Chiral modifications

The chemistry of complexes having achiral ligands is based solely on the geometrical arrangement on titanium. Optically active alcohols are the most favored monodentate ligands. Cyclopentadienyl is also well suited for chiral modification of titanium complexes. 

An alternative approach to asymmetric synthesis that avoids covalent modification of the substrate is chiral modification of the active reagent. This not only streamlines the number of synthetic manipulations, but it simplifies the isolation of the desired product. In the case of zinc carbenoids, such modifications are feasible alternatives to the use of a standard chiral auxiliary. Two important factors combine... 

The conceptual complement to the chiral modification of the catalyst is the temporary modification of the substrate. Unlike the chiral auxiliary strategy, temporary substrate modification has greater latitude in introducing the kind of groups... 

The a-D-glucofuranose derivative 1 was the first reported protic additive used for the chiral modification of an organometallic reagent16. 

Chiral modification of diorganomagnesium compounds with the dilithium salt oi (S)-l,l -bi-naphthalene-2,2 -diol gave reagents with the empirical formula 30. Good to excellent enantiose-lectivities were observed in addition reactions of aliphatic and aromatic reagents to aromatic aldehydes30,31, however, the selectivities were not satisfactory with allylic, vinylic and acetylenic reagents. 

Addition of the analogous methyltitanium reagent to bcnzaldchydc afforded the addition product with only 59% ee34. Use of the methyltitanium reagent obtained via chiral modification by the tartaric acid derived diol 43, did not lead to an improvement of the enantioselectivity42. 

It seems also meaningful to recall that, for both PVL and iPP, the metastable chiral modification is not obtained from solution. This fact is hard to rationalize if polymorphic discrimination occurs on the basis of the secondary nucleation site which should exist also in the presence of the solution it rather points to diffusion and to transport problems in the melt, or thermodynamic control in solution. 

As Figure 14.5 shows, the enantio-differentiating (e.d.) hydrogenation consists of three processes (1) catalyst preparation, (2) chiral modification, and (3) hydrogenation reaction. These processes imply preparation variables for activated nickel, as a base catalyst for modified Ni, modification variables for the activated catalyst, and reaction variables of the hydrogenation processes, respectively. All these factors should be optimized for each type of substrate. 

The chapter Chiral Modification of Catalytic Surfaces [84] in Design of Heterogeneous Catalysts New Approaches based on Synthesis, Characterization and Modelling summarizes the fundamental research related to the chiral hydrogenation of a-ketoesters on cinchona-modified platinum catalysts and that of [3-ketoesters on tartaric acid-modified nickel catalysts. Emphasis is placed on the adsorption of chiral modifiers as well as on the interaction of the modifier and the organic reactant on catalytic surfaces. 

The modification of platinum-group metals by adsorbed chiral organic modifiers has emerged as an efficient method to make catalytic metal surfaces chiral. The method is used to prepare highly efficient catalysts for enantioselective hydrogenation of reactants with activated C = O and C = C groups. The adsorption mode of the chiral modifier is crucial for proper chiral modification of the active metal surfaces. The most efficient chiral modifiers known today are cinchona alkaloids, particularly CD, which yields more than 90% enantiomeric excess in the hydrogenation of various reactants. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

E. R. Grandbois, S. I. Howard and J. D. Morrison (1983). Reduction with chiral modifications of lithium aluminium hydride , in Asymmetric Synthesis. Ed. J. D. Morrison. Orlando, Florida Academic Press, Vol. 2A, p. 71. 

Chiral modifications of the catalyst system are possible, but the synthesis is tedious and the chiral inductions of such complexes have not prevailed so far. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

If the latter reaction proceeds through a closed transition state (e.g., 5 in Scheme 7.2), good diastereocontrol can be expected in the case of trans- and cis-CrotylSiCl3 (2b/2c) [14, 15]. Here, the anh-diastereoisomer 3b should be obtained from trans-crotyl derivative 2b, whereas the syn-isomer 3c should result from the reaction of the cis-isomer 2c (Scheme 7.2). Furthermore, this mechanism creates an opportunity for transferring the chiral information if the Lewis base employed is chiral. Provided that the Lewis base dissociates from the silicon in the intermediate 6 at a sufficient rate, it can act as a catalyst (rather than as a stoichiometric reagent). Typical Lewis bases that promote the allylation reaction are the common dipolar aprotic solvents, such as dimethylformamide (DMF) [8,12], dimethyl sulfoxide (DMSO) [8, 9], and hexamethylphosphoramide (HMPA) [9, 16], in addition to other substances that possess a strongly Lewis basic oxygen, such as various formamides [17] (in a solution or on a solid support [7, 8, 18]), urea derivatives [19], and catecholates [10] (and their chiral modifications [5c], [20]). It should be noted that, upon coordination to a Lewis base, the silicon atom becomes more Lewis acidic (vide infra), which facilitates its coordination to the carbonyl in the cyclic transition state 5. 

DNA sequence analyses and/or to analyze oligonucleotides, DNA-restriction fragments, amino acids or PCR products. Many hundred thousand analytical data points can be accumulated per day using commercially available instruments [55], Therefore chiral modification of such techniques, if successful, should allow for the first time super-high-throughput analyses of enantiomeric purity (ee) [51]. 

Various other applications are conjugate addition, 4 the ultrasound-promoted perfluoralkylation of SMP enamines, the enantioselective fluorodehydroxylation of SMP 1-yl-sulfur trifluoride, asymmetric telomerization of butadiene, the chiral modification of ruthenium clusters, and the application of SMP amide bases. ... 

Chiral Modification of Achiral Organometallic Reagents. The addition of n-Butyllithium or Ethylmagne-sium Bromide to aldehydes or ketones in the presence of (—)-sparteine resulted in the formation of optically active secondary or tertiary alcohols with 20% ee or lower. Optically active acyl sulfoxides (<15% ee) were obtained by acylation of p-Tolylsulfinylmethyllithium. The asymmetric Reformatsky reaction of ethyl bromoacetate with benzaldehyde proceeds with 95% ee, in an exceptional case (eq 1). ... 

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