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.     

Synthesis of 1,4-Cyclohexadiene Carboxylates through a Formal [2+4]-Cycloaddition of Propiolates under Cobalt Catalysis

A low-valent cobalt(I) complex, formed from the reduction of CoBr₂(dppe) with zinc, acts as catalyst for the efficient [2+4] cycloaddition of β-alkyl, cycloalkyl and aryl substituted propiolates to dienes. This transformation yields synthetically relevant 1,4-cyclohexadiene carboxylates in good to excellent yields. Furthermore, the target compounds are novel lead structures for the discovery of fragrance ingredients from the fruity, floral and spicy odor family.     

Synthesis and Odor Properties of Substituted Indane‐2‐carboxaldehydes. Discovery of a New Floral (Muguet) Fragrance Alcohol

Eight substituted indane‐2‐carboxaldehydes (= 2,3‐dihydro‐1H‐indene‐2‐carboxaldehydes), related to conformationally constrained analogues of floral‐type odorants, were synthesized in order to examine the effect of modifying the lipophilic part of the odorants (Schemes 1 and 2). None of the modified compounds showed better olfactive properties than the original ones (Tables 1 and 2), but an intermediate alcohol, 29 , revealed itself as a valuable new member in the family of floral muguet (lily‐of‐the‐valley)‐type odorants.     

A Practical Domino‐Claisen–Cope Sequence in the Synthesis of New Blooming Citrus and Potent Floral Rose Alcohols

Fifty years after its first discovery by Alan Francis Thomas , we describe a versatile, metal and pressure‐free domino‐Claisen–Cope rearrangement using the readily available α ,β‐unsaturated aldehydes 5 or their acetals 5′ and allylic alcohols 6 . This transformation provides a convenient access to a large number of radiant citrus and floral rosy odorants. Odor profiles of novel floral rosy and citrus alcohols 13 , 14 , and 16 were studied. Compound 14ba has a floral, rosy, geranium‐like character and shows unique performance and diffusiveness. Compound 16ba has a clear main citrus odor character with a clean green grapefruit/rhubarb connotation. Both odorants have been successfully introduced to perfumery recently as Rosyfolia ™ ( 14ba ) and Pomelol ™ ( 16ba ).     

Radio-green chemistry and nature resourced radiochemistry

The birth of green chemistry in 1990 influenced every branch of sciences including radiochemistry. The development of new radiochemical methods is now dictated by the green chemistry mandates, especially in terms of choosing solvents and reagents. Though there are numbers of environmentally benign reagents and solvents, but sometime atom economy is not fully maintained in the manufacturing process. A newer trend is to use chemicals from natural resources. This new trend in radiochemistry may be termed as “Nature Resourced Radiochemistry”. The development in last two decades in “Radio-green Chemistry” and “Nature Resourced Radiochemistry” has been briefly discussed in the review.     

NOP – Ein neues organischchemisches Grundpraktikum: Nachhaltigkeit per Internet

The sustainable organic chemistry lab course for the new milennium (NOP) makes use of the possibilities that an interactive website provides compared to a conventional lab course published as a textbook or manual. The prospective synthetic chemist can thus gain a more in‐depth understanding of his/her experiments. Detailed information about analytical methods, background information about the sub‐ stances being used and being formed during the experiment and “management ratios” like substance efficiency and energy efficiency are provided. Last but not least, knowledge about the concept “sustainable development” is being adapted to the domain of synthetic chemistry.     

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).     

Laccase‐Mediated Synthesis of Novel Substituted Phenoxazine Chromophores Featuring Tuneable Water Solubility

Laccases are members of the blue copper oxidases family found in nature. They commonly oxidise a wide range of phenol and aniline derivatives, which in turn are involved in oxidative coupling reactions. Yet, laccases remain rarely described as biocatalysts in organic synthesis. This paper describes the chemical preparation of original sulfonated aminophenol substrates and their enzyme‐mediated dimerisation into phenoxazine chromophores that feature tuneable water solubility as a function of the sulfonyl substituent. The scope and limitations of the biocatalysed synthetic process are outlined. Kinetic data were collected to evaluate the influence of physicochemical parameters. The structure of the novel phenoxazine dyes (“head‐to‐head” or “head‐to‐tail” dimer) was assessed by NMR spectroscopic analysis. Two crystalline compounds were analysed by X‐ray diffraction. Such laccase‐mediated synthesis (a green chemistry process) was proven to be more efficient than the chemical oxidation of o‐aminophenols with silver oxide.     

Facile syntheses of 4‐vinyl‐1,2,3‐triazole monomers by click azide/acetylene coupling

Synthetic strategies for the preparation of a new family of vinyl monomers, 4‐vinyl‐1,2,3‐triazoles, have been developed. These monomers are noteworthy as they combine the stability and aromaticity of styrenics with the polarity of vinylpyridines and the structural versatility of acrylate/methacrylate derivatives. To enable the wide adoption of these unique monomers, new methodologies for their synthesis have been elaborated which rely on Cu‐catalyzed azide/acetylene cycloaddition reactions—“click chemistry”—as the key step, with the vinyl substituent being formed by either elimination or Wittig‐type reactions. In addition, one‐pot “click” reactions have been developed from alkyl halides, which allow for monomer synthesis without isolation of the intermediate organic azides. The high yield and facile nature of these procedures has allowed a library of new monomers including the parent compound, 1‐H‐4‐vinyl‐1,2,3‐triazole, to be prepared on large scales. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2897–2912, 2008     

Derivate der 4-Isocamphanyl-4-oxo-buttersäure und ein neues Theaspirananalogon

The synthesis of some derivatives of the title compound is described and their odour with respect to structure-activity-relationships in dependence on the species and position of osmophoric carbonyl and hydroxyl groups is discussed. Only5 and7 exert a woody odour but without sandalwood tonality, the compounds4 and6 have a fruity fragrance. Moreover, the synthesis of the new analogue11 of theaspirane (3a) is reported.11 has an earthy-herbaceous odour which strongly resembles the aroma of black tea. The homologue of11, the bicyclic tetrahydrofurane9, exerts a similar fragrance with a more woody but less earthy tonality.     

Neutral Tridentate PNP Ligands and Their Hybrid Analogues: Versatile Non‐Innocent Scaffolds for Homogeneous Catalysis

Ligands in coordination chemistry and homogeneous catalysis are traditionally “static” spectators that do not actively participate in the catalytic cycle. However, such classic systems do not provide additional “handles” that could facilitate or trigger alternative productive reaction pathways. Recent advances in the use of novel nitrogen‐centered pincer systems have unveiled interesting opportunities for cooperative catalysis. The chemistry of pyridine‐derived, neutral ligands is discussed, with a specific focus on their non‐innocent behavior and potential as facilitators for metal‐mediated organic transformations. This overview should provide inspiration and an incentive to incorporate non‐innocent ligands and their metal complexes within old and new homogeneously catalyzed reactions.     

Crossing the Boundaries between Marine and Muguet: Discovery of Unusual Lily‐of‐the‐Valley Odorants Devoid of Aldehyde Functions

Since 6‐isopropyl‐ ( 11 ) and 6‐isobutyl‐2H‐benzo[b][1,4]dioxepin‐3(4H)‐one ( 12 ) instead of the expected marine odor had been reported to possess lily‐of‐the‐valley notes, albeit weaker than benchmark odorants, the influence of a cyclopropyl ring instead of a methyl branching on the olfactory properties was investigated. 6‐Cyclopropyl‐ ( 27 ), 6‐(2′‐methylcyclopropyl)‐ ( 32 ) and 6‐(cyclopropylmethyl)‐2H‐benzo[b][1,4]dioxepin‐3(4H)‐one ( 39 ) were thus synthesized from 2,3‐dimethoxybenzaldehyde ( 22 ) by a synthetic sequence consisting of Wittig methylenation/ethylenation/homologation with (methoxymethyl)triphenylphosphonium chloride, followed by cyclopropanation, demethylation, Williamson etherification with 3‐chloro‐2‐(chloromethyl)prop‐1‐ene, and Katsuki–Sharpless oxidation. The odor thresholds of the target structures 27 , 32 , and 39 , which are all floral‐green lily‐of‐the‐valley odorants, lie in the range of that of Lilial ( 1 ), with the 6‐cyclopropyl derivative 27 being the most potent (th 0.065 ng/l air). Particularly impressive was the close resemblance of the 6‐(cyclopropylmethyl) derivative 39 with Bourgeonal ( 3 ), which was rationalized by a superposition analysis.     

Green chemistry: state of the art through an analysis of the literature

Abstract

The literature of green chemistry has undergone a dramatic increase in the new millennium. Besides that, in ad hoc journals, papers of this type are published in journals of general, organic, and catalytic chemistry. The high proportion of communications within this area indicates that this is a hot topic. These reports mainly concern more environment-friendly synthetic methods, based on better catalytic systems, less harmful solvents and, more rarely, “alternative” physical techniques. Although the compliance with the green chemistry postulates is still partial, a trend in this direction is recognizable. For example, the number of preparative papers that introduce an environmental assessment is rapidly increasing.     

Uncatalyzed Hydroamination of Electrophilic Organometallic Alkynes: Fundamental,Theoretical, and Applied Aspects

Simple reactions of the most used functional groups allowing two molecular fragments to link under mild, sustainable conditions are among the crucial tools of molecular chemistry with multiple applications in materials science, nanomedicine, and organic synthesis as already exemplified by peptide synthesis and “click” chemistry. We are concerned with redox organometallic compounds that can potentially be used as biosensors and redox catalysts and report an uncatalyzed reaction between primary and secondary amines with organometallic electrophilic alkynes that is free of side products and fully “green”. A strategy is first proposed to synthesize alkynyl organometallic precursors upon addition of electrophilic aromatic ligands of cationic complexes followed by endo hydride abstraction. Electrophilic alkynylated cyclopentadienyl or arene ligands of Fe, Ru, and Co complexes subsequently react with amines to yield trans‐enamines that are conjugated with the organometallic group. The difference in reactivities of the various complexes is rationalized from the two‐step reaction mechanism that was elucidated through DFT calculations. Applications are illustrated by the facile reaction of ethynylcobalticenium hexafluorophosphate with aminated silica nanoparticles. Spectroscopic, nonlinear‐optical and electrochemical data, as well as DFT and TDDFT calculations, indicate a strong push–pull conjugation in these cobalticenium– and Fe– and Ru–arene–enamine complexes due to planarity or near‐planarity between the organometallic and trans‐enamine groups involving fulvalene iminium and cyclohexadienylidene iminium mesomeric forms.     

Strain‐Promoted Cycloaddition of Cyclopropenes with o‐Quinones: A Rapid Click Reaction

Novel click reactions are of continued interest in fields as diverse as bio‐conjugation, polymer science and surface chemistry. Qualification as a proper “click” reaction requires stringent criteria, including fast kinetics and high conversion, to be met. Herein, we report a novel strain‐promoted cycloaddition between cyclopropenes and o‐quinones in solution and on a surface. We demonstrate the “click character” of the reaction in solution and on surfaces for both monolayer and polymer brush functionalization.     

Damit Blut nicht verklumpt

Inhibitors of platelet aggregation (“anti‐platelets”) constitute a remarkably heterogeneous family of drugs, with regard to both chemistry and biochemistry. The rather uncommon diversity and the continuing search for new anti‐platelet drugs results from the particular requirements: high efficacy associated with good tolerability especially during long‐term treatment, marginal side effects and easy administration. Sophisticated structural modifications to lead compounds are employed to meet these requirements and improve bio‐availability and efficacy. While thromboxane synthesis and ADP receptors are currently the most prominent targets of anti‐platelet drugs, a number of other promising targets are now evaluated and new drugs are on the verge.     

New Vistas in N‐Heterocyclic Silylene (NHSi) Transition‐Metal Coordination Chemistry: Syntheses,Structures and Reactivity towards Activation of Small Molecules

This account is a review on the synthesis and transition‐metal coordination chemistry of N‐heterocyclic silylenes (NHSi’s) over the last 20 years till the present time (2012). Recently, fascinating and novel synthetic methods have been developed to access transition‐metal–NHSi complexes as an emerging class of compounds with a wealth of intriguing reactivity patterns. The striking influence of coordinating NHSi’s to transition‐metal complex fragments affording different reactivities to the “free” NHSi is a connecting theme (“leitmotif”) throughout the review, and highlights the potential of these compounds which lie at the interface of contemporary main‐group and classical organometallic chemistry towards new molecular catalysts for small‐molecule activation.     

Synthesis of High‐Mannose Oligosaccharide Analogues through Click Chemistry: True Functional Mimics of Their Natural Counterparts Against Lectins?

Terminal “high‐mannose oligosaccharides” are involved in a broad range of biological and pathological processes, from sperm‐egg fusion to influenza and human immunodeficiency virus infections. In spite of many efforts, their synthesis continues to be very challenging and actually represents a major bottleneck in the field. Whereas multivalent presentation of mannopyranosyl motifs onto a variety of scaffolds has proven to be a successful way to interfere in recognition processes involving high‐mannose oligosaccharides, such constructs fail at reproducing the subtle differences in affinity towards the variety of protein receptors (lectins) and antibodies susceptible to binding to the natural ligands. Here we report a family of functional high‐mannose oligosaccharide mimics that reproduce not only the terminal mannopyranosyl display, but also the core structure and the branching pattern, by replacing some inner mannopyranosyl units with triazole rings. Such molecular design can be implemented by exploiting “click” ligation strategies, resulting in a substantial reduction of synthetic cost. The binding affinities of the new “click” high‐mannose oligosaccharide mimics towards two mannose specific lectins, namely the plant lectin concanavalin A (ConA) and the human macrophage mannose receptor (rhMMR), have been studied by enzyme‐linked lectin assays and found to follow identical trends to those observed for the natural oligosaccharide counterparts. Calorimetric determinations against ConA, and X‐ray structural data support the conclusion that these compounds are not just another family of multivalent mannosides, but real “structural mimics” of the high‐mannose oligosaccharides.     

A novel approach to tag and identify geranylgeranylated proteins

A recently developed proteomic strategy, the “GG‐azide”‐labeling approach, is described for the detection and proteomic analysis of geranylgeranylated proteins. This approach involves metabolic incorporation of a synthetic azido‐geranylgeranyl analog and chemoselective derivatization of azido‐geranylgeranyl‐modified proteins by the “click” chemistry, using a tetramethylrhodamine‐alkyne. The resulting conjugated proteins can be separated by 1‐D or 2‐D and pH fractionation, and detected by fluorescence imaging. This method is compatible with downstream LC‐MS/MS analysis. Proteomic analysis of conjugated proteins by this approach identified several known geranylgeranylated proteins as well as Rap2c, a novel member of the Ras family. Furthermore, prenylation of progerin in mouse embryonic fibroblast cells was examined using this approach, demonstrating that this strategy can be used to study prenylation of specific proteins. The “GG‐azide”‐labeling approach provides a new tool for the detection and proteomic analysis of geranylgeranylated proteins, and it can readily be extended to other post‐translational modifications.