Solid-Phase Synthesis of N-Alkylated Naltrindoles Using a 3-Nitrobenzyl Safety-Catch Linker

Abstract

We describe an effective solid-phase synthesis of N-substituted naltrindoles using a nitro benzyl safety-catch linker. The linker is stable to both strongly acidic and basic conditions and is cleaved under mildly acidic conditions after conversion of the nitro group to an amide group. Using the linker, a combinatorial synthesis of N-substituted naltrindoles involving the Fischer indole ­synthesis and N-alkylation was accomplished to provide 16 N-substituted naltrindoles.

Key words

combinatorial chemistry - Fischer indole synthesis - linker - opioid - solid-phase synthesis

References

• 1a Seneci P. In Solid-Phase Synthesis and Combinatorial Technology   Wiley-Interscience; New York: 2000. 
• 1b Dorwald FZ. In Organic Synthesis on Solid Phase   Wiley-VCH; New York: 2000. 
• 1c In Handbook of Combinatorial Chemistry   Vol. 1 and 2:  Nicolaou KC. Hanko R. Hartwig W. Wiley-VCH; Weinheim: 2002. 
• 2a Doi T. Hijikuro I. Takahashi T. J. Am. Chem. Soc.  1999,  121:  6749 
• 2b Takahashi T. Inoue H. Yamamura Y. Doi T. Angew. Chem. Int. Ed.  2001,  40:  3230 
• 2c Matsuda A. Doi T. Tanaka H. Takahashi T. Synlett  2001,  1101 
• 3 Wang S.-S. J. Am. Chem. Soc.  1973,  95:  1328 
• For examples of combinatorial synthesis of small molecule library using acid-cleavable linkers, see:
• 4a Doi T. Hijikuro I. Takahashi T. Synlett  1999,  1751 
• 4b Haruta M. Ejima A. Tanaka H. Takahashi T. Heterocycles  2002,  58:  79 
• 4c Ohno H. Kawamura K. Otake A. Nagase H. Tanaka H. Takahashi T. Synlett  2002,  93 
• 4d Fuchi N. Doi T. Cao B. Kahn M. Takahashi T. Synlett  2002,  285 
• 4e Tanaka H. Zenkoh T. Setoi H. Takahashi T. Synlett  2002,  1427 
• 4f Hashimoto M. Mori A. Inoue H. Nagamiya H. Doi T. Takahashi T. Tetrahedron Lett.  2003,  44:  1251 
• 4g Doi T. Fujimoto N. Watanabe J. Takahashi T. Tetrahedron Lett.  2003,  44:  2161 
• 4h Takahashi T. Nagamiya H. Doi T. Griffiths PG. Andrew M. Bray AM. J. Comb. Chem.  2003,  5:  414 
• 4i Tanaka H. Moriwaki M. Takahashi T. Org. Lett.  2003,  5:  3807 
• 4j Takahashi T. Kusaka S. Doi T. Sunazuka T. Omura S. Angew. Chem. Int. Ed.  2003,  42:  5230 
• 5 Kenner GW. MacDermoton JR. J. Chem. Soc., Chem. Commun.  1971,  636 
• 6a Izumi M. Fukase K. Kusumoto S. Synlett  2002,  1409 
• 6b Fürst M. Rück-Braun K. Synlett  2002,  1991 
• 7a Manabe S. Nakahara Y. Ito Y. Synlett  2000,  1241 
• 7b Wu X.-Y. Grathwohl M. Schmidt RR. Org. Lett.  2001,  3:  747 
• 7c Manabe S. Ito Y. Chem. Pharm. Bull.  2001,  49:  1234 
• 8a Portoghese PS. Sultana M. Nagase H. Takemori AE. J. Med. Chem.  1988,  31:  281 
• 8b Portoghese PS. Sultana M. Takemori AE. J. Med. Chem.  1990,  33:  1714 
• 9a Korlipara VL. Takemori AE. Portoghese PS. J. Med. Chem.  1994,  37:  1882 
• 9b Korlipara VL. Takemori AE. Portoghese PS. J. Med. Chem.  1995,  38:  1337 
• 10 Tanaka H. Ohno H. Kawamura K. Ohtake A. Nagase H. Takahashi T. Org. Lett.  2003,  5:  1159 
• For Fisher Indole synthesis using solid-supported ketones, see:
• 11a Hutchins SM. Chapman KT. Tetrahedron Lett.  1996,  37:  4869 
• 11b Yang L. Tetrahedron Lett.  2000,  41:  6981 
• 11c Copper LC. Chicchi GG. Dinnell K. Elliott JM. Hollingworth GJ. Kunts MM. Locker KL. Morrison D. Shaw DE. Tsao K.-L. Watt AP. Williams AR. Swain CJ. Bioorg. Med. Chem. Lett.  2001,  11:  1233 
• 15 Schutz J. Dersch CM. Horel R. Spetea M. Koch M. Meditz R. Greiner E. Rothman RB. Schmidhammer H. J. Med. Chem.  2002,  45:  5378 

12

Spectra of 5aA: ¹H NMR (400 MHz, CD₃OD): δ = 0.25-0.42 (2 H, m), 0.57-0.77 (2 H, m), 1.03 (1 H, m), 1.76-1.87 (1 H, m), 2.40-3.60 (9 H, m), 2.73 (1 H, d, J = 15.6 Hz), 5.55 (1 H, d, J = 17.3 Hz), 5.60 (1 H, d, J = 17.3 Hz), 5.65 (1 H, s), 6.62 (1 H, s), 6.62 (1 H, s), 6.96-7.00 (1 H, m), 7.05-7.09 (1 H, m), 7.16-7.29 (6 H, m), 7.43 (1 H, d, J = 7.8 Hz), 8.54 (1 H, s). ESI-MS: 505 (M + H⁺).

13

The ratio was determined by HPLC-MS analysis of crude material using UV absorption at 254 nm.

14

Spectra of 5aAA: ¹H NMR (400 MHz, CD₃OD): δ = 0.33-0.48 (2 H, m), 0.66-0.85 (2 H, m), 1.11 (1 H, m), 1.72-1.87 (1 H, m), 2.55-3.57 (10 H, m), 4.59 (2 H, s), 4.51-4.67 (2 H, m), 5.66 (1 H, s), 6.66 (1 H, s), 6.66 (1 H, s), 6.96-7.12 (9 H, m), 7.21-7.26 (4 H, m), 7.38 (1 H, d, J = 7.8 Hz), 8.53 (2 H, s). ESI-MS: 595 (M + H⁺).