Asymmetric ortho-substitution

Modification of the electronic and steric properties of BINAP, BIPHEMP, and MeO-BI-PHEP led to the development of new efficient atropisomeric ligands. Although most of them are efficient for ruthenium-catalyzed asymmetric hydrogenation [3], Zhang et al. have recently reported an ortho-substituted BIPHEP ligand, o-Ph-HexaMeO-BIPHEP, for the rhodium-catalyzed asymmetric hydrogenation of cyclic enamides (Scheme 1.2) [31]. 

Starting from the findings of the racemic cross-benzoin condensation [66], and assuming that aldehydes not accepted as donor substrates might still be suitable acceptor substrates, and vice versa, a mixed enzyme-substrate screening was performed in order to identify a biocatalytic system for the asymmetric cross-carboligation of aromatic aldehydes. For this purpose the reactions of 2-chloro-(40a), 2-methoxy- (40b) and 2-methylbenzaldehyde (40c), respectively, were studied with different enzymes in combination with benzaldehyde (Scheme 2.2.7.23) [67]. The three ortho-substituted benzaldehyde derivatives 40a-40c were... 

In most cases chiral carbonyl compounds also afford low stereoselectivity. As for the related Passerini reaction, even the use of aldehydes that are known to give excellent asymmetric induction in the reaction with other kinds of C-nucleophiles, results in low or moderate diastereoisomeric ratios. For example, both norbornyl aldehyde 39 [47] and a-alkoxyaldehyde 40 [3, 48] gave drs lower than 2 1 (Scheme 1.16). The same happens with ortho-substituted chromium complex 41 [49], which usually leads to very high asymmetric induction in other nucleophilic additions. Finally, //-substituted aldehyde 42 [50] gave poor results as well. 

The chiral center most frequently encountered is the asymmetric carbon atom, a tetrahedral C atom, bonded to four different substituents. Chiral centers of this type are known for many other elements (4). However, chiral centers are also found in other polyhedra, e.g., the metal atoms in octahedral compounds containing three bidendate chelate ligands. Chirality axes, present in the atrop isomers of ortho-substituted biaryls, occur in coordination chemistry in appropriately substituted aryl, pyridyl, and carbene metal complexes. Well known examples of planar chirality in organometallic chemistry are ferrocenes, cymantrenes, and benchrotrenes containing two different substituents in 1,2- or 1,3-positions relative to each other (5-5). 

Scheme 9.11 Rh catalyzed asymmetric hydrogenation of ortho substituted arylenamides with a triphosphorus bidentate phosphine phosphoramidite ligand 49.

Planar chiral ortho substituted benzaldehyde chromium complexes are useful compounds for a variety of asymmetric reactions. For example, planar chiral tricarbonylchromium complexes of o-substituted benzaldehydes were reacted with Danishefsky s diene in the presence of Lewis acid at room temperature to afford the chromium-complexed 2,3-dihydro-4-pyranones 25 with high dias-tereoselectivity (Eq. 15) [14]. The high diastereoselectivity of the formation of cycloaddition products 25 is also contributed to an exo-side approach of the diene to anti-oriented carbonyl oxygen of the planar chiral ortho substituted benzaldehyde chromium complexes. When the reaction takes place at lower temperature, aldol-type condensation product 26 was obtained along with the formation of pyranones. The open intermediate 26 was easily transformed to the corresponding cycloaddition product after stirring at room temperature [14]. 

High asymmetric inductions have been achieved in the additions of 2-haloesters or 2-halonitriles (X = Cl, Br) to the aldehyde substituent on the ortho-substituted arene complexes (66), X = Me, MeO. 

Recently, some elegant work was reported on the preparation of chiral ortho-substituted phenol derivatives through intramolecular chirahty transfer by Trost et al. [64]. Chiral substrate 78 was prepared in excellent enantiomeric excess from phenol and racemic aUyUc carbonate through asymmetric O-aUylation with dynamic kinetic asymmetric transformation. They showed that a europium(lll) tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate) Eu(fod)3-catalyzed rearrangement proceeds at 50 °C to give product 79 with complete chirahty transfer. 

Scheme 7.32 Asymmetric addition of arylboronic acids to N-benzylisatins catalyzed by Pd-tetra-ortho-substituted phosphinoimine ligand as reported by Qin and coworkers [51],...

A. Alexakis, F. Rose-Munch, E. Rose et al. - Resolution and Asymmetric Synthesis of Ortho-Substituted Benzaldehyde-Tricarbonyl-Chromium Complexes,... 

Among the chiral alcohols screened for the reaction of 4-methylphenol, (—)-menthol was the most effective giving rise to the hydroxyalkylation product in excellent yield with the asymmetric induction of 48% ee. Much higher asymmetric induction can be realized with some ortho-substituted phenols. 

Zhou Y-G, Tang W, Wang W-B, Li W, Zhang X. Highly effective chiral ortho-substituted BINAPO ligands (o-BINAPO) applications in Ru-catalyzed asymmetric hydrogenations of p-aryl-substituted p-(acylamino)acrylates and P-keto esters. J. Am. Chem. Soc. 2002 124(18) 4952-4953. 

Nishida, G., Noguchi, K., Hirano, M. and Tanaka, K. (2007) Asymmetric assembly of aromatic rings to produce tetra-ortho-substituted axially chiral biaryl phosphorus compounds. Angewandte Chemie International Edition, 46(21), 3951-3954. Heller, B., Gutnov, A., Fischer, C., et al. (2007), Phosphorus-bearing axially chiral biaryls by catalytic asymmetric cross-cyclotrimerization and a first application in asymmetric hydrosilylation. Chemistry—A European Journal, 13(4), 1117-1128. 

This is best illustrated by taking hindered biphenyls as example. If the two ortho positions on each ring be differently substituted and that too with groups large enough to cause steric hindrance, then due to restricted rotation along the central bond, two asymmetric isomers come to exist which become the mirror images of each other with equal and opposite rotations. 

The first report to use diphosphite ligands in the asymmetric hydroformylation of vinyl arenes revealed no asymmetric induction [46]. An important breakthrough came in 1992 when Babin and Whiteker at Union Carbide patented the asymmetric hydroformylation of various alkenes with ee s up to 90%, using bulky diphosphites 2a-c derived from homochiral (2R, 4R)-pentane-2,4-diol (Scheme 4) [17]. Their early results showed that (a) bulky substituents are required at the ortho positions of the biphenyl moieties for good regio- and enantio-selectivity and (b) methoxy substituents in the para positions of the biphenyl moieties always produced better enantio-selectivities than those observed for the corresponding ferf-butyl-substituted analogues. 

The first of two conversions catalyzed by the metalloenzyme tyrosinase is the selective ortho-hydroxylation of a phenol moiety, yielding catechol. Few synthetic systems exist that are capable of selectively performing the same monooxygenase reaction [172-178]. The group of Casella has studied a series of dicopper complexes based on 2,6-disubstituted benzene hgands providing two N3 compartments [179-181] (26a,b) as well as the asymmetrically substituted tripodal amine-based ligand (27) [182]. 

In the case of the formation of the [3-lactam, it was shown that the ability of a compound to crystallize in a chiral space group was increased by using compounds with meta-substituted aryl groups such as 50a-d instead of their ortho- and para-substituted analogues the absolute asymmetric photocyclization of the pyridones resulted in the formation of 51a-d with good ees.[31]... 

Significant levels of syn diastereoselectivities (5 1 to 16 1) were observed for all substrates, with the exception of an ortho-chloro-substituted aryl imine, which provided only 2 1 syn selectivity. The catalyst was viable for a variety of nitroalkanes, and afforded adducts in uniformly high enantioselectivities (92-95% ee). The sense of enantiofacial selectivity in this reaction is identical to that reported for the thiourea-catalyzed Strecker (see Scheme 6.8) and Mannich (see Tables 6.18 and 6.22) reactions, suggesting a commonality in the mode of substrate activation. The asymmetric catalysis is likely to involve hydrogen bonding between the catalyst and the imine or the nitronate, or even dual activation of both substrates. The specific role of the 4 A MS powder in providing more reproducible results remains unclear, as the use of either 3 A or 5 A MS powder was reported to have a detrimental effect on both enantioselectivities and rates of reaction. 

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