ヘテロサイクルの実用的で先天的な炭素-水素機能化
Yuta Fujiwara1, Janice A Dixon, Fionn O'Hara
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature
|December 4, 2012
まとめ
亜鉛硫酸塩は,医学的に重要なヘテロサイクルにアルキルラジカルを直接添加することを可能にします. この温和で操作上シンプルな方法は,薬剤開発における貴重なC-C結合を合成するための新しい経路を提供します.
科学分野:
- 有機化学 オーガニック・ケミストリー
- 薬用化学 薬用化学について
- 合成化学 合成化学とは
背景:
- 窒素に富んだヘテロサイクルは,多くの医薬品における重要な支架である.
- ヘテロサイクルの直接的なC-H機能化は,薬物合成を制限する,それらの固有の性質のために困難です.
- 既存の方法は,しばしば機能化された基板または厳しい条件を必要とします.
研究 の 目的:
- 医学的に重要なヘテロサイクルのC-H機能化のための穏やかで直接的な方法を開発する.
- 先行機能化なしに,アルキル基をヘテロサイクリックコアに導入する.
- 既存のC-H機能化戦略に補完的なアプローチを提供すること.
主な方法:
- アルキルラジカル前駆体として亜鉛硫酸塩を使用しています.
- 軽度の反応条件 (≤50°C) を採用し,敏感な機能群と互換性があります.
- 様々な天然製品,薬物分子,構成要素の反応性をテストする.
主要な成果:
- アルキルラジカルを様々なヘテロサイクルに転移し,新しいC−C結合を形成する.
- 穏やかで,直接的で,操作的にシンプルな機能化の実証.
- 水と空気との互換性,そしてワンポット・タンデム反応の適性.
- Minisci,エレクトロフィリックアロマティック置換,および移行金属媒介法と比較して補完的な反応性.
結論:
- 亜鉛硫酸塩は,ヘテロサイクルの直接的なC-Hアルキル化のための有効で汎用的なツールを提供します.
- この方法は,薬剤発見に関連する複雑なヘテロサイクリック化合物の合成を簡素化します.
- このアプローチは,以前の機能化技術の限界を克服し,広範な適用性を提供します.
関連する概念動画
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01:16Cycloaddition Reactions: Overview
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03:02Organic Compounds
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02:08Introduction to Functional Groups
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02:47Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation
Introduction
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
02:36Regioselectivity and Stereochemistry of Hydroboration
A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.
Hydroboration proceeds in a concerted fashion with the attack of borane on the π bond, giving a cyclic four-centered transition state. The –BH2 group is bonded to the less substituted carbon and –H to the more substituted carbon. The concerted nature requires the simultaneous addition of –H and –BH2 across the same face of the alkene giving syn stereochemistry.