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. In fact, the cyclization of 5 (n=1 or 2, R1=Me, R =CH2OH) under acidic or basic conditions (pyridinium p-toluenesulfonate (PPTS) (ref. 21) in CH2C12 at rt or NaH in DMSO at rt) completely proceeded in the exo-mode to give the cyclized ether 7, as the sole product. The application of Nicolaou's procedure to this type of compounds resulted in producing a, mixture of endo- and exo-cyclized ethers, i.e., the cyclization of hydroxy vinylepoxide 5 (n=1 or 2, R1 =Me, R2=CH=CH2) with PPTS in CH2C12 at room temperature yielded a mixture of 6 and 7 in a ratio of 49:51 (n=1) and 23:77 (n=2), respectively (ref. 7). In order to enhance the endo-cyclization, we introduced a styryl group next to the epoxide (Scheme 7). The cyclization using styrylepoxide 25 (n=1 or 2) did effect the complete endo-cyclization, which suggested that the styryl group effectively served as an efficient regio-controller as expected (ref. 7). The best result for the 6-endo-cyclization of (Z)-styryl-trans-epoxide 25a (n=1) under acidic conditions was obtained by treatment with 0.2 equiv of CSA in C1tC12 at -78 •Ž to give a 90:10 ratio of (E/Z)-styryl- 2,3-trans-26 and (E/Z)-styryl-2,3-cis-2 7. The formation of (E)- and (Z)-olefins is not troublesome for the synthesis of marine polycyclic ethers because the olefin should be cleaved to an aldehyde for the ring elongation. The present 6-endo-cyclization would proceed via two transition states, i (n=1) for concerted cyclization and ii (n=1) for stepwise cyclization via styryl cation, since four isomers were

944 ( 80 ) J . Synth . Org . Chem . , Jpn Scheme 7

28

25

26 27 Table 1. Cyclization of Hydroxy Styrylepoxide 25

produced. The cyclization of 25a under basic conditions was then carried out. Upon treatment of 25a with 10 equiv of NaH in DMSO at room temperature, the cyclization smoothly proceeded in the 6-endo-mode with complete stereoselectivity to give (Z)-styryl-2,3-trans-tetrahydropyran 2 6 (n=1) as the single product in 97% yield. The complete stereoselectivity and retention of the (Z)-configuration of the styryl group supported that this cyclization concertedly proceeded via transition state iii. Thus, the cyclization of (Z)-styryl-trans-epoxide 25a with CSA or NaH proceeded only in the 6-endo-mode with high or complete stereoselectivity, giving the desired 2,3-trans-tetrahydropyran 2 6 (n=1).

i ii iii

The same reaction of (Z)-styryl-cis-epoxide 25b with CSA afforded a mixture of (E/Z)-trans-2 6 and (E/Z)-cis-2 7 in a ratio of 30:70. The reaction of 25b would mainly proceed via the transition state ii (n=1), since the ratio of (Z)-cis-27 obtainable via the concerted mechanism was very low. We then investigated the construction of the oxepane ring system by cyclization of hydroxy styrylepoxides 25 (n=2). The treatment of (Z)-styryl-trans-epoxide 25c with 1.0 equiv of PPTS in CH2C12at room temperature produced a 16:84 mixture of (E)-styryl-2,3-trans- and (E)-styryl-2,3-cis- oxepanes, 26 and 27 (n=2). The reaction of (Z)-styryl-cis-epoxide 25d also provided the same products 26 and 27 in almost the same ratio. Thus, the reaction of 25c and 25d effected the complete 7-endo-cyclization, but the stereochemistry of the main product was 2,3-cis and the double bond completely epimerized to the (E)-configuration. These results suggested that the cyclization of both ethers 25c and 25d predominantly proceeded via transition state ii (n=2) to give the same stable isomer 27 (n=2) as the main product. The present 6-endo-cyclization of hydroxy styrylepoxide was applied to the synthesis of the B-ring system of 2 using model compound 29 (Scheme 8) (ref. 20). The treatment of the styrylepoxide 29a (R=Ph) with PPTS' effected the complete 6-endo-cyclization to give the trans-tetrahydropyran 30a

Vol. 56, No .11 (November 1998) ( 81 ) 945

(R=Ph) as the single product, while NaH treatment afforded a 16:84 mixture of 6-endo- and 5-exo-cyclized compounds 30a and 31a. Therefore, 6-endo-cyclization under acidic conditions should be useful for the total synthesis of hemibrevetoxin B (2). On the other hand, the epoxide 2 9 b (R=H) having a vinyl group gave an almost one-to-one ratio of the endo- and exo-cyclized products 3 0 b and 3 1 b.

Scheme 8

29 30 31 Table 2. Cyclization of 29

3. Total Synthesis of Hemibrevetoxin B (2)

Hemibrevetoxin B (2) was isolated from the culture cells of the red tide organism Gymnodinium breve by Shimizu in 1989 (ref. 2). The characteristic structural feature includes a trans-fused 6,6 ,7,7- tetracyclic ether ring (ABCD-ring system) having ten chiral centers, an a-vinyl aldehyde and a (Z)-diene moiety. This unique complex structure and potent biological activity have attracted the attention of numerous synthetic organic chemists. The first total synthesis of 2 was accomplished by the Nicolaou group in 1992 (ref. 22), and recently Yamamoto (ref. 23) and our groups (ref. 8,9) also completed the total synthesis. Quite recently, the formal total synthesis was reported by the Mori group (ref. 24). As mentioned above, we developed two efficient methods for construction of the B-, C-, and D-ring systems. The remaining problem was the construction of the A-ring system having the side chain. Our strategy involves direct introduction of a C-4 unit as the side chain in one step to the A-ring lactol. This strategy was realized in our model studies (ref. 20), which will be presented in the real total synthesis of hemibrevetoxin B (2). Having established efficient and reliable methods for construction of the A-, B-, C-, and D-ring systems, we next directed our attention to the total synthesis of hemibrevetoxin B (2). Our retrosynthesis based on the newly developed methods is outlined in Scheme 9. Direct introduction of the C-4 unit as the side chain on the A-ring was set at the final stage. Construction of the B-ring system in 3 3 would be achieved by the 6-endo-cyclization of the hydroxy styrylepoxide 3 4. Our strategy includes the most challenging task for the efficient and unique synthesis of the CD-ring system, i.e., the one-step

Scheme 9

Hemibrevetoxin B (2) 32

946 ( 82 ) J . Synth . Org . Chem . , Jpn 33 34

35 36 Geranyl acetate (37)

construction of the 7,7-membered CD-ring system 35 by double rearrangement-ring expansion of the 6,6-membered bicyclic ether 3 6, which would be prepared starting from geranyl acetate (3 7) . The synthesis of the 6,6-membered bicyclic ether 4 5, a substrate for the double rearrangement- ring expansion, is summarized in Scheme 10 (ref. 8). Our synthesis began with allyl alcohol 3 8 prepared from readily available geranyl acetate (3 7). The Sharpless asymmetric epoxidation (AE) (ref. 25) of 38 produced the a-epoxide, which led to the triol 3 9 by regio- and stereoselective ring-opening of the epoxide with PhCO2H and Ti(O-i-Pr)4 (ref. 26) and deprotection of the THP group with Dowex(R) (50W-X2) in Me0H. The allyl alcohol 3 9 was again subjected to the Sharpless AE to give the β-epoxide, which was cyclized to the 6-membered ether 40 by acidic work-up. Proper protection of the hydroxy groups in 40 led to the acetonide 41 in five steps: 1) acetonization , 2) methanolysis of benzoate, 3) silylation, 4) benzylation, and 5) deprotection of the silyl group . The alcohol 41 was converted into the allyl alcohol 42 via introduction of the allyl group , the Wacker oxidation, the Horner-Emmons reaction, and diisobutylaluminum hydride (DIBAH) reduction . The Sharpless AE of 42 followed by hydrogenolysis of the benzyl ether afforded the epoxy alcohol 43 . Treatment of 43 with NaH in DMSO followed by addition of tosylchloride effected 6-exo-cyclization and successive epoxide formation in one pot to give the 6,6-membered bicyclic ether 44. Addition of an allyl group to the epoxide 44, deprotection of the acetonide, and selective acetylation of the primary alcohol (ref . 27) provided the acetate 45. With the requisite substrate for the double rearrangement-ring expansion in hand, we were now ready to try the most challenging task in the total synthesis of hemibrevetoxin B (2) .

Scheme 10

38 39

40 41

Vol.56, No .11 (November 1998) ( 83 ) 947 42 43

44 45

The new efficient procedure using monocWate was applied to the double rearrangement-ring expansion. Upon treatment of the bismonocWate 46 with zinc acetate in Ac0H-1120 at 60 to 80 •Ž, the desired double rearrangement effectively took place to give the 7,7-membered ether, corresponding to the CD-rinqsystem, which was subjectedto methanolysisto give the triol 4 7 (Scheme 11) (ref. 9). Based on the H-NMR analysis, the bismonochlate 46 proved to have an antiperiplanar conformation in respect of the C-0 bond of the tetrahydropyran and monocWate as the leaving group as shown in 46 -A, which is favorable for the formation of the oxonium ion, the transition state of the rearrangement-ring expansion reaction.

Scheme 11

45 46

46-A 47 With the CD-ring system in hand, we focused our attention on the formation of the AB-ring system (Scheme 12). Tosylation of 4 7 and insertion of the cyano group gave the nitrile 4 8. After the double bond of 4 8 was oxidized with 0s04-N-methylmorpholine N-oxide (NMO), the resulting diol was protected as the acetonide 4 9. The nitril 4 9 was converted into an unsaturated ester 5 0 via DIBAH reduction, the Wittig reaction, and protection as the TMS ether. Reduction of 5 0 with DIBAH followed by the Sharpless AE gave the a-epoxide, which was subjected to oxidation with tetrapropylammonium perruthenate (TPAP)-NMO (ref. 28) and the Wittig reaction using Ph3P=CHPh to give the styrylepoxide

948 ( 84 ) J . Synth. Org . Chem . , Jpn

Scheme 12

47 48

49 50

51 52

53 55 54 51. Deprotectionof the silyl group in 51 with n-Bu4NFfollowed by CSA treatmenteffected exclusive endo-cyclizationto give the 6-memberedether, correspondingto the B-ring system,which was subjected to acetylationand silylationto give the TBS ether 5 2. Ozonolysisof the styryl group followedby the Grignardreaction using allylMgCl produced the desired n-alcohol5 3 and the a-isomer 5 4 in 59% and 29% yields, respectively. The latter isomer5 4 was also convertedinto the desired key intermediate5 7 in severalsteps. Ozonolysisof 5 3 followedby treatmentof the resultinglactol with Dowex(R)(50W-X2) in Me0H simultaneouslyeffected 6-membered acetal formation and deprotectionof the acetonideto give the diol, which was cleavedwith sodiumperiodate to give the aldehyde5 5. The final route that led to completionof the total synthesis of hemibrevetoxin B (2) is shown in Scheme 13. The (Z)-dieneunit was first introducedaccording to Nicolaou's procedure(ref. 22). The Wittigreaction of 55 using PhSeCH2CH2CH=PPh3 followed by hydrogen peroxidetreatment provided the (Z)-diene5 6. Then, directintroduction of the C-4 unit as the A-ringside chain was achievedin one step from 5 6 based on our model studies (ref. 20). The reaction of the acetal 56 with CH2=C(CH2OAc)CH2TMSin the presence of TMSOTf in MeCN exclusivelyafforded the 13-axial allylatedproducts: a mixtureof TBS ether 5 7 and deprotecteddiol 5 8. The TBS ether 57 was again treated with TMSOTfin MeCN to give the diol 5 8. Methanolysisof the acetate58 gave allyl alcohol 5 9, which was finallyoxidized with manganesedioxide in ether to give a ,13-unsaturatedaldehyde 2,

Vol . 56 , No . 11 (November 1998) ( 85 ) 949

Scheme 13

55 56

57 58

59 Hemibrevetoxin B (2)

corresponding to hemibrevetoxin B (2) (ref. 9). The1 and13 C-NMR spectra of the synthetic 2 were identical with those of natural hemibrevetoxin B (2). In summary, we have achieved the stereoselective total synthesis of hemibrevetoxin B (2) by a unique synthetic strategy, in which the effectiveness of our recently developed methods was demonstrated. Our total synthesis 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 to the A-ring . The present synthetic strategy which we have developed should be effectively applicable to the synthesis of other marine polycyclic ethers.

Acknowledgement

The author is deeply indebted to his co-workers whose names are indicated in the references cited herein. The author thanks Prof. Y. Shimizu (The University of Rhode Island) for providing the NMR spectra of natural hemibrevetoxin B (2). This work was supported in part by Special Coordination Funds of the Science and Technology Agency, Japan and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan.

References and Notes

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