Synthesis and Olfactory Properties of Spirocyclic Georgywood^® Analogues

Abstract

Spirocyclic analogues of Georgywood^® (3) and unlike-10-acetyl-9,10-dimethylbicyclo[6.4.0]dodec-1(8)-ene (4), in which the acetyl moiety and the methyl substituent of C-10 are part of a cyclopentyl­ or cyclohexyl ring, were synthesized from 8a-homomyrcene (6) and 4-methylenespiro[2.7]decane (13), respectively. 2-(Dimethylaminomethyl)cyclopentanone (7) or the allyl 1-(acetoxymethyl)-2-oxocycloalkanecarboxylates 14 and 18 were employed as methylene cycloalkanone precursors in an ordinary Diels-Alder reaction or in [4+2] cycloadditions on the vinyl cyclopropane system 13 in the presence of Wilkinson’s catalyst. By simple LDA-mediated alkylation of the resulting spirocycles with methyl iodide, further analogues were prepared that provided additional insight into the structural and stereochemical requirements for the typical woody-ambery odor character of Iso E Super^® (1), and that call a binding model proposed by Hong and Corey into question. The best odorants found in this study were (1R*,3S*,1′R*)-3,1′,8′,8′-tetramethyl-3′,4′,5′,6′,7′,8′-hexahydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-2-one (10) and (1R*,1′S*,3′S*)-1,3′-dimethyl-3,4,5,6,7,8,9,10-octahydro-1′H-spiro[benzo[8]annulene-2,1′-cyclohexan]-2′-one (17).

cyclizations - Diels-Alder reactions - Georgywood - odorants - spiro compounds

References

1 Nussbaumer C. Fráter G. Kraft P. Helv. Chim. Acta  1999,  82:  1016 

2 Hong S. Corey EJ. J. Am. Chem. Soc.  2006,  128:  1346 

3a Satyanarayana P. Koteswara Rao P. Ward RS. Pelter A. J. Nat. Prod.  1986,  49:  1061 

3b Tsai I.-L. Lee F.-P. Wu C.-C. Duh C.-Y. Ishikawa T. Chen J.-J. Chen Y.-C. Seki H. Chen I.-S. Planta Med.  2005,  71:  535 

4a Erman M. Williams M. Whelan P. Cardenas C. Antipin M. Perfum. Flavor.  2001,  26:  16 

4b Erman MB, Hoffmann HM, and Cardenas C. inventors; Eur. Patent, EP  985651.  ; Chem. Abstr. 2000, 132, 207981

5 Kraft P. Bajgrowicz JA. Denis C. Fráter G. Angew. Chem. Int. Ed.  2000,  39:  2980 ; Angew. Chem. 2000, 112, 3106

6a Kraft P. Synthesis  1999,  695 

6b Kraft P. Gallo S. Synthesis  2004,  381 

7 Fráter G. Müller U. Schröder F. Tetrahedron: Asymmetry  2004,  15:  3967 

8a Bajgrowicz JA, Bringhen A, Fráter G, and Müller U. inventors; Eur. Patent Appl., EP  743297A1.  ; Chem. Abstr. 1997, 126, 103856

8b Mousseron M. Mousseron-Canet M. Boch J. Compt. Rend.  1958,  247:  1811 

8c Mousseron-Canet M. Mousseron M. Boch J. Bull. Soc. Chim. Fr.  1959,  697 

9a Ratouis R. Combes G. Bull. Soc. Chim. Fr.  1958,  576 

9b Mannich C. Braun R. Ber. Dtsch. Chem. Ges.  1920,  53:  1874 

10 Hall JB, and Sanders JM. inventors; Ger. Offen., DE  2408689.  ; Chem. Abstr. 1974, 82, 4058

11a Tsuji J. Nisar M. Minami I. Tetrahedron Lett.  1986,  27:  2483 

11b Minami I. Nisar M. Yuhara M. Shimizu I. Tsuji J. Synthesis  1987,  992 

11c Friesen RW. In Science of Synthesis   Vol. 1, 1st ed:  Lautens M. Thieme; Stuttgart: 2001.  p.117 

12 Kraft P. In Advances in Flavours and Fragrances: From the Sensation to the Synthesis   Swift KAD. Royal Society of Chemistry; Cambridge: 2002.  p.142 

13

Crystallographic data (excluding structure factors) for the X-ray structure of oxime 9 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 234419. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB1 1EZ, UK [Fax: [phone]; E-mail: [e-mail]].