Transformations of Modified Morita‐Baylis‐Hillman Adducts from Isatins Catalyzed by Lewis Bases

The development of synthetic protocols to access architectures with broad structural and functional diversity from readily available starting materials is very attractive in both organic and medicinal chemistry fields. Toward this objective, the multifunctional isatin‐derived Morita‐Baylis‐Hillman (MBH) adducts provide opportunities to construct a variety of complex scaffolds containing a “privileged” oxindole motif through several catalytic pathways. By forming the ammonium or phosphonium salts with Lewis bases, isatin‐derived MBH adducts can undergo allylic substitutions with a range of nucleophiles, usually in a S_N2′‐S_N2′ pattern. Besides, assisted by Brønsted bases, the corresponding onium salts can be converted into the allylic ylide intermediates, which can undergo various annulation reactions or even 1,3‐difunctionalizations. Moreover, recent cooperative catalysis of Lewis bases and transition metal complexes further puts forward the application of isatin‐derived MBH adducts. This tutorial review covers the significant transformations of isatin‐derived MBH adducts, mostly in an asymmetric version, catalyzed by various Lewis bases over the past decade.     

Lewis base catalyzed enantioselective allylic hydroxylation of Morita-Baylis-Hillman carbonates with water

A Lewis base catalyzed allylic hydroxylation of Morita-Baylis-Hillman (MBH) carbonates has been developed. Various chiral MBH alcohols can be synthesized in high yields (up to 99%) and excellent enantioselectivities (up to 94% ee). This is the first report using water as a nucleophile in asymmetric organocatalysis. The nucleophilic role of water has been verified using (18)O-labeling experiments.     

Synthesis of Chiral Phosphorus Reagents and Their Application in Combination With Lewis Acid as a Cocatalyst in Morita–Baylis–Hillman Reaction

Abstract

Two novel chiral thiophosphoramides and two chiral phosphoramidites were synthesized starting from (S)-α-phenylethylamine and (R)-(+) or (S)-(?)-1,1′-Bi-2-naphthol (BINOL), respectively, and their application in combination with Lewis acid as cocatalysts in asymmetric Morita–Baylis–Hillman (MBH) reaction was investigated. Dramatic rate acceleration (the corresponding adducts were obtained in fair to excellent chemical yield within 15 min–5 h) was observed in these chiral phosphorus reagents/Lewis acid cocatalyzed MBH reaction between 4-nitrobenzaldehyde and activated alkenes, and in one case, moderate enantioselectivity was achieved (the corresponding adduct's ee value is 44%).     

Lewis base assisted Brønsted base catalysis: direct regioselective asymmetric vinylogous alkylation of allylic sulfones

A Lewis base assisted Brønsted base catalysis (LBABB) strategy is applied for direct asymmetric vinylogous alkylation of allylic sulfones with Morita–Baylis–Hillman (MBH) carbonates, in which a strong Brønsted base, tert‐butoxy anion, generated in situ from a tertiary amine catalyst and MBH carbonate, is crucial in activating unstabilized nucleophiles. The γ‐regioselective alkylation products were obtained with good to excellent enantiomeric excess values when catalyzed by a modified cinchona alkaloid.     

Chiral biscinchona alkaloid promoted asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones with Morita-Baylis-Hillman carbonates

A highly diastereo- and enantioselective asymmetric allylic alkylation reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and MBH carbonate by a chiral biscinchona alkaloid catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 97%) with very good diastereo- (up to 98:2 dr) and enantioselectivities (up to 95% ee).     

Chiral phosphine-catalyzed regio- and enantioselective allylic amination of Morita–Baylis–Hillman acetates

Enantioselective allylic substitution of Morita–Baylis–Hillman (MBH) acetates with phthalimide was realized in the presence of a novel l-proline-derived chiral trifunctional phosphine amide ligand to give the corresponding allylic amination adducts in good yields (70–95%) and in modest to good enantioselectivities (34–78% ee’s).     

Multifunctional chiral phosphines-catalyzed highly diastereoselective and enantioselective substitution of Morita-Baylis-Hillman adducts with oxazolones

Multifunctional chiral phosphine (phosphine-thiourea type) L2-catalyzed allylic substitutions of MBH adducts 1 with oxazolones 2 produce the corresponding optically active adducts 3 in good to excellent yields and ee's as well as moderate to good de's under mild conditions. The synergistic interaction between hydrogen bond donor site and nucleophilic site has been discussed, indicating that finely tuning the active sites of the multifunctional phosphine organocatalysts is very important.     

Organocatalytic (1+4)-Annulations of MBH Adducts with Electron-Deficient Systems

Benefited from the rapid development of MBH reaction, the reaction of MBH adducts have been established as the most synthetically useful transformations. However, compared with the well-established allylic alkylations and (3+2)-annulations, the (1+4)-annulations of MBH adducts have not developed rapidly until recently. As a helpful complement to the (3+2)-annulations of MBH adducts, the (1+4)-annulations of MBH adducts opens a robust access to structurally diverse five-membered carbo- and heterocycles. This paper summarizes recent advances in organocatalytic (1+4)-annulations using MBH adducts as 1 C-synthons for the construction of functionalized five-membered carbo- and heterocycles.     

Chiral phosphine-catalyzed asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones or oxindoles with Morita-Baylis-Hillman carbonates

An efficient chiral phosphine-catalyzed asymmetric substitution reaction of MBH carbonates with 3-substituted benzofuran-2(3H)-ones or 3-substituted oxindoles has been described in this context, giving the corresponding allylic alkylation products bearing adjacent quaternary and tertiary stereogenic centers in high yields, moderate diastereoselectivities and high enantioselectivities under mild conditions.     

Highly enantioselective and regioselective substitution of Morita-Baylis-Hillman carbonates with nitroalkanes

A highly enantioselective and regioselective substitution reaction of the Morita-Baylis-Hillman (MBH) carbonates with nitroalkanes catalyzed by a quinidine-derived tertiary amine-thiourea catalyst has been developed. The described method, which is different from most organocatalytic allylic substitutions of the MBH adducts to date, represents a novel approach to regioselectively functionalize the MBH adducts.     

靛红Morita-Baylis-Hillman碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应研究

本课题组近年来发展的通过路易斯碱催化靛红Morita-Baylis-Hillman(MBH)碳酸酯的烯丙基烷基化反应是合成光学纯3,3-二取代2-氧化吲哚化合物的一种有效方法. 在此基础上, 本文研究了手性叔胺催化靛红MBH碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应, 通过亲电反应途径以较高的立体选择性(达86% ee, dr＞95∶5)和高收率(达96%)合成C-3位含季碳手性中心的多官能团氧化吲哚产物. 通过简单的转化可以得到含多个手性中心的2-吲哚酮-3,4'-哌啶环类骨架, 这为进一步合成生理活性物质研究奠定了基础.     

Rhodium-Catalyzed Asymmetric Synthesis of 1,2-Disubstituted Allylic Fluorides

Although there are many methods for the asymmetric synthesis of monosubstituted allylic fluorides, construction of enantioenriched 1,2-disubstituted allylic fluorides has not been reported. To address this gap, we report an enantioselective synthesis of 1,2-disubstituted allylic fluorides using chiral diene-ligated rhodium catalyst, Et₃N ⋅ 3HF as a source of fluoride, and Morita Baylis Hillman (MBH) trichloroacetimidates. Kinetic studies show that one enantiomer of racemic MBH substrate reacts faster than the other. Computational studies reveal that both syn and anti π-allyl complexes are formed upon ionization of allylic substrate, and the syn complexes are slightly energetically favorable. This is in contrast to our previous observation for formation of monosubstituted π-allyl intermediates, in which the syn π-allyl conformation is strongly preferred. In addition, the presence of an electron-withdrawing group at C2 position of racemic MBH substrate renders 1,2-disubstituted π-allyl intermediate formation endergonic and reversible. To compare, formation of monosubstituted π-allyl intermediates was exergonic and irreversible. DFT calculations and kinetic studies support a dynamic kinetic asymmetric transformation process wherein the rate of isomerization of the 1,2-disubstituted π-allylrhodium complexes is faster than that of fluoride addition onto the more reactive intermediate. The 1,2-disubstituted allylic fluorides were obtained in good yields, enantioselectivity, and branched selectivity.     

A highly efficient kinetic resolution of Morita-Baylis-Hillman adducts achieved by N-Ar axially chiral Pd-complexes catalyzed asymmetric allylation

Palladium complexes with an axially chiral N-Ar framework have been developed. These complexes showed high stereoselectivities in asymmetric allylic arylation to achieve the kinetic resolution of Morita-Baylis-Hillman adducts, affording up to 99% ee of (E)-allylation products and 92% ee of recovered Morita-Baylis-Hillman adducts.     

Asymmetric [2,3]-sigmatropic rearrangement of allylic ammonium ylides

An asymmetric Lewis acid-mediated [2,3]-sigmatropic rearrangement of allylic amines has been developed, affording the corresponding homoallylic amines in good yield and excellent enantioselectivities. The rearrangement proceeds by complexation of the chiral Lewis acid to the amine followed by deprotonation and rearrangement.     

Highly diastereo- and enantioselective construction of phthalide-oxindole hybrids bearing vicinal quaternary chiral centers via an organocatalytic allylic alkylation

A diastereo- and enantioselective synthesis of phthalide-oxindole hybrids including congested adjacent quaternary chiral centers was demonstrated through a Lewis base catalyzed asymmetric allylic alkylation reaction of Morita–Baylis–Hillman carbonates of isatins and 3-cyanophthalides. The various hybrid molecules with two valuable pharmacophores-combined frameworks can be obtained in good to high diastereo- and enantioselectivities.     

Thiourea-catalyzed Morita-Baylis-Hillman reaction

Here, we describe our studies on the thiourea-catalyzed Morita-Baylis-Hillman (MBH) reaction. Chemoselective activation of carbonyl compounds via hydrogen bonding to thiourea as a catalyst is the key to drastic rate acceleration of this reaction. The application of chiral bis-thiourea-type organocatalysts, which can form a chiral double hydrogen-bonding network, is effective for enantioselective MBH reaction. A cooperative system of bis-thiourea compounds, synthesized from 1,2-diaminocyclohexane, and a Lewis base effectively promotes the MBH reaction at lower temperature, affording the MBH adducts in 33-95% yield with 44-90% ee. A plausible transition state model of the enantioselective MBH reaction is presented.     

Intermolecular Morita-Baylis-Hillman reactions using dicobalthexacarbonyl complexed acetylenic acetals

An intermolecular Morita-Baylis-Hillman (MBH) reaction using dicobalthexacarbonyl complexed acetylenic acetals as the electrophile is reported. Employing BF₃-OEt₂ as the Lewis acid with a sulfide as the Lewis base MBH adducts were obtained.     

Direct asymmetric allylic alkenylation of N-itaconimides with morita-baylis-hillman carbonates

The asymmetric allylic alkenylation of Morita-Baylis-Hillman (MBH) carbonates with N-itaconimides as nucleophiles has been developed using a commercially available Cinchona alkaloid catalyst. A variety of multifunctional chiral α-methylene-β-maleimide esters were attained in moderate to excellent yields (up to 99%) and good to excellent enantioselectivities (up to 91% ee). The origin of the regio- and stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed regio- and enantioselectivity.     

Phosphine-catalyzed regiospecific allylic amination and dynamic kinetic resolution of Morita-Baylis-Hillman acetates

Exposure of Morita-Baylis-Hillman (MBH) acetates to tertiary phosphine catalysts in the presence of 4,5-dichlorophthalimide enables regiospecific allylic substitution through a tandem S(N)2'-S(N)2' mechanism. Through the use of the chiral phosphine catalyst (R)-Cl-MeO-BIPHEP, chiral racemic MBH acetate 4 is converted to the corresponding allylic amination product in 80% yield and 56% enantiomeric excess, thus establishing the feasibility of dynamic kinetic resolution. [reaction: see text]     

α,β-Divinyl tetrahydropyrroles as chiral chain diene ligands in rhodium(I)-catalyzed enantioselective conjugated additions

A series of α,β-divinyl tetrahydropyrroles, synthesized by asymmetric allylic C-H bond activation/conjugated diene addition reaction of ene-2-dienes, were found to be very efficient chiral chain diene ligands in the rhodium-catalyzed conjugated addition of organoboronic acids to various α,β-unsaturated compounds, achieving the desired chiral adducts with good to excellent yields and ee values.