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Asymmetric Synthesis of 1,3-Amino Alcohols and Tropinone Derivatives From Enantiopure Sulfinimines
Gaspari, Paul
Gaspari, Paul
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2011
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Chemistry
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http://dx.doi.org/10.34944/dspace/1261
Abstract
Heterocycles that contain nitrogen, such as piperidine, pyrrolidine and tropane, are widespread as natural product alkaloids and serve as templates for many bioactive drugs and drug candidates. The intent of this research is to the develop asymmetric syntheses of piperidine-containing syn and anti 1,3-amino alcohols as well as tropinone and tropane-containing derivatives using sulfinimines (N-sulfinyl imines) as precursors for acid-catalyzed cascade cyclizations. Chiral N-sulfinyl b-amino ketones derived from N-sulfinyl b-amino Weinreb amides, serve as novel and direct precursors to syn and anti N-sulfinyl 1,3-amino alcohols through stereoselective reductions. General reduction conditions have been developed for a variety of substrates. This methodology was applied to a concise formal synthesis of the piperidine-containing natural product, (-)-pinidinol, through an intramolecular cascade-cyclization of a masked-oxo N-sulfinyl 1,3-amino alcohol. Special conditions were found for the syn reduction of these substrates. Tropinones and tropanes are structural motifs which encompass many interesting bioactive natural products such as cocaine and scopolamine. The synthesis of these tropinone derivatives, using an asymmetric and intramolecular cascade reaction, allows for facile functionalization of one of the bridgehead carbons. This opens doors to novel derivatives of (-)-cocaine which can be used as potential addiction therapeutics or in new SAR studies of dopamine reuptake transporter blockers. Here a five-membered cyclic imine can be formed through the acid-catalyzed intramolecular cyclization of acyclic ketal-protected N-sulfinyl ketones. After reaction with an acylating agent, the tropinone nucleus can be formed through an intramolecular Mannich reaction of an N-acyl iminium ion.
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