Total Syntheses and Determination of Absolute Configurations of Cep

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Total Syntheses and Determination of Absolute Configurations of Cep-212 and Cep-210, Predicted Biosynthetic Intermediates of Tetrodotoxin Isolated from Toxic Newt Masaatsu Adachi,*,† Tadachika Miyasaka,† Yuta Kudo,‡ Keita Sugimoto,‡ Mari Yotsu-Yamashita,‡ and Toshio Nishikawa*,†

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†

Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan ‡ Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki-Aza-Aoba, Aoba-ku, Sendai 980-8572, Japan S Supporting Information *

ABSTRACT: Total syntheses of Cep-212 and Cep-210, predicted biosynthetic intermediates of tetrodotoxin isolated from the Japanese toxic newt, have been accomplished from geraniol by an intramolecular hetero Diels−Alder reaction as a key step in a highly stereoselective manner. The success of these syntheses enabled us to determine their absolute configurations by using a chiral normal-phase HPLC/MS analysis of the bis-dinitrobenzene derivative of natural Cep-212 and reference derivatives prepared from chemically synthesized enantiomers.

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etrodotoxin (TTX, 1), a toxic principle of puffer fish intoxication,1 is one of the best-known marine natural products.2,3 Since the mechanism underlying TTX intoxication has been revealed to be a specific inhibition of voltage-gated sodium channels (VGSCs),4 tetrodotoxin has been widely used as a biochemical tool in neurophysiology.5 Tetrodotoxin (1) and a variety of its analogues (2, 5−8), including chiriquitoxin (5),6 have been identified from a broad range of marine and terrestrial animals, as shown in Figure 1.7−9 The wide distribution of TTX-bearing marine organisms strongly

indicates that tetrodotoxin is not synthesized by the host animals but is derived from their diet or through symbiosis.10 In toxic marine animals, tetrodotoxin is presumed to be produced by marine bacteria and accumulated via the food chain.7,11,12 On the other hand, the biosynthetic origin of tetrodotoxin in terrestrial animals, such as newt and frog, has been completely unclear. In 2014, Yotsu-Yamashita and co-workers reported the isolation of 4,9-anhydro-10-hemiketal-5-deoxytetrodotoxin (9) along with 4,9-anhydrotetrodotoxin (10) from the Japanese toxic newt, Cynops ensicauda popei (Figure 2).13 Extensive analyses of NMR spectra revealed that 9 was a new analogue of tetrodotoxin consisting of a directly connected C5−C10 bond and an unprecedented 10-hemiketal.14 The structural features of 9, as well as its wide distribution in many toxic newts, speculated that 9 was a precursor of tetrodotoxin in the terrestrial environment. Furthermore, the core skeleton possessing 10 carbons except the guanidine moiety might suggest that a monoterpene would serve as a possible starting substrate for the biosynthetic precursor of tetrodotoxin. On the basis of this hypothesis, Yotsu-Yamashita further researched

Figure 1. Structures of tetrodotoxin (1) and its analogues (2-8).

Received: December 19, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.8b04043 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 1. Retrosynthetic Analysis of Cep-212 (11) and Cep-210 (12)

Scheme 2. Synthesis of Cyclic Vinyl Ether 14 by an Intramolecular Hetero Diels−Alder Reaction and Alcohol 13, a Common Intermediate

Figure 2. Structures of 4,9-anhydro-10-hemiketal-5-deoxytetrodotoxin (9), Cep-212 (11), and Cep-210 (12) and a proposed biosynthetic pathway of TTX (1).

possible biosynthetic intermediates of tetrodotoxin at an early biosynthetic stage and recently succeeded in the isolation of novel cyclic guanidine compounds Cep-212 (11) and Cep-210 (12) from the same toxic newt (Figure 2).15 These chemical structures, consisting of a cis-fused bicyclic skeleton with a sixmembered cyclic guanidine, strongly support the hypothesis that a monoterpene (geranyl guanidine) is a biosynthetic precursor of TTX in terrestrial animals. However, the extremely small amounts of Cep-212 (11) and Cep-210 (12) (130 nmol for 11 and 69 nmol for 12) isolated from natural sources have prevented further detailed investigations such as a determination of their absolute configurations.16 We have been interested in naturally occurring analogues of tetrodotoxin in terms of the biosynthetic investigation as well as for the development of a subtype selective blocker of VGSCs and, thus, have for a long time developed several synthetic methodologies for synthesizing tetrodotoxin and its analogues.17−28 We disclose herein the stereoselective total syntheses of Cep-212 (11) and Cep-210 (12) in an enantioenriched form and determined their absolute configurations using a chiral HPLC/MS analysis by comparison with the naturally occurring products. Our synthetic plan for Cep-212 (11) and Cep-210 (12) is illustrated in Scheme 1. Cep-212 (11) and Cep-210 (12) could be synthesized from a common intermediate 13 possessing an azide group and the requisite stereochemistries at the C-4a, C5, and C-8a positions by reduction of the azide group, guanidine installation, and intramolecular Mitsunobu reaction.29 The common intermediate 13 could be prepared from bicyclic vinyl ether 14 through oxidative cleavage of the vinyl ether moiety. We envisaged that vinyl ether 14 would be synthesized by an intramolecular hetero Diels−Alder reaction30,31 of enone 15 containing an azide substituent at the C8a position for the construction of contiguous stereogenic centers at the C-4a and C-5 positions, stereoselectively. The precursor 15 possessing a quaternary stereogenic center at the C-8a position could be traced back to a known epoxide (16) of geraniol. Enone 15, a precursor for the intramolecular hetero Diels− Alder reaction, was synthesized from geraniol (17) (Scheme 2). According to the methods reported in the literature, 17 was

transformed into azide 18 through Sharpless asymmetric epoxidation32 with L-(+)-DET followed by a regioselective epoxide opening with Et2AlN3.33 Cleavage of the 1,2-diol of 18 with sodium periodate and subsequent Wittig reaction with (acetylmethylene)triphenylphosphorane provided enone 15 in good yield. The key intramolecular hetero Diels−Alder reaction of 15 was next investigated. Exposure of enone 15 to BF3·OEt2 in the presence of MS-4A in CH2Cl2 at −78 °C followed by neutralization with triethylamine provided the cyclic vinyl ether 14 in 73% yield as a single diastereomer.34,35 The high stereoselectivity of the intramolecular hetero Diels− Alder reaction is dictated, as expected, by 1,3-allylic strain between the enone moiety and functional groups at the C-8a position in four possible transition states. The more favored exo transition state TS-B, rather than the endo transition state TS-A, would preferentially yield the desired vinyl ether 14. The vinyl ether moiety of 14 was oxidatively cleaved with 2.2 equiv of m-CPBA at 40 °C to give the desired aldehyde 19 in 59% B

DOI: 10.1021/acs.orglett.8b04043 Org. Lett. XXXX, XXX, XXX−XXX

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dehydrobromination with DBU in benzene gave the α,βunsaturated lactone 28. The stepwise reduction of the α,βunsaturated lactone 28 with DIBAL-H and NaBH4 provided the allylic alcohol 29. To complete the total synthesis of Cep-210 (12), the allylic alcohol moiety of 29 was regioselectively protected as TBS ether 30 and the azide group of 30 was reduced by LiAlH4 (Scheme 5). The subsequent guanidinylation of the resulting

yield.36 Reduction with NaBH4 provided alcohol 13, a common intermediate. Guanidine was next installed for the total synthesis of Cep212 (11). Reduction of the azide group of 13 and subsequent guanidinylation of the resulting amine with N,N′-bis-Boc-Smethylisothiourea in the presence of HgCl2 gave di-Boc guanidine 20 in 58% yield over two steps (Scheme 3). Scheme 3. Total Synthesis of Cep-212 (11)

Scheme 5. Total Synthesis of Cep-210 (12)

Mitsunobu conditions37 with DIAD and PPh3 furnished cyclic guanidine 21. Finally, all of the protective groups of 21 were removed, providing (−)-(4aR,5R,8aR)-Cep-212 (11). The spectroscopic data of the synthesized Cep-212 were identical to those of natural Cep-212.15 Toward the synthesis of Cep-210 (12), the next issue was to prepare allylic alcohol 29 with the desired olefin geometry from the common intermediate 13 (Scheme 4). Acetylation of

amine with N,N′-bis-Boc-S-methylisothiourea in the presence of HgCl2 gave di-Boc guanidine 31 in 88% over two steps. The Mitsunobu reaction with DIAD and PPh3 proceeded smoothly to provide cyclic guanidine 32 in a satisfactory yield. Finally, all of the acid-sensitive protective groups of 32 were removed with TFA followed by treatment with silica gel in MeOH, providing (−)-(4aR,8aR)-Cep-210 (12). The 1H and 13C NMR spectra of the synthesized Cep-210 were identical to those of the natural Cep-210.15 With the synthetic routes to Cep-212 (11) and Cep-210 (12) secured, the remaining task was to determine the absolute configurations of those natural products. It was difficult to measure the optical rotation and CD spectra of natural Cep212 and Cep-210 because the amounts of Cep-212 and Cep210 from nature were negligible. Thus, we attempted to determine these absolute configurations by a chiral reversedphase HPLC comparison between the natural Cep-212 and the synthesized reference enantiomers of Cep-212. The required enantiomer of (−)-(4aR,5R,8aR)-Cep-212 (11) was synthesized by the developed procedure through Sharpless asymmetric epoxidation of geraniol with D-(−)-DET and the intramolecular hetero Diels−Alder reaction, giving (+)-(4aS,5S,8aS)-Cep-212 (11). Unfortunately, despite extensive efforts, the separation of these two enantiomers of Cep212 (11) by chiral reversed-phase HPLC was difficult under suitable conditions for HPLC/MS detection. To overcome these difficulties, we envisaged that a chemical derivatization40 of Cep-212 would enable easy handling as a less polar derivative by using normal-phase HPLC analysis. The derivatization should be simple and reliable, and it must be easy to prepare and purify the derivative in cases where only very small amounts (a few micrograms) of the natural Cep-212 are available. After extensive screening of the conditions for the synthetic Cep-212 by using several acyl, sulfonyl, and chiral derivatizing reagents, we were pleased to find that bis-arylation of the cyclic guanidine moiety of Cep-212 was the optimal method; upon treatment of the synthesized (−)-Cep-212 (11) or (+)-Cep-212 (11) with an excess amount of 2,4-

Scheme 4. Synthesis of Allylic Alcohol 29 from a Common Intermediate 13

13 followed by dehydration of the acetate of 22 provided exoolefin 23 along with endo-olefin in 93% yield (5:1 an inseparable mixture). Hydroboration with BH3·THF in THF followed by oxidation with NaBO338 gave alcohol 24 in 81% yield. Oxidation of the primary alcohol of 24 with Dess− Martin periodinane in the presence of H2O39 gave aldehyde 25 in 64% yield. Deacetylation and oxidation with Fetizon’s reagent afforded lactone 26 as a single diastereomer. α,βUnsaturated lactone 28 was prepared in two steps: αbromination of TMS enolate of 26 with NBS followed by C

DOI: 10.1021/acs.orglett.8b04043 Org. Lett. XXXX, XXX, XXX−XXX

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of tetrodotoxin found in terrestrial animals, by an intramolecular hetero Diels−Alder reaction as a key step. Comparison of the HPLC retention time of the bisdinitrobenzene derivative of natural Cep-212 with reference derivatives prepared from both of these chemically synthesized enantiomers by chiral HPLC/MS successfully determined their absolute configurations. Identification of the absolute configurations of those natural products to those of tetrodotoxin strongly indicates the possibility that Cep-212 and Cep-210 are biosynthetic intermediates of tetrodotoxin. Biochemical investigations using the synthesized Cep-212 and Cep-210 are now in progress.

Scheme 6. Chemical Derivatization of These Synthesized (−)-Cep-212 (11) and (+)-Cep-212 (11)

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b04043.

and purification procedures could also be applicable to synthesis on the scale of a few micrograms. To our delight, the chiral normal-phase HPLC/MS analysis with a CHIRALPAK IC column successfully separated these synthesized bis-aryl derivatives (−)-33 and (+)-33 (t = 17.7 min for (−)-33, t = 18.8 min for (+)-33).41 The natural Cep-212 (ca. 5 μg) was also transformed into bis-aryl derivative 33 under the developed procedures. With this natural derivative 33 and the two chemically synthesized references ((−)-33 and (+)-33) in hand, we next determined the absolute configurations by chiral normal-phase HPLC/MS analysis. As a result, the retention time on the chiral HPLC of the natural derivative 33 was in good accordance with that of the chemically synthesized reference (−)-33 (Figure 3).41

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Experimental procedures, characterization data, and copies of 1H and 13C NMR spectra for all new compounds (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Masaatsu Adachi: 0000-0001-7615-3861 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grants-in-Aid for Scientific Research (B) (16H04915) and (C) (15K07410, 18K05456), a Grant-in-Aid for Challenging Exploratory Research (17K19195), and a Grant-in-Aid for Scientific Research on Innovative Area “Frontier Research on Chemical Communications” (17H06406) from MEXT, Japan, and Shorai Foundation for Science and Technology. T.M. is grateful for a Nagoya University Graduate School of Bioagricultural Sciences “Mizutani Scholarship”. We thank Prof. K. Nakagawa and Dr. J. Ito (Tohoku University) for help with the chiral HPLC/MS analysis.

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REFERENCES

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Figure 3. Chiral normal-phase HPLC/MS analysis: (A) bis-Ar derivative 33 derived from natural Cep-212; (B) bis-Ar derivative (−)-33 derived from (−)-Cep-212 (synthetic, proposed type); (C) bis-Ar derivative (+)-33 derived from (+)-Cep-212 (synthetic, enantiomer).

These results indicate that the absolute configurations of natural Cep-212 are (4aR,5R,8aR) [(−)-Cep-212 (11)]. Since Cep-210 (12) might be biosynthesized from (−)-(4aR,5R,8aR)-Cep-212 (11),15 we suggest that the absolute configurations of natural Cep-210 are also (4aR,8aR) [(−)-Cep-210 (12)]. In conclusion, we have accomplished the first total syntheses of Cep-212 and Cep-210, predicted biosynthetic intermediates D

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(36) Borowitz, I. J.; Gonis, G. Tetrahedron Lett. 1964, 5, 1151. (37) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977. (38) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem. 1989, 54, 5930. (39) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549. (40) For a review on determination of absolute configurations by chemical derivatization using an extremely limited amount of natural products, see: Yasumoto, T. Chem. Rec. 2001, 1, 228. (41) For details of HPLC/MS analysis conditions, see the Supporting Information.

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