14 15 The present method could be further applied to the synthesis of the S- and Y-ring systems of maitotoxin (3) as shown in Scheme 5 (ref. 15). The reactions of 16 and 18 with zinc acetate in Ac0H-H20 at reflux gave the desired oxepanes 17 and 19, corresponding to the S- and Y-ring systems, respectively. The NOE between C 1'-H and C60-Me in 16 and between C r-H and C613-Hin 18 was observed, suggesting the favored conformation for the rearrangement-ring expansion. Scheme 5 16 17 18 19 By repeating the rearrangement-ring expansion reaction, the 6,7-membered bicyclic ether 24, corresponding to the ST- and XY-ring systems of 3, was stereoselectively synthesized starting from the model compound 20 (Scheme 6) (ref. 16). Vol. 56, No.11 (November 1998) ( 79 ) 943 Scheme 6 20 21 22 23 24 2.2. Endo-Cyclization of Hydroxy Styrylepoxide Having solved the problem for construction of the C- and D-ring systems of hemibrevetoxin B (2), we turned our attention to the next problem, i.e., formation of the B-ring system. First, we examined the rearrangement of the ether 7 (R1=H) having a hydrogen atom at the C2-position (Scheme 1). Unfortunately, however, the rearrangement of the corresponding mesylate of 7 (R1=H) did not proceed in good yield (ref. 17). Therefore, we needed to develop an effective means to synthesize the cyclic ether 6 (R1=H). Our attention was focused on the direct cyclization of the epoxy alcohol 5 in the endo-mode (Scheme 1). Several methods for effective endo-cyclization of epoxy alcohols have been reported (ref. 18). Nicolaou et al. accomplished activation of the endo- over exo-cyclization by placing a vinyl group next to the epoxide, i.e., treatment of hydroxy vinylepoxide 5 (n=1 or 2, R1=11, R2=CH=CH2) with 10-camphorsulfonic acid (CSA) effected the endo-cyclization with high regio- and stereoselectivities to give the desired 6 (ref. 19). We have recently investigated a more efficient endo-cyclization by modification of Nicolaou's procedure (ref. 7), because this procedure gave unsatisfactory results for the B-ring construction of hemibrevetoxin B (2) in our model studies using 29b (ref. 20), which will be mentiond later in Scheme 8 . We chose epoxy alcohols 5 (le =Me) with a methyl group as the substrates for our investigation of an effective endo-cyclization (Scheme 1). The endo-cyclization of these epoxy alcohols would be very difficult because the cyclization predominantly occurs in the exo-mode due to the methyl group.