Substrate-directed stereoselective synthesis

This chapter will concentrate on examples of templated synthesis where the template takes the form of a temporary, covalent tether. The intermediate molecule containing both reacting species is in all cases isolable (or potentially so). This distinguishes this intra molecularization approach from substrate-directed stereoselective synthesis. In this case, the template, most frequently a metal, is used in a much more transient sense allowing the potential for developing catalytic systems, which is obviously not possible using a covalently bound template. 

Kim H, Yen C, Preston P, Chin J. Substrate-directed stereoselectivity in vicinal diamine-catalyzed synthesis of warfarin. Org. Lett. 2006 8(23) 5239-5242. 

NeuA, has broad substrate specificity for aldoses while pyruvate was found to be irreplaceable. As a notable distinction, KdoA was also active on smaller acceptors such as glyceraldehyde. Preparative applications, for example, for the synthesis of KDO (enf-6) and its homologs or analogs (16)/(17), suffer from an unfavorable equilibrium constant of 13 in direction of synthesis [34]. The stereochemical course of aldol additions generally seems to adhere to a re-face attack on the aldehyde carbonyl, which is complementary to the stereoselectivity of NeuA. On the basis of the results published so far, it may be concluded that a (31 )-configuration is necessary (but not sufficient), and that stereochemical requirements at C-2 are less stringent [71]. 

Conversely, the addition of enantiomerically pure chiral dialkylboranes to enantiomerically pure chiral alkenes can also take place in such a way that substrate control and reagent control of diastereoselectivity act in the same direction. Then we have a matched pair. It reacts faster than the corresponding mismatched pair and with especially high diastereoselectivity. This approach to stereoselective synthesis is also referred to as double stereodifferentiation. 

The zinc-based Simmons-Smith type procedures frequently require rather harsh conditions in order to provide acceptable cyclopropane yields. Also, the discrimination between allylic alcohols, homoallylic alcohols and olefins without a hydroxyl group is often not very pronounced. These drawbacks are avoided by a new method which substitutes samarium metal (or samarium amalgam) for zinc (Table 4)43. This cnahlcs only allylic alcohols to be cyclo-propanated under very mild conditions, even for highly crowded substrates. The hydroxy-directed diastereofacial selectivity is good to excellent for cyclic olefins. Due to this property, the method has been applied to the stereoselective synthesis of 1,25-dihydroxycholecalciferol44. 

Once we realized that the substrate-directed arylation strategy could promote a rapid increase in the structural complexity of the allylic acetates, we decided to apply it in the total synthesis of biologically active kavalactones, represented by compound 18 in Scheme 7. The key step would be the stereoselective arylation of the substrate 19, which would lead us directly to the core skeleton of these natural products. 

This methodology was also applied to the stereoselective arylation of substituted cyclic compounds to provide highly complex aryl-substituted cyclo-pentene scaffolds with total control of the double bond position. This unique substrate-directed Heck-Matsuda reaction was applied in the total synthesis of the SlPi agonist VPC01091 (130). 

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. 

The asymmetric synthesis of allenes by stereoselective manipulations of enantio-merically pure or enriched substrates relies on the availability of such optically active substrates. In contrast, a direct synthesis of allenes by the reaction of prochiral substrates in the presence of an external asymmetric catalyst is an almost ideal process [102]. Most of the catalytic asymmetric syntheses in organic chemistry involve the creation of chiral tetrahedral carbon centers [103], whereas the asymmetric synthesis of allenes requires the construction of an axis of chirality. 

Recently, another interesting application of nitrilases has been demonstrated for the synthesis of pregabalin-the API of the neurophatic pain drug Lyrica. In this approach, the key step is the resolution of racemic isobutylsuccinonitrile (Scheme 10.8) [18], the process takes place with total regio- and stereoselectivity, and the (S)-acid is obtained and the (R)-substrate can be recycled under basic conditions. To improve the biocatalytic step, directed evolution was applied using the electronic polymerase chain reaction and in the first round of evolution a single C236S mutation led to a mutant with 3-fold increase in activity [19]. 

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