Michael addition of malonate

Compounds described as the 15 -carboxymethyl derivatives (32) of oestrone and oestradiol have been described as haptens, without any evidence as to their configurations at C-15, or their homogeneity. The method of synthesis (via Michael addition of malonic ester to the 15-en-17-one) normally gives 15/8-substituted compounds. Some 15/8-carboxyethylmercaptoandrostane derivatives (33), obtained by addition of methyl 3-mercaptopropionate to androst-15-en-... 

Of the four possible optical isomers, the (+)-( I )-cw-isomer possesses the most characteristic jasmin odor. Methyl dihydrojasmonate is prepared by Michael addition of malonic acid esters to 2-pentyl-2-cyclopenten-l-one, followed by hydrolysis and decarboxylation of the resulting (2-pentyl-3-oxocyclopentyl) malonate, and esterification of the (2-pentyl-3-oxocyclopentyl)acetic acid [136]. 

Recently, Maruoka and coworkers addressed the importance of dual-functioning chiral phase-transfer catalysts such as 70a for obtaining a high level of enantio-selectivity in the Michael addition of malonates to chalcone derivatives (Scheme 5.35) [37]. For instance, the reaction of diethyl malonate with chalcone in... 

A series of diaryl-2-pyrrolidinemethanols have been tested as catalysts for the enan-tioselective Michael addition of malonate esters to nitroalkenes.30 Bis-(3,5-dimethyl-phenyl)[(S)-pyrrolidin-2-yl]methanol (6), easily prepared from L-proline, has been found the most efficient bifunctional organocatalyst, providing up to 56% ee. 

Cobalt(II) complexes prepared in situ from (AcO Co and two novel chiral spiro nitrogen-containing ligands, 7,7/-bis(2-pyridinecarboxamido)-l,l/-spirobiindane (SIPAD) and 7,7/-bis(2-quinolinecarboxamido)-l,l/-spirobiindane (SIQAD), are efficient cata- lysts for the asymmetric Michael addition of malonates to chalcone derivatives. The alkylation products were obtained in high yields with moderate enantioselectives.169... 

The enolate derived from the Schiff base 3 has been added to a,/ -unsaturated esters and ketones with a high level of enantioselectivity. For example, in the presence of 10 mol% lb, the enolate of the glycine derivative 3 was added to cyclohexenone with excellent diastereo-selectivity to give the ketoester 20 with >99% ee (Scheme 7) [15]. Promising results have also been obtained in the Michael additions of malonates to chalcone deriviatives [16], The novel cinchonidinium bromide lg was found to be the most effective catalyst for this transformation, yielding the Michael adduct 21 with 70% ee (Scheme 8). 

Modified cinchona alkaloids 18 and 19, derived from quinine and quinidine, respectively, were utilized by Deng and co-workers for the catalytic asymmetric Michael additions of malonates to nitroolefins [49]. These catalysts effectively promoted the conjugate additions of methylmalonate to a variety of aromatic (90-99% yield 96-98% ee), heteroaromatic (97-99% yield 96-98% ee) and aliphatic (71-86% yield 94% ee) -substituted nitroolefins (Table 6.7). As the two alkaloids... 

Different cyclic products are formed in the double Michael addition of malonic acid ethyl methyl ester to ( vE)-l,5-diphenylpenta-l,4-dien-3-one under basic conditions. Label the stereogenic units in the reaction products with the appropriate stereodescriptors. 

In recent years the use of tandem reaction sequences to create complex cyclic systems in a single reaction has blossomed587-604. Although this area is beyond the scope of the present work, one such process will serve as illustration. Thus, a Michael addition of malonate to... 

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). 

Michael addition to a, -unsaturated aldehydes The Michael addition of malonic ester and acetoacetic ester to a,0-unsaturated aldehydes can be carried out in moderate yields under phase-transfer conditions with sodium or potassium carbonate as base and benzyltriethylammonium chloride as catalyst (equation I). 

This disconnection led to the C3 synthon 48 (and hence to its already familiar synthetic equivalent 44) and C9 amino dialdehyde 47. The Michael addition of malonic ester to acrolein was employed for the synthesis of the key starting material 49. The Claisen ester condensation of the latter followed by decarboxylation and reductive aminolysis led to the preparation of amino-bis-acetal 47a. The respective amino dialdehyde 47, generated in situ by a controlled hydrolysis of the acetal groups of 47a, reacted smoothly with acetonedicarboxylic diester and gave the required adduct 46 in a good yield and nearly complete stereoselectivity. 

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. 

In 2004, Deng and coworkers reported the first preparatively useful results for the catalytic asymmetric Michael additions of malonates to nitrooleftns. They found that... 

Figure 11.4 Enantioselective Michael addition of malonates to cyclic enones.

The stereochemical course of the subsequent Michael addition of malonic ester to the unsaturated ketone (23) proved to be unexpected. The kinetically controlled product 27 of addition was obtained in the presence of sodium methoxide and an excess of dimethyl malonate however, the thermodynamically preferred ester 28, also obtainable by base-catalyzed equilibration of 27, was the major product of the reaction. According to the IR (absence of Bohlmann bands) and NMR spectra, both 27 and 28 contained cis-quinolizidine ring systems formed possibly by reversible retro-Michael cleavage of the C-3 to Aj, bond in 23. This possibility explains the observed rapid destruction of 23 in the presence of very strong base with simultaneous appearance of a UV maximum at 410 nm presufiaably due to the conjugated enone system present in 29. 

Claus, R. E., Schreiber, S. L., Org. Synth. Coll. VoL Vll 1990, 168. Schreiber ozonolysis was decidedly superior to a more classical route proceeding through Michael addition of malonic ester to acrolein (cf Rebert, N. W. Dissertation, Utah State University, Logan, Utah, 1987). 

Michael additions of malonate to allenic sulphoxides (408) proceed efficiently to give homologues (409) which, after [2.3]-sigmatropic... 

Diesters.—Michael addition of malonic ester enolates to chiral a/3-unsaturated aldimines (obtained from optically pure a-amino-acids) gives, after hydrolysis, aldehyde-diesters (125) in variable chemical (26—54%) and optical (36—86%) yields. The amino-acid components are recovered optically pure. Attack of simple nucleophiles on the bromoalkylidene malonate (126) gives cyclopropane diesters (127) in good yields. A ready, five-step route to the bicyclo[l,l,0]butane triester (128) has been described. ... 

Scheme 4.5 68a-catalyzed enantioselective Michael addition of malonates to nitroalkenes and application to the total synthesis of (R)-(-)-baclofen. 

Scheme 4.11 Enantioselective Michael addition of malonic acid half-thioesters to nitroalkenes catalyzed by 70b.

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