Reactions with Prochiral Carbonyl Compounds

Reagents of this type have also proved to be effective for asymmetric Michael additions [52]. 

Another chiral phosphoramidate 16, which possesses stereogenic centers at both phosphorus and carbon atoms, was examined in asymmetric HWE olefination reactions [53]. By fine-tuning of the N-substituents in the structure of the auxiliary, 

Two chiral phosphonic acid derivatives 19a,b, containing a stereogenic phosphorus atom connected to a mercaptoisoborneol moiety, were prepared as a mixture, and were then chromatographically separated. Their ability in asymmetric carbonyl olefination was examined in the reaction with 4-tert-butylcyclohexanone la [56). The two lithium carbanions reacted with the carbonyl group of the substrate to give opposite enantiomers 90a, although no remarkable degree of asymmetric induction was observed (up to 16% ee). 

The chiral phosphonates 31a,e, possessing optically active BINOL as an auxiliary, also demonstrated their ability as asymmetric inducers in the dissymmetrization of carbonyl compounds. In order to achieve both high enantioselectivity and good chemical yield, addition of zinc chloride was quite effective in these transformations [8]. It is known that bicydo[3.3.0]octane derivatives usually adopt either W-, S-, or V-shaped conformations, and the observed stereochemistry of the alkene 92a was best explained by considering an initial approach of the nucleophile to the W-shaped bicyclo[3.3.0]octanone in the direction in which steric interaction between the reagent and the substrate is minimized. 

Recently, a novel C2-symmetric chiral arsine 35 has been prepared from (S)-BINOL and employed in the enantioselective olefination of 4-substituted cyclohexanones to give the alkenes with moderate enantioselectivities of up to 40% ee. Moreover, a reversal in the stereochemistry of the products was observed simply by changing the counter cation of the base from lithium to potassium [64]. 

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Reaction of optically active a-sulphinyl acetate 298a with prochiral carbonyl compounds proceeds with a high asymmetric induction - , the degree of which depends on the nature of substituents at the carbonyl group (equation 252 Table 22) . The jS-hydroxy sulphoxides 422 formed may be transformed to optically active p-hydroxycarboxylic esters 423 (equation 253) and optically active long-chain lactones 424 99 (equation 254). Corey and coworkers have used this method to introduce a chiral centre at C-3 in their synthesis of maytansin °°, and Papageorgiou and Benezra for the synthesis of chiral a-hydroxyalkyl acrylates 425 ° (equation 255). 

The reaction shown in Scheme 39 was also performed starting from a chiral carbamoyl chloride (91, Y = O) derived from (f )-iV-methyl-iV-(l-phenylethyl)amine, in order to study the possible asymmetric induction using prochiral carbonyl compounds. Thus, with pivalaldehyde or benzaldehyde the mixture of diastereomers obtained was ca 1 1. This behavior was also observed with other chiral functionalized organolithium compounds ". ... 

In the classical Passerini reaction [11], an isocyanide is condensed with a carbonyl compound and a carboxylic acid to afford a-acyloxyamides 7 (Scheme 1.2). When the carbonyl compound is prochiral, a new stereogenic center is generated. It is generally accepted that the reaction proceeds through intermediate 6, which rearranges to the product. The way this intermediate is formed is more debated. A possibility is a concerted non-ionic mechanism involving transition state 5. Since the simultaneous union of three molecules is not a very likely process, another possibility is a stepwise mechanism, with the intermediacy of a loosely bonded adduct 4 between the carbonyl compound and the carboxylic acid [2], Since all three... 

In 1951 Bothner-By first attempted asymmetric reductions based on the conversion of lithium aluminum hydride (LAH) into a chiral alkoxy derivative by reaction with (+)-camphor. Since this pioneering work, the use of chirally modified LAH reagents has been the focus of much attention. In 1979, the first virtually complete enantiofacial recognition of prochiral carbonyl compounds was accomplished by using LAH modified with optically pure 2,2 -dihydroxy-1,1 -binaphthyl and a simple alcohol (BINAL-H). Asymmetric reduction with chiral 2,5-dimethylborolane also gave alcohols in high optical yields." Recently, excellent results have been obtained using a chirally modified sodium borohydride... 

Chiral titanium complexes 4 and 5, which were developed as chiral catalysts for asymmetric carbonyl-ene reactions with prochiral glyoxylate esters [50], were first apphed to the catalytic asymmetric allylation of carbonyl compounds by Mikami and Nakai (Scheme 5) [9]. The titanium catalysts are prepared from (S)-binaphthol and diisopropoxytitanium dihahde (X=C1 and Br) in the presence of 4 A molecular sieves. Using these catalysts, glyoxylates are enantio- and diastereoselectively allylated with allylic trimethylsilanes or allylic tributylstan-nanes. High levels of enantioselectivity and syn selectivity are observed for (E)-crotylsilane and -stannane. The syn selective allylation reaction is believed to proceed mainly through an antiperiplanar transition state. 

That is, in order for the phenomenon to be observed, both reactants must show inherent diastereoface selectivity in their reactions with achiral partners. If one of the reactants shows no inherent diastereoface selectivity in its reactions with achiral reactants, then mutual kinetic resolution will not be observed regardless of the stereoselectivity of the other reactant. For an example, consider the case of an enzyme which mediates some reaction, say reduction of the carbonyl group. We can let the enzyme be A and assume that, because of its uniquely-evolved molecular structure, it shows very high inherent diastereoface selectivity (thus, it will reduce prochiral carbonyl compounds to chiral alcohols with very high enantiomeric excess). For B, let us take a chiral aldehyde that shows no inherent diastereoface selectivity in its... 

Brown and Pai have reported [3] that the dissociation problem is also overcome by carrying out the reaction with the Alpine-Borane either as neat reagent or concentrated solutions (>2 M). The reduction of a wide range of prochiral carbonyl compounds with good to excellent asymmetric induction has been achieved. The reduction is performed at 25 °C by using either a 100 or 40% excess (for reactive substrate) of the reagent, synthesized by the hydroboration of commercial available 92% ee (-t)-a-pinene with 9-BBN. On completion of the... 

Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

The efficiency of these chiral host compounds has been shown in highly enantioselective photocyclization and photocycloaddition reactions of prochiral lactams. These substrates, for example 2-quinolone derivatives, are expected to coordinate to lactam 44 with its NH-group as the hydrogen donor and the carbonyl group as the hydrogen acceptor, as depicted in Scheme 15. In this complex, any... 

Asymmetric a-Hydroxylation of Enolates. a-Hydroxy lation of enolates represents one of the simplest and most direct methods for the synthesis of a-hydroxy carbonyl compounds, a key structural unit found in many natural products. Enolate oxidations using (+)- and (—)-(l) and their derivatives generally effect this transformation in good to excellent yields with a minimum of side reactions (e.g. over-oxidation). Furthermore, these reagents are the only aprotic oxidants developed to date for the direct asymmetric hydroxylation of prochiral enolates to optically active a-hydroxy carbonyl compounds. 

Among the carbon electrophiles, carbonyl compounds [113,114] were first applied in the reaction with lithiated ferrocenylalkyl amines (Sect. 4.S.3.3 and Fig. 4-18). Analogously, carboxylic acids are obtained from CO2 [153]. The reactivity pattern of palladated ferrocenylalkyl amines with carbon electrophiles is somewhat different. Carbon monoxide in alcohols leads to the formation of esters of substituted ferrocenecarboxylic acids [124]. With prochiral alcohols, a moderate asymmetric induction is observed [154]. a, -Unsaturated ketones react with palladated ferrocenylalkyl amines not with addition to the carbonyl group, but with substitution of a hydrogen at the carbon—carbon double bond, allowing the introduction of longer side chains at the ferrocene ring (Fig. 4-27c) [124, 152]. 

The majority of aliphatic ketones give the secondary alcohol on reduction at electrodes of carbon, mercury, lead, or platinum. The usual choice of electrolyte has been dilute sulfuric acid, acetate buffer, or a neutral salt solution, which will become alkaline during the course of reaction that consumes protons. Relatively few studies have been recorded of the isomer ratio obtained by reduction of open chain ketones with a prochiral center adjacent to the carbonyl function [32,33]. Results are collected in Table 2, and one aromatic carbonyl compound is included here for convenience. In general, the erythro-alcohol is favored and in an excess over that present in the equilibrium mixture [32,33]. These results are explained in terms of adsorption of intermediates at the electrode surface. For many of the examples in Table 2, the total yield of alcohol is low and this result is not generally typical of aliphatic carbonyl compounds, as can be seen from Table 3. 

Enantioselective protonation of prochiral enols or enolates, which provides synthetic access to optically active carbonyl compounds, is an elegantly simple test reaction for enantioselective reagents and catalysts, for which a number of examples have been described [80]. The only reaction described with alkyl enol ethers concerns the highly enantioselective protonation of enol ethers such as 55 by catalytic antibody 14D9, an antibody raised against hapten 10 [81]. Antibody 14D9 has a practical turnover of /c-at = 0.4 for substrate 55 and produces... 

The reactions of ailylboranes, -silanes and -stannanes with carbonyl compounds and imines always take place with double-bond migration, and the structural stability of the reagent is a common problem that is encountered ( 2.7). The reactions of ailylboranes and -boronates occur without catalysis, while those of allylsilanes and -stannanes usually require the presence of a Lewis add [253], The mechanism of the reactions of allylboron derivatives is concerted, and the addition occurs via a six-membered cyclic transition state. A slightly distorted chair transition state model in which the oxygen of the carbonyl group is coordinated to the boron atom is usually invoked (Figure 6.42). Various steric and polar interactions dictate whether the Si or Re face of the prochiral aldehyde is attacked (models C j... 

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