使用催化不对称的迈克尔反应和并联循环,对 (-) - 斯特里尼因进行enantioselective总合成
Takashi Ohshima1, Youjun Xu, Ryo Takita
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Journal of the American Chemical Society
|December 6, 2002
概括
通过一种催化不对称的迈克尔反应和并联循环,实现了 (-) - 斯特里尼因的酶选择性总合成. 这种实用方法使得尼和相关类化合物的可扩展生产成为可能.
科学领域:
- 有机化学 有机化学
- 总的综合总的综合.
- 药用化学 医学化学
背景情况:
- 斯特里克尼是具有显著生物活性的复杂的醇化物.
- 之前的氨酸合成时间很长,缺乏可扩展性.
- 开发高效的合成路径,以氏化物对于药物发现至关重要.
研究的目的:
- 开发一种高效且可扩展的 (-) - - 斯特尼的酶选择性总合成.
- 建立适用于复杂类结构的新合成方法.
- 提供一个实用的途径,以获取施尼及其类型.
主要方法:
- 在千克尺度上使用 (R) -ALB (0.1 mol %) 的催化不对称迈克尔反应.
- 串联循环,同时构建B和D环.
- 离子循环,因胺还原和化学选择性脱硫的新条件.
主要成果:
- 在关键迈克尔反应中实现了高收益率 (91%) 和反选择性 (>99% ee).
- 在单个串联循环步骤中构建了B和D环,产量>77%.
- 通过使用优化反应条件,成功完成了总合成,避免了染色学.
结论:
- 开发的合成策略对于 (-) - 斯特尼生产来说是实用,可扩展和高效的.
- 新的方法提供了一个强大的平台,用于合成各种斯特里克诺斯类化合物.
- 这项工作显著推进了类化合物合成和药物化学领域.
相关概念视频
Regioselectivity of Electrophilic Additions to Alkenes: Markovnikov's Rule
If a set of reactants can yield multiple constitutional isomers, but one of the isomers is obtained as the major product, the reaction is said to be regioselective. In such reactions, bond formation or breaking is favored at one reaction site over others.
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The hydrohalogenation of an unsymmetrical alkene can yield two haloalkane products, depending on which vinylic carbon takes up the halogen. However, one product usually predominates, where hydrogen adds to the vinylic carbon bearing the...
Reduction of Alkenes: Asymmetric Catalytic Hydrogenation
Catalytic hydrogenation of alkenes is a transition-metal catalyzed reduction of the double bond using molecular hydrogen to give alkanes. The mode of hydrogen addition follows syn stereochemistry.
The metal catalyst used can be either heterogeneous or homogeneous. When hydrogenation of an alkene generates a chiral center, a pair of enantiomeric products is expected to form. However, an enantiomeric excess of one of the products can be facilitated using an enantioselective reaction or an...
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Regioselective Formation of Enolates
As depicted in the figure below, the unsymmetrical ketones can form two possible enolates: less substituted or more substituted enolates. Usually, the thermodynamic enolates are formed from the more substituted α-carbon atom, while the kinetic enolates are formed faster by deprotonation from the less substituted position. The thermodynamic enolates have lower energy, so they are more stable. But the energy required to form kinetic enolates is less.
Conjugate Addition of Enolates: Michael Addition
The attack of a nucleophile at the β carbon of an α,β-unsaturated carbonyl compound is called conjugate addition. Conjugate addition reactions of active methylene compounds, such as β-diketones, β-keto esters, β-keto nitriles, and α-nitro ketones, are called Michael addition reactions.
Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction
α-Substituted ketones or aldehydes can be synthesized from enamines by the Stork enamine reaction, named after its pioneer Gilbert Stork. Enamines are useful synthetic intermediates where the lone pair on nitrogen is in conjugation with the C=C bond. They resemble enolate ions, as the resonance forms of both species have a nucleophilic α carbon.
Aldol Condensation with β-Diesters: Knoevenagel Condensation
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