Diastereoselection, conjugate additions catalysis

Metal-catalyzed reactions have been of major importance in synthetic organic chemistry. Over the past decade, enantio- and diastereoselective metal-mediated domino catalysis has emerged as an effective tool to construct really highly complex molecules in one-pot processes [2, 4b,d]. Among them, enantioseletcive metal-catalyzed conjugate additions (in particular, Cu-catalyzed 1,4-addition to a,P-unsaturated carbonyl compounds) have been useful components of domino reactions [4d, 5]. The generated metal enolates 2 after the additions of nucleophiles readily react with a variety of electrophiles (Scheme 11.1). Enantioselectivity of 3 depends on the first addition of nucleophiles to the P-position of the unsaturated carbonyl compounds 1. 

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. 

The unapplicable in our case Sakurai-route to hydroazulenes prompted us to mal e use of a Mulcaijama-t3rpe annelation. Conjugated addition of Me CuLi to the enone 2 using a very efficient trimethyl-silylchloride catalysis furnished the enolsilylether 3 with remarkable 957o diastereoselectivity Subsequent treatment with TiCl in the presence of 4 molecular sieves smoothly generated the cis-hydroazulene 4 as an 1 1 mixture of C-10 epimers. 

On the other hand, Matsunaga and Shibasaki have observed an opposite syn diastereoselectivity in the enantioselective conjugate addition of a-keto anilides to nitroalkenes under dinuclear nickel catalysis. Indeed, the use of 10 mol% of dinuclear chiral Schiff base nickel catalyst 9 in the presence of HFIP and 5 A MS as additives in 1,4-dioxane as solvent allowed the corresponding Michael adducts to be achieved in moderate to good yields, with good syn diastereoselectivities of up to >90% de and combined with good to excellent enantioselectivities of up to 98% ee (Scheme 2.15). The substrate... 

Conjugate Addition to a, -Unsaturated Carbonyl Compounds Other than Ketones. In addition to a, 8-unsaturated ketones, the silylcuprate reagent also reacts with a, 8-unsaturated aldehydes, esters (eq 13), amides, and nitriles, and with vinyl-sulfoxides without needing Lewis acid catalysis as carbon-based cuprates do. With esters, the intermediate enolates, which have the E geometry (20), may be used directly in highly diastereoselective... 

The ability of the diarylprolinol catalysts to participate in both enamine- and iminium-ion achvations makes them ideal for the sequential addition of nucleophiles and electrophiles through cascade catalysis (Scheme 2.8). Conjugate addition of a nucleophile to the iminium ion forms a transient enamine intermediate 3, which can effectively react with an electrophile in the a-position, forming an a,P-disubstituted adduct. This process commonly proceeds to afford the products in good yields and with high enantio- and diastereoselectivities. If the nucleophile and electrophile are part of the same molecule, cyclic products are obtained. The cascade concept has been widely explored and some illustrative examples are given below [13, 17]. 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

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