Combinatorial Synthesis Via Sodium Benzenesulfinate Part 1: Solution-phase Synthesis of 2-Benzenesulfonylmethyl-5-substituted- thiol-[1,3,4]oxadiazoles Part 2: Traceless Solid-phase Synthesis of Substituted Pyrimidines Kong K.H. and Lam Y.L

Many organic sulfones have been shown to possess antibacterial, antimalarial, anthelmintic, antilepral, antineoplastic, anti-inflammatory and antidiabetic acitivities. These sulfones are commonly prepared from sodium benzenesulfinate 1-0 which plays an important role in organic synthesis. However the application of 1-0 in solid-phase synthesis has received relatively less attention. This project, which comprises two parts; aims to (i) synthesise and examine the biological activities of 2-benzenesulfonylmethyl-5-substituted-thiol-[1,3,4]oxadiazoles, and (ii) examine the use of polymer-bound sodium benzenesulfinate as a traceless linker for the solidphase synthesis of substituted pyrimidines. Part 1: Solution-phase Synthesis of 2-Benzenesulfonylmethyl-5-substituted-thiol-[1,3,4] oxadiazoles Various oxadiazoles and oxadiazolinethiones have been reported to exhibit bactericidal and/or fungicidal activities. As shown in Figure 1.1, compounds 1-1 suppress the immune function and possesses the hepatoprotective activity, compounds 1-2 have the ability to kill the Meloidogyne incognita, and compound 1-3 has been shown to be bioactive against pulmonary adenocarcinoma A549, large intestine cancer HT-29, squamous pulmonary carcinoma Ma44, pancreatic cancer PANC-1, squamous pulmonary carcinoma RERF-LC-AI and non-smat cell lung H460 cells. N N O S Ph N N O S R (CH2)m X CF2 (X=H, Halo, Alkyl; m=3-10 R= p-trifluorophenyl ) N N O S O2N N N N Me2HNHN N H n-Pr 1-1 1-2 1-3 Figure 1.1 General structure of bioactive 2-substituted-thiol-[1,3,4]oxadiazole Due to the diverse bioactivity of 2-substituted-thiol-[1,3,4]oxadiazoles, synthesizing new classes of 2-substituted-thiol-[1,3,4]oxadiazoles has been actively pursued. 1 Student 2 Lecturer Purpose of project Although many biologically interesting organic sulfones have been isolated or prepared, to our knowledge, the synthesis and bioactivities of 2-sulfonylmethyl-5-thiol-[1,3,4]oxadiazoles has not been reported. The aim of this project is to realize the synthesis of this class of compound and examine their bioactivities. Results and Discussion Our synthetic strategy to 2-sulfonylmethyl-5-thiol-[1,3,4]oxadiazoles 1-7 is described in Scheme 1.1. SO2Na SO2 R1 OR O SO2 R1 NHNH2 O SO2 R1 N O NH S SO2 R1 N O N S R2 1-0 1-4 1-5 1-6 1-7 Scheme 1.1 Synthesis of 2-benzenesulfonylmethyl-5-substituted-thiol-[1,3,4]oxadiazole α-Sulfonylesters 1-4 were obtained via sulfinate → sulfone alkylation of sodium benzenesulfinate with different α-bromoesters in the presence of KI and NBu4I (Yields: 9298%). Addition of 1-4 to hydrazine hydrate under refluxing condition gave α-sulfonylcarboxylic hydrazides 1-5 in good yields (Yield: 85-90%). Treatment of 1-5 with carbon disulfide in the presence of potassium hydroxide under refluxing condition gave substituted 5benzenesulfonylmethyl-3H-[1,3,4]oxadiazole-2-thiones 1-6 in 78-84% yield. Based on the successful alkylation of 1-6, it was interesting to investigate the possibility of introducing another bioactive motif, the piperazine moiety to the compound. 1-(2-Chloroethyl)4-substituted-piperazines were used as the alkylating agents. Treatment of 1-6b with 1-(2chloroethyl)-4-pyrimid-2-ylpiperazine in the presence of K2CO3/THF at room temperature did not give the desired 1-7ba and the starting material, 1-6b was recovered. However, when KI was introduced and refluxing condition was applied, 1-7ba was obtained in 75 % yield. This reaction condition was therefore used in the preparation of other analogues of 1-7. A small library of six 2-benzenesulfonylmethyl-5-substituted-thiol-[1,3,4]oxadia-zoles 1-7 was prepared. These compounds are currently being screened for their bioactivity. Part 2: Traceless Solid-phase Synthesis of Substituted Pyrimidines The synthesis of combinatorial compound libraries is rapidly taking on the role of a powerful component within modern lead finding processes that aim at the identification of compounds with novel target activities of interest. In the drug discovery context, the ability to synthesize small organic molecules with high yield on solid support has definite strategic relevance. It facilitates the preparation of compound arrays in multiple parallel syntheses and enables the application of combinatorial methods for the synthesis of large libraries suitable for systematic evaluation in biochemical or biological test systems. In view of the expected biostability and bioavailability, small organics (e.g. heterocycles) rather than chain-like biooligomers are more attractive leads for subsequent medicinal chemistry efforts. The pyrimidyl heterocyclic core is found in numerous natural products and in the pyrimidine and purine bases which constitute the ribo-and deoxyribonucleosides. In addition, a number of synthetic pharmacophores with antibacterial, antimicrobial, antifungal, and antimycotic activities are based upon the pyrimidyl structural motifs. Figure 2.1 shows some bioactive pyrimidines. Pyrimidine sulfonamide 2-1 is a non-peptide antagonist whilst compound 2-2 is used as a veterinary medicine. N N P i (EtO)2(S=)PO