ENANTIOSELECTIVE TOTAL SYNTHESIS OF THE MACROCYCLIC SPERMIDINE ALKALOID (-)-ONCINOTINE

The macrocyclic spermidine alkaloid (-)-oncinotine (1), isolated from Oncinotis nitida (Apocynaceae), was synthesized enantioselectively for the first time based on intramolecular iminium ion cyclization utiliz ing enantiomerically pure )-N-[(benzyloxy)carbonyl]-2-piperidineacetal dehyde (8) as a chiral starting material. The required 8 was derived f rom the erythro adduct 16, which was obtained by diastereoselective 1, 3-dipolar cycloaddition between 2,3,4,5-tetrahydropyridine 1-oxide (4) and -[(tert-butyldiphenylsilyl)oxy]-4-methyl-1-pentene (15). Wittig c ondensation of 8 with [8-(methoxycarbonyl)octyl]triphenylphosphonium i odide (21) followed by saponification provided the chiral piperidine m oiety 23, which was coupled with the N-propyl-1,4-butanediamine segmen t 29 by using diethoxyphosphoryl cyanide in the presence of triethylam ine to afford the tertiary amide 30. Conversion of 30 to the aldehyde 34 via desilylation and Swern oxidation, followed by hydrogenation ove r a palladium hydroxide catalyst under high dilution led to in situ fo rmation of the transient iminium ion 35, which was further hydrogenate d to form 33 in a single operation. Subsequent removal of the Boc prot ecting group resulted in (-)-oncinotine (1).