反式去氫克羅托寧化合物群之新穎合成反應與應用探討

Abstract

反式去氫克羅托寧，是從巴西的巴豆大戟科廣藿香中提煉出來的，通常是拿來當作胃黏膜保護劑，但也可用來治療腹瀉、糖尿病和肝臟炎症。與反式去氫克羅托寧同樣具有天然物裡都有的重要骨架-螺旋與環內酯-的固醇類藥物，可以治療頭痛感冒、減輕肌肉痠痛、降血壓，或是在男性賀爾蒙產生上。除了類固醇類的藥物，目前在文獻上少有報導反式克羅托寧的合成研究。該計劃利用多組分反應，先將炔類與三級膦產生一三雙極的中間體，進而攻擊醛類獲得環內酯的結構。螺旋環內酯是許多天然物裡都有的重要骨架，因此可用此反應建立合成天然物骨架的基礎。螺旋環內酯骨架建立後，將分別探討威提試劑與酮化合物之反應、不對稱迪爾斯-阿爾德反應及不對稱氫化的反應，以達到反式去氫克羅托寧分子之合成。合成出反式去氫克羅托寧後，可透過單一起始物變換及化學修飾，做出一系列的衍生物來探討藥物方面的應用。由於3-丁炔-2-丁酮的反應性差，該計畫之合成停駐於第四步的不對稱Diel-Alder反應，需未來進一步探討。

trans-dehydrocrotonin, a alpha-spiro lactone, extracted from Brazil Croton cajucara, namely Sacacaas medicine, has been used for treatment of diarrhea, liver inflammatory and diabetics as well as gastric ulcers. Steroids possessing spiro lactone moiety were found for treatment of headaches, for pain relieving, and lowering blood pressure or assistance on forming male hormones； trans-DHC also features spiro lactone moiety. Methodology has been established for syntheses of sterodis； however, approaches for syntheses of trans-DHC have not been rationalized. In this project, we challeneg to synthesize trans-DHC and its analogues starting with building up a lactone core structure through generation of a 1,3-dipole via reaction of an acetylene and a phosphine followed by nucleophilic attack on an aldehyde. Some natural products generally feature lactone moiety； this multicomponent reaction provides a straighforward route to build up the core structure. We then study derivatization of the core structure through Wittig reaction with a ketone substrate, asymmetric Diels-Alder reaction, and asymmetric hydrogenation, to achieve synthesis of trans-DHC. The application of such developed methodology for synthesis of DHCs remain ongoing. Problems raised from asymmetric Diels-Alder reaction remain to be solved for accomplishing the target molecules.