Design and synthesis of 5'-homoaristeromycin and 5'-homoneplanocin derivatives Qi Chen and Stewart W. Schneller Department of Chemistry and Biochemistry,

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Design and synthesis of 5'-homoaristeromycin and 5'-homoneplanocin derivatives Qi Chen and Stewart W. Schneller Department of Chemistry and Biochemistry, Auburn University Auburn, AL Introduction: S-Adenosylhomocysteine hydrolase (AdoHcy-ase) is an important target for antiviral agent design 1,2 because of its role in the regulation of S-adenosylmethionine (AdoMet) dependent methylation. 3 Carbocyclic nucleosides 5 represent a prominent class of compounds whose antiviral properties were attributed to their potent inhibition AdoHcy-ase, which in turn affects viral mRNA capping methylation. 1 Within this category, aristeromycin (1), 6 neplanocin A (3), 7 and their 3-deaza analogues, 3-deazaaristeromycin (2) 8 and 3- deazaneplanocin A (4), 4,7 exhibit special promises with broad-spectrum antiviral activity. Significant effort has been directed toward the synthesis and antiviral studies on analogues of 1, 2, 3, and 4 modified in the cyclopentyl ring with the aim of reducing phosphate based toxicity. 5'-homoaristeromycin (5), 9 3-deaza-5'-homoaristeromycin (6), 10 and 3-deaza-5'- homoneplanocin A (9) 11 are particular noteworthy examples with an extended C-5' hydroxymethyl side chain by methylene group. In the rational design of derivatives of 5, 6, and 9, as a means to improve upon its antiviral scope, substituents at the C-8 position have been identified as important targets by us and others 12 for two reasons: 1) The meaningful antiviral properties of C-8 substituted ribofuranosyl derived nucleosides 13 and 2) as probes for the conformational preferences around the N-9 purine/C-1' cyclopentyl linkage. Thus, 5'-homo-8-methylaristeromycin (7), 3-deaza-5'-homo-8-methylaristeromycin (8), and 3- deaza-5'-homo-8-methylneplanocin A (10) became target compounds. Figure 1 Scheme 1 a. 13, PPh 3, DIAD, THF, 12hr; 58%; b. HCl, MeOH, 90%. a. i) Trimethyl orthoacetate, formic acid, 100 ℃ ; ii) NaOH, reflux, 95%; b. i) Hydrazine, propanol. ii) Raney nickel, H 2 O, reflux, 96%; c. DMAP, Boc 2 O, THF, rt, 85%; d. Nu, THF, rt, 90%. Scheme 2 Scheme 4 Conclusion: An efficient synthetic pathway to 8-methyl substituted 5'-homoaristeromycin and 5'-homoneplanocin derivatives (7, 8, and 10) has been developed by employing Mitsunobu reaction with two different heterocyclic bases. This and the antiviral properties of these compounds will be reported. Acknowledgements: This research was supported by funds from Department of Health and Human Services (AI 56540), which is appreciated. Scheme 1 a. 12, PPh 3, DIAD, THF, 12 hr, 68%; b. 9-BBN, THF, rt, 3 hr; H 2 O 2, NaOH, 85%; c. NH 3, MeOH, 100 ℃, 24hr, 94%; d. HCl, MeOH, 3 hr, 80%; e. 13, PPh 3, DIAD, THF, 12 hr; f. 9-BBN, THF; H 2 O 2, NaOH, rt; g. HCl, MeOH. Scheme 3 Chemistry: A retrosynthetic analysis (Scheme 1) revealed that 7 and 8 could be accessible via a coupling reaction of a common precursor cyclopentanol 11 with appropriate functionalized heterocyclic bases 12 and 13. To begin, precursors 11, 12, and 13 were prepared. Cyclopenanol 11 was obtained following an efficient procedure starting from D-ribose reported by our lab Chloro-8-methyladenine (12) was readily available from a reported two-step literature approach starting from 5,6-diamino-4- hydroxypyrimidine. 15 By combining the most efficient and practical steps in existing heterocyclic chemistry literature, we have developed a convenient path way to 13 as shown in Scheme 2. Treatment of starting material 2-chloro-3,4-diaminopyridine (14) with trimethyl orthoacetate gave 15. Since conversion of 15 to 16 could not be achieved under the ammonia/methanol condition, anhydrous hydrazine was applied to 15 to displace the heterocyclic chloro subsituent followed by Raney nickel hydrogenolysis to afford Then, protection of 16 over Boc 2 O to 17 followed by selective deprotection gave 13 via a modified literature procedure.17 With the precursors in hand, we completed the preparation of 7 and 8 using a convergent synthetic approach (Scheme 3). In that direction, Mitsunobu reaction of 11 with 12 provided the coupled product 18. Transformation of the ethylene of 18 to the requisite hydroxyethyl group was accomplished by a hydroboration-oxidation sequence to give 19. Conversion of 19 to 20 was carried out by reaction with hydrazine followed by Raney nickel reduction. Deprotection of 20 with diluted hydrochloride acid gave the target compound 7. Replacing 12 with with 13 in Mitsunobu reaction led to coupled product 21. The bulky bis-Boc group significantly reduced the N-7 product competition with the N-9 product (21). Hydroboration- oxidation and deprotection sequence provided access to the target compound 8. The success in obtaining 8 suggested a similar approach to 10. Mitsunobu reaction of 13 with readily available cyclopentenol gave the coupled product 24. Removing all protecting groups afforded the target compound 10 (Scheme 4). (1) De Clercq, E. Nat. Rev. Drug Discovery 2002, 1, 13. (2) Palmer, J. L.; Abeles, R. H. J. Biol. Chem. 1979, 254, (3) Liu, S.; Wolfe, M. S.; Borchardt, R. T. Antiviral Res. 1992, 19, 247. (4) Rodriguez, J. B.; Comin, M. J. Mini-Rev. Med. Chem. 2003, 3, 95. (5) De Clercq, E. Nucleosides Nucleotides 1998, 17, 625. (6) Yuan, C.-S.; Liu, S.; Wnuk, S. F.; Robins, M. J.; Borchardt, R. T. Adv. Antiviral Drug Des. 1996, 2, 41. (7) De Clercq, E.; Cools, M.; Balzarini, J.; Marquez, V. E.;Borcherding, D. R.; Borchardt, R. T.; Drach, J. C.; Kitaoka, S.; Konno, T, Antimicrobial Agents and Chemotherapy 1989, 33, (8) Siddiqi, S. M.; Chen, X.; Rao, J.; Schneller, S. W.; Ikeda, S.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1995, 38, (9) Yang, M.; Schneller, S. W. Bioorg. Med. Chem. Lett. 2005, 15, 149. (10) Yang, M.; Zhou, J.; Schneller, S. W. Tetrahedron 2006, 62, (11) Shuto, S.; Obara, T.; Saito, Y.; Andrei, G.; Snoeck, R.; De Clercq, E.; Matsuda, A., Journal of Medicinal Chemistry 1996, 39, (12) Kitade, Y.; Kozaki, A.; Miwa, T.; Nakanishi, M. Tetrahedron 2002, 58, (13) de Clercq, E.; Neyts, J. Reviews in Medical Virology 2004, 14, 289. (14) Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004, 69, (15) Koppel, H. C.; Robins, R. K. J. Org. Chem. 1958, 23, (16) Dey, S.; Garner, P. J. Org. Chem. 2000, 65, (17) Crey-Desbiolles, C.; Kotera, M. Biooranic & Medicial Chemistry 2006, 14, (18) Yang, M.; Schneller, S. W. J. Med. Chem. 2005, 48, 5043.