Sniffing Out the Sustainable Future: The Renewability Revolution in Fragrance Chemistry.

In this review, the impact of the transition from today's resource-wasting petrochemical economy towards a 100/100 renewable and biodegradable future is discussed with respect to the fragrance families: "citrus", "green", "fruity", "floral", "floriental", "oriental", "woody", "chypre" and "fougère". After benchmark data on ingredients usage, definitions on biodegradation and sustainability are given. Celebrating the 150th anniversary of synthetic vanillin, its historic synthesis from renewable starting materials serves as introduction. In the grand scheme of things, citrus scents upcycled from the beverages industry, are already an ideal case for 100/100 with new opportunities for artificial essential oils. In the fruity domain, transparent and lactonic ingredients are available in a sustainable manner. However, in the domain of green odorants, there is a lack of green chemistry for important key materials. In the floral family, renewability is more critical than biodegradability, but cost is an issue. Thanks to Ambrox and maltol, florientals and orientals will persist, while woody notes severely lack an Iso E Super replacer. In the chypre genre, patchouli became the new moss, but more musks are increasingly in demand. With their high percentage of linalool and dihydromyrcenol, the construction of fougères could well become a precedent for other families, despite challenges in vetiver and salicylates. Still, the challenges exemplified here create immense opportunities for new perfumery materials.

The Smelling Principle of Vetiver Oil, Unveiled by Chemical Synthesis.

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.

What's Hot, What's Not: The Trends of the Past 20 Years in the Chemistry of Odorants.

This review is the sequel to the 2000 report on the recent advances in the chemistry of odorants and it summarizes the developments in fragrance chemistry over the past 20 years. Following the olfactory spectrum set out in that report, trendsetting so-called captive odorants (patent-protected ingredients unavailable to the market) are presented according to the main odor families: "fruity", "marine", "green", "floral", "spicy", "woody", "amber", and "musky". The design of odorants, their chemical synthesis, and their use in modern perfumery are illustrated with prominent examples. Featured are new fruity odorants that provide signature in the top note, as well as precursor technology. In the green domain, focus is on leafy notes and green pear. New benzodioxepines and benzodioxoles have modernized the marine family and required a revision of the existing olfactophore models. The replacement of Lilial and Lyral kept the industry busy in the floral domain with a plethora of new "muguets". There was continued activity in the domain of rose odorants, especially in the area of rose ketones. Biotechnology became significant, for example, with Clearwood and Ambrofix, and the principal odorants of vetiver oil in the woody family have been found. Fourth and fifth families of musk odorants were also discovered and populated. Thus, new avenues for further explorations into fragrance chemistry have been opened.

The Serendipitous Discovery of a Rose Odorant.

Serendipity has played a role in many groundbreaking scientific discoveries. Key to their identification and exploitation is the ability to recognize the unexpected and invest time trying to understand it. Like any other field of scientific research, total synthesis requires determination and perseverance. When the first-generation route towards a target compound fails, new approaches are developed based on insights gained in the initial studies. Careful analysis of data obtained in a 'failed' approach, e.g. when a reaction did not yield the desired or any expected outcome, can lead to spectacularly improved routes and discoveries that have impact beyond the synthesis of the selected target compound. Serendipity has further led to the identification of intriguing properties that materials or single molecules have, as exemplified by the discovery of electrically conductive polymers. During our total synthesis endeavors towards a complex natural product, we identified a small molecule with interesting olfactory properties, which we decided to investigate further.

Evidence for a shape-based recognition of odorants in vivo in the human nose from an analysis of the molecular mechanism of lily-of-the-valley odorants detection in the Lilial and Bourgeonal family using the C/Si/Ge/Sn switch strategy.

We performed an analysis of possible mechanisms of ligand recognition in the human nose. The analysis is based on in vivo odor threshold determination and in vitro Ca2+ imaging assays with a C/Si/Ge/Sn switch strategy applied to the compounds Lilial and Bourgeonal, to differentiate between different molecular mechanisms of odorant detection. Our results suggest that odorant detection under threshold conditions is mainly based on the molecular shape, i.e. the van der Waals surface, and electrostatics of the odorants. Furthermore, we show that a single olfactory receptor type is responsible for odor detection of Bourgeonal at the threshold level in humans in vivo. Carrying out a QM analysis of vibrational energies contained in the odorants, there is no evidence for a vibration-based recognition.

Synthesis and Olfactory Properties of a 6'-Silasubstituted "Spiro[4.5]-δ-Damascone".

The silicon analogue of the potent spirocyclic δ-damascone odorant 6 was synthesized from allyltrichlorosilane (15) and but-2-en-1-ol (16). The latter was transformed to 3-methylpen-4-enenitrile (11) by Saucy-Marbet reaction with ethoxyethane and subsequent treatment with HONH2 ⋅HCl. The resulting γ,δ-unsaturated nitrile 11 was silylated with 1-allyl-1-chlorosilolane (14), which was prepared from allyltrichlorosilane (15) and the bis-Grignard reagent of 1,4-dichlorobutane. Metathetic ring closure employing the Grubbs I catalyst, followed by DIBAL reduction with non-aqueous work up, Grignard reaction with prop-1-en-1-ylmagnesium bromide, and Attenburrow MnO2 oxidation concluded the synthesis. The target compound was found to be olfactorily related to the spiro[4.5]-δ-damascone lead, but approximately 900 times weaker. In a type of enol Brook rearrangement, it thermally decomposes however to 3,6-dihydro-2H-1,2-oxasilocine (20), which surprisingly is a damascone odorant as well; although, 12 000 times weaker.

Design and enantioselective synthesis of Cashmeran odorants by using "enol catalysis".

Novel Cashmeran odorants were designed by molecular modeling. Their short syntheses involve a novel asymmetric Brønsted acid catalyzed Michael addition of unactivated α-substituted ketones. This key transformation was realized by utilizing a new type of enol activation catalysis and affords different cyclic ketones bearing α-quaternary stereocenters in good to excellent yields and with high enantioselectivity. Subsequent McMurry coupling and Saegusa-Ito oxidation furnished the enantiopure target odorants, one enantiomer of which indeed possesses the typical olfactory aspects of Cashmeran.

Synthesis and olfactory characterization of silicon-containing derivatives of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal.

5-Methyl-4-methylidene-6-(trimethylsilyl)hexanal (1b), a sila analog of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal (1a), and the Si-containing derivatives 2-6 were prepared in multistep syntheses, starting from Cl3 SiH and Cl2 SiMe2 , respectively. Compounds 1b, 2-6, and their new precursors were characterized by elemental analyses (C, H, N) and NMR spectroscopic studies ((1) H, (13) C, (15) N, and (29) Si). To gain more information about the structureodor correlation in the family of lily-of-the-valley or 'muguet' odorants, C/Si analogs 1a/1b and derivatives 2-6 were evaluated for their olfactory properties.

From Cassyrane to cashmeran - the molecular parameters of odorants.

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.

Synthesis by ring-closing alkyne metathesis with selective hydrogenation, and olfactory comparison of (7E)- and (7Z)-cyclohexadec-7-enone (Aurelione(®) ).

Both C=C-bond isomers of cyclohexadec-7-enone (6, Aurelione(®) ) were selectively synthesized via cyclohexadec-7-ynol (16) by ring-closing alkyne metathesis of icosa-2,18-diyn-9-ol (15), employing an in situ-formed catalyst from Mo(CO)6 and 4-(trifluoromethyl)phenol. Pyridinium chlorochromate (PCC) oxidation and subsequent Lindlar hydrogenation afforded the (7Z)-configured isomer (7Z)-6, while hydrosilylation of the intermediate cyclohexadec-7-ynone (17), followed by desilylation, provided the (7E)-configured cyclohexadec-7-enone ((7E)-6). The substrate for the alkyne metathesis was prepared from cycloheptanone (7) by cycloaddition of chloromethylcarbene to its trimethylsilyl enol ether 8, and subsequent ring enlargement of the adduct 9 under rearrangement to 2-methylcyclooct-2-enone (10), which was subjected to Weitz-Scheffer epoxidation and Eschenmoser-Ohloff fragmentation to non-7-ynal (12). Its reaction with the Grignard reagent of 11-bromoundec-2-yne (14), prepared from the corresponding alcohol 13 by Appel-Lee bromination, furnished the icosa-2,18-diyn-9-ol (15). While both isomers of cyclohexadec-7-enone (6) possess warm and powdery musk odors with tobacco-type ambery accents, (7Z)-6 is more animalic and waxy, whereas (7E)-6 was found to be more floral, sweet, and hay-like in tonality. Interestingly, however, with odor detection thresholds of 2.0 ng/l air and 2.3 ng/l air, respectively, both (7Z)-6 and (7E)-6 were found to be almost identical in their odor strength, with the (7Z)-6 being only very slightly more powerful.

A novel oxy-oxonia(azonia)-cope reaction: serendipitous discovery and its application to the synthesis of macrocyclic musks.

This brief review, including new experimental results, is the summary of a talk at the GDCh conference 'flavors & fragrances 2013' in Leipzig, Germany, 11th-13th September, 2013. Musk odorants are indispensable in perfumery to lend sensuality to fine fragrances, a nourishing effect to cosmetics, and a comforting feeling to laundry. We have recently found serendipitously a new oxy-oxonia-Cope rearrangement. In this account, we review the background of oxonia-sigmatropic rearrangements and the discovery of this novel reaction. Special attention is focused on the versatile lactone and lactam formation reactions via [n+4] ring enlargement and the macrocyclization in the synthesis of new macrocyclic musks. The synthesized structures provide new insights into the structure-odor relationships of musks.

Disila-galaxolide and derivatives: synthesis and olfactory characterization of silicon-containing derivatives of the musk odorant galaxolide.

A series of silicon-containing derivatives of the polycyclic musk odorant galaxolide (4 a) was synthesized, that is, disila-galaxolide ((4RS,7SR)-4 b/(4RS,7RS)-4 b), its methylene derivative rac-9, and its nor analogue rac-10. The tricyclic title compounds with their 7,8-dihydro-6,8-disila-6 H-cyclopenta[g]isochromane skeleton were prepared in multistep syntheses by using a cobalt-catalyzed [2+2+2] cycloaddition of the mono- yne H2C=CHCH2 OCH2 C≡CB(pin) (B(pin)=4,4,5,5-tetramethyl-1,3,2-di- oxaborolan-2-yl) with the diynes H2C=C[Si(CH3 )2 C≡CH]2 or H2C- [Si(CH3)2 C≡CH]2 as the key step. Employing [Cr(CO)3 (MeCN)3 ] as an auxiliary, the disila-galaxolide diastereomers (4RS,7SR)-4 b and (4RS,7RS)-4 b could be chromatographically separated through their tricarbonylchromium(0) complexes, followed by oxidative decomplexation. The identity of the title compounds and their precursors was established by elemental analyses and multinuclear NMR spectroscopic studies and in some cases additionally by crystal structure analyses. Compounds (4RS,7SR)-4 b, (4RS,7RS)-4 b, rac-9, and rac-10 were characterized for their olfactory properties, including GC-olfactory studies of the racemic compounds on a chiral stationary phase. As for the parent galaxolide stereoisomers 4 a, only one enantiomer of the silicon compounds (4RS,7SR)-4 b, (4RS,7RS)-4 b, rac-9, and rac-10, smelt upon enantioselective GC-olfactometry, which according to the elution sequence is assumed to be also (4S)-configured as in the case of the galaxolide stereoisomers. The disila-analogues (4S,7R)-4 b and (4S,7S)-4 b were, however, about one order of magnitude less intense in terms of their odor threshold than their parent carbon compounds (4S,7R)-4 a and (4S,7S)-4 a. The introduction of a 7-methylene group in disila-galaxolide (4 b→rac-9) improved the odor threshold by a factor of two. With the novel silicon-containing galaxolide derivatives, the presumed hydrophobic bulk binding pocket of the corresponding musk receptor(s) could be characterized in more detail, which could be useful for the design of novel musk odorants with an improved environmental profile.

Novel silicon-based patchouli odorants of the trialkyl(1-hydroxy-1-methylethyl)silane type: design, synthesis, and olfactory properties.

tert-Butyl(1-hydroxy-1-methylethyl)dimethylsilane (5), a sila-substituted seco derivative of the recently reported patchouli lead structure (4aR*,8aR*)-1,1,8a-trimethyldecahydronaphthalene-4a-ol (4), and a number of related trialkyl(1-hydroxy-1-methylethyl)silanes and further derivatives, compounds 8-24, with different silicon-bound substituents (Me, Et, iPr, cPr, tBu, iBu, cPent, vinyl, SiMe(3)) were synthesized and studied for their olfactory properties. All of the silanes studied exhibit at least one of the main patchouli odor descriptors 'woody,' 'earthy,' and 'camphoraceous,' and some even exhibit all of them. The silanes MeR(2)SiC(OH)Me(2) (12) and R(3)SiC(OH)Me(2) (14) (R=cyclopropyl) were found to resemble natural patchouli oil most closely, with an even lower odor threshold than the natural lead structure (-)-patchoulol (1). To complete this structure-odor relationship study, the carbon analogues of 12 and 14 (Si/C exchange) were also prepared and characterized. Although they show similar olfactory properties to the silanes 12 and 14, the synthesis of the corresponding carbon analogues is far less straightforward than that of the silicon compounds, and only silanes 12 and 14 can be economically produced industrially.

Woody pretzels: spirocycles from vetiver to patchouli and Georgywood.

This review, including new experimental results, is the summary of a talk at the RSC/SCI conference 'flavours & fragrances 2007' in London, Imperial College, 24-26 September, 2007. Though the third dimension of the receptor models of J. E. Amoore rarely was exceeding 4 A, the world of woody odorants such as (+)-cedrol (3; cedarwood), (-)-khusimone (4; vetiver), and (-)-patchoulol (5; patchouli) is anything but flat. Any tricyclic skeleton with a zero-bridge contains a spirocyclic ring system determining its 3D structure, so spirocycles (spira, Lat. pretzel) are the fastest access to the third dimension. In the vetiver family, a spirocyclic mimic 9 of (-)-khusimone (4) was first discovered by chance by Büchi in 1976, and also by chance, we obtained another system, 12, with a characteristic vetiver smell by tandem-Rupe-Nazarov reaction of alkyne diols. A 5-A distance between a quaternary C-atom and a carbonyl group (or alternative HB acceptor) with an alpha-methyl or methylene branching is proposed to be the key to their vetiver odor. Upon scale-up of one of these odorants, 24, we discovered a very powerful (0.067 ng/l) impurity with a most typical patchouli scent: the spirocyclic, sterically crowded hydroxy ketone 33--a most unusual structure for a patchouli odorant. Several spirocyclic hydroxy ketone analogs, also with inverted ring systems such as in 70 and 84, provided new insights into the structure-odor correlation of this family. A superposition analysis indicated the carbonyl function of the hydroxy ketone to overlay on the geminal dimethyl motive of (-)-patchoulol. And indeed, the corresponding hydroxy ketone of patchoulol, 59, synthesized in 13 steps from Cyclal C (63), also emanated a patchouli odor. Finally, the synthesis and olfactory properties of twelve rigid spirocyclic analogs, 95-97, 99-102, and 106-110, of Georgywood (91) are presented that highlight stereochemical requirements for woody odorants and raise doubts about an alpha-helical binding motive postulated by Hong and Corey.

Disila-okoumal: a silicon analogue of the ambergris odorant okoumal.

Two-fold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaphthalene skeleton of the ambery odorant okoumal (5) provides disila-okoumal (6). The okoumal isomers 5 a-d were synthesized from 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethanone (7), and the silicon analogues 6 a-d were synthesized from 1-(5,5,8,8-tetramethyl-5,8-disila-5,6,7,8-tetrahydro-2-naphthyl)ethanone (8). Detailed olfactory properties of 5 a-d and 6 a-d are reported, together with the respective threshold values. All enantiomers of okoumal and disila-okoumal exhibit typical ambery odor notes with woody facets, as is characteristic of okoumal and karanal, but a stereocenter at the 2-position was found to be of utmost importance for the odor thresholds; the lowest value of 0.31 ng per L air was measured for the 2R-configured silicon compounds 6 a and 6 c.