Dissertation > Mathematical sciences and chemical > Chemistry > Organic Chemistry > Organic Chemistry general issues > Synthetic organic chemistry > Asymmetric Organic Synthesis

Enantioselective Catalytic Synthesis of Chiral Five-membered Nitrogeneous Heterocycles and(+)-Gliocladin C

Author Song
Tutor GongLiuZhu
School University of Science and Technology of China
Course Organic Chemistry
Keywords multifunctional chiral silver catalyst isocyanoesters asymmetric formal[3+2] cycloaddition asymmetric organocatalysis amine catalysis phosphoric acid asymmetric alkylation reaction gliocladin C totalsynthesis
CLC O621.34
Type PhD thesis
Year 2013
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Chiral five-membered nitrogen-containing heterocyclic moieties constitute an important type of core structural motif prevalent in numerous natural products and pharmaceutically active substances and have proven to be widely applicable to the total synthesis as building blocks. Great efforts have been devoted to the construction of optically pure heterocycles, leading to the appearance of many elegant catalytic methods. In this dissertation, we have established two new catalytic approaches for the enantioselective synthesis of optically active2,3-dihydropyrroles and hexahydropyrroloindole alkaloids. Most importantly, the asymmetric alkylation reaction has been successfully applied to the enantioselective total synthesis of (+)-gliocladin C.Optically active dihydropyrroles possess a carbon-carbon double bond and thereby can be modulated for a diverse synthetic purpose by exploiting a wide range of reactions working on olefins. We have established the first chiral Lewis acid-catalyzed formal [3+2] cyclization reaction of isocyanoesters with2-oxobutenoate esters in high yields and excellent levels of enantioselectivity by a silver complex of silver acetate and (S)-(2’-hydroxy-1,l’-binaphthyl-2-yl) diphenylphosphine. Most specifically, this is the first successful application of a silver-OH-MOP complex in asymmetric catalysis, together with a finding that the functionality of hydroxyl in this complex plays a crucial role in the control of stereoselectivity. The2,3-dihydropyrrole contains multiple functionalities and thereby can be readily transformed into structurally diverse pyrrolidine derivatives through well-established methods. These findings may point out a strategy for thedesign of new catalysts amenable to such class of cyclization reactions.The hexahydropyrrolo[2,3-b]indole skeleton, especially a quaternary stereogenic center at their C3, is a signature structural element in a wide collection of alkaloids found to exhibit remarkable biological and pharmacological activities.The significance of their structures and biological properties has drawn considerable attention from organic chemists worldwide, we have established a highly enantioselective alkylation reaction of3-hydroxindoles with enalizable aldehydes promoted by the combined catalyst of a chiral primary amine and phosphoric acid, providing an efficient approach to access multiply functionalized3,3’-disubstituted oxindoles, which can function as building blocks for the total synthesis of natural products and biologically active molecules. More interestingly, the addition of ethanol gave relatively higher enatioselectivity. On the basis of our calculations, we proposed that the alcohol might affect the generation rate of cisltrans vinylogous iminium intermediates in the dehydration step and thereby exerts an influence on the stereoselection. The enantioselective total synthesis of (+)-gliocladin C has been accomplished in12steps from3-hydroxyoxindole in19%overall yield by means of this synthetic method.

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