Total Synthesis of (-)-Lepadin F based on a Stereoselective Diels-Alder Reaction Controlled by a Ketolactone-type Dienophile

An efficient approach to the type III lepadin alkaloids (lepadins F and G) has been developed through a key Diels-Alder reaction, in which a novel ketolactone-type dienophile with chiral diol unit is employed to generate the desirable all-cis-trisubstituted cyclohexene with excellent regio- and stereoselectivity control. The subsequent selective sulfonylation of the diol unit followed by S(N)2 cyclization under hydrogenation conditions could construct the substituted piperidine ring. By using this approach, (-)-lepadin F is synthesized from ethyl l-lactate for the first time.

Automated summary

An efficient approach to synthesize type III lepadin alkaloids (lepadins F and G) was developed through a key Diels-Alder reaction using a novel ketolactone-type dienophile with a chiral diol unit to achieve excellent regio- and stereoselectivity control for the desired all-cis-trisubstituted cyclohexene. Subsequent selective sulfonylation of the diol unit followed by S(N)2 cyclization under hydrogenation conditions successfully constructed the substituted piperidine ring.