Asymmetric Synthesis of 1,3-Amino Alcohols and Tropinone Derivatives From Enantiopure Sulfinimines

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.

Grantor dc:publisher

Temple University. Libraries

Year dc:date.issued

2011

Author dc:creator

• Gaspari, Paul

Advisor dc:contributor.advisor

• Davis, Franklin A.

Committee members dc:contributor.committeemember

• Sieburth, Scott McNeill
• Andrade, Rodrigo B.
• Cannon, Kevin C.

• Chemistry
• Chemistry, Organic
• Amino Alcohols
• Asymmetric
• Cocaine
• Pinidinol
• Scopolamine
• Tropinone

Statement dc:rights

• IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

eng

Dc Identifier Other

864885052

OAI identifier oai:identifier

oai:scholarshare.temple.edu:20.500.12613/1279