从 (+) - 3 - 烯中合成 (+) - 烯的14个步骤合成
Lars Jørgensen1, Steven J McKerrall, Christian A Kuttruff
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
概括
具有抗癌性质的化合物 ingenol 的新 14 步合成提供了一种高效和立体控制的方法. 这一突破使得合成类型的制造成为可能,克服了目前因醇及其衍生物的采购方法的局限性.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 合成生物学 合成生物学
背景情况:
- 英格诺和其衍生物具有显著的抗癌活性.
- 美国食品和药物管理局批准的药物Picato,来自ingenol,治疗行动性角质炎.
- 目前从Euphorbia peplus中采购英醇是低效的.
研究的目的:
- 开发一种高效且高度立体控制的 (+) - 英醇合成方法.
- 为了使生物活性 ingenanes 的完全合成类型的创建.
- 为化学生产的 ingenol 和相关化合物提供战略蓝图.
主要方法:
- 从便宜的 (+) - 3 - 烯中合成 (+) - 醇的14个步骤.
- 采用了一种新的两相设计,用于烯总合成.
- 在整个合成过程中实现了高立体控制.
主要成果:
- 在14个步骤中用高立体控制成功合成 (+) - 英醇.
- 开发的合成途径是高效和具有成本效益的,从易于获得的材料开始.
- 证明了复杂的多氧化类烯的双相烯总合成的可行性.
结论:
- 这种新型的合成为隔离或生物工程提供了一个可行的替代方案,用于生产ingenol及其类似物.
- 这种方法通过解决药理学限制,促进了基于 ingenane 的新疗法的开发.
- 验证了双相烯总合成作为复杂分子制备的实用方法.
相关概念视频
Diels–Alder Reaction Forming Cyclic Products: Stereochemistry
The Diels–Alder reaction is one of the robust methods for synthesizing unsaturated six-membered rings. The reaction involves a concerted cyclic movement of six π electrons: four π electrons from the diene and two π electrons from the dienophile.
[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction
The Diels–Alder reaction is an example of a thermal pericyclic reaction between a conjugated diene and an alkene or alkyne, commonly referred to as a dienophile. The reaction involves a concerted movement of six π electrons, four from the diene and two from the dienophile, forming an unsaturated six-membered ring. As a result, these reactions are classified as [4+2] cycloadditions.
Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation
Robinson annulation is a base-catalyzed reaction for the synthesis of 2-cyclohexenone derivatives from 1,3-dicarbonyl donors (such as cyclic diketones, β-ketoesters, or β-diketones) and α,β-unsaturated carbonyl acceptors. Named after Sir Robert Robinson, who discovered it, this reaction yields a six-membered ring with three new C–C bonds (two σ bonds and one π bond).
[3,3] Sigmatropic Rearrangement of 1,5-Dienes: Cope Rearrangement
The Cope rearrangement is classified as a [3,3] sigmatropic shift in 1,5-dienes, leading to a more stable, isomeric 1,5-diene. The reaction involves a concerted movement of six electrons, four from two π bonds and two from a σ bond, via an energetically favorable chair-like transition state.
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.
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.


