Lycopodium Alkaloids: An Intramolecular Michael Reaction Approach

Abstract

The Lycopodium alkaloids possess a rich history that has captured the attention of synthetic chemists across the globe. This large family consists of over 250 known natural products with diverse structural features and noteworthy biological activity. Herein, we interweave the synthetic accomplishments by others in the field with our own unified strategy to accessing multiple subfamilies of the Lycopodium alkaloids. This discussion includes lycopodine, the C10-hydroxy Lycopodium alkaloids (10-hydroxylycopodine, deacetylpaniculine and paniculine), pelletierine, cermizine D, fastigiatine, himeradine A, clavolonine and 7-hydroxylycopodine. A unifying feature of much of the work discussed within this account is the use of intramolecular Michael additions to construct key ring systems within the Lycopodium alkaloids. Examples include the use of an intramolecular keto-sulfone Michael reaction and an intramolecular heteroatom Michael reaction.1 General Background on Lycopodium Alkaloids2 Development of a Strategy for Lycopodium Alkaloids2.1 Generalized Strategy2.2 Known Syntheses of C10-Functionalized Lycopodium Alkaloids3 Quinolizidine-Type Alkaloids3.1 Background3.2 Development of the Heteroatom Michael Reaction3.3 Synthesis of the Core Lycopodine Building Block: Pelletierine3.4 Total Synthesis of Cermizine D3.5 Synthesis of the Eastern Half of Himeradine A4 Lycopodine-Type Alkaloids4.1 Total Syntheses of Lycopodine4.1.1 Earlier Racemic Syntheses4.1.2 Approach Toward the Tricyclic Skeleton of Lycopodine: Intramolecular Mannich4.1.3 Enantioselective Total Syntheses of Lycopodine4.2 Total Syntheses of Clavolonine (8-Hydroxylycopodine)4.3 Total Synthesis of 7-Hydroxylycopodine4.4 Synthetic Route for 10-Hydroxy Lycopodium Alkaloids4.4.1 Background4.4.2 Total Syntheses4.4.3 Impact of the C10-Stereochemistry5 Conclusion

Second-Generation Synthesis of (+)-Fastigiatine Inspired by Conformational Studies

“…Himeradine A has attracted the interest of organic chemists. , The structurally similar lyconadine family of natural products have generated a great deal of interest and a variety of creative synthetic strategies . Syntheses of Lycopodium alkaloids has been recently reviewed …”

Strategies for the Asymmetric Construction of Pelletierine and its Use in the Synthesis of Sedridine, Myrtine, and Lasubine

“…An alternative method to prepare pelletierine by an intramolecular aza‐Michael‐type reaction (IMAMR) was also considered. Racemic Cbz‐protected pelletierine 17 was prepared by a straight‐forward four‐step process from 5‐amino pentanol 21 .…”

Enantioselective Total Syntheses of Lyconadins A–E through a Palladium‐Catalyzed Heck‐Type Reaction

“…Notably, lyconadins D and E ( 4 and 5 ) are the first new fastigiatine‐type alkaloids from L. complanatum . With favorable bioactivity and impressive structural complexity, these lycopodium alkaloids has served as attractive targets in the chemistry community . Remarkable total synthetic triumphs have been achieved by Smith ( 1 , 2 ), Sarpong ( 1 ), Fukuyama ( 1 – 3 ), Waters ( 3 ), Dai ( 1, 3 ), Shair ( 1 , 2, 6 – 8 ), Rychnovsky ( 8 ), but total syntheses of lyconadins D and E ( 4 , 5 ) has not been realized.…”