A highly efficient procedure for the oxidation of the 5'-position of adenosine analogues

Dess-Martin periodinane oxidizes the 5'-hydroxyl group of adenosine analogues as exemplified with the case of cordycepin. The yield for the oxidation of cordycepin was almost quantitative in reproducible runs. This method for adenosine and its analogues is far more attractive than methodologies using EDC . HCl and DMSO, DCC and DCAA in DMSO, TPAP and NMO, CrO 3 in pyridine, DMSO with trichloroacetic anyhydride, or oxidations which proceed through either the oxime or the 1,3-diphenylimidazolidine derivative to furnish the aldehyde.

In an effort to synthesize novel cordycepin analogues with functionalized substitution at the 4'-position, we have focused on the utililization of the carboxaldehyde (1) as the key intermediate for providing entry to this class of compounds.While there are a few examples in the literature of nucleoside 5'-carboxaldehydes, access to these key intermediates in sugarmodified nucleoside synthesis is exceedingly difficult.This is particularly the case for adenosine analogues.For example, Rosenberg and co-workers noted that oxidation of 2'-deoxy-3'-O-tertbutyldiphenylsilyl nucleosides and 2',3'-O-isopropylidene derivatives of nucleosides worked well under the Swern conditions [DMSO /(COCl) 2 ] in most cases except for adenosine derivatives. 6n alternate route to adenosine 5'-carboxaldehyde proceeds through the 1,3diphenylimidazolidine or oxime derivatives. 7However, this procedure is somewhat cumbersome and the yields are modest.Because adenosine 5'-carboxaldehyde derivatives represent attractive intermediates from which many novel adenosine targets can readily be synthesized, we developed a highly efficient procedure for this oxidation and our report communicates these results.

Results and Discussion
Our successful Dess-Martin oxidation of adenosine or its derivatives (e.g., cordycepin) depends on a judicious selection of protecting groups for both the hydroxyl groups and the N 6 -position of the nucleobase.For example, for the synthesis of 3'-deoxyadenosine 5'-carboxaldehyde intermediate (1), we devised an efficient protection-deprotection strategy as shown in Scheme 1. Adenosine (2) was converted in three steps to compound 3, 8,9 by selective 2',5'-disilylation (61% yield), followed by treatment with phenyl chlorothionoformate and 4-dimethylaminopyridine (DMAP) in dichloromethane (60% yield), 10 and subsequent Barton radical deoxygenation reaction at C-3 (85% yield). 11Compound 3 can be deprotected to cordycepin and this approach represents an excellent method to produce gram quantities of this antiviral compound.
It was found that the order of the next two steps was very important in terms of yield.The N 6 -position of intermediate 3 was first protected using benzoyl chloride in pyridine (95% yield). 12Selective 5'-desilylation was subsequently accomplished using TFA-H 2 O-THF (1:1:4) (96% yield). 13Finally, Dess-Martin periodinane was used to oxidize the 5'-hydroxyl group to the aldehyde 1 (98% yield). 14Compound 1 can be deprotected in almost quantitative yield.Although several other oxidation conditions were explored, including EDC .HCl and DMSO, 15 DCC and DCAA in DMSO, 16 TPAP and NMO, 17 CrO 3 in pyridine and DMSO with trichloroacetic anyhydride, 18 only the Dess-Martin periodinane oxidation in CH 2 Cl 2 proceeded with high efficiency.
In summary, N 6 -benzoyl-2'-O-(tertbutyldimethylsilyl)-3'-deoxy-4'-formyladenosine 1 can be synthesized in an efficient and facile manner using a judicious protecting group strategy and the Dess-Martin periodinane for the oxidation step.The more robust benzamide and tertbutyldimethyl silyl ether protections are far superior for this oxidation than the acetyl protecting group.The aldehyde produced is a key intermediate is useful in the synthesis of many 4'substituted adenosine nucleosides of antiviral interest.

Experimental Section
General Procedures. 1 H and 13 C NMR spectra were recorded on Varian Mercury Plus 400 MHz or Varian Inova 500 MHz NMR spectrometers.High resolution ESI or FAB mass spectral data were obtained through the Nebraska Center for Mass Spectrometry.Column chromatographic separations were carried out using 230-400 mesh silica gel.