Cyclization Cascade of Allenyl Azides: Synergy Between Theory and Experiment

Abstract

Collaborative work between experimentalists and computational chemists have demonstrated a stong synergy which allowed the rationalization of allenyl azide chemistry and permited the development of an efficient synthetic tool aimed at the preparation of several alkaloids. Saturated allenyl azides undergo a reaction cascade involving key diradical intermediates that follow the Curtin-Hammett model whereas unsaturated allenyl azides form indolidene intermediates that furnish the final indole products via electrocyclic ring closure events taking place out of the Curtin-Hammett regime. The regiochemistry of the reaction cascade with the latter substrates can be manipulated by Cu(I) addition to the reaction mixture.

Synthesis studies on the Melodinus alkaloid meloscine

“…6d Attempts to prepare and cyclize allenyl azide substrates related to 22 with either ortho -NO 2 or ortho -BOCHN groups on the aryl ring did not afford any bicyclic product. These failures left the ortho -bromo alternative as the most attractive option, as detailed below.…”

“…This allene-forming procedure has proven quite reliable and robust for forming allenyl azide cyclization substrates. 6d The product allenyl azide exhibited only marginal stability and so it was heated immediately in refluxing toluene to initiate the cascade cyclization sequence and furnish the meloscine model system C/D bicyclic core 23 in good yield.…”

“…Advances in allenyl azide cascade cyclization chemistry 6 has enabled the development of a synthesis strategy for meloscine that features efficient formation of the C/D ring azabicyclo[3.3.0]octane core with complete relative stereochemical control at C(7) and C(16). In this strategy, allenyl azide 19 plays a pivotal role; thermolysis of this species is expected to proceed through a reaction sequence involving first [3 + 2] cycloaddition to deliver an unisolable triazoline 18 whose subsequent fragmentation is driven by release of strain.…”

“…In this strategy, allenyl azide 19 plays a pivotal role; thermolysis of this species is expected to proceed through a reaction sequence involving first [3 + 2] cycloaddition to deliver an unisolable triazoline 18 whose subsequent fragmentation is driven by release of strain. 6d,g Loss of N 2 from 18 should furnish the singlet diyl 17 , which is poised for formal electrocyclization through a conrotatory pathway to provide the C/D ring bicyclic product 16 as the diastereomer shown. 6d,g Two further operations are required in order to convert 16 into the target meloscine; (1) union of the aryl ring with a carboxylic acid derivative, which would be revealed by deprotecting the OBO function, to deliver lactam ring B, and (2) construction of tetrahydropyridine ring E from the extant C(20) and nitrogen substituents.…”

“…6d,g Loss of N 2 from 18 should furnish the singlet diyl 17 , which is poised for formal electrocyclization through a conrotatory pathway to provide the C/D ring bicyclic product 16 as the diastereomer shown. 6d,g Two further operations are required in order to convert 16 into the target meloscine; (1) union of the aryl ring with a carboxylic acid derivative, which would be revealed by deprotecting the OBO function, to deliver lactam ring B, and (2) construction of tetrahydropyridine ring E from the extant C(20) and nitrogen substituents. At the outset of this work, it was not obvious which of these two operations should be executed first, so maintaining flexibility to pursue both options via appropriate choice of P and P 1 was built into the plan.…”