Unsaturated Oxo−Nitriles:  Stereoselective, Chelation-Controlled Conjugate Additions

Abstract

Addition of Grignard reagents to the unsaturated oxo−nitrile 10 (4-hydroxy-4-methyl-6-oxocyclohex-1-enecarbonitrile) provides conjugate addition products with virtually complete stereocontrol. Mechanistic evidence supports a chelation-controlled conjugate addition via alkylmagnesium alkoxide intermediates. Diverse Grignard reagents having sp3-, sp2-, and sp-hybridized carbons react with comparable efficiency, with even sterically demanding nucleophiles adding with complete stereocontrol. Unsaturated oxo−nitriles that are incapable of chelation afford diastereomeric conjugate addition products through an unusual boatlike transition state. Collectively, these reactions illustrate the complementary stereoselectivity of chelation-controlled conjugate additions to hydroxylated, unsaturated oxo−nitriles and stereoelectronically controlled conjugate additions to enones.

Synthesis of 1,4-Diazepanes and Benzo[b][1,4]diazepines by a Domino Process Involving theIn SituGeneration of an Aza-Nazarov Reagent

“…The residue was purified by silica gel column chromatography, eluting with a gradient from hexane to 19:1 hexane/ethyl acetate, to yield 184 mg (33%) of compound 2c and 277 mg (33%) of a second product, identified as diethyl ( E )-3-hydroxy-3-(pent-2-en-1-yl)­pentanedioate. NMR data of the compound 2c thus obtained were identical to those found in the literature …”

Synthesis of the C20−C26 Building Block of Halichondrins via a Regiospecific and Stereoselective SN2‘ Reaction

“…Assuming that this conformational preference is reflected in the transition state and also that the hydroxyl group directs the delivery of a “Me” anion, one would expect that the proposed reaction preferentially proceeds through the transition state resembling Ia , to furnish the desired vinyl iodide in a stereo- and regioselective manner. , Relevant to the proposed delivery of a “Me” anion by a hydroxy group, Gallina demonstrated that N -phenylcarbamate group is an effective directing group in a cuprate-mediated S N 2‘ reaction, whereas Nakamura showed that the stereochemical outcomes of cuprate-mediated S N 2‘ reactions of δ-alkoxy allylic chlorides are explained by simple steric effects. To the best of our knowledge, there is no study reported in which a hydroxyl group serves as a directing group in an organocuprate-mediated addition in an acyclic system. , Also, there is no study reported on the stereochemical course of an organocuprate-mediated S N 2‘ reaction for an acyclic homoallylic alcohol or its derivatives . It should also be noted that an impressive level of regio- and enantioselectivity has been realized in chiral-auxiliary based, asymmetric S N 2‘ reactions in recent years, and these reactions could be applied selectively to transform I (X = a leaving group bearing a chiral-auxiliary) into II , but we opted to study the hydroxyl-directed S N 2‘ displacement because of the simplicity of the synthetic operations as well as the cost considerations.…”

γ-Hydroxy Unsaturated Nitriles: Chelation-Controlled Conjugate Additions

“…Anionic conjugate addition reactions are profoundly influenced by chelation . The effect of chelation is succinctly illustrated in the addition of Grignard reagents to the hydroxylated α,β-unsaturated oxonitriles 2 (Scheme ) …”