Synthesis of Lipophilic N9-Benzylguanine Derivatives

Jeremy E. B. McCallum; Kenneth G. Huston; Jacqueline M. McSweeney; Brandie G. Rucker

doi:10.1055/s-0030-1259037

LETTER

Synthesis of Lipophilic N ⁹-Benzylguanine Derivatives

Jeremy E. B. McCallum*, Kenneth G. Huston, Jacqueline M. McSweeney, Brandie G. Rucker
Loyola Marymount University, 1 LMU Drive, Los Angeles, CA 90045, USA
Fax: +1(310)3382905; e-Mail: jmccallu@lmu.edu;

Abstract

All articles of this category

Abstract

Lipophilic N ⁹-benzylguanine derivatives were synthesized from the arylalkylation of 2-N-acetylguanine with substituted benzyl bromides.

Key words

2-N-acetylguanine - benzylation - nucleobases - regioselectivity - HMBC

Full Text

References

References and Notes

<A NAME="RS03810ST-1">1</A> Hegi ME. Liu L. Herman JG. Stupp R. Wick W. Weller M. Mehta MP. Gilbert MR. J. Clin. Oncol. 2008, 26: 4189

<A NAME="RS03810ST-2">2</A> Ljungman M. Chem. Rev. 2009, 109: 2929

<A NAME="RS03810ST-3">3</A> Castilho MS. Postigo MP. de Paula CBV. Montanari CA. Oliva G. Andricopulo AD. Bioorg. Med. Chem. 2006, 14: 516

<A NAME="RS03810ST-4">4</A> Murthy D. Brakta M. Ellis LO. Med. Chem. Res. 2003, 12: 13

<A NAME="RS03810ST-5">5</A> Nair V. Uchil V. Neamati N. Bioorg. Med. Chem. Lett. 2006, 16: 1920

<A NAME="RS03810ST-6">6</A> Chern JW. Wise DS. Shewach DS. Daddona PE. Townsend LB. Eur. J. Med. Chem. 1994, 29: 3

<A NAME="RS03810ST-7">7</A> Kasibhatla SR. Hong K. Biamonte MA. Busch DJ. Karjian PL. Sensintaffar JL. Kamal A. Lough RE. Brekken J. Lundgren K. Grecko R. Timony GA. Ran Y. Mansfield R. Fritz LC. Ulm E. Burrows FJ. Boehm MF. J. Med. Chem. 2007, 50: 2767

<A NAME="RS03810ST-8">8</A> Chen L. Kode N. Murthy D. Phadtare S. Med. Chem. Res. 2005, 14: 445

<A NAME="RS03810ST-9">9</A> McCallum JEB. Kuniyoshi CY. Foote CS. J. Am. Chem. Soc. 2004, 126: 16777

<A NAME="RS03810ST-10">10</A> Sheu C. Kang P. Khan S. Foote CS. J. Am. Chem. Soc. 2002, 124: 3905

<A NAME="RS03810ST-11">11</A> Sheu C. Foote CS. J. Am. Chem. Soc. 1995, 117: 474

<A NAME="RS03810ST-12">12</A> Sheu C. Foote CS. J. Am. Chem. Soc. 1995, 117: 6439

<A NAME="RS03810ST-13">13</A> Davis JT. Spada GP. Chem. Soc. Rev. 2007, 36: 296

<A NAME="RS03810ST-14">14</A> Marlow AL. Mezzina E. Spada GP. Masiero S. Davis JT. Gottarelli G. J. Org. Chem. 1999, 64: 5116

<A NAME="RS03810ST-15">15</A> Forman SL. Fettinger JC. Pieraccini S. Gottarelli G. Davis JT. J. Am. Chem. Soc. 2000, 122: 4060

<A NAME="RS03810ST-16">16</A> Ma L. Iezzi M. Kaucher MS. Lam Y.-F. Davis JT. J. Am. Chem. Soc. 2006, 128: 15269

<A NAME="RS03810ST-17">17</A> Szalai VA. Singer MJ. Thorp HH. J. Am. Chem. Soc. 2002, 124: 1625

<A NAME="RS03810ST-18">18</A> Kawanishi S. Oikawa S. Ann. N. Y. Acad. Sci. 2004, 1019: 278

<A NAME="RS03810ST-19">19</A> Kawai K. Fujitsuka M. Majima T. Chem. Commun. 2005, 11: 1476

<A NAME="RS03810ST-20">20</A> Bollinger JM. Comisarow MB. Cupas CA. Olah GA. J. Am. Chem. Soc. 1967, 89: 5687

<A NAME="RS03810ST-21">21</A> Cardona L. Fernandez I. Garcia B. Pedro JR. Tetrahedron 1986, 42: 2725

N ^² -Acetyl- N ⁹ -(3,5-di- tert -butylbenzyl)guanine (9): Purification was achieved through flash chromatography using a CombiFlash® system (regioisomer 9 being more polar than regioisomer 10) with a gradient of CH₂Cl₂-MeOH (100:0→50:50) and subsequent recrystallization in EtOH-H₂O (32%). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.07 (s, 1 H, H-8), 7.31 (s, 1 H, ArH), 7.08 (s, 2 H, ArH), 5.27 (s, 2 H, CH₂), 2.16 (s, 3 H, CH₃), 1.23 (s, 18 H, 2 × t-Bu). ^¹³C NMR (400 MHz, DMSO-d ₆): δ = 173.5, 155.0, 150.8, 148.7, 147.9, 139.8, 135.9, 121.3, 121.1, 119.9, 46.7, 34.5, 31.1, 23.8. HRMS (ESI+): m/z [MH]⁺ calcd: 396.2400; found: 396.2408.

N ^² -Acetyl- N ⁷ -(3,5-di- tert -butylbenzyl)guanine (10): Purification was achieved through flash chromatography using a CombiFlash® system (regioisomer 9 being more polar than regioisomer 10) with a gradient of CH₂Cl₂-MeOH (100:0→50:50) and subsequent recrystallization in EtOH-H₂O (32%). ^¹H NMR (400 MHz, CDCl₃): δ = 7.79 (s, 1 H, H-8), 7.39 (s, 1 H, ArH), 7.23 (s, 2 H, ArH), 5.53 (s, 2 H, CH₂), 2.37 (s, 3 H, CH₃), 1.29 (s, 18 H, 2 × t-Bu). ^¹³C NMR (400 MHz, CDCl₃): δ = 173.4, 156.8, 153.5, 151.8, 148.0, 142.8, 134.5, 122.7, 122.0, 112.2, 51.3, 34.9, 31.4, 24.1. HRMS (ESI+): m/z [MH]⁺ calcd: 396.2400; found: 396.2408.

N ⁹ -(3,5-Di- tert -butylbenzyl)guanine (1): Purification was achieved through flash chromatography using a CombiFlash® system with a gradient of CH₂Cl₂-MeOH (100:0→50:50) and subsequent recrystallization in EtOH-H₂O (71%). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 10.67 (s, 1 H, NH), 7.76 (s, 1 H, H-8), 7.28 (s, 1 H, ArH), 7.11 (s, 2 H, ArH), 6.48 (s, 2 H, NH₂), 5.13 (s, 2 H, CH₂), 1.22 (s, 18 H, 2 × t-Bu). ^¹³C NMR (400 MHz, DMSO-d ₆): δ = 157.1, 153.8, 151.4, 150.8, 137.7, 136.5, 121.5, 121.2, 116.5, 46.5, 34.6, 31.3. HRMS (ESI+): m/z [MH]⁺ calcd: 354.2294; found: 354.2294.

N ^² -Acetyl- N ⁹ -[3,5-bis( tert -butyldimethylsilyloxy)-benzyl]guanine (11): Purification was achieved through flash chromatography using a CombiFlash® system (regioisomer 11 being more polar than regioisomer 12) with a gradient of CH₂Cl₂-MeOH (100:0→50:50) and subse-quent recrystallization in EtOH-H₂O (33%). ^¹H NMR (400 MHz, CDCl₃): δ = 7.64 (s, 1 H, H-8), 6.27 (s, 3 H, ArH), 5.06 (s, 2 H, CH₂), 2.36 (s, 3 H, CH₃), 0.94 (s, 18 H, 2 × t-Bu), 0.16 (s, 12 H, 4 × CH₃). ^¹³C NMR (400 MHz, CDCl₃): δ = 171.7, 157.2, 156.8, 149.3, 147.3, 139.3, 137.3, 120.5, 112.8, 112.0, 47.4, 25.7, 24.5, 18.3, -4.31. HRMS (ESI+): m/z [MH]⁺ calcd: 544.2775; found: 544.2778.

N ^² -Acetyl- N ⁷ -[3,5-bis( tert -butyldimethylsilyloxy)-benzyl]-guanine (12): Purification was achieved through flash chromatography using a CombiFlash® system (regioisomer 11 being more polar than regioisomer 12) with a gradient of CH₂Cl₂-MeOH (100:0→50:50) and subse-quent recrystallization in EtOH-H₂O (33%). ^¹H NMR (400 MHz, CDCl₃): δ = 7.75 (s, 1 H, H-8), 6.44 (s, 2 H, ArH), 6.30 (s, 1 H, ArH), 5.41 (s, 2 H, CH₂), 2.37 (s, 3 H, CH₃), 0.94 (s, 18 H, 2 × t-Bu), 0.16 (s, 12 H, 4 × CH₃). ^¹³C NMR (400 MHz, CDCl₃): δ = 173.5, 157.2, 156.5, 153.4, 148.4, 142.8, 137.1, 113.3, 112.3, 112.1, 50.8, 25.7, 24.6, 18.3,
-4.31. HRMS (ESI+): m/z [MH]⁺ calcd: 544.2775; found: 544.2777

N ⁹ -[3,5-Bis( tert -butyldimethylsilyloxy)benzyl]guanine (2): Purification was achieved through flash chroma-tography using a CombiFlash® system with a gradient of CH₂Cl₂-MeOH (100:0→50:50) and subsequent recrystal-lization in EtOH-H₂O (66%). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 10.58 (s, 1 H, NH), 7.73 (s, 1 H, H-8), 6.43 (s, 2 H, NH₂), 6.29 (s, 2 H, ArH), 6.17 (s, 1 H, ArH), 5.08 (s, 2 H, CH₂), 0.89 (s, 18 H, 2 × t-Bu), 0.12 (s, 12 H, 4 × CH₃). ^¹³C NMR (400 MHz, CDCl₃): δ = 156.8, 156.2, 153.7, 151.2, 139.8, 137.4, 116.5, 111.7, 110.4, 45.3, 25.5, 17.9, -4.6. HRMS (ESI+): m/z [MH]⁺ calcd: 502.2670; found: 502.2667.

<A NAME="RS03810ST-28">28</A> Madre M. Panchenko N. Zhuk R. Geenevasen JA. Van den Burg A. Koomen G.-J. Synthesis 1999, 775

<A NAME="RS03810ST-29">29</A> Kjellberg J. Johansson NG. Tetrahedron 1986, 42: 6541

Synthesis of Lipophilic N 9-Benzylguanine Derivatives

Synthesis of Lipophilic N ⁹-Benzylguanine Derivatives