Base selection, generators

Funk OF, Kettmann V, Drimal J, Langer T. Chemical function based pharmacophore generation of endothelin-A selective receptor antagonists. J Med Ghent 2004 47 2750-60. 

It should be noted here that a regioselective control may also be exerted by just controlling the experimental conditions. Thus, working under strictly kinetic conditions (low temperature, absence of oxygen and slow addition of the ketone to an excess of a solution of an aprotic base) the less substituted enolate of carvomenthone can also be selectively generated and may be then submitted to different kind of reactions. However, reversible reactions like the Michael addition would equilibrate the reaction mixture to the thermodynamically more stable enolate. 

As described previously, the Shapiro reaction requires stoichiometric amounts of base to generate the alkyllithium reagents. An efficient catalytic method of the Shapiro reaction, which showed excellent regio- and stereo-selectivity, has also been reported. Indeed, the combination of ketone phenyl aziridinylhydrazones 116 and a catalytic amount of hthium amides leads to the corresponding alkene 117 in good overall yield (equation... 

Kinetic control can be achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent. Kinetic control requires a rapid, quantitative and irreversible deprotonation reaction 2-6. The use of a very strong, sterically hindered base, such as lithium diisopropylamide or triphenylmethyllithium (trityllithium), at low temperature (— 78 °C) in an aprotic solvent in the absence of excess ketone has become a general tool for kinetic control in selective enolate formation. It is important to note that the nature of the counterion is sometimes important for the regioselectivity. Thus, lithium is usually better than sodium and potassium for the selective generation of enolates by kinetic control. 

Recognition of fluoride in aqueous media is particularly difficult due to the strongly hydrated nature of the anion. Shinkai and co-workers have demonstrated that ferrocene-boronic acid 27 acts as a selective redox sensor for fluoride which operates in H20 [23]. The favourable interaction between boron and fluoride (a hard acid and hard base, respectively) generates a stability constant of 700 M"1 for the fluoride-ferrocenium complex. Stability constants for both the bromide and chloride complexes are <2 M"1. 

Problem 1 stresses the use of appropriate bases for generating enolate anions. Problems 2-4 deal with selectivity issues encountered in enolate anion reactions. The syntheses of TMs in Problems 5 and 6 require the selection of specific reagents to achieve chemo-, stereo-, or enantioselective carbon-carbon bond formations. 

Initial efforts to prepare benzoic acid 28 from methyl or ethyl 4-aminobenzoate and biphenyl-2-carboxylic acid (27) afforded poor yields of 28 (48% and 7%, respectively). However, acylation of 4-aminobenzoic acid with biphenyl-2-carbonyl chloride was found to provide 28 in excellent yield (95%) when DMAP was employed as a base. Selective acylation of the anilinic nitrogen of 26 with benzoic acid 28 was accomplished in analogy with the first-generation process synthesis by conversion of 28 to the corresponding acid chloride (SOCl2, CH3CN) followed by acylation of 26 in acetonitrile. Subsequent addition of ethanolic hydrogen chloride to the reaction mixture resulted in the precipitation of conivaptan HCl (1), which was isolated in 90% yield. 

The principal factor to be considered in partition-based selection is the set of characteristics that is used to define the chemical space. The first report of such an approach was by Mason et al. [58], who generated partitions defined by six global molecular properties that had been chosen to... 

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