DAST 매개 Lossen 재배열을 통한 비대칭 옥사졸리디논 합성 및 담즙산 유도체 기반 LNP 지질 합성에 관한 연구

국문 초록 (Abstract)

본 연구는 DAST 반응성과 담즙산 기반 지질 설계라는 두 가지 주제를 중심으로 수행되었다. 첫 번째 연구에서는 DAST가 하이드록사믹산 및 아마이드 기질에 작용하여 isocyanate 중간체를 거치는 Lossen형 재배열을 일으킬 수 있음을 확인하였다. 특히 비대칭 알돌 화합물에 도입된 카이랄 보조제를 통해 조절한 입체 배위가 DAST 기반 재배열 과정 전반에서 보존되는 경로로 반응이 진행됨을 확인하였다. 이를 이용해 온화한 조건에서 비대칭 oxazolidinone을 합성하는 경로를 제시하였다. 두 번째 연구에서는 LCA, DCA, CA의 스테로이드 골격 (head)과 세 종류의 알킬 알코올 (tail)을 조합하여 총 9종의 담즙산 유래 지질 라이브러리를 구축하였다. 합성은 TBS 보호–EDC/DMAP 결합–TBAF 탈보호의 단순한 3단계로 진행하였으며, 이를 통해 재현성 있는 합성을 달성하였다. 결과는 담즙산의 입체적 특징과 tail 구조 변화를 독립적으로 조절할 수 있어 스테로이드 기반 지질의 구조–물성 관계를 탐구할 수 있는 기반을 마련한다. 종합하면, 본 연구는 DAST 기반 Lossen 재배열의 새로운 반응 경로를 검증하여 유기합성 반응성 이해를 확장하고, 담즙산 구조를 활용한 새로운 LNP 이온화 지질 설계 체계를 제안함으로써, 합성유기화학 및 지질 전달체 연구 분야에 기여한다. 본 연구에서 구축한 반응성과 구조 설계 원리는 향후 다양한 기질 확장, LNP 조성 연구 및 합성 전략 개발에 중요한 기반이 될 것으로 기대된다.

다국어 초록 (Multilingual Abstract)

This thesis consists of two major research topics aimed at expanding synthetic methodologies and establishing a new design platform for steroid-based lipids. In the first part, the reactivity of diethylaminosulfur trifluoride (DAST) toward hydroxamic acids and amides was investigated. Particular attention was given to asymmetric aldol substrates bearing a chiral auxiliary, which served to establish and stabilize the initial stereochemical configuration. Upon conversion to the corresponding hydroxamic acids, these substrates underwent a DAST-promoted Lossen-type rearrangement in which retention of configuration was consistently observed, demonstrating that the chiral information remained intact even after auxiliary cleavage and during N–O activation. Experimental evidence further confirmed that the rearrangement proceeds through an isocyanate intermediate—previously proposed only at a conceptual level—thus validating a mechanistically distinct pathway. Based on this reactivity, a mild and practical route to asymmetric oxazolidinones was developed, and the influence of substrate structure on reaction outcome and stereochemical fidelity was systematically analyzed, thereby enriching the mechanistic understanding of DAST-promoted structural transformations.
In the second part, a nine-member bile acid–derived lipid library was constructed by combining three bile acid head groups (LCA, DCA, CA) with three alcohol tails varying in chain length and branching. The synthesis employed a concise three-step sequence—TBS protection, EDC/DMAP-mediated esterification, and TBAF deprotection—and a practical purification strategy using silica plug filtration to address solubility and purification challenges inherent to steroidal intermediates. The resulting library provides a modular platform enabling systematic exploration of structure–property relationships in steroid-based lipids, particularly how asymmetric steroidal curvature and tailored hydrophobic tails cooperatively influence molecular packing and assembly behavior.
Overall, this work identifies and validates a novel DAST-promoted Lossen rearrangement pathway that proceeds with retention of configuration, broadening the scope of sulfur-based activation chemistry, and introduces a rational, modular design strategy for bile acid–derived lipids applicable to lipid nanoparticle (LNP) development. The insights gained from these studies establish a foundation for future expansion of substrate scope, linker diversification, and functional lipid design for drug-delivery applications.

목차 (Table of Contents)

• 초록
• Ⅰ 서론 1
• 1. Oxazolidin-2-ones 1
• 1.1. Oxazolidinone 1
• 1.2. Classical synthetic methods for oxazolidinone 4
• 1.3. Lossen rearrangement 8
• 2. DAST (Diethylaminosulfur trifluoride) 10
• 2.1. DAST 10
• 2.2. Classical applications of DAST 12
• 2.3. DAST-promoted rearrangement reactions 16
• 2.3.1. Structural rearrangements of sulfoxide and sulfone 16
• 2.3.2. Beckmann-type rearrangement of oxime 17
• 2.3.3. Lossen-type rearrangement of hydroxamic acid and amide 18
• 2.3.4. DAST- promoted Lossen rearrangement 20
• 3. Lipid Nanoparticles, LNPs 21
• 3.1. LNPs as drug delivery carriers 21
• 3.2. Structural components of LNPs 22
• 3.3. Importance of synthetic lipid research and the role of chemical methodology · 24
• 4. Novel lipid design based on the bile acid scaffold 25
• 4.1. Direction of the present study 25
• 4.2. Chemical characteristics of bile acid scaffolds 26
• 4.3. Significance of bile acid–based lipid design 28
• 4.4 Design concepts and structural features of bile acid–based lipids 28
• 4.4.1. Design concepts 30
• 4.4.2. Structural composition 31
• 4.4.3. Combinatorial structural diversity 32
• 5. Research significance of this study 34
• Ⅱ 본론 36
• 1. Part 1. Concise asymmetric synthesis of oxazolidin-2-ones via DAST-promoted
• Lossen rearrangement 36
• 1.1. Asymmetric aldol and chiral auxiliary 36
• 1.2. Mechanism of DAST-promoted Lossen rearrangement 38
• 1.3. Optimization of DAST-promoted Lossen rearrangement 40
• 1.4. Substrate scope 48
• 2. Part 2. Bile acid-derived lipids for LNPs 51
• 2.1. Reaction design and protecting-group strategy 51
• 2.1.1. Functional group positions and selective transformations of the bile acid
• scaffold 51
• 2.1.2. EDC/DMAP esterification 52
• 2.1.3. TBS protection strategy 53
• 2.2. Optimization of reaction conditions 55
• 2.3. Construction of the 3×3 bile acid-derived lipid library 58
• 2.4. Significance of the synthetic design for structure–property relationship analysis
• · 60
• Ⅲ 결론 63
• Ⅳ 실험방법 66
• Ⅴ 참고문헌 93
• Ⅵ 영문 논문제출서 95
• Ⅶ 영문 인준서 96
• Ⅷ 영문 초록(ABSTRACT) 97