【作者】 刘伟军；

【导师】 龚流柱；

【作者基本信息】 中国科学技术大学 ， 有机化学， 2010， 博士

【摘要】 很多天然产物、具有生物活性和药物活性的分子、多功能材料以及重要的有机合成中间体中都含有手性杂环结构单元。不对称催化合成手性杂环化合物是非常直接有效的方法,因此受到了很多有机化学家的关注。本文分别介绍了不对称催化合成手性的咪唑烷和顺式缩水甘油酰胺的新方法。光学活性的咪唑烷是一类有着广泛用途的有机合成中间体。亚胺叶立德和亚胺的1,3-偶极环加成反应,一步构建多个手性中心,是合成咪唑烷非常有效和原子经济的方法。到目前为止,不对称催化的亚胺叶立德和亚胺之间的1,3-偶极环加成反应还没有报道,这也说明不对称催化合成手性咪唑烷是一个难题。本文首次报道了手性布朗斯特酸催化的亚胺叶立德和亚胺之间的1,3-偶极环加成反应。醛、胺基酯和芳香胺—锅反应,高立体选择性地得到手性的咪唑烷。反应呈现负的非线性效应,由此我们推测反应的机理是两分子磷酸分别活化亚胺叶立德和亚胺的双活化过程。同时,该反应进一步说明手性布朗斯特酸活化的1,3-偶极子是一类重要的不对称1,3-偶极环加成反应的中间体。光学活性的缩水甘油酯和酰胺是一类非常重要的手性分子。合成该类分子的方法已经报道很多,并且取得了很大的成功,主要包括α,β-不饱和化合物的不对称环氧化和Darzens反应。但是关于顺式缩水甘油酯和酰胺的立体专一性合成的报道不多。本文报道了一例高立体选择性和高对映选择性的Darzens反应,即通过四异丙氧钛和(R)-联二萘酚原位制备手性钛配合物作为催化剂,催化醛和重氮乙酰胺反应,合成高光学活性的缩水甘油酰胺。该方法底物范围非常广,芳香醛、杂芳香醛、不饱和醛以及脂肪醛都能很好的参与反应,并取得非常好的结果。我们利用该反应成功实现了抗癌药物Taxol侧链和药物中间体(-)-Bestatin的合成。更多还原

【Abstract】 Chiral heterocyclic molecules are core structural element present in numerous natural products, biological active molecules and mutifuctional material, as well as important building blocks in organic synthesis. Catalytic asymmetric methods to access these compounds would be hihyly valuable and had attracted organic chemists’ great interest. In this manuscript, we have developed two new approaches for catalytical asymmetric synthesis of optically active imidazolidines and cis-glycidic amides, respectively.Optically active imidazolidines are important intermediates with broad applications to organic synthesis. The 1,3-dipolar cycloaddition of azomethine ylides to imines with concomitant creation of multiple stereogenic centers represents an efficient and atom-economic method for the manufacture of these compounds. However, to date, the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides to imines has not yet appeared and therefore remains an important challenge. In this manuscript, we have described the first Br(?)nsted acid catalyzed asymmetric 1, 3-dipolar cycloaddition between azomethine ylides and imines that directly assembles aldehydes, amino esters, and anilines into synthetically useful chiral imidazolidines with high levels of stereoselectivity. The negative NLE revealed two molecules of chiral phosphoric acids participated in the catalysis by the activation of both azomethine ylides and imines. This reaction has further demonstrated that the chiral Br(?)nsted acid-activated dipoles are versatile intermediates for the creation of new enantioselective 1,3-dipolar cycloadditions.The optically active glycidic esters and amides have.been one of the most of important classes of chiral molecules. The well established methods to access these optical compounds include asymmetric catalytic epoxidation ofα,β-unsaturated carbonyl compounds and Darzens reaction. Despite these elegant advances, relatively few protocols have been available for accessing either the cis-glycidic esters or amides. We have described a highly diastereo-and enantioselective Darzens reaction of aldehydes with diazoacetamides catalyzed by a chiral titanium complex formed in situ from commercially available Ti(O-i-Pr)4 and (R)-binaphthol, solely giving cis-glycidic amides with excellent enantiomeric purity. The protocol tolerated a broad scope of structurally diverse aldehydes, including aromatic, heteroatomatic, unsaturated, and aliphatic aldehydes. This new method has high potential in the enantioselective synthesis of biologically active substances as demonstrated by the preparation of the side chains of taxol and the chiral building block of (-)-bestatin.更多还原