Michael cyclic enones with malonates

Scheme 2.13 Enantioselective Michael reaction of cyclic enones with malonates with the use of chiral heterohimetallic aluminium(in) lithium(i) bis(hinaphtholate).

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

The Michael addition of malonates to cyclic enones, catalyzed by chiral Ru( 6-arcnc)(p-lolucncsulfonyl-1,2-diaminc), has been performed to afford the adduct with excellent enantiomeric excess [91,92]. A related catalyst was designed to perform sequentially the Michael addition to cyclic enone and the enantioselective hydrogenation of the ketone. Thus, the chiral ruthenium catalyst B containing trans hydride and borohydride ligands was able to enan-tioselectively (96% ee) promote the Michael addition of malonate to cyclo-hexenone. Further in situ catalytic hydrogenation (400 psi H2) was performed and led to excellent diastereoselectivity trans/cis 30/1 [93] (Scheme 43). 

The formation of carbon-carbon bonds by conjugate addition of carbonucleophiles to a,/3-unsaturated systems has been studied intensively and reviewed over the past few years . Interestingly, applications with simple, unstabilized lithium enolates are relatively rare. Most reported examples are limited to the addition of stabilized enolates, such as those derived from malonates or acetoacetates. Nevertheless, some diastereo- and enantioselective versions of the conjugate addition, even with unstabilized lithium enolates, are well known. In 2004, Tomioka and coworkers studied the influence of a chiral diether (191) on the 1,4-addition of lithium ester enolates (189) to a,-unsaturated ketones (equation 51) . Their investigations showed that good enantioselectivities were obtained with cyclic enones, like 2-cyclopentenone (190) addition to a mixture of 189 and 191 gave the desired 1,4-adduct (R)-192 with 74% ee, but only 47% yield. Unfortunately, also the Peterson product 193 was formed in a yield of 22% by initial 1,2-addition of the enolate to the Michael acceptor. 

The first chiral aluminum catalyst for effecting asymmetric Michael addition reactions was reported by Shibasaki and coworkers in 1986 [82], The catalyst was prepared by addition of two equivalents of (i )-BINOL to lithium aluminum hydride which gave the heterobimetallic complex 394. The structure of 394 was supported by X-ray structure analysis of its complex with cyclohexenone in which it was found that the carbonyl oxygen of the enone is coordinated to the lithium. This catalyst was found to result in excellent induction in the Michael addition of malonic esters to cyclic enones, as indicated in Sch. 51. It had previously been reported that a heterobimetallic catalyst prepared from (i )-BINOL and sodium and lanthanum was also effective in similar Michael additions [83-85]. Although the LaNaBINOL catalyst was faster, the LiAlBINOL catalyst 394 (ALB) led to higher asymmetric induction. 

The higher activity of primary amines in the reaction involving enones as Michael acceptors has also been extended to the use of different bifunctional catalysts (Scheme 3.19), which usually contain a primary amine functionality connected to a basic site by means of a chiral scaffold, as is the case in the use of 280 and 55. These diamine catalysts have been found to be excellent promoters of the Michael reaction of enones with cyclic 1,3-dicarbonyl compounds and malonates respectively, the tertiary amine basic site present at the catalyst structure being responsible for assisting in the deprotonation of the Michael donor in order to increase the concentration of the nucleophile species. In a different approach, bifunctional thiourea-primary amine catalyst 56a has also... 

Furthermore, three-component coupling tandem Michael-aldol reactions were achieved by trapping the aluminium enolate intermediate with an aldehyde (Scheme 19.16a). Initiated by the asymmetric Michael addition of malonic esters to cyclic enones, several natural products were synthesised... 

The mechanism as shown in Scheme 9.4 indicates that La-BINOL firstly reacts with malonate to give intermediate 1. Subsequently, the intermediate I further reacts with cyclic enone to afford the lanthanum enolate II in an enan-tioselective manner. The chiral Michael adduct is formed by the reaction of enolate II with malonate. 

By comparing with the alkali metal free La-BINOL catalyst, the (/ )-LSB-catalyzed Michael reactions of malonate to cyclic enone proceeded smoothly with high enantioselectivities even at room temperature. The reaction between 2-cyclohexen-l-one and dibenzyl methylmalonate completed in 12 hours at room temperature to afford adduct in 96% yield and 90% ee. When dimethyl malonate was used, 98% yield with 83% ee of the product was obtained. Switching the dimethyl analog diethyl malonate also furnished similar product yield and enantioselectivity (97% yield and 81% ee). 

In addition to the simple malonates, the La-O-linked-BINOL complex was also found to be effective for handling asymmetric Michael addition of various a-substituted malonates to cyclic enone. Under this catalyst system, the Michael adducts could be obtained in 55-86% yields with... 

With the multifunctional primary amine-thiourea catalyst (which was prepared from (l/ ,2/ )-l, 2-diaminocyclo-hexane and 9-amino (9-deoxy) epiquinine) in the absence of additives, the asymmetric Michael addition of malonate to cyclic enone proceeded well to afford 1,4-adducts in excellent yields and enantioselectivities (Table 9.10). Particularly noteworthy is that all examined malonates afforded higher than 95% enantioselectivities. In general, the reaction could even complete within a short period of time (12-18 hours) to give >90% yields and high enantioselectivity (93-96% ee) when the reactions were carried out at an elevated reaction temperature. Moreover, the reaction of 2-cyclohepten-l-one also afforded more than 90% ee and 83% yield. Furthermore, the use of 4,4-dimethylcyclohex-2-enone resulted in 77% yield with 91% ee. Only 2-cyclo-penten-l-one furnished medium yield and enantioselectivity. In contrast to previous reports, this reaction system exhibits excellent catalytic activity in asymmetric Michael addition with a broad scope of both malonate and cyclic enone. 

Zhao and co workers [54] developed simply primary-secondary diamine catalysts derived from primary amino acids. This type of catalysts such as 105 was found to catalyze the asymmetric Michael addition of malonates to acyclic a,p-unsaturated ketones with good activity and excellent enantioselectivity (Scheme 5.27). Liang and coworkers designed a new primary amine catalyst combining two privileged skeletons, cinchona and cylohexanediamine [55], The obtained optimal catalysts 107 and 110 were applicable to the Michael additions reactions of malonate or nitroalkanes to a,p-unsaturated ketones. The reactions worked well with both cyclic and acyclic enones (Scheme 5.28). 

Cyclic ketones or acetone react with nitro-olefins, giving the corresponding -adducts hy action of the potassium salt of chiral p-chlorophenyl amino acid catalyst (18 examples, 40-99% anti syn 42 58-4 96 ee 61-95%). Malonates,2-nitroalkanes or p-ketoesters are useful Michael donors and can react with enones in the presence of lithium salts of primary amino acids to create a new carhon-carhon hond at the p-position of the ketone (Scheme 12.9). However in some cases p-amino acids were more efficient than the a-amino acids. ... 

NAP-MgO acts as a bifunctional heterogeneous catalyst for the Claisen-Schmidt condensation (CSC) of benzaldehydes with acetophenones to yield chalcones, followed by asymmetric epoxidation (AE) to afford chiral epoxy ketones in moderate to good yields and impressive enantioselectivities (ee s). NAP-MgO, in combination with the chiral auxiliary (11 ,21 )-(- -)-1,2-diphenyl-1,2-ethylenediamine (DPED), catalyzed the asymmetric Michael addition of malonates to cyclic and acyclic enones. 

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. 

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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