Conformationally Locked Carbocyclic Nucleosides: Synthesis of the 1-Methyl-6-oxabicyclo[3.1.0]hexane Scaffold

Abstract

This paper describes the racemic and stereoselective ­synthesis of novel conformationally locked 3′-methyl-2′,3′-oxirane-fused carbocyclic nucleosides (nucleosides numbering). The key step is the direct coupling of an alcohol bearing the 1-methyl-6-oxa­bicyclo[3.1.0]hexane scaffold with diversely substituted purine ­nucleobases under Mitsunobu reaction conditions providing only the N⁹ target molecules.

carbocyclic nucleosides - conformationally locked ­nucleosides - Mitsunobu reaction - stereoselective synthesis - lipase regioselectivity

References and Notes

1a Marquez VE. In Advances in Antiviral Drug Design   Vol 2:  De Clercq E. JAI Press Inc.; Greenwich, CT: 1996.  p.89-146  

1b Carbohydrate Mimics: Concepts and Methods   Chapleur Y. Wiley-VCH; Weinheim: 1998. 

1c Recent Advances in Nucleosides: Chemistry and Chemotherapy   Chu CK. Elsevier Science; Amsterdam: 2002. 

2a Agrofolio LA. Challaud SR. Acyclic, Carbocyclic and l-Nucleosides   Kluwer Academic Publishers; Dordrecht, Boston, London: 1998. 

Recent reviews:

2b Crimmins MT. Tetrahedron  1998,  54:  9229 

2c Ferrero M. Gotor V. Chem. Rev.  2000,  100:  4319 

2d Rodriguez JB. Comin MJ. Mini-Rev. Med. Chem.  2003,  3:  95 

3a Herdewijn P. De Clercq E. Balzarini J. Vanderhaeghe H. J. Med. Chem.  1985,  28:  550 

3b Marquez VE. Lim M. Med. Res. Rev.  1986,  6:  1 

3c Roberts S. Biggadike K. Borthwick AD. Kirk B. In Topics in Medicinal Chemistry   Leeming PR. Royal Society of Chemistry; London: 1988. 

3d Saunders J. Cameron JM. Med. Res. Rev.  1995,  15:  497 

For selected recent syntheses and references cited therein, see:

4a Caamaño O. Gomez G. Fernández F. Garcia MD. Garcia-Mera X. De Clercq E. Synthesis  2004,  2855 

4b Takagi C. Sukeda M. Kim H.-S. Wataya Y. Yabe S. Kitade Y. Matsuda A. Shuto S. Org. Biomol. Chem.  2005,  3:  1245 

4c Yang M. Schneller SW. Bioorg. Med. Chem.  2005,  13:  877 

4d Santaniello E. Ciuffreda P. Alessandrini L. Synthesis  2005,  509 

4e Cho JH. Bernard DL. Sidwell RW. Kern ER. Chu CK. J. Med. Chem.  2006,  49:  1140 

4f Yang M. Zhou J. Schneller SW. Tetrahedron  2006,  62:  1295 

4g Agrofoglio LA. Curr. Org. Chem.  2006,  10:  333 

For selected recent syntheses and references cited therein, see:

5a Moon HR. Lee HJ. Kim KR. Lee KM. Lee SK. Kim HO. Chun MW. Jeong LS. Bioorg. Med. Chem.  2004,  14:  5641 

5b Kim JW. Choi BG. Hong JH. Bull. Korean Chem. Soc.  2004,  25:  1812 

5c Zhu X.-F. Nydegger F. Gossauer A. Helv. Chim. Acta  2004,  87:  2245 

5d Gonzalez-Moa MJ. Besada P. Teijeira M. Teran C. Uriate E. Synthesis  2004,  543 

5e Quadrelli P. Scrocchi R. Caramella P. Rescifina A. Piperno A. Tetrahedron  2004,  60:  3643 

5f Yang Y.-Y. Meng W.-D. Qing F.-L. Org. Lett.  2004,  6:  4257 

5g Hegedus LS. Cross J. J. Org. Chem.  2004,  69:  8492 

5h Wang J. Jin Y. Rapp KL. Bennett M. Schinazi RF. Chu CK. J. Med. Chem.  2005,  48:  3736 

5i Meillon J.-C. Griffe L. Storer R. Gosselin G. Nucleosides, Nucleotides Nucleic Acids  2005,  24:  695 

5j García MD. Caamaño G. Fernández F. Lopez C. De Clercq E. Synthesis  2005,  925 

5k 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 

5l Roy A. Schneller SW. Keith KA. Hartline CB. Kern ER. Bioorg. Med. Chem.  2005,  13:  4443 

5m Jin YL. Hong JH. Bull. Korean Chem. Soc.  2005,  26:  1366 

5n Oh CH. Hong JH. Bull. Korean Chem. Soc.  2005,  26:  1520 

5o Kim A. Hong JH. Bull. Korean Chem. Soc.  2005,  26:  1767 

5p Jiang MX.-W. Jin B. Gage JL. Priour A. Savela G. Miller MJ. J. Org. Chem.  2006,  71:  4164 

5q Ludek OR. Krämer T. Balzarini J. Meier C. Synthesis  2006,  1313 

5r García MD. Caamaño O. Fernández F. Abeijon P. Blanco JM. Synthesis  2006,  73 

5s Gosselin G. Griffe L. Meillon J.-C. Storer R. Tetrahedron  2006,  62:  906 

For selected recent syntheses and references cited therein, see:

6a Ishikura M. Matsumoto K. Hasunuma M. Katagiri N. Heterocycles  2003,  60:  2737 

6b Choi Y. George C. Comin MJ. Barchi JJ. Kim HS. Jacobson KA. Balzarini J. Mitsuya H. Boyer PL. Hughes SH. Marquez VE. J. Med. Chem.  2003,  46:  3292 

6c Choi Y. Moon HR. Yoshimura Y. Marquez VE. Nucleosides, Nucleotides Nucleic Acids  2003,  22:  547 

6d Comin MJ. Rodriguez JB. Russ P. Marquez VE. Tetrahedron  2003,  59:  295 

6e Kim KW. Hong JH. Bull. Korean Chem. Soc.  2004,  25:  668 

6f Ishikura M. Matsumoto K. Murakami A. Heterocycles  2004,  64:  241 

6g Paoli L. Piccini S. Rodriguez M. Sega A. J. Org. Chem.  2004,  69:  2881 

6h Moon HR. Kim KR. Kim BT. Hwang KJ. Chun MW. Jeong LS. Nucleosides, Nucleotides Nucleic Acids  2005,  24:  709 

6i Tchilibon S. Joshi BV. Kim S.-K. Duong HT. Gao Z.-G. Jacobson KA. J. Med. Chem.  2005,  48:  1745 

6j Joschi BV. Moon HR. Fettinger JC. Marquez VE. Jacobson KA. J. Org. Chem.  2005,  70:  439 

6k Comin MJ. Parrish DA. Deschamps JR. Marquez VE. Org. Lett.  2006,  8:  705 

7 Audran G. Acherar S. Monti H. Eur. J. Org. Chem.  2003,  92 

8

Nucleoside numbering.

9a Mitsunobu O. Synthesis  1981,  1 

9b Jenny TF. Horlacher J. Previsani N. Benner SA. Helv. Chim. Acta  1992,  75:  1944 

9c Review: Hughes DL. Org. Prep. Proced. Int.  1996,  28:  127 

10 Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  John Wiley and Sons, Inc.; New York: 1999.  p.150 

11 Corey EJ. Venkateswarlu A. J. Am. Chem. Soc.  1972,  94:  6190 

12a Sharpless KB. Michaelson RC. J. Org. Chem.  1973,  38:  6136 

12b Sharpless KB. Teranichi AY. Backväll J.-E. J. Am. Chem. Soc.  1977,  99:  3120 

13

Characterization of Selected New Compounds.
Compound (±)-7: IR (neat): ν = 3321, 1752, 1148, 1053 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 4.27 (t, J = 7.8 Hz, 1 H), 3.95 (ABX, J = 11.4, 5.4, 4.9 Hz, 2 H), 3.28 (s, 1 H), 2.79 (br s, OH), 2.38 (dt, J = 9.0, 4.7 Hz, 1 H), 1.98 (s, 3 H), 1.76 (dd, J = 13.4, 7.8 Hz, 1 H), 1.48 (dt, J = 13.4, 8.3 Hz, 1 H), 1.32 (s, 3 H). ¹³C NMR (400 MHz, CDCl₃): δ = 170.7 (C), 72.3 (CH), 65.3 (CH), 65.0 (CH₂), 64.0 (C), 41.4 (CH), 33.1 (CH₂), 20.7 (CH₃), 15.5 (CH₃). Anal. Calcd for C₉H₁₄O₄: C, 58.05; H, 7.58. Found: C, 57.91; H, 7.61. Compound (±)-1a: white solid; mp 150 °C (dec.). IR (KBr): ν = 3291, 3115, 1667, 1609 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.42 (s, 1 H), 7.95 (s, 1 H), 6.14 (br s, 1 H), 5.00 (dd, J = 9.5, 2.9 Hz, 1 H), 3.81 and 3.72 (ABX, J = 10.9, 4.5, 3.5 Hz, 2 H), 3.56 (s, 1 H), 3.01 (m, 1 H), 2.61 (dt, J = 14.5, 9.5 Hz, 1 H), 2.49-2.42 (m, 1 H), 2.25 (dt, J = 14.5, 2.9 Hz, 1 H), 1.62 (s, 3 H), 0.93-0.87 (m, 2 H), 0.65-0.59 (m, 2 H). ¹³C NMR (400 MHz, CDCl₃): δ = 155.9 (C), 152.9 (CH), 148.5 (C), 139.6 (CH), 120.0 (C), 69.3 (C), 66.2 (CH), 62.8 (CH₂), 55.6 (CH), 44.5 (CH), 34.4 (CH₂), 23.7 (CH), 15.4 (CH₃), 2 × 7.4 (CH₂). Anal. Calcd for C₁₅H₁₉N₅O₂: C, 59.79; H, 6.36; N, 23.24. Found: C, 59.98; H, 6.33; N, 23.04.
Compound (±)-1b: white solid; mp 170 °C (dec.). IR (KBr): ν = 3278, 3107, 1678, 1600 cm^-1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.19 (s, 1 H), 8.13 (s, 1 H), 7.21 (br s, 2 H), 4.91 (d, J = 7.2 Hz, 1 H), 4.77 (t, J = 4.5 Hz, 1 H), 3.79 (s, 1 H), 3.55 (m, 1 H), 3.38 (m, 1 H), 2.27-2.18 (m, 2 H), 1.88 (d, J = 12.6 Hz, 1 H), 1.49 (s, 3 H). ¹³C NMR (400 MHz, DMSO-d ₆): δ = 156.2 (C), 152.5 (CH), 149.6 (C), 139.2 (CH), 118.9 (C), 68.1 (C), 64.1 (CH), 61.6 (CH₂), 54.2 (CH), 44.5 (CH), 33.6 (CH₂), 15.5 (CH₃). Anal. Calcd for C₁₂H₁₅N₅O₂: C, 55.16; H, 5.79; N, 26.80. Found: C, 54.85; H, 5.84; N, 26.59.
Compound (±)-1c: white solid; mp 190 °C (dec.). IR (KBr): ν = 3305, 3172, 1676, 1615 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.76 (s, 1 H), 7.28 (br d, J = 3.6 Hz, 1 H), 5.86 (br s, 2 H), 4.78 (t, 4.9 Hz, 1 H), 4.72 (d, J = 7.2 Hz, 1 H), 3.70 (s, 1 H), 3.49 (dt, J = 10.8, 4.9 Hz, 1 H), 3.30 (dt, J = 10.8, 4.9 Hz, 1 H), 3.02 (br s, 1 H), 2.27-2.07 (m, 2 H), 1.86 (d, J = 14.0 Hz, 1 H), 1.47 (s, 3 H), 0.69-0.61 (m, 2 H), 0.60-0.53 (m, 2 H). ¹³C NMR (400 MHz, DMSO-d ₆): δ = 160.3 (C), 156.1 (C), 151.5 (C), 135.3 (CH), 113.6 (C), 68.0 (C), 64.2 (CH), 61.7 (CH₂), 53.6 (CH), 44.6 (CH), 33.3 (CH₂), 24.0 (CH), 15.6 (CH₃), 2 × 6.6 (CH₂). Anal. Calcd for C₁₅H₂₀N₆O₂: C, 56.95; H, 6.37; N, 26.56. Found: C, 57.23; H, 6.39; N, 26.35.

14

General Procedure.
Diisopropyl azodicarboxylate (DIAD, 0.72 mL, 3.6 mmol, 1.5 equiv) was added dropwise to a solution of PPh₃ (950 mg, 3.6 mmol, 1.5 equiv) in fresly distilled THF (50 mL) kept under Ar atmosphere at 0 °C. The mixture was stirred for 30 min and then the purine base was added (3.6 mmol, 1.5 equiv). The mixture was stirred for an additional 30 min and then a solution of epoxide 7 (450 mg, 2.4 mmol, 1 equiv) in dry THF (5 mL) was added slowly. The cooling bath was removed and the mixture allowed to warm to r.t. The mixture was stirred for 12 h at r.t.(chloropurine) or 12 h at r.t. then 4 h at 40 °C (adenine, 2-aminochloropurine). The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column (gradients hexane-EtOAc as eluent). Compounds 8 (66% yield) and 9 (56% yield) were obtained pure as white solids, but 10 was contaminated with inseparable triphenylphosphine oxide.

15

Triphenylphosphine oxide present with 10 was conveniently eliminated during this ammonia deprotective step by triturating the insoluble alcohol 12 with CH₂Cl₂ before aminocyclopropanation. Using this protocol, pure 12 was obtained in 53% overall yield from 7.