Asymmetric Homoenolate Additions to Acyl Phosphonates through Rational Design of a TailoredN-Heterocyclic Carbene Catalyst

Abstract

A highly selective NHC-catalyzed synthesis of γ-butyrolactones from the fusion of enals and α-ketophosphonates has been developed. Computational modeling of competing transition states was employed to guide a rational design strategy and achieve enhanced levels of enantioselectivity with a new tailored C1-symmetric biaryl saturated imidazolium-derived NHC catalyst. This new annulation is compatible with a wide range of acyl phosphonates and α,β-unsaturated aldehydes.

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes

“…145 In a collaboration with the Cheong group, computer modeling led to the identification of chiral NHC D 7 as the optimal catalyst for the reaction. When catalyst D 7 and MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene) were used experimentally, the products form in good yields (54 to 93%) and enantioselectivity (78 – 91% ee), but with modest diastereoselectivity (up to 3:1 dr) (Scheme 71).…”

Recent advances in employing homoenolates generated by N-heterocyclic carbene (NHC) catalysis in carbon–carbon bond-forming reactions

“…23 Reactions of homoenolates generated from sterically demanding b-disubstituted enals have also been reported. Computational modeling of transition states allowed the rational design of a chiral NHC generated from the imidazolium salt 49, which provided excellent levels of enantioselectivity for the lactone products (Scheme 12).…”

A new chiral C1-symmetric NHC-catalyzed addition to α-aryl substituted α,β-disubstituted enals: enantioselective synthesis of fully functionalized dihydropyranones

“…5 Dozens of intriguing chemical entities with improved complexity and diversity have been readily constructed in a stereocontrolled fashion via α,β-unsaturated acyl azolium intermediates. 6,7 With our ongoing interest in the exploration of practical asymmetric organoctalysis, 8 we envisioned that the 35 elusive asymmetric activation of challenging α-aryl substituted α,β-disubstituted enals might be achieved using C 1 -symmetric biaryl-saturated imidazolium. 9 Herein we present the first asymmetric Michael addition to α-aryl substituted α,βdisubstituted enals through oxidative NHC catalysis, giving rise 40 State In our initial study, several achiral NHC catalysts were screened to evaluate their ability to promote the reaction of αphenyl substituted enal 1a and acetyl acetone 2a by using 55 diazabicyclo[5.4.0]undecene (DBU, 10 mol%) and oxidant 4 in THF at 10 o C (Fig.…”

“…But the steric influence of the substituents at meta-or para-position of the phenyl was not obvious (entries 3-7 versus entries [8][9][10][11][12]. Electron-donating substituents gave higher levels 35 of reactivity and enantioselectivity compared to those substrates with electron-withdrawing substituents (Table 2, entries 3-5, 8-10 versus entries [6][7][11][12][13][14][15][16][17]. Notably, satisfactory results could be obtained when the bulky substituent at the para position of the phenyl group or the α-position of enal (Table 2, entries 15 and 40 18).…”