Imines prochiral

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 synthesis of 2,3-diamino acids can be accomplished by the addition of chiral enolates to prochiral imines. For example, reaction of morpholine-2-one 103, derived from (S)-phenylglycinol, with N-benzyl ben-zaldimine in the presence of pyridine and para-toluenesulfonic acid at high... 

An even more impressive example of catalytic efficiency has recently been disclosed by Novartis (Bader and Bla.ser, 1997). The key step in a proce.ss for the synthesis of the optically active herbicide, (S)-metolachlor involves asymmetric hydrogenation of a prochiral imine catalysed by an iridium-ferrocenyldipho-sphine complex (see Fig. 2.36). 

Among the most active catalysts for the asymmetric transfer hydrogenation of prochiral ketones and imines to chiral alcohols and amines are arene-ruthenium(II) amino-alcohol (or primary/ secondary 1,2-diamine)-based systems, with an inorganic base as co-catalyst, developed by Noyori139-141 and further explored by others (Scheme 27).142-145... 

Prochiral imines can be hydrogenated to the corresponding amines with extremely high enan-tioselectivities in H20/ethyl ethanoate biphasic systems, using Rh1 complexes of sulfonated phosphines 342 The cationic rhodium complex [Rh(NBD)(131)]+ was an active catalyst for hydrogenation of 2-ethanamido-propenoic acid in aqueous solution.343... 

As an extension of the asymmetric hydrogenation of prochiral ketones to enantiomerically enriched alcohols, the reduction of imines has been a topic of interest in obtaining chiral amines of high enantiomeric purity. Several entries to enantiomerically enriched amines based on the approaches outlined above are available. These asymmetric hydrogenations have proved to be more difficult than those for prochiral ketones, but nevertheless show good promise. 

As outlined in Section II,E, ketone and imine groups are readily hydrogenated via a hydrosilylation-hydrolysis procedure. Use of chiral catalysts with prochiral substrates, for example, R,R2C=0 or R,R2C=N— leads to asymmetric hydrosilylation (284, 285 Chapter 9 in this volume) and hence optically active alcohols [cf. Eq. (41)]. 

The development of chiral phosphorus ligands has made undoubtedly significant impact on the asymmetric hydrogenation. Transition metal catalysts with efficient chiral phosphorus ligands have enabled the synthesis of a variety of chiral products from prochiral olefins, ketones, and imines in a very efficient manner, and many practical hydrogenation processes have been exploited in industry for the synthesis of chiral drugs and fine chemicals. 

In this chapter, we review the growing family of phospholane-based chiral ligands, and specifically examine their applications in the field of enantioselective hydrogenation. In general, this ligand class has found its broadest applicability in the reduction of prochiral olefins and, to a significantly lesser extent, ketones and imines this is reflected in the composition of the chapter. Several analogous phosphacycle systems have also been included, where appropriate. 

Chiral amines can also be produced using aminotransferases, either by kinetic resolution of the racemic amine or by asymmetric synthesis from the corresponding prochiral ketone. The reaction involves the transfer of an amino group, a proton and two electrons from a primary amine to a ketone, and proceeds via an intermediate imine adduct. A variety of chiral amines can be obtained with high to very high ee-values. Several transformations have been developed and can be carried out on a 100-kg scale [94]. 

Preparation of enantiomerically pare secondary amines by catalytic asymmetric hydrogenation or hydrosilylation of imines is as important as the preparation of alcohols from ketones. However, asymmetric hydrogenation of prochiral ON double bonds has received relatively less attention despite the obvious preparative potential of this process.98... 

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. 

Attempts to induce stereochemical control in the reduction of prochiral ketones and imines have been reported using chiral ammonium borohydrides [e.g. 16] (see Chapter 12). 

Prochirality Planar molecules possessing a double bond such as alkenes, imines, and ketones, which do not contain a chiral carbon in one of the side chains, are not chiral. When these molecules coordinate to a metal a chiral complex is formed, unless the alkene etc. has C2V symmetry. In other words, even a simple alkene such as propene will form a chiral complex with a transition metal. So will trans-2-butene, but cis-2-butene won t. If a bare metal atom coordinates to cis-2-butene the complex has a mirror plane, and hence the complex is not chiral. It is useful to give some thought to this and find out whether or not alkenes and hetero-alkenes form chiral complexes. One can also formulate it as follows complexation of a metal to the one face of the alkene gives rise to a certain enantiomer, and complexation to the other face gives rise to the other enantiomer. 

Asymmetric catalytic hydrogenation is unquestionably one of the most significant transformations for academic and industrial-scale synthesis. The development of tunable chiral phosphorous ligands, and of their ability to control enantioselectivity and reactivity, has allowed asymmetric catalytic hydrogenation to become a reaction of unparalleled versatility and synthetic utility. This is exemplified in the ability to prepare en-antiomerically enriched intermediates from prochiral olefins, ketones, and imines through asymmetric hydrogenation, which has been exploited in industry for the synthesis of enantiomerically enriched drugs and fine chemicals. 

By analogy with the enantioselective reduction of prochiral ketones to chiral alcohols an attractive method for producing enantiomerically pure amines would be enantioselective reductive amination of a ketone via enzymatic reduction of an imine intermediate (Scheme 6.11). Unfortunately the required enzymes-amine... 

This type of catalytic strategy has recently been extended to enantio-selective addition of alkyllithiums to certain prochiral imines (Scheme 18) (35). Relevantly, in the presence of a small amount of a chiral ether ligand, 1-naphthyllithium reacts with a sterically hindered imine of l-fluoro-2-naphthaldehyde (conjugate addition/elimination) to afford a binaphthyl compound in greater than 80% ee. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

Allylic alkylations using a benzophenone imine of glycine methyl ester as a prochiral nucleophile and chiral phosphine ligands on palladium produced optical yields up to 57% (equation 354).436... 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

Asymmetric hydrosilylation of prochiral carbonyl compounds, imines, alkenes and 1,3-dienes has been extensively studied and continues to be one of the most important subjects in the hydrosilylation reactions. This topic has been reviewed at each stage of its development as a useful synthetic method based on asymmetric catalytic processes1,3,187-189. In the last decade, however, substantial progress has been made in the efficiency of this reaction. Accordingly, this section summarizes the recent advances in this reaction. 

TABLE 6. Asymmetric reduction of prochiral imines via hydrosilylation catalyzed by (S,S)-(EBTHI)Ti complex" in THF... 

Asymmetric hydrosilylation of prochiral imine IV-oxides (nitrones) (209-211) catalyzed by R Cl SH—)-tolbinap]2(NEt3) with H2SiPh2 gives the corresponding /V,/V-disLibslihilcd hydroxylamines (212-214) with high enantiomeric purity (equations 82-84)230. 

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