Solid-Phase Assisted N-1 Functionalization of Azamacrocycles

Morag Oliver; Michael R. Jorgensen; Andrew D. Miller

doi:10.1055/s-2004-815404

LETTER

Solid-Phase Assisted N-1 Functionalization of Azamacrocycles

Morag Oliver^a, 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;

Abstract

Alle Artikel dieser Rubrik

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

Volltext

Referenzen

References

1a Caravan P. Ellison JJ. McMurry TJ. Lauffer RB. Chem. Rev. 1999, 99: 2293

1b Bianchi A. Calabi L. Corana F. Losi P. Maiocchi A. Paleari L. Valtancoli B. Coord. Chem. Rev. 2000, 204: 309

2a Aoki S. Kawatani H. Goto T. Kimura E. Shiro M. J. Am. Chem. Soc. 2001, 123: 1123

2b Reany O. Gunnlaugsson T. Parker D. Chem. Commun. 2000, 473

3a Epstein DM. Chappell LL. Khalili H. Supkowski RM. Horrocks WDW. Morrow JR. Inorg. Chem. 2000, 39: 2130

3b McCue KP. Morrow JR. Inorg. Chem. 1999, 38: 6136

3c Morrow JR. Amin S. Lake CH. Churchill MR. Inorg. Chem. 1993, 32: 4566

4a Anderson CJ. Welch MJ. Chem. Rev. 1999, 99: 2219

4b Volkert WA. Hoffman TJ. Chem. Rev. 1999, 99: 2269

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

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

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

8 Helps IM. Parker D. Morphy JR. Chapman J. Tetrahedron 1989, 45: 219

9a Patinec V. Yaouvanc JJ. Clement JC. Handel H. Tetrahedron Lett. 1995, 36: 79

9b Patinec V. Yaouanc JJ. Handel H. Clement JC. Abbayes HD. Inorg. Chim. Acta 1994, 347

10 Chuburu F. Baccon ML. Handel H. Tetrahedron 2001, 2385

11a Guillaume D. Marshall GR. Synth. Commun. 1998, 28: 2903

11b Bender JA. Meanwell NA. Wang T. Tetrahedron 2002, 3111

12

Novabiochem catalogue 2002/3, Merck Biosciences.

13 Nash IA. Bycroft BW. Chan WC. Tetrahedron Lett. 1996, 37: 2625

14 Leclercq F. Cohen-Ohana M. Sbsrbati A. Herscovici J. Scherman D. Byk G. Bioconjugate Chem. 2003, 14: 112

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

16a Eisenwiener K.-P. Powell P. Mäcke HR. Bioorg. Med. Chem. Lett. 2000, 10: 2133

16b Heppeler A. Froidevaux S. Mäcke HR. Jermann E. Behe M. Powell P. Hennig M. Chem.-Eur. J. 1999, 5: 1974

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): ν_max = 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): ν_max = 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.