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Synlett 2003(15): 2354-2358  
DOI: 10.1055/s-2003-43337
LETTER
© Georg Thieme Verlag Stuttgart · New York

Pd-Catalysed Synthesis of 5-Substituted Proline Derivatives from Acetylene-Containing Amino Acids

Bart C. J. van Esseveldta, Floris L. van Delfta, Jan M. M. Smitsb, René de Gelderb, Floris P. J. T. Rutjes*a
a Department of Organic Chemistry, NSRIM, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax: +31(24)3653393; e-Mail: rutjes@sci.kun.nl;
b Department of Inorganic Chemistry, NSRIM, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Further Information

Publication History

Received 2 September 2003
Publication Date:
21 November 2003 (online)

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Abstract

2,5-Disubstituted pyrrolines have been synthesised via Pd-catalysed 5-endo-dig cyclisations of substituted acetylene-containing amino acids. It has also been shown that these pyrrolines can be efficiently transformed into the corresponding saturated proline derivatives.

Key words

Pd-catalysis - amino acids - acetylenes - cyclisations - proline derivatives

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All new compounds were obtained in analytically pure form and were appropriately characterised by IR, mp, 1H and 13C NMR, high resolution mass data and rotational values.

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Crystallographic data of structures 21 and 26 have both been deposited at the Cambridge Crystallographic Data Centre and have been allocated the deposition numbers CCDC 212273 and CCDC 212274, respectively.

17

To determine the enantiopurity of compound 24, racemic 24 was synthesised and separated on a Chiralcel OD column (eluant: i-PrOH/hexane = 1:9). Using this assay, the ee of pyrroline 24 was determined to be >99%.

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Spek, A. L. PLATON, A Multipurpose Crystallographic Tool, 2002, Utrecht University, Utrecht, The Netherlands.

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Typical experimental procedures and data were as follows.
Formation of Enyne 6: To a solution of 5 (418 mg, 1.17 mmol) in DMF (20 mL), K2CO3 (808 mg, 5.85 mmol) and Pd(PPh3)4 (71 mg, 0.06 mmol) were added and the reaction mixture was stirred at 80 °C. Upon completion (TLC), the reaction mixture was poured into sat. aq. NaHCO3 (40 mL) and the aqueous layer was extracted with Et2O (30 ml, 3×). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (EtOAc/heptane = 1:9) to afford 6 (45 mg, 0.22 mmol, 19%) as a yellow solid. Rf = 0.23 (EtOAc/heptane = 1:9). IR(neat): 3448, 3354, 1705, 1614, 1591, 1487, 1441 cm-1. Mp 49.4 °C. 1H NMR (300 MHz, CDCl3): δ = 7.44 (m, 2 H), 7.31 (m, 3 H), 5.59 (s, 1 H), 4.57 (br s, 2 H), 3.82 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 164.0, 141.2, 131.1, 128.3, 128.1, 123.4, 100.3, 86.6, 85.7, 52.8. HRMS (EI) calcd for C12H11NO2: 201.0790. Found: 201.0792.
Formation of Pyrroline 24: To a solution of 18 (396 mg, 1.11 mmol) in MeCN (12 mL), PdCl2(MeCN)2 (29 mg, 0.11 mmol) was added and the reaction mixture was refluxed. Upon completion (TLC), the reaction mixture was concentrated in vacuo and the crude product was purified by chromatography (EtOAc/heptane = 1:3) to afford 24 (192 mg, 0.54 mmol, 48%) as a white solid. Rf = 0.36 (EtOAc/heptane = 1:2); [α]D +82.9 (c 1.0, CH2Cl2). Mp 88.3 °C. IR(neat): 2947, 1736, 1595, 1493, 1444 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.54 (m, 4 H), 7.29 (m, 5 H), 5.35 (dd, J = 2.1, 3.6 Hz, 1 H), 4.91 (dd, J = 2.1, 9.3 Hz, 1 H), 3.81 (s, 3 H), 2.56 (ddd, J = 2.4, 3.6, 17.1 Hz, 1 H), 2.42 (s, 3 H), 2.31 (ddd, J = 2.1, 9.6, 17.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 171.9, 144.9, 144.2, 134.2, 132.6, 129.6, 129.0, 128.0, 128.0, 127.9, 115.3, 63.5, 53.0, 32.7, 21.7. HRMS (EI) calcd for C19H19NO4S: 357.1035. Found: 357.1032.
Formation of Proline Derivative 26: To a solution of 24 (120 mg, 0.34 mmol) in CH2Cl2 (6 mL), Et3SiH (0.27 mL, 1.70 mmol), TFAA (0.24 mL, 1.70 mmol) and TFA (0.13 mL, 1.70 mmol) were added at 0 °C. The reaction mixture was allowed to reach r.t. and stirred until the reaction had reached completion (TLC). The reaction mixture was concentrated in vacuo and purified by chromatography (EtOAc/heptane = 1:4) to afford a diastereomeric mixture of 26 and the trans-isomer 27 (26/27 = 9:1, 90 mg, 0.25 mmol, 74%). Purification of this mixture by chromatography (EtOAc/heptane = 1:5) followed by crystallisation from Et2O gave diastereomerically pure 26 as a white solid. Rf = 0.60 (EtOAc/heptane = 1:1); [α]D -68.9 (c 0.5, CH2Cl2). Mp 130.3 °C. IR(neat): 1745, 1597, 1495, 1344 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.52 (d, J = 8.4 Hz, 2 H), 7.40 (m, 2 H), 7.18 (m, 5 H), 4.77 (t, J = 6.6 Hz, 1 H), 4.57 (t, J = 6.3 Hz, 1 H), 3.79 (s, 3 H), 2.36 (s, 3 H), 2.04 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 172.5, 143.3, 141.1, 135.4, 129.2, 128.1, 127.7, 127.2, 127.0, 65.1, 62.2, 52.7, 36.1, 29.7, 21.8. HRMS (EI) calcd for C19H21NO4S: 359.1191. Found: 359.1183.