Prochiral compounds amination

Asymmetric deprotonation of a prochiral compound having a sufficiently acidic C-H bond can be performed by a lithium amide generated from an enantio-pure secondary amine or by an organolithium reagent in the presence of a chiral tertiary amine [557, 559]. A chiral mixed aggregate is usually formed [77, 81, 974], and the reaction of this intermediate with electrophiles (including proton sources) can lead to a predominant enantiomer. 

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 asymmetric nickel-catalyzed hydroalumination of prochiral terminal alkenes using adducts of BujAl and chiral amines was reported in 1981 [74], Among the different amines investigated, (-)-N,N-dimethylmenthylamine (DMMA) gave the best enantioselectivities. For example, reaction of 2,3,3-trimethyl-l-butene (39) at room temperature with 0.33 equiv. of the DMMA/iBu3Al adduct in the presence of 0.6 mol% of Ni(mesal)2 gave, after oxidation of the intermediate organoaluminum compounds, 2,3,3-trimethyl-l-butanol 40 in 76% yield and 27% ee (Scheme 2-19). 

Hydrosilylation of imine compounds was also an efficient method to prepare amines. The hydrosilylation product TV-silylamines can readily be desilylated upon methanol or water treatment, yielding the corresponding amines. The amines can be converted to their corresponding amides by subsequent acyl anhydride treatment. The first attempt to hydrogenate prochiral imines with Rh(I) chiral phosphine catalysts was made by Kagan102 and others. These catalysts exhibited low catalytic activity, and only moderate ee was obtained. 

In a series of reports between 1991 and 1997 Yamaguchi showed that rubidium salts of L-proline (9) catalysed the conjugate addition of both nitroalkanes [29, 30] andmalonates [31-33] to prochiral a,p-unsaturated carbonyl compounds in up to 88% ee (Scheme 1). Rationalisation of the selectivities observed involved initial formation of an iminium ion between the secondary amine of the catalyst and the a,p-unsaturated carbonyl substrate. Subsequent deprotonation of the nucleophile by the carboxylate and selective delivery using ion pair... 

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 ". ... 

Access to this type of compound is illustrated in Scheme 30 by the preparation of retro-sulfonamide tripeptide Boc-Pro-Leuijt[NH—S02]Gly-NH2(78). The two false termini used are the prochiral gem-diamino analogue of Leu and sulfoacetic acid. Amide to amine conversion according to Hofmann, carried out on the dipeptide Boc-Pro-Leu-NH2 (76) with iodobenzene l,l-bis(trifluoroacetate) gave the gem-diamino derivative 77. Coupling of the resulting gem-diamino derivative with methyl (chlorosulfonyl)acetate, followed by amida-tion of the intermediate methyl ester, afforded the desired pseudopeptide 78J1341 Full experimental details have not yet been reported. 

Among the many reactions of these species is the conversion to chiral species such as 18-D-XIX. This compound can be obtained in enantiomerically pure form and can be converted to the CpRe(NO)PPh3 ion.69 This ion is a chiral Lewis base that binds a variety of prochiral molecules (olefins, ketones, aldehydes, amines). With these adducts one may conduct numerous reactions where enantiomeric excesses >98% are obtained. As an example, a prochiral methyl ketone will bind selectively, as in 18-D-XX and is then subject to attack by R X to produce only one enantiomer of the RR MeCO product. 

Chiral derivatives or compounds having a prochiral group in the reactive center are frequently present among substrates, amines, and aldehydes used as reagents in Mannich synthc.sis. When at least two out of the three reagents are chiral or prochiral, the resulting Mannich base will be made up of a diastcrcomeric mixture of products. The main possible combinations of chiral or prochiral couples of reactants leading to diastereo-meric derivatives are reported in Fig. 36. 

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]. 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

Hydrosilylation of unsaturated organic molecules is an attractive organic reaction. Asymmetric hydrosilylation of prochiral ketones or imines provides effective routes to optically active secondary alcohols or chiral amines (Scheme 756). These asymmetric processes can be catalyzed by titanium derivatives. The ( A ebthi difluoro titanium complex has been synthesized from the corresponding chloro compound.1659 This compound results in a very active system for the highly enantioselective hydrosilylation of acyclic and cyclic imines and asymmetric hydrosilylation reactions of ketones including aromatic ketones.1661,1666,1926-1929 An analogous l,l -binaphth-2,2 -diolato complex catalyzes the enantioselective hydrosilylation of ketones.1... 

Despite the obvious potential of cinchona alkaloids as bifunctional chiral catalysts of the nucleophilic addition/enantioselective protonation on prochiral ketenes, no further contribution has appeared to date and only a few papers described this asymmetric reaction with other catalysts [13], When the reaction is carried out with soft nucleophiles, the catalyst, often a chiral tertiary amine, adding first on ketene, is covalently linked to the enolate during the protonation. Thus, we can expect an optimal control of the stereochemical outcome of the protonation. This seems perfectly well suited for cinchona analogues and we can therefore anticipate successful applications of these compounds for this reaction in the near future. 

Although prochiral or chiral alcohols and carboxylic acid esters initially served as the primary classes of substrates, compounds susceptible to processing via these two routes now encompass diols, a- and 3-hydroxy acids, cyanohydrins, chlorohydrins, diesters, lactones, amines, diamines, amino alcohols, and a-and 3-amino acid derivatives. Gotor and Arroyo have reviewed the use of biocatalysts for the preparation of pharma-eeutical intermediates and fine ehemieals. Some specific examples are indieated below. 

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