Morita-Baylis-Hillman reaction asymmetric

Other successful H-bond catalysis apphcations have been introduced by Schaus and Sasai involving asymmetric Morita-Bayhs-Hilhnan (Scheme 11.13c) and aza-Morita-Baylis-Hillman reactions (Scheme 11.13d), respectively. Intriguingly, derivatized BINOL systems 33 and 34 provided optimal selectivities. 

The promoters of the so-called chalcogenide Morita-Baylis-Hillman reaction are Kataoka and co-workers who employed sulfide and TiCl for dual Lewis acid-base activation. Later, in 1996 the ability of the combination of sulfide/TBDMSOTf to promote the reaction was reported [110], Asymmetric version of the Baylis-Hillman reaction has been achieved by using chiral sulfide in place of SMe. The best ee was 94% in combination with a high yield of 88% in 5 h (Scheme 39) [ 111 ]. 

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

Asymmetric aza Morita-Baylis-Hillman reactions of N-sulfonylimines or N-sulfinimines with Michael accepters in the presence a Lewis base catalyst to give the corresponding chiral a-methylene-/ -amino compounds have been described [27]. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

According to another NMR study, the mechanism of bifunctional activation in the asymmetric aza-Morita-Baylis-Hillman reaction (Scheme 7) involves rate-limiting proton transfer (116) in the absence of added protic species155 (in consonance with the report summarized in Scheme 5144), but exhibits no autocatalysis. Addition of Brpnsted acids led to substantial rate enhancements through acceleration of the elimination step. Furthermore, it was found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the reaction product by proton exchange at the stereogenic centre. This behaviour indicates that the spatial arrangement of a bifunctional chiral catalyst for the asymmetric aza-Morita-Baylis-Hillman reaction is crucial not only for the stereodifferentiation within the catalytic cycle but also for the prevention of subsequent racemization.155... 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

Asymmetric organocatalytic Morita-Baylis-Hillman reactions offer synthetically viable alternatives to metal-complex-mediated reactions. The reaction is best mediated with a combination of nucleophilic tertiary amine/phosphine catalysts, and mild Bronsted acid co-catalysts usually, bifunctional chiral catalysts having both nucleophilic Lewis base and Bronsted acid site were seen to be the most efficient. Although many important factors governing the reactions were identified, our present understanding of the basic factors, and the control of reactivity and selectivity remains incomplete. Whilst substrate dependency is still considered to be an important issue, an increasing number of transformations are reaching the standards of current asymmetric reactions. 

Chiral Amines Derived from Asymmetric Aza Morita Baylis Hillman Reaction... 

Some of the catalyst systems used in the asymmetric aldol reaction are also effective in related reactions. Thus, bifunctional catalysts and L-prohne-based organocatalysts have been used to good effect in the nitroaldol reaction and Mannich reaction. The latter process is also effectively catalysed by enantiomeri-cally pure Bronsted acids. Furthermore, much recent progress has been made in the development of a catalytic asymmetric Morita-Baylis-Hillman reaction using Lewis/Bronsted acid catalysts and bifunctional catalysts. 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

There have been only a few reports on asymmetric versions of the intramolecular MBH reaction Scheme 1.105 shows one representative example. The intramolecular Morita Baylis Hillman reaction has been achieved with unprecedented levels of enantioselectivity by using a co-catalyst system involving pipecolinic acid and iV-methylimidazole cyclic MBH products 289 were... 

Scheme 19.22 Proposed mechanism for the asymmetric Morita-Baylis-Hillman reaction.

In 2006, Berkessel and coworkers reported a new and improved iso-phoronediamine-derived bisthiourea organocatalyst for the asymmetric Morita-Baylis-Hillman reaction. Employing 20 mol% of catalyst 67 and N,iV,iV, iV -tetramethylisophoronediamine (TMIPDA) as base under neat reaction conditions, the adduct of 2-cyclohexen-l-one with cyclohex-anecarbaldehyde was obtained in 75% yield and 96% enantiomeric excess... 

Miller reported asymmetric aza-Morita-Baylis-Hillman reactions employing allenoate 22 as an a,p-unsaturated carbonyl component in the... 

Scheme 22.3 Asymmetric aza-Morita-Baylis-Hillman reaction catalysed by Sasai s bifunctional chiral pyridine catalyst.

Scheme 22.4 Asymmetric aza-Morita-Baylis-Hillman reaction between imine and allenoate catalysed by Miller s peptide-based pyridine catalyst.

Peptide-based imidazole catalyst 63 in the presence of L-proline as a cocatalyst promoted asymmetric Morita-Baylis-Hillman reactions between methyl vinyl ketone and aromatic aldehydes (Scheme 22.14). The combination... 

Scheme 22.14 Asymmetric Morita-Baylis-Hillman reaction catalysed by a cocatalyst system consisting of peptide catalyst 63 and t-proline.

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