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An efficient synthesis of 6′-isoneplanocin A and 6΄-isohomoneplanocin A is reported. The key steps in the synthesis include an enyne metathesis and a regioselective oxidation.
Inhibition of S-adenosyl-L-homocysteine hydrolase (AdoHcy hydrolase) has been recognized as an important approach to develop new antiviral agents.1 As one of the most potent inhibitors of AdoHcy hydrolase, the naturally occuring carbocyclic nucleoside neplanocin A (1) has shown significant broad antiviral activities.2 However, this antiviral potential is limited by its toxicity as a result of phosphorylation of the C-5′ primary hydroxyl group.3 In seeking ways to circumvent this undesirable transformation, 5′-homoneplanocin A (2) with a C-5΄ extended side-chain was synthesized and found to have significant activity against HBV and HCV without associated toxicity.4 Other C-5΄ neplanocin A modifications have considered adding a methyl group to enhance the steric interference to phosphorylation at this site5 and removal of the C-5' hydroxyl or C-4' hydroxymethyl substituents.6 Apio-neplanocin A 37 and apio-homoneplanocin A 4,8 which are the C-3' isomers of 1 and 2, have been reported. While failing to inhibit AdoHcy hydrolase, 3 was found to have biological activity as a potent, selective A3 adenosine receptor agonist.7b The failure of 3 and 4 to inhibit the hydrolase could be the consequence of their C-3΄-tertiary center.9
In our pursuit of neplanocin A analogues with non-toxic, antiviral potential, the 6′-iso analogues 5 and 6 emerged as worthy targets. An enantiomerically efficient preparation of the 6΄-isoneplanocin A analogues 5 and 6 from D-ribose is reported here.
The synthesis began with the protected glycol enal 7,10 which can be prepared in large scale from inexpensive D-ribose in 2 steps (Scheme 1). Ethynylmagnesium bromide addition to 7 gave enyne 8, which was protected as its tert-butyldimethylsilyl derivative 9. An enyne metathesis11 of substrate 9 gave product 10 in excellent yield. The α- and β- isomers of 10 could not be separated at this stage and were used directly in the next step. Taking advantage of the different reaction rate between a terminal alkene and an internal one in the Sharpless asymmetric dihydroxylation,12 the highly regioselective products 11 and 12 were achieved by treating 10 with AD-mix-α in the absence of methanesulfonamide. The two isomers (α and β) were easily isolated by flash column chromatography and the ratio of α isomer to β isomer was ca. 4:5.13 The α isomer 11 was then chosen to synthesize neplanocin A analogue 5 while the β isomer 12 was selected for homoneplanocin A analogue 6.
Oxidative cleavage of 11 (to 13) (Scheme 2) followed by reduction using Luche reagent produced 14. Removal of the TBS group of 14 with TBAF (to 15) and selective protection of the primary hydroxyl group with TBS yielded 16. The Mitsunobu coupling4 of 16 with one equivalent of adenine14 (to 17) followed by desilylation afforded 18. The target compound 6′-isoneplanocin A (5)15 was achieved by removal of the isopropylidene of 18 under acidic conditions.
To achieve 6 (Scheme 3), the primary alcohol of 12 was first benzoylated (to 19) that was followed by mesylation to 20. Reduction of 20 using lithium aluminum hydride removed the mesyl, benzoyl and TBS groups to afford diol 21, whose crystal structure (Figure 2) was obtained (which further supported the previous stereochemical assignment of 11 and 12).16 The primary hydroxyl of 21 was selectively protected with a TBS group. Because of difficulties using Mitsunobu conditions to invert the allylic hydroxyl group of 22, an oxidation-reduction approach was selected. Thus, 22 was first oxidized using IBX (2-iodoxybenzoic acid) in refluxing EtOAc17 to afford enone 23. This was followed by a Luche reduction to avail the desired α isomer 24. Pursuing steps similar to the synthesis of 5, Mitsunobu coupling4 of 24 with one equivalent of adenine14 and followed by removal of hydroxyl protection completed the synthesis of 6.18
In summary, an efficient pathway to the 6′-isoneplanocin A targets 5 and 6 has been developed. The antiviral data associated with this new class of carbocyclic nucleosides is forthcoming.
This research was supported by funds from Department of Health and Human Services (AI 56540). We thank Drs. Thomas Albrecht-Schmitt and John Gorden, Auburn University, for securing the X-ray data for 21.
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