Bioisosteric analog

With respect to the coupling reactions of stannylthiazoles with aryl halides, the union of 4-chlorobromobenzene and 2-tributylstannylthiazole constructed arylthiazole 53 [37]. The Stille reaction of 3-bromobenzylphosphonate (54) and 2-tributylstannylthiazole led to heterobiaryl phosphonate 55, which may be utilized as a substrate in a Wadsworth-Homer-Emmons reaction or a bioisosteric analog of a carboxylic acid [38], The phosphonate did not interfere with the reaction. In addition, the coupling of 5-bromo-2,2-dimethoxy-l,3-indandione (56) and 2-tributylstannylbenzothiazole resulted in adduct 57, which was then hydrolyzed to 5-(2 -benzothiazolyl)ninhydrin [39]. 

One method for preparing imidazolylstannanes is direct metalation followed by treatment with RjSnCl [21]. l-Methyl-2-tributylstannylimidazole, derived in such manner, was coupled with 3-bromobenzylphosphonate (26) to furnish heterobiaryl phosphonate 27 [22], Under the same reaction conditions, 4-bromobenzylphosphonate led to the adduct in 69% yield, whereas only 24% yield was obtained for 2-bromobenzylphosphonate. The low yield encountered for the ortho derivative may be attributed to the steric factors to which the Stille reaction has been reported to be sensitive [23]. Heterobiaryl phosphonates such as 27 are not only substrates for the Wadsworth-Homer-Emmons reaction, but also bioisosteric analogs of the carboxylic acid group. 

To correctly address the problem of identification of target-specific privileged motifs, one should take into account the phenomenon of bioisosterism [26]. Thus, several different bioisosteric structures can constitute only one distinct privileged structural motif. In order to include all possible bioisosteric analogs into one cluster, we use a special algorithm of ChemoSoft based on a collection of rules for bioisosteric conversions described in literature. AH bioisosteric analogs are considered similar with similarity coefficient 1 if they have identical substituents around the central bioisosterically transformed fragment. 

Pyrroles 779 and 781 were regioselectively acylated with ethoxycarbonyl isothiocyanate, affording acylated thioamides 780 and 782, respectively, as intermediates in the synthesis of pyrroloamidines, guanidine bioisostere analogs (Equations 184 and 185) <2001JME1217>. 

Phosphonate analogs to phosphate esters, in which the P—0 bond is formally replaced by a P—C bond, have attracted attention due to their stability toward the hydrolytic action of phosphatases, which renders them potential inhibitors or regulators of metabolic processes. Two alternative pathways, in fact, may achieve introduction of the phosphonate moiety by enzyme catalysis. The first employs the bioisosteric methylene phosphonate analog (39), which yields products related to sugar 1-phosphates such as (71)/(72) (Figure 10.28) [102,107]. This strategy is rather effective because of the inherent stability of (39) as a replacement for (25), but depends on the individual tolerance of the aldolase for structural modification close... 

Figure 10.28 Complementary routes for the stereoselective synthesis of hydrolytically stable sugar phosphonates, either from the bioisosteric phosphonate analog of DHAP or from phosphonylated aldehydes.

In the past several years a number of reports have appeared describing cardiovascular and diuretic effects associated with benzo[ Jthiophene derivatives. Among these was the study of the benzo[6 Jthiophene analog (371) of the j8 -adrenergic blocking agent propanolol, which is the a -naphthol ether. The compounds showed comparable activity, showing that benzo[6 Jthiophene may function as a bioisostere of naphthalene also. 

The 1,3,4-oxadiazole moiety, in analogy to the 1,2,4-oxadiazole discussed in Section 11.2.5.1, has been used extensively as an ester or amide bioisostere, but also has only recently been applied as an amide replacement in actual peptide segments.1104-1071 The synthesis of the peptide surrogate 1,3,4-oxadiazole derivative 60 is shown in Scheme 18.11021 The N-protected amino acid Boc-Ala-OH (56) was coupled with ethanol to form the ester 57 which was subsequently reacted with hydrazine to form the amino acid hydrazide 58.11(1X1 The hydrazide 58 was reacted with ethyl oxalyl chloride at — 30 °C to room temperature to provide the diacylhydrazide 59. This intermediate was subsequently dehydrated with thionyl chloride in refluxing toluene to form the desired 1,3,4-oxadiazole 60 in >95% ee. Although the overall yields are only moderate, the reported enantioselectivities of the final compounds are very good (Table 4).11021... 

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