Total Synthesis of Sulindac and iso-Sulindac via Stereoselective Vinylogous Stork Enamine Claisen-Schmidt Condensation = VSECSC 반응을 통한 설린닥과 설린닥 이성질체의 전합성 연구

다국어 초록 (Multilingual Abstract)

Sulindac, a sulfinylindene derivative prodrug, is a nonsteroidal anti-inflammatory drug (NSAID), which approved by the FDA in 1978. Sulindac has been known for their biological activities such as analgesic, antipyretic, and anti-inflammatory activities and its derivatives are reported as anti-cancer, anti-nociceptive activity, and antioxidant potency. Even now, research is ongoing for the expansion of their potential properties and application. Structurally, sulindac has a unique 1,2,3-trisubstituted indene skeleton bearing a synthetically formidable (Z)-benzylidene substituent at C-1, one methyl unit at C-2, and acetic acid moiety at C-3 and it contains a chiral center at the S atom. Given the interesting biological activities and an intriguing architecture, they are an unarguably attractive target for both synthetic chemists and biologists.
Herein, the efforts are described toward the synthesis of sulindac and unprecedented iso-sulindac. The key feature of a synthetic route includes the stereoselective construction of the (Z)-selective sulindac skeleton through vinylogous Stork enamine Claisen-Schmidt condensation. This synthetic strategy was expected to be applicable for the synthesis series of novel sulindac analogs.

목차 (Table of Contents)

• Table of Contents ⅰ
• List of Table ⅲ
• List of Figures ⅰⅴ
• List of Schemes ⅴ
• Abbreviations ⅴⅰ
• Abstract 1
• Ⅰ. Introduction 2
• 1. Overview of sulindac 2
• 2. Previous reported synthetic studies 3
• 2-1. Shuman’s synthesis 3
• 2-2. Maguire’s synthesis 4
• 2-3. Greenwald’s synthesis 5
• 2-4. Dai’s synthesis 6
• 3. Vinylogous Stork enamine type condensation 7
• Ⅱ. Results and Discussion 8
• 1. Retrosynthetic analysis 8
• 2. Optimization of stereoselective vinylogous Stork enamine type condensation 9
• 3. Syntheses of sulindac and iso-sulindac 10
• Ⅲ. Conclusion 13
• Ⅳ. Experimental Section 14
• 1. Chemical synthesis 14
• 1-1. General procedure 14
• 1-2. Synthesis and spectral data of compounds 14
• Ⅴ. References 25
• Ⅵ. Appendix 27
• Ⅶ. Abstract in Korean 56