Design And Synthesis Of Novel Ezetimibe Isomers With A Re-organized Backbone And Synthesis Of Aza/Oxa Spirocycles By Radical Translocation/Cyclization Reactions

This dissertation is divided into two parts. In the first part, novel Ezetimibeisomers with a reorganized backbone were designed, synthesized both as amixture and the optically active form, and evaluated for their anti-cholesterolactivity in a rat feeding experiment. The absolute configuration of the opticalactive isomers were determined by X-ray and chemical correlations. In thesecond part, a cascade of radical translocation / cyclization of N-allyl-N-(2'-bromophenyl) amide of heterocyclic carboxylic acids and their N-propynylanalogs were investigated. This sequence of transformations provide a convenientmethod for the preparation of aza/oxa spiro-γ-lactams that are useful β-turnmimetics in drug discovery.In part one, Chapter One summarizes the anti-cholesterolemia drugs withemphasis on the development of ezetimibe in the literature. Ezetimibe inhibits theabsorption of dietary or recyclized cholesterol in the intestine and can be usedeither alone or in combination with a statin which inhibits the synthesis ofcholesterol in the liver. As reported in the literature, the pharmacophore has thefollowing features: (1) azetidinone is the required backbore;(2) N-phenyl isrequired, but could tolerate a range of substituents;(3) the phenyl tethered with 3carbon chain at 3-position of the azetidinone is needed;(4) p-hydroxy orp-methoxyphenyl at 4-position is a necessity;(5) unlike the chiral center at C-4,which shows a clear preference for S configuration, both 3S and 3R forms oftendemonstrate comparable activity. These SAR results in particular the last pointregarding the stereochemistry at 3-position prompted us to consider swampingthe substituents between N-position and 3-position.In Chapter Two, at first, a mixture of four hydroxy-methylated isomers ofthe target compounds in equal amount were synthesized and evaluated in a ratcholesterol-feeding experiment. Racemic trans-3-(4'-Fluoro-phenyl)-1,4-bis-(4'-methoxy-phenyl)-azetidin -2-one was prepared by the Staudinger reaction of2-(4'-fluorophenyl) acetyl chloride and N-(4'-methoxybenzylidene) -4-methoxybenzenamine, followed by removal of N-4'-methoxyphenyl by cericammonium nitrate to afford trans-3-(4'-fluorophenyl)-4-(4'-methoxyphenyl)azetidin-2-one. Ethyl 3-(4'-Fluoro-phenyl)-3'-hydroxy – propionate wassynthesized by Reformatsky reaction between 4-Fluoro-benzaldehyde and ethylbromo-acetate, and the 3-hydroxy was protected by TBDMSCl. The ester wasreduced to its alcohol, then converted to tert-Butyl-[1-(4'-fluoro-phenyl)-3-iodo-propoxy] -dimethyl-silane. 3-(4'-Fluoro-phenyl)-1-(3'-(4''-fluorophenyl) -3'-hydroxypropyl)-4-(4'-methoxyphenyl) azetidin-2-one wassynthesized by N-alkylation of racemic trans-3-(4'-fluorophenyl) -4-(4'-methoxyphenyl) azetidin-2-one with racemic tert-Butyl-[1-(4'-fluorophenyl)-3-iodo-propoxy] -dimethylsilane after removing the TBDMS. This mixturereduced the total serum cholesterol (TC) significantly in the preliminaryrat-feeding experiment. This result encouraged us to prepare both thehydroxy-methylated diastereomers as well as their hydroxy analogs in theoptically active form.Secondly, four optically active hydroxy-methylated isomers and fouroptically active hydroxy analogs were prepared and evaluated in a ratcholesterol-feeding test. The optically active isomers were obtained by couplingthe optically active trans-3-(4'-fluorophenyl)-4-(4'-methoxyphenyl/hydroxyphenyl) azetidin-2-one with the optically active 1-(4'-Fluorophenyl)-3-iodo-propan-1-ol. The optically active trans-3-(4'-fluorophenyl) -4-(4'-methoxyphenyl/hydroxyphenyl) azetidin-2-one was prepared by a (S)-1-(4'-methoxyphenyl) ethanamine induced Staudinger reaction between 2-(4'-fluorophenyl) acetyl chloride and (4'-methoxybenzylidene/benzyloxy-benzylidene)-(S) -[1-(4'-methoxyphenyl) -ethyl]-amine, followed by removingthe auxiliary by ceric ammonium nitrate. The two forms of optically active1-(4'-Fluorophenyl)-3-iodo-propan-1-ol were obtained by reduction of3-chloro-1-(4'-fluorophenyl)-propan-1-one catalyzed by (R) or (S)-CBS. Theabsolute configuration of all optically active isomers were determined by either aX-ray experiment or chemical correlations. 3-(S)-(4'-fluorophenyl) -1-[3'-(4''-fluoro-phenyl)-3'-(S)-hydroxypropyl]-4-(R)-(4'-methoxyphenyl) -azetidin-2-onereduced TC and its 3-(R)-4-(S)-3'-(S) isomer raise HDL-cho clearly in thepreliminary rat-feeding experiment with high cholesterol and high fat diet.In the second part, a convenient method for the preparation of aza/oxaspiro-γ-lactams by a cascade of radical translocation / cyclization reactions wasinvestigated. Chapter Three summarizes spirolactams and 1,5-radicaltranslocation reactions in literatures. Spirolactams, with fixed angles resemblingnaturally occurring β-turns of peptides, are of interest in the pursuit ofpeptidomimetic drugs. Thus far, their synthesis has primarily involvedintramolecular Mitsunobu reaction, amide-coupling reaction, or Michael additionfollowed by subsequent nitro-reductive cyclization reactions. 1,5-Radicaltranslocation reactions in which the key bond-forming radical was generated byintramolecular abstraction of an atom (usually hydrogen) or group by a radicalcenter, subsequently reacts with a site normally unreactive towards externalreagents have been well developed. They have been employed in the synthesis ofnatural products with unusual structural features and spirocarboncycles.In Chapter Four, aza/oxa spiro-γ-lactams were prepared by an aryl radicalinitiated cascade of radical translocation / cyclization reactions of N-allyl-N-(2'-bromophenyl) amide of heterocyclic carboxylic acids and its N-propynylanalogs. N-Boc L-proline, (±) -N-Boc piperidine-2-carboxylic acid, or (±)-tetrahydrofuran-2-carboxylic acid coupled with 2-bromo-or 4-methoxy-2-bromoaniline to provide amides, which reacted with allyl bromide to affordN-Boc or O radical precursors. The N-Boc was cleaved by hydrochloric acid inethyl acetate to give N-H precursors. Aza/Oxaspirolactams were obtained fromthe radical precursors through radical translocation and 5-exo cyclization reaction.The stereochemical configuration of 7-(4'-methoxyphenyl) -9-methyl-1,7-diaza-spiro [4. 4] nonan-6-one was determined on the basis of X-ray diffractionanalysis and a NOESY spectrum. The stereochemical structures of the rest ofspirolactams were assigned by analogy with their NMR spectra. In addition,tricyclic spirolactams was prepared by a domino 1, 5-radical translocationreactions.