エポチロンへの非常に簡潔な経路:エポチロン490の総合合成と評価
Kaustav Biswas1, Hong Lin, Jon T Njardarson
1Bioorganic Chemistry, Preclinical Pharmacology Core Facility and Analytical Pharmacology Core Facility, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
Journal of the American Chemical Society
|August 15, 2002
まとめ
この研究は,リングクロージングオレフィンメタテシス (RCM) を使用したエポチロンの新しいステレオスペシフィック合成を提示しています. 新しいRCM減少プロトコルは,抗腫瘍薬の開発とアナログ合成のためのエポチロンフレームワークを効率的に生成します.
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
- 化学生物学 化学生物学とは
背景:
- エポチロンは有望な抗腫瘍剤の一種です.
- 以前の環閉オレフィンメタテシス (RCM) を用いたエポチロンの合成では,ステレオコントロールが欠けていた.
- エポチロン490 (3) は,エポチロン合成のためのRCMの再評価を促した.
研究 の 目的:
- エポチロンの簡潔でモジュラーでステレオ選択的な実験室合成を開発する.
- 効率的なエポチロンフレームワーク生成のための新しいRCM減少プロトコルの確立.
- 構造-活性関係 (SAR) 研究のための新しいエポチロンアナログの合成を探求する.
主な方法:
- マクロリド環を形成するために,ステレオ特異の環閉オレフィンメタテシス (RCM).
- チラルのチタン媒介アルドール条件は,C3-(S) -アルコールの後期導入のために.
- 新しく形成されたオレフィンの選択的ダイミド還元.
- アナログ合成のための新しいオレフィン機能化.
主要な成果:
- 最終合成ステップとしてRCMを実行することで,望ましいE-olefinの64%の収量を達成しました.
- 選択的ダイミド還元により,臨床候補である12,13-デソキシエポチロンBが得られました.
- この新しい経路は,細胞毒性および微小管の親和性スクリーニングのための新しいアナログの構築を容易にした.
- エポチロン490は,不利な薬理動力学により,異種移植におけるインビボ性能が悪かったが,薬理動力学的基準に基づいて,ヒトでの使用は有望である.
結論:
- エポチロンの新しい,ステレオ選択的RCMベースの合成が成功裏に開発されました.
- RCM減量プロトコルは,エポチロンアナログと臨床候補である12,13-デソキシエポチロンBへの効率的な経路を提供します.
- エポチロン490は,臨床前のモデルでインビボ効果が低いことを示したが,その薬理 Profil farmakokinetiknyo manunjuakkan,潜在的治療価値は,ヒトである.
関連する概念動画
02:29Ethers from Alcohols: Alcohol Dehydration and Williamson Ether Synthesis
Overview
Ethers can be prepared from organic compounds by various methods. Some of them are discussed below,
Preparation of Ethers by Alcohol Dehydration
In this method, in the presence of protic acids, alcohol dehydrates to produce alkenes and ethers under different conditions. For example, in the presence of sulphuric acid, dehydration of ethanol at 413 K yields ethoxyethane, whereas it yields ethene at 443 K.
Ethers can be prepared from organic compounds by various methods. Some of them are discussed below,
Preparation of Ethers by Alcohol Dehydration
In this method, in the presence of protic acids, alcohol dehydrates to produce alkenes and ethers under different conditions. For example, in the presence of sulphuric acid, dehydration of ethanol at 413 K yields ethoxyethane, whereas it yields ethene at 443 K.
02:43E1 Reaction: Stereochemistry and Regiochemistry
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02:38Structure and Nomenclature of Epoxides
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03:00Preparation of Epoxides
Overview
Epoxides result from alkene oxidation, which can be achieved by a) air, b) peroxy acids, c) hypochlorous acids, and d) halohydrin cyclization.
Epoxidation with Peroxy Acids
Epoxidation of alkenes via oxidation with peroxy acids involves the conversion of a carbon–carbon double bond to an epoxide using the oxidizing agent meta-chloroperoxybenzoic acid, commonly known as MCPBA. Since the O–O bond of peroxy acids is very weak, the addition of electrophilic oxygen of peroxy acids to...
Epoxides result from alkene oxidation, which can be achieved by a) air, b) peroxy acids, c) hypochlorous acids, and d) halohydrin cyclization.
Epoxidation with Peroxy Acids
Epoxidation of alkenes via oxidation with peroxy acids involves the conversion of a carbon–carbon double bond to an epoxide using the oxidizing agent meta-chloroperoxybenzoic acid, commonly known as MCPBA. Since the O–O bond of peroxy acids is very weak, the addition of electrophilic oxygen of peroxy acids to...
02:57Sharpless Epoxidation
The conversion of allylic alcohols into epoxides using the chiral catalyst was discovered by K. Barry Sharpless and is known as Sharpless epoxidation. The use of a chiral catalyst enables the formation of one enantiomer of the product in excess. This chiral catalyst is mainly a chiral complex of titanium tetraisopropoxide and tartrate ester (specific stereoisomer). The stereoisomer used in the chiral catalyst dictates the formation of the enantiomer of the product. In other words, the use of...
02:24Acid-Catalyzed Ring-Opening of Epoxides
Epoxides that are three-membered ring systems are more reactive than other cyclic and acyclic ethers. The high reactivity of epoxides originates from the strain present in the ring. This ring strain acts as a driving force for epoxides to undergo ring-opening reactions either with halogen acids or weak nucleophiles in the presence of mild acid. The acid catalyst converts the epoxide oxygen, a poor leaving group, into an oxonium ion, a better leaving group, making the reaction feasible. The...