Download PDF
Synlett 2004(3): 453-456  
DOI: 10.1055/s-2004-815404
LETTER
© Georg Thieme Verlag Stuttgart · New York

Solid-Phase Assisted N-1 Functionalization of Azamacrocycles

Morag Olivera, Michael R. Jorgensen*b, Andrew D. Miller*a
a Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London, SW7 2AZ, UK
e-Mail: a.miller@imperial.ac.uk;
b IC-Vec Ltd., Flowers Building, Armstrong Road, London, SW7 2AZ, UK
Fax: +44(20)75945803; e-Mail: m.jorgensen@icvec.com;
Further Information

Publication History

Received 20 November 2003
Publication Date:
12 January 2004 (online)

    Permissions and Reprints All articles of this category

Abstract

A simple solid-phase assisted strategy for the N-1 functionalization of azamacrocycles is described. Compounds such as cyclen, cyclam and piperazine can be selectively modified by ­temporary attachment to solid-phase resins providing an efficient and clean method to prepare biomedically interesting moieteies.

Key words

solid-phase synthesis - azo-macrocycles - protecting groups - contrast agents

    References

  • 1a Caravan P. Ellison JJ. McMurry TJ. Lauffer RB. Chem. Rev.  1999,  99:  2293 
    CrossrefGoogle Scholar
  • 1b Bianchi A. Calabi L. Corana F. Losi P. Maiocchi A. Paleari L. Valtancoli B. Coord. Chem. Rev.  2000,  204:  309 
    CrossrefGoogle Scholar
  • 2a Aoki S. Kawatani H. Goto T. Kimura E. Shiro M. J. Am. Chem. Soc.  2001,  123:  1123 
    CrossrefGoogle Scholar
  • 2b Reany O. Gunnlaugsson T. Parker D. Chem. Commun.  2000,  473 
    CrossrefGoogle Scholar
  • 3a Epstein DM. Chappell LL. Khalili H. Supkowski RM. Horrocks WDW. Morrow JR. Inorg. Chem.  2000,  39:  2130 
    CrossrefGoogle Scholar
  • 3b McCue KP. Morrow JR. Inorg. Chem.  1999,  38:  6136 
    CrossrefGoogle Scholar
  • 3c Morrow JR. Amin S. Lake CH. Churchill MR. Inorg. Chem.  1993,  32:  4566 
    CrossrefGoogle Scholar
  • 4a Anderson CJ. Welch MJ. Chem. Rev.  1999,  99:  2219 
    CrossrefPubMedGoogle Scholar
  • 4b Volkert WA. Hoffman TJ. Chem. Rev.  1999,  99:  2269 
    CrossrefPubMedGoogle Scholar
  • 5a Bridger GJ. Skerlj RT. Thornton D. Padmanabhan S. Martellucci SA. Henson GW. Abrams MJ. Yamamoto N. Vreese KD. Pauwels R. Clercq ED. J. Med. Chem.  1995,  38:  366 
    Google Scholar
  • 5b Clercq ED. Yamamoto N. Pauwels R. Baba M. Schols D. Nakashima H. Balzarini J. Debyser Z. Murrer BA. Schwartz D. Thornton D. Bridger G. Fricker S. Henson G. Abrams M. Picker D. Proc. Natl. Acad. Sci. U.S.A.  1992,  89:  5286 
    Google Scholar
  • 6 Bridger GJ, Abrams MJ, Henson GW, MacFarland RT, and Calandra GB. inventors; PCT Int. Appl. CAN  138:147724. 
  • 7 Alcock NW. Kingston RG. Moore P. Peirpoint C. J. Chem. Soc., Dalton Trans.  1984,  1937 
    CrossrefGoogle Scholar
  • 8 Helps IM. Parker D. Morphy JR. Chapman J. Tetrahedron  1989,  45:  219 
    CrossrefGoogle Scholar
  • 9a Patinec V. Yaouvanc JJ. Clement JC. Handel H. Tetrahedron Lett.  1995,  36:  79 
    CrossrefGoogle Scholar
  • 9b Patinec V. Yaouanc JJ. Handel H. Clement JC. Abbayes HD. Inorg. Chim. Acta  1994,  347 
    CrossrefGoogle Scholar
  • 10 Chuburu F. Baccon ML. Handel H. Tetrahedron  2001,  2385 
    CrossrefGoogle Scholar
  • 11a Guillaume D. Marshall GR. Synth. Commun.  1998,  28:  2903 
    CrossrefGoogle Scholar
  • 11b Bender JA. Meanwell NA. Wang T. Tetrahedron  2002,  3111 
    CrossrefGoogle Scholar
  • 13 Nash IA. Bycroft BW. Chan WC. Tetrahedron Lett.  1996,  37:  2625 
    CrossrefGoogle Scholar
  • 14 Leclercq F. Cohen-Ohana M. Sbsrbati A. Herscovici J. Scherman D. Byk G. Bioconjugate Chem.  2003,  14:  112 
    CrossrefGoogle Scholar
  • 15 Sabatino G. Chinol M. Paganelli G. Papi S. Chelli M. Leone G. Papini AM. Luca AD. Ginanneschi M. J. Med. Chem.  2003,  46:  3170 
    CrossrefGoogle Scholar
  • 16a Eisenwiener K.-P. Powell P. Mäcke HR. Bioorg. Med. Chem. Lett.  2000,  10:  2133 
    Google Scholar
  • 16b Heppeler A. Froidevaux S. Mäcke HR. Jermann E. Behe M. Powell P. Hennig M. Chem.-Eur. J.  1999,  5:  1974 
    Google Scholar
12

Novabiochem catalogue 2002/3, Merck Biosciences.

17

Chloranil test: To 1-5 mg of resin add one drop of acetaldehyde in DMF followed by one drop of 2% p-chloranil in DMF. Allow to stand at r.t. for 5 min blue beads indicate the prescence of secondary amines.

18

Sample data for production of protected cyclic amines. Product: Tri-Boc cyclen (15). FT-IR (film): νmax = 3417 (amine), 2960 (alkyl), 1712 (carbonyl), 1681 (amide), 1470 (alkyl) cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.45 [C(CH3)3 × 2], 1.46 [C(CH3)3], 3.25-3.34 (4 H, m, CH2 × 2), 3.39-3.46 (8 H, m, CH2 × 4), 3.54-3.59 (4 H, m, CH2 × 2). 13C NMR (100 MHz, CDCl3): δ = 28.1 [C(CH3)3], 28.2 [C(CH3)3 × 2], 46.8 (CH2 × 2), 47.6 (CH2 × 2), 50.7 (CH2 × 2), 52.7 (CH2 × 2), 82.0 [C(CH3)3], 82.2 [C(CH3)3 × 2], 156.8 (COOt-Bu × 2), 157.8 (COOt-Bu). MS (ESI+ve): m/z = 473 (M + H). FAB-MS: m/e calcd for C23H45N4O6 (M + H): 473.3316; found: 473.3339. HPLC analysis: t R = 24.0 min, column Vydac C-4 peptide, mobile phases MeCN (0.1% TFA) and H2O (0.1% TFA), gradient H2O/MeCN, 0-20 min [100/0] to [0/100], 20-25 min [0/100], 25.1 min [100/0], 40.0 min [100/0], flow rate 1 mL/min.

19

Sample data for production of selectively protected polyacetic acid derivatives. Product: Tri-t-Bu-DOTA (21). FT-IR (film): νmax = 3540 (amine), 2957 (alkyl), 2933(alkyl), 2850 (alkyl), 1744(carbonyl), 1632 (amide), 1454(alkyl) cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.42 [27 H, s, C(CH3)3 × 3], 2.71-2.82 (4 H, m, CH2 × 2), 2.97-3.12 (8 H, m, CH2 × 4), 3.26-3.31 (4 H, m, CH2 × 2), 3.37 (2 H, s, CH2COOt-Bu), 3.36 (2 H, s, br, CH2COOH), 3.70 (4 H, s, CH2COOt-Bu × 2). 13C NMR (100 MHz, CDCl3): δ = 28.0 [C(CH3)3 × 3], 48.3 (CH2 × 2), 50.1 (CH2 × 2), 53.2 (CH2 × 2), 53.3 (CH2), 53.4 (CH2), 55.6 (CH2COOt-Bu), 55.9 (CH2COOt-Bu × 2), 56.7 (CH2COOH), 81.6 [C(CH3)3], 81.7 [C(CH3)3 × 2], 167.4 (COOt-Bu), 169.8 (COOt-Bu × 2), 170.5 (COOH). MS (FAB+ve): m/z = 573 (M + H). FAB-MS: m/e calcd for C28H53N4O8 (M + H): 573.3863; found: 573.3885. HPLC analysis t R = 22.0 min, column Vydac C-4 peptide, mobile phases MeCN (0.1% TFA) and H2O (0.1% TFA), gradient H2O/MeCN, 0-20 min [100/0] to [0/100], 20-25 min [0/100], 25.1 min [100/0], 40.0 min [100/0], flow rate 1 mL/min.