Development of an enantioselective route toward the Lycopodium alkaloids: total synthesis of lycopodine

Abstract

Synthesis of a C(15)-desmethyl tricycle core of lycopodine has been accomplished. Key steps in the synthetic sequence include organocatalytic, intramolecular Michael addition of a keto sulfone and a tandem 1,3-sulfonyl shift/Mannich cyclization to construct the tricyclic core ring system. Synthetic work toward this natural product family led to the development of N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide, an organocatalyst which facilitates enantioselective, intramolecular Michael additions. A detailed mechanistic discussion is provided for both the intramolecular Michael addition and the sulfone rearrangement. Finally, the application of these discoveries to the enantioselective total synthesis of alkaloid lycopodine is described.

Figure 1

Four Major Subclasses of the Lycopodium alkaloids.

Scheme 1

Retrosynthetic Strategy for Lycopodine.

Scheme 2

Key Michael / Mannich Sequence.

Scheme 3

Development of Racemic Protocol for Intramolecular, Keto Sulfone Michael Addition.

Scheme 4

Synthesis of Novel Sulfonamide 31.

Scheme 5

Enantioselective Synthesis of the Lycopodine Tricyclic Core 37.

Scheme 6

Synthesis of the Key Enone Intermediate.

Scheme 7

Possible Mechanistic Pathway for Diastereoselective Michael Addition.

Scheme 8

Diastereoselective Michael Addition of 8.

Scheme 9

Enantioselective Total Synthesis of Lycopodine.

Scheme 10

Possible Mechanistic Pathway for Tricycle Formation.

Scheme 11

Probing the Mechanistic Pathway for Sulfone Rearrangement / Mannich Cyclization.