The Liu Synthesis of Zygadenine

Zygadenine (3) is one of the most highly oxygenated of the Veratrum alkaloids. Tuoping Luo of Peking University devised a route to 3 based on the intramolecular Diels-Alder cyclization of 1 to 2 (J. Am. Chem. Soc. 2023, 145, 20202. DOI: 10.1021/jacs.3c08039).

The cis-fused enone 4 was readily prepared from the Hajos-Parrish ketone ( 2020 October 5). Conjugate addition of cyanide followed by β-elimination, and then addition of furyl lithium and mixed ketal formation led to the unsaturated nitrile 5. Oxidative cleavage of the furan followed by further oxidation then completed the assembly of the acid 6.

The protected amine 10 was assembled starting from the Weinreb amide 7. Addition of the furyl lithium 8 followed by epimerization led to the more stable cis ketone 9. Diastereoselective addition of methyl magnesium bromide followed by deprotection and protection then gave 10.

The free amine 10 was acylated with the carboxylic acid 6 to give the amide 1. Nominally, four diastereomers could have been formed in the subsequent Diels-Alder cyclization. In fact, the desired 2 was the only diastereomer observed.

Free radical generation by the reduction of the bromide of 2 was followed by intramolecular conjugate addition, to give 11. Reduction and deoxygenation removed the ketone, then oxidative cleavage of the nitrile to the ketone set the stage for β-elimination of the dihydrofuran. The resulting dienone 12 had everything in place to complete the synthesis of zygadenine (3), through a series of oxidations and reductions. The first of the oxidations was the conversion of the dienone 12 to the α-diketone 13.

In a parallel account, Professor Luo reported an alternative endgame for the synthesis, taking advantage of neighboring group participation. This also allowed the total synthesis of other more highly oxygenated Veratrum alkaloids, including the long-sought germine (Nature Commun. 2024, 15, 7639. DOI: 10.1038/s41467-024-52134-7).