Synthesis and odor properties of Phantolide analogues

Phantolide analogues 1a–1d were newly synthesized to evaluate their odor profiles. The enantiomers of 1a and 1b were also synthesized. Both (S) enantiomers of 1a and 1b had musk odor although weakly, and but neither of the (R) enantiomers 1a and 1b had musk odor. During the investigations, we encountered the undesirable racemization in Friedel-Crafts reaction of the intermediate (S)-5.     

Synthesis and Optical Resolution of the Floral Odorant (±)‐2,3‐Dihydro‐2,5‐dimethyl‐1H‐indene‐2‐methanol,and Preparation of Analogues

The title compound (±)‐ 1 , a recently discovered, valuable, floral‐type odorant, has been synthesized by a straightforward procedure (Scheme 1). To determine the properties of the enantiomers of 1 , their separation by preparative HPLC and the determination of their absolute configuration by X‐ray crystallography were carried out (Figure). Furthermore, the analogues 2 – 6 were synthesized, either from differently methylated 2‐methylindan‐1‐ones (Schemes 2 and 3) or, in the case of the 2,4,6‐trimethylated homologue 6 , by a completely different synthetic approach (Scheme 4). An evaluation of (+)‐(S)‐ 1 , (−)‐(R)‐ 1 , and (±)‐ 1 showed only minor differences in terms of odor (Table).     

Synthesis of Benzodioxepinone Analogues via a Novel Synthetic Route with Qualitative Olfactory Evaluation

Marine odorants represent a minor yet diverse class of substances within the fragrance industry, of which 7‐methyl‐2H‐1,5‐benzodioxepin‐3(4H)‐one ( 1 ) is commercially known as Calone 1951^®, a synthetic first in the area of marine‐fragrance chemistry. To determine the extent to which the characteristic marine odor of Calone 1951^® corresponds to the substitution at the benzo portion of the molecule, a variety of aromatic substituents were incorporated into the benzodioxepinone structure (Scheme 1, Table 3). In light of the difficulty experienced in applying patented literature to deriving the analogues 12 – 18 , particularly those with electron‐withdrawing substituents, an alternative synthetic scheme was implemented for the construction of all analogues in favorable yields (Scheme 4, Table 3). Formation of the hydroxy‐protected dihalo alkylating agent 24 via epoxide cleavage of epichlorohydrin (Scheme 3) allowed etherification favoring dihalo displacement and subsequent intramolecular ring closure (→ 26a – g ). THP Deprotection followed by oxidation of the alcohols 27a – g to the ketones 12 – 18 provided a general pathway to the benzodioxepinone products. The influence of the substituent nature on odor activity revealed a diverse scope of olfactory character (Table 4).     

The (+)‐cis‐ and (+)‐trans‐Olibanic Acids: Key Odorants of Frankincense

Frankincense (olibanum) is one of the oldest aromatic materials used by humans, but the key molecular constituents contributing to its characteristic odor remained unknown. Reported herein is the discovery that (1S,2S)‐(+)‐trans‐ and (1S,2R)‐(+)‐cis‐2‐octylcyclopropyl‐1‐carboxylic acids are highly potent and substantive odorants occurring in ppm amounts in all of the frankincense samples analyzed, even those showing radically different volatile compositions. These cyclopropyl‐derived acids provide the very characteristic old churchlike endnote of the frankincense odor.     

Diastereoselektivität der Geruchswahrnehmung von Alkoholen der Iononreihe

Diastereoselective Odor Perception of Alcohols in the Ionone Series The characteristic odor of the diastereoisomers 1 and 2 of 1-(2,2,6-trimethylcyclohexyl)-3-hexanol is configuration dependent, the trans-alcohol 1 being identified as the sensorily active component. Structure modification of model 1 / 2 , for example substitution on C(2), C(13), and C(14) (ionon numbering) by CH₃ groups, introduction of double bonds in the 3- or 4-position, and isosteric substitution of C(7) by an O-atom, leads to analogues revealing an unequivocal relation between stereochemistry and odor. The specific odor of alcohol 1 is generally released when all substituents are in an equatorial position; the resulting analogy with the molecular size and shape of odoriferous steroids suggests that the release of the particular scent can be correlated with a steroid-resembling receptor event.     

Investigation of an Olfactoryly Active Ring-Like Conformer of a Chain-Type Odorant, (3S)-3,7-dimethyloctanal,by computer calculation and graphics

The odor of (3S)-3,7-dimethyloctanal, a chain-type odorant, has some resemblance to that of ethyl (1 R, 6S)-2,2,6-trimethylcyclohexane-1-carboxylate, a ring-type odorant. We investigated the ring-like conformers of (3S)-3,7-dimethyloctanal. Two approaches, (i) systematic conformational analysis and (ii) construction of the initial structure by referring to the structure of the ring-type odorant, were considered in the search for ring-like conformers of the chain-type odorant. As a result, it was found that two stable ring-like conformers of (3S)-3,7-dimethyloctanal, obtained from the two approaches, resembled conformers of ethyl (1R, 6S)-2,2,6-trimethylcyclohexane-1-carboxylate in their three-dimensional structural features. The shapes of the two ring-like ones were not exactly the same but were quite similar. Therefore, the two ring-like conformers were considered to approximate the olfactoryly active conformer that binds and stimulates the same odor receptor as that for ethyl (1R,6S)-2,2,6-trimethylcyclohexane-1-carboxylate. In addition, ring-like conformers of another chain-type odorant, 2-methylpent-2-enal, were investigated to check the validity of the calculation method used.     

Synthesis and Qualitative Olfactory Evaluation of Benzodioxepine Analogues

Marine fragrances, particularly Calone 1951^® (=7‐methyl‐2H‐1,5‐benzodioxepin‐3(4H)‐one; 1 ) has carved a minor but distinct niche in the broad field of fragrance chemistry. By focusing on the polar structure fragment of the benzodioxepinone parent compound, we set out to determine the molecular influence on the dominant marine note attributed to the Calone 1951^® structure. A selection of one‐step modifications of the ketone 1 resulted in a range of odor‐active conformers with diverse olfactory attributes. The synthesis of a range of benzodioxepine analogues, i.e., of 3 – 11 , is presented alongside olfactory evaluation (Tables 2 and 3). Removal of the carbonyl group of 1 and increasing the size of the aliphatic ring portion (see 6 and 7 ) introduced sweetness and a predominant loss of the marine character.     

Synthesis and odor description of optically active cyclopropanated analogues of geraniol,nerol, nor-leaf alcohol,and matsutake alcohol

Both enantiomers of cyclopropanated analogues of geraniol, nerol, nor-leaf alcohol, and matsutake alcohol were synthesized and their odor properties evaluated. Odor characters in enantiomeric pairs were similar in the geraniol series. The (+)-(2R,3S)-nerol derivative showed various odor aspects. From the results of nor-leaf alcohol derivatives, an interaction between the (2-re,3-re)-face of nor-leaf alcohol and the human olfactory receptor was suggested. The odor of (3R)-matsutake alcohol derivative was superior to the enantiomer.     

1‐Methoxyhexane‐3‐thiol,a Powerful Odorant of Clary Sage (Salvia sclarea L.)

The peculiar and highly diffusive odor signal of flowering clary‐sage plants (Salvia sclarea L.) was identified to derive from trace amounts of 1‐methoxyhexane‐3‐thiol ( 1 ) by mass‐spectrometry analysis and confirmed by comparison with synthetic racemic thiol (±)‐ 1 . The enantiomers (S)‐ and (R)‐ 1 were prepared by enantioselective synthesis, and the absolute configuration of (S)‐ 1 was fully corroborated by X‐ray‐diffraction analysis of the crystalline thioester (1′S,1S)‐ 2 . Compound (S)‐ 1 is one of the most powerful odorants known, with a detection threshold of 0.04⋅10⁻³ ng/l air, and is, with its herbaceous‐green, alliaceous, and perspiration profile, key to the fragrance of clary‐sage flowers and of the freshly distilled essential oil. As a consequence of its unique odor, 1 was also suspected to be part of the volatiles of a Ruta species where it was subsequently identified together with its homologue, 1‐methoxyheptane‐3‐thiol ( 3 ), 1‐methoxy‐4‐methylpentane‐3‐thiol ( 4 ), and the known 4‐methoxy‐2‐methylbutane‐2‐thiol ( 5 ). The syntheses of (±)‐ 3 and (±)‐ 4 as well as of the enantiomer (R)‐ 4 are described. In both natural fractions, the ratio (S)‐ 1 /(R)‐ 1 was slightly in favor of the (S)‐enantiomer. Natural 4 has (R)‐configuration.     

Axially Dissymmetric Bis(triaryl)phosphines in the Biphenyl series: Synthesis of (6,6′-dimethylbiphenyl-2,2′-diyl)bis(diphenylphosphine) (‘BIPHEMP’) and analogues,and their use in Rh(I)-catalyzed asymmetric isomerizations of N,N-diethylnerylamine

The axially dissymmetric diphosphines (?)-(R)- and (+)-(S)-(6-6′-dimethylbiphenyl-2,2′-diyl)bis(diphenyl-phosphine) ((?)-(R)- 10 and (+)-(S)- 10 ; ‘BIPHEMP’) have been synthesized, starting from (R)- and (S)-6,6′-dimethylbiphenyl-2,2′-diamine ((R)- and(S)- 16 ), respectively, via Sandmeyer reaction, liathiation, and phosphinylation. Moreover, racemic 4,4′- dimethyl- and 4,4′-bis(dimethylamino)-substituted analogues 11 and 12 respectively, and the 6,6′-bridged analogues 1,11-bis(diphenylphosphino)-5,7-dihydrodibenz[c,e]oxepin (13) were synthesized and resolved into optically pure (R)- and(S)-enantiomers via complexation with di-μ-chlorob is {(R)-2-[1-(dimethylamino)ethyl]pheny-C? N}dipalladium(II) ((R)- 18 ). The molecular structures of the diphosphines (S)- 10 and (R)- 13 and of two derived cationic Rh(I) complexes,[Rh((S)- 10 )(nbd)]BF₄ and [Rh((R)- 13 )(nbd)]BF 4 were determined by x-ray analyses. Absolute configurations were established for (+)-(S)- 10 by X-ray analyses of both the free diphosphine and of the derived Rh(I) complex, and for (?)-(R)- 13 by X-ray analysis of the derived Rh(I) complex. Configurational assignments for the substituted BIPHEMP analogues 11 12 were achieved by means of ¹H-NMR comparisons. The BIPHEMP ligand 10 and analogues 11 , 12 and 13 are the first examples of optically active bis(triaylphosphines) containing the axially dissymmetric biphenyl moiety. All these new diphosphines proved to be excellent asymmetry-inducing ligands in Rh(I)-catalyzed isomerizations of N,N-diethylnerylamine affording citronellat enamine of 98-99% ee.     

Syntheses and Odor Descriptions of Cyclopropanated Compounds. Part 5

Analogs of methyl jasmonate (=methyl (1R*,2R*)‐3‐oxo‐2‐[(Z)‐pent‐2‐enyl]cyclopentaneacetate; MJA) bearing a cyclopropane ring, double bond, or a F‐substituent were synthesized, and their odor characteristics were examined. Most of the analogs with the same stereochemical properties as methyl epijasmonate showed odor properties superior to MJA. Interestingly, the enol acetate of MJA had a diffusive orchid‐like note.     

Novel Access to Furan-3-thiols and Derivatives,Impact Meat-Flavor Compounds

A versatile process for the preparation of a number of 3-thio-substituted furans 1–4 is described. These products have very low odor thresholds and are thus potent flavor compounds. Fur-3-yl thiocyanates 10a , b as well as other S-containing analogues ( 2b , 7a , b , and 8 ) were prepared by a Michael-type addition of thiocyanic acid, thioacetic acid, alakanethiols, and sodium thiosulfate to alkynones 6 or 15 , followed by cyclization (Schemes 3 and 4). The thiocyanates 10a, b were converted to mixed disulfides 3 , symmetric disulfides 4 , thioethers 2 , and thiols 1 , using ‘hard’ or ‘soft’ nucleophiles or reducing agents, respectively (Scheme 6).     

Structure–Activity Relationship in the Domain of Odorants Having Marine Notes

We synthesized or re‐synthesized a large series of 2H‐1,5‐benzodioxepin‐3(4H)‐ones 9 (Scheme 1), 4,5‐dihydro‐1‐benzoxepin‐3(2H)‐ones 10 (Schemes 3 and 4) and 5,6,8,9‐tetrahydro‐7H‐benzocyclohepten‐7‐ones 11 (Schemes 5 and 6), since the lead compound for the olfactory note of perfumes based on marine accords is a well‐known benzodioxepinone named Calone 1951^® ( 9b ). We meticulously described the odor profile of each synthesized compound and discussed relevant structure–odor relationships (Tables 1–3). In particular, we revealed a correlation between the conformation of the seven‐membered ring and the activities of these compounds (Table 4 and Fig. 3). We also clarified the effect of the position and the size of the alkyl substituent at the aromatic ring.     

Asymmetric Synthesis and Binding Study of New Long‐Chain HPA‐12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA‐12 with long aliphatic chains were prepared as their (1R,3S)‐syn and (1R,3R)‐anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization‐induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA‐12 analogues in concise 4‐ to 6‐step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time‐resolved FRET‐based homogeneous (HTR‐FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10‐ to 1000‐fold enhancement of the protein binding, with the highest effect being observed for a n‐hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3‐deoxyphytoceramide aliphatic analogues. The 1,3‐syn stereoisomers were systematically more potent than their 1,3‐anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)‐syn HPAs.     

New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections

Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3‐deazaneplanocin A, galidesivir, GS‐6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS‐6620, remdesivir and pyrazofurin) are C‐nucleosides, and two of them (GS‐6620, remdesivir) also contain a phosphoramidate part. The C‐nucleoside and phosphoramidate (and for the adenine analogues the 1′‐cyano group as well) may be considered as essential attributes for their antiviral activity.     

Enzyme‐Mediated Preparation of Enantiomerically Pure p‐Menthan‐ 3,9‐diols and Their Use for the Synthesis of Natural p‐Menthane Lactones and Ethers

The diastereoselective preparation of the p‐menthane‐3,9‐diols (±)‐ 12 , (±)‐ 13a , (±)‐ 13b , and (±)‐ 18 and the study of their enzymic resolution is described (Scheme 1). The corresponding enantiomer‐enriched diols obtained by means of the lipase‐mediated kinetic acetylation of the racemic diols are suitable synthetic precursors of many relevant p‐menthane monoterpenes. Their usefulness is shown in the preparation of different natural products of this class that are interesting for industrial purposes because of their odor qualities, i.e., of the enantiomeric form of 3‐hydroxy‐p‐menthan‐9‐oic acid lactone 1 , of mintlactone 2 , of the 3,9‐epoxy‐p‐menth‐1,8(10)‐diene 10 , and of the pheromone vesperal 11 (Schemes 2 and 3).     

Validation of a headspace trap gas chromatography and mass spectrometry method for the quantitative analysis of volatile compounds from degraded rapeseed oil

Due to lipid oxidation, off‐flavors, characterized by a fishy odor, are emitted during the heating of rapeseed oil in a fryer and affect the flavor of rapeseed oil even at low concentrations. Thus, there is a need for analytical methods to identify and quantify these products. To study the headspace composition of degraded rapeseed oil, and more specifically the compounds responsible for the fishy odor, a headspace trap gas chromatography with mass spectrometry method was developed and validated. Six volatile compounds formed during the degradation of rapeseed oil were quantified: 1‐penten‐3‐one, (Z)‐4‐heptenal, hexanal, nonanal, (E,E)‐heptadienal, and (E)‐2‐heptenal. Validation using accuracy profiles allowed us to determine the valid ranges of concentrations for each compound, with acceptance limits of 40% and tolerance limits of 80%. This method was then successfully applied to real samples of degraded oils.     

Synthesis and Biological Activity of a Series of Methylene-Expanded Oxetanocin Nucleoside Analogues

Summary.  A series of methylene-expanded oxetanocin nucleoside analogues, e.g. analogues of 2 and the known antiviral nucleosides AZT, FLT, and ddC (3) were prepared by a very direct route beginning with the readily available (S )-glycidol 4 and proceeding via the dihydrofuran-3-methanols 9a,b. Biological testing of these modified nucleosides indicates that they are non-cytotoxic compounds with generally weak antiviral activity. However, the guanosine analogue 2G showed pronounced activity vs. herpes simplex virus type 1 (HSV-1) in cell culture and was HSV-1-encoded thymidine kinase dependent. This compound is therefore an interesting new lead structure for the development of new anti-HSV agents. Received September 3, 2001. Accepted September 17, 2001     

Isoform-selective modulators for metabotropic glutamate receptors and protein kinase C:Synthesis and biological evaluation

The synthetic studies for some known modulators of metabotropic glutamate receptors (mGluRs) such as (S)-αM4CPG,(1S,3fi)-ACPD,L-CCG-I are described.Based on the structure of αM4CPG several new conformationally constrained analogues are design ed and synthesized.Among them APICA is a selective antagonist for group II mGluRs.Also,a new benzolactam-V8 analogue is found to have better isoform-selectivity for protein kinase C family.Three different protocols for synthesizing benzolactam-V8 analogues are developed to meet the requirement for delivering more analogues to test.