Biological Relevance and Synthesis of C-Substituted Morpholine Derivatives

Roel Wijtmans; Mandy K. S. Vink; Hans E. Schoemaker; Floris L. van Delft; Richard H. Blaauw; Floris P. J. T. Rutjes

doi:10.1055/s-2004-816003

REVIEW

Biological Relevance and Synthesis of C-Substituted Morpholine Derivatives

Roel Wijtmans^a, Mandy K. S. Vink^b, Hans E. Schoemaker^b,c, Floris L. van Delft^a, Richard H. Blaauw^d, Floris P. J. T. Rutjes^a,b
^a Department of Organic Chemistry, NSRIM, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax: +31(24)365 3393; e-Mail: rutjes@sci.kun.nl;
^b Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
^c DSM Life Science Products, PO Box 18, 6160 MD Geleen, The Netherlands
^d Chiralix BV, Toernooiveld 100, 6525 EC Nijmegen, The Netherlands

Abstract

Alle Artikel dieser Rubrik

Abstract

C-Functionalized morpholines are found in a variety of natural products and biologically active compounds, but have also for other reasons been applied in organic synthesis. This review deals with the biological relevance of C-substituted morpholines, their synthesis and important applications in other syntheses.

1 Introduction
2 Biological Relevance of Morpholines
2.1 Naturally Occurring Morpholines
2.2 Bioactive Morpholines
2.2.1 Antidepressants
2.2.2 Appetite Suppressants
2.2.3 Antitumor Activity
2.2.4 Antioxidants
2.2.5 Miscellaneous
3 Morpholine Synthesis
3.1 Synthesis from Amino Alcohols
3.2 Synthesis from Epoxides
3.3 Synthesis via Organometallic Reactions
3.4 Synthesis from Olefins
3.5 Synthesis from Carboxylic Acid Derivatives
3.6 Miscellaneous
4 Morpholines as Synthetic Tools
4.1 The Williams Chiral Auxiliary
4.2 Chiral Auxiliaries
5 Conclusions

Key words

morpholines - heterocycles - medicinal chemistry - asymmetric synthesis - natural products

Volltext

Referenzen

References

1 Otto WG. Angew. Chem. 1956, 68: 181

2 Lin C. Huang P. Lu C. Wu R. Hu W. Wang J. Tetrahedron 1997, 53: 2025

3 Minami Y. Yoshida K. Azuma R. Saeki M. Otani T. Tetrahedron Lett. 1993, 34: 2633

4 Yoshida K. Minami Y. Azuma R. Saeki M. Otani T. Tetrahedron Lett. 1993, 34: 2637

5 Iida K. Ishii T. Hirama M. Otani T. Minami Y. Yoshida K. Tetrahedron Lett. 1993, 34: 4079

6 Iida K. Fukuda S. Tanaka T. Hirama M. Imajo S. Ishiguro M. Yoshida K. Otani T. Tetrahedron Lett. 1996, 37: 4997

7 Bobzin SC. Faulkner DJ. J. Org. Chem. 1991, 56: 4403

8 Somei M. Aoki K. Nagaham Y. Nakagawa K. Heterocycles 1995, 41: 5

9 Ciminiello P. Dell"Aversano C. Fattorusso E. Forino M. Magno S. Ianaro A. Di Rosa M. Eur. J. Org. Chem. 2001, 49

10 Melloni P. Della Torre A. Lazzari E. Mazzini G. Meroni M. Tetrahedron 1985, 41: 1393

11 Fang QK. Han Z. Grover P. Kessler D. Senanayake CH. Wald SA. Tetrahedron: Asymmetry 2000, 11: 3659

12 Kelley JL. Musso DL. Boswell GE. Soroko FE. Cooper BR. J. Med. Chem. 1996, 39: 347

13 Rothman RB. Katsnelson M. Vu N. Partilla JS. Dersch CM. Blough BE. Baumann MH. Eur. J. Pharmacol. 2002, 51

14 D’Arrigo P. Lattanzio M. Fantoni GP. Servi S. Tetrahedron: Asymmetry 1998, 9: 4021

15 Kim D. Ryu DH. Lee JY. Lee N. Kim Y. Kim J. Chang K. Im G. Kim T. Choi W. J. Med. Chem. 2001, 44: 1594

16 Mosher CW. Wu HY. Fujiwara AN. Acton EM. J. Med. Chem. 1982, 25: 18

17 Acton EM. Tong GL. Mosher CW. Wolgemuth RL. J. Med. Chem. 1984, 27: 638

18 Acton EM. Tong GL. Taylor DL. Filppi JA. Wolgemuth RL. J. Med. Chem. 1986, 29: 1225

19 Guilloneau C. Charton Y. Ginot Y. Fouquier-d’Hérouël M. Bertrand M. Lockhart B. Lestage P. Goldstein S. Eur. J. Med. Chem. 2003, 38: 1

20 Chrysselis MC. Rekka EA. Siskou IC. Kourounakis PN. J. Med. Chem. 2002, 45: 5406

21 Chrysselis MC. Rekka EA. Kourounakis PN. J. Med. Chem. 2000, 43: 609

22 Araki K. Kuroda T. Uemori S. Moriguchi A. Ikeda Y. Hirayama F. Yokoyama Y. Iwao E. Yakushiji T. J. Med. Chem. 1993, 36: 1356

23 Sakurai N. Sano M. Hirayama F. Kuroda T. Uemori S. Moriguchi A. Yamamoto K. Ikeda Y. Kawakita T. Bioorg. Med. Chem. Lett. 1998, 8: 2185

24 Nozulak J. Vigouret JM. Jaton AL. Hofmann A. Dravid AR. Weber HP. Kalkman HO. Walkinshaw MD. J. Med. Chem. 1992, 35: 480

25 Hale JJ. Mills SG. MacCoss M. Finke PE. Cascieri MA. Sadowski S. Ber E. Chicchi GG. Kurtz M. Metzger J. Eiermann G. Tsou NN. Tattersall FD. Rupniak NMJ. Williams AR. Rycroft W. Hargreaves R. MacIntyre DE. J. Med. Chem. 1998, 41: 4607

26 Hale JJ. Mills SG. MacCoss M. Dorn CP. Finke PE. Budhu RJ. Reamer RA. Huskey SW. Luffer-Atlas D. Dean BJ. McGowan EM. Feeney WP. Chiu SL. Cascieri MA. Chicchi GG. Kurtz M. Sadowski S. Ber E. Tattersall FD. Rupniak NMJ. Williams AR. Rycroft W. Hargreaves R. Metzger J. MacIntyre DE. J. Med. Chem. 2000, 43: 1234

27 Harrison T. Owens AP. Williams BJ. Swain CJ. Williams A. Carlson EJ. Rycroft W. Tattersall FD. Cascieri MA. Chicchi GG. Sadowski S. Rupniak NMJ. Hargreaves R. J. Med. Chem. 2001, 44: 4296

28 Zhao MM. McNamara JM. Ho G. Emerson KM. Song ZJ. Tschaen DM. Brands KMJ. Dolling U. Grabowski EJJ. Reider PJ. J. Org. Chem. 2002, 67: 6743

29 Brands KMJ. Payack JF. Rosen JD. Nelson TD. Candelario A. Huffman MA. Zhao MM. Li J. Craig B. Song ZJ. Tschaen DM. Hansen K. Devine PN. Pye PJ. Rossen K. Dormer PG. Reamer RA. Welch CJ. Mathre DJ. Tsou NN. McNamara JM. Reider PJ. J. Am. Chem. Soc. 2003, 125: 2129

30 Lai JT. Synthesis 1984, 122

31 Rychnovsky SD. Beauchamp T. Vaidyanathan R. Kwan T. J. Org. Chem. 1998, 63: 6363

32 Sun G. Savle PS. Gandour RD. a’Bhaírd NN. Ramsay RR. Fronczek FR. J. Org. Chem. 1995, 60: 6688

33 Bouron E. Goussard G. Marchand C. Bonin M. Pannecoucke X. Quirion J. Husson H. Tetrahedron Lett. 1999, 40: 7227

34 Corral C. Lissavetzky J. Manzanares I. Darias V. Expósito-Orta MA. Martín Conde JA. Sánchez-Mateo CC. Bioorg. Med. Chem. 1999, 7: 1349

35 Uozumi Y. Tanahashi A. Hayashi T. J. Org. Chem. 1993, 58: 6826

36 Trost BM. Calkins TL. Oertelt C. Zambrano J. Tetrahedron Lett. 1998, 39: 1713

37 Vernier J. Hegedus LS. Miller DB. J. Org. Chem. 1992, 57: 6914

38 Berrée F. Debache A. Marsac Y. Carboni B. Tetrahedron Lett. 2001, 42: 3591

39 Jiang B. Xu M. Org. Lett. 2002, 4: 4077

40 Lai J. Shi X. Gong Y. Dai L. J. Org. Chem. 1993, 58: 4775

41 Nishi T. Ishibashi K. Nakajima K. Iio Y. Fukazawa T. Tetrahedron: Asymmetry 1998, 9: 3251

42 Nishi T. Ishibashi K. Takemoto T. Nakajima K. Fukazawa T. Iio Y. Itoh K. Mukaiyama O. Yamaguchi T. Bioorg. Med. Chem. Lett. 2000, 10: 1665

43 Takemoto T. Iio Y. Nishi T. Tetrahedron Lett. 2000, 41: 1785

44 Dahlgren A. Johansson P. Kvarnström I. Musil D. Nilsson I. Samuelsson B. Bioorg. Med. Chem. 2002, 10: 1829

45 Kardassis G. Brungs P. Nothhelfer C. Steckhan E. Tetrahedron 1998, 54: 3479

46 Hadley MS. King FD. Martin RT. Tetrahedron Lett. 1983, 24: 91

47a Schoemaker HE. Kruk C. Speckamp WN. Tetrahedron Lett. 1979, 20: 2437

47b Schoemaker HE. Speckamp WN. Tetrahedron 1980, 36: 951

48 Ley SV. Michel P. Synlett 2001, 1793

49 Kim YB. Choi EH. Keum G. Kang SB. Lee DH. Koh HY. Kim Y. Org. Lett. 2001, 3: 4149

50 Du M. Hindsgaul O. Synlett 1997, 395

51 Sinclair PJ. Zhai D. Reibenspies J. Williams RM. J. Am. Chem. Soc. 1986, 108: 1103

52 Wiliams RM. Sinclair PJ. Zhai D. Chen D. J. Am. Chem. Soc. 1988, 110: 1547

53 Van den Nieuwendijk AMCH. Warmerdam EGJC. Brussee J. Van der Gen A. Tetrahedron: Asymmtery 1995, 6: 801

54 Warmerdam EGJC. Brussee J. Kruse CG. Van der Gen A. J. Org. Chem. 1993, 1063

55 Williams RM. Zhai W. Tetrahedron 1988, 17: 5425

56 Williams RM. Zhai D. Sinclair PJ. J. Org. Chem. 1986, 51: 5021

57 Ramer SE. Cheng H. Palcic MM. Vederas JC. J. Am. Chem. Soc. 1988, 110: 8526

58 Williams RM. Fegley GJ. J. Am. Chem. Soc. 1991, 113: 8796

59 Williams RM. Fegley GJ. Tetrahedron Lett. 1992, 33: 6755

60 Williams RM. Im M. Tetrahedron Lett. 1988, 29: 6075

61 Bender DM. Williams RM. J. Org. Chem. 1997, 62: 6690

62 Van den Nieuwendijk AMCH. Benningshof JCJ. Wegmann V. Bank RA. Te Koppele JM. Brussee J. Van der Gen A. Bioorg. Med. Chem. Lett. 1999, 9: 1673

63 Van den Nieuwendijk AMCH. Kriek MAJN. Brussee J. Van Boom JH. Van der Gen A. Eur. J. Org. Chem. 2000, 3683

64 Jain RP. Albrecht BK. DeMong DE. Williams RM. Org. Lett. 2001, 3: 4287

65 Aoyagi Y. Jain RP. Williams RM. J. Am. Chem. Soc. 2001, 123: 3472

66 Williams RM. Im M. J. Am. Chem. Soc. 1991, 113: 9276

67 Williams RM. Zhai W. Aldous DJ. Aldous SC. J. Org. Chem. 1992, 57: 6527

68 Pansare SV. Bhattacharyya A. Tetrahedron 2003, 59: 3275

69 Ito H. Ikeuchi Y. Taguchi T. Hanzawa Y. J. Am. Chem. Soc. 1994, 116: 5469

70 Harwood LM. Lilley IA. Tetrahedron Lett. 1993, 34: 537

71 Chinchilla R. Falvello LR. Galindo N. Nájera C. J. Org. Chem. 2000, 65: 3034

72 Tohma S. Endo A. Kan T. Fukuyama T. Synlett 2001, 1179

73 Lei F. Chen Y. Sui Y. Wang D. Synlett 2003, 1160

74 Endo A. Yanagisawa A. Abe M. Tohma S. Kan T. Fukuyama T. J. Am. Chem. Soc. 2002, 6552

75 Agami C. Couty F. Lin J. Mikaeloff A. Poursoulis M. Tetrahedron 1993, 49: 7239

76 Agami C. Comesse S. Kadouri-Puchot C. J. Org. Chem. 2000, 65: 4435

77 Segat-Dioury F. Lingibé O. Graffe B. Sacquet M. Lhommet G. Tetrahedron 2000, 56: 233

78a Villeneuve G. DiMaio J. Drouin M. Michel AG. J. Chem. Soc., Perkin Trans. 2 1994, 1631

78b Anthony NJ. Gomez RP. Holtz WJ. Murphy JS. Ball RG. Lee T. Tetrahedron Lett. 1995, 36: 3821

78c Norman BH. Kroin JS. J. Org. Chem. 1996, 61: 4990

78d Llinares M. Devin C. Azay J. Bergé G. Fehrentz JA. Martinez J. Eur. J. Med. Chem. 1997, 32: 767

79 Norman BH. Kroin JS. Tetrahedron Lett. 1995, 36: 4151

80 Vinkovi V. unji V. Tetrahedron 1997, 53: 689

81 Enders D. Meyer O. Raabe G. Runsink J. Synthesis 1994, 66

82 Harwood LM. Drew MGB. Hughes DJ. Vickers RJ. J. Chem. Soc., Perkin Trans. 1 2001, 1581

83 Currie GS. Drew MGB. Harwood LM. Hughes DJ. Luke RWA. Vickers RJ. J. Chem. Soc., Perkin Trans. 1 2000, 2982

84 Myers AG. Kung DW. Zhong B. Movassaghi M. Kwon S. J. Am. Chem. Soc. 1999, 121: 8401

85 Myers AG. Kung DW. J. Am. Chem. Soc. 1999, 121: 10828