Morita Baylis Hillman Products Research Articles

Engineering the simply asymmetric Morita–Baylis–Hillman reactions in a sodium phosphate buffer system: from enzyme‐ to proline‐catalyzed transformation

AbstractBACKGROUNDThe Morita–Baylis–Hillman (MBH) reaction is an important carbon–carbon bond‐forming reaction. However, most MBH reactions suffer disadvantages such as high amounts of catalyst and hazardous solvents, long reaction time, low reactivity and selectivity. In this study, simple, cost‐effective and eco‐friendly asymmetric MBH reactions are developed.RESULTSFollowing our previous study that the commercial Candida antarctica lipase B (lipase CalB)‐catalyzed MBH reaction can be activated by introducing an amide compound as a co‐catalyst, the recombinant lipase CalBs (rCalBs) with polyamino acid tails are first attempted to be used in the same MBH reaction, but unfortunately chiral MBH products are not obtained. Enoate reductase (ER) is found to give asymmetric transformation of the MBH reaction with a conversion of 36.9% and enantiomeric excess (e.e.p) of 6.8% when other enzyme resources are expanded. According to the observation that the surface amino acids of ER may be key factors in achieving the MBH reaction, single amino acids are subsequently selected to catalyze the MBH reactions, and the reverse configuration of (R)‐ and (S)‐MBH products with e.e.p of 63.9% and 62.1% for single l‐proline‐ and d‐proline‐catalyzed MBH reactions are reached only in 4 h, respectively.CONCLUSIONProline can afford the asymmetric MBH reaction in a sodium phosphate buffer only in 4 h without the help of the other co‐catalyst in our study, which is superior to those reported. The study aims to introduce a novel phenomenon observed from enzyme‐catalyzed to proline‐catalyzed MBH reactions. © 2022 Society of Chemical Industry (SCI).

Substrate Profiling of the Cobalt Nitrile Hydratase from Rhodococcus rhodochrous ATCC BAA 870.

The aromatic substrate profile of the cobalt nitrile hydratase from Rhodococcus rhodochrous ATCC BAA 870 was evaluated against a wide range of nitrile containing compounds (>60). To determine the substrate limits of this enzyme, compounds ranging in size from small (90 Da) to large (325 Da) were evaluated. Larger compounds included those with a bi-aryl axis, prepared by the Suzuki coupling reaction, Morita–Baylis–Hillman adducts, heteroatom-linked diarylpyridines prepared by Buchwald–Hartwig cross-coupling reactions and imidazo[1,2-a]pyridines prepared by the Groebke–Blackburn–Bienaymé multicomponent reaction. The enzyme active site was moderately accommodating, accepting almost all of the small aromatic nitriles, the diarylpyridines and most of the bi-aryl compounds and Morita–Baylis–Hillman products but not the Groebke–Blackburn–Bienaymé products. Nitrile conversion was influenced by steric hindrance around the cyano group, the presence of electron donating groups (e.g., methoxy) on the aromatic ring, and the overall size of the compound.

Asymmetric Morita-Baylis-Hillman Reaction: Catalyst Development and Mechanistic Insights Based on Mass Spectrometric Back-Reaction Screening.

An efficient protocol for the evaluation of catalysts for the asymmetric Morita-Baylis-Hillman (MBH) reaction was developed. By mass spectrometric back-reaction screening of quasi-enantiomeric MBH products, an efficient bifunctional phosphine catalyst was identified that outperforms literature-known catalysts in the MBH reaction of methyl acrylate with aldehydes. The close match between the selectivities measured for the forward and back reaction and kinetic measurements provided strong evidence that the aldol step and not the subsequent proton transfer is rate- and enantioselectivity-determining.

Asymmetric Morita–Baylis–Hillman reaction catalyzed by pepsin

Pepsin from porcine gastric mucous shown catalytic promiscuity was first discovered to catalyze the Morita–Baylis–Hillman (MBH) reaction between aromatic aldehydes with 2-cyclohexen-1-one or 2-cyclopenten-1-one in a two-phase medium of phosphate buffer/cyclohexane in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO). The best results of the corresponding MBH products up to 77% yield and 38% ee were achieved.

Bifunctional (Thio)urea–Phosphine Organocatalysts Derived from d-Glucose and α-Amino Acids and Their Application to the Enantio­selective Morita–Baylis–Hillman Reaction

Novel (thio)urea–tertiary phosphines were developed for use as bifunctional organocatalysts readily available from naturally occurring molecules: saccharides and amino acids. The efficiency of the organocatalysts was demonstrated in the asymmetric Morita–Baylis–Hillman (MBH) reaction of aromatic aldehydes with acrylates. The MBH products were obtained in good yields (up to 85%) and with high enantioselectivities (up to 87% ee).

ChemInform Abstract: Phosphine‐Catalyzed Reactions of Activated Olefins Tethered to Cycloalkanones. Substrate‐ and Solvent‐Controlled Synthesis of Bicyclo[3.2.1]octanones, Mixed Acetals, and Morita—Baylis—Hillman Products.

The n-Bu3P organocatalyzed reaction of cycloalkanones, i.e., cyclopentanones or 1,3-cyclopentanediones tethered to actived olefins, afforded selectively and in high yields three different types of products: bicyclo[3.2.1]octanones, mixed acetals, and Morita–Baylis–Hillman products. The progress of the reaction was closely related to the reaction medium and to the length of the tether located between the cyclopentanone (-dione) and the activated olefin.

ChemInform Abstract: Organocatalytic Asymmetric Allylic Alkylation of Morita—Baylis—Hillman Carbonates with Phosphorus Ylides: Synthesis of Chiral 3‐Substituted 2,4‐Functionalized 1,4‐Pentadienes.

AbstractIn the presence of a cinchona alkaloid derived tertiary amine catalyst phosphorous ylides (I) undergo efficient asymmetric allylic substitution of O‐Boc protected Morita—Baylis—Hillman products (II) to yield the chiral pentadiene (IV) after reaction of the allylic adducts with formaldehyde.

Base-catalyzed reaction between isatins and N-Boc-3-pyrrolin-2-one

The base-catalyzed reaction between isatins and N-Boc-3-pyrrolin-2-one yields Morita–Baylis–Hillman (MBH) adducts instead of the expected aldol products in good to high yields (up to 97%). Various organic and inorganic bases are efficient catalysts for this reaction. Our study excluded the Morita–Baylis–Hillman mechanism for the formation of the MBH-type products. The MBH products are most likely formed as a result of the subsequent isomerization of the original aldol products between isatins and N-Boc-3-pyrrolin-2-one.

Phosphine-Catalyzed Reactions of Activated Olefins Tethered to Cycloalkanones. Substrate- and Solvent-Controlled Synthesis of Bicyclo[3.2.1]octanones, Mixed Acetals, and Morita–Baylis–Hillman Products

The n-Bu3P organocatalyzed reaction of cycloalkanones, i.e., cyclopentanones or 1,3-cyclopentanediones tethered to actived olefins, afforded selectively and in high yields three different types of products: bicyclo[3.2.1]octanones, mixed acetals, and Morita-Baylis-Hillman products. The progress of the reaction was closely related to the reaction medium and to the length of the tether located between the cyclopentanone (-dione) and the activated olefin.

ChemInform Abstract: Asymmetric Allylic Monofluoromethylation and Methylation of Morita—Baylis—Hillman Carbonates with FBSM and BSM by Cooperative Cinchona Alkaloid/FeCl2 Catalysis.

AbstractAsymmetric allylic monofluoromethylation of Morita—Baylis—Hillman products with FBSM (II) proceeds with high yields and enantioselectivities in the presence of (DHQD)2AQN organocatalyst.

A Cooperative Catalysis Approach to the Morita-Baylis-Hillman Reaction of Aryl Vinyl Ketones

The Morita-Baylis-Hillman (MBH) reaction of aryl vinyl ketones has been achieved for the first time through cooperative catalysis of proline and brucine N-oxide. A unique mode of activation of the aldehydes through proline iminium intermediates has been identified as a key reaction parameter for the successful MBH reaction of aryl vinyl ketones. The reaction pathways leading to 1:2 MBH products under typical nucleophilic catalysis conditions were investigated. A systematic study revealed two different reaction pathways leading to 1:2 MBH products: (1) the second reaction of normal MBH products with aryl vinyl ketones as a dominating reaction pathway at the initial stage of the reaction, and (2) the aldol reaction pathway of Rauhut-Currier products with aldehydes (auto-catalysis by alcohol products) as a major reaction pathway during the later stage of reaction.

Brucine N-oxide-catalyzed Morita–Baylis–Hillman reaction of vinyl ketones: a mechanistic implication of dual catalyst system with proline

The brucine N-oxide promoted Morita-Baylis-Hillman (MBH) reaction of vinyl ketones with aldehydes has been achieved. The corresponding asymmetric version of MBH reaction was also investigated, and the electron-deficient aryl aldehydes have emerged as suitable reaction partners for vinyl ketones; where proline was employed as a co-catalyst. In this dual catalyst system, proline is believed to form iminium intermediates with electron-deficient aryl aldehydes, while the N-oxide activates vinyl ketones to provide enolates through conjugate addition. Upon the combination of these two intermediates, the MBH products with high enantioselectivities are obtained by controlling of the rate-determining step through H-bridged chair-like transition state. Intrinsically, the resulting MBH products, alcohols, are found to interfere with the formation of both intermediates, enolates and proline iminium intermediates, thus the observed enantioselectivity of products attenuates upon further reaction conversion, possibly due to autocatalysis. This current study sheds lights on the synthetic utility of iminium species, derived from electron-deficient aryl aldehydes and proline.

Dual Catalyst Control in the Enantioselective Intramolecular Morita—Baylis—Hillman Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Dual Catalyst Control in the Enantioselective Intramolecular Morita−Baylis−Hillman Reaction

The intramolecular Morita-Baylis-Hillman (MBH) reaction has been achieved with unprecedented levels of enantioselectivity. Using a co-catalyst system involving pipecolinic acid and N-methylimidazole, cyclic MBH products have been obtained with enantiomer ratios of 92:8 (84% ee). In addition, reactions may be carried out with a "kinetic resolution quench" involving acetic anhydride and an asymmetric acylation catalyst such that ee enhancement occurs to deliver products with >98% ee with an isolated yield of 50%. [reaction: see text]

Alkaloids‐Catalyzed Regio‐ and Enantioselective Allylic Nucleophilic Substitution of tert‐Butyl Carbonate of the Morita—Baylis—Hillman Products.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantiospecific photochemical carbon skeletal rearrangement of Morita–Baylis–Hillman products in water

Asymmetric carbon skeletal rearrangements of Morita–Baylis–Hillman products, α-hydroxymethylenones, under photochemical irradiation in water are described, wherein the asymmetric induction mechanism is discussed in detail.

Alkaloids-catalyzed regio- and enantioselective allylic nucleophilic substitution of tert-butyl carbonate of the Morita–Baylis–Hillman products

The alkaloids-catalyzed regio- and enantioselective allylic nucleophilic substitution reactions of tert-butyl carbonate of the Morita–Baylis–Hillman products with pronucleophiles are reported. A number of pronucleophiles, such as nitrogen, oxygen, and active carbon pronucleophiles have been used in this facile reaction. In general, the reaction proceeded efficiently to give the substitution product in good yields with high regioselectivity and medium enantioselectivity.