Structure-odor relationships of α-santalol derivatives with modified side chains

(Z)-α-Santalol, which has a unique woody odor, is a main constituent of sandalwood essential oil. We investigated the structure-odor relationship of (Z)-α-santalol and its derivatives, focusing on the relationship between the structure of the side chain and the odor of the compounds. Various α-santalol derivatives (aldehydes, formates, and acetates) were synthesized from (Z)- and (E)-α-santalol, which were prepared from (+)-3-bromocamphor through modifications of a reported synthetic route. The Z- and E-isomers of α-santalols have different double-bond configurations in the side chain. Analogues with saturated side chains were also prepared from the corresponding α-santalols, and the odors of the all the prepared compounds were evaluated. We found that the odors of the Z-isomers (woody) were similar to those of the corresponding saturated compounds, but clearly different from the odors of the corresponding E-isomers (odorless, fresh, or fatty). These results indicate that the relative configuration of the side chain with respect to the santalane frame plays an important role in the odor of α-santalol. E-configuration in the side chain eliminates the woody odor character of α-santalol and its examined derivatives, whereas the Z-configuration or saturation of the carbon side chain does not.     

QSAR of α-campholenic derivatives with sandalwood odor, and molecular design

Abstract  

Quantitative structure–activity relationship (QSAR) studies have been carried out in a series of α-campholenic derivatives with sandalwood odor based on quantum-chemical data derived by use of the Hartree–Fock (HF) method. To build QSAR models, a multiple linear regression method was used. The models obtained have good predictive ability and are of high statistical significance, with good correlation coefficients, and p values less than 0.05. The models contribute also to identification of important quantum-chemical aspects of the sandalwood odor. On the basis of the QSAR models built, several new sandalwood compounds were designed and the best candidate for experimental synthesis was suggested.     

Study of the structural and electronic origin of the sandalwood odor of some terpenylcyclohexanols

Abstract  

The correlation between structural and electronic features and the sandalwood odor of some terpenylcyclohexanols is established on the basis of quantum chemical calculation methods. A definite structural fragment with electronic properties determining the origin of the odor is revealed. The effects of HOMO–LUMO energy gaps and total energies of some terpenylcyclohexanols on their odor intensity are investigated.     

Conformational Parameters of the Sandalwood-Odor Activity: Conformational calculations on sandalwood odor

The conformational parameters responsible for sandalwood odor were investigated by the “active-analog approach”. The pharmacophoric (osmophoric) pattern of sandalwood-odor molecules can be outlined as three points: the OH group (point PI), a lipophilic group (point P2) 2.9–3.0 Å distant from the OH group, and a bulky rigid group (point P3), represented as a dummy atom in the middle of the alicyclic system (norbornane bicycle or cyclopentene ring) or a quaternary C-atom. This concept was tested on a series of representative sandalwood-odor compounds and on some structurally similar, but odorless substances.     

A rapid method for molecular shape comparison of medium-sized molecules. Conformational calculations on sandalwood odor,IV

Summary A fast method of a surface comparison of two or more molecules to be matched is presented. The Van der Waals surfaces of molecules are described by points calculated as the intersection of grid lines with the molecular surface. The mean surface of various molecules with the same biological activity can be constructed. It is used for further comparisons with similar molecules lacking this activity. Deviations of any molecular surface from the mean surface can be mapped onto the surface. The method was tested on a distinct group of sandalwood odor molecules and it was shown that such matching and comparison procedures are useful in the investigation of odor structure-activity relationships proposed as CAFD (computer aided fragrance design).Dedicated to Prof. Dr. W. Fleischhacker, on occasion of his 60th anniversary     

Enantioselectivity in Odor Perception: Synthesis and Olfactory Properties of Iso‐β‐Bisabolol,a New Natural Product

The odorous trace constituent iso‐β‐bisabolol ( 4 ) was isolated from East Indian and Western Australian sandalwood oil and synthesized by using the (E/Z)‐triene 12 (iso‐γ‐bisabolene) as a key intermediate. Only one of four stereoisomeric forms of 4 , (6R,7R)‐ 4a , is odor active, having a strong floral, muguet‐like, very pleasant scent.     

Enantioselectivity in Odor Perception

The 3‐methyl‐4‐(tricyclo[5.2.1.0^2,6]dec‐4‐en‐8‐ylidene)butan‐2‐ols (=Fleursandol^®; rac‐ 10 ), a new class of sandalwood odorants, were synthesized in their enantiomerically pure forms by use of tricyclo[5.2.1.0^2,6]dec‐4‐en‐8‐ones 17 and ent‐ 17 and (tetrahydro‐2H‐pyran‐2‐yl)‐protected 4‐bromo‐3‐methylbutan‐2‐ols 22 and ent‐ 22 as starting materials (Schemes 2–4). Only four of 16 possible stereoisomers of rac‐ 10 possess the typical, very pleasant, long‐lasting sandalwood odor (Table 1). The (2S,3R,4E,1′R,2′R,6′R,7′R)‐isomer ent‐ 10a is by far the most important representative, with an odor threshold of 5 μg/l in H₂O.     

Preparative separation of α- and β-santalenes and (Z)-α- and (Z)-β-santalols using silver nitrate-impregnated silica gel medium pressure liquid chromatography and analysis of sandalwood oil

The major sesquiterpene constituents of East-Indian sandalwood oil (Z)-α- and (Z)-β-santalols have shown to be responsible for most of the biological activities and organoleptic properties of sandalwood oil. The work reported here describes the strategic use of medium pressure liquid chromatography (MPLC) for the separation of both α- and β-santalenes and (Z)-α- and (Z)-β-santalols. Silver nitrate impregnated silica gel was used as the stationary phase in MPLC for quantitative separation of α- and β-santalenes and (Z)-α- and (Z)-β-santalols with mobile phases hexane and dichloromethane, respectively. The purities of α-santalene and (Z)-α-santalol obtained were >96%; however, β-santalene and (Z)-β-santalol were obtained with their respective inseparable epi-isomers. Limits of quantification (LoQ) relative to the FID detector were measured for important sesquiterpene alcohols of heartwood oil of S. album using serial dilutions of the standard stock solutions and demonstrated that the quality of the commercial sandalwood oil can be assessed for the content of individual sesquiterpene alcohols regulated by Australian Standard (AS2112-2003), International Organization for Standardization ISO 3518:2002 (E) and European Union (E. U.).     

Evaluation of the quality of sandalwood essential oils by gas chromatography-mass spectrometry

Trade and historic oils from 'sandalwoods', labelled as Amyris balsamifera, Eremophila mitchelli, Fusanus acuminatus (= Santalum acuminatum), Santalum album, S. austrocaledonicum, S. latifolium, S. spicatum and S. yasi, were assessed using gas chromatography-mass spectrometry (GC-MS). Using GC-MS, none of the oils assessed complied with the internationally recognised standard of a 90% santalol content, and only about half of the trade sandalwood oils met with recent International Organisation for Standardisation standards. The majority of trade oils, reportedly from S. album, contained approximately 50-70% santalols (Z-alpha and Z-beta). Thus, the internationally recognised specification (90% santalols) for S. album requires re-evaluation by more efficient analysis methods. In view of the issues associated with the quality of sandalwood oils being traded, specifications of > or = 43% Z-alpha-santalol and > or = 18% Z-beta-santalol for S. album oil estimated by GC-MS are suggested. GC-MS are recommended as it assists with authentication and quality control issues associated with sandalwood oils.     

Riechstoffsynthesen mit Fencholenaldehyd

Summary With respect to the molecular requirements on sandalwood aroma chemicals the synthesis of some derivatives of the title compound is described. The synthesis of the new homofencholenic aldehyde affords the connection of the 2,2,4-trimethylcyclopentenylsystem with a santalol analogous side chain by condensation with propionic aldehyde. In contrast to the sandalwood odour of -compholenic derivatives the analogous fencholenic compounds possess only woody notes.

     

Odds and Trends: Recent Developments in the Chemistry of Odorants

Fragrance chemistry is, together with the closely related area of flavor chemistry, one of the few domains, if not the only one, in which chemists can immediately experience structure–activity relationships. This review presents structure–odor correlations and olfactophore models for the main odor notes of perfumery: “fruity”, “marine”, “green”, “floral”, “spicy”, “woody”, “amber”, and “musky”. New trendsetters and so‐called captive odorants of these notes are introduced, and recent activities and highlights in fragrance chemistry are summarized. The design of odorants, their chemical synthesis, and their use in modern perfumery is discussed. Our selection is guided and illustrated by creative fragrances, and features new odorants which encompassed current trends in perfumery. New odorants for grapefruit and blackcurrant, for galbanum, and leafy top notes are presented. Compounds with fashionable marine, ozonic, and aquatic facets are treated, as well as new odorants for classical lily‐of‐the‐valley, rose, and jasmine accords. Compounds with sweet and spicy tonalities are also discussed, as are the most recent developments for woody notes such as sandalwood and vetiver. We conclude with musky and ambery odorants possessing uncommon or unusual structural features. Some odor trends and effects are illustrated by microencapsulated fragrance samples, and areas where there is need for the development of new synthetic materials and methodologies are pointed out. Thus, chemists are invited to explore fragrance chemistry and participate in the design and synthesis of new odorants. This review gives the latest state of the art of the subject.     

Conformational calculations on odoriferous molecules of sandalwood,I. The search for the odoriferous principle of sandalwood oil

The conformations of two relatively rigid molecules with sandalwood odor have been investigated by molecular mechanics and the semiempirical method AM1. A comparison between both geometries shows that a common structural element exists in the relative rearrangement of a carbinol function and a quarternary carbon atom. The distance of these two centers as well as the electron density agree well in both structures.

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Rechnungen zur Konformation von Molekülen mit Sandelholzgeruch, 1. Mitt.: Die Suche nach dem Geruchsprinzip des Sandelholzöles

Zusammenfassung Die Konformationen zweier relativ starrer Moleküle mit Sandelholzgeruch wurden mit molekularmechanischer und mit einer semiempirischen Methode (AM1) bestimmt. Ein Vergleich der beiden molekularer Geometrien zeigt ein gemeinsames Strukturelement und zwar die relative Anordnung der Carbinolfunktion zu einem quartären Kohlenstoffatom. Sowohl deren Abstand als auch deren Elektronendichte stimmen in beiden Verbindungen überein.

     

A Chemical Investigation of the Volatile Constituents of East Indian Sandalwood Oil (SantalumalbumL.)

Distillation foreruns from East Indian sandalwood oil (Santalum album L .), representing 5–8% of the oil, have been investigated using fractional distillation, preparative column chromatography, gas liquid chromatography (GLC.), and chemical treatments. This allowed the isolation and characterization by their spectral data of 46 compounds. 32 of them were newly identified sandalwood oil constituents including 4 novel substances: santalone ( 2 ), 4-methylcyclohexa-1,3-dien-1-yl methyl ketone ( 4 ), 5,6-dimethyl-5-norbornen-exo-2-ol ( 7 ), and (E)-5-(2,3-dimethyl-3-nortricyclyl)-pent-3-en-2-one ( 20 ). The other constituents identified were 1-furfuryl-pyrrole ( 10 ) and 10 phenols accompanied by 17 terpene and sesquiterpene derivatives. Endo-2,endo-3-dimethyl-norbornan-exo-2-ol ( 6 ), an α-santenol ( z ), precursor, was present in the last group of constituents. The compounds 2, 4, 6, 7, 20 have been synthesized as well as another novel constituent, endo-2-mythyl-3-methylidene-norbornan-exo-2-ol ( 5 ).     

Structural and Configurational Dependence of the Sensory Process in Steroids

Structural modifications of testosterone and 19-nortestosterone have led to the synthesis of over 60 androstane and estrane derivatives whose sensory evaluation has allowed molecular parameters to be established for release of a ‘steroid-type’ scent. Odor perception with O-containing compounds in both classes has been found to be regioselective . Osmophoric groups at C(3) were found to be the most active and specific. Functionality at C(2) is accompanied to a large extent by anosmic defects, and O-containing substituents at C(1) and C(4) appear to affect the receptor membrane in exceptional cases. A further characteristic of the ‘steroid-type’ scent is diastereoselectivity. The odor intensity of axial 2- and 3-hydroxysteroids is far greater than that of the equatorial epimers, and epimeric hydroxy-groups in the 1-, 4-, and 5-positions lead to almost complete absence of odor. In addition, only steroids with ‘normal’ ring junctions and configuration were found to be odorants, whereas compounds with cis-junctions between rings A and B, or C and D, were found to be practically inactive, Steroids therefore folow the ‘triaxial rule of odor sensation’. The most remarkable feature of our findings with steroid odorants is enantioselectivity

1 The term ‘regioselective’ is currently used for a reaction in which formation of one structural (or positional) isomer is favored over another. For convenience we use ‘regioselective’, ‘diastereoselective’ or ‘enantioselective’ for substrate-receptor interactions in which one positional isomer, diastereoisomer or enantiomer leads to a different sensory response (in quality and/or intensity) than another.

. Whereas with C ₁₉ -steroids of the ‘natural’ enantiomeric series the perception threshold is extremely low (<6 ppb), the corresponding ‘unnatural’ enantiomers have been found essentially odorless by a panel of 30 persons. This appears to be the first reported instance of a total enantioselective response to an odorant.     

Synthesis of novel hapten derivatives of 1alpha,25-dihydroxy-vitamin D3 and its 20-epi analogue

Hapten derivatives of 1alpha,25-dihydroxyvitamin D(3) and its 20-epimer were synthesized and conjugated to a carrier protein for raising polyclonal antibodies. The haptens were linked through spacers at C-16, thereby exposing both the A-ring and the side chain of the molecules, to maximize antibody specificity. The spacers were introduced via stereoselective hydroboration of 16-ene intermediates as the key step. In immunoassays, the antibodies raised toward the natural hormone were selective to this compound over derivatives with modifications in the A-ring or the side chain. The antibodies toward the 20-epimer, however, were unable to recognize modifications in the side chain.     

Organic Hollow Mesoporous Silica as a Promising Sandalwood Essential Oil Carrier

As film-forming agents, fillers and adsorbents, microplastics are often added to daily personal care products. Because of their chemical stability, they remain in the environment for thousands of years, endangering the safety of the environment and human health. Therefore, it is urgent to find an environmentally friendly substitute for microplastics. Using n-octyltrimethoxysilane (OTMS) and tetraethoxysilane (TEOS) as silicon sources, a novel, environmentally friendly, organic hollow mesoporous silica system is designed with a high loading capacity and excellent adsorption characteristics in this work. In our methodology, sandalwood essential oil (SEO) was successfully loaded into the nanoparticle cavities, and was involved in the formation of Pickering emulsion as well, with a content of up to 40% (w/w). The developed system was a stable carrier for the dispersion of SEO in water. This system can not only overcome the shortcomings of poor water solubility and volatility of sandalwood essential oil, but also act as a microplastic substitute with broad prospects in the cosmetics and personal care industry, laying a foundation for the preparation and applications of high loading capacity microcapsules in aqueous media.     

Identification of 2,3-butanedione (diacetyl) as the compound causing odor events at trace levels in the Llobregat River and Barcelona's treated water (Spain)

A study of organic compounds imparting sweet and buttery odor problems in the Llobregat River (northeast Spain) and in treated water was conducted. Solid-phase microextraction (SPME), gas chromatography-olfactometry, and flavor profile analysis (FPA) were used as analytical methodologies to identify the compound responsible for odor incidents. 2,3-Butanedione (diacetyl) with a concentration range of 0.90-26 microg/l in river water samples entering the water treatment plant was identified as the compound causing the odor events. Flavor profile analysis establishes 0.05 microg/l as its odor threshold concentration (OTC) in water, with an odor recognition concentration of 0.20 microg/l. The analyses were carried out with SPME-GC-MS and parameters affecting SPME extraction such as selection of the fiber (carboxen-polydimethylsiloxane), extraction time (30 min), temperature (60 degrees C), and ionic strength were evaluated. Quality parameters of the optimized method gives good linearity (r2 > 0.999), a limit of detection (0.08 microg/l) similar to the OTC of the compound, and good reproducibility (R.S.D. < 20%). The SPME method was applied to identify the compound causing the odor.     

Total syntheses of (±)-α-acorenol, β-acorenol, α-epi-acorenol and β-epi-acorenol via an Ireland ester Claisen rearrangement and RCM reaction sequence

Total syntheses of (±)-α- and β-acorenols and (±)-α- and β-epi-acorenols, spiro[4.5]decane sesquiterpenes, isolated from the western Australian sandalwood oil, have been accomplished employing a combination of Ireland ester Claisen rearrangement and RCM reactions for an efficient construction of the spiro[4.5]decane present in acoranes.