Investigation of conjugate addition/intramolecular nitrone dipolar cycloadditions and their use in the synthesis of dendrobatid alkaloid precursorsNitrone dipolar cycloaddition routes to piperidines and indolizidines. Part 10. For part 9, see ref. 1.

Abstract

The sequential intramolecular conjugate addition of the oxime 13 followed by intramolecular dipolar cycloaddition of the intermediate nitrone 14 affords a mixture of the isoxazolidines 15, 16 and 17. The tricyclic 6,5,5-adduct 15 is believed to be the product of kinetic control and can be equilibrated with the epimeric tricyclic 6,5,5-isoxazolidine 17 through a beta-elimination/conjugate addition process. Conditions have been developed for the two-step conversion of the ketone 12 under thermodynamic control into the racemic tricyclic 6,6,5-adduct 16 which is the core precursor of all the known histrionicotoxin alkaloids.

Intramolecular nitrone dipolar cycloadditions: control of regioselectivity and synthesis of naturally-occurring spirocyclic alkaloids

“…In this paper, we describe experiments to identify the causes of this surprising regiocontrol, which complement the recent reports of Stockman [21][22][23] and ourselves, 13 and show how this regiocontrol can be used to synthesise various natural histrionicotoxins.…”

“…The signals were consistent with those of a pure sample of 27 which we isolated later (see Scheme 7). By analogy with Horsley's work, 13 we propose that the other unidentified adduct is diastereomer 28 (Scheme 4).…”

“…In addition to this material, a pure sample of another compound (2%) was isolated and characterised by 1 H NMR spectroscopy. By analogy with Horsley's work 13 and comparison with the data corresponding to similar compounds, we propose that this compound is the diastereomer 30. The remaining mixed fractions appeared to contain a mixture of 27 and another unidentified adduct (5%).…”

“…These alkaloids have attracted significant attention from the synthetic community. [4][5][6][7][8][9][10][11][12] Over the years, there have been several contributions to this body of literature from our group, [7][8][9][13][14][15][16] including the only syntheses of the histrionicotoxins HTX-259A, HTX-285C and HTX-285E (2, 3 and 4 respectively), which bear differing sidechains. 17 Herein, we provide further detail of the synthetic work and describe the results of some investigations into the intriguing regioselectivity of dipolar cycloaddition observed during the key cascade hydroxylamine-alkyne cyclisation/nitrone cycloaddition to form the azaspirocyclic core.…”

“…A further benefit of the cyano substituent was the anticipation that it could lower the activation energy for the formation of the required 6,6,5-adduct by improving the frontier orbital interactions between the HOMO (dipole) and LUMO (dipolarophile). 13 This issue has recently been examined from a computational perspective. 20 By generating the reactive nitrone functionality 12 in situ by the cycloreversion of the styrene adduct 11 in the presence of a pendant cyano-substituted dipolarophile, we found that it was possible to synthesise the required 6,6,5-adduct 13 in excellent yield (Scheme 2).…”