Michael addition diastereoselective

Successful methodology for diastereoselective Michael additions with chirality in the donor is so far limited to chiral cyclic enolates. The stereocontrol is mainly due to shielding of one of the jr-faces of the enolate by the ring substituent that resides at the stereogenic center. The (nmv-diastereoselective Michael addition of (5)-2-methyl-3-vinylcyclopentanonc illustrates this principle154-157. 

This modification was used in the synthesis of (-)-avenaciolide. The key step is the trans-diastereoselective Michael addition of the lithium enolate of tert-butyl 2-(phenylse-leno)propionate (THF, — 78 CC) to (R)-5-octyl-2(5//)-furanone and subsequent trans-diastereoselective iodonation318. u e... 

The (//(-configured center is formed by a diastereoselective Michael addition of piperidazine to the (4 )-cster 400, easily available from mannitol, and a subsequent cyclization gives the corresponding lactam 401. Small amounts of by-products 402 and 403 are also formed (Equation 56) <1996HCA1995>. 

Maraval et al 39) synthesized core- and periphery-functionalized ruthenium and palladium dendritic diphosphines (Fig. 12) that were applied in three reactions (Stille coupling, Knoevenagel condensation, and diastereoselective Michael addition). The catalyst was recovered by using the precipitation strategy. 

The phosphine-containing ruthenium dihydride dendrimer 33 was found to be an active catalyst for the diastereoselective Michael addition of ethyl cyanoacetate to diethyl ethylidenemalonate in THF (Scheme 12). The dendritic catalyst showed an activity and selectivity similar to those of the reference compound RuH2(PPh3)4 (100% conversion after 24 h and a diastereoselectivity of 7/3) (40). The dendritic catalyst was recycled twice by precipitation with diethyl ether without loss of activity or selectivity. Complex 34 showed similar activity and recoverability over three runs like that of complex 33. 

Scheme 6.57 Representative products of the 12-catalyzed enantio- and diastereoselective Michael addition of a-substituted P-ketoesters to trom-P-nitrostyrene.

Scheme 36 Synthesis of 1-Oxoethylene Peptides by Diastereoselective Michael Addition 83 ...

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

Diastereoselective Michael additions of enolates, prepared from the chiral amides (127) and (128), to prochiral a.p-unsaturated esters were utilized in the synthesis of (+)-dehydroiridodiol (129) and its isomer (130 Scheme 49).143... 

Stabilized lithiated sulfoximines (112) undergo highly diastereoselective Michael additions to cyclic enones at —78 °C under kmetically controlled conditions. At room temperature, the initially formed adducts (113) undergo intramolecular substitution of the sulfonimidoyl group, with inversion of configuration to afford the corresponding cyclopropanes (114).92... 

The efficiency of this method is highlighted by highly diastereoselective Michael addition arising from specific chelation control by metals. Using the concept of these catalytic reactions, asymmetric carbon-carbon bond-formation can be performed. Reactions of isopropyl 2-cyanopropanoate with vinyl ketones were conducted highly enantioselectively in the presence of RhH(CO)(PPh3)3 with (S,S)-(R,R)-TRAP [14] (R = C6H4-p-OMe 99%, 89% ee) [15]. 

Enantiomeric enriched a-thiosulfoxides 391 can be prepared by addition of a-thiomethyllithiums to p-tolyl sulfinate601. The deprotonation of p-tolyl (p-tolylsulfanyl)methyl sulfoxide (403) took place with w-BuLi at — 78 °C to afford the enantioenriched lithium derivative 404602. The addition to benzaldehyde followed by methylation of the hydroxy group and deprotection gave a-methoxyphenylacetaldehyde with 70% ee. This chiral formyl anion gave diastereoselectively Michael addition to a-substituted cyclopentenones603. The acylation of compound 404 followed by LAH reduction allowed the diastereoselective preparation of compounds 405 up to 99% de (Scheme 105)604. 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

Diastereoselective Michael Additions. The super Quats have also proven to be effective auxiliaries in diastereoselective conjugate additions to a,p-unsaturated carbonyl species. The... 

Alternatively, isoxazolidin-5-yl acetates were obtained by reduction and acetylation of suitable isoxazolidin-5-ones, which, in turn, were prepared by diastereoselective Michael addition of hydroxylamines to unsaturated esters or by nucleophilic addition of enolates to nitrones and subsequent cyclization of the resulting hydroxylamines. For example, the two diastereomeric isoxazolidinones 552 were converted into thymidine analogues 590 (Scheme 146) <1997JOC7430, 1998T6587, 2000TL9239, 2005CRC775>. 

Diastereoselective Michael additions of LiCCls <19990L2165> and Grignard reagents <2004TA793> to A -crotonyl- and A -fumaroylcamphorsultams 582, respectively, were performed. Grignard addition to acrylates 582 (R = COCH=CHMe), followed by a-alkylation, allowed the preparation of a key intermediate for synthesis of... 

Recently, Zhao et al. reported the use of 2-trimethylsilanyloxy-methyl-pyrrolidine functionalized chiral dendrimer catalysts (Figure 4.20) for catalytic enantio- and diastereoselective Michael addition of aldehydes to nitrostyrenes (Scheme 4.15)... 

Scheme (17). Asymmetric synthesis of lignans utilizing a diastereoselective Michael addition to chiral 2(5//)-furanones the Koga approach...

Alkylations. CS2CO3 has shown some unique properties as a base. It promotes (9-aIkylation of 2-pyrimidinone, diastereoselective Michael addition, and tandem alkylation/Wittig reaction to form ethoxycyclopentadienes with good results. 

Nitrocyclohexanols were synthesized by a double and diastereoselective Michael addition followed by ring closure (Eq. 45). When performed in the presence of KF-alumina under solvent-free conditions, an important microwave effect was observed ... 

Caminade and Majoral reacted phosphorus-containing dendrimers with various transition metal complexes (Fig. 7) [ 113 ]. Via phosphane, diphosphane, or P=N-P=S ligands, they were able to incorporate several metals (Pd, Pt, Rh, Au, Fe, W, Zr) either in the core or in the periphery of their dendrimers. The dendritic palladium and ruthenium complexes 7 have been introduced in Stille couplings, Knoevenagel condensations and diastereoselective Michael additions. A positive dendritic effect and high stability of dendritic Pd complexes has been observed. Separation occurred by precipitation with ether and reuse was reported. 

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