Conjugate additions chiral amine catalysts

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... 

In 2007, the Jorgensen group reported a highly enantioselective procedure for the conjugate addition of oximes to a,p-unsaturated aldehydes in the presence of a chiral amine catalyst (296). This protocol was later expanded to the one-pot synthesis of optically active p-diols by carrying out a vinylogous addition of oxime 317 to different a,p-unsaturated aldehydes in the presence of catalyst 276 followed by a direct reduction of the primary addition product with LiAlHj (297). 

Inert aryl methanes (122, Y/Z = H/NO2) have been activated as nucleophiles towards enals, using a chiral amine catalyst under mild conditions, giving enantioselective direct conjugate addition product (123) in high yield and ee ... 

MacMillan has shown that electron-rich aromatic compounds can participate as nucleophiles in enantioselective conjugate additions to aldehydes in the presence of chiral amine catalysts such as 150 [126, 127]. The process owes its success to the formation of a putative chiral iminium intermediate 151, derived from the unsaturated aldehyde and imidazolidinone 150, that is activated and poised for diastereoselective conjugate addition (Equation 26) [126]. As illustrated for cinnamaldehyde (149), the pyrrole adduct 153 was obtained in 87 % yield and 93 % ee. 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Sibi et al. [66] reported the first examples of highly enantioselective conjugate amine additions [67] by use of catalytic amounts of a chiral Lewis acid complex. Addition of 0-benzylhydroxyamine 87 (1.1 equiv.) to the pyrazole-derived crotonamide 86 proceeded smoothly in the presence of stoichiometric amounts of the chiral catalyst prepared from the bis(oxazoline) 50 and MgBr2 OEt2 with high enantiomeric excess (96 % ee) (Sch. 37). This conjugate addition reaction was equally effective with catalytic amounts of the chiral Lewis acid (92 % ee with 30 mol % 88 % ee with 10 mol %). A re face amine addition to the s-cis substrate bound to the chiral complex with tetrahedral- or ds-octahedral arrangements XXXII and XXXni accounts for the product stereochemistry observed (Fig. 7). 

In addition to chiral acids, amines and amine salts have been used to catalyze conjugate addition. These catalysts presumably function by formation of iminium... 

Some attempts to use aliphatic alcohols as nucleophiles in the enantioselec-tive conjugate addition to enals have been carried out, but with no success with regard to the stereochemical control (Scheme 3.29). For example, the conjugate addition of methanol to several aliphatic enals using axially chiral amines derived from BINOL as catalysts proceeded with enantioselectivities around 50% ee and also a 31c-catalyzed intramolecular reaction leading to the formation of the tetrahydropyrane skeleton has been reported to proceed with 57% ee. 

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