Bioisostere Formation

Further development of the reaction led to zinc bis(sufinate) salts as stable, scalable reagents for this reaction, many of which are now commercially available. Treatment of the zinc salt with t-butyl hydroperoxide generates a trifluoromethyl radical. Heteroaromatic systems can undergo HAS with this electrophilic radical at innately nucleophilic sites in the aromatic ring, though choice of solvent can impact the regioselectivity of this reaction. 

---

Figure 3.1 Peptidomimetic chemistry attempts to produce a non-peptidic drug to mimic a bioactive peptide. In Step A, the smallest bioactive fragment of the larger peptide is identified in Step B, a process such as an alanine scan is used to identify which of the amino acids are important for bioactivity in Step C, individual amino acids have their configuration changed from the naturally occurring L-configuration to the unnatural D-configuration (in an attempt to make the peptide less naturally peptidic ) in Step D, individual amino acids are replaced with atypical unnatural amino acids and amino acid mimics in Step E the peptide is cychzed to constrain it con-formationally finally, in Step F, fragments of the cyclic peptide are replaced with bioisosteres in an attempt to make a non-peptidic organic molecule.

The frequently observed bioisosteric relation of benzene and thiophene applies to the clonidine series as well. Reaction of the thiophenyl thiourea (85-1), in which the amine group is flanked by substituents as in the prototype, with methyl iodide and a base gives the corresponding methyl thioether (85-2). Treatment of that intermediate with ethylene diamine leads to the formation of an imidazoline ring and the antihypertensive agent, tiamenidine (85-3) [90], shown as its imino tautomer. 

Biologically active molecules containing amide bonds suffer usually of pharmacokinetic liability. In order to increase their stability, bioisosteric transformation of the carboxamide have been performed and yielded a lot of successful examples especially in the area of petidomimetic. The isosteric replacements for peptidic bonds have been summarized by Spatola and by Fauchere. " The most used and well-established modihcations are iV-methylation, configuration change (o-conhguration at Ca), formation of a retroamide or an a-azapeptide, use of aminoisobutyric or dehydroamino acids, replacement of the amidic bond by an ester [depsipeptide], ketomethylene, hydroxyethyl-ene or thioamide functional group, carba replacement of the amidic carbonyl, and use of an olefinic double bond (Figure 15.33). 

A representative set of such structures (7.80-7.86) is shown, all of which result in the formation of aldol adducts with high ee. Replacement of the carboxylic acid moiety with a bioisosteric tetrazole results in a catalyst (7.80) that is both more reactive than L-proline (7.66) and more readily soluble in organic solvents such as THF.38a.b jji a similar vein, acyl sulfonamides such as (7.81) give good enantios-electivities in the aldol reaction with aromatic aldehydes in organic solvents such as dichloromethane and acetone. 3 The addition of stoichiometric amounts of water increases the activity of tetrazole (7.80) further and this allows the use of aldehydes such as chloral monohydrate (7.87) and formaldehyde, which have an affinity for water and are generally poor substrates for the catalytic asymmetric aldol reaction. 38 = Catalysts (7.82)38 (7.33) 3Sd ijpophilic substiments,... 

---