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Herein, we disclose a photoredox-assisted cobalt-catalyzed asymmetric alkylative Barbier-type addition reaction of ketones to address the aforementioned challenges, thereby allowing for the construction of highly congested tetrasubstituted carbon centers. The alkyl addition fragments could be either readily accessible unactivated alkyl halides or redox-active esters generated through a decarboxylative pathway. Both types of alkyl electrophiles include primary, secondary, and tertiary ones, thus affording diverse enantioenriched tertiary alcohols with a broad substrate scope. This enantioselective protocol is applied for the expedient synthesis of core structure of <i>Sofdra</i>, a very recent FDA-approved drug in 2024. 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This reaction possesses the advantage of circumventing the preparation of moisture- and air-sensitive organometallic reagents. However, the catalytic Barbier reaction of ketones to construct tetrasubstituted stereogenic centers is largely underdeveloped, despite its great potential for accessing synthetically challenging chiral tertiary alcohol. Particularly, the leveraging of unactivated alkyl electrophiles as coupling components is still rarely exploited. Herein, we disclose a photoredox-assisted cobalt-catalyzed asymmetric alkylative Barbier-type addition reaction of ketones to address the aforementioned challenges, thereby allowing for the construction of highly congested tetrasubstituted carbon centers. The alkyl addition fragments could be either readily accessible unactivated alkyl halides or redox-active esters generated through a decarboxylative pathway. Both types of alkyl electrophiles include primary, secondary, and tertiary ones, thus affording diverse enantioenriched tertiary alcohols with a broad substrate scope. This enantioselective protocol is applied for the expedient synthesis of core structure of <i>Sofdra</i>, a very recent FDA-approved drug in 2024. 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引用次数: 0
摘要
巴比耶反应是醛或酮与有机亲电子体在末端金属还原剂存在下发生的还原型加成反应,为碳-碳键的形成提供了一种直接而有效的方法。这种反应的优点是可以避免制备对湿气和空气敏感的有机金属试剂。然而,尽管在获得具有合成挑战性的手性三元醇方面具有巨大潜力,但以酮为催化剂构建四取代立体中心的巴比耶反应在很大程度上仍未得到充分开发。特别是,利用未活化的烷基亲电体作为偶联组分仍然很少被利用。在此,我们公开了一种光氧化辅助钴催化的酮类不对称烷基巴比尔型加成反应,以应对上述挑战,从而构建高度拥挤的四取代碳中心。烷基加成片段既可以是容易获得的未活化烷基卤化物,也可以是通过脱羧途径生成的具有氧化还原活性的酯。这两种类型的烷基亲电体都包括伯、仲和叔醇,因此可以得到具有广泛底物范围的各种对映体富集叔醇。这种对映体选择性方案被用于快速合成索非达的核心结构,索非达是一种最近于 2024 年获得美国 FDA 批准的药物。新开发的双噁唑啉膦(NPN)配体在这一不对称还原加成过程中实现了高对映选择性。
Catalytic Asymmetric Barbier Reaction of Ketones with Unactivated Alkyl Electrophiles.
The Barbier reaction is a reductive-type addition of an aldehyde or ketone with an organic electrophile in the presence of a terminal metal reductant, providing a straightforward and efficient method for carbon-carbon bond formation. This reaction possesses the advantage of circumventing the preparation of moisture- and air-sensitive organometallic reagents. However, the catalytic Barbier reaction of ketones to construct tetrasubstituted stereogenic centers is largely underdeveloped, despite its great potential for accessing synthetically challenging chiral tertiary alcohol. Particularly, the leveraging of unactivated alkyl electrophiles as coupling components is still rarely exploited. Herein, we disclose a photoredox-assisted cobalt-catalyzed asymmetric alkylative Barbier-type addition reaction of ketones to address the aforementioned challenges, thereby allowing for the construction of highly congested tetrasubstituted carbon centers. The alkyl addition fragments could be either readily accessible unactivated alkyl halides or redox-active esters generated through a decarboxylative pathway. Both types of alkyl electrophiles include primary, secondary, and tertiary ones, thus affording diverse enantioenriched tertiary alcohols with a broad substrate scope. This enantioselective protocol is applied for the expedient synthesis of core structure of Sofdra, a very recent FDA-approved drug in 2024. The newly developed bisoxazolinephosphine (NPN) ligand enables high enantioselectivity in this asymmetric reductive addition process.
期刊介绍:
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