Michael addition stereochemical control

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

The asymmetric Michael addition of active methylene or methyne compounds to electron deficient olefins, particularly a,P-unsaturated carbonyl compounds, represents a fundamental and useful approach to construct functionalized carbon frameworks [51]. The first successful, phase-transfer-catalyzed process was based on the use of well-designed chiral crown ethers 69 and 70 as catalyst. In the presence of 69, P-keto ester 65 was added to methyl vinyl ketone (MVK) in moderate yield but with virtually complete stereochemical control. In much the same way, crown 70 was shown to be effective for the reaction of methyl 2-phenylpropionate 67 with methyl acrylate, affording the Michael adduct 68 in 80% yield and 83% ee (Scheme 11.15) [52]. 

Anti stereochemistry in six-membered rings Conformational control from a chiral centre in the cyclohexenone Remote stereochemical control in five-membered rings prostaglandins Regio- and stereochemical control in open chain compounds Asymmetric induction by a chiral auxiliary on the enolate Tandem Michael-Michael Reactions One Conjugate Addition Follows Another Double Michael or Diels-Alder reaction ... 

Stereochemical control in the double conjugate addition Tandem Reactions as Polymerisation Terminated by Cyclisation The MIMIRC sequence with vinylphosphonium salts Tuning the MIMIRC sequence with different Michael acceptors Heterocycles by Tandem Conjugate Additions Tandem conjugate addition and Mannich reaction Tandem Conjugate Addition and Aldol Reaction... 

Lewis-acid-promoted Michael additions complement the enolate (2) and enamine reactions (vide supra). Since a variety of methods exist for the generation of enol ethers and ketene acetals, often with good stereochemical and regiochemical control (vide infra), the Mukaiyama-Michael reaction often permits a degree of stereochemical and regiochemical control that is not easily possible in enolate and enamine reactions. Additionally, the reaction occurs under formally acidic conditions, so it can be used with base-sensitive substrates. 

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. 

Scheme 2.4 Stereochemical issues to be controlled in Michael additions proceeding via enamine intermediates.

Yamagishi et al. recently presented a novel method for the stereoselective synthesis of phosphinic pseudopeptide isosteres starting from an enantiopure a-aminoalkyl-//-phosphinate on both a-carbon and phosphorus atoms (36, Scheme 18) [99]. In particular, substrates 37 derived from a stereoretentive Michael addition of aminophosphinates 36 to tert-butyl acrylate, were diastereoselectively alkylated in the Pi position with diastereoisomeric ratios (dr) ranging from 14 1 to 29 1. The stereochemical outcome of this process is highly controlled by the chirahty at the phosphorus atom and the nature of the amino protecting group. 

Yamazaki et al. employed the Evans oxazolidinone enolate in diastereoselective Michael additions to /I-CF3 acrylates to afford intermediate allyl silyl ketene acetals [8]. The products were isolated as ca. 2 1 mixtures of pentenoic acids and Michael addition adducts (Scheme 4.59). The rearrangement of the silyl ketene acetal was catalyzed by PdCl2(CH3CN)2. The rearrangement apparently occurred via the Z-silyl ketene acetal and exhibited high 1,2-asymmetric induction. Aspects of stereochemical control and Pd catalysis have been discussed previously (cf Scheme 4.25). 

However, the maximum level of stereochemical control in these processes with a variety of electrophiles (CH2=CHC02Me, CHz -CHCN, BrCHjCH—CH2, BrCH2C02Et) was below 60% optical purity (corresponding to a ratio no better than 4 1). These results appear to be the result of kinetic control in die transition state for carbon-carbon bond formation. On the other hand, reactions widi mediyl vinyl ketraie can be run under either kinetic or thermodynamic control and the level of stereochemical control is higher under the latter conditions. Likewise, the enamine ftom 2-methoxymethylpyrrolidine (derived from proline) adds in a Michael fashion to nitrostyrenes (equation 29) " and in a simple addition mode to acyliminoacetates (equation 30) with very high levels of asymmetric induction. 

Such an approach for the synthesis of optically active a-methylene-8-lactones was further extended to include enamines derived from (J )- or (S)-dihydrocarvone and (R)- or (S)-l-phenylethylamine in the Michael addition step [71]. In such a manner, a synthesis of all four enantiomericaUy pure diastereoisomers of 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromen-2-one was accomplished. Furthermore, the possibihty to control stereochemical outcome of the Michael addition step by employing chiral phosphinate auxihary in the starting dicyclohexylammonium acrylate was also demonstrated by KrawcTyk and coworkers [72]. 

Racemic cx-fluoro-p-ketophosphonates (549) have been used in stereoselective Michael addition to nitroalkenes (550) promoted by the trifunctional thiourea organocatalyst (552). The reaction afforded highly functionalised a-fluoro-p-keto-y-nitrophosphonates (551) in high yields (up to 99%) and with excellent stereochemical control (96-99% ee and 3 1-34 1 d.r.) (Scheme 159). ... 

One year later, the same group achieved the four-component conpling of enals, protecting hydroxylamine (A -methoxycarbmate), aryamines, and acetone by a combination of (5)-prolinol silyl ether and (5)-proline [18], affording orthogonally protected 1,3-diamine motif efficiently with excellent stereochemical control (Scheme 9.17). Mechanistically, the reaction proceeds via a (S)-prolinol silyl ether-catalyzed aza-Michael addition of protected hydroxylamines to a,p-unsaturated enals followed by an (S)-proline-promoted Mannich reaction of the p-amino aldehyde... 

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