Bioisosteric tetrazole

Validated hits were mostly carboxylic acids or bioisosteres (tetrazole, sulfonamides)... 

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,... 

As a direct appUcation a potent C2-symmetric HIV-1 protease inhibitor (with two tetrazoles as carboxyl group bioisosteres) was prepared in one pot [77]. The process involved microwave-promoted cyanation followed by conversion of the nitrile group in a tetrazole with azide (Scheme 64). It is notable that the fimctionahzation was achieved so smoothly without side reactions such as the ehmination of water. 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

The majority of NMDA agonists are closely related to the structure of glutamic acid. Thus, 4-methylene-L-glutamic acid (4.211) is a potent NMDA agonist. Bioisosteric replacement of a carboxylate group also produces agonists D,L-(tetrazol-5-yl)glycine (4.212), in which a tetrazole bioisostere replaces a carboxylate, is a potent NMDA... 

Bioisosteres can seem strange and nonobvious. For example, a bioisostere for a carboxylic acid is a tetrazole ring. Although a carboxylic acid and tetrazole ring may... 

FIGURE 11.6 Angiotensin-ll receptor antagonists with tetrazole bioisosteres... 

The Uppsala team then turned their attention to the development of a fast and efficient procedure that allowed conversion of aryl halides to benzoni-triles and aryl tetrazoles by microwave heating. The aryl bromide 11 was subjected to the optimized reaction conditions, which delivered the bis-tetrazole 15 in a two-step yield of 82% (Scheme 8, Kt = 0.56 nM), demonstrating the potential of the method for medicinal chemistry [61]. The tetrazole functionality is one of the most utilized carboxylic acid bioisosteres. 

The tetrazole moiety is an excellent bioisosteric replacement for a carboxylic acid, being a small, polar, acidic heterocycle. 

Liljebris, C., Larsen, S. D., Ogg, D., Palazuk, B. J., Bleasdale, J. E. Investigation of potential bioisosteric replacements for the carboxyl groups of peptidomimetic inhibitors of protein tyrosine phosphatase IB identification of a tetrazole-containing inhibitor with cellular activity. J. Med. Chem. 2002, 45(9), 1785-1798. 

Biot, C., Bauer, H., Schirmer, R. H., Davioud-Charvet, E. 5-Substituted tetrazoles as bioisosteres of carboxylic adds. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials. J. Med. Chem. 2004, 47(24), 5972-5983. 

The prototypical representatives of the group are the carboxylic acids. However, a huge number of bioisosteres such as sulfonic or phosphonic acids, tetrazoles or 3-hydrox-yisoxazoles are available (see Chapter 15). In addition functions like esters, amides, peptides, aldehydes, primary alcohols and related functions can work as prodrugs or bioprecursors (see Chapter 36). 

The tetrazole ring on the biphenyl system is used here as a carboxyl bioisostere, with the sole hydrogen atom being neutralized to a potassium salt, the marketed form of the drug. 

Since -CN4H and -CO2H have a similar spatial demand, bioisosterism is observed. Tetrazoles form poorly soluble, explosive copper and silver salts. 

For every biologically active carboxylic acid, there is a bioisosteric compound in which the carboxyl group is replaced by a tetrazol-5-yl moiety. The tetrazole compounds are degraded biologically more slowly than carboxylic acids. For instance, the tetrazole analogue 11 of nicotinic acid reduces the fatty acid and cholesterol levels in blood. 

In a recent example, aryl-carboxylic solubilization was used to solubilize core-modified porphyrins. Solubilizing aryl carboxylic functions were also replaced by their tetrazole or 1,2,4-oxadiazolone bioisosteres in the design... 

The tetrazole functional group is of particular interest in medicinal chemistry, because of its potential role as a bioisostere of the carboxyl group. In this context, Schulz et al. have demonstrated the synthetic utility of the cyano group of arylni-trile boronates as a source of tetrazole derivatives under microwave conditions. The reaction is conducted with azidotrimethylsilane and dibutyltin oxide as catalyst to provide aryltetrazole boronates in yields ranging from 60 to 93% [56]. In the same manner, microwaves may assist successful conversion of sterically hindered nitriles into tetrazoles [57]. 

Another interesting type of 1,3-dipolar cycloaddition with azides involves condensation with nitriles as dipolarophiles to form tetrazoles. These products are of particular interest to the medicinal chemist, because they probably constitute the most commonly used bioisostere of the carboxyl group. Reaction times of many hours are typically required for the palladium-catalyzed cyanation of aryl bromides under the action of conventional heating. The subsequent conversion of nitriles to tetrazoles requires even longer reaction times of up to 10 days to achieve completion. Under microwave irradiation conditions, however, the nitriles are rapidly and smoothly converted to tetrazoles in high yields. An example of a one-pot reaction is shown in Scheme 11.54 [110], in which the second step, i.e. the cycloaddition, was achieved successfully under the action of careful microwave irradiation. The flash heating method is also suitable for conversion of 212 and 214 to tetrazoles 213 and 215, respectively, on a solid support, as shown in Scheme 11.54. 

The importance of the tetrazole group in medicinal chemistry is easily understood if one remembers it is the most commonly used bioisostere of the carboxyl group. 

Noting the similarity of tetrazole pK values to those of carboxylic acids, tetra-zoles have often been used as bioisosteric replacements for CO2H in pharmacologically active compounds. Tetrazoles alkylate and acylate on N-1 or N-2 depending on substituents at C-5, however selective 1-alkylations by quatemisation of 2-tri-w-butylstannyl derivatives have been reported. ... 

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