Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2008 Dec 29.
Published in final edited form as: J Am Chem Soc. 2006 Jul 12;128(27):8734–8735. doi: 10.1021/ja0625430

Efficient Synthetic Access to the Hetisine C20-Diterpenoid Alkaloids. A Concise Synthesis of Nominine via Oxidoisoquinolinium-1,3-Dipolar and Dienamine-Diels–Alder Cycloadditions

Kevin M Peese 1, David Y Gin 1,†
PMCID: PMC2610465  NIHMSID: NIHMS82034  PMID: 16819859

The hetisine natural products are a family of complex C20-diterpenoid alkaloids isolated from the Aconitum, Consolida, Delphinium, Rumex, and Spiraea genera, plants that have been widely used in traditional herbal medicine.1 Several of the more than 100 members of the hetisine alkaloids, exemplified by nominine (1, Chart 1),2 kobusine (2),3 and hetisine (3),4 exhibit a diverse spectrum of biological activities, including potent vasodilating, antiarrhythmic, immunomodulating, and analgesic activities, in vivo.1 Although the hetisine alkaloids have been known for more than a half-century, the majority of synthetic efforts directed at these complex targets have involved only a handful of synthetic model preparations of aza-polycyclic substructures.5 In fact, the total synthesis of any member of the hetisine alkaloids remained elusive until the recent landmark work of Muratake and Natsume, in which a 40-step synthesis of (±)-nominine (1) was accomplished in 2004.6 We now report a convergent, dual-cycloaddition approach to the hetisine alkaloids, illustrated by an exceedingly concise synthesis of the antiarrhythmic agent nominine (1).

Chart 1.

Chart 1

Open in a new tab

Consideration of the structure of nominine (1) in a conformational representation (Scheme 1) reveals a potentially expedient route to the hetisine core via two cycloaddition processes (i.e., 4). These include an aza-1,3-dipolar cycloaddition (1,3-DC) to construct the bridged pyrrolidine ring, followed by a Diels-Alder (DA) reaction to assemble the [2.2.2]-bicyclic substructure within 1. Because functional group compatibility issues would likely preclude a tandem double-cycloaddition event, synthetic efforts commenced with the preparation of a substrate incorporating the requisite dipole-dipolarophile complement in conjunction with a latent diene-dienophile pair.

Scheme 1.

Scheme 1

Open in a new tab

Synthesis of a suitable dipolarophile precursor was accomplished in a short series of steps, beginning with ortho-lithiation of p-anisaldehyde dimethyl acetal (5, Scheme 2),7 followed by its nucleophilic addition to 2-chloro-N-methoxyl-N-methylacetamide, to provide the aryl ketone 6 (52%). Subsequent exchange of the α-chloro substituent in 6 to its α-azido counterpart (NaN3, 95%) and acid-catalyzed rearrangement afforded the cyclic bis(acetal) 7 as a 3:2 mixture of diastereomers (99%). The dipolarophile component was accessed efficiently from 3-methylcyclohexenone (8), in which conjugate cyanation8 followed by enolate trapping with Tf2O led to enol triflate 9 (81%). Sequential nitrile reduction to the aldehyde (DIBAL-H, 92%) and Pd0-catalyzed cross coupling with Zn(CN)29 provided the ene-nitrile dipolarophile 10 (85%), ready to be condensed with the aza-dipole precursor 7. This convergent step was accomplished with a Staudinger–aza-Wittig reaction (7, 10, PBu3) in conjunction with imine reduction (NaBH-(OAc)3) to afford the amine 11 (79%) as a mixture of four diastereomers. All four diastereomers 11 were then converged via TFA-catalyzed MeOH extrusion and isomerization to the 4-oxido-isoquinolinium betaine 12 (93%), which served as a suitable aza-1,3-dipole.

Scheme 2 a.

Scheme 2 a

Open in a new tab

a Reagents and conditions: (a) t-BuLi,Et2O, −23°C;ClCH2C(O)N(OMe)Me, 52%; (b) NaN3, acetone, 23 °C, 95%; (c) AcCl, MeOH, 23 °C, 99% (3:2 dr); (d) AlEt2CN, benzene, 23 °C; TBAT, Tf2O, benzene, 23 °C, 81%; (e) DIBAL-H, PhMe, 0 °C, 92%; (f) Zn(CN)2, Pd(PPh3)4, DMF, 60 °C, 85%; (g) 7, 10, PBu3, NaBH(OAc)3, CH2Cl2, 23 °C, 79% (3:3:2:2 dr); (h) 10% TFA in CH2Cl2, 0 °C, 93%.

1,3-Dipolar cycloadditions involving oxidopyridinium betaines have proven to be valuable in alkaloid synthesis;10 however, the use of oxidoisoquinolinium betaines in this capacity is comparatively rare.11 When a solution of betaine 12 in THF (5 mM) was heated in a sealed tube at 180 °C (Scheme 3), intramolecular cycloaddition occurred with 97% conversion to provide an easily separable mixture of pyrrolidine constitutional isomers 15 and 16, each arising from differential facial approach of the dipole-dipolarophile partners. While the desired cycloadduct 15 was formed as the minor constituent (15:16, 1:3.6),12 the isomeric ratio was verified to be the result of thermodynamic selection. Indeed, the cycloaddition event was found to be reversible under the reaction conditions, thereby enabling reiterative thermal re-equilibration of the isolated undesired cycloadduct 16 to enhance the production of 15 with minimal loss of material.

Scheme 3 a.

Scheme 3 a

Open in a new tab

a Reagents and conditions: (a) THF, 180 °C; 97% conversion to 15 and 16, (1:3.6, with reversible recycling 15 ⇄ 16); (b) NaBH4, EtOH, 23 °C; (c) SOCl2, CH2Cl2, reflux; (d) Bu3SnH, AIBN, PhH, reflux, 68% (3 steps); (e) DIBAL-H, PhMe, 0 °C, 85%; (f) Ph3P=CH2, THF, 23 °C, 96%; (g) Na0, Me2CHOH, THF, −78 °C; HCl(aq), 97%; (h) 9:1 MeOH/pyrrolidine, 60 °C, 78%; (i) Ph3P=CH2, THF, 70 °C, 77%; (j) SeO2, t-BuOOH, CH2Cl2, 23 °C, 66% (dr 7:1).

Advancement of the cycloadduct 15 continued with a ketone-to-methylene reduction to form 17 (NaBH4; SOCl2; Bu3SnH, AIBN, 68% overall) and conversion of the nitrile to the alkene 18 (DIBAL-H; Ph3P=CH2, 82% overall) to reveal the dienophile functionality. Birch reduction (Na0, Me2CHOH, THF, NH3, −78 °C)13 of the aromatic ring in 18 and acidic workup led to the formation of the β,γ-unsaturated cyclohexenone 19 (97%), which, upon exposure to pyrrolidine in MeOH at 60 °C, afforded the intramolecular Diels-Alder adduct 21 in 78% yield after silica gel chromatography. Although not explicitly detected, a small equilibrating quantity of the dienamine isomer 20 was presumably formed and funneled productively to the committed [4+2] cycloaddition. The final steps of the synthesis involved Wittig methylenation of the ketone 21 (Ph3P=CH2, 77%) followed by diastereoselective SeO2 allylic hydroxylation14 to afford nominine (1, 66%, 7:1 dr), whose structure was verified by X-ray analysis.

Through the establishment of a dual cycloaddition strategy, a short total synthesis of (±)-nominine (1) was accomplished in a 15-step sequence with only a single protective group manipulation. Notable features include a reversible intramolecular 4-oxidoiso-quinolinium betaine 1,3-dipolar cycloaddition as well as a pyrrolidine-induced dienamine isomerization/Diels-Alder cascade. This rapid synthetic access into the hetisine skeleton should pave the way for the construction of other, more highly oxidized, members of the C20-diterpenoid alkaloids such as the antiarrhythmic guan-fu bases.1

Supplementary Material

si. Supporting Information Available.

Experimental details (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgments

This research was supported by the NIH-NIGMS (GM67659), Abbott, Eli Lilly, Johnson & Johnson, Merck, and Pfizer. A Pharmacia (Pfizer) predoctoral fellowship to K.M.P. is acknowledged. We thank Dr. H. Muratake for supplying spectral data for 1.

References

  • 1.Wang FP, Liang XT. In: The Alkaloids. Cordell GA, editor. Vol. 59. Academic Press; San Diego, CA: 2002. pp. 1–280. [Google Scholar]
  • 2.(a) Ochiai E, Okamoto T, Sakai S, Saito A. Yakugaku Zasshi. 1956;76:1414–1418. [Google Scholar]; (b) Sakai S, Yamamoto I, Yamaguchi K, Takayama H, Ito M, Okamoto T. Chem Pharm Bull. 1982;30:4579–4582. [Google Scholar]
  • 3.(a) Suginome H, Shimanouti F. Justus Liebigs Ann Chem. 1940;545:220–228. [Google Scholar]; (b) Okamoto T. Chem Pharm Bull. 1959;7:44–49. [Google Scholar]; (c) Pelletier SW, Wright LH, Newton GM, Wright H. J Chem Soc, Chem Commun. 1970:98–99. [Google Scholar]
  • 4.(a) Jacobs WA, Craig LC. J Biol Chem. 1942;143:605–609. [Google Scholar]; (b) Przybylska M. Can J Chem. 1962;40:566–568. [Google Scholar]
  • 5.(a) Somei M, Okamoto T. Chem Pharm Bull. 1970;18:2135–2138. [Google Scholar]; (b) van der Baan JL, Bickelhaupt F. Recl Trav Chim Pays-Bas. 1975;94:109–112. [Google Scholar]; (c) Shibanuma Y, Okamoto T. Chem Pharm Bull. 1985;33:3187–3194. [Google Scholar]; (d) Kwak Y, Winkler JD. J Am Chem Soc. 2001;123:7429–7430. doi: 10.1021/ja010542w. [DOI] [PubMed] [Google Scholar]; (e) Muratake H, Natsume M. Tetrahedron Lett. 2002;43:2913–2917. [Google Scholar]; (f) Williams CM, Mander LN. Org Lett. 2003;5:3499–3502. doi: 10.1021/ol0353060. [DOI] [PubMed] [Google Scholar]; (g) Peese KM, Gin DY. Org Lett. 2005;7:3323–3325. doi: 10.1021/ol051184v. [DOI] [PMC free article] [PubMed] [Google Scholar]; (h) Williams CM, Mander LN, Bernhardt PV, Willis AC. Tetrahedron. 2005;61:3759–3769. [Google Scholar]
  • 6.Muratake H, Natsume M. Angew Chem, Int Ed. 2004;43:4646–4649. doi: 10.1002/anie.200460332. [DOI] [PubMed] [Google Scholar]
  • 7.Karl J, Gust R, Spruss T, Schneider MR, Shönenberger H, Engel J, Wrobel K, Lux F, Haeberlin ST. J Med Chem. 1988;31:72–83. doi: 10.1021/jm00396a012. [DOI] [PubMed] [Google Scholar]
  • 8.Nagata W, Yoshioka M, Hirai S. J Am Chem Soc. 1972;94:4635–4643. [Google Scholar]
  • 9.Tschaen DM, Desmond R, King AO, Fortin MC, Pipik B, King S, Verhoeven TR. Synth Commun. 1994;24:887–890. [Google Scholar]
  • 10.(a) Katritzky AR, Takeuchi Y. J Am Chem Soc. 1970;92:4134–4136. [Google Scholar]; (b) Dennis N, Katritzky AR, Takeuchi Y. Angew Chem, Int Ed Engl. 1976;15:1–9. doi: 10.1002/anie.197600011. [DOI] [PubMed] [Google Scholar]; (c) Joshi RA, Ravindranathan T. Indian J Chem, Sect B. 1984;23:300–302. [Google Scholar]; (d) Katritzky AR, Dennis N. Chem Rev. 1989;89:827–861. [Google Scholar]; (e) śliwa W. Heterocycles. 1996;43:2005–2029. [Google Scholar]; (f) Rumbo A, Mouriño A, Castedo L, Mascareñas JL. J Org Chem. 1996;61:6114–6120. doi: 10.1021/jo960854v. [DOI] [PubMed] [Google Scholar]; (g) Smith MP, Johnson KM, Zhang M, Flippen-Anderson JL, Kozikowski AP. J Am Chem Soc. 1998;120:9072–9073. [Google Scholar]; (h) Sung MJ, Lee HI, Chong Y, Cha JK. Org Lett. 1999;1:2017–2019. doi: 10.1021/ol9911932. [DOI] [PubMed] [Google Scholar]
  • 11.(a) Dennis N, Katritzky AR, Takeuchi Y. J Chem Soc, Perkin Trans. 1972;1:2054–2057. [Google Scholar]; (b) Garling DL, Cromwell NH. J Org Chem. 1973;38:654–658. [Google Scholar]; (c) Dennis N, Katritzky AR, Parton SK. Chem Pharm Bull. 1975;23:2899–2903. [Google Scholar]; (d) Dennis N, Katritzky AR, Parton SK. J Chem Soc, Perkin Trans 1. 1976:2285–2288. [Google Scholar]; (e) Hanaoka M, Wada A, Yasuda S, Mukai C, Imanishi T. Heterocycles. 1979;12:511–514. [Google Scholar]; (f) Dicesare JC, Burgess JP, Mascarella SW, Carroll FI. J Heterocycl Chem. 1994;31:187–192. [Google Scholar]; (g) Edmunds JJ, Cheng X, Tobias B. J Chem Soc, Perkin Trans 1. 1996:2005–2008. [Google Scholar]; h Constable KP, Blough BE, Carroll FI. Chem Commun. 1996:717–718. [Google Scholar]
  • 12.1H NMR analysis of the 1,3-dipolar cycloadditions revealed production of a clean 21:76:03 mixture of 15:16:12, respectively, with quantitative mass recovery. Silica gel separation of isomers provided pure 15 (20%) and 16 (70%).
  • 13.(a) Rabideau PW, Marcinow Z. Org React. 1992;42:1–334. [Google Scholar]; (b) Wentland MP, Albertson NF, Pierson AK. J Med Chem. 1980;23:71–74. doi: 10.1021/jm00175a013. [DOI] [PubMed] [Google Scholar]
  • 14.(a) Umbreit MA, Sharpless KB. J Am Chem Soc. 1977;99:5526–5528. [Google Scholar]; (b) Furber M, Mander LN. J Am Chem Soc. 1987;109:6389–6396. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

si. Supporting Information Available.

Experimental details (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

NIHMS82034-supplement-si.pdf (946.5KB, pdf)

RESOURCES