"由具有2-羧基與4-烷氧基取代之1,3-丁二烯進行狄爾斯–阿爾德反應以合成克流感"

Abstract

流行性感冒是一種嚴重的急性呼吸道感染，長期威脅人類健康，克流感是在臨床上用來有效治療流感的藥物之一。狄爾斯–阿爾德反應是在有機合成化學上最有效轉換的反應之一，因為其不只可以在一個步驟建構兩個新的碳–碳單鍵，更可以形成四個連續的立體中心，並有很好的位置和立體選擇性。因此化學家利用狄爾斯–阿爾德反應來建構克流感主要的環己烯結構。 我們成功合成出新穎的二烯前驅物214，此溴化合物214在鹼性條件下生成共軛二烯，其同時具有推電子的3-戊烷氧基與拉電子的羧基，容易進行二聚化反應。若加入活性好的烯烴，則可以成功捕捉二烯中間產物，進行狄爾斯–阿爾德反應。尤其利用反丁烯二酸雙烷基酯263捕捉二烯，可以得到預期的狄爾斯–阿爾德反應的產物264。我們利用雙羧酸化合物243形成醯基疊氮的衍生物，並經Curtius重排反應，成功得到克流感的前驅物250b (外消旋混合物)，將兩個非鏡像異構物成功分離的關鍵步驟在於進行單一第三丁氧羰基的保護，得到均為反向的化合物249b。 根據之前的方法進一步成功合成出反丁烯二酸雙烷基酯269其接上由Evans團隊開發的手性輔助劑惡唑烷酮，溴化合物214在鹼性條件下與手性反丁烯二酸雙烷基酯269進行不對稱狄爾斯–阿爾德反應，得到兩個異構物271和272其比例為60:40，可惜的是嘗試水解手性惡唑烷酮並沒有成功。未來我們將利用反丁烯二酸雙烷基酯接上含(–)-麻黃素衍生之手性硫醇當作親二烯，希望狄爾斯–阿爾德反應的產物其硫醇基團將來可以容易被水解。

Influenza is a severe health problem to cause serious acute respiratory infection and endanger humans for a long time. Oseltamivir is one of the effective anti-influenza drugs in clinical use. Diels–Alder reaction is one of the most powerful transformations in synthetic organic chemistry. Not only does this strategy construct two new C–C σ-bonds in one step, but it also forms a cyclohexene system up to four contiguous stereocenters with good regio- and stereoselectivity. Therefore, many chemists have developed the methods using Diels–Alder reactions to construct the cyclohexene core structure of oseltamivir. We synthesized a novel diene precursor 214. Under basic conditions, the bromo compound 214 formed a conjugated diene, which bears both electron-donating 3-pentoxy and electron-withdrawing carboxy substituents. This diene intermediate easily underwent dimerization, but was trapped in situ with activated alkenes, particularly dialkyl fumarate 263 to afford the desired Diels–Alder adduct 264. Using this method, dicarboxylic acid 243 was successfully applied to synthesize an oseltamivir precursor 250b (in racemic mixture) via a sequence of reactions that comprise acyl azide formation and Curtius rearrangement. A key step was to separate the mono-Boc protected all-trans compound 249b from its diastereomer. As an approach to obtain the optically active oseltamivir, further synthesized the fumarate 269 with chiral oxazolidinone, which is a chiral auxiliary initially developed in Evans’ group. The asymmetric Diels–Alder reaction of bromo compound 214 with chiral fumarate 269 under basic condition afforded a mixture of two isomers 271 and 272 in a ratio of 60:40. Unfortunately, attempts to hydrolyze the chiral oxazolidinone products failed. In the future, we will investigate a fumarate dienophile with the chiral thiol auxiliary derived from (–)-ephedrine. Hopefully, hydrolysis of the thioester moiety in the Diels–Alder product will be easily carried out.