Lepadine alkaloids

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>. 

Miscellaneous ring closure reactions involving carbon-carbon bond formation are shown in Scheme 72 and 73. An oxidation-cyclization-oxidation process was effected by PCC to convert alcohols 197 to 4-piperidones 198 <04JOC3226>. Intramolecular alkylation was used to covert chiral enaminone 199 to 200, a key intermediate in the total synthesis of lepadin alkaloids... 

StereocontroUed construction of decahydroquinoline systems of lepadin alkaloids 13KGS249. 

Perhydropyrido[l,2-A][l,2]oxazines are applied as key intermediates in a stereospecific total syntheses of (-)-pumiliotoxin C and 5-e/ /-pumiliotoxin C(96JCS(P1)1113), and the marine alkaloid)—)-lepadins A, B, C (OOOL2955). (2-Pyridyl)propionic acids 13 can be regioselectively prepared via 2,3,4, 4fl,7,8-hexahydropyrido[l,2-A][l,2]oxazin-2-ones 12 (00OL4007). 

Kibayashi and coworkers described the stannane-mediated reduction of xanthate (70) in their work towards the preparation the marine alkaloid (—)-lepadin B (equation 42)272, while Danishefsky and his associates provide an elegant, fully synthetic route to the neurotrophic tricycloilliconone (71) involving the reduction of xanthate (72) (equation 43)277. 

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... 

On the other hand, Steffan isolated lepadin B from the tunicate Clavelina lepadiformis, and, four years later, Andersen and co-workers isolated lepadin B, and C along with lepadin A from the same tunicate. Professor Andersen also reported lepadin A and B showed significant cytotoxic activity toward a variety of murine and human cancer cell lines. The absolute stereochemistry of these alkaloids was also unknown. 

Lepadins constitute a class of recently discovered antimalarial marine alkaloids. These molecules are decahydroquinoline derivatives bearing a linear eight-carbon chain isolated from two marine invertebrates of Australian origin, Clavelina lepadiformis [49] and Didemnum sp. [50]. 

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. 

In 2008, Blechert et al. reported the total synthesis of e/jt-lepadin F (89) and G (90) by a tandem ene-yne-ene RCM [74]. Lepadins are members of marine alkaloids with decahydroquinoline framework. As a key step in their synthesis (Fig. 26) they planned to construct the decahydroquinoline core skeleton by a selective tandem ene-yne-ene RCM of the dienyne precursor (91). Craiceivably, two different reaction pathways could be expected (1) initiation of metathesis may occur at the terminal double bond followed by two consecutive RCMs to afford the desired 6/6 bicycle (92) or (2) initiation may occur on the disubstituted alkene followed by tandem RCMs to produce the undesired 5/7 bicycle (93). Considering the preference of initiation on monosubstituted double bond as well as the directing effect of free hydroxyl group, pathway (1) may be more favored. Gratilyingly, treatment of dienyne (91) with 10 mol% Gmbbs I catalyst smoothly provided the desired 6/6 bicycle (92) in 90% yield. 

Tsuneki H, You Y, Toyooka N, Sasaoka T, Nemoto H, Dani JA, Kimura I. Marine alkaloids (—)-pictamine and (—)-lepadin B block neuronal nicotinic acetylcholine receptors. Biol. Pharm. Bull. 2005 28(4) 611-614. 

Toyooka N, Okumura M, Takahata H. Enantioselective total synthesis of the marine alkaloid lepadin B. J. Org. Chem. 1999 64(7) 2182-2183. 

Ozawa T, Aoyagi S, Kibayashi C. Total synthesis of the marine alkaloid (—)-lepadin B. Org. Lett. 2000 2(19) 2955-2958. 

Ozawa, T, Aoyagi, S., and Kibayashi, C. (2001) Total synthesis of the marine alkaloids (-)-lepadine A, B, and C based on stereocontrolled intramolecular acylnitroso Diels-Alder reaction. J. Org. Chem., 66, 3338-3347. 

StefFan, B. (1991) Lepadin A, a decahydroquinoline alkaloid from the tunicate Clavelina kpadiformis. Tetrahedron, 47, 8729-8732. 

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