Enantioselective synthesis of β-amino esters

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Enantioselective synthesis of β-amino esters


Author: Wang, Jun
Title: Enantioselective synthesis of β-amino esters
Degree: Ph.D.
Year: 2010
Subject: Hong Kong Polytechnic University -- Dissertations
Beta lactam antibiotics -- Synthesis.
Amino acids -- Synthesis.
Chiral drugs -- Synthesis.
Enantioselective catalysis
Department: Dept. of Applied Biology and Chemical Technology
Pages: xiv, 265 leaves : ill. ; 30 cm.
InnoPac Record: http://library.polyu.edu.hk/record=b2343012
URI: http://theses.lib.polyu.edu.hk/handle/200/5701
Abstract: β-Amino esters are useful building blocks for preparation of useful pharmaceutical products, natural products and polypeptides with unique structural scaffolds. Enantiomerically pure β-amino acids and their derivatives have attracted attention due to their significantly important pharmaceutical applications, such as anti-platelet, immunological response modifiers, anti-hypertensive agents and anticancer agents. Given the significance of β-amino acids, it is not surprising that the development of their synthesis in an optically pure form has become an important and challenging endeavour for organic chemists in recent years. The developed methods include a number of impressive advances in the field of stereoselective synthesis of β-amino esters. However, there are rooms for further development in order to meet the ultimate goal that desired β-amino esters be prepared in one step from simple precursors and in optically pure forms. In this thesis, we initiated our efforts to broaden the substrate and nucleophile scope, and to develop novel, direct and practical protocols for accessing a series of chiral β-amino esters. In addition, a survey of effective ligands to stimulate and optimize the reaction conditions is reported. My research efforts in this field are as follows: I) To develop a practical method for the preparation of chiral β-amino esters via a one-pot nickel-catalyzed imino-Reformatsky reaction from easily available materials with 40-84% yields and excellent diastereoselectivities (>98%). The modified Reformatsky reaction broadened the scope of Mannich acceptors. To the best of our knowledge, this method provides the first practical synthesis of enantiopure β-amino ester bearing β-electron-rich substitution via the asymmetric Mannich reaction. II) To explore the first catalytic enantioselective addition of terminal alkynes to β-imino esters. This reaction provides an efficient and direct synthetic approach to β³-alkynyl β²,²-dimethyl amino esters with 73-97% yields and 48-90% ee. The rich chemistry of alkynyl functionality makes the presentmethod a powerful and versatile approach to a wide range of optically active β²,²-dimethyl amino acid derivatives. III) To develop a simple and efficient method to synthesize β³-alkynyl amino esters by a new copper-catalyzed conjugate addition of terminal alkynes. Various γ,δ-alkynyl-β-amino esters were obtained in moderate to good yields in one step. However, all the ligands we examined could not afford acceptable ee value under the reaction conditions. IV) To further extend the application of phosphoramidite ligands in copper(II)-catalyzed conjugate addition of dialkylzinc reagents to β-enamidomalonate with up to 95% ee, providing valuable substrates for the synthesis of enantiopure β-amino esters. V) To synthesize a series of chiral diene ligands and to examine the efficiency of the ligands in the arylation of β-amino acrylates. β³-Aryl amino esters were obtained in good yields (56-99% yield) and excellent enantioselectivities (96-98% ee) by a [RhOH(diene)]₂-catalyzed conjugate addition of boron reagents to β-phthalimide acrylates.

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