Sunday, August 23, 2015

Application of Catalytic Asymmetric Olefin Hydroamination to Estrone Conjugation

            The synthesis of optically active a-branched chiral aliphatic amines often relies on enzymatic resolutions or stoichiometric auxiliaries, such as the Davis/Ellman tert-butylsulfinimine. Fukuyama’s nosylate alkylation/de-sulfonylation sequence is another effective way to access secondary amines in a stereocontrolled fashion and can also be used to construct medium-sized rings. However, the Fukuyama secondary amine synthesis is a multistep approach requiring unproductive protecting group manipulations to access chiral amines.
            Recently, Stephen Buchwald’s group has developed a copper-catalyzed intermolecular hydroamination reaction that effectively converts unactivated internal olefins (Science 2015) and styrenes (JACS 2015) into enantioenriched a-branched amines. The catalytic cycle of this powerful transformation is initiated by enantiodetermining hydrocupration involving the addition of copper(I) hydride across the double bond of the olefinic substrate. This furnishes a secondary alkylcopper intermediate in an enantioselective fashion. The intermediary organocopper compound is susceptible to a chain-walking mechanism consisting of iterative b-hydride elimination/migratory insertion steps that lead to the formation of undesired achiral by-products. This pathway is completely suppressed under the new Buchwald conditions. Rather, electrophilic interception of the transiently generated alkylcopper species with a customized hydroxylamine ester furnishes the intended amine product with release of copper benzoate. The latter is reconverted to ligated copper hydride by a stoichiometrically applied hydrosilane reagent. The electronic properties of the amine transfer reagent used in the process were optimized for electrophilic reactivity toward the secondary alkylcopper intermediate and resistance against reductive N-O bond cleavage upon exposure to hydrosilane. The axially-chiral ligand, DTBM-SEGPHOS (structure shown above), is highly active for promoting hydrocupration, yet effectively discerns between prochiral faces of a minimally differentiated olefin such as 2-butene. The method has been integrated into a cascade sequence that generates optically active pyrrolidines in one step from readily available precursors. The chemistry was also successfully demonstrated in the context of conjugation of chemically complex API-type substrates. For example, a vinylarene prepared in one step from Claritin (loratidine) could be coupled with an amine transfer reagent derived from estrone benzyl ether to afford the conjugated steroidal adduct (structure shown in the Scheme above) in good yield and with a high level of stereocontrol. The new Buchwald protocol has enormous potential for future pharmaceutical applications and provides and answer to the long-standing synthetic challenge of forging nitrogen-carbon bonds from abundant alkene precursors and amines.

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