The Application Of Pictet-Spengler-type Cyclization Reactions In The Design And Synthesis Of Pyrimidine-fused Heterocyclic Scaffolds

In this dissertation, three novel pyrimidine-fused heterocyclic scaffods were designed and synthesized by using Pictet-Spengler-type cyclization reactions and 7,8,9-trisubstituted dihydropurine derivatives were synthesized via a"tert-Amino Effect"cyclization. These scaffolds are useful in preparation of libraries based on priviledged structures in drug discovery.In Chapter One, the application of privileged structures, pyrimidine-fused heterocycles, benzodiazepines and medium-sized rings in drug design were reviewed. The Pictet-Spengler-cyclization reactions in organic synthesis and our efforts to develop new synthetic methods to prepare novel pyrimidine-fused heterocyclic scaffolds were summarized.Priviledged structures represent a class of molecules capable of binding to multiple receptors with high affinity. Design and synthesis of structurally diverse libraries based on privileged structures were an efficient way to discover lead compounds. As a structural component of key biomolecules, pyrimidine moiety has been widely employed in design of privileged structures in medicinal chemistry. Benzodiazepines were first coined as the privileged substructure by Evans et al. in 1988. These compounds show a variety of biological effects predominately ascribed to their actions in the central nervous system. The medium-sized rings are the structural cores of a large number of biologically important natural products and serve as target molecules for numerous synthetic studies. Pictet-Spengler-cyclization reaction was an efficient method in synthesis of tetrahydroisoquinoline and tetrahydro-β-carbolines and has been used to prepare nitrogen containing heterocyclic compounds. The aim and significance of the dissertation were to design and synthesize pyrimidine-fused heterocycles scaffolds via Pictet-Spengler-type cyclization reaction. In Chapter Two, an efficient method was developed for the construction of novel heterocyclic scaffolds 5,6-dihydropyrimido[4,5-b][1,4]benzodiazepines, 4-chloropyrimido[b,f][1,5]benzodiazocines and pyrimidine-fused indolodiazocines via a Pictet-Spengler-type cyclization reaction. This new method complements the existing chemistries for the preparation of pyrimidine-fused heterocycles derivatives. The resulting compounds may be suitable for further manipulations, such as nucleophilic substitution reactions of the 4-chloro group to yield products with more diversity. Therefore, this new reaction is applicable to the preparation of large libraries of novel scaffolds that are of interest in drug discovery.The starting pyrimidines 5-amino-4-(N-methylphenylamino)-6-chloropyrimidins were readily prepared by a known two-step process from commercially available 4,6-dichloro-5-nitropyrimidine and N-methylanilines in high yields. The cyclization reactions of 5-amino-4-(N-methylphenylamino)-6-chloropyrimidins with various aldehydes were investigated and these reactions proceeded smoothly to yield products in the presence of excess amount of trifluoroacetic acid. The desired cyclization products were obtained in moderate to excellent yields (44–95%). Higher yields were isolated when electron-withdrawing groups present in aromatic aldehydes, which may be attributed to their higher reactivity towards imine formation and stabilization effect on the imine intermediates. The effect of substituents on the reactivity of precursors was explored by varying its position and changing the electronegativity. Para- and meta-methyl substitutions of the anilino phenyl were well tolerated and the desired cyclized products were isolated in good to excellent yields. However, a para-fluoro substitution led to significant decrease in reaction rate and only 19% of the desired product was isolated after 6 days of reaction. Unfortunately, all attempts on the reactions between 5-amino-4-(N-methylphenylamino)-6-chloropyrimidins and various ketones, such as acetone, butan-2-one and acetophenone, failed to generate the desired products.As an on-going endeavor to create novel heterocyclic scaffolds we have explored applications of iminium ion cyclization reactions to the synthesis of pyrimidine-fused medium-sized heterocycles. Under the same conditions above, the starting pyrimidines 5-amino-4-(N-alkyllbenzylamino)-6-chloropyrimidins reacted with both aliphatic and aromatic aldehydes. In general, these reactions produced the desired 4-chloropyrimido[b,f][1,5]benzo- diazocines in moderate to good yields(32-90%). When an aliphatic aldehyde was employed, the reaction proceeded faster compared to those with an aromatic aldehyde. This observation could be explained by a previously proposed mechanism that entailed an intramolecular electrophilic substitution of the benzene ring by an iminium ion intermediate. When an aromatic aldehyde was employed, an electron-withdrawing group should decrease the electron-deficiency of the carbonyl, so to decrease the basicity of imine intermediate, which in turn slows down the intramolecular cyclization; while an aliphatic aldehyde forms a more reactive iminium ion for electrophilic substitution. This was supported by the fact that the reactions with aromatic aldehydes bearing an electron-withdrawing group were slower. Higher yields were obtained when electron-withdrawing groups were present in aromatic aldehydes, which may be attributed to their higher reactivity towards imine formation and stabilization effect on the imine intermediates.However, when the precursor was not electron-rich enough, 7,8,9-trisubstituted dihydropurine derivative was obtained. When we attempted to synthesized the 9-membered pyrimidine fused heterocycles, the desired products was failed to generate and 7,8,9-trisubstituted dihydropurine derivative was obtained.Based on the results, it was logical to attempt to further expand the scope of this cyclization reaction to 5-amino-4-(N-methyl-(indo-2-yl)-amino)-6-chloropyrimidins and aldehydes. As shown in results, pyrimidine reacted with various aldehydes to produce the desired products in good yields. When an aliphatic aldehyde was employed, the reaction proceeded faster and the yield was higher compared to the ones with an aromatic aldehyde. On the other hand, when an aromatic aldehyde was employed, the yield and the reaction rate were not influenced by electronic properties of its substituents.In Chapter Three, we reasoned the formation of 7,8,9-trisubstituted dihydropurine derivative was due to the competition of the"tert-amino effect"and applied it to the synthesis of a series of dihydropurine analogs.The reactions of pyrimidines with aromatic aldehydes proceeded smoothly under trifluoroacetic acid (TFA) conditions to give the desired 7,8,9-trisubstituted dihydropurine derivatives.It was found that the products were unstable upon standing and preliminary analysis indicated that hydrolysis of the 4-chloro group might be occurring. The replacement of the chloro group by the pyrrolidinyl group led to stablized products. When R was 4-chloro group, the reaction with an aliphatic aldehyde gave an even more unstable product which might undergo a hydrolysis of the 4-chloro group and oxidation, to lead to a zwitterion compound. The replacement of the chloro group in pyrimidine by the pyrrolidinyl group led to stablized products.Unfortunately, all attempts on the synthesis of 7,8,9-trisubstituted dihydropurine derivatives with furan and thiophene failed to generate the desired products.