15 th Brazilian Meeting on Organic Synthesis – 15 th BMOS – November 10-13, 2013 - Campos do Jordão, Brazil Ring expansions of (R)-(–)-carvone to cycloheptenoid chirons Leandro de C. Alves, André L. Desiderá, Kleber T. de Oliveira and Timothy J. Brocksom* Departmento de Química, Universidade Federal de São Carlos, São Carlos – SP, Brazil *brocksom@terra.com.br. www.lqbo.ufscar.br (R)-(–)-carvone; ring expansion; cycloheptenone, X-ray structure assignment INTRODUCTION In the course of our studies on the synthesis of perhydroazulene terpenes, 1 we have developed a synthetic route (Scheme 1, Route A) to the cycloheptenone chiron 6 from (R)-(–)-carvone (1). Herein we present our corrected structural assignment of 4a, 2 as confirmed by X-ray analysis, and describe an attractive alternative route towards 6 (Scheme 1, Route B). RESULTS AND DISCUSSION The formation of the TMS-protected cyanohydrins 2a and 2b and the Corey-Chaykovsky epoxidation to 3a and 3b, led to 90:10 ratios determined by GC and NMR analysis of trans:cis nucleophilic addition relative to the isopropenyl group of (R)-(–)-carvone (1). O (R)-(–)-carvone 1 Me 3 SiO NC 2a 3a O KCN, Me3SiCl, NaI Me 3 SiO NC 2b O 3b py, MeCN, 60h r.t., 90-95% Me3SI, NaH DMSO/THF 1:1 0ºC, 4h, 85-94% 90:10 90:10 Route A Route B HO H 2 N LiAlH4, Et2O 0ºC to r.t. 24h, 75-80% HO H 2 N 4a 4b NH O O DMF, reflux 1h 5a HO 5b N O O HO N O O 90:10 NH 2 NH 2. H 2 O EtOH, reflux, 1h NaNO2 1,25M HOAc 10% O Route A = 65-70% Route A = 44-53% over 3 steps (~80% per step) Route B = 20-30% over 4 steps (~75% per step) 90:10 6 O R Scheme 1. Synthetic routes from (R)-(–)-carvone (1) to the cycloheptenone 6. The corrected assignment of the stereochemistry 2 of 2a was made by X-ray diffraction (Figure 1) and nOe irradiations of the major amino-alcohol 4a, obtained by reduction of the cyanohydrin mixture 2a/2b. Figure 1. Structure of the major amino-alcohol 4a obtained by X-ray diffraction, and indication of observed nOe. (Ellipsoids shown at 40% probability level). Epoxide opening of 3a/3b (Scheme1, route B) was accomplished by phthalimide in DMF at reflux. Hydrazinolysis of the phthalimido-alcohols 5a and 5b produced the same amino-alcohols 4a/4b obtained in Route A. The last step is the totally regioselective Tiffeneau-Demjanov rearrangement, which leads to the key intermediate cycloheptenone 6. CONCLUSION Addition of the two nucleophiles to (R)-(–)-carvone (1) was determined to be 90:10, in favour of the trans relationship to the isopropenyl group. A new synthetic route to 6 is presented with advantages of scaling up, minimum usage of chromatography, and avoiding the use of cyanide. ACKNOWLEDGEMENTS To FAPESP (2011/13993-2, 2013/06532-4), CAPES and CNPq for financial support and fellowships; Firmenich S.A. for the donation of (R)-(–)-carvone. Part of this work was executed at the University of Cambridge, and the authors are grateful to Prof. Steven V. Ley and Dr Sean Newton. REFERENCES 1 Brocksom, T. J., Brocksom, U., Sousa, D. P, Frederico, D. Tetrahedron Asym., 2005, 16, 362. Faria, M. L; Magalhães, R. A.; Silva, F. C.; Matias, L. G. O.; Ceschi, M. A.; Brocksom, U; Brocksom, T. J. Tetrahedron Asym., 2000,11, 4093 2. Alves, L de C.; et al. 14 th BMOS, 2011. .