Preparation of Novel Bridged Bicyclic Thiomorpholines as Potentially Useful Building Blocks in Medicinal Chemistry

Abstract

Thiomorpholine and thiomorpholine 1,1-dioxide are important building blocks in medicinal chemistry research, and some analogues containing these moieties have entered human clinical trials. Analogues containing bridged bicyclic thiomorpholines have also shown interesting biological profiles. 3-Thia-6-azabicyclo[3.1.1]heptane, 3-thia-8-azabicyclo[3.2.1]octane, and their corresponding 1,1-dioxide counterparts were prepared as novel bicyclic thiomorpholine building blocks. Each heterocycle was synthesized from an inexpensive starting material by straightforward chemistry.

Key words

stereoselective synthesis - heterocycles - bicyclic compounds - pyrroles - hydrogenation

• References

• 1a Ravula SB, Yu J, Tran JA, Arellano M, Tucci FC, Moree WJ, Li B.-F, Petroski RE, Wen J, Malany S, Hoare SR. J, Madan A, Crowe PD, Beaton G. Bioorg. Med. Chem. Lett. 2012; 22: 421
• 1b Biava M, Porretta GC, Poce G, Supino S, Deidda D, Pompei R, Molicotti P, Manetti F, Botta M. J. Med. Chem. 2006; 49: 4946
• 1c Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D, Skotnicki JS. Bioorg. Med. Chem. Lett. 2006; 16: 1605
• 2a Haynes RK, Fugmann B, Stetter J, Rieckmann K, Heilmann H.-D, Chan H.-W, Croft SL, Vivas L, Rattray L, Stewart L, Peters W, Robinson BL, Edstein MD, Kotecka B, Kyle DE, Beckermann B, Gerisch M, Radtke M, Schmuck G, Steinke W, Wollborn U, Schmeer K, Römer A. Angew. Chem. Int. Ed. 2006; 45: 2082
• 2b Nagelschmitz J, Voith B, Wensing G, Römer A, Fugmann B, Haynes RK, Kotecka BM, Rieckmann KH, Edstein MD. Antimicrob. Agents Chemother. 2008; 52: 3085
• 3a Barbachyn MR, Hutchinson DK, Brickner SJ, Cynamon MH, Kilburn JO, Klemens SP, Glickman SE, Grega KC, Hendges SK, Toops DS, Ford CW, Zurenko GE. J. Med. Chem. 1996; 39: 680
• 3b Villemagne B, Crauste C, Flipo M, Baulard AR, Déprez B, Willand N. Eur. J. Med. Chem. 2012; 51: 1
• 4a Huang X, Chen D, Wu N, Zhang A, Jia Z, Li X. Bioorg. Med. Chem. Lett. 2009; 19: 4130
• 4b Hoffmann T, Koblet A, Peters J.-U, Schnider P, Sleight A, Stadler H. WO 2005/002577, 2005 ; Chem. Abstr. 2005, 142, 134463
• 5a Roecker AJ, Coleman PJ, Mercer SP, Schreier SD, Buser CA, Walsh ES, Hamilton K, Lobell RB, Tao W, Diehl RE, South VJ, Davide JP, Kohl NE, Yan Y, Kuo LC, Li C, Fernandez-Metzler C, Mahan EA, Prueksaritanont T, Hartman GD. Bioorg. Med. Chem. Lett. 2007; 17: 5677
• 5b Zask A, Kaplan J, Verheijen JC, Richard DJ, Curran K, Brooijmans N, Bennett EM, Toral-Barza L, Hollander I, Ayral-Kaloustian S, Yu K. J. Med. Chem. 2009; 52: 7942
• 5c Kiely JS, Hutt MP, Culbertson TP, Bucsh RA, Worth DF, Lesheski LE, Gogliotti RD, Sesnie JC, Solomon M, Mich TF. J. Med. Chem. 1991; 34: 656
• 5d Zhang Y, Rothman RB, Dersch CM, de Costa BR, Jacobson AE, Rice KC. J. Med. Chem. 2000; 43: 4840
• 5e Wang X, Berger DM, Salaski EJ, Torres N, Hu Y, Levin JI, Powell D, Wojciechowicz D, Collins K, Frommer E. Bioorg. Med. Chem. Lett. 2009; 19: 6571
• 5f Trujillo JI, Huang W, Hughes RO, Rogier DJ, Turner SR, Devraj R, Morton PA, Xue C.-B, Chao G, Covington MB, Newton RC, Metcalf B. Bioorg. Med. Chem. Lett. 2011; 21: 1827
• 6 Jordis U, Sauter F, Siddiqi SM. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1989; 28: 294
• 7 Fried F, Prasad RN, Gaunce AP. J. Med. Chem. 1967; 10: 279
• 8a Wishka DG, Beagley P, Lyon J, Farley KA, Walker DP. Synthesis 2011; 2619
• 8b Walker DP, Eklov BM, Bedore MW. Synthesis 2012; 44: 2859
• 8c Walker DP, Bedore MW. Tetrahedron Lett. 2012; 53: 6332
• 9 Guanti G, Riva R. Tetrahedron: Asymmetry 2001; 12: 605
• 10 Kozikowski AP, Tückmantel W, Reynolds IJ, Wroblewski JT. J. Med. Chem. 1990; 33: 1561
• 11a Guertin KR, Kende AS. Tetrahedron Lett. 1993; 34: 5369
• 11b Griffith WP, Ley SV, Whitcombe GP, White AD. J. Chem. Soc., Chem. Commun. 1987; 1625
• 12 Sasaki NA, Sagnard I. Tetrahedron 1994; 50: 7093
• 13a Donohoe TJ, Headley CE, Cousins RP. C, Cowley A. Org. Lett. 2003; 5: 999
• 13b Donohoe TJ, Sintim HO, Hollinshead J. J. Org. Chem. 2005; 70: 7297
• 14 We identified a nonchromatographic technique for purification for diester 18 that provided the material in a similar purity and yield to Donohoe’s protocol; see the experimental section for further details.
• 15 It has been shown that catalytic hydrogenation of pyrrole 18 using platinum on carbon at atmospheric pressure gives a 96% yield of pyrrolidine 19: see ref. 16.
• 16 Chênevert R, Jacques F, Giguère P, Dasser M. Tetrahedron: Asymmetry 2008; 19: 1333
• 17 Kemp DS, Curran TP. J. Org. Chem. 1988; 53: 5729