Stereoselective synthesis of piperidines

Adriaenssens, Louis (2008) Stereoselective synthesis of piperidines. PhD thesis, University of Glasgow.

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This thesis is divided into two parts. The first part describes the production of a small stereodiverse library of 2-substituted piperidines. Novel chiral titanium alkylidene reagents ii alkylidenated resin-bound esters i to give acid-labile resin-bound enol ethers iii. These were cleaved to give amino ketones iv. The switch in the nature of the resin from acid-stable to acid-labile is key to the purity of the amino ketones iv, as during cleavage only the acid-sensitive enol ethers iii are cleaved, leaving the unreacted esters i on the resin. The amino ketonse iv were cyclized using TMSC1 to give cyclic iminium salts v. Diastereoselective reduction of the iminium salts v with NaBH(OAc)[sub]3 gave piperidines vi which, after cleavage of the chiral protecting group gave the desired enantiomerically-enriched, 2-substituted piperidines vii.
The piperidines vii were produced in good overall yield, high purity, and good to excellent stereochemical purity. By switching the enantiomer of the phenylethylamine chiral protecting group used, either enantiomer of the desired piperidine could be produced at will.
The second part of the thesis describes a solution-phase route to 2,6-syn substituted piperidin-4-ones xii inspired by the Petasis-Ferrier rearrangement. Imino esters x derived from [Beta]-amino acids viii were methylenated using the Petasis reagent, dimethyltitanoce, to give imino enol ethers xi containing nucleophilic and electrophilic functionality in the same molecule. The mild microwave conditions used for the methylenation geve the enol ethers xi in minutes. Potentially, the reaction takes advantage of selective heating of the polar Petasis reagent in a non polar solvent system so that the rate determining decomposition of the Petasis reagent is accelerated without affecting any sensitive substrate. Acidic conditions activated the imine and induced cyclization to give the desired 2,6-syn piperidin-4-ones xii in good yield and excellent diastereoselectivity. A small library of piperidinones was produced to demonstrate the method.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: piperidine, synthesis, stereoselective
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Hartley, Dr. Richard C.
Date of Award: 2008
Depositing User: Mr Louis V Adriaenssens
Unique ID: glathesis:2008-49
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 06 Mar 2008
Last Modified: 10 Dec 2012 13:15

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