Uses
As important intermediates in various areas such as peptide synthesis, asymmetric synthesis, medicinal chemistry, and polymer chemistry. The fluorous prolins were synthesized from commercially available N-Boc-4-methylene- L-proline.
Synthesis
Example 2. Preparation of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid
To a suspension of methyltriphenylphosphonium bromide (236.4 g, 2.7 eq.) in tetrahydrofuran (1 L) was rapidly added potassium tert-butoxide (75.6 g, 2.75 eq.) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours, followed by cooling again to 0 °C. At this temperature, (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (56.2 g, 0.245 mol) was added batchwise keeping the reaction temperature below 5 °C. The reaction mixture was then cooled to room temperature and stirred for 2 hours. The reaction mixture was then warmed to room temperature and stirred overnight. Upon completion of the reaction, the mixture was cooled to 0 °C and the reaction was quenched with saturated sodium bicarbonate solution (500 mL) and water (200 mL). The solvent was removed by concentration under reduced pressure and the aqueous phase was extracted with tert-butyl methyl ether (2 x 400 mL). The aqueous phase was filtered through a diatomaceous earth pad, acidified with 6N hydrochloric acid (200 mL) and extracted with ethyl acetate (2 x 1 L). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (0.7 L) and extracted with 0.5N sodium hydroxide solution (0.7 L and 0.3 L). The aqueous phase was acidified with 6N hydrochloric acid (100 mL) and extracted with ethyl acetate (1 L and 0.8 L). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a 50% ethyl acetate solution in cyclohexane (150 mL), and the solvent was slowly evaporated to give a pale yellow solid, which was filtered and dried to give (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (26 g). The mother liquor was concentrated under reduced pressure to give the same light yellow solid, which was filtered and dried to give additional product (10 g). In total, 36 g of product (65% yield) was obtained as a white solid. In addition, the residue contained 18 g of product with 80% purity.
1H NMR (500 MHz, CDCl3): δ 5.04-5.02 (m, 2H), 4.53 (dd, J = 8.4, 3.2 Hz, 0.5H), 4.42 (d, J = 9.3 Hz, 0.5H), 4.09-3.98 (m, 2H), 3.05-2.69 (m, 2H), 1.49 and 1.43 (2s, 9H).
References
[1] Patent: WO2012/158861, 2012, A2. Location in patent: Page/Page column 19-20
[2] Patent: WO2010/43877, 2010, A1. Location in patent: Page/Page column 51; 52
[3] Patent: WO2007/25307, 2007, A2. Location in patent: Page/Page column 309
[4] Patent: WO2017/35353, 2017, A1. Location in patent: Paragraph 0759
[5] Patent: CN107954990, 2018, A. Location in patent: Paragraph 0080; 0082; 0083; 0153; 0222
