Regioselective Aryne Annulations of Enamides and Stereoselective Synthesis of (+)-Xylogiblactone B and (+)-Xylogiblactone C Achieved through Kinetic Resolution = Enamides 의 위치선택적 아린 고리화 및 Kinetic Resolution 을 통한 (+)-Xylogiblactone B and (+)-Xylogiblactone C 의 입체선택적 합성

다국어 초록 (Multilingual Abstract)

The synthesis of quinoline and chroman derivatives via aryne intermediates has emerged as a powerful and versatile approach in modern organic synthesis. Arynes highly reactive species generated in situ enable the efficient construction of complex heterocyclic frameworks through a broad range of cycloaddition and insertion reactions. This strategy offers a direct and atom-economical pathway to access quinoline and chroman scaffolds, which are considered privileged structures in both medicinal chemistry and materials science. Quinoline derivatives are well known for their diverse pharmacological properties, including antimalarial, anticancer, and antimicrobial activities. Chroman compounds, meanwhile, are key structural motifs in numerous natural products and bioactive molecules. In addition to aryne based methodologies, this research explores the application of asymmetric synthesis a fundamental technique for the selective formation of one enantiomer of a chiral compound. Asymmetric synthesis offers high enantioselectivity, synthetic efficiency, and the ability to construct architecturally complex molecules with precise stereochemical control. Complementarily, kinetic resolution is employed to separate enantiomers based on their differing reactivities with chiral catalysts or reagents. This method enables the isolation of highly enantiopure compounds from racemic mixtures and allows for the recovery of unreacted enantiomers, making it particularly valuable when direct asymmetric synthesis is difficult or inefficient. This study focuses on the development of efficient synthetic strategies for constructing dihydroquinolin-4-one and chroman-4-imine derivatives via aryne intermediates, with particular attention to controlling regioselectivity and diastereoselectivity in these transformations. Furthermore, the work involves the establishment of an asymmetric hydrogenation protocol for dihydroquinolin-4-one, the application of kinetic resolution in asymmetric aldol reactions of racemic aldehydes, and the structural elucidation of (+)-Xylogiblactone B, along with the total synthesis of (+)-Xylogiblactone C. Collectively, this research integrates aryne chemistry with advanced stereoselective methods, providing valuable tools for the synthesis of complex and biologically relevant heterocyclic compounds.

국문 초록 (Abstract)

아라인(aryne) 중간체를 통한 퀴놀린(quinoline) 및크로만(chroman) 유도체의 합성은 현대 유기합성에서 강력하고 다재다능한 접근법으로떠오르고있습니다. 인시투(in situ)로 생성되는 아라인은 반응성이 매우높은종으로, 다양한고리첨가(cycloaddition) 및 삽입 반응을 통해 복잡한 헤테로고리 구조를효율적으로 구축할 수 있게 해줍니다. 이 전략은 퀴놀린과 크로만 골격에 직접적이고 원자경제적인(atom-economical) 경로를 제공하며, 이들 구조는 의약화학과 소재 화학 모두에서 중요한 구조로 간주됩니다. 퀴놀린 유도체는항말라리아, 항암, 항균 활성 등 다양한 약리학적 특성으로 잘 알려져 있습니다. 한편, 크로만화합물은 수많은 천연물 및 생리활성 분자의 핵심 구조 모티프입니다. 아라인 기반 방법론 외에도, 본 연구는 키랄 화합물의 한 가지 엔안티오머(enantiomer)를 선택적으로 형성하기 위한 기본적인 기술인 비대칭합성(asymmetric synthesis)의 적용을 탐구합니다. 비대칭 합성은 높은 엔안티오선택성(enantioselectivity), 합성 효율성 및 정밀한 입체화학적 제어를 통해 복잡한 분자를 구축할 수 있는 능력을 제공합니다. 보완적으로, 키랄 촉매 또는 시약과의 반응성 차이를 기반으로 엔안티오머를 분리하는 방법인 동역학적분(kineticresolution)도 활용됩니다. 이 방법은 라세믹 혼합물(racemic mixtures)에서 매우 높은 광학 순도의 화합물을 분리하고, 반응하지 않은 엔안티오머를 회수할수있어, 직접적인 비대칭 합성이 어렵거나 비효율적인 경우에 특히 유용합니다. 본 연구는 아라인 중간체를 이용하여 디하이드로퀴놀린(dihydroquinolin-4-one) 및 크로만-4-이민(chroman-4-imine) 유도체를 구축하기 위한 효율적인 합성 전략 개발에 중점을 두며, 이들 전환에서의 위치선택성(regioselectivity) 및 디아스테레오선택성(diastereoselectivity) 제어에 특히 주목합니다 . 또한 , 디하이드로퀴놀린 -4- 온의 비대칭 수소화(asymmetrichydrogenation) 방법 개발, 라세믹 알데하이드의 비대칭 알돌 반응에서의 동역학적 분리 적용, (+)-Xylogiblactone B의 구조 분석 및 (+)-XylogiblactoneC의 전합성(total synthesis)도 포함됩니다. 이 연구는 아라인 화학과 고급 입체선택적 방법을 통합하여, 복잡하고 생물학적으로 중요한 헤테로고리 화합물의 합성을 위한 귀중한 도구를 제공합니다.

목차 (Table of Contents)

• List of Table
• List of Scheme
• List of Figure
• (Abstract) 1
• 1. Introduction 4
• 1.1 Aryne chemistry: fundamentals and reactivity 4
• 1.1.1 Properties of aryne and historical discovery 4
• 1.1.2 Preparation of arynes 10
• 1.1.3 Arynes in advanced organic synthesis 14
• 1.1.3.1 Molecular rearrangements 14
• 1.1.3.2 Asymmetric aryne reactions21
• 1.2 Biologically relevant structures derived from aryne reactions25
• 1.2.1 Quinoline derivatives 25
• 1.2.2 Chroman derivatives 28
• 1.3 Noyori asymmetric hydrogenation 31
• 1.3.1 Kinetic resolution of asymmetric transfer hydrogenation 33
• 1.3.2 Dynamic kinetic resolution of asymmetric transfer hydrogenation .35
• 1.4 Introduction to Xylogiblactones 38
• 1.4.1 Origin and significance of Xylogiblactones 38
• 1.5 Synthetic strategy and key methodologies for the construction of
• (+)-Xylogiblactones 40
• 1.5.1 Kinetic resolution of racemic aldehydes 40
• 1.5.2 Application of the Anti-Felkin-Anh model in allenoate addition 43
• 1.5.3 Transition-metal catalyzed allene cyclizations.46
• 1.5.4 Asymmetric synthesis and correction of stereochemistry of
• (+)-Xylogiblactone A 51
• 2. Result and Discussion 55
• 2.1 Regioselective aryne annulations of enamides55
• 2.1.1 Aryne annulation to dihydroquinolinone 57
• 2.1.1.1 Mechanistic insights 57
• 2.1.1.2 Optimization of reaction conditions 59
• 2.1.1.3 Substrate scope 62
• 2.1.1.4 Kinetic resolution via Noyori ’ s asymmetric transfer
• hydrogenation 67
• 2.1.2 Aryne annulation to chroman-4-imine 73
• 2.1.2.1 Asymmetric aryne annulation strategies and regiochemical
• pathways 73
• 2.1.2.2 Mechanistic insights 79
• 2.1.2.3 Optimization of reaction conditions 81
• 2.1.2.4 Substrate scope 83
• 2.1.2.5 Post-synthetic derivatization 85
• 2.2 Total synthesis of (+)-Xylogiblactones B and C 87
• 2.2.1 Retrosynthetic analysis and strategy 88
• 2.2.2 Preparation of racemic aldehydes 90
• 2.2.3 Kinetic resolution via allenoate addition 96
• 2.2.4 Au(I)-catalyzed cyclization Xylogiblactones 99
• 3. Conclusion and Outlook 103
• 3.1 Regio- and stereoselective annulation reactions involving arynes 103
• 3.2 Asymmetric transfer hydrogenation of dihydroquinolin-4-one 106
• 3.3 Total synthesis and structural elucidation of (+)-Xylogiblactones B and C
• 108
• 4. Experiment110
• 4.1 General methods 110
• 4.2 Synthesis of N-tosyl-2-enamides 112
• 4.3 Synthesis of (S)-tert-butylsulfinylamides117
• 4.4 Synthesis of dihydroquinolin-4-one 120
• 4.5 Synthesis of chroman-4-imine 127
• 4.6 Applications of dihydroquinolin-4-one and chroman-4-imine units 133
• 4.7 Asymmetric transfer hydrogenation product 137
• 4.8 Synthesis of (+)-Xylogiblactone C141
• 5. References 151
• 6. Abstract in the Korean Language 160
• 7. NMR Spectral Data 163
• 8. X-ray Crystallographic Data 207
• 9. List of Publish 213
• 10. Ackonwledgment 214
• List of Table
• Table 1. Investigation into the conversion of 1a with 2aa to 3a 61
• Table 2. Investigation of substrate generality in the transformation of 1 and 2ato 3 64
• Table 3. Impact of N-sulfonylamides on the annulation reaction 66
• Table 4. Optimum conditions for hydrogenation reaction 72
• Table 5. Investigation of the optimal conditions for the transformation of 4ainto 5a 76
• Table 6. Investigation into the conversion of 1a with 2ba to 4 82
• Table 7. Investigation of substrate generality in the transformation of 1 and 2bto 4 84
• Table 8. Optimization of epoxide opening conditions 93
• Table 9. Investigation of alternative substrates for epoxide opening 95
• List of Scheme
• Scheme 1. The first evidence about the existence of aryne8
• Scheme 2. Proposed structures of aryne from Bachmann and Clarke8
• Scheme 3. Formation of aryne from fluorobenzene 9
• Scheme 4. 14C labeling experiments for the existence of aryne10
• Scheme 5. Methods for aryne synthesis 10
• Scheme 6. Generation of aryne species by using strong bases 13
• Scheme 7. Generation of aryne using o-(trimethylsilyl)phenyl triflate 14
• Scheme 8. Pioneering work on rearrangement reactions involving arynes 16
• Scheme 9. Molecular rearrangement reactions involving arynes using
• Kobayashi’s method17
• Scheme 10. Mechanism of aryne insertion into the amide bond18
• Scheme 11. Methods of molecular rearrangement 20
• Scheme 12. Mechanism of the aryne-mediated aza-Claisen rearrangement . 21
• Scheme 13. Enantioselective synthesis of triple helicenes23
• Scheme 14. Asymmetric electrochemical arylation of cyclic -ketocarbonyls24
• Scheme 15. Recent synthetic methods of quinoline derivatives 27
• Scheme 16. Recent synthetic methods of chroman derivatives 30
• Scheme 17. Hydrogenation of allylic alcohol using Noyori catalyst 33
• Scheme 18. Hydrogenation of carbonyl group using Noyori catalyst 34
• Scheme 19. Dynamic kinetic resolution of carbonyl compound throughasymmetric hydrogenation36
• Scheme 20. Development of a new asymmetric hydrogenation strategy with aNoyori catalyst 37
• Scheme 21. Peptide-catalyzed kinetic resolution of branched aldehydes .. 41
• Scheme 22. Kinetic resolution of racemic aldehyde 42
• Scheme 23. Stereochemical routes for the anti-Felkin−Anh 44
• Scheme 24. Allenoate additions of chiral (S)-amine45
• Scheme 25. Gold-mediated transformation of allenic ketones into substitutedfurans 48
• Scheme 26. Gold-catalyzed ring closure of bromoallenones towardhalogenated furans 49
• Scheme 27. Gold-catalyzed cycloisomerization of allenic esters 50
• Scheme 28. Asymmetric synthesis of (+)-Xylogiblactone A 54
• Scheme 29. The mechanism of dihydroquinolin-4-one 57
• Scheme 30. Methods for removing the tosyl group 66
• Scheme 31. Initial investigation of 1 with 2b to 4 73
• Scheme 32. Aryne-mediated regiochemical transformation 78
• Scheme 33. The synthetic mechanism of chroman-4-imine 79
• Scheme 34. Synthetic manipulations of 4a 85
• Scheme 35. Synthetic route design for (+)-Xylogiblactones B and C89
• Scheme 36. Synthetic of racemic aldehyde 14 and 1591
• Scheme 37. Kinetic resolution through the allenoate -addition 99
• Scheme 38. Cyclization using a gold catalyst 101
• Scheme 39. Selective annulation with aryne 105
• Scheme 40. Kinetic resolution was evidenced by HPLC 107
• Scheme 41. The synthetic route for (+)-Xylogiblactones B and C 109
• Scheme 42. Synthesis of N-tosyl-2-enamides 112
• Scheme 43. Synthesis of (S)-tert-Butylsulfinylamides 117
• Scheme 44. Synthesis of dihydroquinolin-4-one 120
• Scheme 45. Synthesis of chroman-4-imine 127