非常規Diels-Alder反應立體選擇性及其機制之理論計算化學研究 A Computational Study on the Anomalous Exo Selectivity in Diels-Alder Reactions

Date
2016
Authors
黃麒彰
Huang, Ci-Jhang
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Diels-Alder反應是公認有機合成建立六員環一強大工具,能夠在一步驟反應中最多產生四個相鄰位置的立體中心,因此在實驗合成被運用的情形顯而易見,尤其常見於建立複雜的生化分子以及自然產物之合成。在過去Diels-Alder加成反應其立體選擇性的預期往往因著endo途徑diene與dienophile兩分子間存在著二級軌域作用(secondary orbital interactions) 而取得endo選擇性(Alder’s endo rule)。具有exo選擇性的Diels-Alder反應特殊例子亦存在,但大多數必須具有環狀結構並且要在路易斯酸等催化條件下方可生成。最新的研究顯示,簡單的dienes與dienophiles反應系統亦能在非催化的熱反應條件下生成exo選擇性的產物,但相關理論細節尚待釐清。 因此,本篇論文旨在透過理論計算化學研究、探討Diels-Alder反應在一系列dienes、dienophiles於不同拉電子基條件下endo以及exo立體選擇性變化,詳細的探討Diels-Alder反應其取代基效應、過渡狀態結構主導立體選擇性之關鍵因素,為這類特別之非常規的exo選擇性提出反應條件及反應機制。 透過理論計算化學的探究,我們證實了簡單(非環狀)、只含部份取代的dienes與dienophiles反應系統確實可在熱反應條件下生成exo選擇性產物。其原理可大致說明如下:藉由diene之C2位置大基團以及diene之C4位置取代基的修飾,可以增加dienophile拉電子基與diene之取代基在endo途徑的立體阻礙使其不利生成endo加成物。除此之外,dienophile之Cβ位置使用具π系統的取代基以增加exo過渡狀態兩分子間的交互作用同樣可以有效提升exo選擇性。 期望藉由本篇論文之成果,使實驗合成不僅可透過調控立體效應與穩定效應自由地獲得專一選擇性,讓這系列起始物結構與反應條件皆相對單純之Diels-Alder加成反應在實驗設計上有更多的發展與應用潛力。
The Diels-Alder reaction is a powerful tool for the construction of six-membered rings with up to four stereogenic centers in a single step makes this reaction highly attractive, especially in constructing complex biologically active molecules and natural products. Traditionally, the selective predictions of the products rely heavily in consideration of the secondary orbital interactions that stabilize the endo pathway (Alder's endo rule). Exo selective Diels-Alder reactions in special cases have been reported, but are mostly limited to catalytic conditions involving reactants and/or Lewis acids with bulky or cyclic structures. We investigate theoretically the endo and exo reaction pathways for the Diels-Alder cycloadditions between various dienes and dienophiles with different substituents and electron-withdrawing groups. In this study, we investigate in detail the substitutional group effect on the stereoselectivity of Diels-Alder reactions, and propose a mechanism for the anomalous exo selectivity for these special cases. We propose that the stereoselectivity is derived from the competition between different interaction forces in two pathways. Specifically, the endo pathway is disfavored by the streic repulsion between the electron-withdrawing group of the dienophile and the C2,C4-substituents of the diene. Moreover, the secondary orbital interactions may also be exploited in a converse manner to enhance the exo selectivity by introducing π-conjugation at the trans-Cβ of the dienophile. We expect that the results proposed by this study will provide valuable guidelines for organic synthesists to utilize more versatile strategies in accordance with the principles of green chemistry.
Description
Keywords
Diels-Alder反應, 二級軌域作用, 扭曲/作用能分析, Diels-Alder reactions, Secondary orbital interactions, Distortion/Interaction analysis
Citation
Collections