左旋噻咪唑在外消旋二級醇動力學分割反應之探討與4-二甲基胺基吡啶衍生之新有機催化劑的開發
Abstract
掌性2-羥基羧酸酯分子結構，常見於藥物分子及生物活性分子，過去有許多關於二級醇之動力學光學分割的文獻研究，但以2-羥基羧酸酯為起始物的相關探討，卻是付之闕如。本論文探討使用外消旋2-羥基羧酸酯為起始物，以便宜又容易獲得的左旋噻咪唑為光學分割劑（10 mol%）、甲苯為溶劑，添加1.0當量的三乙基胺，以0.6當量的異丁酸酐為醯化試劑，在-75 oC與濃度0.05M的條件下，與2-羥基羧酸酯進行動力學光學分割二級醇反應，得到較好的產率及鏡像超越值。利用之前得到高鏡像選擇性之R-form 2-羥基羧酸酯，經由HPLC圖譜分析，確定本研究回收之起始物是以S-form為主，醯化產物則是以R-form為主。
另一方面，4-二甲基胺基吡啶衍生催化劑，在外消旋二級醇之動力學光學分割的應用上，有不錯的成果，本研究嘗試修飾已知的催化劑結構，合成具4-二甲基胺基吡啶結構之新有機催化劑，目前的合成策略雖可得到催化劑93，但產率不如預期，期望未來發展新合成策略，提升合成步驟的總產率，得到預期的新有機催化劑。
Chiral 2-hydroxyalkanoates are frequently important core structures in biologically active and pharmaceutical compounds. Several publications about kinetic resolution of racemic secondary alcohols were reported, but rare case used 2-hydroxyalkanoates as the starting materials. In this thesis, the reaction was carried out using 2-hydroxyalkanoates 76a (0.05 M) and isobutyric anhydride (0.6 equiv) as starting materials in toluene under -75 oC in the presense of triethylamine (1.0 equiv) and (−)-tetramisole (10 mol%) as a catalyst. The absolute stereochemistry of the recovered alcohol and acylated product were determined by the comparison with the HPLC and X-ray analyses which were studied in our group. In addition, chiral 4-(dimethylamino)pyridine derivatives have been used as efficient catalysts in kinetic resolution of secondary alcohols. Design and synthesis of new organocatalyst by insertion of 4-(dimethylamino)pyridine moiety into known catalyst is an important work. In this study, a new 4-(dimethylamino)pyridine derived catalyst 93 was synthesized successfully but in low chemical yield. Further modification of synthetic strategy to improve the result is underway in our group.
Chiral 2-hydroxyalkanoates are frequently important core structures in biologically active and pharmaceutical compounds. Several publications about kinetic resolution of racemic secondary alcohols were reported, but rare case used 2-hydroxyalkanoates as the starting materials. In this thesis, the reaction was carried out using 2-hydroxyalkanoates 76a (0.05 M) and isobutyric anhydride (0.6 equiv) as starting materials in toluene under -75 oC in the presense of triethylamine (1.0 equiv) and (−)-tetramisole (10 mol%) as a catalyst. The absolute stereochemistry of the recovered alcohol and acylated product were determined by the comparison with the HPLC and X-ray analyses which were studied in our group. In addition, chiral 4-(dimethylamino)pyridine derivatives have been used as efficient catalysts in kinetic resolution of secondary alcohols. Design and synthesis of new organocatalyst by insertion of 4-(dimethylamino)pyridine moiety into known catalyst is an important work. In this study, a new 4-(dimethylamino)pyridine derived catalyst 93 was synthesized successfully but in low chemical yield. Further modification of synthetic strategy to improve the result is underway in our group.
Description
Keywords
動力學分割, 4-二甲基胺基吡啶, 有機催化劑, 外消旋二級醇, kinetic resolution, 4-(dimethylamino)pyridine, organocatalyst, racemic secondary alcohols