Construction Of Chiral Spiro Pyrrolidines And Synthesis Of Chiral Aliphatic Amines Via Rhodium Catalytic Asymmetric Hydrogenation

This PhD dissertation contain two parts. Firstly, catalytic asymmetric1,3-dipolar cycloaddition of azomethine ylides (cyclic and acyclic imino esters) with electron deficient olefins for constructing spiro pyrrolidines have been studied. And then chiral aliphatic amines have been synthesized via rhodium catalytic asymmetric hydrogenation.1, Construction of chiral spiro pyrrolidines via catalytic asymmetric [3+2] cycloaddition.1,3-dipolar cycloaddition is one the most important and classic methods for the synthesis of five-membered heterocycles. In1963, Huisgen introduced the concept of'dipolar cycloaddition', and in2002, Zhang and J(?)rgensen reported the first catalytic asymmetric1,3-dipolar cycloaddition of azomethine ylides with electron deficient olefins for the synthesis of chiral pyrrolidines, respectively. Since then, the catalytic asymmetric version of this cycloaddition was found to be the common access for the construction of chiral pyrrolidines. Gong reported the pathbreaking synthesis of chiral spiro pyrrolidines via chiral phosphoric acid catalytic asymmetric1,3-dipolar cycloaddition of azomethine ylides with N-protected2-oxoindolin-3-ylidenes in2009. In past years, translate metal catalytic asymmetric reactions have been remarked with mild reaction conditions, low catalyst loading, high regioselectivity and enantioselectivity. In this part of my PhD dissertation, asymmetric construction of chiral spiro pyrrolidines via copper or silver catalytic1,3-dipolar cycloaddition of azomethine ylides with cyclic alkenes was studied.Chiral spirooxindole-pyrrolidines, which bearing three contiguous stereogenic centers and one spiro quaternary carbon center have been achieved via AgOAc/TF-BiphamPhos catalytic asymmetric1,3-dipolar cycloaddition of azomethine ylides with N-unprotected2-oxoindolin-3-ylidenes. Under mild conditions, a broad scope of imino esters and methyleneoxindoles were compatible and providing the synthetically useful adducts in high yields and excellent diastereoselectivities but moderate enantioselectivities.The catalytic asymmetric1,3-dipolar cycloaddition of azomethine ylides with other a,a,?-trisubstituted enones such as alkylidenecycloketones and3-alkylidene-4-chromanones have also been studied. Spiro heterocyclic compounds which contains a pyrrolidine motif and a spiro quaternary stereogenic carbon center have been successfully constructed via Ag1(or Cu')/TF-BiphamPhos catalytic asymmetric1,3-dipolar cycloaddition of azomethine ylides with ?,?,?-trisubstituted alkylidenecycloketones. Subsequent Baeyer-Villiger oxidation of the cycloadducts led to the expedient preparation of synthetically useful spiro[pyrrolidine- tetrahydropyranone] and spiro [pyrrolidine-isochroman-1-one] without loss of the diastereo-and enantiomeric excesses. Additionally, a facile synthesis of highly functional spiro[4-chromanone-3,3'-pyrrolidine] in excellent stereoselectivity has also been developed while3-alkylidene-4-chromanone as the dipolarophile in the catalytic asymmetric1,3-dipolar cycloaddition.We have successfully developed the first catalytic asymmetric1,3-dipolar cycloaddition of cyclic imino esters generated from homoserine lactones and aromatic aldehydes with various electron deficient olefins, and constructed the spiro(butyrolactonepyrrolidines) with a spiro quaternary stereogenic carbon center on the2position of pyrrolidines with high yields, high diastero-/enantioselectivities.A facile access to bioactive5-aza-spiro[2,4]-heptanes has been successfully developed via catalytic asymmetric endo-selective1,3-dipolar cycloaddition of azomethine ylides (cyclic or acyclic imine esters) with both a?-unsubstituted and a-substituted cyclopropylidene acetates. Tetrasubstituted alkenes have been introduced as the dipolarophiles for the first time and the spiro heterocycles with contiguous quaternary stereogenic centers at2,3and4-positions of the pyrrolidine ring were provided in good yields (up to90%) and high diastereoselectivities (95:5->98:2dr) and excellent enantioselectivities (87-98%ee).2, Synthesis of Chiral Aliphatic Amines through Asymmetric HydrogenationChiral amines are found in many biologically active molecules and it is estimated that over70%pharmaceutical products contain amines. A great deal of attentions have been devoted to the preparation of chiral amines and their application as building blocks in pharmaceutical synthesis, which has become an attractive area in synthetic sciences ranging from classic resolution, enzymatic processes and catalytic transformations through man-made catalysts. Several efficient methods have been developed for preparing aromatic chiral amines, however, a facile synthesis of chiral aliphatic amines remains challenging. A catalytic hydrogenation for the efficient synthesis of broad range of chiral aliphatic amines (e.g.5000turnovers,>99%ee) from readily available materials was developed. The successfully application of this method in the syntheses of a number of key pharmaceutical building blocks is also presented.