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

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.

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

References

<A NAME="RG22803ST-1A">1a</A> Zhang J. Wang W. Xiong C. Hruby VJ. Tetrahedron Lett.  2003,  44:  1413 

<A NAME="RG22803ST-1B">1b</A> Del Valle JR. Goodman M. Angew. Chem. Int. Ed.  2002,  41:  1600 

<A NAME="RG22803ST-1C">1c</A> Flamant-Robin C. Wian Q. Chiaroni A. Sasaki NA. Tetrahedron Lett.  2002,  58:  10475 

<A NAME="RG22803ST-1D">1d</A> Davis FA. Fang T. Goswami R. Org. Lett.  2002,  4:  1599 

<A NAME="RG22803ST-1E">1e</A> Van Betsbrugge J. Van Den Nest W. Verheyden P. Tourwé D. Tetrahedron  1998,  54:  1753 

<A NAME="RG22803ST-2A">2a</A> Damour D. Herman F. Labaudinière R. Pantel G. Vuilhorgne M. Mignani S. Tetrahedron  1999,  55:  10135 

<A NAME="RG22803ST-2B">2b</A> Schumacher KK. Jiang J. Joullié MM. Tetrahedron: Asymmetry  1998,  9:  47 

<A NAME="RG22803ST-3A">3a</A> Fournie-Zaluski M.-C. Coric P. Thery V. Gonzalez W. Meudal H. Turcaud S. Michel J.-B. Roques BP. J. Med. Chem.  1996,  39:  2594 

<A NAME="RG22803ST-3B">3b</A> Manfré F. Pulicani JP. Tetrahedron: Asymmetry  1994,  5:  235 

<A NAME="RG22803ST-4A">4a</A> Molina MT. Valle CD. Escribano AM. Ezquerra J. Pedregal C. Tetrahedron  1993,  49:  3801 

<A NAME="RG22803ST-4B">4b</A> Ezquerra J. Mendoza JD. Pedregal C. Ramirez C. Tetrahedron Lett.  1992,  33:  5589 

<A NAME="RG22803ST-5A">5a</A> Wallén EAA. Christiaans JAM. Gynther J. Vepsäläinen J. Tetrahedron Lett.  2003,  44:  2081 

<A NAME="RG22803ST-5B">5b</A> Halab L. Bélec L. Lubell WD. Tetrahedron  2001,  57:  6439 

<A NAME="RG22803ST-5C">5c</A> Collado I. Ezquerra J. Pedregal C. J. Org. Chem.  1995,  60:  5011 

<A NAME="RG22803ST-6A">6a</A> Knight DW. Redfern AL. Gilmore J. J. Chem. Soc., Perkin Trans. 1  2002,  622 

<A NAME="RG22803ST-6B">6b</A> Knight DW. Redfern AL. Gilmore J. Chem. Commun.  1998,  2207 

<A NAME="RG22803ST-7">7</A> van Esseveldt BCJ. van Delft FL. de Gelder R. Rutjes FPJT. Org. Lett.  2003,  5:  1717 

<A NAME="RG22803ST-8A">8a</A> Wolf LB. Tjen KCMF. ten Brink HT. Blaauw RH. Hiemstra H. Schoemaker HE. Rutjes FPJT. Adv. Synth. Catal.  2002,  344:  70 

<A NAME="RG22803ST-8B">8b</A> Wolf LB. Tjen KCMF. Rutjes FPJT. Hiemstra H. Schoemaker HE. Tetrahedron Lett.  1998,  39:  5081 

This trifunctional amino acid(propargylglycine) is commercially available, but in our group also readily prepared via a chemo-enzymatic procedure that has been developed in collaboration with DSM Research (Geleen, The Netherlands):

<A NAME="RG22803ST-9A">9a</A> Wolf LB. Sonke T. Tjen KCMF. Kaptein B. Broxterman QB. Schoemaker HE. Rutjes FPJT. Adv. Synth. Catal.  2001,  343:  662 

<A NAME="RG22803ST-9B">9b</A> Sonke T. Kaptein B. Boesten WHJ. Broxterman QB. Kamphuis J. Formaggio F. Toniolo C. Rutjes FPJT. Schoemaker HE. In Stereoselective Biocatalysis   Patel RN. Marcel Dekker; New York: 2000.  p.23 

<A NAME="RG22803ST-10">10</A> Tykwinski RR. Angew. Chem. Int. Ed.  2003,  42:  1566 

<A NAME="RG22803ST-11">11</A> IJsselstijn M. Kaiser J. van Delft FL. Schoemaker HE. Rutjes FPJT. Amino Acids  2003,  24:  263 

<A NAME="RG22803ST-12">12</A> Rutjes FPJT. Wolf LB. Schoemaker HE. J. Chem. Soc., Perkin Trans. 1  2000,  4197 

<A NAME="RG22803ST-13">13</A>

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.

Similar elimination of p-toluenesulfinic acid from sulfonamide moieties has previously been observed:

<A NAME="RG22803ST-14A">14a</A> Ferreira PMT. Maia HLS. Monteiro LS. Tetrahedron Lett.  2002,  43:  4491 

<A NAME="RG22803ST-14B">14b</A> Ferreira PMT. Maia HLS. Monteiro LS. Sacramento J. J. Chem. Soc., Perkin Trans. 1  2001,  3167 

<A NAME="RG22803ST-15">15</A> Rudisill DE. Stille JK. J. Org. Chem.  1989,  54:  5856 

<A NAME="RG22803ST-16">16</A>

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.

<A NAME="RG22803ST-17">17</A>

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%.

<A NAME="RG22803ST-18">18</A>

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

<A NAME="RG22803ST-19">19</A> For a review on N-acyliminium ions and related structures, see: Speckamp WN. Moolenaar MJ. Tetrahedron  2000,  56:  3817 

<A NAME="RG22803ST-20">20</A>

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. R_f = 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. R_f = 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. R_f = 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.