Citrate appears to be the main determinant of CaOx crystallization rates and crystal morphology in the presence of nTHP as well as SF-THP. Its effects appear to predominate over those of THP, since even promotory SF-THP is turned into a crystallization inhibitor in the presence of citrate. This re-emphasizes at a morphological level what has been concluded from functional as well from clinical studies, namely that citrate is needed in urine at equimolar concentrations to calcium in order to prevent the formation of large crystal aggregates in presence of abnormal THP.
Minimum‐energy calculations and the conformation of the (11Z)‐retinylidium moiety in bovine rhodopsin called into doubt that the function of the dienone motif of a new class of musk odorants 1–6 was to stiffen and planarize the compounds. To investigate the function and importance of these double bonds, the three most potent representatives of the family of dienone musks were partially and fully hydrogenated, and the products were evaluated for their olfactory properties. Stryker's method using the Osborn complex and the procedure of Evans and Fu utilizing catecholborane were used for the reduction of the α,β‐double bonds, palladium on CaCO3 was used for the reduction of the γ,δ‐double bonds, and palladium on charcoal was used for the complete hydrogenation of the dienone systems in 2–4. trans‐Configured cyclopentyl derivatives 23 and 24 were synthesized from 4,4‐dimethylcyclohex‐2‐en‐1‐one by Weitz–Scheffer epoxidation, sodium borohydride reduction, rearrangement to the corresponding carbaldehyde using lithium bromide in toluene/HMPT, cuprate alkylation with the tert‐butyl Gilman reagent, aldol condensation with acetone, and optional hydrogenation with palladium on charcoal. Of the synthesized derivatives, only the γ,δ‐unsaturated enones (i.e., 9, 12, and 15) have a typical musk odor, indicating that the γ,δ‐double bond interacts electronically with the musk receptor(s). As enones 9, 12, and 15 are, however, less intense than the parent compounds (i.e., 2–4), the α,β‐double bond seems to intensify the odor strength due to conformational effects. Conformational effects also seem to favor compounds with an endocyclic γ,δ‐double bond over acyclic dienone systems for their intensity and musk character. In acyclic compounds 10 and 13, the α,β‐double bond introduces violet–orris facets.
Vetiver oil, produced on a multiton‐scale from the roots of vetiver grass, is one of the finest and most popular perfumery materials, appearing in over a third of all fragrances. It is a complex mixture of hundreds of molecules and the specific odorant, responsible for its characteristic suave and sweet transparent, woody‐ambery smell, has remained a mystery until today. Herein, we prove by an eleven‐step chemical synthesis, employing a novel asymmetric organocatalytic Mukaiyama–Michael addition, that (+)‐2‐epi‐ziza‐6(13)en‐3‐one is the active smelling principle of vetiver oil. Its olfactory evaluation reveals a remarkable odor threshold of 29 picograms per liter air, responsible for the special sensuous aura it lends to perfumes and the quasi‐pheromone‐like effect it has on perfumers and consumers alike.
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.
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