Unsymmetrical 1,6-Additions To Conjugated Systems

Copper/ruthenium relay catalysis enables 1,6-double chiral inductions with stereodivergence

“…The ensuing asymmetric 1,6-Michael addition followed by chiral Ru-hydridepromoted asymmetric reduction would result in the stereodivergent synthesis of highly functionalized ζ-hydroxy amino ester derivative containing remote 1,6-nonadjacent stereocenters and β,γunsaturation, which are pervasive structural units not only in a plethora of nature products and bioactive molecules, but also worked as key synthetic intermediates (Scheme 1c). [76][77][78] The envisaged copper/ruthenium relay catalyzed dehydrogenation/1,6-Michael addition/hydrogen-ation process, has some challenges that need to be overcome: (1) the competitive reactions among 1,6-vs 1,4-addition lead to difficult control of regioselectivity (site selectivity), in most cases, the partial positive charge density is less at the δ-position than the β-position; [79][80][81][82][83][84] meanwhile the undesired Ru-H reduction 85,86 of C=C double bonds in α,β,γ,δ-unsaturated ketone intermediate needs be suppressed to improve the reaction efficiency; (2) the control of stereoselectivity, since the initial-formed stereocenter is formed at the remote 6-position of later-formed chiral hydroxy center (five bonds between the two stereocenters);…”

“…[76][77][78] The copper/ruthenium relay-catalyzed dehydrogenation/1,6-Michael addition/hydrogenation process, thus envisaged, has some challenges that must be overcome: (1) the competitive reactions among 1,6-vs. 1,4-addition lead to difficult control of regioselectivity (site selectivity). In most cases, the partial positive charge density is less at the d-position than the b-position; [79][80][81][82][83][84] meanwhile the undesired Ru-H reduction 85,86 of C]C double bonds in a,b,g,d-unsaturated ketone intermediate must be suppressed to improve the reaction efficiency; (2) the control of stereoselectivity, as the initialformed stereocenter is formed at the remote 6-position of the chiral hydroxy center (ve bonds between the two stereocenters) formed later; (3) the control over the E/Z geometry 87 of dienyl ketone-based asymmetric 1,6-addition reaction; (4) the potential base-promoted position isomerization of the b,g-C]C double bond of Michael addition intermediate (chiral ketone) into the thermodynamically favored conjugated enone. 88 Herein, we reported the stereodivergent synthesis of highly functionalized chiral z-hydroxy amino ester derivatives containing remote 1,6-nonadjacent stereocenters and a unique b,gunsaturation moiety through dehydrogenation/1,6-Michael addition/hydrogenation relay process between diphenyl ketimine ester/peptides and racemic branched dienyl carbinols enabled by bimetallic copper/ruthenium relay catalysis.…”

Nucleophilic Substitution of Hydrogen Facilitated by Quinone Methide Moieties in Benzo[cd]azulen-3-ones

“…Nucleophiles participate in addition or substitution reactions of electron-deficient unsaturated molecules. While additions are common for nonaromatic alkenes, aromatic compounds usually undergo substitution reactions. , The upper reaction pathway in Scheme shows the well-established nucleophilic aromatic substitution reaction (S N Ar) in which the nucleophile (Nu) attacks the electron-deficient arene to form a σ X -adduct that is stabilized by elimination of the nucleofugal leaving group (NLG, e.g., halogens). The competing attack of the nucleophile at a CH-position and the subsequent formation of a σ H -adduct has been shown to proceed even faster than the formation of a σ X -adduct (the lower reaction pathway, Scheme ).…”

“…The conjugate addition of nucleophiles to electron-deficient alkenes has its place among the well-established synthetic methods . However, polyunsaturated compounds are challenging reactants because the regioselectivity (e.g., 1,2-, 1,4-, and 1,6-addition) depends on the nature of the nucleophile as well as steric and electronic effects …”

Copper-catalyzed asymmetric 1,4-conjugate addition of Grignard reagents to linear α,β,γ,δ-unsaturated ketones

“…2 However, due to an additional electrophilic site, the use of a,b,g,d-unsaturated Michael acceptors in asymmetric reactions remains a challenge and investigations are currently ongoing to control the formation of specific regioisomers (1,2-, 1,4-, as well as 1,6-products) with high enantioselectivity. [3][4][5][6][7][8] Over the past few years, Hayashi et al have developed several successful examples of rhodium-and iridium-catalyzed 1,6-ACAs to both cyclic and linear a,b,g,d-unsaturated compounds, utilizing arylnucleophiles. 4 More recently, the same group also reported the cobalt-catalyzed 1,6-ACA of (triisopropylsilyl)-acetylene to a,b,g,dunsaturated carbonyl compounds.…”