Pergamon Tetrahedron Letters, Vol. 38, No. 11, pp, 2007-2010, 1997 © 1997 Elsevier Science Ltd All rights reserved, Printed in Great Britain n~^ .~_.~..~.~.._. 0040-4039/97 $17.00 + 0.00 PII: 5OOzl.O zlcU3~3( ~/)UUZ 1 ~ Y 9-Fluorenemethyl H-Phosphonothioate, a Versatile Reagent for the Preparation of H-Phosphonothioate, Phosphorothioate, and Phosphorodithioate Monoesters Jadwiga Jankowska, Jacek Cie~lak, and Adam Kraszewski* Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznafi, Poland Jacek Stawifiski* Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden. Abstract: Simple and efficient synthesis of a new H-phosphonothionylating reagent, 9- fluorenemethyl H-phosphonothioate, was developed. The synthetic utility of the reagent has been demonstrated in the preparations of nucleoside H-phosphonothioate, nucleoside phosphorothioate, and nucleoside phosphorodithioate monoesters. © 1997 ElsevierScienceLtd. All rightsreserved. Owing to their favourable chemical and enzymatic properties, oligonucleoside phosphorothioate I and oligonucleoside phosphorodithioate 2 analogues are in focus of pharmaceutical sciences as potential antisense and antigene therapeutics2,3. To expand synthetic methodologies available for the preparation of these types of compounds 4-6, we have recently developed an efficient synthesis of nucleoside H-phosphonothioate monoesters7 and showed, that these compounds, after conversion to H-phosphonothioate diesters in the chlorophosphates promoted condensations 8,9, provide a convenient entry to nucleoside phosphorothioate, phosphorodithioate and phosphoroselenothioate analogues. Since H-phosphonothioate diesters are useful synthetic intermediates for the preparation of phosphate analogues difficult to obtain by other routes 9-11, we have been searching for a H-phosphonothionyl group- transferring reagent, which would make this methodology even more versatile and efficient. Our primary goal was to develop an alternative method for the synthesis of nucleoside H-phosphonothioates7 and to provide an easy access to phosphate monoesters analogues, namely, to nucleoside phosphorothioates and nucleoside phosphorodithioates12. Having at hand an efficient method for the formation of H-phosphonothioate diesters from the corresponding monoesters 8,9, as a viable approach we considered to use an alkyl H-phosphonothioate monoester with a 13-eliminating group as an H-phosphonothionyl transferring reagent. The procedure would thus consist of generating a nucleoside alkyl H-phosphonothioate, from which the corresponding nucleoside H- phosphonothioate, nucleoside phosphorothioate, or nucleoside phosphorodithioate may be produced after further chemical transformations. 2007