Prochiral imine

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). 

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... 

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. 

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 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. 

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. 

In 2001, p-lactams have been reported to be obtained via Staudinger reaction with complete m-diastereoselection starting from prochiral imine chromium complexes (Scheme 14), [63]. 

Scheme 14 cw-Diastereoselective synthesis of (3-lactams using prochiral imine chromium complexes... 

Prochiral imines to chiral amines Chiral enamine reductions Ir/Perfluoroalkyl modified-phosphinodihydrooxazoles/B(ArF)4 (it,R)-Et-DuPHOS-Rh+X X = B(f)4 or CF3S03]... 

Asymmetric addition of PhLi, coordinated by the chiral ligand 200, to the prochiral imine complex 199 generates 201. Discrimination between enantiotopic sites at C(2) and C(6) occurs. Then the 5,6-mmv-disubstituted 1,3-cyclohexadienal 202 was prepared with 93% ee by electrophilic attack of propargyl bromide [50],... 

Carbohydrate-derived auxiliaries exhibit an efficient stereoselective potential in a number of nucleophilic addition reactions on prochiral imines. a-Amino acids, P amino acids and their derivatives can be synthesized in few synthetic steps, and with high enantiomeric purity. A variety of chiral heterocycles can readily be obtained from glycosyl imines by stereoselective transformations, providing evidence that carbohydrates have now been established as useful auxiliaries in stereoselective syntheses of various interesting classes of chiral compounds. 

Asymmetric hydrosilylation of imines followed by hydrolysis of the JV-silyl-amine intermediate yields chiral amines. The Kagan group hydrosilylated a series of prochiral imines with both polymethylhydrogensiloxane and diphenyl ... 

Gluszynska, A., Rozwadowska, M. D. Enantioselective addition of methyllithium to a prochiral imine-the substrate in the Pomeranz-Fritsch-Bobbitt synthesis of tetrahydroisoquinoline derivatives mediated by chiral monooxazolines. Tetrahedron Asymmetry 20M, 15, 3289-3295. 

Scheme 2 The ADH of a prochiral imine performed on a large scale in industry...

Similarly, an iridium catalyst with a specific ferrocenylphosphine ligand (Scheme 2) is used in the production of the chiral amine (5)-metolachlor, a herbicide, by the asymmetric direct hydrogenation of a prochiral imine. ... 

While some influence of the degree of sulfonation of chiral BDPP on the enantioselectivity in the reduction of some dehydroamino acids was noticed by Sinou and co-workers [26], this effect was more pronounced in the reduction of prochiral imines [42,43]. Enantioselectivities up to 96% were observed in the reduction of these imines using monosulfonated BDPPms in association with rhodium [Eq. (5)], while tetra- and disulfonated BDPP gave lower enantioselectivities (34 and 2% ee, respectively). 

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