Ladybird beetles, commonly referred to as ladybugs, are part of the Coccinellidae family, which comprises approximately 5,200 species worldwide. Folk wisdom attributes good fortune to these insects, while farmers leverage their voracious appetites for aphids for pest control. Notably, in the 1880s, several of the species were imported to California to control insects which were threatening to destroy citrus orchards.
Ladybird beetles employ a chemical defense mechanism known as reflex bleeding. When perturbed, Ladybird beetles exude a bitter, toxic, foul-smelling fluid called hemolymph. Hemolymph is known to contain several alkaloids, including hyperaspine, an alkaloid with a fused-decalin ring system characterized by four stereogenic centers. The structure of hyperaspine, along with adaline, calvine, adalinine, and other alkaloids isolated from the Coccinellidae family, is based on 2-methylperhydro-9b-azaphenalene.
My research has focused on a synthesis of (+)-hyperaspine with the intent of extending N-acyliminium ion cyclization methodology. Reactions involving such ions work similarly to the Mannich and Pictet-Spengler reactions, but overcome limitations in iminium ion reactivity inherent to such reactions. They also frequently proceed with good stereocontrol.
We envisioned accessing (+)-hyperaspine through an N-acyliminium ion cyclization that would afford the A ring with control of the two stereogenic centers at C4a and C6. The cyclization precursor was to be prepared from two key fragments, a chiral alcohol and a chiral carboxylic acid. The stereocenter at C8 was to be introduced via Evans’ chiral oxazolidinone chemistry to afford the chiral carboxylic acid, which would control stereochemistry at C4a and C6. The stereocenter at C3 was to be derived from β-hydroxybutyrate, the aforementioned chiral alcohol.
This dissertation will focus on the various approaches to the N-acyliminium ion intermediate through the investigation of several different pathways. Each of these pathways concentrates on the oxidation state of C4a to access the relevant urethane. We re-attempted to synthesize (+)-hyperaspine with sound methodology, however, we could not generate the N-acyliminium ion precursor 72. In conclusion, although we were not able to successfully synthesize hyperaspine, we were still able to demonstrate that N-acyliminium ion cyclizations are useful on substrates with a urethane functional group.