110 H. GOBIND KHORANA 



O 



R'OH + (I) + limited base -> R'O— P— OR 



CI 

 (HI) 



O O 



II II 



(III) + R"OH + base ^ R'O— P— OR" -» R'O— P— OR" 



OR OH 



In the nucleotide field the reagent was used in the synthesis of what is 

 now known to be uridylyl-(5' — » 5')-uridine by Gulland and Smith 10 as 

 early as 1947. Two molar equivalents of 2',3 / -0-benzylidene uridine (then 

 regarded as 3',5'-0-benzylidene uridine) were made to react with one 

 equivalent of the reagent and the phenyl group was removed from the 

 presumed initially formed neutral ester by treatment with alkali. More 

 recently, by using the crystalline and highly reactive, mono-p-nitrophenyl- 

 phosphorodichloridate 11 (II), thymidylyl-(5' — > 5')-thymidine was pre- 

 pared from 3'-0-acetyl thymidine. 12 The approach has, however, proved 

 unsatisfactory so far in the successive phosphorylations of two different 

 nucleoside derivatives to form C 3 '-C 5 < internucleotide bonds. 8 In any case, 

 in the synthesis of the unsymmetrical phosphodiester bonds, the formation 

 of some of the symmetrical products would appear to be unavoidable. 



b. The Use of Halogeno and Other Activated Nucleosides 



This approach utilizes the principle that has been used in the synthesis of 

 sugar-1-phosphates, namely the reaction of an alkyl halide with the salt of 

 a phosphate ester. It was used in the synthesis of adenylyl-(5' — > 50-uri- 

 dine 13 by treating a suitably protected derivative of the silver salt of adeno- 

 sine-5'-phosphate with 2',3'-0-isopropylidene-5'-deoxy-5'-iodouridine and 

 the subsequent removal of the protective groups. The approach is severely 

 limited by the inaccessibility of the corresponding halogenated derivatives 

 of other nucleosides. An alternative method for the activation of hydroxylic 



ROH + Ar— N=C=N— Ar -^ Ar— N=C— NH— Ar 



I 

 O— R 



(IV) 

 



II II II 



(IV) + (R'0) 2 — P— OH -+ (R'0) 2 P— OR + Ar— NHCNH— Ar 

 Ar = Aromatic 



10 J. M. Gulland and H. Smith, J. Chem. Soc. p. 1532 (1948). 

 » A. F. Turner and H. G. Khorana, J. Am. Chem. Soc. 81, 4651 (1959). 

 12 W. E. Razzell and H. G. Khorana, J. Biol. Chem. 234, 2105 (1959). 

 IS D. T. Elmore and A. R. Todd, J. Chem. Soc. p. 3681 (1952). 



