Development of New Carbon-Carbon Bond Formations and Application to the Total Synthesis of Biologically Active Compounds

국문 초록 (Abstract)

Part A.

탈탄산 반응을 통한 새로운 탄소–탄소 결합 반응의 개발

전이금속촉매를 이용한 교차반응은 구조적으로 다양한 유기 분자를 생산하기 위해 가장 유용한 반응으로 알려져 있다. 특히 비활성 탄소–수소 결합의 직접적인 조작을 통한 새로운 탄소–탄소 결합 반응의 개발은 다양한 유기화합물의 기본 골격을 직접적으로 합성할 수 있는 가장 매력적인 연구 분야이다.
최근 전이금속 촉매를 이용한 알데하이드 또는 알코올과 다양한 지향성기 (예., 피리딘, 옥심, 아세트아닐라이드, 인돌)를 가진 방향족 화합물의 산화적 아실화 반응이 보고되고 있다. 그러나, 알데히드 동등체인 α-oxocarboxylic acids를 이용한 전이 금속촉매 하 탈탄산 교차반응은 아직 많은 연구가 되어 있지 않다.
본 논문에서는 O-phenylcarbamates와 O-methyl ketoximes 의 팔라듐 촉매를 이용한 효과적인 산화적 ortho-아실화 반응을 개발하였다. 본 반응은 다양한 기질 내 ortho 탄소-수소 결합을 선택적으로 활성화하여 목적하는 아릴 케톤 화합물을 우수한 수율로 합성할 수 있다. 또한 oxime 지향기는 가수 분해 후 케톤 화합물로의 변환이 가능하며, carbamate 지향기는 가수 분해 후 phenol 화합물로의 변환이 용이하여 관련 생리활성 화합물의 전합성에 매우 용이하게 적용될 수 있다.
또한 상기 화학 반응은 생리활성 천연물의 중요 골격 구조로 알려져 있는 3-isochromanone화합물의 직접적인 합성에 적용될 수 있는 유용한 합성법이다. 현재 본 연구팀은 기 개발된 합성법을 이용하여 다양한 천연물 및 의약품의 전합성 연구를 진행 중에 있다.

주제어: 아실화, 탈탄산, 팔라듐, 탄소–수소 결합 활성화, α-Keto Acids



Part B.

촉매 반응의 탄소–탄소 결합 형성을 통한 (+)-Fluvastatin 유도체와 (+)-trans-Aerangis Lactone의 전합성

3-Hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) 환원 효소 억제제인 스타틴은 혈중 콜레스테롤 수치를 감소시켜 각종 심혈관 질환을 치료할 수 있는 물질로서 알려져 있다. 특히, fluvastatin (LescolTM)은 3-hydroxy-3-methylglutaric acid가 mevalonic acid로 전환되는 것을 억제시키는 약리 기전을 가지고 있으며, 20~40 mg을 매일 투여하면 저밀도 지단백 콜레스테롤 수치를 20~30% 낮추는 것으로 알려져 있다. 이러한 강력한 약리 효과와 흥미로운 구조적 특징때문에 스타틴은 매력적인 합성 대상으로 주목을 받고 있다.
Lactone은 맛과 향기의 중요한 성분으로, 식품과 향수의 첨가제로 광범위하게 사용된다. 많은 lactone은 수분 작용과 종자 발아 자극을 유도함으로써 흥미로운 생물학적 활성을 나타내며, 페로몬, 방부제에도 포함되어 있는 물질이다. 특히, δ-lactones은 다양한 생물학적 활성을 나타내는 수많은 천연물의 주요 골격구조로 알려져 있다. δ-Lactone의 대표적인 예인 trans-aerangis lactone은 Aerangis confusa와 Aerangis kirkii의 향기 구성요소로서 1993년 Kaiser에 의해 최초 보고 되었다.
전이 금속 촉매를 이용한 탄소-탄소 결합 연구의 일환으로, 우리는 촉매적 접근 방법을 이용한 다양한 생리활성 화합물의 효율적인 합성법 개발을 연구하고 있다.
본 논문은 (+)-fluvastatin 유도체와 (+)-trans-aerangis lactone의 비대칭 전합성에 대한 새로운 촉매적 접근방법을 보고한다. 주요 합성단계로는 iridium 촉매를 이용한 비대칭 카보닐 알릴화 및 크로틸화 반응, ruthenium촉매를 이용한 올레핀화 반응, copper 촉매를 이용한 인돌의 위치선택적 C-3 아릴화 반응이 있다.

주제어: 스타틴, 플루바스타틴, 애란지스 락톤, 전합성, 촉매반응

다국어 초록 (Multilingual Abstract)

Abstract: Part A

Development of New Carbon–Carbon Bond Formation via Decarboxylative Cross-Coupling Reactions

Transition metal-catalyzed cross-coupling reaction has emerged as a powerful tool available for synthetic chemists to produce structurally diverse organic molecules. In particular, carbon–carbon cross-coupling reactions involving selective activation of carbon–hydrogen bonds has become an attractive alternative to traditional cross-coupling reactions, because such methods avoid a multistep preparation of preactivated starting materials and a production of stoichiometric metallic waste. Thus, cross-coupling reactions via C–H bond activation can lead to an improved overall efficiency of the desired transformation.
Recently, transition-metal-catalyzed oxidative acylation of sp2 C–H bonds in aromatic compounds with various directing groups, e.g., pyridines, oximes, acetanilides, and indole, with aldehydes or alcohols have been reported. However, transition metal-catalyzed decarboxylative cross-coupling reaction using aryl carboxylic acids as coupling partners is relatively unexplored.
Herein we described a novel method for Pd-catalyzed oxidative ortho-acylation of O-phenylcarbamates and O-methyl ketoximes with α-oxocarboxylic acids under ammonium persulfate as a convenient oxidant via C–H bond activation. These transformations have been applied to a wide range of substrates, and typically proceed with excellent level of region- and chemoselectivity as well as with high functional group tolerance. Also, we demonstrated a palladium-catalyzed decarboxylative acylation of phenylacetamides with α-oxocarboxylic acids via C–H bond activation. This protocol provides efficient access to a range of ortho-acyl phenylacetamides, which can be easily converted to 3-isochromanone derivatives. Further applications of this method to the synthesis of biologically active compounds are in progress.

Key words: Acylation, Decarboxylative, Palladium, C–H Activation, α-Keto Acids



Abstract: Part B

Total Synthesis of (+)-Fluvastatin Analogue and (+)-trans-Aerangis Lactone via Catalytic Carbon–Carbon Bond Formations

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have become the most frequently prescribed agent for the treatment of hypercholesterolemia due to the compelling evidence of their effect on reducing the rates of cardiovascular events. In particular, Fluvastatin (LescolTM) inhibits the enzyme that reduces 3-hydroxy-3-methylglutaric acid to mevalonic acid, thus blocking the biosynthesis of cholesterol and lowers low-density lipoprotein cholesterol levels by 20-30% at a daily dose of 20-40 mg. Because of their potent pharmacological effects and interesting structural features, statins have attracted considerable attention as powerful synthetic targets.
Lactones are important flavor and aroma constituents that are extensively used as additives in food and perfume. Many lactones exhibit interesting biological activities as attractants for pollination and seed germination stimulants. They also act as allergens, pheromones, antiseptics, and cardiotonic agents. In particular, δ-lactones appear as a ubiquitous structural motif in a number of natural products that display a wide range of biological activity. As representative examples of δ-lactones, trans-aerangis lactones were first reported by Kaiser in 1993 as the main odoriferous components of the African moth orchids Aerangis confusa and Aerangis kirkii.
As part of an ongoing research program directed toward the development of trasition metal-catalyzed carbon-carbon bond forming reactions, we have been interested in developing efficient routes to the asymmetric synthesis of biologically active compounds.
In this paper, we present a new catalytic strategy for the asymmetric total synthesis of (+)–fluvsatatin analogue and (+)–trans-aerangis lactone, including catalytic carbon-carbon bond formations, i.e., iridium-catalyzed enantioselective carbonyl allylation or crotylation, and rhuthenium-catalyzed intermolecular metathesis, Cu-catalyzed C-3 arylation of indoles.

Key words: Statins, Fluvastatin, Aerangis Lactone, Total Synthesis, Catalytic

목차 (Table of Contents)

• ABSTRACT 1
• Part A. Development of New CarbonCarbon Bond Formations via Decarboxylative Cross-Coupling Reactions 3
• I. Introduction 3
• 1. Decarboxylative cross-coupling reactions 4
• 1.1. Synthesis of biaryls via decarboxylative couplings with bimetallic catalysts 4
• 1.1.1 Applications in synthesis 5
• 1.2. Synthesis of biaryls via Decarboxylative couplings with monometallic systems 6
• 1.3. Synthesis of ketones via decarboxylative couplings 7
• 1.4. Decarboxylative cross-coupling of alkynyl carboxylic acids 8
• 1.5. Decarboxylative allylation 8
• 2. Oxidative decarboxylative couplings 9
• 2.1. Decarboxylative Heck reaction 9
• 2.2. Decarboxylative coupling with boronic acids 11
• 2.3. Decarboxylative coupling with C-H activation 12
• 2.3.1. Direct arylation 12
• 2.3.2. Coupling of αamino acids 15
• 2.3.3. Oxidative acylation 16
• II. Results and Discussion 18
• 1. Pd-catalyzed decarboxylative acylation of O-phenylcarbamates with α-oxocarboxylic acids at room temperature 18
• 2. Palladium-catalyzed decarboxylative acylation of O-methyl ketoximes with α-keto acids 25
• 3. Pd(II)-catalyzed decarboxylative acylation of phenylacetamides with α-oxocarboxylic acids via C-H bond activation 31
• III. Conclusion 37
• Part B. Total Synthesis of (+)-Fluvastatin Analogue and (+)-trans-Aerangis Lactone via Catalytic CarbonCarbon Bond Formations 38
• 1. A catalytic approach to the synthesis of (+)-fluvastatin analogue 38
• 2. Asymmetric synthesis of (+)-trans-aerangis lactone 44
• Experimental Sections 49
• 1. Pd-catalyzed decarboxylative acylation of O-phenylcarbamates with α-oxocarboxylic acids at room temperature 49
• 2. Palladium-catalyzed decarboxylative acylation of O-methyl ketoximes with α-keto acids 56
• 3. Pd(II)-catalyzed decarboxylative acylation of phenylacetamides with α-oxocarboxylic acids via C-H bond activation 64
• 4. A catalytic approach to the synthesis of (+)-fluvastatin analogue 72
• 5. Asymmetric synthesis of (+)-trans-aerangis lactone 80
• References and Notes 83
• 국문초록 91
• Appendix 93