Enantioselective domino reactions of carbonyl compounds via polar and radical pathways catalyzed by a chiral oxazaborolidinium ion

국문 초록 (Abstract)

도미노 (domino) 반응은 단일 반응 조건 하에서 중간체 분리 없이 여러 개의 결합을 연속적으로 형성할 수 있어, 효율적인 분자 합성을 위한 유용한 전략으로 활용되고 있다. 이러한 특성은 복잡한 카이랄 분자를 높은 수율과 입체선택성으로 구축하는데 효과적으로 작용하며, 카이랄 빌딩 블록, 의약품, 천연물 등의 합성법 개발에 폭넓게 응용되고 있다. 본 박사 학위 논문은 카이랄 옥사자보롤리디늄 이온 (COBI) 촉매 하의 도미노 반응 개발에 관한 것으로, 연속 1,2-첨가/아실 이동을 통한 극성 반응과 연속 1,4-첨가/균일 방향족 치환 반응을 통한 라디칼 반응에 대해 서술하였다.
첫 번째 연구로, COBI 촉매 하에 알데하이드와 α-다이아조 에스터 간의 입체선택적 연속 1,2-첨가/아실 이동 반응을 통한 형식적 C-C 결합 삽입 반응을 진행하였다. 이 반응을 통해 알데하이드, 케톤, 에스터 작용기를 모두 포함하는 비고리형 4차 탄소 입체 중심 화합물을 높은 수율 (최대 97%)과 높은 입체선택성 (최대 >99% ee)으로 합성할 수 있었다. 또한, 범밀도 함수 이론 (DFT) 계산을 통해 C-C 결합 삽입 반응의 입체선택적 경로를 증명하였고, n→π* 비공유 상호작용 분석을 통해 높은 입체선택성의 근거를 제시하였다.
두 번째로, 가시광선 하에 COBI 촉매와 이리듐 기반 감광제를 이용한 입체선택적 연속 라디칼 1,4-첨가/균일 방향족 치환 반응을 개발하였다. 이를 통해 두 개의 연속된 입체 중심을 갖는 테트라하이드로퀴놀린 유도체를 단일 반응에서 효율적으로 합성할 수 있었으며, 높은 수율 (최대 97%)과 높은 입체 선택성 (최대 99% ee)을 달성하였다. 이후 라디칼 포착 실험, 양자 수율 측정, 순환 전압 전류법 실험, 발광 소광 실험 등 다양한 메커니즘 연구를 수행했고, 폐쇄형 촉매 사이클 (closed catalytic cycle)로 수행되는 라디칼 메커니즘을 제안하였다.
마지막으로, 가시광선 하에 COBI 촉매와 이리듐 기반 감광제를 이용한 비대칭 촉매 반응을 α-옥시알킬 및 α-싸이오알킬 라디칼의 반응으로 확장하여 라디칼 1,2-첨가 반응을 수행하였다. 해당 연구를 통해 다양한 생리활성 및 의약품에서 자주 발견되는 β-하이드록시 에터 및 싸이오에터 골격을 높은 수율 (최대 93%)과 높은 입체선택성 (최대 85% ee)으로 합성할 수 있었다.

다국어 초록 (Multilingual Abstract)

Domino reactions enable multiple bond-forming events in a single process, improving atom economy and time efficiency. These advantages highlight the potential of catalytic asymmetric domino reactions as powerful strategies for the efficient synthesis of complex chiral molecules. Consequently, such reactions have been widely applied in the synthesis of pharmaceuticals, natural products, and chiral building blocks. This dissertation describes the development of enantioselective domino reactions catalyzed by chiral oxazaborolidinium ion (COBI), encompassing both polar and radical reactions.
The first reaction is tandem 1,2-addition/acyl shift, serving as the catalytic asymmetric formal C-C bond insertion reaction of aldehydes with α-diazoesters. This method allowed for the construction of acyclic all-carbon quaternary stereocenter bearing aldehyde, ketone, and ester groups in high yields (up to 97%) and excellent enantioselectivities (up to >99% ee). Density functional theory (DFT) calculations demonstrated a preference for C-C bond insertion reaction and rationalized the high enantioselectivity, which was further supported by noncovalent interaction (n→π*) analysis.
Next, the enantioselective tandem radical 1,4-addition/homolytic aromatic substitution (HAS) reaction was developed under visible-light photoredox conditions. In this process, α-aminoalkyl radicals were employed with α,β-unsaturated esters to afford tetrahydroquinoline (THQ) derivatives bearing two vicinal stereocenters in a single operation, achieving high yields (up to 97%) and excellent enantioselectivities (up to 99% ee). With various mechanistic studies including radical trapping experiment, quantum yield measurement, cyclic voltammetry, and luminescence quenching experiment, I proposed a radical addition mechanism proceeding via a closed catalytic cycle.
In further study, I extended the photoredox catalysis strategy to the enantioselective radical 1,2-addition of α-oxyalkyl and α-thioalkyl radicals with aldehydes. With COBI catalyst, highly optically active β-hydroxy ether and thioether were obtained in high yields (up to 93%) and high enantioselectivities (up to 85% ee).

목차 (Table of Contents)

• 1. Introduction 1
• 1.1. Introduction of Catalytic Asymmetric Domino Reaction 1
• 1.2. Introduction of Chiral Oxazaborolidinium Ion Catalyst 5
• 1.3. Introduction of Diazo Compounds for Homologation Reactions 7
• 2. Catalytic Asymmetric Formal C-C Bond Insertion Reaction of Glyoxal with Diazoester 10
• 2.1. Introduction 10
• 2.2. Results and Discussion 15
• 2.3. Conclusion 29
• 2.4. Experimental Section 30
• 2.4.1. General Information 30
• 2.4.2. Preparation of Glyoxal Compounds 31
• 2.4.3. Preparation of Diazo Compounds 31
• 2.4.4. Preparation of Chiral Oxazaborolidinium Ion (COBI) Catalyst 32
• 2.4.5. General Procedure for Enantioselective Synthesis of α-Alkyl-α-Formyl-β-Ketoesters 4 34
• 2.4.6. Characterization of α-Alkyl-α-Formyl-β-Ketoesters 35
• 2.4.7. Chemical Transformations of α-Allyl-α-Formyl-β-Ketoesters 62
• 2.4.7.1. Chemical Transformations of 4b to 7 62
• 2.4.7.2. Chemical Transformations of 4b to 8 63
• 2.4.7.3. Chemical Transformations of 8 to 9 65
• 2.4.7.4. Chemical Transformations of 4b to 10, 4j' and 4o' 67
• 2.4.7.5. Chemical Transformations of 10 to 11 71
• 2.4.7.6. Chemical Transformations of 4b to 12 72
• 2.4.8. X-ray Crystallographic Structure 74
• 3. Enantio- and Diastereoselective Tandem Radical 1,4-Addition/Homolytic Aromatic Substitution for the Synthesis of Tetrahydroquinoline via Visible-light Photoredox Catalysis 76
• 3.1. Introduction 76
• 3.2. Results and Discussion 80
• 3.3. Conclusion 102
• 3.4. Experimental Section 103
• 3.4.1. General Information 103
• 3.4.2. Preparation of α-Silyl Amines 104
• 3.4.3. Preparation of α,β-Unsaturated Esters 105
• 3.4.4. Preparation of Chiral Oxazaborolidinium Ion (COBI) Catalyst 106
• 3.4.5. General Procedure for Enantioselective Tandem Giese Addition/Homolytic Aromatic Substitution Reaction 107
• 3.4.6. Characterization of Tetrahydroquinolines 17 108
• 3.4.7. Chemical Transformations of Tetrahydroquinoline 149
• 3.4.7.1. Chemical Transformation of 17v to 18v 149
• 3.4.7.2. Chemical Transformation of 17x to 18x 151
• 3.4.8. X-ray Crystallographic Structure 153
• 3.4.9. Radical Trapping Experiment 155
• 3.4.10. Quantum Yield Analysis 156
• 3.4.11. Light On/Off Experiment 158
• 3.4.12. Cyclic Voltammetry Experiments 159
• 3.4.13. Stern-Volmer Luminescence Quenching Analysis 162
• 4. Further Study 163
• 4.1. Enantioselective Radical 1,2-Addition of α-Oxyalkyl and α-Thioalkyl Radical via Visible-light Photoredox Catalysis 163
• 5. Conclusion 168
• 6. References 170