From prochiral substrates

Asymmetric synthesis involves the enantioselective conversion of a prochiral substrate to an optically active product. From an economic and environmental standpoint the chiral entity should function catalytically, and can involve either a chemical or a biochemical catalyst. 

Examples of the use of all of these technologies for the production of optically active compounds on an industrial scale, are provided in the text. The emphasis will be on examples which illustrate environmental considerations. 

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In the area of [3 + 2]-cycloadditions (1,3-dipolar cycloadditions), chiral silver catalysts have been utilized extensively for the enantioselective formation of five-membered rings from prochiral substrates. For example, Zhang and co-workers360 have reported the highly enantioselective Ag(i)-catalyzed [3 + 2]-cycloaddition of azomethine ylides to electron-deficient alkenes. Thus, reaction of ct-imino esters 442 with dimethyl maleate in the presence of catalytic amounts of silver(i) acetate and the chiral bisferrocenyl amide phosphine 443 provided the chiral pyrrolidines 444 with high stereoselectivities and chemical yields (Scheme 131). Only the endo-products were isolated in all cases. 

The successful execution of AHRs for the formation of 6,6- and 6,5-ring systems from prochiral substrates clearly suggested an extension of the method to the formation of 5,5-systems, which form the backbone of a large number of natural products. The use of prochiral cyclopentadienyl systems, however, involves the... 

One of the easiest ways to prepare chiral polymers is the polymerization of optically pure monomers. These monomers can be derived or isolated from the chiral pool, be synthesized from prochiral substrates using asymmetric catalysis, or be obtained by lipase-catalyzed resolution of a racemate followed by further synthetic manipulation. 

Breitgoff, D., Essert, T. Laumen, K., and Schneider, M.P. Hydrolytic Enzymes in Organic Synthesis - Chiral Building Blocks from Prochiral Substrates. In. F.E.C.S. Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod., 3rd, Vol. 2, VCH Weinheim, 1987, pp. 127-147. 

This implies all chiral centers are created at the time of the Diels-Alder reaction, but some are formed prior to the Diels-Alder and some after. It is important to specify the timing of the reactions and their sequence. If chiral centers are created from prochiral substrates, control of the geometry of diene and alkene is important. If chiral centers are incorporated into the diene and alkene, an asymmetric synthesis is required, possibly using a chiral starting material. 

D.i.d. Diquinanes. The successful execution of AHRs for the formation of 6,6- and 6,5-ring systems from prochiral substrates clearly suggested an extension of the method to the formation of 5,5-systems, which form the backbone of a large number of natural products. The use of prochiral cyclopentadienyl systems, however, involves the generation of a rr-allylpalladium species, which must then be trapped with a suitable nucleophile. " The greater reactivity of the 1,3-diene substrate toward the silver salts used in the reactions and the propensity for undesirable side reactions such as Diels-Alder cycloadditions must also be borne in mind. The former problem, in fact, figures prominently in the first example of an AHR-based diquinane synthesis to be published (Scheme... 

Enantioselective oxidation catalysis to yield chiral products from prochiral substrates using polyoxometalate catalysts has not been observed until recently. However, in a combined effort of several research groups it has been shown that the racemic vanadium-substituted sandwich type polyoxometalate, [(V 0)2ZnW(ZnW9034)2] , is an extremely effective catalyst (up to 40 000 turnovers) at near ambient temperatures, for the enantioselective epoxidation of aUyHc alcohols to the 2R,3R-ejx)xyalcohol with the sterically crowded chiral hydroperoxide, TADOOH, as oxygen donor [31], Scheme 8.6. 

The hand-in-glove fit of a chiral substrate into a chiral receptor is relatively straightforward, but it s less obvious how a prochiral substrate can undergo a selective reaction. Take the reaction of ethanol with NAD+ catalyzed by yeast alcohol dehydrogenase. As we saw at the end of Section 9.13, the reaction occurs with exclusive removal of the pro-R hydrogen from ethanol and with addition only to the Re face of the NAD+ carbon. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

Encapsulated rhodium complexes were prepared from Rh-exchanged NaY zeolite by complexation with (S)-prolinamide or M-tert-butyl-(S)-prolinamide [73,74]. Although these catalysts showed higher specific activity than their homogeneous counterparts in non-enantioselective hydrogenations, the hydrogenation of prochiral substrates, such as methyl (Z)-acetamidocinnamate [73] or ( )-2-methyl-2-pentenoic acid [74], led to low... 

In turn, a lipase-promoted acylahon of prochiral substrates 104, using lipases from Candida cylinracea and Chromobacterium viscosum and methyl isobutyrate or acetoxime isobutyrate as the acyl donors, gave the product 105 in yields up to 80% and with ees up to 75% (Equahon 50). ... 

The efficiency of the new ligands was examined in enantioselective hydrogenation of some prochiral substrates. Itaconic ester hydrogenation using in situ prepared Rh-complexes was the first test reaction chosen. The best results from... 

Complex 7-AI2O3/PTA/ (/< ./< )-(Mc-DuPHOS)Rh(COD) 1 (1) was prepared and tested in the hydrogenation of the prochiral substrate methyl-2-acetamidoacrylate (MAA). After full conversion, the products were separated from the catalyst and analyzed for Rh and W content and product selectivity. The catalyst was re-used three times. Analytical results show no rhodium leaching is observed. Complex 1 maintains its activity and selectivity in each successive run. The first three runs show tungsten (W) leaching but after that no more W is detectable. The leached W comes from the excess of PTA on alumina. The selectivity of both tethered and non-tethered forms gave the product in 94% ee. 

The subject of asymmetric synthesis generally (214, 215) gained new momentum with the potential use of transition metal complexes as catalysts. The use of a complex with chiral ligands to catalyze a synthesis asymmetrically from a prochiral substrate is advantageous in that resolution of a normally obtained racemate product may be avoided, for example,... 

The bis-DIOP complex HRh[(+)-DIOP]2 has been used under mild conditions for catalytic asymmetric hydrogenation of several prochiral olefinic carboxylic acids (273-275). Optical yields for reduction of N-acetamidoacrylic acid (56% ee) and atropic acid (37% ee) are much lower than those obtained using the mono-DIOP catalysts (10, II, 225). The rates in the bis-DIOP systems, however, are much slower, and the hydrogenations are complicated by slow formation of the cationic complex Rh(DIOP)2+ (271, 273, 274) through reaction of the starting hydride with protons from the substrate under H2 the cationic dihydride is maintained [cf. Eq. (25)] ... 

However, the exquisite selectivity of hydrolase enzymes is, perhaps, best illustrated by their ability to produce optically active compounds from prochiral and mew-substrates. In both these cases a theoretical yield of 100% for optically pure material is possible (Scheme 4)[12, 13]. 

The reasons for the increasing acceptance of enzymes as reagents rest on the advantages gained from utilizing them in organic synthesis Isolated or wholecell enzymes are efficient catalysts under mild conditions. Since enzymes are chiral materials, optically active molecules may be produced from prochiral or racemic substrates by catalytic asymmetric induction or kinetic resolution. Moreover, these biocatalysts may perform transformations, which are difficult to emulate by transition-metal catalysts, and they are environmentally more acceptable than metal complexes. 

Figure 10.5 Some examples of the formation of chiral compounds from prochiral starting substrates with a double bond.

Figure 10.6 Example of the fonmtion of chiral compound from prochiral meso-substrates.

Usually the enantiomeric excess is calculated for a standard conversion process a single irreversible batch reaction in a homogeneous solution starting from racemic or prochiral substrate. However, if the assumptions that were used for the derivation of Eqns. (10.14), (10.15) and (10.17) do not hold, different equations apply, and the enantiomeric excess may be higher or lower. Table 10.3 shows an overview of some modifications, including some potential improvements (substrate racemization) and problems (equilibration) that were treated in Chapter 2. Clearly, many modifications will lead to a decrease rather than to an increase of the enantiomeric excess. 

The asymmetric transamination from chiral a-amino acids 1021 and amino acid derivatives (57) (esters 86,103), amino alcohols 104 ) to carbonyl functions in prochiral substrates (58) (a-keto acids 102), a-keto esters 86,103), ketones 103b d) was described... 

A diastereoface-differentiating reaction is a reaction in which one diastereomer is produced more than the other from the substrate containing both chirality and sp2-prochirality, as shown in Fig. 17. Both sides of the molecular plane of such a molecule are called diastereofaces. One of the diaslereomers could be produced more than the other when the catalyst or reagent differentiates one of the diastereofaces and performs an addition reaction. Thus, we call this type of reaction a "diastereoface-differentiating reaction."... 

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