• 10.1021/jo9917691
  • The Journal of Organic Chemistry
  • Volume 65
  • April 2000
  • pp 2172-2178

Experimental Yields Lower than Literature


Victor E. Marquez et. al. first introduced the concept of locked conformations, 2'-exo (North) and 3'-exo (South), of ribose ring in nucleosides. In this article the synthetic methodology and successful synthesis of receamic and conformationally locked South configured purine nucleoside has been discussed. I have reproduced the synthesis of Compound (10) from Compound (5) in similar yields, in order to generate series of nucleoside analogs of biological relevance. 

Synthesis of Compound (5), (E)-4-(Phenylmethoxy)but-2-en-1-ol (5), is not reported in this article. I used 2-butyne-1,4-diol as the starting material. After monoalkylation with benzylbromide in basic condition (yield - 60%) followed by reduction of the triple bond with selctive reducing agent, Red-Al, ( yield - 90%) gave (E) configured compound (5). 

2-[(4-methoxyphenyl)-methoxy]acetic acid was used as a protecting group for compound (6). This synthesis was also not reported here. I used Bromo acetic acid and 4-Methoxy benzyl alcohol in sodium hydride in reflux condition to obtain substituted acetic acid, (yield 70%).

Compond (6) was obtained by protecting Compound (5) with 2-[(4-methoxyphenyl)-methoxy]acetic acid, using coupling reagent DCC and DMAP, as reported. Flash chromatography with the reported solvent system (Ethyl acetate and Hexane) gave glycolate ester compound (6), yield 85% (reported 99%). 

Compound (6) underwent an enolate Claisen-Ireland rearrangement in the presence of LDA and Trimethyl Silyl chloride with reproducible diastereoselectivity to give the desired (2R,3R)-alpha, beta -unsaturated acid, compound (7), yield 80% - 87% (reported 91%).

Activation of the acid compound (7), with carbonyldiimidazole followed by Dieckmann
condensation with methyl 2-lithioacetate, similar to as reported, produced the alpha-ketoester compound (8), yield 70% (reported 89%).

Compound (8) underwent a diazo transfer with tosyl azide in the presence of triethylamine to give the diazo compound (9) in 70% yield (reported 95%). These reactions are very moisture senstitive which can cause huge difference in yields.  

Finally thermolysis of compound (9) was done with copper(II) acetylacetonate as catalyst, which formed the corresponding bicyclo[3.1.0]hexane system in 50% yield (reported yield 78%). The diastereomers were seperated by flash chromatography to give pure compound (10 and compound (11), which were charachterized by NMR.

Generation of the South configured raceamic scaffold, compound (10) and compound (11), helped me to design synthesis of potential ligands of purinergic receptors. 

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