Diversity‐Oriented Synthesis of Enantiopure N‐Protected β,β‐Dialkylserines.

Dettwiler, James E.; Lubell, William D.

doi:10.1002/chin.200433205

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“…GRIGNARD REAGENT TO CARBOXYLATES The copper-catalyzed cascade addition of vinyl Grignard reagent to a carboxylate has proven to be an effective alternative for synthesizing homoallylic ketones 2 from a variety of esters. Inspired by the isolation of homoallylic ketone 2j as major side-product from addition of excess vinyl magnesium bromide to methyl N-(Boc)serinate during studies to synthesize β-hydroxyvaline, 8,9 an examination of the literature found that vinyl Grignard converted, respectively, to bis-and tris-homoallylic ketones 6 (Scheme 4). 19,20 Homoallylic ketones with methyl and phenyl substituents resulted from reacting substituted vinyl Grignard reagents on p-methoxybenzoate (e.g., racemic 7a−12a), 21 N-Boc-β-alaninate (e.g., racemic 7b−12b), 21 and N-Boc-4-hydroxyprolinate (e.g., 14).…”

Section: Cu-catalyzed Cascade Addition Of Vinylmentioning

confidence: 99%

Applications of γ,δ-Unsaturated Ketones Synthesized by Copper-Catalyzed Cascade Addition of Vinyl Grignard Reagents to Esters

2018

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CONSPECTUS: γ,δ-Unsaturated ketones, so-called homoallylic ketones, have served as versatile building blocks for the synthesis of a variety of heterocycles, carbocycles, natural products, and reactive intermediates. Procured by a variety of processes, including conjugate addition of vinyl organometallic reagents to unsaturated ketones, allylation of silyl enol ethers, and rearrangements, homoallylic ketones are often synthesized by step-intensive methods. The cascade addition of 2 equiv of vinyl Grignard reagent to a carboxylate was reported by the Lubell laboratory in 2003 to give effective access to homoallylic ketones from a variety of aromatic, aliphatic, and α-amino methyl esters. Employing readily accessible vinyl magnesium halides in the presence of a catalytic amount of copper salt, this cascade reaction provides high yields of homoallylic ketones with minimal side product by a process featuring the assembly and collapse of a tetrahedral intermediate with expulsion of alkoxide ion, followed by conjugate addition to the resulting enone. Application of the cascade reaction to the synthesis of various homoallylic ketones has provided versatile building blocks for the synthesis of targets for different applications. For example, by employing (hetero)aryl di-and tricarboxylates as precursors, copper-catalyzed cascade additions have provided donor−acceptor and star-shaped monomers for optical-electronic materials. Amino ester starting materials have given homoallylic ketones for the synthesis of various peptidomimetics, including heteroarylalanines, hydroxyethylene isoesters, and diazepinone turn mimics. Moreover, anthranilate has served as building block to prepare various pyrrole, quinoline, benzodiazepine, and benzotriazepine heterocyles. In addition, cascade additions on hydroxyprolinates have given access to bipyrrole precursors of the prodigiosin family of natural products. In the interest to highlight the utility of the copper-catalyzed cascade addition of vinyl Grignard reagents to carboxylates, this Account provides details on the broad scope of substrates that deliver homoallylic ketone products as well as an overview of the wide range of applications in which this method may impact including materials and peptide science, heterocycle and natural product synthesis, and medicinal chemistry.

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