依泽替米贝异构体和1，5-自由基转移法合成氮杂螺环的研究
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摘要
本论文分为两部分:设计和合成降胆固醇新药依泽替米贝(ezetimibe)异构体以及1,5-自由基转移反应在合成氮杂螺环γ-内酰胺类化合物中的应用研究。
第一部分应用模仿创新(Me-better)药物开发方法分别设计、合成了依泽替米贝结构重组的异构体及其类似物,利用单晶X-射线实验和化学相关法确定了其绝对构型,并通过大鼠实验验证了其药理活性。实验表明,新设计的药物可以明显降低血清中总胆固醇含量,或升高高密度脂蛋白-胆固醇含量。
第二部分利用芳基自由基引发的1,5-自由基转移反应,从N-烯丙基/炔丙基-N-(2-溴苯基) -(2-杂环烷基)甲酰胺合成了氮/氧杂螺环-γ-内酰胺类化合物,并对其反应规律进行了探索。通过单晶X-ray衍射实验和核磁共振NOSEY实验,确定了产物7-对甲氧基苯基-9-甲基-1,7-二氮杂螺[4.4]环辛酮的空间构型。
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 or
p-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 coupling
the 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.
第一部分应用模仿创新(Me-better)药物开发方法分别设计、合成了依泽替米贝结构重组的异构体及其类似物,利用单晶X-射线实验和化学相关法确定了其绝对构型,并通过大鼠实验验证了其药理活性。实验表明,新设计的药物可以明显降低血清中总胆固醇含量,或升高高密度脂蛋白-胆固醇含量。
第二部分利用芳基自由基引发的1,5-自由基转移反应,从N-烯丙基/炔丙基-N-(2-溴苯基) -(2-杂环烷基)甲酰胺合成了氮/氧杂螺环-γ-内酰胺类化合物,并对其反应规律进行了探索。通过单晶X-ray衍射实验和核磁共振NOSEY实验,确定了产物7-对甲氧基苯基-9-甲基-1,7-二氮杂螺[4.4]环辛酮的空间构型。
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 or
p-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 coupling
the 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.
引文
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