Carvone synthesis

The preferred industrial method of carvone synthesis utilizes the selective addition of nitrosyl chloride to the endocyclic double bond of limonene. If a lower aliphatic alcohol is used as solvent, limonene nitrosochloride is obtained in high yield. It is converted into carvone oxime by elimination of hydrogen chloride in the presence of a weak base. Acid hydrolysis in the presence of a hydroxylamine acceptor, such as acetone, yields carvone [88]. 

Abad, A., Agullo, C., Cunat, A.C., and Garcia, A.B. (2005) Syntheses of oxygenated spongiane diterpenes from carvone, synthesis of dorisenone C. Tetrahedron, 61, 1961-1970. 

A second method makes use of the lactone (31) from acetone dicarboxylate (40) and for which a synthesis from (—)-carvone has been reported (41). Displacement of chlorine from the 6-aminopenici11anic acid (6-APA) derived P-lactam (32) by (33) illustrates yet another approach to the dia2oketone (28) (42). 

The example given above of the selection of deoxycholic acid as a SM for the synthesis of cortisol also illustrates the use of a chiral natural substance as synthetic precursor of a chiral TGT. Here the matching process involves a mapping of individual stereocenters as well as rings, functional groups, etc. The synthesis of helminthosporal (105) from (-i-)-carvone (106)21 and the synthesis of picrotoxinin (107) from (-)-carvone (108)22 amply demonstrate this approach employing terpenes as chiral SM s. 

The activity of the FePeCli6-S/tert-butyl hydroperoxide (TBHP) catalytic system was studied under mild reaction conditions for the synthesis of three a,p-unsaturated ketones 2-cyclohexen-l-one, carvone and veibenone by allylic oxidation of cyclohexene, hmonene, and a-pinene, respectively. Substrate conversions were higher than 80% and ketone yields decreased in the following order cyclohexen-1-one (47%), verbenone (22%), and carvone (12%). The large amount of oxidized sites of monoterpenes, especially limonene, may be the reason for the lower ketone yield obtained with this substrate. Additional tests snggested that molecular oxygen can act as co-oxidant and alcohol oxidation is an intermediate step in ketone formation. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

Jenniskens LHD, Groot A, Enantioselective synthesis of R-(-)-Ligularenolide and the progesterone receptor figand R-(-)- PF1092C starting from S-(+)-carvone, Tetrahedron 54 5617—5622, 1998. 

The main renewable resource for L-carvone is spearmint oil (Mentha spicata), which contains up to 75% of this flavour chemical. There also exists a synthetic process for the manufacturing of L-carvone, which is based on (-t)-limonene, which is available as a by-product of the citrus juice industry as a major component of orange peel oil (Scheme 13.4). The synthesis was developed in the nineteenth century and starts with the reaction of (-t)-limonene and nitrosyl chloride, which ensures the asymmetry of the ring. Treatment with base of the nitrosyl chloride adduct results in elimination of hydrogen chloride and rearrangement of the nitrosyl function to an oxime. Acid treatment of the oxime finally results in l-carvone. 

Scheme 13.4 Chemical synthesis of l-carvone from (+)-limonene...

Carbene cyclization 36 Carvone (starting material) 33 Citlalitrione synthesis 24 C-H Activation 122 C-H to alcohol 157... 

A second method makes use of the lactone from acetone dicarboxylate and for which a synthesis form (-)-carvone has been reported. 

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