Chiral substrates, asymmetric addition

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

There are many reports on the asymmetric addition of nucleophiles to carbon-nitrogen double bonds [6]. However, the majority of these reports are based on substrate control and rely on chiral auxiliaries in imines. Moreover, almost all of these reports are just for aldo-imine cases [7]. 

Nucleophilic addition of metal alkyls to carbonyl compounds in the presence of a chiral catalyst has been one of the most extensively explored reactions in asymmetric synthesis. Various chiral amino alcohols as well as diamines with C2 symmetry have been developed as excellent chiral ligands in the enantiose-lective catalytic alkylation of aldehydes with organozincs. Although dialkylzinc compounds are inert to ordinary carbonyl substrates, certain additives can be used to enhance their reactivity. Particularly noteworthy is the finding by Oguni and Omi103 that a small amount of (S)-leucinol catalyzes the reaction of diethylzinc to form (R)-l-phenyl-1 -propanol in 49% ee. This is a case where the... 

Chiral phosphoric acids mediate the enantioselective formation of C-C, C-H, C-0, C-N, and C-P bonds. A variety of 1,2-additions and cycloadditions to imines have been reported. Furthermore, the concept of the electrophilic activation of imines by means of phosphates has been extended to other compounds, though only a few examples are known. The scope of phosphoric acid catalysis is broad, but limited to reactive substrates. In contrast, chiral A-triflyl phosphoramides are more acidic and were designed to activate less reactive substrates. Asymmetric formations of C-C, C-H, C-0, as well as C-N bonds have been established. a,P-Unsaturated carbonyl compounds undergo 1,4-additions or cycloadditions in the presence of A-triflyl phosphoramides. Moreover, isolated examples of other substrates can be electrophil-ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found utility as specific acid catalysts of selected asymmetric transformations. 

Although desirable, the recovery of a chiral auxiliary is not always crucial. Some techniques employ a, -unsaturated carbonyl compounds containing a disposable stereogenic center, which is removed after the (asymmetric) conjugate addition step has been performed. This concept appears to be useful only if the chiral substrate is easily accessible in high enantiomeric purity. 

Arai et al. also reported another BINOL-derived two-center phase-transfer catalyst 31 for an asymmetric Michael reaction (Scheme 6.11) [8b]. Based on the fact that BINOL and its derivatives are versatile chiral catalysts, and that bis-ammonium salts are expected to accelerate the reaction due to the two reaction sites - thus preventing an undesired reaction pathway - catalyst 31 was designed and synthesized from the di-MOM ether of (S)-BINOL in six steps. After optimization of the reaction conditions, the use of 1 mol% of catalyst 31a promoted the asymmetric Michael reaction of glycine Schiff base 8 to various Michael acceptors, with up to 75% ee. When catalyst 31b or 31c was used as a catalyst, a lower chemical yield and selectivity were obtained, indicating the importance of the interaction between tt-electrons of the aromatic rings in the catalyst and substrate. In addition, the amine moiety in catalyst 31 had an important role in enantioselectivity (34d and 34e lower yield and selectivity), while catalyst 31a gave the best results. 

A DFT study of enolborane addition of o -heteroatom-substituted aldehydes has focused on the relevance of the Cornforth and polar Felkin-Anh (PKA) models for asymmetric induction.154 Using chiral substrates, MeCH(X)CHO, polar (X = F, Cl, (g) OMe) and less polar (X = SMe, NMe2, PMe2) substituents have been examined. The former favour Cornforth TS structures, the latter PKA. TS preferences have been correlated with the relative energy of the corresponding rotamer of the uncomplexed aldehyde. An in-depth study of addition of ( > and (Z)-enolborane nucleophiles to 2-methoxypropanal successfully predicts experimentally determined diastereofacial selectivities. 

The direct strong steric interaction between substrate substituents and ligand substituents has been demonstrated in asymmetric addition of diethylzinc to aldehydes catalysed by sterically congested ferrocenyl aziridino alcohol derivatives.114 In addi- tion, this non-bonded steric repulsion influenced enantioselectivities significantly, and even led to inversion of the absolute configuration. This fact was further confirmed by theoretical calculations and the design of a new chiral ferrocenyl aziridino alcohol ligand. 

On the basis of their observation that achiral 2,2 -bipyridyl promotes the reaction between crotyltrichlorosilane and benzaldehyde, the Barrett group screened chiral pyridine molecules as Lewis-base catalysts for this reaction [175]. The pyridinylox-azoline 164a was identified as the most efficient organocatalyst. In the presence of this catalyst, which was, however, used in stoichiometric amounts, asymmetric addition of (E)-crotyltrichlorosilane 158b to aldehydes gave the anti products (S,S)-159 in yields of 61-91% and with enantioselectivity from 36 to 74% ee (Scheme 6.76) [175], Diastereoselectivity is high, because only the anti diastereomers were obtained. Aromatic aldehydes and cinnamylaldehyde were used as substrates. 

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

E. L. Eliel, Application of Cram s Rule Addition of Achiral Nucleophiles to Chiral Substrates, in Asymmetric Synthesis (J. D. Morrison, Ed.), Vol. 2, 125, AP, New York, 1983. 

The asymmetric catalytic reduction of ketones (R2C=0) and imines (R2C=NR) with certain organohydrosilanes and transition-metal catalysts is named hydrosilylation and has been recognized as a versatile method providing optically active secondary alcohols and primary or secondary amines (Scheme 1) [1]. In this decade, high enantioselectivity over 90% has been realized by several catalytic systems [2,3]. Therefore the hydrosilylation can achieve a sufficient level to be a preparative method for the asymmetric reduction of double bond substrates. In addition, the manipulative feasibility of the catalytic hydrosilylation has played a major role as a probe reaction of asymmetric catalysis, so that the potential of newly designed chiral ligands and catalysts can be continuously scrutinized. 

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