Study Of Asymmetric Addition Of Imine Induced By Chiral Amine Auxiliaries

Many biological molecules in nature, such as saccharides, amino acids andproteins, are chiral. Asymmetric synthesis is an important method to preparechiral molecules in laboratories. It has become a focus in the field of organicsynthesis and medicinal chemistry. Asymmetric synthesis induced by chiralauxiliary is the most important approach. Due to commercial availability andexcellent stereoselectivity in the reaction, chiral amines are extensively used aschiral auxiliaries in synthesis of nitrogen-containing compounds. For examples,asymmetric nucleophilic addition of organometallic reagents to imines, Streckerreaction and Staudinger reaction have been reported. The present research involves nucleophilic addition of imines employingamino alcohols and amino ethers as chiral auxiliaries and removal of chiralauxiliaries, amine as chiral auxiliaries in asymmetric Staudinger reaction, themodel study of conjugate addition of Grignard reagents to amino alcoholderived oxazolidine and the attempt in the solid phase synthesis. The asymmetric additions of imines induced by chiral amine auxiliariesare reviewed in chapter one. Phenylethylamine, amino alcohols and derivatives,and amino acids and derivatives are the commonly used as chiral auxiliaries inthe nucleophilic addition of organometallic reagents to imines, Staudingerreaction, Strecker reaction, hetero Diels-Alder reaction, Friedel–Crafts reaction,etc. The applications of amino alcohols and derivatives in the nucleophilicaddition of imines are introduced in details. Despite good selectivity, the majorproblem is that the removal of chiral auxiliary is limited by the reactants and thestructure of chiral auxiliary. Therefore, searching for simple and efficientcleavage condition is of important. The applications of polymer-supportedamino alcohol as chiral auxiliary in solid phase asymmetric synthesis are brieflypresented in this chapter. Amino alcohols and oxazolidinones, oxazolines havebeen used in solid phase synthesis while oxazolidines are rarely reported in solidphase synthesis. Nucleophilic addition to polymer-supported oxazolidine has notbeen reported in the literatures. In chapter two, amino ether induced asymmetric nucleophilic additions ofimines were investigated. (R)-2-methoxy-1-phenylethylamine was preparedfrom (R)-phenylglycine via esterification, Boc protection, reduction,methylation, and deprotection of Boc group. Organometallic addition to theimine derived from the above chiral amine and 1-naphthylcarboxaldehyde wasinvestigated. 1,2-Adduct N-2'-methoxy-1'-(phenylethyl)-1-(1-naphthyl)-pentylamine was obtained in high diastereoselectivity. Hydrogenolysis removal of thechiral auxiliary under Pd/C caused cleavage of undesired C-N bond at thenaphthalene side to yield (R)-2-methoxy-1phenylethylamine and alkylnaphthalene. To prepare chiral naphthalenemethylamine, a modification was made on thestructure of amino ether auxiliary. Both p-Methoxyphenyl and p-methoxybenzylare known protective groups for nitrogen in amide. They can be selectivelyremoved by oxidatiion under cerium ammonium nitrate (CAN) while otherbenzyl groups in the molecule are not affected. Thus(R)-2-methoxy-1-(4-methoxyphenyl)-ethylamine was introduced to replace(R)-2-methoxy-1-phenylethylamine as chiral auxiliary. It has been foundnucleophilic addition of butyllithium to the corresponding imine of1-naphthylcarboxaldehyde gave the 1,2-adduct in moderate yield (77%) andgood diastereoselectivity (97:3). The diastereoisomer products were separatedvia silica-gel chromatography. The chiral auxiliary was selectively removedfrom the 1,2-adduct under CAN to give optically activenaphthalenemethylamine. Six optically active naphthalenemethylamines andbenzylamines were prepared. The yields of asymmetric nucleophilic additionwere 63-83%, and the diastereoisomeric ratios were 94:6-99:1. In chapter three, the effect of chiral amine auxiliaries on asymmetricStaudinger reaction under Mukaiyama reagent was studied. First,(S)-phenylethylamine was used as a chiral auxiliary. The general rule of trans/cisof cycloaddition products was summerized via the [2+2] reactions of imines andketenes. That is the trans/cis of products obtained via Staudinger reaction wasattributed to the E or Z configuration of the zwitterionic intermediate. When theα site of the precusor of ketene was smaller group such as heteroatom oxygen,the zwitterionic intermediate was existed in E configuration, cis β-lactamswere obtained as the major product. While as the α site of the precursor ofketene was a large group such as phenyl group and phthalation amino group,trans β -lactams were obtained as major product. (S)-Phenylethylamineauxiliary has no significant effect on the stereoselectivity of the reaction. Otherchiral auxiliaries such as amino alcohol, amino ethers were used in this reaction,but the stereoselectivity of [2+2] reaction are lower (1:1-1:3). Based on the importance of amino alcohols in the asymmetric synthesis,chapter four dealt with the model study of the synthesis of polymer-supportedamino alcohol and its application in the conjugate addition of oxazolidine in thesolution phase, and attempt in solid phase synthesis. The model amino alcoholwas synthesized from (R)-p-hydroxyphenylglycine in 51% overall yield viaesterification, Boc protection, reduction, benzylation, and deprotection of Bocgroup. The conditions of this synthetic route were mild and the yield of eachstep was moderate. It could be possible to apply it in solid phase synthesis. Theamino alcohol was condensed with 1-naphthylcarboxaldehyde to give thecorresponding oxazolidine which underwent the asymmetric conjugatereaction by Grignard reagents to give 1,4-adduct dihydronaphthalene in 73%yield. The optical power was similar to the results reported in the literature. Theamino alcohol was recovered in 89% without loss of the optical property. Twodisubstituted dihydronaphthalene and three trisubstituted dihydronaphthalenewere synthesized in 53-76% and 71-84% recovery of chiral auxiliary. Finally weattempted to apply the model route of amino alcohol in solid phase synthesis,monitoring and characterization of solid phase reaction and products werecarried through by FT-IR spectra. In conclusion, this thesis presented (R)-2-methoxy-1-(4-methoxyphenyl)-...