Michael donors cyclic ketones

The substrate 292 was specifically designed to prepare five-membered systems via a sequence of inter- and intramolecular Michael additions. This option is viable when active Michael acceptors such as methyl vinyl ketone are used, otherwise competing Michael reactions between two molecules of 292 are difficult to avoid. The reaction proceeds through intermediate 293, which contains both a Michael donor and acceptor site and undergoes spontaneous conversion into the cyclic product 294. 

When the Michael donors have a sufficiently low pKa, the Michael addition can be catalyzed by a base. The first catalytic asymmetric conjugate addition was achieved by Wynberg et al. in 1975 using cinchona bases [la]. They performed the reaction of cyclic P-ketoesters such as 1 with methyl vinyl ketone in the presence of quinine and... 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

In a much more recent report, conveniently O-protected a-hydroxymethyl aryl ketones were also successfully employed as Michael donors in the conjugate addition to methyl acrylate and acrylonitrile using a cinchonine-based ammonium salt as catalyst. Bis-quinidine-based ammonium salt 105 has also shown to be useful in the reaction of cyclic p-ketoesters to methyl and ethyl acrylate. ... 

The Barbas group further identified catalyst Id for asymmetric Michael additions using brine as the reaction medium 10 mol% diamine Id/TFA at ambient temperature afforded q n-Michael adducts in high yields and good to excellent stereoselectivities for cyclic ketones. The stereoselectivities decreased when aliphatic aldehydes were used as donors (Scheme 9.13). Moreover, the same authors demonstrated the first example of sym-metrical/unsymmetrical a,a-diallgrlaldehydes as donors in asymmetric Michael reactions to produce adducts featuring an all-carbon quaternary stereocentre. The use of 30 mol% (S )-l-(2-pyrrolidinylmethyl)pyrrolidine la in combination with an equal amount of TFA yielded products with moderate to high levels of diastereo- and enantioselectivity (Scheme 9.14). ... 

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. ... 

L-Ascorbic acid reacts as a Michael donor with acrolein or methyl vinyl ketone the products can be converted to cyclic acetals as shown in Scheme 5- The analogue (15) of ascorbic acid has been made as indicated in Scheme 6 the halogen at C-3... 

Another type of compound having the furo-furanone skeleton, in which a C—C bond was formed at C-2 of 3, has been achieved by using 3 as a Michael carbanion donor to various a, 3-unsaturated carbonyl compounds. Thus, it gives 94a when combined with methyl vinyl ketone, which can then be converted to the cyclic acetal upon reaction with methyl alcohol in the presence of an acid (83T2137). The reaction was extended to acrolein, a-methyl acrolein, and crotonaldehyde to give 94c. Its application with 2-cyclohexen-l-one required an unexpected acid catalysis to give 94b. On the other hand, extending the reaction to a cyclic enedione,... 

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. 

In 2002, Itoh and Kanemasa found that the combined use of both amine and chiral Lewis acid (R,R)-DBFOX-Ph complex of Ni(II) can be an active catalyst for enantioselective Michael addition of nitromethane or malononitrile to unsaturated carbonyl compounds [37a,b]. Recently, they have reported a new enol ketone synthesis through the reactions between cyclic 1,3-dicarbonyl donors and a,p-unsaturated carbonyl acceptors under the double catalytic activation conditions (10mol% each) of Ni(11)-perchlorate hexahydrate and (2,2,6,6-tetramethylpiperidine (TMP) (114))(Scheme 16.33) [38a,b]. Thus, 1,3-cyclohexanedione (112) is allowed to react with 4-bromo-l-crotonoyl-3,5-dimethylpyrazole (113), in THF at room temperature in the presence of both catalytic amounts to give 4,7,7-trimethyl-3,4,5,6,7,8-hexahy-drobenzopyran-2(H),5-diones (115) in good yields along with high enantioselectivity up to 99% ee. 

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