Lepadin structure

A stereospecific route to enantiopure all-cis-2,3,6-trisubstituted piperidines relies on a cyclization step that is dependent upon temperature, and choice and quantity of base (Scheme 42) <2003TL3963>. Further intramolecular alkylation reactions reported include that of the chiral enaminone to the bicylic structure 35, a key intermediate toward the synthesis of lepadin alkaloids (Equation 80) <2004AGE4222>. 

A number of a, a -disubstituted 3-piperidinol alkaloids have been found in Cassia or Prosopis species,[1] and, quite recently, alkaloids including this structural unit have also been isolated from ascidian.[2] Many of these alkaloids showed interesting pharmacological activities such as anesthetic, analgestic, and antibiotic activities. Clavepictines A and B, and pictamine, isolated from tunicate, by Cardellina, II[3] or Faulkner[4] and co-workers, possess 3-piperidinol structure. Lepadins A, B, and C, isolated from tunicate, by Steffan[5] and Andersen[6] and coworkers, also have this structural unit. We designed lactam 1 as a useful... 

Fig. (9) Chemical structures of the active lepadin E (35) and the inactive lepadin D (36)...

Bicyclo [2.2.2] structures such as 9 are readily available by the addition of, in this case, methyl acrylate to an enantiomerically-pure 2-methylated dihydropyridine. Andre B. Charette of the Universite de Montreal found J. Am. Chem. Soc. 2008,130, 13873) that 9 responded well to ring-opening/ring-closing metathesis, to give the octahydroquinoline 10. Functional group manipulation converted 10 into the Clavelina alkaloid (+)-Lepadin B 11. 

Considering that two complex structures differing only at a remote and highly insulated stereocenter could stiU be differentiated spectroscopically, we were prompted to synthesize (+)-lepadin G and its C5 epimer in an attempt to concisely determine its correct relative stereochemistry. Therefore, total syntheses of both (-l-)-lepadin G and... 

---