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The Search for New Amber Ingredients by Anubhav P. S. Narula International Flavors & Fragrances, 1515 Highway 36, Union Beach, New Jersey 07735, USA (e-mail: [email protected])

There is a constant need for developing new fragrance ingredients in the flavor and fragrance industry, as it allows perfumers to create unique and differentiating perfumes for fine as well as functional products. Among all the categories of notes used in perfume creation, amber notes are indispensible and ubiquitous in their presence in all perfumes. Not only amber notes impart high performance and substantivity to fragrances, but they are paramount in the development of classic and legendary fragrances. This article is based on the plenary lecture delivered at the flavor & fragrance 2013 conference of the German Chemical Society in Leipzig, Germany. The strategy, rationale, and the various synthetic approaches that led to the discovery of two new very powerful, woody, amber materials, Amber Xtreme (1) and Trisamber (2), are delineated.

Introduction. – This article provides a brief overview of our ongoing efforts and pursuits at International Flavors & Fragrances (IFF) in quest of new molecules 1) with superior performance, and unique and differentiating olfactory properties. Since the dawn of perfumery, ambergris [2] and amber odorants have played a key role in perfumes. Indeed, amber molecules have become indispensible to the performance of perfumes and are present ubiquitously in both fine and functional fragrances. There is a wide diversity when it comes to structural motifs of amber odorants [3]. Therefore, finding a new amber odorant has become not only an arduous task but a challenge, because the new amber odorant discovered must beat the performance and hedonics of existing benchmarks. After an intensive search and in-depth investigation spanning over years, we were able to discover and commercialize Amber Xtreme (1) and Trisamber (2), two new amber molecules [4] [5] (Fig. 1), which belong to a completely new class of structural backbone. Further, these two amber molecules were found to beat the performance and hedonics of several key benchmark amber odorants that are much appreciated in the flavor and fragrance arena. Indeed Amber Xtreme and Trisamber belong to the most powerful amber odorants known when compared to existing amber notes in terms of the strength and intensity. Results and Discussion. – Our investigation began with a simple idea in quest for an Ambrox-related structure. Ambrox (3) is not only used in multi-ton quantities in perfume industry but has been prized for its performance and odor since its inception. A perusal of the structure of ( )-Ambrox (3, Fig. 1) reveals that it has a tricyclic ring motif with a five-membered tetrahydrofuran THF ring attached to a methylated 1)

For Part 1, see [1].  2014 Verlag Helvetica Chimica Acta AG, Zrich

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Fig. 1. Structures of the new proprietary amber ingredients 1 and 2 vs. Ambrox (3)

decalin skeleton. As another feature, it has a well-defined trans-configuration among the three fused rings. This trans-rearrangement of rings and axial configuration of the three Me is the key to low threshold of ( )-Ambrox (3). A few subtle changes in configuration of rings or the addition or loss of certain Me groups configuration, makes its performance less interesting in odor or even odorless [6] in some cases. Keeping these facts in mind about the configurational requirements for amber odor, we began our investigation. Rationale. Our strategy was based on the fact that g,d-unsaturated ketones are commonly found as green, galbanum perfumery ingredients 2 ) such as Galbaniff, allyl Herbac, Hexalon, and Galbascone. Furthermore, the g,d-unsaturated ketone functionality can be easily prepared by Claisen rearrangement [7] of ketones with either allylic or methallyic alcohols, or by the mono-alkylation of ketones with allyl or methallyl chloride under basic or phase-transfer conditions. Therefore, it was envisioned, from the structure odor relationship point of view, that if one could develop a methodology for converting a g,d-unsaturated ketone to terahydrofuran moiety, then a green odorant might turn into an amber odorant. To test this idea, we started our investigation with the readily available allyl Herbac (4) and Galbaniff (5) and reduced them with LiAlH4 to the corresponding alcohols 6 and 7, and subjected them to cyclization with MsOH in MeNO2 , which gave the corresponding desired ethers 8 and 9, respectively. This transformation is outlined in Scheme 1. As expected, the odor of these new THF derivatives turned from green, galbanum to amber, woody. Encouraged by this finding, we embarked on an investigation program to prepare various acyclic, cyclic, bicyclic and tricyclic THF derivatives starting with diverse skeletons, hoping to find a new amber note. Preparation and Odor Evaluation of Bicyclic and Monocyclic THF Derivatives by a Novel Methodology. Following the novel methodology developed and described in Scheme 1, we prepared the THF-derivatives 10, 11, 12, and 13 from the corresponding allyl or methallyl ketones intermediates, which were derived from cyclooctanone, 14, cyclododecanone, 15, and Orivone 16 backbones. The odor descriptors of many of these novel bicyclic THF derivatives 10, 11, 12, and 13, and the acyclic THF derivatives 17 – 24 are given in Scheme 2 and Fig. 2. Many of these new THF derivatives had odor descriptors ranging from weak woody, ambery, green, to minty. These novel compounds were part of the initial structure odor correlation exercise; we explored to refine our 2)

Registered fragrance ingredients of International Flavors and Fragrances Inc.

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Scheme 1. Cyclization of Allyl Herbac and Galbaniff to the THF Derivatives 8 and 9

Scheme 2

hypothesis, and thus chose skeletons/backbones for continued research in structure odor activity relationships that might ultimately lead to structural motifs with superior hedonics and performance that would be better than existing ingredients. Synthesis of Novel Amber Structures or Oxabicyclooctanes Prepared from the Campholenic Skeleton. Since many sandalwood ingredients 3 ) [7] such as Bacdanol, Polysantol, Santaliff, Ebanol, and Javanol, and cassis molecule like Cassiffix [8] [9] are widely used in perfumery, and were conceived from a campholenic skeleton, 3)

Bacdanol and Santaliff are registered fragrance ingredients of International Flavors and Fragrances Inc., while Ebanol and Javanol are registered fragrance ingredients of Givaudan SA. Polysantol is a registered fragrance ingredient of Firmenich SA.

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Fig. 2. Odor descriptions of the THF derivatives 17 – 24

we attempted to prepare a few novel ethers from campholenic aldehyde (25). Hence, we prepared several oxabicyclooctane derivatives [10] as depicted in Scheme 3 by a multi-step synthesis starting from dihydrocampholenic aldehyde (26). The preparation of these novel compounds 30 – 34 involved a thermal Diels Alder reaction of a-methylidene dihydrocampholenic aldehyde, 27, with dienes such as Scheme 3. Oxabicyclooctanes from Dihydrocampholenic Aldehydes

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butadiene, isoprene; and 2,3-dimethylbutadiene, respectively; followed by reduction of the aldehydic Diels Alder adducts to the corresponding alcohols using LiAlH4 . On cyclization with MsOH, these alcoholic adducts furnished the bicyclooxaoctanes 30 and 31 (ex butadiene), 32 and 33 (ex isoprene), and 34 (ex dimethylbutadiene). The oxabicylooctanes 30 and 31 (ex butadine) smelled ambery, woody, musky, tobacco, whereas the oxabicylooctanes 32 and 33 (ex isoprene) possessed a very ambery, woody odor with an ionone feeling. In addition, the oxabicyclooctane 34 (ex dimethylbutadiene) also smelled dry, woody, and ambery with fruity aspects. It is worth mentioning that we also prepared 32 and 33 by Pd/C-catalyzed hydrogenation of Cassiffix (35) as outlined in Scheme 4. It was interesting to note that a cassis odorant became an amber odorant. Scheme 4. Dihydro-Cassiffix by Hydrogenation of Cassiffix

Synthesis of Alkyl- and Aryl-substituted Oxabicyclooctanes ex Campholenic Aldehyde. Inspired by the above structure odor relationships, and encouraged by the ambery smell of oxabicyclooctanes 30 – 34, we conceived a synthetic route to another class of alkyl- and aryl-substituted cyclopenta[b]furan derivatives [11] from campholenic aldehyde as delineated in Scheme 5. These THF derivatives were prepared in two steps by the addition of appropriately substituted Grignard reagent, derived from methyl, propyl, phenyl, benzyl, and 2-phenylethyl bromide, respectively, to 25 to afford the corresponding alcohols [12] , followed by cyclization with MsOH to the substituted cyclopenta[b]furan derivatives 37, 38, and 39 (cf. Scheme 5 for odor descriptions). Scheme 5. Novel (Arylalkyl)- and Alkyl-cyclopenta[b]furans from Campholenic Aldehyde (25)

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Unfortunately, this type of substituted cyclopenta[b]furan compounds did not possess any amber odor qualities; therefore, we turned our attention to building THF derivatives from isolongifolane, cedrane, and pentamethylindane skeletons. THF Derivatives from the Isolongifolane Skeleton. Several amber molecules 4 ) used in perfumery are based on the isolongifolene (40) skeleton. In particular Piconia 41 and the recently discovered Ambermax [13] stand out for their hedonics. Therefore, we extended our standard methodology of THF-derivatives formation to Piconia and prepared 44 and 45 (Scheme 6) via ally- and methallyl-Piconia, 42 and 43. respectively. Both these compounds showed weak, woody ambery notes. THF Derivatives from the Cedrane Skeleton. Since many important fragrance ingredients 5 ) such as Cedramber, Vertofix, Cedryl Methyl Ketone, Andrane, and Ambrocenide feature a cedrane backbone, we turned our efforts next to THP ethers 46 starting with cedrone (48), which is available from Andrane (49). Cedrone (48) was alkylated with allyl and methallyl bromide using NaH to give allyl cedrone (50) and methallyl cedrone (51), which, on reduction with LiAlH4 (LAH) followed by cyclization with MsOH, gave the desired cedrane THF derivatives 46 and 47 as depicted in (Scheme 7). As expected, compound 47 [14] smelled very strong, ambery, and woody, thus corroborating our hypothesis for the search of new amber odorants. Discovery of Amber Xtreme and Trisamber. THF Derivatives from Pentamethylindane Skeleton. Having gained insight and inspiration from our structure odor relationship studies thus far, we targeted the design of the THF derivative 2 (Trisamber ) with a Cashmeran backbone. This effort was based on several considerations with regard to pentamethylindane skeleton. First, the pentamethylindane skeleton was the basis for the invention of such iconic and widely used fragrance ingredients 6 ) as Cashmeran (52) and Galaxolide, and, second, our modeling studies carried out for 2 in comparison to Ambrox (3) revealed a nearly perfect fit. Hence, by using our standard methodology, dihydro-Cashmeran (53) was subjected to Claisen rearrangement with allylic alcohol which to provide allyl-dihydro-Cashmeran (54) in good yield. This, on reduction with LiAlH4 , furnished g,d-unsaturated alcohol 55 in Scheme 6

4) 5) 6)

Piconia is a registered fragrance ingredient of International Flavors and Fragrances Inc. Cedramber, Vertofix, and Andrane are registered fragrance ingredients of International Flavors and Fragrances Inc., while Ambrocenide is a registered fragrance ingredient of Symrise. Galaxolide and Cashmeran is a registered fragrance ingredient of International Flavors and Fragrances Inc.

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Scheme 7

high yield. Cyclization of 55 gave 2 (Scheme 8). On perfumery evaluation, compound 2 was found to have a very strong, ambery, woody odor. The performance and hedonics of 2 in many functional and fine fragrance applications was superior to several existing amber ingredients in the IFF perfumery catalog. Therefore, compound 2 was recommended for commercialization and subsequently trademarked as Trisamber [5]. Discovery of Amber Xtreme or Methyl Trisamber (1). A few years after the commercialization of Trisamber (2), just as a curiosity motivated by the structure odor relationship perspective, we envisaged the synthesis of methyl-Trisamber Scheme 8. Route to Trisamber (2) from Cashmeran (52)

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Scheme 9. Route to Amber Xtreme (1) from Cashmeran (52)

(1), enouraged by the fact that there are many examples 7 ) in the literature [15] where incorporation of an additional Me group increases the intensity and performance 2 – 3 times over the parent compounds. Hence, by applying the same methodology described before, methyl-Trisamber was prepared as outlined in Scheme 9. First, dihydroCashmeran (53) was converted to dihydro-methallyl-Cashmeran (56) by Claisen rearrangement with methallyl alcohol, followed by reduction with LiAlH4 to the corresponding dihydro-methally-Cashmeran alcohol (57), which, on cyclization with MsOH, furnished Amber Xtreme (1). To our delight and amazement, methyl-Trisamber was not only found to have a 2 – 3 times more powerful odor than Trisamber (2), but its performance in functional and fine fragrance perfumery applications was even superior to that of Trisamber (2). In consequence, it was introduced to perfumery as Amber Xtreme (1). Lastly, it is worth mentioning here that Amber Xtreme is primarily a mixture of two isomers: the cisisomer 58 and the trans-isomer 59 (Fig. 3). Subsequently, based on in-depth perfumery

Fig. 3. Odor differences of the Amber Xtreme isomers 7)

Linalool vs. ethyl linalool, maltol vs. ethyl maltol, vanillin vs. ethyl vanillin.

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experiments, it was uncovered that the most powerful and major odor-donating amber component in Amber Xtreme [4] is the cis-isomer 58. Miscellaneous Structures Obtained in Search for Novel Amber Odorants. Before concluding this article, we would point out that, in our quest for new amber odorants we also prepared the tertiary alcohols 60 – 63 and derivatives such as the tertiary acetate 64 [16], along with several enol ethers like 65 and 66 [17], and several tertiary methyl ethers such as 67, starting from well-known fragrance ingredients with carbonyl functions like dihydro-Cashmeran (53), Piconia (41), and Iso E Super 8 ). This part of our research efforts was also presented at the Leipzig meeting. The majority of these new compounds were found to have woody, ambery smells as delineated in Fig. 4. It is worth mentioning here that the best known tertiary alcohol with amber, ambergris odor is the naturally occurring Ambrinol (68).

Fig. 4. Odor descriptions of the THF derivatives 60 – 66

Conclusions. – This account has provided just a glimpse into IFFs relentless research efforts expended in the discovery of Amber Xtreme (1) and Trisamber (2), two new captive materials with a powerful amber, woody odor. Invention of Amber Xtreme, and Trisamber also represents a triumph of structure odor relationship 8)

Iso E Super is a registered fragrance ingredient of International Flavors and Fragrances Inc.

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reasoning and modeling approach applied in the successful quest of new, differentiating molecules. The author wishes to acknowledge his colleagues at IFF, whose names are cited in the following references, for their dedicated synthetic work, and several renowned perfumers for their expert fragrance evaluations of the new chemicals disclosed in this article. IFFs commitment to introduce new differentiating fragrance molecules for sensorial pleasure of perfumers, customers, and consumers everywhere is deeply appreciated.

REFERENCES [1] A. P. S. Narula, Chem. Biodiversity, 2004, 1, 1992. [2] G. Ohloff, W. Pickenhagen, P. Kraft, 8. Odorants of Animal Origin, in Scent and Chemistry – The Molecular World of Odors, Verlag Helvetica Chimica Acta, Zrich, Wiley-VCH, Weinheim, 2012, p. 364. [3] G. Ohloff, W. Pickenhagen, P. Kraft, 3. Structure Odor Relationships , in  Scent and Chemistry – The Molecular World of Odors, Verlag Helvetica Chimica Acta, Zurich, Wiley-VCH, Weinheim, 2012, p. 97. [4] A. P. S. Narula, E. M. Arruda, to International Flavors & Fragrances, Inc., U.S. Pat. 7,312,187 (Chem. Abstr. 2004, 141, 38754). [5] A. P. S. Narula, E. M. Arruda, A. T. Levorse Jr., C. E. J. Beck, to International Flavors & Fragrances, Inc., U.S. Pat. 7,160,852 (Chem. Abstr. 2004, 141, 38754). [6] G. Ohloff, W. Giersch, W. Pickenhagen, A. Furrer, B. Frei, Helv. Chim. Acta 1985, 68, 2022. [7] M. Hiersemann, U. Nubbemeyer, The Claisen Rearrangement, Wiley-VCH, Weinheim, 2007. [8] A. P. S. Narula, J. D. De Virgilio, C. Benaim, A. V. Ouwerkerk, O. Gillotin, to International Flavors & Fragrances, Inc., U.S. Pat. 5,087,707 (Chem. Abstr. 1992, 116, 152090). [9] A. P. S. Narula, J. D. De Virgilio, C. Benaim, A. V. Ouwerkerk, O. Gillotin, to International Flavors & Fragrances, Inc., U.S. Pat. 5,070,073 (Chem. Abstr. 1992, 116, 129322). [10] A. P. S. Narula, J. D. De Virgilio, F. T. Schiet, C. E. J. Beck, C. J. Vinals, M. R. Hanna, to International Flavors & Fragrances, Inc., U.S. Pat. 5,240,907 (Chem. Abstr. 1994, 120, 133913). [11] A. P. S. Narula, J. D. De Virgilio, to International Flavors & Fragrances, Inc., US Pat. 5,281,576 (Chem. Abstr. 1994, 120, 200194). [12] A. P. S. Narula, J. D. De Virgilio, to International Flavors & Fragrances, Inc., U.S. Pat. 5,276,211 (Chem. Abstr. 1994, 120, 245555). [13] J. A. Bajgrowicz, I. Frank, to Givaudan SA, PCT Int. Appl. WO 2007,030,963, 2007 (Chem. Abstr. 2007, 146, 359009). [14] A. P. S. Narula, E. M. Arruda, A. J. Janczuk, to International Flavors & Fragrances, Inc., U.S. Pat. 7,419,943 (Chem. Abstr. 2006, 144, 260129). [15] G. Ohloff, W. Pickenhagen, P. Kraft, 3. Structure Odor Relationships, in Scent and Chemistry – The Molecular World of Odors, Verlag Helvetica Chimica Acta, Zrich, Wiley-VCH, Weinheim, 2012, p. 61. [16] A. P. S. Narula, J. J. Koestler, M. R. Hanna, H. Hattab, F. C. A. Thibaudea, C. E. J. Beck, to International Flavors & Fragrances, Inc., U.S. Pat. 5,733,866 (Chem. Abstr. 1998, 128, 221473). [17] A. P. S. Narula, J. J. Koestler, P. J. Hartong, M. R. Hanna, C. E. J. Beck, to International Flavors & Fragrances, Inc., U.S. Pat. 7,665,698 (Chem. Abstr. 1997, 127, 253001). Received December 24, 2013

The search for new amber ingredients.

There is a constant need for developing new fragrance ingredients in the flavor and fragrance industry, as it allows perfumers to create unique and di...
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