効率的な単一および二重イリジウム触媒型ステレオ選択的水素化によりトランス-ブタン-1,2,4-トリオールにアクセス
Kurt Püntener1, Anna-Lena Glass1, Leonardo Tensi2
1Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
Journal of the American Chemical Society
|November 10, 2025
まとめ
イリジウム触媒を使用した新しい二重触媒システムは,医薬品の合成のために高度にエナチオセレクティブな非対称な水素化を実現します. この方法は,以前のプロトコルと比較して効率が向上し,コストが低下します.
科学分野:
- 有機合成
- 非対称な触媒
- 薬剤化学
背景:
- キラル医薬品の合成には,しばしば複雑な多段階のプロセスが必要です.
- ケトリデクタゼを使用する既存の方法は,非効率的または高価である可能性があります.
- より効率的で費用対効果の高い非対称化水素化技術が必要である.
研究 の 目的:
- 特定のケトエステルの非対称な水素化のための新しい1ポット合成方法論を開発する.
- GDC-6599の合成に不可欠なキラルトリオルの構成要素である (2R,4R) -4-クロロフェニル) -ブタン-1,2,4-トリオル ((R,R) -7a) を生成する.
- 単一触媒または酵素アプローチの改善として二重触媒システムの有効性を調査する.
主な方法:
- 4-(4-クロロフェニル) - 2 - ヒドロキシ - 4 - ケト - ブタリック - 2 - 酸エチルエステルの非対称な水素化
- 鉛の触媒 (LC) を使って,Ir/(S) -SpiroPAPと,Ir/(R,R) -Ms-DPENの助力触媒 (AC) を使った.
- シングルLCとダブル触媒システムを比較した1つのポット,連続した反応配列を調査した.
主要な成果:
- 二重触媒システムは,LC単独 (7:1,71%) と比較して,ダイアステレオ選択性 (トランス/シス比18:1) と出力率 (77%) を著しく高めました.
- ACは最初の水素化ステップでエナチオセレクティブ性を改善し (96% ee),全体的なeeを高めた (90-94% ee).
- PNNリガンドを持つ新しいLCは,比較可能な品質,最高収量 (81%) および低コストを達成しました.
結論:
- 新しい二重触媒系が初めて薬剤のステレオ選択合成に成功しました.
- この方法論は,より効率的で,費用対効果が高く,ターゲットトリオルのビルディングブロックへの高度な選択的経路を提供します.
- 開発されたシステムは,複雑なキラル分子を合成するための既存のプロトコルに有望な代替案を提供します.
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