形式[3+3]氮雜環化加成: Schulzeines的形式合成

Abstract

本文利用市售之3,5-甲/卞氧基取代的苯甲醛102/103出發，以超音波震盪優化之亨利反應，能得高於Ojima教授所報導之65%產率，得到共軛硝基化合物104/105產率(84%/92%)，並經過量氫化鋁鋰同時將雙鍵與硝基完全還原得到伯胺化合物106/107，以醋酸酐進行乙醯化生成108/109，以施勒納皮耶拉爾斯基反應(Bischler-Napieralski reaction)使其進行分子內脫水環化生得關鍵中間體3,4-二氫異喹啉111/112，經一系列溶劑與反應物的複合研究探索，發現以丙烯酸、對二甲苯為形式[3+3]氮雜環化加成之最佳條件，可成功得到1,2-哌啶酮化合物116/119，完成Schulzeine之關鍵三環骨架。以119繼續進行，經雙鍵還原和α胺基的建立，生成可分離之非鏡像化合物31/32，完成Schulzeine分子之形式合成。再以化合物31進行Schulzeine衍生物的研究，於酸性環境移除Boc保護基得到伯胺化合物20後，便與諸多擁有長碳鍊性質或藥性潛力的羧酸進行分子間偶聯反應，得到一系列的醯胺衍生物。

Using the commercially available 3,5-dimethoxybenzaldehyde (102) and 3,5-bis(benzyloxy)benzaldehyde (103) as the starting material, we found the ultrasound-assisted Henry reaction with nitromethane afforded the corresponding nitrostyrenes 104 and 105 in 84% and 92% yields respectively; the newly developed protocol for the synthesis of 104 is superior to the Ojima's original report (65% of 104). Treating 104 and 105 separately with excess of LiAlH4 gives the corresponding exhaustively reduced amines 106 and 107. Acylation of 106/107 with acetic anhydride gives 108/109. With the application of the Bischler-Napieralski reaction, we can obtain the key intermediates 3,4-dihydroisoquinoline 111/112. After a series of reaction optimizations, we found that the best condition for the formal [3+3] aza-cycloaddition of 111/112 is using acrylic acid as the three-carbon donor and p-xylene as the solvent; the desired 1,2-piperidinone 116/119 can be prepared in good yields. Through sequential alkene reduction and α-amination reaction of 119, we can prepare the separable diastereomers 31/32, thus completing the formal synthesis of schulzeines. Under the acid condition, the Boc group of 31 was facilely removed giving the primary amine 20. We then successfully synthesize the schulzeine derivatives of biomedicinal potentials by the coupling of 20 with a range of long-chain fatty acids and privileged scaffolds.