Enantiospecific catalysts

Another example of this preference is found in the enantiospecific syntheses of tritium-labeled leukotrienes(/i). Commercially available 3-nonyn-l-ol was converted to its phosphorane (16) and Wittig-coupled with the unsaturated aldehyde (17) to afford 18, which was reduced over Lindlar catalyst to give 19. 

Tocopherol can be produced as the pure 2R,4 R,8 R stereoisomer from natural vegetable oils. This is the most biologically active of the stereoisomers. The correct side-chain stereochemistry can be obtained using a process that involves two successive enantioselective hydrogenations.28 The optimum catalyst contains a 6, 6 -dimethoxybiphenyl phosphine ligand. This reaction has not yet been applied to the enantioselective synthesis of a-tocopherol because the cyclization step with the phenol is not enantiospecific. 

Cyclopentadienyl ligands have become extremely important in catalysis for metal such as Ti, Zr, and Hf (Chapter 10) and in academic studies of related elements such as Ta. Ethylene polymerisation with the use of CpiTiCE (alkylated with aluminium alkyl compounds) has been known for many decades, but the intensive interest in derivatives of these compounds started in the early 1980 s following the discovery of MAO (methaluminoxane - see chapter 10) which boosted metallocene catalyst activities by several orders of magnitude. Commercial interest focussed on ethylene copolymers (LLDPE where more homogeneous comonomer incorporation resulted in greatly improved copolymer properties) and in enantiospecific polymerisations for propene, styrene, etc. 

Summarising, in the chain-end control mechanism the last monomer inserted determines how the next molecule of 1-alkene will insert. Several Italian schools [7] have supported the latter mechanism. What do we know so far Firstly, there are catalysts not containing a stereogenic centre that do give stereoregular polymers. Thus, this must be chain-end controlled. Secondly, whatever site-control we try to induce, the chain that we are making will always contain, by definition, an asymmetric centre. As we have mentioned above, the nature of the solid catalysts has an enormous influence on the product, and this underpins the Cossee site-control mechanism. Thus both are operative and both are important. Occasionally, chain-end control alone suffices to ensure enantiospecifity. 

Statistical analysis is important and relatively easy. Suppose we have a fully atactic polymer which we analyse for the triad content for isotactic polymer. Only three methyl resonances due to triads are observed, and the statistical ratio of mm, rr, and mr is 1 1 2. Thus even in the atactic polymer our isotactic content is 25% Pentad analysis, however, would give only 8% mmmm isotactic content Especially for catalysts with low enantiospecificity it is worthwhile keeping this in mind. 

The formal view. The formal view is much simpler. The racemic catalysts have a twofold axis and therefore C2-symmetry. Both sites of the catalysts will therefore preferentially co-ordinate to the same face (be it re or si) of propene. Both sites will show the same enantiospecificity the twofold axis converts one site in the other one. Subsequently, insertion will lead to the same enantiomer. According to the definition of Natta, this means that isotactic polymer will be formed. If the chain would move from one site to the other without insertion of a next molecule of propene, it will continue making the same absolute configuration at the branched carbon atom. Hence, no mistake occurs when this happens. 

The benefits of C2-symmetry are due to the reduction of the number of possible catalyst-substrate isomers that may form, and the number of enantiospecific pathways (Helmchen, Pfaltz [9]). As they reasoned, there is no fundamental reason why a C2-symmetric ligand is superior qualitate qua to a Ci-symmetric ligand. Two different co-ordinating ligands (P-X as shown above, or P-N, discussed here) could lead to more control, as the attack may... 

Solution-state NMR studies suggest that the catalysts containing l- and D-Pro adopt p-turns and p-hairpins in solution,respectively. Reactions exhibit first-order dependence on catalyst 24, consistent with a monomeric catalyst in the ratedetermining step of the reaction. These catalysts exhibit enantiospecific rate acceleration, in comparison to the reaction rate when NMI is employed as catalyst. An isosteric replacement of an alkene for a backbone amide in a tetrapeptide catalyst (catalysts 32 and 33, Fig. 4) has lent credence to a proposed mechanism of rate acceleration [31). While catalyst 32 exhibits a fcrei=28 with substrate 27, alkene-containing catalyst 33 is not selective in this kinetic resolution and also affords a reduced reaction rate. This suggests that the prolyl amide is kinetically significant in the stereochemistry-determining step of the reaction. 

Basic research on the synthesis of analogs of the biologically active form of vitamin D3, la,25-dihydroxy vitamin D3 (la,25(OH)2D3) has led to the development of an important new field in medicinal chemistry [84]. We have also reported symmetry assisted enantiospecific synthesis of the A-ring of the vitamin D hybrid analogs, 19-nor-22-oxa-la,25(OH)2D3 (Sch. 29) [85], It should be noted here that extremely high 1,3-frans selectivity was achieved by combining the (f )-BINOL-Ti catalyst and the (i )-ene substrate without geminal disubstitution. 

Switzer JA, Kothari HM, Poizot P, Nakanishi S, Bohannan EW (2003) Enantiospecific electrodeposition of a chiral catalyst. Nature 425 490... 

Insertion of propene into alkylzirconium model compounds derived from isospecific bis-indenyl catalysts may lead to low enantiospecificity [65]. Thus, site control alone does not lead to high stereoregularities. Molecular mechanics calculations [66] and a thorough analysis of the substituent effect on the statistical distribution of microstructure defects indicate that, firstly, the polymer chain assumes the energetically most favourable position with respect to the (asymmetric) site. According to Corradini, the indenyl ligand or the chlorine atoms of the lattice will direct the pol)rmer chain. The polymer chain occupies the "free space" near the site. In Fig. 6.21 we have schematically drawn this for the TiCls... 

Tsai, S. W. and Dordick, J. S., Extraordinary enantiospecificity of lipase catalysis in organic media induced by purification and catalyst engineering, Biotechnol. Bioeng., 52, 296-300, 1996. 

Scheme4.Antibody A5, elicited to hapten 15, catalyzes the highly enantiospecific reduction of a-ketoamide 16 (>99% de) with sodium cyanoborohydride (NaCNBHj) as a cofactor. This is a good example of an achiral hapten generating a catalyst possessing exquisite chiral discrimination...

Unsaturated acyl oxazolidinones 1 undergo enantiospecific [2 + 2] cycloadditions with 1,1-di-methylthioethylene and a catalyst consisting of a 1 1 mixture of diisopropoxytitanium dichloride and the chiral diol 243,44. The cyclobutane 3 is obtained in excellent yield with high enantiomeric excess. This is the first example of the enantiospecific [2 + 2] cycloaddition yielding a cyclobutane using an external chiral auxiliary as a chiral catalyst. Unfortunately, the scope of this reaction is quite limited since it fails with vinyl ethers, silyl enol ethers and ketene silyl acetals. 

Alkylation by aziridines is of interest because it can introduce the 2-aminoethyl group which is found in many biologically active indoles. Zinc triflate was found to be the best catalyst for effecting enantiospecific alkylation of indoles by l-(Cbz)aziridine-2-carboxylate esters <89TL4073>. Aziridine (31) was used to stereospecifically introduce an a-methyltryptophan side-chain using BF3 as the catalyst (Equation (80)) <90CPB564>. 

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