Rational Substrate Design

The MCR is a combination ofa series of two-component reactions where the product of the first reaction reacts with the third input to give a second product, which in turn 

It is conceivable that if one used a-isocyanoacetic acid derivatives having a less a-acidic proton and if the reaction conditions were sufficiently mild to prevent the a-deprotonation, then one could expect to have a reaction sequence initiated by the nucleophilicity of the isocyanide, consequently leading to a completely different product. 

Based on this novel three-component synthesis of 5-aminooxazoles and by designing reaction partners, a two-fold four-component (ABC2) synthesis of m-cyclophane 21 was devised by reacting a diamine (22), a bis-a-isocyanoacetamide 

3) Reaction of methyl a-(4-nitrophenyl) a-isocyanoacetate with an amine and an aldehyde afforded the 5-methoxyoxazole instead of imidazoline. In this case, the high acidity of the a-proton of substituted a-isocyanoacetate made the resulting enolate very stable, and hence inactive [24], 

Using relatively rigid, umbrella-shaped or kinked bifundional building blocks can often result in the conformational preorganization of cyclization precursors, which can in turn favor the formation of one particular macrocycle [37]. In practice, high 

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Rational substrate design, using elevated Si pillars for example, offers another possible approach [134]. Here the CNTs grow between elevated pillars. The micrometer pillars limit the practicality of the technique as well as restricting the maximum packing density. As a result, techniques based on electric field and gas flow alignment show perhaps the most promise. They are rapid, parallel processes that offer simplicity and the ability to fabricate high density arrays in a variety of directions. 

Rational substrate design, with appropriately functionalized aryl azides, has been shown to afford a variety of fused heteroaromatic polycycles. One report by Smalley et al. from the University of Salford describes exploitation of the Dimroth process to afford l,2,3-triazolo[l,5-a]quinazolines from o-azidobenz-aldehyde (42), o-azidoacetophenone, and benzonitrile with various active methylene substrates. It is interesting that the authors found an organic base, piperidine, was optimal for some substrates, while either sodium ethoxide or Amberlite resin worked better for others. 

SCHEME 4.6 Regiocontrol through rational substrate design. 

Raub, T.J. (2006) P-glycoprotein recognition of substrates and circumvention through rational drug design. Molecular Pharmaceutics, 3, 3-25. 

The lipase-catalysed access to enantiomerically pure compounds remains a versatile method for the separation of enantiomers. The selected examples shown in this survey demonstrate the broad applicability of lipases in terms of substrate structures and enantioselectivity. More recently, modem molecular biology methods such as rational protein design and especially directed evolution103 will further boost the development of tailor-made lipases for future applications in the synthesis of optically pure compounds. It has been already shown that a virtually non-enantioselective lipase (E=l.l in the resolution of 2-methyldecanoate) could be evolved to become an effective biocatalyst (E>50). Furthermore, variants were identified which showed opposite enantiopreference. 

The examples provided in this Chapter demonstrate that directed evolution resembles a very useful tool to create enzyme activities hardly accessible by means of rational protein design (Table 14.1). Even if the desired substrate specificity is known from other biocatalysts - e.g. phospholipase A1 activity - the advantage of the directed evolution approach resides in the already achieved functional expression of a particular protein. Thus bottlenecks arising from the identification of enzymes by traditional screening and cultivation methods can be circumvented. In addition, directed evolution can dramatically reduce the time required for the provision of a suitable tailor-made enzyme, also because cloning and functional expression of the biocatalyst has already been achieved. 

Sakai T (2004) Rational strategies for highly enantioselective lipase-catalyzed kinetic resolutions of very bulky chiral compounds substrate design and high-temperature biocatalysis. Tetrahedron Asymmery 15 2765-2770... 

Mimicking the secondary structure of peptides has become one of the most important tools for rational drug design (44-47). These methods induce the synthetic analog to adopt a set of target conformations, which are designed to mimic the bioactive conformation predicted in the native substrate from biophysical techniques. Molecular surrogates... 

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