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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 December 23.
Published in final edited form as:
Tetrahedron Lett. 2009 December 23; 50(51): 7156–7158.
doi:  10.1016/j.tetlet.2009.10.016
PMCID: PMC2796805

Synthesis of the 6′-iso analogues of neplanocin A and 5′-homoneplanocin A


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.

Keywords: carbocyclic nucleosides, Grubbs reaction, Mitsunobu reaction


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.

Scheme 1
Reagents and conditions: (a) HC[equivalent]CMgBr, THF, 86%; (b) TBSCl, imidazole, CH2Cl2, 83%; (c) 1st generation Grubbs catalyst, ethylene, CH2Cl2, 86%; (d) AD-mix-α, t-BuOH/H2O, 83%.

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.

Scheme 2
Reagents and conditions: (a) NaIO4, MeOH/H2O, 92%; (b) NaBH4, CeCl3•7 H2O, MeOH, 92%; (c) TBAF, THF; (d) TBSCl, imidazole, CH2Cl2, 82% in two steps from 14; (e) DIAD, PPh3, 1 eq. adenine, THF; (f) TBAF, THF, 46% in two steps from 16; (g) HCl, ...

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

Figure 2
X-ray structure of 21.
Scheme 3
Reagents and conditions: (a) BzCl, Et3N, CH2Cl2, 97%; (b) MsCl, Et3N, CH2Cl2; (c) LiAlH4, THF, 72% in two steps; (d) TBSCl, imidazole, CH2Cl2, 97%; (e) IBX, EtOAc; (f) NaBH4, CeCl3•7 H2O, MeOH, 86% in two steps from 22; (g) DIAD, PPh3, 1 eq. adenine, ...

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.

Figure 1
Neplanocin A and related analogues


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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References and Notes

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3. Wolfe MS, Borchardt RT. J. Med. Chem. 1991;34:1521. [PubMed]
4. Yang M, Schneller SW, Korba B. J. Med. Chem. 2005;48:5043. [PubMed]
5. Shuto S, Minakawa N, Niizuma S, Kim H-S, Wataya Y, Matsuda A. J. Med. Chem. 2002;45:748. [PubMed]
6. Wolfe MS, Lee Y, Bartlett WJ, Borcherding DR, Borchardt RT. J. Med. Chem. 1992;35:1782. [PubMed]
7. (a) Moon HR, Kim HO, Lee KM, Chun MW, Kim JH, Jeong LS. Org. Lett. 2002;4:3501. [PubMed] (b) Lee JA, Moon HR, Kim HO, Kim KR, Lee KM, Kim BT, Hwang KJ, Chun MW, Jacobson KA, Jeong LS. J. Org. Chem. 2005;70:5006. [PubMed]
8. (a) Kim J-H, Kim HO, Lee KM, Chun MW, Moon HR, Jeong LS. Tetrahedron. 2006;62:6339. (b) Chun MW, Lee HW, Kim J-H, Kim HO, Lee KM, Pal S, Moon HR, Jeong LS. Nucleosides Nucleotides Nucleic Acids. 2007;26:729. [PubMed]
9. Paisley SD, Wolfe MS, Borchardt RT. J. Med. Chem. 1989;32:1415. [PubMed]
10. Yang M, Ye W, Schneller SW. J. Org. Chem. 2004;69:3993. [PubMed]
11. Mori M, Sakakibara N, Kinoshita A. J. Org. Chem. 1998;63:6082. [PubMed]
12. Sharpless KB, Amberg W, Bennani YL, Crispino GA, Hartung J, Jeong K, Kwong H, Morikawa K, Wang Z, Xu D, Zhang X. J. Org. Chem. 1992;57:2768.
13. The configuration of the protected allylic hydroxyl group was assigned by comparing the NMR spectrum of 11 with the Sharpless oxidation product of 10α (see below). For this purpose, and were readily separated by column chromatography and their structures assigned by 1H NMR spectroscopy (that is, Ha of is a singlet while Ha of is multiplet; Hb of is a doublet while Hb of is a triplet).
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14. A was observed when more than one equivalent of adenine was used. However, A could be converted to 5 and 6 under the acidic deprotection.
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15. Selected data for 5: 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 8.06 (s, 1H), 7.21 (s, 2H), 5.92 (s, 1H), 5.33 (d, 1H, J=5.6 Hz), 5.04 (m, 1H), 4.84 (m, 2H), 4.47 (m, 2H), 3.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 156.5, 152.8, 150.1, 145.2, 141.0, 129.1, 120.0, 76.4, 71.8, 65.4, 58.3. HRMS calcd for C11H13N5O3 263.1018, found 263.1017.
16. Crystallographic data (excluding structure factors) for the structure in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 744708. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or
17. Ocejo M, Vicario JL, Badia D, Carrillo L, Reyes E. Synlett. 2005:2110.
18. Selected data for 6: 1H NMR (400 MHz, MeOD-d4): δ 8.14 (s, 1H), 8.10 (s, 1H), 5.96 (s, 1H), 5.45 (m, 1H), 4.59 (m, 1H), 4.55 (m, 1H), 3.55 (m, 2H), 2.08 (m, 1H), 1.90 (m, 1H); 13C NMR (100 MHz, MeOD-d4): δ 154.4, 150.8, 148.1, 141.3, 139.2, 128.6, 75.1, 70.5, 65.2, 57.6, 41.8, 30.0. HRMS calcd for C12H15N5O3 277.1175, found 277.1182.