Chiral stereoselective metalation

The use of chiral transition-metal complexes as catalysts for stereoselective C-C bond forming reactions has developed into a topic of fimdamental importance. The allyhc alkylation is one of the best known of this type of reaction. It allows the Pd-catalyzed substitution of a suitable leaving group in the allylic position by a soft nucleophile. 

To date, direct asymmetric synthesis of optically active chiral-at-metal complexes, which by definition leads to a mixture of enantiomers in unequal amounts thanks to an external chiral auxiUary, has never been achieved. The most studied strategy is currently indirect asymmetric synthesis, which involves (i) the stereoselective formation of the chiral-at-metal complex thanks to a chiral inductor located either on the ligand or on the counterion and then (ii) removal of this internal chiral auxiliary (Fig. 4). Indeed, when the isomerization of the stereogenic metal center is possible in solution, in-... 

Other chiral ligands such as BINAP (where BINAP is bis(diarylphosphino)-1,1 binaphthyl) or aminophosphines are also efficient for stereoselective synthesis of chiral-at-metal Ru complexes [39-41]. 

Chiral-at-metal cations can themselves serve as chirality inducers. For example, optically pure Ru[(bipy)3] proved to be an excellent chiral auxihary for the stereoselective preparation of optically active 3D anionic networks [M(II)Cr(III)(oxalate)3]- n (with M = Mn, Ni), which display interesting magnetic properties. In these networks all of the metalhc centers have the same configuration, z or yl, as the template cation, as shown by CD spectroscopy and X-ray crystallography [43]. 

Figure 1.10 Preinsertion intermediates for secondary propene insertion into primary polypropylene chain for (a) isospecific model complex based on (R, R)-coordinatedisopropyl-bis(l-indenyl) ligand and (b) syndiospecific model complex based on isopropyl(cyclopentadienyl-9-fluorenyl) ligand for R chirality at metal atom. Stereoselectivity of isospecific model site is in favor of opposite monomer prochiral faces for primary and secondary insertions (cf. Figures 1.4 and 1.10a). Stereoselectivity of syndiospecific model site is in favor of same monomer prochiral face for primary and secondary insertions (cf. Figures 1.6a and 1.1 Ob).

Unsaturated organic compounds are reduced by various neutral and anionic metal hydrides with or without transition metal catalysts. Certain chiral transition metal complexes, when used as catalysts, exhibit unique regio- and stereoselectivity. 

In addition, the reader may realize that axis of rotation can still be present in some chiral Cp-metal complexes (e.g., a C2 axis in the enantiomeric forms in 22 and 23, a C5 axis in 24). With rotation axes present the systems are not asymmetric, only dissymmetric (i.e., lacking mirror symmetry). This is, however, sufficient to induce the existence of enantiomeric forms (218). Moreover, it is known from numerous examples that chiral ligands with C2 symmetry can provide for a higher stereoselectivity in (transition metal-catalyzed) reactions than comparable chiral ligands with a total lack of symmetry. The effect is explained by means of a reduced number of possible competing diastereomeric transition states (218). Hence, rotational symmetry elements may be advantageous for developing useful Cp-metal-based catalytic systems. 

The chirality of the phenylalanine derivative 10 is used for a direct, stereoselective a-alkylation (Scheme 2) [19]. After treatment with base and reaction with an electrophile the a-alkylated amino acid 11 is obtained in up to 88 % ee. It is not yet clear whether the deprotonated species is an enolate with a chiral nitrogen atom (12) or a chiral, a-metallated compound (13). The protecting groups on the nitrogen seem to play an important role. It is not yet possible to alkylate other phenylalanine derivatives by means of this reaction. 

In addition to stereoselective metalation, other methods have been applied for the synthesis of enantiomerically pure planar chiral compounds. Many racemic planar chiral amines and acids can be resolved by both classical and chromatographic techniques (see Sect. 4.3.1.1 for references on resolution procedures). Some enzymes have the remarkable ability to differentiate planar chiral compounds. For example, horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidation of achiral ferrocene-1,2-dimethanol by NAD to (S)-2-hydroxymethyl-ferrocenealdehyde with 86% ee (Fig. 4-2la) and the reduction of ferrocene-1,2-dialdehyde by NADH to (I )-2-hydroxymethyl-ferrocenealdehyde with 94% ee (Fig. 4-2lb) [14]. Fermenting baker s yeast also reduces ferrocene-1,2-dialdehyde to (I )-2-hydroxymethyl-ferro-cenealdehyde [17]. HLADH has been used for a kinetic resolution of 2-methyl-ferrocenemethanol, giving 64% ee in the product, (S)-2-methyl-ferrocenealdehyde... 

The reaction is stereoselective, and by simply varying the attachment point of the chiral pro-metal auxiliary to the starting arene, all four possible monoketal diastere-omers were shown to be accessible. 

Chiral crotylboronates (216) and (217) were among the first chiral allyl metal reagents to be used in double asymmetric reactions. The example in Scheme 47, however, shows that (217) induces only modest changes in the stereoselectivity of the reactions of (249), thus underscoring the need for highly enantioselective chiral reagents. 

Of all the chiral allyl metal reagents repotted to date, the one that is most effective in demanding cases of mismatched double diastereoselection is the a-methoxycrotylboronate (268) developed by Hoffmann. Two illustrative cases are presented in Scheme 52. First, the reaction of (280) and (/ )-(268) provides the 3,4-anti-4,5-anti diastereomer (281) with roughly 84% stereoselectivity. This is remarkable in view of the very high intrinsic diastereofacial selectivity (98 2) for the 3,4-anti-4,5-syn diastereomer exhibited by the structurally related aldehyde (147 Table 4). The second involves ([283), which with (5)-(268) provides 3,4-anti-4,5-anti (284) with 73% stereoselection. By way of comparison, the a-chlorocrotylboronate (5)-(237) is incapable of overriding the intrinsic diastereofacial preference of (283), giving 3,4-anti-4,5-syn diastereomer (E)-(285) with 92% selectivity (compare also 277, Scheme 51). 

In principle a metal atom may also be stereogenic (and therefore influence the stereoselectivity), but a separate category is not needed since chiral nonracemic metal complexes containing achiral ligands are rare in asymmetric synthesis [53]. 

A facinating application of homogeneous catalysis is asymmetric catalysis. The 2001 Nobel Prize in Chemistry was given for research in the field of chiral transition metal catalysts for stereoselective hydrogenations and oxidations. 

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