R-group selection

Interestingly, mixed magnesate reagents, RMe2MgLi (R Me), conld transfer the R group selectively to ketones (equations 15-18). Snrprisingly, readily enohzable ketones such as /3-tetralone were ethylated in excellent yields (eqnation 18). 

The construction of R-group selectivity profiles based on in silico R-group contributions allowed us to identify structural determinants for selectivity where a small modification in the R-groups results in significant difference in selective profiles. 

The R-group selectivity knowledge coupled with the availability of X-ray data for many of the kinase/PDE structures provides substrates for scientists to formulate novel lead transformation ideas for inhibitor compounds with better physicochemical properties. 

The criticisms in the previous paragraphs lead to a question If Hansch analysis is of such questionable value, then why has an entire chapter of this textbook been devoted to the subject Despite the fading utility of classical QSAR methods such as Hansch analysis, the logic behind Hansch analysis is invaluable to medicinal chemistry. Synthetic chemists in the pharmaceutical industry intuitively consider the ideas used to construct Hansch equations. Ideas such as electronics, sterics, and lipophilicity underlie traditional SAR approaches in the laboratory. Critical analysis of activity data and emphasis on seeking holes in R-group selection are also fundamental to successful SAR on a lead. Through the study of Hansch analysis, all these crucial ideas are presented in a rational framework that helps demonstrate their relevance. Just as importantly, Hansch analysis provides the foundation for the next generation of QSAR comparative molecular field analysis. 

R-Group Selection Problem Given a library, select molecules for the individual R-groups in order to form a smaller sublibrary with an enriched number of hits for the target protein. 

Several approaches based on ligand de novo design software have been published for R-group selection problems. Kick et al. [124] applied a variant of the BUILDER program [125] to the preselection of substituents for a... 

A synthesis of the important biosynthetic intermediate mevalonic acid starts with the enzymatic hydrolysis of the diester A by pig liver esterase. The pro-R group is selectively hydrolyzed. Draw a three-dimensional structure of the product. 

In contrast to ordinary chiral aldehydes (having no ability to be chelated), the reaction of 9-allyl-9-borabicyclo[3.3.1]nonane(allyl-9-BBN) with the corresponding chiral imines 4 produces the isomer syn-6 either exclusively or predominantly (Cram selectivity Table 8)5,6. The very high 1,2-asymmetric induction is explained by a six-membered. chair-like transition state, in which the inline R group occupies an axial position due to the stereoelectronic effect of imines (R CH = NR). 

E.R.H. Walker, The Functional Group Selectivity of Complex Hydride Reducing Agents, Soc. Reviews 5, 23 (1976). 

When the nitrogen of the substrate contains a chiral R group, both the Stork enamine synthesis and the enamine salt method can be used to perform enantio-selective syntheses. " ... 

Radical addition to conjugated systems is an important part of chain propagation reactions. The rate constants for addition of cyclohexyl radical to conjugated amides have been measured, and shown to be faster than addition to styrene. In additions to RCH=C(CN)2 systems, where the R group has a chiral center, the Felkin-Ahn rule (p. 148) is followed and the reaction proceeds with high selectivity. Addition of some radicals, such as (McsSijaSi-, is reversible and this can lead to poor selectivity or isomerization. ... 

Afonso, Gois, and co-workers followed this report with an unexpected decarbonylation of diazo-acetamides (Scheme 9.14) using 43-NHC (Fig. 9.8) [58]. The reaction generated three different products, with low selectivity for the decarbonylated product. The authors tested other substrates with different R groups and bulk at the amine position but found no correlation to the amount of decarbonylation product formed. However, 43-IPr was more selective than 43-SIPr for the decarbonylation product. The authors attributed the decarbonylation to the axial coordination of the NHC ligand to the dirhodium (11) complexes. 

The concept of minimum AE and maximum Emw is illustrated with the generalized sequence shown in Scheme 4.7 under stoichiometric conditions with complete recovery of reaction solvents, catalysts, and post-reaction materials. Markush structures are used to show both variable R groups and necessarily invariant atoms. This analysis is useful in studying combinatorial hbraries where a constant scaffold structure is selected and then is decorated with, in principle, an unlimited number of possible R groups. 

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