Enantioselective aza MBH reaction

Very few efficient catalytic enantioselective versions of MBH reaction were known up to 1999 despite a considerable amount of efforts devoted to the field. A breakthrough came in 1999 when Hatakeyama and coworkers discovered that p isocupreidine (P ICD) is an efficient catalyst for the MBH reaction [11]. Meanwhile, the use of small organic molecules as catalysts to perform asymmetric transformations has received increasing attention over the past decade. Therefore, chiral multifunctional orga nocatalysts have also been developed rapidly to promote successful enantioselective MBH/aza MBH processes. This chapter mainly summarizes recent advances in the design and synthesis of small organic molecules for the enantioselective aza MBH reactions from 2000. On the basis of these enantioselective aza MBH reactions, a variety of chiral amines can be easily prepared under mild conditions. 

Table 13.3 imines. Selected examples for the enantioselective aza MBH reaction of aromatic and aliphatic... 

On the basis of the above mechanistic assumption, the authors assumed that the p-ICD-amide-p-naphthol dual catalytic system should favor the (5)-aza-MBH product regardless of the nature of the Michael acceptors used and investigated the reaction between A -tosylimine 158 and alkyl vinyl ketone, which is known to provide the (i )-aza-MBH adduct. They developed a new p-ICD-amide (160) and found that an achiral protic additive was capable of inverting the p-ICD and p-ICD-amide (160) catalyzed enantioselective aza-MBH reaction between A -sulfonylimines and MVK/EVK, therefore providing another solution to the enantio-complementarity associated with this family of catalysts (Scheme 2.77). °... 

More recently, Liu and co-workers reported trifunctional organocatalyst-promoted counterion catalysis for aza-MBH reactions at ambient temperature. Fast and enantioselective aza-MBH reactions between electron-deficient or electron-rich aromatic iV-tosylimines and MVK were achieved at ambient temperature using asymmetric counterion-directed catalysis promoted by trifunctional organocatalysts CP45 with a Bronsted base as the activity switch after protonation with benzoic add (Scheme 2.134). 

As an efficient catalyst for enantioselective aza-MBH reaction, bifunctional phosphine catalyst CP17 has also been immobilized on a series of den-drimers. The dendrimer-immobilized catalyst CP44 was more effective than catalyst CP17 for the aza-MBH reaction of A-sulfonyl imines with MVK, EVK or acrolein. The catalyst could be separated easily from the reaction mixture by simple filtration after the reaction and reused without obvious loss of activity (Scheme 2.233). ... 

A phosphine sulfonamide derived from L-threonine promotes aza-Morita-Baylis-Hillman (aza-MBH) reactions of sulfinylimines in up to 96% yield and 97% ee. A review describes the synthesis of chiral amines under mild conditions via catalytic asymmetric aza-MBH reactions. Proline/DABCO (l,4-diazabicyclo[2.2.2]octane) co-catalysis of enantioselective aza-MBH reactions gives good to high yields and up to 99%... 

Sasai and coworkers reported that a chiral BINOL derived amine 16a catalyzed asymmetric aza MBH reaction of N tosyl imines with acrolein and alkyl vinyl ketones [22]. The corresponding aza MBH adducts were obtained in good to excellent yields with high enantiomeric excesses (Table 13.4). Replacing the tPr group with other substituents in amine 16a provided less effective catalysts regarding yield or enantioselectivity [23]. 

Recently, Liu has developed a Bronsted acid activated trifunctional organocatalyst, based on the BINAP scaffold, that was used for the first time to catalyze aza MBH reactions between N tosylimines and MVK with fast reaction rates and good enantioselectivity at room temperature. This trifunctional catalyst containing a Lewis base, a Bronsted base and a Bronsted acid, required add activation to confer its enantioselectivity and rate improvement for both electron rich and electron deficient imine substrates. The role of the amino Lewis base of 27 was investigated and found to be the activity switch in response to an acid additive. The counterion of the acid additive was found to influence not only the excess ratio but also the sense of asymmetric induction (Scheme 13.23) [36]. 

Bifunctional organocatalysts, particularly, (S)-3-(N-isopropyl-N-3-p5nidi-nylaminomethyl) BINOL for enantioselective aza-Morita-Baylis-Hillman (aza-MBH) reactions 07Y1089. 

Contrary to the view that applying chiral solvents in synthesis cannot result in appreciable enantioselectivities, Leitner et al. have reported the first example of an asymmetric reaction in which a chiral reaction medium induces a high level of enantioselectivity. Using a specifically designed ionic liquid (312) with a chiral anion as the only source of chirality, up to 84% ee was obtained in the aza-MBH reaction of N-Ts arylaldimines with MVK (Scheme 1.124), which is comparable with values obtained with the best catalysts for the asymmetric aza-MBH reaction in conventional solvents (94% ee, 83% ee ). Possible bifunctional interaction of the zwitterionic intermediate of the aza-MBH reaction with the chiral anion of a CIL-312 containing a hydrogen-bond donor was proposed (Figure 1.6). 

Most recently, Xu et al. have demonstrated the first example of a diastereo-and enantioselective aza-MBH-type reaction by the asymmetric synthesis of p-nitro-y-enamines via a (li ,2i )-diaminocyclohexane thiourea derivative (182) mediated tandem Michael addition and aza-Henry reaction in good yields (up to 95%) with high enantioselectivities (up to 91% ee) and diastereoselectivities (up to 1 99 dr) (Scheme 2.90) easily prepared A -tosylimines and nitroalkene are employed as the starting materials. ... 

More recently, Ito et al. also reported biphenol-based bifunctional catalyst CP43 for the aza-MBH reaction of A-tosylimines with MVK (Scheme 2.133). High enantioselectivity (up to 96% ee) was achieved by CP43 with a catalyst loading of 1 mol.%. 

In screening thiourea catalysts for the asymmetric aza-MBH reaction, Jacobsen et have developed a highly enantioselective catalytic aza-MBH reaction of various A-nosyl imines with methyl acrylate. High enantioselectivities... 

The group of Rueping has developed an enantioselective synthesis of chromenones through a Michael reaction and cychzation process between diketones and unsaturated aldehydes [136]. Furthermore, this reaction can be also followed with the addition of tryptamine to afford indoloquinolizidines [137]. An aza-MBH reaction was used in the enantioselective synthesis of isoindoHnes. In this... 

For example, Sasai and coworkers reported the metal-free bifunctional Binol derivative 67 as an effective catalyst for an enantio-selective aza MBH reaction. " In the presence of 10 mol% of 67, methyl vinyl ketone and a series of tosylamines 66a-e were converted to adducts 68a-e in high yields with 88-95% ee. It has been rationalized that both the 2-hydroxy and pyridine moieties of 67 contributed to this highly enantioselective transformation. 

Miller and coworkers have performed kinetic studies on a pyridylalanine-peptide catalyzed enantioselective coupling of allenoates 16 and N-acyl imines 17 to investigate the mechanism of the aza-MBH reaction [20]. In the catalytic cycle of a typical MBH/aza-MBH reaction, the proton transfer step or C-C bond formation is often considered as the rate-determining step. However, through mechanistic... 

Shi and coworkers almost simultaneously demonstrated the similar asymmetric aza-MBH reaction of N-protected imines 78 or N-protected a-amidoalkyl phenyl sulfones 80 with MVK catalyzed by 3-ICD or catalyst 81, affording highly enanti-oselective aza-MB H products in good yields with high enantioselectivities (Scheme 31,25) [34], Besides mild reaction conditions and operational simplicity since it avoided the handing of unstable preformed imines, the reaction was found to be general with respect to various N-protected imines. Subsequently, Shi s group reported a [3-ICD-catalyzed asymmetric MBH reaction of isatin derivatives 83 with... 

Takizawa and Sasai developed a new class of acid-base chiral organocatalysts (122 and 123) bearing an imidazole unit for aza-MBH reaction of conjugated nitroalkenes (Scheme 31.32) [46]. The acidic phenolic hydroxy groups and basic imidazole unit cooperatively activate nitroalkenes to promote the aza-MBH reaction in good yields with moderate enantioselectivities. They also investigated the substrate scope of this catalytic system under the optimized reaction conditions. Regardless of whether the aromatic substituent of imine 125 is electron-... 

In 2009, Hu s group first used trifunctional chiral phosphanes to catalyze an asymmetric aza-MBH reaction between N-tosylimines and MVK with fast reaction rates and good enantioselectivity at room temperature (Scheme 31.33) [47]. This... 

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