Aldehydes asymmetric conjugate addition

On the other hand, S/O ligands have been developed to a lesser extent, but their efficient use as chiral ligands was proven in the enantioselective addition of diethylzinc to aldehydes and also in the copper-catalysed asymmetric conjugate addition. 

In a recent study of asymmetric conjugate addition, Simon Woodward and co-workers8 required a series of enones 43. Some they made with lithium enolates 41 of ketones or esters 40 added to aldehydes to give the aldols 42 that were dehydrated to the enones 43 with concentrated HC1. 

Rigidified binuclear zinc chelates are formed, and their asymmetry promotes the facial diastereodifferentiation of the aldehyde carbonyl group in a highly enantiose-lective reaction ( 2.5.1,6.5.1). Chiral aminoalcohols and diamines are the most efficient ligands to promote asymmetric conjugate additions of lithio- or magne-siocuprates to a,p-unsaturated carbonyl compounds [112] ( 7.10.1). 

Initially, an alternative approach to C14 methyl incorporation was explored based on asymmetric conjugate addition (Scheme 6). Aldehyde 10 was homologated to aldehyde 15 using a Wittig reaction with the ylide generated from methoxymcthyl phosphonium chloride. The unsaturated acyl oxazolidinone 17 was then formed with high -selectivity using phosphonate 16 in the presence of base and lithium chloride. Various... 

Florhydral has the methyl group p to the aldehyde. One possible approach is an asymmetric conjugate addition, but again asymmetric reduction of the acid (or allyhc alcohol) is preferable, since the required alkene is easy to make by aldol chemistry. Here we show one example with the acid and one with the alcohol, but either are possibihties in both cases. 

The direct asymmetric conjugate addition of simple aldehydes to electrophiles is crucial in organic reactions. Barbas et al. developed the first example of a highly stereoselective direct Michael reaction that involved adding unmodified aldehydes to nitro-olefins. After various p3Trolidine-diamines were screened, (S)-2-(morpholinomethyl)pyrrolidine Ic was determined to be the ideal catalyst for obtaining satisfactory stereoselectivity in the reaction. These reactions afforded various 2,3-disubstituted y-formyl nitroalkanes with satisfactory yields and moderate to good enantioselectivity (Scheme 9.12). ... 

S)-Pyrrolidine trifluoromethanesulfonamide 3a is a highly active catalyst for the asymmetric conjugate addition of aldehydes and ketones to nitroalkenes. The use of catalyst 3a (20 mol%) in i-PrOH at 0 °C, afforded a,a-dialkyl aldehydes with good to high yields and high to excellent levels of diastereo- and enantioselectivity (Scheme 9.20). In addition, the reactions of various cyclic and acyclic ketones with aromatic nitro-olefins indicated the usefulness of the catalyst. " Computational results corresponded with the observed stereoselectivities of 3a-catalysed Michael reactions. 

Scheme 2.20 anri-Selective asymmetric conjugate addition of aldehydes to nitrooleflns... 

Lately, sulfones have become especially important substrates in organocatalysis [87]. First studies on the asymmetric conjugate addition of aldehydes to vinyl sulfones were carried out by Alexakis and Mossd employing as catalyst bipyrrolidine 30 (25 mol%) for the addition of linear and a-branched aldehydes to l,l-bis(benzenesulfonyl)ethylene [88], Large excess of aldehyde (10 equivalents) was required and moderate levels of enantioselection were obtained for linear aldehydes (53-80% ee), while reactions with a-branched nucleophiles led to racemic or very low selectivities (0-12% ee). With respect to the mechanism, the acyclic synclinal model proposed by Seebach and GoUnski [70] involving a trans enamine intermediate was postulated. 

The asymmetric conjugate addition of activated methylenes to a, P-unsaturated aldehydes has been studied with a wide variety of nucleophiles such as malonates, 1,3-diketones, P-ketoesters, malononitriles, benzylic methylenes, and suhbnyl nucleophiles. 

Scheme 2.121 Asymmetric conjugate addition of carbamates to a.p-unsatuiated aldehydes...

The amine-catalysed asymmetric conjugate addition of aldehydes to nitroalkenes is a powerful tool for stereoselective carbon-carbon bond formation, and hence, a large number of chiral amine catalysts have been developed to date. ° In most amine-catalysed reactions, q n-conjugate adducts were obtained as major diastereomers. For instance, the reaction catalysed by a chiral pyrrolidine (5 )-6 gave a sy -conjugate adduct with excellent enantioselectivity (Scheme 17.13). In contrast, the reaction using a biphenyl-based amine catalyst (S)-7 is complementary to most amine-catalysed... 

Silyl nitronates, the preactivated nucleophiles of nitroalkanes, are also applicable in the asymmetric conjugated addition reaction with a,(S-unsaturated aldehydes, ketones, and nitroalkenes. Maruoka and co-workers [115] found that AT-spiro... 

In 2010, Chen and co-workers [134] developed the first organocatalytic asymmetric conjugate addition of a, 3-unsaturated aldehydes via iminium catalysis. In the presence of diarylprolinol silylether 7 and o-fluorobenzoic acid (OFBA), the reaction proceeded well to afford the highly valued adducts with excellent enantioselectivities and with up to outstanding diastereoselectivities (Scheme 5.67). To emphasize the synthetic utility of the reaction, a number of natural-product-like or drug-like molecules with versatile skeletons have been efficiently constructed from the corresponding Michael adducts. 

Wu EH, Hong R, Khan JH, Liu XF, Deng L (2006) Asymmetric Synthesis of Chiral Aldehydes by Conjugate Additions with Bifunctional Organocatalysis by Cinchona Alkaloids. Angew Chem Int Ed 45 4301... 

Finally, Kim reported the asymmetric conjugate addition of organoboronic acids to y-hydroxy a,p-unsaturated aldehydes catalysed by diarylprolinol silyl ethers, which afforded the corresponding p-substituted y-lactols in good yields. High enantioselectivities of up to 91% ee were obtained in the case of... 

In a study of organocatalytic asymmetric conjugate addition (ACA) of nitroalkenes to aldehydes, ESI-MS has been used to identify intermediates and the stereoselective step. Starting with quasi-enantiomeric reaction products, MS is used for back-reaction 0 screening and supports the enamine mechanism (over the enol route). 0... 

Wu F, Hong R, Khan J, Liu X, Deng L. Asymmetric synthesis of chiral aldehydes by conjugate additions with bifunctional organocatalysis by Cinchona alkaloids. Angew. Chem. Int. Ed. 2006 45(26) 4301-A305. 

Asymmetric conjugate addition of aldehydes to acrylate esters has been achieved through catalysis by a bifunctional enamine-metal Lewis acid and by an axially chiral amino diol. " ... 

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