A New Synthetic Route to the Skeleton of Saxitoxin, a Naturally Occurring Blocker of Voltage ─ Gated Sodium Channels Yusuke Sawayama and Toshio Nishikawa ＊

Home , Saxitoxin

Department of Applied Biological Sciences, Graduate School of Bioagricultural Sciences, Nagoya University Nagoya 464 ─ 8601, Japan

(Received July 2, 2012; E ─ mail: [email protected])

Abstract: Saxitoxin is as potent and specic blocker of voltage ─ gated sodium channels as tetrodotoxin. This unique biological activity has established the importance of these two small natural products in neurophysio- logical experiments. In order to nd new blockers of the voltage ─ gated sodium channels, an efcient synthetic route to the skeleton of saxitoxin was developed. This new synthetic route is based on two key reactions (i) cascade cyclization of a guanidino ─ acetylene initiated by the bromocation (Br ＋) and (ii) transformation of the geminal ─ dibromomethylene moiety to enol acetate, and culminated in the total synthesis of decarbamoyl ─ α ─ saxitoxinol, a naturally ─ occurring analog of saxitoxin.

1． Introduction Saxitoxin (1, STX) and tetrodotoxin (2, TTX) are famous marine natural products isolated as toxic principles of para- lytic shellsh poison (PSP) and puffersh intoxication, respectively (Figure 1). 1 These two small natural toxins exert their potent toxicity by specic blockage of sodium ion inux through voltage ─ gated sodium channels (VGSC) without interfering with any other ion channels such as potassium or chloride channels on the neuro cell membrane. 2 Due to this unique biological property and their high afnity for the VGSC, STX and TTX have played signicant roles in the identication and elucidation of the biological function(s) of the channel proteins. 3

Figure 2. (a) The schematic structure of VGSC and (b) the subtypes (isoforms) of human VGSC. Figure 1. Saxitoxin (1, STX) and tetrodotoxin (2, TTX), naturally occurring VGSC blockers.

Recently, genetic analyses have revealed that ten subtypes

(isoforms) of VGSC (Na v 1.1 ─ 1.9 and Na x) are expressed in different organs of mammals, and that each subtype has different and unique biological functions (Figure 2). 4 For example,

Na v 1.5 is predominantly expressed in cardiac muscle, while

Na v 1.7 and 1.8 are found in central neurons and are responsi-

ble for the sensation of pain. Interestingly, Na v 1.5, 1.7 and 1.9 are not inhibited by STX and TTX (so ─ called TTX ─ resistant sodium channels). Subtype ─ selective VGSC inhibitors therefore are highly desired, not only for analyses of channel biological functions, but also for the development of drugs for the treatment of epilepsy, pain and arrhythmia. Several subtype ─ selective inhibitors based on the structures of TTX and STX 5 have been reported (Figure 3); 4,9 ─ anhydro ─ TTX (3), a natu- 6 ral analog of TTX, selectively inhibited Na v 1.6, compound 4,

a simplied analog of STX shows inhibitory activity of Na v Figure 3. Subtype ─ selective inhibitors of VGSC.

1 178 （ 70 ） J. Synth. Org. Chem., Jpn.

有機合成化学70-11＿0006論文_Sawayama.indd 70 2012/10/19 14:05:24 7 1.1 and 1.2, and STX ─ related compound 5 inhibits Na v 1.4 ration of diverse STX analogs for developing subtype ─ selective 8 and 1.5. On the other hand, A ─ 803467 (6), a compound struc- blockers of VGSC. turally unrelated to TTX or STX, was also reported to be a Initial Synthetic Strategy

potent and selective blocker of Na v 1.8, and has been devel- Our initial idea for the synthesis of STX arose with recog- oped as a therapeutic agent for neuropathic and inammatory nition of the single carbon chain in the STX core skeleton, pain. We have also been interested in developing subtype ─ which inspired us to conceive a new synthetic route commenc- selective inhibitors of VGSC based on STX and TTX. 9 This ing from a simple intermediate B as shown in Scheme 1. We account describes the details of our synthetic efforts toward envisioned that the tricyclic skeleton of STX would be con- STX, focusing on synthesis of the guanidine ─ containing core structed from a bis ─ guanidino ─ acetylene A by double halocy- structure as well as the underlying logic and strategy. 10 clizations (A to C & C to D) for the synthesis of the two cyclic guanidines, and an intramolecular N ─ alkylation for the pyrro- 2． Synthetic Strategy Toward the STX Skeleton lidine synthesis (D to E). We expected these three cyclizations Saxitoxin (1) is a representative densely ─ functionalized would proceed in cascade fashion, or in one ─ pot. The precur-

natural product. The molecular formula (C 10H 19N 7O 4), and the sor A for this cascade cyclization could be readily prepared by structure containing two cyclic guanidiniums and a hydrated bis ─ guanylation of an anti ─ diaminoacetylene B, a relatively ketone clearly indicate the special features that characterize a simple compound. 18 heteroatom ─ rich small molecule. Since more than thirty ana- This strategy relies on two reactions; (i) cascade bromocy- logs of STX have been isolated from nature, a synthetic route clizations (halocyclizations) of a guanidino ─ acetylene, and (ii) to STX should enable access to these various analogs, includ- transformation of the geminal ─ dibromomethylene moiety to a ing neosaxitoxin (7, N ─ hydroxylated), gonyautoxin 3 (8, sulfo- ketone (E to STX skeleton). When we initiated this project, a nated) and zetekitoxin AB (9) shown in Figure 4. 11 few examples of the former transformation had been reported. 19 ─ 21 and the latter transformation had been reported only for specic substrates (vide infra). First of all however, we prepared a possible precursor 10, and attempted the cascade reaction by exposing it to sources of the bromocation (Br ＋)

such as NBS and pyridinium tribromide (PyHBr 3) (Scheme 2). However, to our disappointment, the desired bicyclic guanidine 12 was not obtained at all. Instead, ve ─ membered guanidine 11 was obtained in a poor yield under a limited range of conditions, while six ─ membered cyclic guanidine product was not detected. When the product 11 was isolated and exposed to Br ＋ again, the second cyclization did not proceed. These results Figure 4. Naturally ─ occurring Analogs of STX. led us to suppose that the rate of ve ─ membered cyclization was much faster than that of six, and that the ve ─ membered Due to its unique structure as well as its potent biological ring product might not be a suitable precursor for the second activity, STX has been an attractive synthetic target for natural cyclization. However, we had not yet understood the whole product synthesis since its structure elucidation in 1970s. 12 To picture concerning the bromocyclization of guanidino ─ acety- date ve researchers Kishi, 13 Jacobi, 14 Du Bois, 15 Nagasawa 16 lenes. We therefore decided at this stage to investigate optimi- and Looper 17 have independently reported elegant total syn- zation of the conditions and the regioselectivites for the bro- theses of STX and its analogs. Although their synthetic routes mocyclization of guanidino ─ acetylenes by utilizing model are all unique and efcient, a simpler, more versatile synthetic compounds. route has been desired to make possible the expeditious prepa- In the halocyclization of a guanidino ─ acetylene, there are

Scheme 1. Our initial synthetic strategy for construction of the STX skeleton.

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有機合成化学70-11＿0006論文_Sawayama.indd 71 2012/10/19 14:05:28 Scheme 2. The rst attempt at a cascade bromocyclization of Scheme 3. Two possible modes of bromocyclization for (a) propar- bis ─ guanidino ─ acetylene 10. gyl guanidine F and (b) homopropargyl guanidine I for the synthesis of the STX skeleton.

two possible modes of cyclization; the exo ─ and endo ─ modes (Scheme 3). Propargyl guanidine F can undergo 5 ─ exo ─ dig cyclization and/or 6 ─ endo ─ dig cyclization, leading to ve ─ membered ring product G and/or six ─ membered ring product ＋ H, respectively (Scheme 3(a)). On the other hand, homo- the source of bromocation (Br ), no reaction was observed, propargyl guanidine I can undergo 5 ─ endo ─ dig cyclization indicating the poor reactivity of this reagent. We next exam- ＋ and/or 6 ─ exo ─ dig cyclization leading to ve ─ membered ring ined pyridinium tribromide (PyHBr 3) as a more reactive Br product J and/or six ─ membered ring product K (Scheme 3(b)). source (Table 1). When 13a was treated with PyHBr 3 in the Although both 6 ─ endo ─ dig and 5 ─ endo ─ dig cyclizations may presence of K 2CO 3 in CH 2Cl 2, simple bromination of the be possible according to the Baldwin’s rules, 22 we anticipated alkyne moiety took place to give dibromoalkene 15 in a good that the exo ─ mode of cyclization would proceed preferentially yield (entry 1). The same reaction when conducted in a bipha- in both cases to yield the desired cyclic guanidine products G sic solvent system comprising of CH 2Cl 2 and H 2O (1:1) and K, respectively. afforded the spiro ─ hemiaminal 16a as a single diastereomeric product in moderate yield (entry 2). This result indicates that 3． Bromocyclization of Guanidino ─ acetylenes the expected six ─ membered ring product 14 further reacted ＋ 3.1 Bromocyclization of Homopropargyl Guanidines with an excess amount of Br to give the compound 16a by Bromocyclization of homopropargylguanidine to give the trapping of an iminium ion intermediate by an internal six ─ membered cyclic guanidine was examined rst. Com- hydroxy group. The similar spiro ─ product 16b was obtained in pounds 13a ─ c were selected as model substrates having the better yield, when mono ─ protected guanidine 13b was treated same carbon number as the STX skeleton, and exposed to a under the same conditions (entry 3). In order to intercept and variety of conditions for bromination. Our preliminary experi- isolate the six ─ membered ring product 14, substrate 13c with ments revealed that bromocyclization was better than iodocy- the hydroxy group protected with TBS was exposed to the clization because of product stability. When NBS was used as same conditions (entry 4). However, the expected product 14

Table 1. Bromocyclization of homopropargyl guanidines 13a ─ c.

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有機合成化学70-11＿0006論文_Sawayama.indd 72 2012/10/19 14:05:34 was not obtained, and instead aminopyrimidine 17 was Scheme 4. Proposed mechanism of bromocyclization of 13a ─ c. obtained in low yield as the sole product, formed by aromatization through deprotonation of the iminium intermediate. These model experiments led us to conclude that (i) the biphasic solvent system is crucial for this bromocyclization of 13, (ii)

the rst cyclized product 14 is too reactive toward PyHBr 3to isolate, however, (iii) spiro ─ hemiaminal 16 can be isolated when a hydroxy group is present in the substrate. A reaction mechanism and a role for the biphasic solvent system in the bromocyclization are proposed as illustrated in

Scheme 4. Guanidino ─ acetylenes 13a ─ c react with PyHBr 3 to generate bromonium ion intermediates L, which are attacked by the internal guanidine to form the six ─ membered cyclic guanidines 14. In the absence of water, dibromoalkene 15 is obtained, probably because cyclization is inhibited by proton- ation of the guanidine with HBr even in the presence of pow-

der K 2CO 3 as a base. On the other hand, aqueous K 2CO 3 efciently neutralizes HBr to maintain the nucleophilicity of the guanidine group, resulting in production of 14. Since the resulting bromoenamines 14 are more reactive than 13a ─ c toward Br ＋, iminium ion intermediates M are spontaneously generated and trapped with an internal hydroxy group when present to afford dibromo ─ spiro ─ hemiaminals 16. When the hydroxy group of the intermediate M is protected with TBS, deprotonation and then aromatization give aminopyrimidine 17. These conditions are applicable to bromocyclization of a fully functionalized compound 29 for synthesis of the STX skeleton. The preparation of 29 is shown in Scheme 5. Reac- treated with triethylamine to afford aziridine 22. 25 The aziri- 23 tion of (S ) ─ Garner’s aldehyde 18 with the lithium acetylide dine was then guanylated with Boc, Cbz ─ protected methyliso- derived from a siloxybutyne in the presence of HMPA gave 19 thiourea 23 to give a 1:1 diastereomeric mixture of product with high diastereomeric ratio (＞10:1). 24 Mesylation of the 25. 26 The unique structure of the product allowed differentia- resulting propargyl alcohol, followed by removal of all the tion between the two primary hydroxy groups and hence selec- protective groups of 20 yielded amino alcohol 21, which was tive protection of the remaining free hydroxy group as its TBS

Scheme 5. Synthesis of spiro ─ hemiaminal guanidine 30.

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有機合成化学70-11＿0006論文_Sawayama.indd 73 2012/10/19 14:05:41 ether, while the masked alcohol could then be protected as its gyl guanidines 34a,b, fully functionalized precursors for the acetate to afford 27 in high yield. Regioselective ring opening synthesis of the STX skeleton were synthesized as shown in of the aziridine with sodium azide and removal of the TBS Scheme 6. The two hydroxy groups of aziridine 22 prepared group provided 28. Removal of the Boc group with TFA from 20, were protected as TBS ethers to give 31, then the Ns afforded 29, a precursor for bromocyclization. To our delight, group was introduced to the aziridine to yield 32. 28 When 32 29 underwent bromocyclization under the same conditions we was treated with aqueous ammonia, followed by guanylation had already optimized to form spiro ─ six ─ membered cyclic with isothiourea 31 gave propargyl guanidine 34a. Treatment guanidine 30 as a single diastereomer in good overall yield. 27 of 34a with TBAF led to selective removal of TBS to afford Since the spiro ─ hemiaminal structure of 30 could be trans- 34b. formed into an iminium ion intermediate under acidic condi- Bromocyclization of 34a,b was then investigated. Repre- tions, 30 is a potential precursor for formation of the second sentative results are listed in Table 2, which shows that exclu- cyclic guanidine. sive exo ─ mode cyclizations occurred in all cases, just as we had 3.2 Bromocyclization of Propargylguanidines expected. In sharp contrast to the bromocyclization of homo- We next examined bromocyclization of propargylguani- propargylguanidines described in 3.1, the propargylguanidine dine for synthesis of ve ─ membered cyclic guanidines. Propar- 34a reacted with NBS in dichloromethane to afford the desired product 35 in 45% yield (entry 1). When two equivalents of NBS were utilized, the product 35 was not detected but amino- Scheme 6. Preparation of propargylguandines 34a,b. imidazole 36 was obtained instead (entry 2). This result indicates that the compound 35 reacts with the excess NBS to afford aminoimidazole 36 through aromatization. Upon treat-

ment of 34a with PyHBr 3 in the biphasic system (CH 2Cl 2 and

aqueous K 2CO 3), the yield of 35 was improved to 70% yield (entry 3). When the substrate 34b was exposed to three equiva-

lents of PyHBr 3 under similar conditions, spiro ─ hemiaminal guanidine 37 was obtained in 74% yield as a ca. 2:1 diastereo- mixture at the spiro center, and the aromatized product 36 was not obtained (entry 4). The products 35 and 37 are potentially useful intermediates for preparing STX through a second bromocyclization. 4． Attempts at Stepwise Cyclizations We had established new methodology for the synthesis of ve ─ and six ─ membered cyclic guanidine compounds by bromocyclization of propargyl and homopropargyl guanidines, respectively. Since these products can be regarded as precursors for the second guanidine cyclization, we next attempted to install the second guanidine function and to construct the bis ─ cyclic guanidine structure as represented by step C to D in Scheme 1.

Table 2. Bromocyclization of propargyl guanidines 34a and 34b.

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有機合成化学70-11＿0006論文_Sawayama.indd 74 2012/10/19 14:05:46 Scheme 7. Attempts at a second bromocyclization of 38 and 42.

4.1 Approach from Five ─ membered Cyclic Guanidine We therefore decided to transform this function to a ketone Compounds before reduction of the azide. Hydrolysis of geminal ─ dibromo-

In order to attempt the second bromocyclization forming a methylene groups with AgNO 3 has been reported only for spe- six ─ membered guanidine, a monoprotected guanidine was cic substrates with the bromo substituents at a benzylic posi- introduced into 35 on the basis of the results of model studies tion. 31 However, such conditions did not work at all in the case described in 3.1. Mono ─ Boc protected guanidine 38 was pre- of 30. In the course of trial and error experiments, we seren- pared from 35 in three steps; removal of the Ns group, 29 gua- dipitously found a novel reaction, which transformed the gemi- nylation with 23 and hydrogenolysis of the Cbz group nal ─ dibromomethylene to an enol acetate when the compound

(Scheme 7). The resulting 38 was then exposed to the condi- 30 was simply treated with Ac 2O and Et 3N in CH 2Cl 2 at room

tions (PyHBr 3, K 2CO 3 in CH 2Cl 2─ H 2O) optimized for bromo- temperature to acetylate the guanidine (Scheme 8). The prod- cyclization of guanidino ─ acetylenes. However, the desired bis ─ uct 45 was not isolated due to its instability, but the corre- guanidine 40 (R 1=TBS, R 2=Boc) was not detected, and instead sponding diol 47 was isolated and fully characterized after aminoimidazole 39 was obtained. On the other hand, mono ─ Cbz protected guanidine 42 was prepared from 35 by removal Scheme 8. Transformation of geminal ─ dibromomethylene to enol of the Ns group, guanylation with 41, desilylation and migra- acetate. tion of Cbz by treatment with benzoic acid, 30 and was then exposed to the same bromocyclization conditions. However, this time neither the desired product 40 (R 1=R 2=Cbz) nor the aromatized product was obtained. In this specic case, an unexpected product was obtained in a good yield. To our sur- prise, the structure was deduced proved to be 43, through X ─ ray crystallographic analysis of 44 derived from 43. These results indicate that substrates 38 and 42 did react with the bromocation (Br ＋) to form iminium ion intermediates, however, cyclization with the internal guanidine did not proceed. Rather deprotonation from the iminium ion intermediate took place to afford 39 in the case of 38 as substrate, while a series of neighboring group participations yielded 43 in the case of 42. We reason that the iminium cation center and the second guanidine function are too close to cyclize in these two cases. 4.2 Approach from Six membered Cyclic Guanidine Compounds ─ For stepwise synthesis of the STX skeleton from six ─ membered cyclic guanidine 30, installation of the second guanidine functionality was examined. However, reduction of the azide group proved to be difcult, probably because of steric hin- drance due to the neighboring geminal ─ dibromo substituents.

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有機合成化学70-11＿0006論文_Sawayama.indd 75 2012/10/19 14:05:51 reduction with NaBH followed by hydrolysis of the acetate of 4 5． An Alterative Synthetic Strategy to STX Skeleton by the primary hydroxy group. Hence we had fortunately estab- Cascade Cyclization lished new conditions for the crucial transformation in our synthetic plan for STX, although the reaction’s mechanism, In the bromocyclization of 29, formation of the spiro ─ scope & limitations have not been claried yet. 32 hemiaminal structure of product 30 was indispensable for pre- As we expected, the azide group of 47 was successfully venting aromatization from the iminium ion intermediate

reduced under the Staudinger conditions (Me 3P in CH 2Cl 2) (Scheme 5). However, the same spiro ─ structure was too stable and then guanylated to give 48, a precursor of the second to hydrolyze for the second cyclization with an internal guani- cyclization (Scheme 9). However, despite many efforts to dine. We considered another possibility, that of trapping the achieve cyclization by utilizing a variety of Lewis acids and iminium ion intermediate by the other hydroxy group, leading Brønsted acids, the desired product 50 was not detected, and to bicyclic intermediate P through O as shown in Scheme 10. starting material 48 was recovered. These results indicate that If a leaving group is present on the other end of this substrate, the spiro ─ hemiaminal of 48 is too stable under acidic condi- an intramolecular N ─ alkylation would then give a tricyclic tions to generate an iminium ion intermediate 49. Thus, at this compound in a one ─ pot reaction (P to Q). The resulting Q crucial juncture, we modied the original synthetic plan on the possessing the oxaazabicyclo[3.2.1]octane structure is a possi- basis of the experimental results obtained in this study. ble precursor for STX synthesis (vide infra). This consideration led us to examine compound N (R 1=carbamate, R 2=sulfonyl group) as a precursor for this new cascade cyclization. Compound 53, equivalent to precursor N, was prepared in Scheme 9. Attempted synthesis of bicyclic guanidine 50. ve steps from intermediate 27 of Scheme 5 (Scheme 11). The

aziridine of 27 reacted with NaN 3 at the propargylic position, and the TBS ether of the product was transformed to the cor-

Scheme 10. Alternative synthetic strategy for the STX skeleton.

Scheme 11. Synthesis of oxaazabicyclo[3.2.1]octane 58.

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有機合成化学70-11＿0006論文_Sawayama.indd 76 2012/10/19 14:05:58 responding mesylate 51 in two steps. Due to the labile nature 6． Conclusion of the homopropargyl mesylate, cleavage of the acetyl group was carried out under mild conditions utilizing KCN in etha- This account describes the details of our efforts directed nol to yield 52. 33 Removal of the Boc group with TFA followed toward concise synthesis of the STX skeleton. Our initial idea by treatment with an ion exchange resin gave 53, the precursor for a one ─ step construction of this structure shown in

for bromocyclization. When 53 was treated with PyHBr 3, Scheme 1 has not been realized yet, however, the new route

K 2CO 3 in the biphasic solvent system, the desired oxaazabicy- designed on the basis of our own experimental results did pro- clo[3.2.1]octane 58 was obtained as anticipated. 34 The reaction vide an efcient entry to the STX skeleton. In particular, two is proposed to proceed as shown in Scheme 11. In this way a new reactions (i) a cascade reaction initiated by bromocyliza- cascade reaction involving the formation of ve bonds (C ─ Br x tion of a guanidino ─ acetylene and (ii) transformation of the 2, C ─ O x 1, C ─ N x 2) was realized. geminal ─ dibromomethylene moiety to enol acetate play pivotal roles in the success of the new route. Since the tricyclic com- 5． Completion of the Synthesis of STX Skeleton pound 58 is both efciently synthesized and stable, it will be With tricyclic compound 58 in hand, transformation to the employed as a common intermediate for the synthesis of a STX skeleton was then examined (Scheme 12). To our delight, variety of analogs of STX for developing subtype ─ selective the geminal ─ dibromomethylene group of 58 was successfully inhibitors of VGSC. Along these lines, the synthesis of zeteki- transformed into the corresponding enol acetate under the toxin AB (9) and other analogs of STX from 58 are currently acetylation conditions we had found. Reduction of the unsta- under investigation in this laboratory. This research was car-

ble product with NaBH 4 gave alcohol 59 as a single product. ried out as a part of the Ph.D. study of Y. S., one of the The azide group was then reduced under the Staudinger condi- authors of this account. tions to an amine, which was guanylated to give 60. The three On the other hand, the bromocyclization of guanidino ─ Cbz groups of 60 were removed under hydrogenolysis condi- acetylenes also provides a new general methodology for ef-

tions and subsequent treatment with B(TFA) 3 in TFA at room cient construction of ve ─ and six ─ membered cyclic guani- 35 temperature furnished tricyclic compound 63. Under these dines. For example, since a similar spiro ─ hemiaminal ─ guani- conditions, iminium ion 62 was generated and trapped by the dine structure is found in crambescin B (64) shown in 37 guanidine group. This product 63, decarbamoyl ─ α ─ saxitoxinol Figure 5, a marine natural product, synthetic studies towards is a natural product, named as Lyngbya wollei toxin 4, isolated 64 based on the bromocyclization strategy are also in progress. from cyanobacterium Lyngbya wollei by Oshima and co ─ work- ers. 36

Scheme 12. Construction of the STX skeleton and total synthesis of decarbamoyl ─ α ─ saxitoxinol 63.

Figure 5. Crambescin B (64), a marine natural product.

Acknowledgement We are grateful to Prof. Yasukatsu Oshima (Kitasato Uni- versity) for providing NMR spectra of compound 63. X ─ ray crystallographic analysis of 44 was carried out by Prof. Atsushi Wakamiya (Kyoto University) and Prof. Shigehiro Yamaguchi (Nagoya University), whom we thank. This research was nan- cially supported by a Grant ─ in ─ aid for scientic research and G ─ COE program from JSPS, a Grant ─ in ─ Aid for Scientic Research on Innovative Areas from MEXT, the Naito foundation, and Nagase Science and Technology Foundation. Y. S. thanks the SUNBOR scholarship and Nagoya University scholarship for outstanding graduate students.

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F.; Honore, P.; Shieh, C. ─ C.; Chapman, M.; Joshi, S.; 27） When the corresponding salt with TFA was employed for this cycliza- Zhang, X. ─ F.; Kort, M.; Carroll, W.; Marron, B.; Atkinson, R.; tion, the yield of 30 decreased. Thomas, J.; Liu, D.; Krambis, M.; Liu, Y.; McGaraughty, S.; Chu, K.; 28） Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Tetrahedron Roeloffs, R.; Zhong, C.; Mikusa, J. P.; Hernandez, G.; Gauvin, D.; 1999, 55, 2183. Wade, C.; Zhu, C.; Pai, M.; Scanio, M.; Shi, L.; Drizin, I.; Gregg, R.; 29） Narayan, R. S.; VanNieuwenhze, M. S. Org. Lett. 2005, 7, 2655. Matulenko, M.; Hakeem, A.; Gross, M.; Johnson, M.; Marsh, K.; 30） Albrecht, C.; Barnes, S.; Böckemeier, H.; Davies, D.; Dennis, M.; Wagoner, P. K.; Sullivan, J. P.; Faltynek, C. R.; Krafte D. S. Proc. Evans, D. M.; Fletcher, M. D.; Jones, I.; Leitmann, V.; Murphy, P. J.; Natl. Acad. Sci. USA 2007, 104, 8520. (b) McGaraughty, S.; Chu, K. Rowles, R.; Nash, R.; Stephenson, R. A.; Horton, P. 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(c) Yamashita ─ Yotsu, M.; Kim, Y. 790. H.; Dudley, S. C.; Choudhary, G.; Pfahnl, A.; Oshima, Y.; Daly, J. W. 34） Du Bois reported the synthesis of a similar compound to 57 (see ref. Proc. Natl. Acad. Sci. USA 2004, 101, 4346. (d) Furman, F. A.; 15b). Furman, G. J.; Mosher, H. S. Science 1969, 165, 1376. 35） The conditions were identical to those employed in the total synthesis 12） (a) Schantz, E. J.; Ghazarossian, V. E.; Schnoes, H. K.; Strong, F. M.; of saxitoxin by Du Bois and Nagasawa (see Ref. 15 and 16). Springer, J. P.; Pezzanite, J. O.; Clardy, J. J. Am. Chem. Soc. 1975, 97, 36） Onodera, H.; Satake, M.; Oshima, Y.; Yasumoto, T.; Carmichael, W. 1238. (b) Bordner, J.; Thiessen, W. E.; Bates, H. A.; Rapoport, H. J. W. Nat. Toxins 1997, 5, 146. Am. Chem. Soc. 1975, 97, 6008. 37） (a) Jares ─ Erijman, E. A.; Ingrum, A. A.; Sun, F.; Rinehart, K. L. J. 13） (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc. Nat. Prod. 1993, 56, 2186. (b) Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 1977, 99, 2818. (b) Kishi, Y. Heterocycles 1980, 14, 1477. (c) Hong, C. 58, 2828. Y.; Kishi, Y. J. Am. Chem. Soc. 1992, 114, 7001. 14） (a) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc. 1984, 106, 5594. (b) Martinelli, M. J.; Brownstein, A. D.; Jacobi, P. A.; Polanc, S. Croat. Chem. Acta 1986, 59, 267. (c) Jacobi, P. A. In Strate- gies and Tactics in Organic Synthesis; Lindberg, T., Ed.; Academic PROFILE Press: New York, 1989; Vol. 2, p 191. 15） (a) Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926. (b) Toshio Nishikawa is a Professor of Graduate Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. School of the Bioagricultural Sciences, Na- 2007, 129, 9964. (c) Andresen, B. M.; Du Bois, J. J. Am. Chem. Soc. goya University. He was born in 1962, and 2009, 131, 12524. (d) Mulcahy, J. V.; Du Bois, J. J. Am. Chem. Soc. received his B.Sc. (1985) from Shizuoka Uni- 2008, 130, 12630. versity (Prof. Daisuke Uemura), and his 16） (a) Iwamoto, O.; Koshino, H.; Hashizume, D.; Nagasawa, K. Angew. M.Sci (1987) and Ph.D. degrees (1995) from Chem. Int. Ed. 2007, 46, 8625. (b) Iwamoto, O.; Shinohara, R.; Nagoya University under the direction of Nagasawa, K. Chem. Asian J. 2009, 4, 277. (c) Iwamoto, O.; Prof. Minoru Isobe. From 1988 to 2005, he Nagasawa, K. Org. Lett. 2010, 12, 2150. worked as an assistant Professor at Nagoya 17） Bhonde, V. R.; Looper, R. E. J. Am. Chem. Soc. 2011, 133, 20172. University, and as associate Professor from 18） This strategy is similar to that of the total synthesis of STX by 2005 to 2008, and was promoted to Professor Looper (ref. 17). They synthesized the STX skeleton by a silver (I) and in 2008. He received Incentive Award in Syn- iodine ─ mediated one ─ pot cascade cyclization from a bis ─ guanidino ─ thetic Organic Chemistry, Japan (2002). His acetylene. research interests are centered on natural 19） Hydroaminations of guanidino ─ acetylenes have recently been products synthesis along with the develop- reported: (a) Gainer, M. J.; Bennett, N. R.; Takahashi, Y.; Looper, R. ment of new synthetic reactions and chemical E. Angew. Chem. Int. Ed. 2011, 50, 684. (b) Ermolat’ev, D. S.; Bariwal, biology. J. B.; Steenackers, H. P. L.; De Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew. Chem. Int. Ed. 2010, 49, 9465. (c) Perl, N. R.; Ide, N. D.; Prajapati, S.; Perfect, H. H.; Durón, S. G.; Gin, D. Y. J. Am. Chem. Soc. 2010, 132, 1802. (d) Giles, R. L.; Sullivan, J. D.; Steiner, A. M.; Yusuke Sawayama received his B.Sc. (2006) Looper, R. E. Angew. Chem. Int. Ed. 2009, 48, 3116. and M.Sc. (2008) under the direction of Prof. Minoru Isobe and Ph.D. degree (2011) under 20） Noguchi, M.; Okada, H.; Watanabe, M.; Okuda, K.; Nakamura, O. Tetrahedron 1996, 52, 6581. the direction of Prof. Toshio Nishikawa of Nagoya University. He joined Dainippon 21） Recently, Looper reported an iodocyclization between guanidine and olen (see ref. 17). Sumitomo Pharma Co., Ltd. (2011), where he is currently a researcher. His research in- 22） (a) Baldwin, J. E. J. Chem. Soc., Chem. Commum. 1976, 734. (b) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 736. terests are in the areas of medicinal chemistry, natural product synthesis, and bioor- 23） Garner, P.; Park, J. M. Org. Synth. 1998, Coll. Vol. 9, 300. ganic chemistry. 24） Fujisawa, T.; Nagai, M.; Koike, Y.; Shimizu, M. J. Org. Chem. 1994, 59, 5865. 25） When the corresponding TFA salt of 21 was employed in the next reaction, triuoroacetylation of the product was observed. To avoid

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