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Synlett 2006(9): 1315-1318  
DOI: 10.1055/s-2006-939718
LETTER
© Georg Thieme Verlag Stuttgart · New York

Macrocycles via Doebner Reaction Followed by Macrolactonization

Bernd Henkel*, Marta Lis, Katrin Illgen, Robert Eckl
Morphochem AG, Gmunder Strasse 37-37A, 81379 München, Germany
Fax: +49(89)78005555; e-Mail: bernd.henkel@morphochem.de;
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Publication History

Received 1 March 2006
Publication Date:
22 May 2006 (online)

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Abstract

The synthesis of 14 different macrocycles is reported. Upon reacting different formylphenoxyacetic acid derivatives with 5-aminopentanol and a diketo compound, eight different Doebner product intermediates were obtained. These intermediates were then subjected to cyclization by using polymer-bound carbodiimide to give macrolactones. Both the monomers and the dimers could be isolated and characterized. In some cases trimers could be seen from the HPLC-MS. The ratios and distribution of the different-sized rings are discussed.

Key words

macrocycles - multicomponent reactions - lactones - ­heterocycles - tandem reactions

14

Amine (2 mmol) and aldehyde (2 mmol) were dissolved in 3 mL of a 1:1 mixture of CH2Cl2 and EtOH. After 30 min stirring at r.t. pyruvic acid derivative (2 mmol) was added. The mixture was stirred for 16 h. The solvent was removed and the remainder taken up in Et2O for solidifying. Compounds 4, 5 and 6 could be used for the next step without purification. All other compounds were purified via preparative HPLC (column Grom-Sil 120 ODS-5, 10 × 4 cm, 10 µm, flow 50 mL/min, gradient 20-100% A in 15 min, solvent A = MeOH + 0.5% AcOH, solvent B = H2O + 0.5% AcOH). Yields of 1-8 are given in Table [1] .

16

Compound 1 (250.8 mg, 0.6 mmol) was dissolved in 5 mL of anhydrous CH2Cl2 together with N,N-dimethylamino-pyridine (15.9 mg, 0.13 mmol). Then, N-cyclohexyl-N′-methyl polystyrene (Novabiochem, 750 mg, 1.2 mmol) was added and the mixture agitated overnight at r.t. Resin was filtered off and thoroughly washed with CH2Cl2. The combined solvents were evaporated and the remainder was subjected to preparative HPLC (column Waters SunFire Prep C18 OBD, 19 × 50 mm, 5 µm, flow 30 mL/min, gradient 20-90% A in 15 min, solvent A = MeOH + 0.03% formic acid, solvent B = H2O + 0.03% formic acid). Yield of 9: 60 mg (25%), 17: 28 mg (5.8%), 25: 6 mg (0.8%).
Compound 9: 1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s, CH3), 1.10-1.80 (6 H, m, CH2CH2CH2), 2.79-2.88 (1 H, t, CH of CH2, J = 13.3 Hz), 3.51-3.61 (1 H, t, CH′ of CH2, J = 13.3 Hz), 4.02-4.14 (2 H, m, CH2), 4.76-4.82 (1 H, d, CH of CH2, J = 17.2 Hz), 4.92-4.98 (1 H, d, CH′ of CH2, J = 17.2 Hz), 6.06 (1 H, s, CH), 6.76-6.88 (3 H, m, Harom), 7.16-7.22 (1 H, d, J = 8.6 Hz, Harom). 13C NMR (100 MHz, CDCl3): δ = 24.3, 25.4, 25.8, 26.1, 40.5, 43.0, 54.2, 64.4, 67.7, 110.2, 118.1, 122.0, 124.8, 127.0, 129.8, 154.5, 155.5, 164.5, 168.9, 202.5.
Compound 17: 1H NMR (400 MHz, DMSO-d 6): δ = 1.10 (18 H, s, CH3), 1.14-1.68 (12 H, m, 2 × CH2CH2CH2), 3.30-3.54 (4 H, m, 2 × CH2), 4.06-4.18 (4 H, m, 2 × CH2), 4.83-4.93 (4 H, m, 2 × CH2), 5.83 (2 H, s, 2 × CH), 6.70-6.78 (2 H, m, Harom), 6.85-6.92 (2 H, m, Harom), 6.95-7.03 (2 H, m, Harom), 7.17-7.26 (2 H, m, Harom). 13C NMR (100 MHz, DMSO-d 6): δ = 22.4, 24.6, 25.3, 27.0, 40.1, 42.5, 54.1, 64.3, 67.3, 110.0, 118.5, 122.1, 125.2, 127.4, 129.9, 156.0, 156.3, 165.0, 168.5, 202.7.
Compound 25: No NMR spectra could be recorded due to lack of substance.