Synthesis of an Isomer of the Oxaspirobicyclic Tetronic Acid Unit of the CCK-B Receptor Antagonist Tetronothiodin

Abstract

An isomer of the oxaspirobicyclic tetronic acid unit of the CCK-B Receptor antagonist tetronothiodin, diastereoisomeric at the spiro centre, has been synthesized in five steps from dienol 4.

Key words

tetronothiodin - Diels-Alder - Dieckmann - spiro tetronic acid - CCK

References

• 1 Kuwahara T. Kudoh T. Nagase H. Takamiya M. Nakano A. Ohtsuka T. Yoshizaki H. Arisawa M. Eur. J. Pharmacol.  1992,  221:  99 
• 2a Dourish CT. Hill DR. Trends Pharmacol. Sci.  1987,  8:  207 
• 2b Moran T. Robinson P. Goldrich MS. McHuge P. Brain Res.  1986,  362:  175 
• 3 Dourish CT. Rycroft W. Iversen SD. Science  1989,  245:  1509 
• 4 Dourish CT. O’Neil MF. Coughlan J. Kitchener SJ. Hawley D. Iversen SD. Eur. J. Pharmacol.  1990,  176:  35 
• 5a Ravard S. Dourish CT. Trends Pharmacol. Sci.  1990,  11:  271 
• 5b Hughes J. Boden P. Costall B. Domeney A. Kelly E. Horwell DC. Hunter JC. Pinnock RD. Woodruff GN. Proc. Natl. Acad. Sci. U.S.A.  1990,  87:  6728 
• 6a Kuwahara T. Kudoh T. Nagase H. Takamiya M. Nakano A. Ohtsuka T. Yoshizaki H. Arisawa M. Eur. J. Pharmacol.  1992,  221:  99 
• 6b Ohtsuka T. Kudoh T. Shimma N. Kotaki H. Nakayama N. Itezono Y. Fujisaki N. Watanabe J. Yokose K. Seto H. J. Antibiot.  1992,  45:  140 
• 6c Watanabe J. Fujisaki N. Fujimori K. Anzai Y. Oshima S. Sano T. Ohtsuka T. Watanabe K. Okuda T. J. Antibiot.  1993,  46:  1 
• 6d Ohtsuka T. Kotaki H. Nakayama N. Itezono Y. Shimma N. Kudoh T. Kuwahara T. Arisawa M. Yokose K. J. Antibiot.  1993,  46:  11 
• 6e Ohtsuka T. Nakayama N. Itezono Y. Shimma N. Kuwahara T. Yokose K. Seto H. J. Antibiot.  1993,  46:  18 
• 6f Kuwahara T. Kudoh T. Nakano A. Yoshizaki H. Takamiya M. Nagase H. Arisawa M. Neurosci. Lett.  1993,  158:  1 
• 6g Murayama T. Matsumori Y. Iwata N. Ito M. Taniguchi T. Chihara K. Matsui T. Jap. J. Cancer Res.  1996,  87:  743 
• 10 Davis FA. Chen B.-C. Chem. Rev.  1992,  92:  919 
• 11a Davis FA. Mancinelli PA. Balasubramanian K. Nadir U. J. Am. Chem. Soc.  1979,  101:  1044 
• 11b Davis FA. Stringer OD. J. Org. Chem.  1982,  47:  1744 
• 11c Davis FA. Vishwakarma LC. Billmers JM. Finn J. J. Org. Chem.  1984,  49:  3241 
• 11d Davis FA. Lamendale J. Nadir U. Kluger EW. Sedergran TC. Panunto TW. Billmers R. Jenkins R. Turchi IJ. Watson WH. Chen JS. Kimura M. J. Am. Chem. Soc.  1980,  102:  2000 
• 11e Glinski MB. Freed JC. Durst T. J. Org. Chem.  1987,  52:  2749 
• 12 Belletire JL. Fry DK. J. Org. Chem.  1988,  53:  4724 
• 13a Ireland RE. Thompson WJ. J. Org. Chem.  1979,  44:  3041 
• 13b Roush WR. Sciotti RJ. J. Org. Chem.  1998,  63:  5473 
• 13c Roush WR. Reilly ML. Koyama K. Brown BB. J. Org. Chem.  1997,  62:  8708 
• 14 Ishihara J. Nonaka R. Terasawa Y. Tadano K. Ogawa S. Tetrahedron: Asymmetry  1994,  5:  2217 

7

The stereochemical assignment for diene 4 was based on the coupling constant between H-3 and H-4 (J = 18 Hz), consistent with the E isomer.

8

Triene 9 was prepared in 82% yield by reaction of alcohol 4 with diphenylvinylsilyl chloride in dichloromethane at r.t. in the presence of triethylamine.

9

The stereochemical assignment for lactol 10 was based on NOE data and on the coupling constant between the hydrogen atoms at the ring junction positions (J = 4.5 Hz), consistent with the cis isomer.

15

Analytical data: IR(neat): ν_max = 3378, 2923, 1782, 1613
cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.74-0.84 (1 H, m), 1.1 (3 H, d, J = 5.2 Hz), 1.19 (1 H, s), 1.31 (3 H, t, J = 8.0 Hz), 1.41-1.49 (1 H, m), 1.60 (3 H, s), 1.76-1.79 (2 H, m), 1.97-2.03 (1 H, m), 2.33-2.40 (2 H, m), 3.59-3.71 (2 H, m), 4.3 (2 H, q, J = 8.0 Hz), 5.3 (1 H, s). ¹³C NMR (100.6 MHz, CDCl₃): δ = 194, 167, 166, 138, 121, 95, 85, 62, 60, 41, 36, 35, 31, 23, 19, 15. MS (EI): m/z (%) = 310 (100) [M⁺] , 199, 134, 120, 91, 60. Found: 310.14124; C₁₆H₂₂O₆ requires 310.14164.