Stereoselective Synthesis of Novel Ptilomycalin A Analogs via Successive 1,3-Dipolar Cycloaddition Reactions and their Ca2+-ATPase Inhibitory Activity

Angelina Georgieva; Manabu Hirai; Yuichi Hashimoto; Tadashi Nakata; Yasushi Ohizumi; Kazuo Nagasawa

doi:10.1055/s-2003-40195

SPECIALTOPIC

Stereoselective Synthesis of Novel Ptilomycalin A Analogs via Successive 1,3-Dipolar Cycloaddition Reactions and their Ca²⁺-ATPase Inhibitory Activity

Angelina Georgieva^c, Manabu Hirai^b, Yuichi Hashimoto^a, Tadashi Nakata^c, Yasushi Ohizumi^b, Kazuo Nagasawa*^a
^a Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
e-Mail: nagasawa@iam.u-tokyo.ac.jp;
^b Department of Pharmaceutical Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
^c Institute of Physical and Chemical Research (RIKEN), Wako, Saitama 351-0198, Japan

Abstract

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Abstract

The pentacyclic guanidine compounds 4 and 5 were stereoselectively synthesized as novel ptilomycalin A and crambescidin analogs. The synthetic method involves successive 1,3-dipolar cycloaddition reactions which effectively access the key intermediates, trans- and cis-2,5-disubstituted pyrrolidine 8 having hydroxyl groups at the β-positions on their side chains. Among the analogs synthesized, 4b and 5b exhibited significant inhibitory activity against Ca²⁺-ATPase.

Key Words

ptilomycalin A - 1,3-dipolar cycloaddition - nitrone - pentacyclic guanidine - Ca²⁺-ATPase inhibitory activity

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References

1a Kashman Y. Hirsh S. McConnell OJ. Ohtani I. Kusumi T. Kakisawa H. J. Am. Chem. Soc. 1989, 11: 8925

1b Ohtani I. Kusumi T. Kakisawa H. Kashman Y. Hirsh S. J. Am. Chem. Soc. 1992, 114: 8472

1c Ohtani I. Kusumi T. Kakisawa H. Tetrahedron Lett. 1992, 33: 2525

2a Jares-Erijman EA. Sakai R. Rinehart KL. J. Org. Chem. 1991, 56: 5712

2b Jares-Erijman EA. Ingrum AL. Carney JR. Rinehart KL. Sakai R. J. Org. Chem. 1993, 58: 4805

3 Berlinck RGS. Braekman JC. Daloze D. Bruno I. Riccio R. Ferri S. Spampinato S. Speroni E. J. Nat. Prod. 1993, 56: 1007

4 Ohizumi Y. Sasaki S. Kusumi T. Ohtani II. Eur. J. Pharmacol. 1996, 310: 95

5a Snider BB. Shi Z. J. Org. Chem. 1992, 57: 2526

5b Snider BB. Shi Z. Tetrahedron Lett. 1993, 34: 2099

5c Snider BB. Shi Z. J. Org. Chem. 1993, 58: 3828

5d Snider BB. Shi Z. J. Am. Chem. Soc. 1994, 116: 549

6a Murphy PJ. Williams HL. Hursthouse MB. Malik KMA. J. Chem. Soc., Chem. Commun. 1994, 119

6b Murphy PJ. Williams HL. J. Chem. Soc., Chem. Commun. 1994, 819

6c Murphy PJ. Williams HL. Hibbs DE. Hursthouse MB. Malik KMA. Tetrahedron 1996, 52: 8315

6d Moore CG. Murphy PJ. Williams HL. McGown AT. Smith NK. Tetrahedron Lett. 2003, 44: 251 , and references cited therein

7a Overman LE. Rabinowitz MH. Renhowe PA. J. Am. Chem. Soc. 1995, 117: 2657

7b Coffey DS. McDonald AI. Overman LE. Stappenbeck F. J. Am. Chem. Soc. 1999, 121: 6944

8a Grillot AL. Hart DJ. Tetrahedron 1995, 51: 11377

8b Anderson GT. Alexander MD. Taylor SD. Smithrud DB. Benkovic SJ. Weinreb SM. J. Org. Chem. 1996, 61: 125

9 Braekman JC. Daloze D. Tavares R. Hajdu E. Van Soest RWM. J. Nat. Prod. 2000, 63: 193

10 Palagiano E. De Marino S. Minale L. Riccio R. Zollo F. Iorizzi M. Carre JB. Debitus C. Lucarain L. Provost J. Tetrahedron 1995, 51: 3675

11 Nagasawa K. Georgieva A. Nakata T. Tetrahedron 2000, 56: 187

12 Pichon M. Figadere B. Tetrahedron: Asymmetry 1996, 7: 927

13a Tufariello JJ. Mullen GB. Tegeler JJ. Trybulski EJ. Wong SC. Ali SA. J. Am. Chem. Soc. 1979, 101: 2435

13b Tufariello JJ. Puglis JM. Tetrahedron Lett. 1986, 27: 1489

14a Ali SA. Wazeer MIM. Tetrahedron Lett. 1993, 34: 137

14b Ali SA. Wazeer MIM. Tetrahedron 1993, 49: 4339

15 Goti A. Cacciarini M. Cardona F. Brandi A. Tetrahedron Lett. 1999, 40: 2853

16 Nagasawa K. Georgieva A. Koshino H. Nakata T. Kita T. Hashimoto Y. Org. Lett. 2002, 4: 177

17a Kim KS. Qian L. Tetrahedron Lett. 1993, 34: 7677

17b Iwanowicz EJ. Poss MA. Lin J. Synth. Commun. 1993, 23: 1443

18 Ritter AR. Miller MJ. J. Org. Chem. 1994, 59: 4602

19 Nakamura Y. Kobayashi J. Gilmore J. Mascal M. Rinehart KL. Nakamura H. Ohizumi Y. J. Biol. Chem. 1986, 261: 4139