| Abstract
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The 2,5-dialkyl pyrrolidines and 2,6-dialkyl piperidines constitute an interesting class of nitrogen-containing, heterocyclic natural products which are challenging synthetic targets for organic chemists. Electrophilic cyclizations of amines, amides, or carbamates onto neighboring olefins have previously been explored as construction strategies. Of these procedures, few studies have investigated the stereoselectivity of reactions to produce the trans dialkyl pyrrolidine or piperidine nucleus as compared to the cis dialkyl diastereomers. These efforts have successfully explored the iodine induced cyclization of usd\epsilonusd- and usd\deltausd-unsaturated N-alkoxyamines which have afforded preferential formation of trans-2,5-dialkyl pyrrolidines and trans-2,6-dialkyl piperidines, respectively. Further chemical manipulation of the resultant usd\betausd-iodopyrrolidines demonstrated anchimeric assisted displacement which allowed intramolecular capture of the intermediate aziridinium salt leading to the formation of butyrolactones. The resultant 2,5-dialkylated pyrrolidino butyrolactones are systems observed in several of the Stemona alkaloids. Furthermore, examination of methodology for the enantioselective preparation of N-alkoxyamines as precursors for our electrophilic cyclizations was examined. Our interests in the enantioselective synthesis of N-alkoxyamines, and in the stereoselective construction of trans-2,6-dialkyl piperidines, was applied to the synthesis of ()-andrachamine. The reported natural product was isolated from a shrub found in Pakistan which has been used as a folk remedy for sore eyes and poor eyesight in its native land. Developing principles of acyclic stereocontrol, it was shown that one hydroxyl stereocenter could be used to establish the remaining stereogenic centers in andrachamine. It was observed that reduction of usd\betausd-hydroxy E-oximes preferentially formed syn-1,3-N-alkoxyamino alcohols while reduction of the stereoisomeric usd\betausd-hydroxy Z-oximes favored formation of anti-1,3-N-alkoxyamino alcohols. The further stereoselective iodocyclization of our N-alkoxyamine products led to selective formation of the trans-2,6-disubstituted piperidine nucleus of andrachamine. A novel electrophilic cyclization of an allylic N-alkoxyamine forming a bicyclic syn 3,5-dialkyl isoxazolidine allowed introduction of the final hydroxyl stereocenter in the natural product. Using this strategy, all four trans diastereomers of andrachamine were prepared. Our studies have established that the assigned stereochemistry of the natural product is incorrect.
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