Recent Advances in Catalytic Systems for the Mechanistically Complex Morita–Baylis–Hillman Reaction

Abstract

Since its discovery in the late 1960s, the Morita–Baylis–Hillman (MBH) reaction has remained a powerful carbon–carbon σ-bond-forming transformation, producing small polyfunctionalized molecules. While commonly catalyzed by Lewis basic organic molecules such as tertiary amines and phosphines, several advances in functional catalysts and reaction conditions have been made in order to improve the reaction rate, substrate scope, and enantioselectivity. The goal of this Review is to give an updated summary of the main improvements made in catalytic systems for the MBH reaction over the past decade until nowadays. We hope this account will instigate further investigations in order to circumvent the remaining challenges of this fascinating transformation.

Building Enzymes through Design and Evolution

“…Early computational enzyme design efforts targeted reactions previously achieved with catalytic antibodies. More recently, the interplay of design and evolution has led to the development of an efficient and enantioselective enzyme for the more challenging Morita–Baylis–Hillman (MBH) reaction. , This chemical transformation couples α,β-unsaturated carbonyls with carbon electrophiles and is typically catalyzed by small molecule auxiliary nucleophiles such as 1,4-diazabicyclo[2.2.2]­octane (DABCO) and 4-dimethylaminopyridine (DMAP) . A modestly active designed MBHase that uses a His23 residue as the key catalytic nucleophile to accelerate the coupling of para -nitro benzaldehyde and cyclohexenone, served as a starting template for directed evolution (Figure B) .…”

“…60,61 This chemical transformation couples α,β-unsatu- rated carbonyls with carbon electrophiles and is typically catalyzed by small molecule auxiliary nucleophiles such as 1,4diazabicyclo[2.2.2]octane (DABCO) and 4-dimethylaminopyridine (DMAP). 62 A modestly active designed MBHase 60 that uses a His23 residue as the key catalytic nucleophile to accelerate the coupling of para-nitro benzaldehyde and cyclohexenone, served as a starting template for directed evolution (Figure 1B). 61 Introduction of 24 mutations gave rise to an engineered enzyme BH32.14 with an ∼160 fold improvement in k cat compared with the starting variant (0.35 min −1 and 0.13 h −1 , respectively).…”

Efficient synthesis of 3‐sulfonyl‐1,2‐dihydroquinolines via tandem aza‐Michael addition/cyclizations of N‐acyl‐protected 2‐aminobenzaldehyde with vinyl sulfones

“…Despite these significant achievements, employing 2-aminobenzaldehyde derivatives as a substrate to access functionalized 1,2-DHQs are always in great demand. To the best of our knowledge, the MBH alcohols could easily achieve when applying the N-acyl-protected 2-aminobenzaldehyde with electron-deficient alkene, such as methyl acrylate or acrylonitrile, through MBH reaction based on reported literature (Scheme 1E) [38][39][40][41][42][43]. In contrast, when the vinyl sulfones as nucleophile reacted with the N-acyl-protected 2-aminobenzaldehyde, the reaction could allow for the production of 3-sulfonyl-1,2-DHQs (Scheme 1E, this work) via aza-Michael addition/ cyclizations which display a different reactivity to apply activated alkenes with sulfone moiety other than electronwithdrawing groups in MBH reactions.…”

Fluoroalkylation of Activated Allylic Acetates through Radical–Radical Coupling: Organophotoredox/DABCO Catalytic System

“…In this context, the development of efficient and selective methods for the introduction of fluoroalkyl groups onto complex molecular frameworks has become an active area of exploration. 3,4 In this study, we propose the utilization of commercially available fluorinated carboxylic salts 4 in conjunction with an activated allylic acetate 5 group with an organophotoredox/DABCO catalyst system to achieve fluoroalkylation through radical− radical coupling 6 reactions. This approach capitalizes on the benefits offered by visible light-mediated organophotoredox catalysis 7 and the synergistic base properties of DABCO, 8 including enhanced selectivity, broad functional group compatibility, and mild reaction conditions.…”

“…This approach capitalizes on the benefits offered by visible light-mediated organophotoredox catalysis 7 and the synergistic base properties of DABCO, 8 including enhanced selectivity, broad functional group compatibility, and mild reaction conditions. The activated allylic carbon source is provided by Morita−Baylis−Hillman adducts (MBHAs), 5,9 which have garnered significant interest as versatile building blocks in various fields 10 and seen amplified interest from medicine. 11 Despite that Lewis base catalysis 12 has enabled the generation of allylic phosphorus ylides from MBHAs for diverse annulations, 9,13 the exploration of radical−radical coupling has been limited.…”