Synthesis of multisubstituted halo -olefins via Pd-catalyzed cross -coupling reactions. Applications in nucleoside chemistry

The enzyme S-adenosyl-L-homocysteine (AdoHcy) hydrolase effects hydrolytic cleavage of AdoHcy to adenosine (Ado) and L-homocysteine (Hcy). The cellular levels of AdoHcy and Hcy are critical because AdoHcy is a potent feedback inhibitor of crucial transmethylation enzymes. Also, elevated plasma levels of Hcy in humans have been shown to be a risk factor in coronary artery disease. ^ On the basis of the previous finding that AdoHcy hydrolase is able to add the enzyme-sequestered water molecule across the 5',6'-double bond of (halo or dihalohomovinyl)-adenosines causing covalent binding inhibition, we designed and synthesized AdoHcy analogues with the 5',6'-olefin motif incorporated in place of the carbon-5' and sulfur atoms. From the available synthetic methods we chose two independent approaches: the first approach was based on the construction of a new C5'-C6' double bond via metathesis reactions, and the second approach was based on the formation of a new C6'-C7' single bond via Pd-catalyzed cross-couplings. Cross-metathesis of the suitably protected 5'-deoxy-5'-methyleneadenosine with racemic 2-amino-5-hexenoate in the presence of Hoveyda-Grubb's catalyst followed by standard deprotection afforded the desired analogue as 5' E isomer of the inseparable mixture of 9'R/S diastereomers. Metathesis of chiral homoallylglycine [(2S)-amino-5-hexenoate] produced AdoHcy analogue with established stereochemistry E at C5'atom and S at C9' atom. The 5'-bromovinyl analogue was synthesized using the bromination-dehydrobromination strategy with pyridinium tribromide and DBU. ^ Since literature reports on the Pd-catalyzed monoalkylation of dihaloalkenes (Csp2-Csp3 coupling) were scarce, we were prompted to undertake model studies on Pd-catalyzed coupling between vinyl dihalides and alkyl organometallics. The 1-fluoro-1-haloalkenes were found to undergo Negishi couplings with alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective affording pure Z-fluoroalkenes. The highest yields were obtained with PdCl 2(dppb) catalyst, but the best stereochemical outcome was obtained with less reactive Pd(PPh3)4. Couplings of 1,1-dichloro-and 1,1-dibromoalkenes with organozinc reagents resulted in the formation of monocoupled 1-halovinyl product. ^

Synthesis of multisubstituted halo-olefins via Pd-catalyzed cross-coupling reactions : applications in nucleoside chemistry

The enzyme S-adenosyl-L-homocysteine (AdoHey) hydrolase effects hydrolytic cleavage of AdoHcy to adenosine (Ado) and L-homocysteine (Hcy). The cellular levels of AdoHcy and Hcy are critical because AdoHcy is a potent feedback inhibitor of crucial transmethylation enzymes. Also, elevated plasma levels of Hcy in humans have been shown to be a risk factor in coronary artery disease. On the basis of the previous finding that AdoHcy hydrolase is able to add the enzyme-sequestered water molecule across the 5',6'-double bond of (halo or dihalohomovinyl)-adenosines causing covalent binding inhibition, we designed and synthesized AdoHcy analogues with the 5',6'-olefin motif incorporated in place of the carbon-5' and sulfur atoms. From the available synthetic methods we chose two independent approaches: the first approach was based on the construction of a new C5'- C6' double bond via metathesis reactions, and the second approach was based on the formation of a new C6'-C7' single bond via Pd-catalyzed cross-couplings. Cross-metathesis of the suitably protected 5'-deoxy-5'-methyleneadenosine with racemic 2-amino-5-hexenoate in the presence of Hoveyda-Grubb's catalyst followed by standard deprotection afforded the desired analogue as 5'E isomer of the inseparable mixture of 9'RIS diastereomers. Metathesis of chiral homoallylglycine [(2S)-amino-5-hexenoate] produced AdoHcy analogue with established stereochemistry E at C5'atom and S at C9' atom. The 5'-bromovinyl analogue was synthesized using the brominationdehydrobromination strategy with pyridinium tribromide and DBU. Since literature reports on the Pd-catalyzed monoalkylation of dihaloalkenes (Csp2-Csp3 coupling) were scarce, we were prompted to undertake model studies on Pdcatalyzed coupling between vinyl dihalides and alkyl organometallics. The 1-fluoro-1- haloalkenes were found to undergo Negishi couplings with alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective affording pure Zfluoroalkenes. The highest yields were obtained with PdCl 2(dppb) catalyst, but the best stereochemical outcome was obtained with less reactive Pd(PPh3)4 . Couplings of 1,1- dichloro-and 1,1-dibromoalkenes with organozinc reagents resulted in the formation of monocoupled 1-halovinyl product.

Novel approaches for the synthesis of C-5 modified pyrimidine nucleosides

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF 5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. ^ In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.^

Novel Approaches for the Synthesis of C-5 Modified Pyrimidine Nucleosides

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.