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 utilizing enantiomerically pure (2 S )- N -[(benzyloxy)carbonyl]-2-piperidineacetaldehyde ( 8 ) as a chiral starting material. The required 8 was derived from the erythro adduct 16, which was obtained by diastereoselective 1,3-dipolar cycloaddition between 2,3,4,5-tetrahydropyridine 1-oxide ( 4 ) and (3 S )-3-[( tert -butyldiphenylsilyl)oxy]-4-methyl-1-pentene ( 15 ). Wittig condensation of 8 with [8-(methoxycarbonyl)octyl]triphenylphosphonium iodide ( 21 ) followed by saponification provided the chiral piperidine moiety 23, which was coupled with the N -propyl-1,4-butanediamine segment 29 by using diethoxyphosphoryl cyanide in the presence of triethylamine to afford the tertiary amide 30 . Conversion of 30 to the aldehyde 34 via desilylation and Swern oxidation, followed by hydrogenation over a palladium hydroxide catalyst under high dilution led to in situ formation of the transient iminium ion 35, which was further hydrogenated to form 33 in a single operation. Subsequent removal of the Boc protecting group resulted in (−)-oncinotine ( 1 ).