A flexible, practical, and stereoselective synthesis of enantiomerically pure trans-5-oxohexahydropyrrolo[3,2-b]pyrroles (pyrrolidine-trans-lactams), a new class of serine protease inhibitors, using acyliminium methodology

Journal of Organic Chemistry

Volumn 64, Issue 14, 1999, Pages 5166-5175

  Macdonald, Simon J F ^a   Clarke, Geoffrey D E ^a   Dowle, Michael D ^a   Harrison, Lee A ^a   Hodgson, Simon T ^a   Inglis, Graham G A ^a   Johnson, Martin R ^a   Shah, Prit ^a   Upton, Richard J ^a   Walls, Steven B ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

LACTAM DERIVATIVE; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR;

ARTICLE; CHIRALITY; DRUG MECHANISM; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOMER; REACTION ANALYSIS; STEREOCHEMISTRY;

EID: 0033000366     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo990306s     Document Type: Article

References (55)

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5. (a) Macdonald, S. J. F.; Belton, D. J.; Buckley, D. M.; Spooner, J. E.; Anson, M. S.; Harrison, L. A.; Mills, K.; Upton, R. J.; Dowle, M. D.; Smith, R. A.; Molloy, C. R.; Risley, C. J. Med. Chem. 1998, 41, 3919-3922.
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10. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
11. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
12. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
13. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
14. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
15. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
16. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
17. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
18. HNE for respiratory diseases: (a) Stockley, R. A. Am. J. Respir. Crit. Care Med. 1994, 150, S109-S113. (b) Vender, R. L. J. Invest. Med. 1996, 44, 531-539. Reviews of HNE inhibitors: (c) Hlasta, D. J.; Pagani, E. D. Ann. Rep. Med. Chem. 1994, 195. (d) Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127. Leading references for HNE inhibitors from pharmaceutical companies and academia follow. Merck: (e) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462. Zeneca: (f) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.; Bryant, C.; Damewood, J. R.; Earley, J.; Feeney, S. W.; Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med. Chem. 1997, 40, 3173-3181. Sterling Winthrop: (g) Hlasta, D. J.; Ackermann, J. H.; Court, J. J.; Farrell, R. P.; Johnson, J. A.; Kofron, J. L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.; Franke, C. A. J. Med. Chem. 1995, 38, 4687-4692. Hoechst: (h) Burkhart, J. P.; Mehdi, S.; Koehl, J. R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg. Med. Chem. Lett. 1998, 8, 63-64. Wichita State University: (i) Kuang, R.; Venkataraman, R.; Ruan, S.; Groutas, W. C. Bioorg. Med. Chem. Lett. 1998, 8, 539-544.
19. (a) Sommeroff, C. P.; Nadel, J. A.; Basbaum, C. B.; Caughey, G. H. J. Clin. Invest. 1990, 85, 682-689.
20. (b) Thompson, A. B.; Daughton, D.; Robbins, R. A.; Ghafouri, M. A.; Oehlerking, M.; Rennard, S. I. Am. Rev. Respir. Dis. 1969, 140, 1527-1537.
21. In-house models were developed by Robin A. Smith and colleagues. Details will be published in due course.
22. Koot, W.-J.; Hiemstra, H.; Speckamp W. N. Tetrahedron: Asymmetry 1993, 4, 1941-1948.
23. Thaning, M.; Wistrand L.-G. J. Org. Chem. 1990, 55, 1406-1408 and references therein.
24. Pellegata, R.; Pinza, M.; Pifferi, G. Synthesis 1978, 614-616.
25. 4 and HCl in dioxan. However, excess borohydride is needed, and the reaction is not homogeneous.
26. Borthwick, A. D.; Crame, A.; Exall, A.; Mason, A.; Pennell, A. Tetrahedron Lett. 1999, 40, 3061-2.
27. We have also explored the use of the boron enolates of isopropyl valerate derivatives attached to a chiral auxiliary (see ref 28).
28. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868-2877. Oare, D. E.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157-172. Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650-657. Otera, J.; Fujita, Y.; Fukuzumi, S. Synth. Lett. 1994, 213-214.
29. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868-2877. Oare, D. E.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157-172. Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650-657. Otera, J.; Fujita, Y.; Fukuzumi, S. Synth. Lett. 1994, 213-214.
30. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868-2877. Oare, D. E.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157-172. Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650-657. Otera, J.; Fujita, Y.; Fukuzumi, S. Synth. Lett. 1994, 213-214.
31. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868-2877. Oare, D. E.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157-172. Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org. Chem. 1991, 56, 650-657. Otera, J.; Fujita, Y.; Fukuzumi, S. Synth. Lett. 1994, 213-214.
32. The (2-cyclopropyl-1-ethoxy-E-vinyloxy)trimethylsilane and the (1-ethoxy-2-ethyl-1-butenyloxy)trimethylsilane react with 15 to give the corresponding products in good yield.
33. + 258 (5%).
34. 2O fail to improve the β/α ratio.
35. Wilcox, C. S.; Babston, R. E. J. Org. Chem. 1984, 49, 1451-3.
36. Adam, W.; Wang, X. J. Org. Chem. 1991, 56, 7244-50.
37. The racemate 2 may be separated into its enantiomers by preparative HPLC on a 2 in. Merck AD column, eluting with 15% ethanol/heptane with a flow rate of 50 mL/min. The injection volume is 25 mL, and the detector wavelength is 215 nm. The throughput of material is limited by the solubility of 2 in the mobile phase (100 mg/ 25 mL). The 6S,6aS,3aR enantiomer 28 elutes first and can be obtained in satisfactory purity without recycling. The 6R,6aR,3aS enantiomer elutes second and requires one to two recycles to obtain material of satisfactory purity.
38. (R,S)-2,4-Diaminobutyric acid dihydrochloride costs ca. £10/g. (S)-2,4-Diaminobutyric acid dihydrochloride costs ca. £20/g from Aldrich Chemical Co.
39. (R)-Asn costs £25/100 g, (S)-Asn costs £14/100 g, (R)-Met costs £23/25 g, and (S)-Met costs £17/100 g from Aldrich Chemical Co.
40. Curphey, T. J. J. Org. Chem. 1979, 44, 2805-2807.
41. Maddaluno, J.; Corruble, A.; Leroux, V.; Ple, G.; Duhamel, P. Tetrahedron: Asymmetry 1992, 1239-1242.
42. There is a tosyl-derived byproduct formed in this reaction, and its removal by chromatography also leads to degradation of some of the product.
43. Galan, A.; de Mendoza, J.; Prados, P.; Rojo, R.; Echavarren, A. M. J. Org. Chem. 1991, 56, 452-454.
44. Comparison of the circular dichroism spectra of the synthetic material (mainly 28), the pure enantiomers 28 and 29 separated by chiral HPLC, and the C-6 allyl analogues of 28 and 29 (whose absolute stereochemistry had been determined by X-ray experiments) gave consistent results reconfirming the assignment of absolute stereochemistry.
45. 19F NMR of the crude mixture indicated an 83:14:3 mixture of isomers. Attempted deprotection of the trifluoroacetamide failed, and reaction of 39 with lithium ethoxide led to ring opening of the oxazolidinone to give 40 in 60% yield rather than its displacement. (matrix presented)
46. 19F NMR of the crude mixture indicated an 83:14:3 mixture of isomers. Attempted deprotection of the trifluoroacetamide failed, and reaction of 39 with lithium ethoxide led to ring opening of the oxazolidinone to give 40 in 60% yield rather than its displacement. (matrix presented)
47. 19F NMR of the crude mixture indicated an 83:14:3 mixture of isomers. Attempted deprotection of the trifluoroacetamide failed, and reaction of 39 with lithium ethoxide led to ring opening of the oxazolidinone to give 40 in 60% yield rather than its displacement. (matrix presented)
48. Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem. 1982, 47, 104-109.
49. Bodansky, M. Principles of Peptide Synthesis; Springer-Verlag: Berlin, 1984; p 161.
50. Pozdnev, V. F. Tetrahedron Lett. 1995, 36, 7115-7118.
51. Initially, the terf-butyl carbamate amide 42 was treated with excess methyl iodide in ethyl acetate to give the sulfonium iodide 43. Intramolecular cyclisation with sodium hydride gave the pyrrolidone 44 in 18% yield. After protecting the ring NH of 44 as its benzyl carbamate derivative (25% yield), deprotection of the tert-butyl carbamate and reprotection as the trifluoroacetamide (32% yield), analytical chiral HPLC showed the resultant pyrrolidone 14 to be racemic. (matrix presented) (33) An attempt to avoid the use of n-butyllithium by reaction of 42 with potassium carbonate, 18-crown-6, and benzyl chloroformate in a variety of solvents gave little or low yields of product 45.
52. Attempts to convert the acid 41 directly into the protected amide 45 via formation of the mixed anhydride and treatment with the lithium anion of benzyl carbamate failed.
53. 3 in MeCN leads only to demethylation to give 45. Warming 46 in toluene at 110 °C for 3 h gives 3:1 demethylation 45 to cyclization 47. Further experiments to avoid methyl iodide by using trimethylsulfonium iodide (cf. Abood, N. A.; Flynn, D. L.; Laneman, S. A.; Nosal, R.; Schretzman, L. A. US patent 5,484,946, 1996) also failed to give acceptable yields of product.
54. The piperidinocrotonic acid 54 was readily prepared in good yield by reacting ethyl 4-bromocrotonate with piperidine and potassium carbonate in acetonitrile followed by hydrochloric acid hydrolysis of the ester.
55. Reider, P. J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 955-957.