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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)

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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

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Novabiochem catalogue 2002/3, Merck Biosciences.

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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.

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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.

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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.