Nickel-Catalyzed Asymmetric Heteroatom Propargyl Substitution Reaction

Alkyne moiety are widely found in many natural products,fine chemicals and synthetic drugs,which are important synthetic intermediates in organic synthesis.Propargylation is one of the most important basic reactions in organic synthesis,which is an effective strategy to build carbon-carbon bonds and carbon-heteroatom bonds.Asymmetric catalysis plays an important role in modern organic synthesis because of its advantages,such as direct and efficient,mild reaction conditions,good stereoselectivity and the modern concept of green synthetic.Therefore,it is of great significance to develop the methodology of asymmetric catalytic propargylation.In this dissertation,a nickel-catalyzed asymmetric propargyl substitution reaction of internal propargyl esters with oxygen or nitrogen nucleophiles was designed,and carbonoxygen bonds and carbon-nitrogen bonds were constructed.Finally,the method was applied to the synthesis and transformation of various compounds containing oxypropyl hydroxylamine and axial chiral diene structure leading to excellent results.In the past decades,transition-metal-catalyzed asymmetric propargyl substitution of terminal alkynes with carbon or nitrogen centered nucleophiles has been well developed.In contrast,the asymmetric oxypropargyl substitution of internal alkynes is still in its infancy.Consequently,we realized the asymmetric oxypropargylation of internal alkynes through the nickel/chiral sodium binaphthyl dicarboxylate dual catalytic system,which constructed the carbon-oxygen bond with high stereoselectivity.Through this method,we have synthesized a series of compounds containing oxyacetylene propyl hydroxylamines and their derivatives with up to 99%ee.We further synthesized the related bioactive molecule and natural product through the method,such as(S)-potent firefly luciferase inhibitors and(S)-dihydroyashabushiketol,which provides a new strategy for the divergent development of propargylation reactions.Allenes are a kind of compounds with unique cumulative carbon-carbon double bond structure,which are also important synthetic intermediates in organic synthesis.Importantly,chiral allenes are widely found in natural products and drugs with biological activities,and used as chiral ligands for asymmetric catalytic reactions.Asymmetric catalytic synthesis of allenes is still a challenging field in organic synthetic chemistry.Therefore,we designed and synthesized a series of sulfonyl hydrazine reagents,combining nickel-catalyzed asymmetric propargyl substitution reaction with[3,3]-σ-rearrangement reaction to further realize the asymmetric synthesis of allenes.We constructed carbon-nitrogen bonds by this method,and synthesized a series of chiral 1,3-disubstituted allenes with up to 98%ee.Finally,we also achieved the total synthesis of several allene natural products,such as methyl(S)-8-hydroxy-5,6-octadienoate,(S)laballenic acid,(S)-phlomic acid and(S)-Δ9,10-pentacosadiene.