Lycopodium alkaloids Mannich reaction

Lycoflexine (1), isolated from Lycopodium clavatum var. inflexum, is a representative of a new skeleton hitherto not encountered in this group of alkaloids. Lycoflexine showed in its mass spectrum a base peak at mje 84 which had not been previously encountered in mass spectra of Lycopodium alkaloids. The structure was solved by X-my crystallographic analysis of its hydrobromide derivative. Lycoflexine may be biogenetically related to the known fawcettimine (2), which also occurs in L. clavatum var. inflexum, by invoking an intramolecular Mannich reaction on an initially formed immonium salt (3). 

Heathcock and co-workers have now published full details of their synthetic work amongst lycopodium alkaloids which demonstrates further the powerful use of the intramolecular Mannich reaction in synthesis. ... 

Let s look at another alkaloid whose structure screams Mannich reaction for an endgame. Luciduline is one member of the Lycopodium family of alkaloids. This is a large family of natural products. A few structures are shown here (50-54). Luciduline (55) is a )8-aminoketone. This is precisely the difunctional relationship that results from the Mannich reaction. Thus, a strategy that passes through 56 en route to 55 seems likely to succeed. Aminoketone 56 is a 1,5-difunctional compound and, in principle, should be available using normal carbonyl chemistry. We will see an example of this later, but the first synthesis of luciduline approached 56 from 1,6-difunctional intermediate 57. One versatile method for the preparation of 1,6-dicarbonyl compounds is the oxy-Cope rearrangement. We saw this in the Evans synthesis of juvabione (Chapter 5) and indeed, this is the methodology used by Evans and Scott in their synthesis of luciduline (58 57). 

Luciduline is one of the simpler Lycopodium alkaloids. In an elegant synthesis of this molecule, Scott and Evans constructed the desired tricyclic skeleton from the key decalin ketoamine (D) by an intramolecular Mannich reaction, C-11 being derived from formaldehyde. The c/i-decalin-2,6-dlonesuitable for preparation of (D) was obtained by the oxy-Cope rearrangement of a bicyclo[2-2-2]octene derivative (A) which allowed controlled introduction of the desired sites of asymmetry. 

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