Palladium catalyzed synthesis of nucleosides: The total syntheses of adenosine and uridine synthesis of important nucleoside Q analogues

Nucleosides and nucleotides play key roles in a variety of biochemical processes. Nucleoside Q is a hypermodified nucleoside discovered in 1968 in E. coli tRNA. Its structure was determined by total synthesis. Few total syntheses of Q or Q related structures have been reported, and they wholly begin from chiral starting material. Furthermore, it has been established that the substituent at the C4 position of pyrrolo [2,3-d] pyrimidine ribofuranosides can greatly effect the reactivity at the C5 position. Finally, all of the reported complete syntheses of the side chain segment of Q have involved resolution rather than asymmetric synthesis.; The palladium catalyzed asymmetric allylic alkylation reaction is a useful synthetic reaction with many avenues for achieving an asymmetric reaction. In the desymmetrization of meso compounds, the asymmetric event is the enantiotopic ionization of leaving groups. This strategy has been employed to produce very efficient and highly enantioselective syntheses of adenosine and uridine nucleosides. The synthesis of adenosine was accomplished in 9 steps from furan in an overall yield of 17%. The synthesis of uridine was accomplished in 8 steps in an overall yield of 18%.; The palladium catalyzed asymmetric allylic alkylation (AAA) reaction may be used to desymmetrize meso compounds and lead toward synthetically useful products. Palladium catalyzed allylic alkylation reactions---asymmetric or not---using pyrrolopyrimidine nucleophiles was not successful. The results were not effected by changes in ligand, palladium source, base, solvent, concentration, temperature, reaction time, allylic coupling partner structure or pyrrolopyrimidine structure. We finally became convinced that pyrrolopyrimidine is simply a better ligand for palladium than it is a nucleophile in the reaction. This idea is supported by the lack of appearance of any product. Appearance of even a small amount of product (comparable to amount of catalyst used) would suggest a need to increase the turnover by modification of the reaction conditions. Azide was found to be a useful nucleophile which could be reduced and used as a building block to obtain pyrrolopyrimidine products. A three-component coupling was developed which allows great versatility toward the completion of a route to nucleoside Q.; Addition of the C-H bond of a terminal alkyne across the pi-bond of an alkyne creates a valuable and useful conjugated enyne. Although such reactions have been observed with a variety of transition metal catalysts, they often produce mixtures arising from the reactivity of the adducts toward further addition. In some cases, mixtures of regioisomers result. In some cases, the reactions are limited to hydrocarbons or terminal alkynes. The catalyst reported here does not have the above limitations and gives excellent yields of enyne products. This reaction provides a general entry to conjugated enynes which represent a key fragment of biologically interesting molecules represented by neocarzinostatin chromophore and calicheamycin.