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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Am Chem Soc. Author manuscript; available in PMC 2008 December 29.
Published in final edited form as:
PMCID: PMC2610465

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

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).

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.

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
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%; ...

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
a Reagents and conditions: (a) THF, 180 °C; 97% conversion to 15 and 16, (1:3.6, with reversible recycling 15 [right arrow over left arrow] 16); (b) NaBH4, EtOH, 23 °C; (c) SOCl2, CH2Cl2, reflux; (d) Bu3SnH, AIBN, PhH, reflux, 68% (3 steps); (e) DIBAL-H, ...

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


Supporting Information Available:

Experimental details (PDF). This material is available free of charge via the Internet at


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.


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