Asymmetric catalysis in fragrance chemistry: a new synthetic approach to enantiopure Phenoxanol®, Citralis® and Citralis Nitrile®

Asymmetric addition of dimethylzinc to alkylidenmalonates mediated by phosphorous ligands: A new synthetic route to floral fragrances

“…These three synthetic fragrances posses floral and fruity notes (rose, lily‐of‐the‐valley, citrus) and are commercially available in racemic form. An efficient asymmetric synthesis of Phenoxanol, as well as its transformation in Citralis and Nitrile Citralis, was reported by Matteoli14 who also reported the odor profiles of the single enantiomers, showing a significant difference in odor threshold between compounds with opposite configuration and, for Phenoxanol, also in olfactorily notes. Such a synthetic procedure was based on the asymmetric hydrogenation of ( Z )‐ or ( E )‐allylic alcohols with Ru‐2,2′‐bis(diphenylphosphino)‐1,1′‐binaphtalene (BINAP) complexes giving products in high enantiomeric excesses, but requiring high hydrogen pressure (100 atm) and long reaction times (48 h) for the complete conversion.…”

“…In fact, the asymmetric conjugate addition of dimethylzinc to unsaturated compounds can be a very direct method to obtain a methyl‐substituted stereogenic center, a structural motif that often plays an important role in determining the biological activity of numerous natural compounds. In particular, we focused our attention on the development of new synthetic approaches for the preparation in optically active form of some valuable fragrances such as 3‐methyl‐5‐phenyl‐pentanol (Phenoxanol) and the structurally related fragrances 3‐methyl‐5‐phenyl‐pentanaldehyde (Citralis) and 3‐methyl‐5‐phenyl‐pentanenitrile (Nitrile Citralis)13, 14 (Scheme ), choosing 3‐phenylpropylidenmalonate ( 5 ) as starting substrate on which to test the asymmetric addition.…”

Iron‐Catalyzed Stereoselective Cross‐Coupling Reactions of Stereodefined Enol Carbamates with Grignard Reagents

“…The Fe‐catalyzed cross‐coupling between ( E )‐ 1 and hexylmagnesium bromide, for comparison, gave 13 in an E / Z ratio of 65:1 and 96 % yield (Table ). Olefin 26 is an important precursor to the fragrances phenoxanol, citralis, and citralis nitrile, and the starting olefin geometry plays a critical role in the asymmetric synthesis of these chiral fragrant molecules . The highest stereoselectivity for the synthesis of 26 that we could find was achieved by a reductive debromination of the corresponding vicinal dibromide with an E / Z ratio of 5.25:1 with an overall yield of 65 % .…”

Iron‐Catalyzed Stereoselective Cross‐Coupling Reactions of Stereodefined Enol Carbamates with Grignard Reagents

“…Olefin 26 is an important precursor to the fragrances phenoxanol, citralis,a nd citralis nitrile,a nd the starting olefin geometry plays acritical role in the asymmetric synthesis of these chiral fragrant molecules. [18] Theh ighest stereoselectivity for the synthesis of 26 that we could find was achieved by ar eductive debromination of the corresponding vicinal dibromide with an E/Z ratio of 5.25:1 with an overall yield of 65 %. [19] As can be seen in Table 2, the Fe-catalyzed cross-coupling between (E)-1 and phenethylmagnesium chloride gave 26 in an E/Z ratio of > 50:1 and 82 %yield.…”