From Cassyrane to Cashmeran – The Molecular Parameters of Odorants

Abstract

This review, including some new experimental results, is the summary of a talk at the 'flavors & fragrances 2013' conference in Leipzig, organized jointly by the GDCh, the Liebig-Vereinigung, and the EuCheMS. After times of searching for natural odor principles and serendipitous discoveries by chemical inspiration, directed odorant design today offers the highest hit rates for the discovery of new odorants, although serendipity still plays a role. Keeping intact the electronic shape required for a certain olfactophore-binding geometry, one can add or subtract structural elements, rigidify molecular structures, or introduce more structural flexibility. To find out which structural features are critical, the 'seco-approach', in which different fragments are removed by cutting strategic bonds, is the most analytical. Following this approach, such ingredients as Serenolide, Sylkolide, and Pomarose were designed. Transferring this design principle from the family of damascones to that of the theaspiranes led to the discovery of Cassyrane, though completely different structural features turned out to be relevant. Application of the seco-concept to a 3,7a-substituted 2,6,7,7a-tetrahydro-1H-inden-5-yl musk lead structure derived from carotol resulted in the discovery of a new family of dienone musks with novel structure-odor correlations. However, cutting the C(2)-O bond of Cassyrane and oxidizing the resulting seco-structure to the 1,2,5,1″-tetradehydro derivative links the family of dienone musks with that of blackcurrant odorants, but the resulting target structures turned out to be potent orris odorants. (3E,5E)-5-(tert-Butyl)octadeca-3,5-dien-2-one even possesses the lowest odor threshold in the whole ionone family (0.036 ng/l air), which could be rationalized by a superposition analysis on (-)-cis-γ-irone. In the course of the synthesis of these high-impact orris odorants, we discovered that, depending on the reaction conditions, the dehydration step of the intermediate 5-hydroxyalk-3-yn-2-ones was accompanied by a carbenium-ion rearrangement. Depending on the substitution pattern, these rearrangement products and their derivatives possessed interesting musky-woody olfactory properties reminiscent of Cashmeran, demonstrating that the same structural elements can code for completely different odors, i.e., cassis, musk, orris, violet, and Cashmeran-type, depending only on their spatial arrangement.

Design and Enantioselective Synthesis of Cashmeran Odorants by Using “Enol Catalysis”

“…High proportions of around 25 % of Cashmeran were used by Maurice Roucel in "Dans Tes Bras" (Frederic Malle, 2008), and by Alessandro Gualtieri in "Duro" (Nasomatto, 2007). [2] The enantiomers of 1 possess similar odors and the same odor thresholds (th), within the standard deviation (see the Supporting Information). Although this odor profile is highly desirable in perfumery, almost no other odorants are known with the typical odor profile of Cashmeran.…”

“…Although this odor profile is highly desirable in perfumery, almost no other odorants are known with the typical odor profile of Cashmeran. [2] The enantiomers of 1 possess similar odors and the same odor thresholds (th), within the standard deviation (see the Supporting Information). Herein, we present the successful design and enantioselective preparation of a new class of bicyclic Cashmeran odorants.…”

“…Very recently, a tert-butyl-substituted 5,5-dimethylcyclopentenyl butanone (2) was discovered that displays a typical Cashmeran odor with pronounced musk facets in the direction of Moxalone but with a rather high odor threshold of 25.0 ng L À1 air compared to that of Cashmeran (1, 0.89 ng L À1 air, Figure 1). [4] The importance of the g,ddouble bond for the musk character was proven by comparison of hydrogenated and dehydrogenated analogues of 2; [4] however, the central parameters are the relative distances of the bulky quaternary C atoms to the osmophoric carbonyl function (H-bond acceptor) in the flexible butanone side chain of 2.…”

Heiße Luft oder cooler Duft? Die Trends der letzten 20 Jahre in der Riechstoffchemie

“…Die Konformere konnten mit den olfaktorischen Eigenschaften korreliert werden. [27,28] Das Isomer (2S,5R)-15 hatte dabei mit Abstand den niedrigsten Geruchsschwellenwert.…”

Design und enantioselektive Synthese von Cashmeran‐Riechstoffen mithilfe der “Enol‐Katalyse”

“…Dessen ungeachtet sind fast keine weiteren Riechstoffe mit Cashmeran-Profil bekannt. [2] Die Enantiomere von 1 haben ähnliche Geruchseigenschaften und innerhalb der Standardabweichung auch dieselben Schwellenwerte (siehe die Hintergrundinformationen). Im Folgenden werden das erfolgreiche Design und die enantioselektive Synthese einer neuen Klasse von bicyclischen Cashmeran-Riechstoffen vorgestellt, das uns zur Entwicklung einer neuartigen Brønsted-Säure-katalysierten asymmetrischen Michael-Addition inspirierte und die "Enol-Katalyse" als neue universelle organokatalytische Aktivierungsmethode etabliert.…”