EPC syntheses of trifluorocitronellol and of hexafluoropyrenophorin - A comparison of their physiological properties with the nonfluorinated analogs

European Journal of Organic Chemistry

Volumn , Issue 10, 1999, Pages 2533-2544

  Götzö, Stephan P ^a   Seebach, Dieter ^a   Sanglier, Jean Jacques ^b  

^a ETH ZURICH   (Switzerland)

^b NOVARTIS PHARMA AG   (Switzerland)

Author keywords

(S) 4,4,4 Trifluoro 3 hydroxybutanoic acid; 2 Trifluoromethyl 3 hydroxypropanoic acid (F3 Roche acid); Chiral CF3 containing synthetic building blocks; Cyclizations; Natural products; Olfactory comparison

Indexed keywords

CITRONELLOL; FLUORINE DERIVATIVE; HEXAFLUOROPYRENOPHORIN; TRIFLUOROCITRONELLOL; UNCLASSIFIED DRUG;

ANTIMICROBIAL ACTIVITY; ARTICLE; CHEMICAL REACTION; CRYSTALLIZATION; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOMER; NONHUMAN; STEREOSPECIFICITY;

EID: 0037925652     PISSN: 1434193X     EISSN: None     Source Type: Journal    
DOI: 10.1002/(sici)1099-0690(199910)1999:10<2533::aid-ejoc2533>3.3.co;2-f     Document Type: Article

References (72)

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2. For books and reviews covering the synthesis and use of chiral nonracemic organofluorine derivatives see: J. T. Welch, Selective Fluorination in Organic and Bioorganic Chemistry, ACS Symposium Series 456, 1996; R. Filler, Y. Kobayashi, L. M. Yagupolskii, Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, London, New York, Tokyo, 1993; EPC-synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedicinal Targets (Ed.: V. A. Soloshonok), John Wiley and Sons, Ltd., Chichester, in press; K. Iseki, Tetrahedron 1998, 54, 13887-13914.
3. For books and reviews covering the synthesis and use of chiral nonracemic organofluorine derivatives see: J. T. Welch, Selective Fluorination in Organic and Bioorganic Chemistry, ACS Symposium Series 456, 1996; R. Filler, Y. Kobayashi, L. M. Yagupolskii, Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, London, New York, Tokyo, 1993; EPC-synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedicinal Targets (Ed.: V. A. Soloshonok), John Wiley and Sons, Ltd., Chichester, in press; K. Iseki, Tetrahedron 1998, 54, 13887-13914.
4. For books and reviews covering the synthesis and use of chiral nonracemic organofluorine derivatives see: J. T. Welch, Selective Fluorination in Organic and Bioorganic Chemistry, ACS Symposium Series 456, 1996; R. Filler, Y. Kobayashi, L. M. Yagupolskii, Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, London, New York, Tokyo, 1993; EPC-synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedicinal Targets (Ed.: V. A. Soloshonok), John Wiley and Sons, Ltd., Chichester, in press; K. Iseki, Tetrahedron 1998, 54, 13887-13914.
5. Resolution and synthetic application: C. von dem Bussche, C. Cescato, D. Seebach, Chem. Ber. 1992, 725, 2795-2802.
6. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
7. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
8. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
9. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
10. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
11. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
12. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
13. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
14. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
15. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
16. Resolution: M. Acs, C. von dem Bussche, D. Seebach, Chimia 1990, 44, 90-92. Synthetic application: D. Seebach, P. Renaud, W. B. Schweizer, M.F. Züger, M.-J. Brienne, Helv. Chim. Acta 1984, 67, 1843-1853, D. Seebach, P. Renaud, Helv. Chim. Acta 1985, 68, 2342-2349; D. Seebach, A.K. Beck, P. Renaud, Angew. Chem. 1986, 98, 96-97; Angew. Chem. Int. Ed. Engl. 1986, 25, 98-99; A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291-295; C. von dem Bussche, D. Seebach, Chem. Ber. 1992, 125, 1273-1281; M. Gautschi, D. Seebach, Angew. Chem. 1992, 104, 1061-1062; Angew. Chem., Int. Ed. Engl. 1992, 31, 1083-1085; M. Gautschi, W. B. Schweizer, D. Seebach, Chem. Ber. 1994, 127, 565-579; A.R. Sting, D. Seebach, Tetrahedron 1996, 52, 279-290.
17. Resolution: S. P. Götzö, D. Seebach, Chimia 1996, 50, 20-23.
18. Pyrenophorin, vermiculin, grahamimycin, colletodiol, conglobatin, elaiophylidin, gloeosporon and myxovirescin, see: D. Seebach, M. A. Maestro, M. Sefkow, G. Adam, S. Hintermann, A. Neidlein, Liebigs Ann. Chem. 1994, 701-717; D. Seebach, G. Adam, R. Zibuck, W. Simon, M. Rouilly, W. L. Meyer, J. F. Hinton, T. A. Privett, G. E. Templeton, D. K. Heiny, U. Gisi, H. Binder. Liebigs Ann. Chem. 1989, 1233-1240, and references cited in these papers.
19. Pyrenophorin, vermiculin, grahamimycin, colletodiol, conglobatin, elaiophylidin, gloeosporon and myxovirescin, see: D. Seebach, M. A. Maestro, M. Sefkow, G. Adam, S. Hintermann, A. Neidlein, Liebigs Ann. Chem. 1994, 701-717; D. Seebach, G. Adam, R. Zibuck, W. Simon, M. Rouilly, W. L. Meyer, J. F. Hinton, T. A. Privett, G. E. Templeton, D. K. Heiny, U. Gisi, H. Binder. Liebigs Ann. Chem. 1989, 1233-1240, and references cited in these papers.
20. Note, that the natural (R,R)-pyrenophorin (1a) is homochiral with the (S,S)-hexafluoropyrenophorin (1d).
21. B. Seuring, D. Seebach, Liebigs Ann. Chem. 1978, 2044-2073.
22. Pyrenophorin is one of the most popular simple targets for EPC syntheses. For two most recent examples, see: R. V. Hoffman, T. Patonay, N. P. Nayyar, J. Tao, Tetrahedron Lett. 1996, 37, 2381-2384; Y. Kobayashi, K. Kishihara, K. Watatani, Tetrahedron Lett. 1996, 37, 4385-4388.
23. Pyrenophorin is one of the most popular simple targets for EPC syntheses. For two most recent examples, see: R. V. Hoffman, T. Patonay, N. P. Nayyar, J. Tao, Tetrahedron Lett. 1996, 37, 2381-2384; Y. Kobayashi, K. Kishihara, K. Watatani, Tetrahedron Lett. 1996, 37, 4385-4388.
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27. (matrix presented)
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33. 3) and was fully characterized.
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41. 3-Roche acid to this propanol derivative.
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46. Formed quantitatively when the corresponding bromide (18, X = Br instead of I) is treated with the potassium salt of ethyl acetoacetate.
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52. Caprylate ester of 3-(trifluoromethyl)-6,6-dimethylheptanol.
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57. The signal is only partially resolved.
58. One coupling constant is smaller than 1 Hz.
59. 1H-NMR spectroscopy.
60. M. Kroner, Dissertation, University of Stuttgart, 1988.
61. 2O/pentane, 1:1) = 0.42].
62. Storing the crude product overnight at -20°C did not cause any change in the yield of the product.
63. 13C-NMR spectra could be recorded.
64. 4 + nH, n = 1-4), see also 10b.
65. T. J. de Boer, H. J. Baker, Org. Synth., Coll. Vol. 1963, 4, 250-253.
66. The doublets of the two diastereoisomers have the same chemical shift and are not resolved.
67. 1H-NMR spectra, the product 17 seemed to be pure, whereas traces of an impurity had to be present, which enabled the THP protecting group to migrate in the subsequent tosylation or iododeoxygenation steps. Purification by FC (slightly basic solvent) resulted in the removal of this impurity.
68. An excess of alcohol 17 was used as separation of products from unreacted TosCl is sometimes difficult. Nevertheless, an excess TosCl and pyridine as solvent was later shown to be advantageous.
69. The signals are only partially resolved.
70. The signals are not resolved.
71. The yields ranged from 85 to 75%.
72. This material was produced from 6.98 mmol of tosylate 33. The calculation of the overall yield (33 → 40) takes into account the losses through analysis.