Spiropiperidine Sultam and Lactam Templates: Diastereoselective Overman Rearrangement and Metathesis followed by NH Arylation,The Journal of Organic Chemistry

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Spiropiperidine Sultam and Lactam Templates: Diastereoselective Overman Rearrangement and Metathesis followed by NH Arylation
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2017-11-13 00:00:00 , DOI: 10.1021/acs.joc.7b02096
Luis A. Martinez-Alsina ₁ , John C. Murray ₁ , Leanne M. Buzon ₁ , Mark W. Bundesmann ₁ , Joseph M. Young ₂ , Brian T. O’Neill ₁

Affiliation

We report the diastereoselective synthesis of novel spiropiperidine templates for use in SAR studies of β-secretase (BACE) inhibitors and also as versatile ligands for other receptor types. The overall synthetic approach stems from chiral starting material benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and employs an Overman rearrangement to control the stereochemistry at the quaternary center. This process is followed by a Grubbs metathesis to close a five-membered “top” ring to form an α,β-unsaturated lactam or an α,β-unsaturated sultam. We also demonstrate that this chemistry can accommodate additional substituents on the lactam/sultam ring and allows late stage sequential functionalization of the amine and amide nitrogens to rapidly produce diverse analogues.

中文翻译：

Spiropiperidine Sultam和Lactam模板：非对映选择性超人重排和复分解，然后进行NH酰化

我们报告了新型螺哌啶模板的非对映选择性合成，可用于β-分泌酶（BACE）抑制剂的SAR研究，也可作为其他受体类型的通用配体。整个合成方法均来自手性原料苄基（S）-2-甲基-4-氧杂哌啶-1-甲酸苄酯，并采用Overman重排控制四级中心的立体化学。在该过程之后，进行了格鲁布斯复分解，以封闭五元“顶”环，形成一个α，β-不饱和内酰胺或一个α，β-不饱和内酰胺。我们还证明了这种化学方法可以容纳内酰胺/舒马酰胺环上的其他取代基，并允许胺和酰胺氮的后期顺序功能化，以快速产生各种类似物。

更新日期：2017-11-16

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