Enones enantioselective Michael addition

Tan also found that guanidine 21, acting as a base to activate the o [3], X [3] tautomers of diaryl phosphine oxides, catalyzes the asymmetric phospha-Michael reachon of aryl nitroalkenes (Scheme 5.42) [76]. He later employed 21 to realize highly enantioselective Michael additions of dithiomalonate and 3-keto thioesters with a range of acceptors, including maleimides, cyclic enones, furanone, and acyclic 1,4-dicarbonylbutenes [77]. 

The copper-catalyzed enantioselective Michael addition of organometallic reagents to enones was the first successful application of phosphoramidite chiral ligands in catalysis [4, 43]. Since this early report, substantial enhancement of the enantioselectivity and/or of the substrate scope has been achieved through an untiring effort to optimize the ligand structure [5a, 44]. 

Enantioselective Michael additions of aldehydes to enones using imidazolidinones as organocatalysts show evidence of enamine intermediates.217 Several co-catalysts -mainly phenols - raise the yield and/or ee. 

Diphenylprolinol methyl ether catalyses the enantioselective Michael addition of simple aldehydes to simple enones.219... 

Enantioselective Michael additions.1 The addition of tin(II) enolates to enones can proceed enantioselectively when activated by trimethylsilyl triflate and in the presence of a chiral diamine such as 1. 

Alexakis et al,231 reported copper-catalyzed enantioselective Michael additions in the presence of various 2-arylcyclohexyl-substituted phosphites. Ligand 279 turned out to be particularly efficient for the 1,4-addition of organozinc reagents to cyclopentadec-2-enone. Whereas Et2Zn gave the addition product with 87% ee, the corresponding reaction of dimethylzinc furnished (R)-(—)-muscone with an enantiomeric excess of 79% ee (Scheme 74). 

As these examples show, cyclic enones are normally used as substrates for copper-catalyzed enantioselective Michael additions. In some cases, however, good stereoselectivities were also attained with acyclic enones of type 11. Thus, van Klaveren, van Koten et al. [9] employed the copper arenethiolate 13 as catalyst for the 1,4-addition of methylmagnesium iodide to benzylideneacetone and obtained adduct 12 (R = = Me) with 76 % ee. Interestingly, this... 

Enantioselective Michael addition of thiols to enones is a useful reaction for the synthesis of sex pheromones [26] and terpenes [27]. For example, enantioselective Michael additions of thiols to 2-cyclohexenone (64) and maleic acid esters in the presence of chiral bases such as cinchona alkaloids [28, 29] and optically active amino alcohols [30, 31] have been reported. It has also been found that the enantioselective Michael addition reaction proceeds efficiently in an inclusion crystal... 

Figure 11.4 Enantioselective Michael addition of malonates to cyclic enones.

The Pd diaquo complex of BINAP 19 efficiently catalyzed the diastereoselective and enantioselective Michael addition of the y3-keto ester 20 to 3-penten-2-one (21), and the Michael adduct 22 was obtained in 89 % yield (diastereomeric ratio = 8/1) and the ee of the major isomer was 99%. Thus, congested vicinal tertiary and quaternary carbon centers were constructed. It is interesting to know that the Pd aquo complex 19 allows the successive supply of a Bronsted base and a Bronsted acid. The former activates the carbonyl compound to give the chiral palladium enolate and the latter cooperatively activates e enone [4]. 

Scheme 3.20 Enantioselective Michael addition of nitroalkanes to cyclic enones catalyzed by chiral secondary amines.

Scheme 4.31 Enantioselective Michael addition of malononitrile and cyanosulfones to enones.

Scheme 4.33 Chiral guanidine-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to enones.

Scheme 4.36 Enantioselective Michael addition of alkenylboronic acids and alke-nylboronates to enones.

Similarly, Yoshida developed an enantioselective Michael addition of malonates to enones by using a primary p-amino acid, O-tert-butyldiphe-nylsilyl (TBDPS) (S)-p-homoserine, lithium salt 15 (Scheme 2.10). ... 

Subsequently, the highly enantioselective Michael addition of malonates and 1,2,4-triazole to cyclic and acyclic enones, as well as the first phospha-Michael reaction of cyclic enones and diaryl phosphine oxides was reported using a similar catalyst.In 2012, Huang, Wang and coworkers demonstrated that primary amine-thiourea 39 can efficiently catalyse the... 

Ley et al. have demonstrated that the pyrrolidinyl tetrazole catalyst, depicted in Scheme 1.13, could be used to efficiently induce the enantioselective Michael addition of malonates to oi,p-unsaturated enones. Cyclic, acyclic and aromatic enones could be involved in this process, and the reaction with the most efficient ethyl malonate provided, in the presence of piperidine as an additive, the corresponding Michael products in high yields with good to excellent enantioselectivities, as shown in Scheme 1.13. 

Recently, the mechanism of enantioselective Michael addition of malonic esters and keto esters to cyclic conjugated enones catalyzed by Ru bifunctional complexes 1 was studied in detail. ... 

In 2006, catalytic enantioselective Michael addition of ketene silyl acetals to cyclic and acyclic a, P-enones was devised using the chiral BLA (3a) (Scheme 1.6) [8]. Various Michael donors and ketene silyl acetals can be employed for this process. Here again, the use of triphenylphosphine oxide is crucial to trap any catalytically active silyl cation species. In addition, the combined use of triphenylphosphine oxide and a stoichiometric amount of 2,6-diisopropylphenol (which acts as a scavenger of silyl cation species) is sometimes required to get both high enantioselectivity and the chemical yield. This enantioselective methodology was applied to the asymmetric synthesis of a key intermediate of caryophyllene. 

Enantioselective Michael addition catalyzed by chiral aluminum Lewis acid is one of the most important methods to obtain enantiomerically pure compounds. As an early work in this fleld, in 1986, Shibasaki and coworkers reported catalytic enantioselective Michael addition of malonates to cyclic enones catalyzed by Li-Al bimetallic catalyst (72) (ALB) derived by premixing LiAlH4 and 2 equivalent of (R)-BINOL in THF (Scheme 6.86) [106, 107]. The structure of (R)-ALB was confirmed by X-ray crystallographic analysis of ALB-cyclohexenone complex. One notable advantage of ALB catalyst is that it works nicely in the tandem Michael-aldol sequence. 

Enantioselective Michael addition of malonates to a,p-unsaturated carbonyls with Al(salen) complex was firstly reported by Jha and Joshi in 2001. They reported the formation of Al-Na bimetallic Al(salen) complex (73b) from (R,R)-salen and NaAlH2(OCH2CH20Me), and catalytic activity for catalytic enantioselective Michael addition of malonic diesters to cyclic a,P-enones (Scheme 6.93) [111]. In the reaction of cyclopentenone with various malonates, this catalyst resulted in good chemical yield and moderate enantioselectivity. 

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