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A formal synthesis of perhydrohistrionicotoxin

Daniel L. Comins* and Xiaoling Zheng

Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA

In 1971, Wiktop and coworkers reported the isolation of (-)-histrionicotoxin (1), (Figure 1), an alkaloid with a skeleton of a piperidine-containing spirocyclohexane unit, from skin extracts of the "arrow poison frog" Dendrobates histrionicus.1 Both 1 and its perhydroderivative 2 are equally bioactive alkaloids, which are useful tools in neuroscience for the study of the mechanisms involved in the transynaptic transmission of neuromuscular impulses.2 In recent years, the synthesis of the histrionicotoxin family has attracted attention not only due to its interesting biological activity in conjunction with its scarcity (ca. 200 ug per frog), but also due to the challenge of making this unique azaspirocyclic skeleton with a certain spatial arrangement of amino and hydroxy groups.

1 R1 = CH2-HC = CH-C...triple...CH

R2 = HC = CH-C...triple...CH

2 R1 = C5H11

R2 = Bu

Figure 1 Structures of histrionicotoxin (1) and perhydrohistrionicotoxin (2).

Since the first total synthesis of (+/-)-perhydrohistrionicotoxin (PHTX) 2 by Corey in 1975,3a organic chemists have continued to investigate different approaches toward the stereoselective construction of this azaspiro[5.5]undecane skeleton. Numerous reports have appeared on synthetic studies in this series;3,4 however, only four of them have addressed the problem of asymmetric synthesis of the alkaloids.4

The successful asymmetric reactions involving 2,3-dihydro-4-pyridones developed by the Comins group5 have been applied to the synthesis of optically pure alkaloids. By careful consideration, a synthetic plan was designed to prepare (-)-PHTX (2) utilizing a photocycloaddition of a chiral 2,3-dihydro-4-pyridone as a key step. The azaspiro skeleton of 2 would be built in a stereoselective manner via a short and convergent route. To test this approach a racemic synthesis was initiated according to the plan outlined in Scheme 1.

Scheme 1

The natural product (+/-)-(PHTX) (2) would be synthesized by the reduction of amino ketone 3 with LiAl (O-But)3H in THF.4a Amino ketone 3 would be generated by deprotection of the ketal and tert-BOC groups of 4. Compound 4 would be the product of a ring-opening reaction of the photoadduct 5 using the reducing agent SmI2. Intermediate 5 would arise by the intramolecular photocycloaddition of a 2,3-dihydro-4-pyridone with a nine-carbon tether side chain containing a C=C bond and a protected ketone functionality at the position next to the double bond. The photosubstrate 6 would be prepared by alkylation of 4-methoxy-2-pentyl-1,2-dihydropyridine 7 at the C-6 position with an alkyl iodide, containing the whole side chain, via ortho-lithiation and subsequent electrophilic substitution.6 The introduction of a pentyl group at the C-2 position of 7 would be obtained by pentyl Grignard addition to an N-acylpyridinium salt.

According to the synthetic strategy for PHTX (2) (Scheme 1), a linear nine-carbon side chain at C-6 of 6 was required. We prepared the iodide 8 using classical chemistry, and began studies directed at joining this unit with dihydropyridine 7 to give dihydropyridone 6 on acidic workup.

Readily available 4-methoxypyridine was treated with phenyl chloroformate and subsequently pentyl Grignard. The product 9 was treated with potassium tert-butoxide to make the N-BOC derivative of 1,2-dihydropyridine 7. The a-lithiation of 7 followed by treatment with the electrophile 8 resulted in recovery of unreacted starting material. Although this reaction was repeated with prolonged reaction times and various other conditions, we were not successful in generating the desired product 6.

Scheme 2

Several other methods to introduce the required side chain at C-6 of the pyridone 6 were attempted. One approach involved a coupling reaction of 6-iodo-1,2-dihydropyridine 10, prepared by iodination of dihydropyridine 7, with excess alkyl Grignard reagent catalysed by NiCl2(dppp).7 Unfortunately, this reaction offered less than 5% of cross-coupled product 11. Another was a coupling reaction between 6-iodo-2,3-dihydro-4-pyridone 12, prepared from the hydrolysis of 10, and an alkylzinc reagent utilizing the palladium ctalyst, PdCl2(dppf).8 The material isolated from this reaction was a mixture of both 13 and reduced compound 14 in the ratio of approximately 1:1. Since attempts at introducing the entire side chain 8 were unsuccessful, the strategy for incorporation of the tethered olefin was changed.

Scheme 3

It was found that alkylation of dihydropyridine 7 with a 1,3-dihalopropane led to the formation of 6-(3'-halopropyl)dihydropyridine 15 and 16. The coupling of the alkyl iodide 16 with the lithium anion of trimethylsilyl (TMS) hexenylcyanohydrin ether 17 by nucleophilic substitution provided intermediate 18. Upon acidic and then basic hydrolysis, the cyanohydrin TMS ether was converted to the unsaturated diketone 18 in an 82% yield. Although this result is a linear transformation of 4-methoxypyridine to the required 2,6-disubstituted 2,3-dihydro-4-pyridone, the extra steps to prepare the side chain piece 8 were avoided.

Scheme 4

Protection of the keto carbonyl group on the side chain was done by forming the ethylene glycol ketal 6. The formation of the ketal 6 was regioselective due to the amide character of the dihydropyridone carbonyl, which disfavours the ketal formation. The diketal product 19 was formed as less than 1/3 of the isolated product; however, 19 was found to be easily converted to the desired 6 upon mild acidic hydrolysis.

Scheme 5

Through this process the substrate for the [2+2] photocycloaddition was prepared. Irradiation of photosubstrate 6 provided a product mixture of 5 (major) and 20 (minor) in yields up to 90%. From 1H NMR the ratio of major to minor product was determined to be ca. 6:1. Because the separation of the two isomers was unsuccessful, the photoadduct mixture 5 and 20, was used directly in the reductive ring opening.

Scheme 6

As in earlier model studies,9 the ring opening of the photoadducts 5 and 20 was realized by using SmI2. Only one product was isolated and purified to give a white solid in 52% yield. The product was determined to be 4, the ring opened compound derived from the major isomer of the photocycloadduct from 6. There was no ring-opened product observed for the minor isomer possibly due to its consumption in the course of the reduction. Thus, the problem of isomer separation was eliminated. This reaction is another example of a reductive ring-opening of a-ketocyclobutane systems with SmI2.9 The reduction conditions are so mild that the BOC, ketone and ketal groups remained intact.

Scheme 7

After obtaining 4, which contains the azaspiro skeleton of PHTX, it was required to reduce and deoxygenate the C-4 keto group. This was accomplished using Winkler's approach,4a used in his PHTX synthesis. Generation of the enolate by treating with lithium bis(trimethylsilyl)amide, and trapping the anion as the vinyl triflate gave a mixture of 21 and 22 in a 90% yield with a 9:1 ratio. The enolate formed was mostly located at the less hindered a-carbon to the carbonyl group no matter in what order the base was added. This regioselectivity is beneficial to the synthesis and the reason will be explained later. Subsequent hydrogenation with PtO2 in ethyl acetate gave product 24 in 80% yield, with recovery of the unreacted vinyl triflate isomer 22. It was found that this material could be reduced only after removal of the N-BOC group. This result suggests that the vinyl triflate moiety of isomer 22 is hindered by the nearby ketal group and the tert-butyl group. On removing the BOC group, it is supposed that the conformational strain was released and the bulky groups moved away from the vinyl triflate so that the hydrogenation could occur.

Scheme 8

Further manipulations of 24, including removal of the ketal and N-BOC groups, were attempted. The first attempt involved acid-catalysed hydrolysis of the dioxolane,10 followed by removal of the BOC protecting group with trifluoroacetic acid.

Treatment of ketal 24 with a catalytic amount of PPTS in aqueous acetone under reflux for 3 h produced two products. Unfortunately, the minor product was shown to be the desired spiro-ketone 25. The major product was determined to be the ring-opened enone 26, generated through a subsequent reaction after the ketal was hydrolysed. A pathway for this side reaction is shown below (Scheme 10).

Scheme 9

Scheme 10 Proposed pathway for the formation of 26

Further work on improvement of this deprotection to raise the yield of spiroketone 25 is in progress.

Finally, treatment of 25 with trifluoroacetic acid resulted in the cleavage of the tert-butyl carbamate and gave amino ketone 3. Since the amino ketone 3 has been obtained, the final transformation is to convert the carbonyl group at C-8 to the axial alcohol of 2. This reaction has been reported by Winkler and coworkers.4a Thus, we have accomplished a formal synthesis of (+/-)-perhydrohistrionicotoxin 2. The success of this racemic synthesis will lead to the accomplishment of an asymmetric synthesis of (-)-perhydrohistrionicotoxin utilizing our asymmetric synthesis of 2,3-dihydro-4-pyridones.5 Currently, this effort is underway in our laboratories.

Scheme 11


  1. Daly, J.W., Karle, I. L., Myers, C. W., Tokuyama, T., Waters, J. A.; Wiktop, B. Proc. Natl. Acad. Sci. U.S.A., 1971, 68, 1870.
  2. For reviews: Daly, J. W. and Spande, T. F. in Alkaloids: Chemical and Biological Perspectives, ed. Pelletier, S. W. Wiley, New York, 1986; vol. 4, ch. 1, pp. 1-274; Daly, J. W., Garraffo, H. M., and Spande, T. F. in The Alkaloids, ed Codell, G. A. Academic Press, San Diego, 1993, vol. 43, pp. 185-288.
  3. For synthetic work and leading references on the histrionicotoxins, see: (a) Corey, E. J.,

    Arnett, J. F., Widiger, G. N. J. Am. Chem. Soc. 1975, 97, 430. (b) Carey, S. C., Aratani, M., Kishi, Y. Tetrahedron Lett., 1985, 26, 5887. (c) Evans, D. A., Thomas, E. W., Cheropeck, R. E. J. Am. Chem. Soc., 1982, 104, 3695. (d) Venit, J.J., Dipierro M. and Magnus, P. J. Org. Chem., 1989, 54, 4298. (e) Thompson, C.M. , Heterocycles, 1992, 34, 979.

  4. (a) Winkler, J. D. and Hershberg, P. M. J. Am. Chem. Soc., 1989, 111, 4852. (b) Stork, G., Zhao, K. J. Am. Chem. Soc. 1990, 112, 5875. (c) Zhu, J., Royer, J. Quirion, J.-C. and Husson, H.-P. Tetrahedron Lett., 1991, 32, 2485. (d) Maezaki, N.; Fukuyama, H., Yagi, S., Tanaka, T., Iwata, C. J. Chem. Soc., Chem. Commun., 1994, 1835.
  5. Comins, D. L., Joseph, S. P., Goehring, R. R. J. Am. Chem. Soc., 1994, 116, 4719; Comins, D. L., Goehring, R. R., Joseph, S. P., O'Connor, S. J. Org. Chem., 1990, 55, 2574 and references cited therein.
  6. Comins, D. L., Lamunyon, D. H. Tetrahedron Lett., 1989, 30, 5053.
  7. (a) Babudi, F., Fiandanese, V., Naso, F., Punzi, A. Tetrahedron Lett., 1994, 35, 2067; (b) Tamao, K., Kodama, S-i; Nakatruka, T. Kiso, Y., Kumada, M. J. Am. Chem. Soc., 1975, 97, 4405.
  8. (a) Hayashi, T., Konishi, M., Kobori, Y., Kumada, M., Higuchi, T., Hirotsu, K. J. Am. Chem. Soc., 1984, 106, 158. (b) Migani, G., Leising, F., Meyrueix, R., Samson, H. Tetrahedron Lett., 1990, 31, 4743.
  9. Comins, D. L., Zheng, X. J. J. Chem. Soc., Chem. Commun., 1994, 2681.
  10. Hagiwara, H., Uda, H. J. Chem. Soc., Chem. Commun., 1987, 1351.