The Logothetis Reaction: Solenopsin B (Taber), Swaisonine (Cha), Indolizidine 223AB (Taber), Quinolizidine 217A (Pearson), FR66979 (Ciufolini)

The work on dipolar cycloaddition by Huisgen and others primarily focused on strained or polarized alkenes as dipolarophiles. In contrast, in 1965 Anestis L. Logothetis of DuPont CR&D reported that the intramolecular cyclization of the azido alkene 1 proceeded smoothly to give the imine 3, by way of the aziridine 2 (J. Am. Chem. Soc. 1965, 87, 749. DOI: 10.1021/ja01082a013). The later observation by Hisashi Yamamoto of Nagoya University that cyclic imines such as 3 can be reduced selectively to either the cis or the trans 2,5-dialkyl piperidine (J. Am. Chem. Soc. 1983, 105, 2831. DOI: 10.1021/ja00347a052) set the stage for the use of the Logothetis reaction in target-directed synthesis.

The structure of the ant venom solenopsin B (6) had been determined, but the absolute configuration had not yet been established. Starting with the enantiomerically-pure alcohol 4 prepared by chiral auxiliary control, we were able to demonstrate that natural 6 is (R,R), as illustrated (J. Org. Chem. 1988, 53, 2968. DOI: 10.1021/jo00248a013).

Swaisonine (9), isolated from the fungus Rhizoctonia leguminicola, is a powerful inhibitor of α-mannosidase. Jin Kun Cha, now at Wayne State University, assembled 9 by the cyclization to the imine 8 of the azide derived from the tosylate 7 (J. Am. Chem. Soc. 1989, 111, 2580. DOI: 10.1021/ja00189a034).

Indolizidine 223AB (12) is one of the many alkaloids exuded by Central American frogs of the genus Dendrobates. With the availability of a convenient protocol for the enantioselective Noyori hydrogenation of β-keto esters, we were able to prepare the azide 10 in enantiomerically-pure form, and cyclize it to 11. It is noteworthy that the subsequent ring closure to 12 proceeded with a single inversion of absolute configuration (J. Org. Chem. 1992, 57, 5990. DOI: 10.1021/jo00048a037).

The Dendrobates exudate also contains more complex alkaloids, as exemplified by quinolizidine 217A (15). William H. Pearson, then at the University of Michigan, assembled the azide 13 as a racemic mixture of diastereomers. Cyclization followed by reduction and saponification furnished the diastereomerically-pure crystalline acid 14, that was carried on to 15 (J. Org. Chem. 1998, 63, 9910. DOI: 10.1021/jo981695d).

FR66979 (18), isolated from Streptomyces sandaensisis, is a novel antibiotic with exceptionally potent antitumor activity. Marco A. Ciufolini, now at the University of British Columbia, observed that the triazine initially formed by the cyclization of the azide 16 was stable. Brief irradiation converted it to the corresponding aziridine, that was opened to the benzoazocene 17 by homo-Brook rearrangement (Angew. Chem. Int. Ed. 2002, 41, 4688. DOI: 10.1002/anie.200290017).

Many other applications can be envisioned for the aziridines/cyclic imines/endocyclic enamines generated by the Logothetis reaction. The work of Enrique Mann of the Instituto de Quimica Orgánica General ( 2013, December 30; 2017, April 24) is particularly creative.