Metalated Nitriles: Internal 1,2‐Asymmetric Induction

Fleming, Fraser F.; Liu, Wang; Ghosh, Shalini; Steward, Omar W.

doi:10.1002/ange.200701550

Cited by 1 publication

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References 27 publications

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“…Alkylations of acyclic nitriles containing vicinal methyl and phenyl groups, or a trisubstituted alkene, are exceptionally diastereoselective (Scheme 10). 14,47 The chiral environment arises because deprotonation of nitrile 57 preferentially affords planar N-lithiated nitrile 58 in conformation 58″ rather than 58′ because positioning the small nitrile group on the same side as the vicinal methyl group avoids a severe methyl−methyl gauche interaction. Acylation from conformer 58″ occurs opposite the phenyl ring to afford ester nitrile 59 as a single diastereomer.…”

Section: ■ Diastereoselective Alkylations Of Acyclic Metalated Nitrilesmentioning

confidence: 99%

C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity

Yang

Fleming

2017

Acc. Chem. Res.

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Metalated nitriles are exceptional nucleophiles capable of forging highly hindered stereocenters in cases where enolates are unreactive. The excellent nucleophilicity emanates from the powerful inductive stabilization of adjacent negative charge by the nitrile, which has a miniscule steric demand. Inductive stabilization is the key to understanding the reactivity of metalated nitriles because this permits a continuum of structures that range from N-metalated ketenimines to nitrile anions. Solution and solid-state analyses reveal two different metal coordination sites, the formally anionic carbon and the nitrile nitrogen, with the site of metalation depending intimately on the solvent, counterion, temperature, and ligands. The most commonly encountered structures, C- and N-metalated nitriles, have either sp or sp hybridization at the nucleophilic carbon, which essentially translates into two distinct organometallic species with similar but nonidentical stereoselectivity, regioselectivity, and reactivity preferences. The hybridization differences are particularly important in Si displacements of cyclic nitriles because the orbital orientations create very precise trajectories that control the cyclization selectivity. Harnessing the orbital differences between C- and N-metalated nitriles allows selective cyclization to afford nitrile-containing cis- or trans-hydrindanes, decalins, or bicyclo[5.4.0]undecanes. Similar orbital constraints favor preferential Si displacements with allylic electrophiles on sp centers over sp centers. The strategy permits stereoselective displacements on secondary centers to set contiguous tertiary and quaternary stereocenters or even contiguous vicinal quaternary centers. Stereoselective alkylations of acyclic nitriles are inherently more challenging because of the difficulty in creating steric differentiation in a dynamic system with rotatable bonds. However, judicious substituent placement of vicinal dimethyl groups and a trisubstituted alkene sufficiently constrains C- and N-metalated nitriles to install quaternary stereocenters with excellent 1,2-induction. The structural differences between C- and N-metalated nitriles permit a rare series of chemoselective alkylations with bifunctional electrophiles. C-Magnesiated nitriles preferentially react with carbonyl electrophiles, whereas N-lithiated nitriles favor S2 displacement of alkyl halides. The chemoselective alkylations potentially provide a strategy for late-stage alkylations of polyfunctional electrophiles en route to bioactive targets. In this Account, the bonding of metalated nitriles is summarized as a prelude to the different strategies for selectively preparing C- and N-metalated nitriles. With this background, the Account then transitions to applications in which C- or N-metalated nitriles allow complementary diastereoselectivity in alkylations and arylations, and regioselective alkylations and arylations, with acyclic and cyclic nitriles. In the latter sections, a series of regiodivergent cyclizations are described that prov...

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Section: ■ Diastereoselective Alkylations Of Acyclic Metalated Nitrilesmentioning

confidence: 99%