酮、醛及高活性烯類的有機不對稱 Michael 加成反應之研究

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2012

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本篇碩士論文分為三個主題。在第一個主題中,我們探討酮類 4 與雙甲酯烯類 12 的 Michael 加成反應。由於過去文獻中,此類型反應的活性相當不好,所以,我們嘗試將我們實驗室開發的催化劑應用在此反應中。經過各項條件仔細地篩選,在不須添加劑的溫和條件下,與環己酮 4a 反應可得到產物 11,產率:10-95%,非鏡像異構物比:75/25->95/5,鏡像超越值:32-96%;與其他酮類 4 反應可得產物 34,產率:74-83%,非鏡像異構物比:70/30-80/20,鏡像超越值:63-93%。 在第二個主題中,我們將重心放在 1,3-茚二酮(1,3-indandione)的烯類衍生物 56a 與環己酮 4a 所進行的 Michael 加成反應。除了一般常見地一次 Michael 加成產物外,我們發現環己酮 4a 對 1,3-茚二酮烯類衍生物 56a 進行完 Michael 加成反應後,可再次進行 Aldol 加成之連續性反應,最終可得具有五個掌性中心的 9-雙環[3.3.1]壬酮(bicyclo[3.3.1]nonan-9-one)衍生物 58/59。然而,研究過程並沒有相當順利,經催化劑、溶劑、添加劑、掌性、非掌性…等等條件篩選後,卻一直沒有重要進展,故第二主題仍需要往後更進一步的研究。 接著,在第三個主題中,我們將重心放在環己酮 4a 與苯甲醯乙腈(benzoylacetonitrile)烯類衍生物 60 的新類型反應。在以掌性一級胺作為催化劑的條件下,產生了具三個掌性中心的全取代二氫哌喃(full substituted dihydropyrans) 62,產率:32-90%,非鏡像異構物比:3.2/1-9.0/1,鏡像超越值:60-96%。此外,我們發現醛類61 必須使用掌性的二級胺作為催化劑,才能夠進行反應,得到產物 63,產率:75-87%,非鏡像異構物比:1/1.3-1/3.0,優異的鏡像超越值:83-95%。
The thesis is divided into three parts. In first part, the investigation of Michael addition reactions of ketone 4 towards alkylidene dimethylmalonates 12 was carried out. Due to the reported results regarding to the low reactivity in literature, we therefore decided to start our study using the catalysts developed in our group. After careful optimization of reaction conditions, we found that all the desired products 11 and 34 were smoothly generated in the presence of our developed catalyst without any additive (11: 10-95% yields, 75/25 to 95/5 dr, 32-96% ee; 34: 74-83% yields, 70/30 to 80/20 dr, 63-93% ee). In second part, we turned our attention to the asymmetric Michael addition reactions of cyclohexanone (4a) to alkylidene indandione such as 56a. The unexpected, organocatalytic domino reaction (Michael addition/Aldol addition) of cyclohexanone (4a) and alkylidene indandione 56a underwent smoothly to provide interesting bicyclo[3,3,1]nonan-9-one analogs 58 and 59 with five stereocenters. However, there is no further improvement for the synthesis of 58 and 59 after the screening of catalysts, solvents, additives, or etc. The reaction conditions should be optimized in future study. A new type of domino reactions of cyclohexanone 4a to alkylidenes of benzoylacetonitrile 60 was studied in the third part. In the presence of chiral primary amine as an organocatalyst, fully substituted dihydropyrans 62 with three stereogenetic centers can be afforded in 32-90% yields, with good stereoselectivities (3.2/1 to 9.0/1 dr; 60-96% ee). On the other hand, it is necessary to utilize a chiral secondary amine as an organocatalyst to promote the domino reactions of aldehydes and alkylidenes of benzoylacetonitrile 60 to furnish the corresponding adducts 63 in good yields (75-87%) with moderate diastereoselectivities (1/1.3-1/3.0 dr) and high enantioselectivities (83-95% ee).

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不對稱, , , Michael 加成反應, 連續性反應, 烯類, Asymmetrical, Ketones, Aldehydes, Michael Addition, Domino reaction, Alkenes

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