Click Chemistry: A Straightforward Route to Decorated Prolines

Abstract

The synthesis of α-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected α-propynyl proline in the presence of Cu(I).

alkynes - amino acids - azides - α-substituted prolines - 1,2,3-triazoles

References and Notes

1 For a review on the stereoselective synthesis of α-alkyl-prolines, see: Cativiela C. Díaz-de-Villegas MD. Tetrahedron: Asymmetry  2000,  11:  645 

For other reviews on α,α-disubstituted α-amino acids, see:

2a Cativiela C. Díaz-de-Villegas MD. Tetrahedron: Asymmetry  1998,  9:  3517 

2b Nájera C. Synlett  2002,  1388 

2c Park K.-H. Kurth MJ. Tetrahedron  2002,  58:  8629 

2d Kotha S. Acc. Chem. Res.  2003,  36:  342 

2e Ohfune Y. Shinada T. Eur. J. Org. Chem.  2005,  5127 

2f Toniolo C. Formaggio F. Kaptein B. Broxterman QB. Synlett  2006,  1295 

2g Vogt H. Bräse S. Org. Biomol. Chem.  2007,  5:  406 

3 Lubec G. Labudova O. Seebach D. Beck A. Hoeger H. Hermon M. Weninger M. Life Sci.  1995,  57:  2245 

4 Becker DP. DeCrescenzo G. Freskos J. Getman DP. Hockerman SL. Li M. Mehta P. Munie GE. Swearingen C. Bioorg. Med. Chem. Lett.  2001,  11:  2723 

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6a Shin-ya K. Kim J.-S. Furihata K. Hayakawa Y. Seto H. Tetrahedron Lett.  1997,  38:  7079 

6b Watanabe H. Okue M. Kobayashi H. Kitahara T. Tetrahedron Lett.  2002,  43:  861 

7 Kolb HC. Finn MG. Sharpless KB. Angew. Chem. Int. Ed.  2001,  40:  2004 

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8b Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 

9 For a recent review, see: Bock VD. Hiemstra H. van Maarseveen JH. Eur. J. Org. Chem.  2006,  51 

10a Appukkuttan P. Dehaen W. Fokin VV. Van der Eychen E. Org. Lett.  2004,  6:  4223 

10b Khanetskyy B. Dallinger D. Kappe CO. J. Comb. Chem.  2004,  6:  884 

For the synthesis of other proline-derived triazoles by azide-alkyne cycloadditions, see:

11a Yan Z.-Y. Niu Y.-N. Wei H.-L. Wu L.-Y. Zhao Y.-B. Liang Y.-M. Tetrahedron: Asymmetry  2006,  17:  3288 

11b Paul A. Bittermann H. Gmeiner P. Tetrahedron  2006,  62:  8919 

12 During our study, the preparation of racemic α-trifluoro-methyl azahistidine analogues using the same approach has been reported: Shchetnikov GT. Peredukov AS. Osipov SN. Synlett  2007,  136 

13a Seebach D. Boes M. Naef R. Schweizer WB. J. Am. Chem. Soc.  1983,  105:  5390 

13b Seebach D. Sting AR. Hoffmann M. Angew. Chem. Int. Ed.  1996,  35:  2708 

14a Pooński T. Tetrahedron  1985,  41:  603 

14b Orsini F. Pellizzoni F. Forte M. Sisti M. Bombieri G. Benetollo F. J. Heterocycl. Chem.  1989,  26:  837 

14c Wang H. Germanas P. Synlett  1999,  33 

14d Amedjkouh M. Ahlberg P. Tetrahedron: Asymmetry  2002,  13:  2229 

15 A related compound of 5 (NBoc instead of NCbz) has been previously prepared in racemic form by propargylation of Boc-Pro-OMe: Ikeda M. Kugo Y. Kondo Y. Yamazaki T. Sato T. J. Chem. Soc., Perkin Trans. 1  1997,  3339 

16

1-Benzyl 2-Methyl (2 R )-2-Prop-2-ynylpyrrolidine-1,2-dicarboxylate (4): To a solution of compound 5 (0.56 mmol, 197 mg) in MeOH (3 mL) in a microwave reaction tube was added TMSCl (2.89 mmol, 365 µL). The mixture was stirred for 2.5 h at 40 °C using an irradiation power of 150 W with simultaneous cooling of the reaction vessel with a stream of compressed air. The solvent was removed under reduced pressure, and a sat. solution of NaHCO₃ (3 mL) was added followed by carbobenzyloxy chloride (CbzCl, 0.62 mmol, 87 µL) at 0 °C. The reaction mixture was allowed to warm to r.t., stirred overnight at r.t., and diluted with EtOAc. The two layers were separated, the aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluent: PE-Et₂O, 1:1) to give pure 7 (154 mg, 73%; mixture of two rotamers at r.t.) as a colourless oil. TBAF (1 M, 0.62 mmol, 0.6 mL) was added dropwise to a solution of proline 7 (0.41 mmol, 154 mg) in THF (10 mL). The mixture was stirred at r.t. for 2 h, and then the solvent was removed at reduced pressure. The residue was dissolved in CH₂Cl₂ and H₂O and the two layers were separated. The aqueous layer was extracted with CH₂Cl₂ and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluent: PE-Et₂O, 1:1) to give pure 4 (67 mg, 55%; mixture of two rotamers at r.t.) as a colourless oil. Compound 4: R _f 0.37. ¹H NMR (400 MHz, DMSO-d ₆, 110 °C): δ = 7.28-7.40 (m, 5 H, Ph), 5.09 (br s, 2 H, CH ₂Ph), 3.66 (ddd, J = 5.3, 7.8, 10.2 Hz, 1 H, 5-H_a), 3.59 (br s, 3 H, OMe), 3.51 (dt, J = 7.3, 10.2 Hz, 1 H, 5-H_b), 3.05-3.17 (m, 1 H, CHHCº), 2.81 (dd, J = 2.6, 17.0 Hz, 1 H, CHHCº), 2.64 (t, J = 2.6 Hz, 1 H, ºCH), 2.32 (m, 1 H, 3-H_a), 2.15 (m, 1 H, 3-H_b), 1.97-2.07 (m, 1 H, 4-H_a), 1.89-1.96 (m, 1 H, 4-H_b). Anal. Calcd for C₁₇H₁₉NO₄: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.57; H, 6.63; N, 4.93.

17a Alvarez SG. Alvarez MT. Synthesis  1997,  413 

17b Ju Y. Kumar D. Varma RS. J. Org. Chem.  2006,  71:  6697 

17c Hu X. Nguyen KT. Jiang VC. Lofland D. Moser HE. Pei D. J. Med. Chem.  2004,  47:  4941 

18a Szarek WA. Achmatowicz O. Plenkiewicz J. Radatus BK. Tetrahedron  1978,  34:  1427 

18b Esteves AP. Rodrigues LM. Silva ME. Gupta S. Oliveira-Campoça AMF. Machalickyb O. Mendonça AJ. Tetrahedron  2005,  62:  8625 

19

General Procedure: To a mixture of proline 4 (1 equiv) and azide 8 (1.2 equiv) in a mixture of H₂O and t-BuOH (1:1) in a microwave reaction tube were added copper turnings (0.2 equiv) and copper sulfate (0.7 equiv). The mixture was stirred for 15-20 min at 125 °C, using an irradiation power of 100 W with simultaneous cooling. It was then diluted with H₂O and CH₂Cl₂ and the two layers were separated. The aqueous layer was extracted with CH₂Cl₂ and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to afford analytically pure proline 9.

20

1-Benzyl 2-Methyl (2 R )-2-{[1-(4-Ethoxy-4-oxobutyl)-1 H -1,2,3-triazol-4-yl]methyl}pyrrolidine-1,2-dicarboxylate (9c): R _f 0.28 (PE-Et₂O, 1:1). ¹H NMR (400 MHz, DMSO-d ₆, 110 °C): δ = 7.52 (s, 1 H, triazole), 7.29-7.41 (m, 5 H, Ph), 5.12 (s, 2 H, CH ₂Ph), 4.34 (t, J = 6.9 Hz, 2 H, NCH ₂CH₂CH₂CO₂Et), 4.08 (q, J = 7.1 Hz, 2 H, CH ₂CH₃), 3.63 (br s, 3 H, OMe), 3.46-3.58 [m, 2 H, C(2)CHH + 5-H_a], 3.23 [d, J = 14.6 Hz, 1 H, C(2)CHH], 3.02-3.10 (m, 1 H, 5-H_b), 2.24-2.32 (m, 1 H, 3-H_a), 2.27 (t, J = 7.3 Hz, 2 H, CH ₂CO₂Et), 2.02-2.10 (m, 3 H, 3-H_b + CH ₂CH₂CO₂Et), 1.67-1.79 (m, 1 H, 4-H_a), 1.29-1.41 (m, 1 H, 4-H_b), 1.20 (t, J = 7.1 Hz, 3 H, CH₂CH ₃). Anal. Calcd for C₂₃H₃₀N₄O₆: C, 60.25; H, 6.59; N, 12.22. Found: C, 59.98; H, 6.90; N, 11.98.

For previous examples of triazole-linked glycosyl amino acids and peptides, see:

21a Kuijpers BHM. Groothuys S. Keereweer AR. Quaedflieg PJLM. Blaauw RH. van Delft FL. Rutjes FPJT. Org. Lett.  2004,  6:  3123 

21b Lin H. Walsh CT. J. Am. Chem. Soc.  2004,  126:  13998 

22 Kolb HC. Sharpless KB. Drug Discovery Today  2003,  8:  1128