Michael reactions, asymmetric cyclic enones

The use of the carbanion derived from the chloroallylphosphonate (163) in the enantioselective synthesis of cyclopropanes (164) by Michael addition to a,P-unsaturated ketones has been the subject of a short review (Scheme 18). Denmark s group have published full details of the asymmetric Michael addition reactions of cyclic enones with carbanions derived from l,3,2-oxa2aphosphor-inane 2-oxides (165) and (167). y-Addition to give (166) predominates although the extent of this depends on the ring size of the Michael acceptor. The level of diastereoselectivity depends on the stereochemistry of the allylphosphonate used ... 

Anilide 2a catalysed asymmetric intramolecular Michael reaction of formyl enones to chiral cyclic keto-aldehydes in excellent yields with good stereoselectivity (eqn. (1) in Scheme 6.3). The intramolecular Michael addition of a ketosulfone to an unsaturated ketone (eqn. (2) in Scheme 6.3) catalysed by 15e has heen used as a key step in the synthesis of the carbon tricyclic framework of Lycopodine. The same sulfonylprolinamide served as catalyst in the construction of all-carhon substituted quaternary stereocentre via Robinson-type annulation process (eqn. (3) in Scheme 6.3). 

Similarly, copper derivatives of hydrazones add in Michael fashion to cyclic enones to give products that are susceptible to further modification (Scheme 40). Good yields of 1,4-addition products are obtained on addition of the chiral cuprate reagents (26) to unsaturated esters, aldehydes, and ketones the asymmetric induction, however, is <1%. Prolinol has a more pronounced effect in that i -3-methylcyclohexanone is produced in 15.5% optical yield on reaction of... 

Organocatalysis Continuing efforts to harness the cooperative activity of bifunctional organocatalysts have led to the examinations of chiral calix[4]arenes containing amino phenol stractures and chiral per-6-amino-P-cyclodextrin in the asymmetric sulfa-Michael reactions to cyclic and acylic enones.The preliminary results indicated that further structural modification would be required to allow more efficient asymmetric catalyst systems. 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

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 Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

The asymmetric Michael addition of nonstabilised ketone enolates has proved difficult, with most success achieved using 1,3-dicarbonyls as donors. However, Shibasaki and coworkers have achieved high ees in the addition of a-hydroxyketones with both aromatic Michael acceptors such as (11.32) and also cyclic enones and alkyl vinyl ketones, using bifiinctional zinc catalysts prepared from linked BINOL (11.33). These catalysts are also effective in the asymmetric aldol reaction (see Section 7.1) and incorporate two zinc atoms, one of which activates the acceptor carbonyl group and the other forms a zinc enolate with the donor. In addition, catalysts of this type have been used to good effect in the addition of P-ketoesters to cyclic enones. 

TABLE 5.13. Asymmetric Michael Reaction Between Various Cyclic Enones and Malonates Catalyzed by NAP-MgO in the Presence of a Chiral Auxiliary (DPED) at 20 °C... 

In the presence of TMSOTf, BFs.OEtz and dimethyl sulfide, the iminium ions 204 (masked as N,0-acetals) have been employed to couple with a very board range of readily available Michael acceptors, including acrolein and acrylates, in both an inter- and intramolecular MBH-type reaction to give densely functionalized heterocycles 207 (Scheme 1.78). The process has been rendered asymmetric and high enantioselectivity is obtained in reactions of iminium ions 210 (masked as N,0-acetals) and cyclic enones (Scheme 1.79). Finally, the usefulness of the methodology has been exemplified in a short synthesis of ( + )-heliotridine 208 and (-)-retronecine 209 (Scheme 1.78). ... 

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... 

Other Metal Complexes Apart from metal complexes derived from BINOL, other metal complexes, such as the lithium-aluminum amiuo diol complex, " aluminum and nickel salen complex, ruthenium diamine complex, and ruthenium phosphinite diamine complex were also found applicable for the asymmetric Michael addition of 1,3-dicarbonyl compound to cyclic enone. All these metal complexes afforded about 90% of asymmetric induction in the Michael reaction of 2-cyclohexen-l-one and malonate. 

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. 

A highly enantioselective organocatalytic Michael addition of 4-hydroxycouma-rines and related compounds to a,p-unsaturated ketones has been also achieved using imidazolidine catalyst 137 [213]. The reaction, which gives high yields and enantioselectivities for a wide range of cyclic 1,3-dicarbonyl compounds and enones, has been successfully employed for the asymmetric synthesis of the anticoagulant warfarin (Scheme 2.78) and derivatives [213], With respect to the reaction mechanism, very recent studies have demonstrated that the truly active catalyst in the process was the chiral diamine 138, which is formed in catalytic amounts under the reaction conditions by reaction with the hydroxycoumarine (Schane 2.79)... 

The first example of an asymmetric formal [3+3] annulation of cyclic ketones (67) with enones (64) was reported in 2007 by Tang and co-workers [43]. They reported the formation of bicyclo[3.3.1] skeleton (68) via a Michael-aldol reaction,... 

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