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Studies on the Development of Novel Divergent Cycloaddition Catalysis

Title
Studies on the Development of Novel Divergent Cycloaddition Catalysis
Authors
전현지
Issue Date
2019
Department/Major
대학원 화학·나노과학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
이상기
Abstract
The major purpose of the research is the development of novel catalytic reactions for regio- and stereodivergent cycloadditions to construct heterocyclic moieties. Three different types of divergent catalytic reactions have been investigated. In Chapter 1, sequential dual catalytic reaction comprised of a Cu(I)-catalyzed azide-alkyne cycloadditions, known as ‘click chemistry’, followed by a Rh(II)-catalyzed reaction of the resulting N-sulfonyl 1,2,3-traizoles with Morita-Baylis-Hillman(MBH) adducts was investigated. In this reaction, the alpha-imino Rh(II)-carbenes, generated in situ from N-sulfonylated 1,2,3-triazoles, which can easily be synthesized by Cu(I)-catalyzed dipolar cycloaddition of 1-alkynes and sulfonyl azides, interact with acyclic/cyclic MBH adducts through 1,3-insertion into the O-H bond, followed by rapid [3,3]-sigmatropic rearrangement to afford highly functionalized alpha-methylene-delta-oxo-gamma-amino carbonyl compounds. In addition, this reaction protocol showed broad substrate scope toward for both triazole and MBH adduct to produce various delta-oxo-gamma-amino carbonyl compound in excellent yields. It has also been demonstrated that the sequential Cu(I) and Rh(II) tandem dual catalytic reaction could be possible to allow the all-in-one-pot synthesis of alpha-methylene-delta-oxo-gamma-amino carbonyl compounds. In Chapter 2, the research is development of cooperative dual catalytic divergent dipolar cycloadditions. Through cooperative dual catalytic system, two catalytic cycles with two different catalysts are work concurrently, each catalyst converts the non-polar precursor molecules to metal-associated reactive dipoles, which then may rapidly undergo cycloaddition to afford a cycloadduct. In this process, alpha-imino Rh(II)-carbenes, generated in situ from N-sulfonylated 1,2,3-triazoles in the presence of Rh(II) catalyst, could serve as imino-nucleophilic/C-electrophilic 1,3-dipole equivalent. Meanwhile, alkoxy pi-allyl Pd(II)-complexes, produced catalytically from vinyl ethylene carbonates(VECs) with Pd(0) catalyst via decarboxylation pathway, could act as O-nucleophilic/C-electrophilic 1,3-dipole equivalent. The generated 1,3-dipole equivalents were combined each other to undergo [3+3] dipolar cycloaddition affording 6-membered 3-vinylated-1,4-oxazines. Unprecedentedly, alkoxy pi-allyl Pd(II)-complexes could be isomerized when olefin isomerization process is involved in palladium catalytic cycle with different reaction parameters. This unprecedent alkoxy pi-allyl Pd(II)-complexes could act as O-nucleophilic/C-electrophilic 1,4-dipole equivalent to produce 7-membered 5-methyl-1,4-oxazepines via [3+4] dipolar cycloaddition. Mechanistic studies using deuterium-labeled VECs suggested that the isomerization of VECs is involved in the generation of -allyl Pd(II)-complex. In Chapter 3, the stereodivergent synthesis of stereoisomeric spiro-furanindolines through ligand-controlled palladium-catalyzed dipolar cycloadditions have been investigated. Stereodivergent (enantio- and diastereodivergent) catalysis is one of the most fascinating yet challenging strategies, because complete control of both absolute and relative configuration remains a formidable challenge. It has been envisioned that the alkoxy pi-allyl Pd(II)-complexes, generated in situ from the VECs, could act as a 1,3-dipole equivalent, which may undergo [3+2] dipolar cycloadditions with stable N-methylindolinylidene dipolarophiles to offer stereoisomeric spiro-furanindolines selectively. The suitable reaction parameters for both enantio- and diastereoselectivity could be controlled mainly by choice of chiral ligands. Fortuitously, this reaction method only produced the 4 different stereoisomeric spiro-finranindolines based on the stereochemistry of N-methylindol-inylidene as (E) from. And also this reaction protocol showed broad functional group tolerance toward N-methylindolinylidenes in good to excellent yields with moderate diastereoselectivities, and excellent enatioselectivities. ;졸업논문 연구의 가장 큰 목적은 전이금속촉매를 이용하여 자리선택적이고 입체 선택적인 고리화합반응의 개발이다. 따라서, 이 졸업논문은 크게 3가지의 주제로 나눠져 서로 다른 촉매시스템을 통한 자리선택적이거나 입체선택적인 반응에 대해 연구한다. 첫 번째 주제는 Cu 촉매와 Rh 촉매를 이용한 delta-oxo-gamma-amino 화합물 생성에 관한 연구이다. 논문에서 쓰이는 alpha-imino Rh(Ⅱ)-carbene은 1-alkyne과 sulfonyl azide가 구리촉매하에서 cycloaddition 반응을 통해 만들어지는 N-sulfonyl 1,2,3-triazole의 ring-chain tautomerization으로 쉽게 형성되는 물질로, 여러 nucleophile과 만나 다양한 화합물을 형성한다. 이 논문에서는 Morita-Baylis-Hillman 물질과 반응시켜 자연에서 형성하기 어려운 delta-oxo-gamma-amino 화합물을 형성해냈다. 두 반응을 한 반응용기내에서 순차적으로 진행시켜 반응의 효율성을 높이고, 이는 앞으로 다른 아미노산 유도체를 유기화학적으로 합성하는 방법에 영향을 줄 것이라 사료된다. 두번째 연구주제는 Rh 촉매에 의해 활성화된 triazole을 Pd 촉매에 의해 활성화된 alkoxy-pi-allyl 중간체와 반응시켜 1,4-oxazine 생성물을 얻는 것이다. 특히, 이 반응은 Pd 촉매에 의해 isomerization이 일어나면 서로 다른 alkoxy-pi-allyl 중간체를 형성하게 되고 1,4-oxazepine 생성물을 합성할 수 있었다. 이 반응을 통해 촉매에 의해 자리선택적으로 고리화합반응이 일어나는 것을 확인 할 수 있었고, 더 나아가 입체선택적인 반응까지 연구 중에 있다. 이 반응 또한 한 반응용기안에서 두 가지 이상의 촉매를 이용해서 반응이 일어나는 다단계 연속 촉매반응으로 반응의 효율성을 한 층 더 개발시키는 역할을 한다. 마지막으로, 전이금속 촉매를 이용한 입체선택성 고리화합물 형성에 대한 연구를 진행하였다. 입체선택성은 보통 거울상이성질체와 부분이성질체를 모두 조절하는 촉매반응을 일컷는 것으로, 그 간의 연구는 주로 거울상이성질체를 조절하는 연구에 집중되어져왔다. 이 논문에서는 거울상이성질체 뿐만 아니라 부분이성질체를 동시에 조절하여 하나의 반응으로 두가지 이상의 입체선택적 화합물을 얻어내는 입체선택성 촉매반응을 개발하였다. 앞서 Pd 촉매에서 활성화된 alkoxy-pi-allyl 중간체를 사용하여 반응시킨 결과 서로 다른 거울상이성질체를 가지는 부분이성질체를 합성하였고, 이 역시도 한 반응을 통해 다양한 화합물을 얻을 수 있다는 점에서 촉매반응의 효율성을 개발시키는 역할을 한다. 이렇듯 세 가지 서로 다르지만 결론적으로 촉매반응의 효율성을 확대하는 실험을 진행하였고, 이는 앞으로의 유기화학분야에서 크게 이용될 것이라 생각된다.
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