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Abstract
The total synthesis of (±)-adalinine, a piperidinone alkaloid isolated from the European two-spotted ladybird Adalia bipunctata , was completed in ten steps and in 13% overall yield. Central to this undertaking was (i) the spirocyclization of an N-alkoxy- N-acylnitrenium ion, which was generated by the oxidation of a methyl hydroxamate with phenyliodine(III) bis(trifluoroacetate), onto a pendant arene to rapidly access the 6,6'-disubstituted piperidinone ring of the natural product and (ii) exploitation of the cyclohexa-2,5-dienone system generated in this process as a latent 1,6-ketoaldehyde.
An advanced intwinediate for the diastereoselective total synthesis of fasicularin, a tricyclic alkaloid isolated from the marine invertebrate Nephteis fasicularis, was similarly constructed utilizing a π-facial selective spirocyclization of an N-alkoxy-N-acylnitrenium onto a pendant 2,4-disubstituted arene. Luehe reduction of the resulting cyclohexa-2,5-dienone system followed by acid-catalyzed rearrangement transposed a vinylogous ester to afford a cyclohexa-2,4-dienone system, which was subsequently transformed to an enol triflate. Sonogashira coupling between the enol triflate and a propargylic silyl ether installed the remaining carbon atoms present in the natural product.
Lastly, 2-oxa-1-azaspirodienones were prepared by the endo-trig spirocyclization of N-acyl-N-alkoxyaryl nitrenium ions. Cleavage of the endocyclic N-O bond in these substrates potentially provides access to substituted cyclohexyl systems, which could serve as a template for the total synthesis of natural products, such as (-)-tetrodotoxin. The spirocyclization tolerated various N-acyl groups including benzoyl, carbobenzoxy, carbo-2,2,2-trichloroethoxy, carboisobutoxy and acetyl; however, N-benzoyl substrates generally afforded higher yields. Seven-, six- and five-membered 2-oxa-1-azaspirodienones were obtained in good yields. Furthermore, the reaction was demonstrated to be diastereoselective. The requisite hydroxamates were prepared from alcohols by Mitsunobu reaction with N-hydroxyphthalimide followed by hydrazinolysis and acylation of the resulting alkoxyamines with an appropriate acid chloride.
