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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 fragranceindustry, as it allows perfumers to create unique and differentiating perfumes for fine as well as functionalproducts. Among all the categories of notes used in perfume creation, amber notes are indispensible andubiquitous in their presence in all perfumes. Not only amber notes impart high performance andsubstantivity to fragrances, but they are paramount in the development of classic and legendaryfragrances. This article is based on the plenary lecture delivered at the flavor & fragrance 2013 conferenceof the German Chemical Society in Leipzig, Germany. The strategy, rationale, and the various syntheticapproaches 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 andpursuits at International Flavors & Fragrances (IFF) in quest of new molecules1) withsuperior performance, and unique and differentiating olfactory properties. Since thedawn of perfumery, ambergris [2] and amber odorants have played a key role inperfumes. Indeed, amber molecules have become indispensible to the performance ofperfumes and are present ubiquitously in both fine and functional fragrances. There is awide 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 ofexisting benchmarks. After an intensive search and in-depth investigation spanningover years, we were able to discover and commercialize Amber Xtreme� (1) andTrisamber� (2), two new amber molecules [4] [5] (Fig. 1), which belong to a completelynew class of structural backbone. Further, these two amber molecules were found tobeat the performance and hedonics of several key benchmark amber odorants that aremuch appreciated in the flavor and fragrance arena. Indeed Amber Xtreme� andTrisamber� belong to the most powerful amber odorants known when compared toexisting amber notes in terms of the strength and intensity.

Results and Discussion. – Our investigation began with a simple idea in quest for anAmbrox�-related structure. Ambrox� (3) is not only used in multi-ton quantities inperfume 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 ringmotif with a five-membered tetrahydrofuran THF ring attached to a methylated

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 1629

� 2014 Verlag Helvetica Chimica Acta AG, Z�rich

1) For Part 1, see [1].

decalin skeleton. As another feature, it has a well-defined trans-configuration amongthe three fused rings. This trans-rearrangement of rings and axial configuration of thethree Me is the key to low threshold of (�)-Ambrox� (3). A few subtle changes inconfiguration of rings or the addition or loss of certain Me groups configuration, makesits performance less interesting in odor or even odorless [6] in some cases. Keepingthese facts in mind about the configurational requirements for amber odor, we beganour investigation.

Rationale. Our strategy was based on the fact that g,d-unsaturated ketones arecommonly found as green, galbanum perfumery ingredients2) such as Galbaniff�, allylHerbac�, Hexalon�, and Galbascone�. Furthermore, the g,d-unsaturated ketonefunctionality can be easily prepared by Claisen rearrangement [7] of ketones witheither allylic or methallyic alcohols, or by the mono-alkylation of ketones with allyl ormethallyl chloride under basic or phase-transfer conditions. Therefore, it wasenvisioned, from the structure�odor relationship point of view, that if one coulddevelop a methodology for converting a g,d-unsaturated ketone to terahydrofuranmoiety, then a green odorant might turn into an amber odorant.

To test this idea, we started our investigation with the readily available allylHerbac� (4) and Galbaniff� (5) and reduced them with LiAlH4 to the correspondingalcohols 6 and 7, and subjected them to cyclization with MsOH in MeNO2, which gavethe corresponding desired ethers 8 and 9, respectively. This transformation is outlinedin 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 aninvestigation program to prepare various acyclic, cyclic, bicyclic and tricyclic THFderivatives starting with diverse skeletons, hoping to find a new amber note.

Preparation and Odor Evaluation of Bicyclic and Monocyclic THF Derivatives by aNovel Methodology. Following the novel methodology developed and described inScheme 1, we prepared the THF-derivatives 10, 11, 12, and 13 from the correspondingallyl or methallyl ketones intermediates, which were derived from cyclooctanone, 14,cyclododecanone, 15, and Orivone� 16 backbones. The odor descriptors of many ofthese novel bicyclic THF derivatives 10, 11, 12, and 13, and the acyclic THF derivatives17– 24 are given in Scheme 2 and Fig. 2. Many of these new THF derivatives had odordescriptors ranging from weak woody, ambery, green, to minty. These novel compoundswere part of the initial structure�odor correlation exercise; we explored to refine our

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)1630

2) Registered fragrance ingredients of International Flavors and Fragrances Inc.

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

hypothesis, and thus chose skeletons/backbones for continued research in struc-ture�odor activity relationships that might ultimately lead to structural motifs withsuperior hedonics and performance that would be better than existing ingredients.

Synthesis of Novel Amber Structures or Oxabicyclooctanes Prepared from theCampholenic Skeleton. Since many sandalwood ingredients3) [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,


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

Scheme 2

3) Bacdanol and Santaliff are registered fragrance ingredients of International Flavors and FragrancesInc., while Ebanol and Javanol are registered fragrance ingredients of Givaudan SA. Polysantol is aregistered fragrance ingredient of Firmenich SA.

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 amulti-step synthesis starting from dihydrocampholenic aldehyde (26).

The preparation of these novel compounds 30 –34 involved a thermal Diels�Alderreaction of a-methylidene dihydrocampholenic aldehyde, 27, with dienes such as


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

Scheme 3. Oxabicyclooctanes from Dihydrocampholenic Aldehydes

butadiene, isoprene; and 2,3-dimethylbutadiene, respectively; followed by reduction ofthe aldehydic Diels�Alder adducts to the corresponding alcohols using LiAlH4. Oncyclization with MsOH, these alcoholic adducts furnished the bicyclooxaoctanes 30 and31 (ex butadiene), 32 and 33 (ex isoprene), and 34 (ex dimethylbutadiene). Theoxabicylooctanes 30 and 31 (ex butadine) smelled ambery, woody, musky, tobacco,whereas the oxabicylooctanes 32 and 33 (ex isoprene) possessed a very ambery, woodyodor with an ionone feeling. In addition, the oxabicyclooctane 34 (ex dimethylbuta-diene) also smelled dry, woody, and ambery with fruity aspects. It is worth mentioningthat we also prepared 32 and 33 by Pd/C-catalyzed hydrogenation of Cassiffix� (35) asoutlined in Scheme 4. It was interesting to note that a cassis odorant became an amberodorant.

Synthesis of Alkyl- and Aryl-substituted Oxabicyclooctanes ex CampholenicAldehyde. Inspired by the above structure�odor relationships, and encouraged by theambery smell of oxabicyclooctanes 30– 34, we conceived a synthetic route to anotherclass of alkyl- and aryl-substituted cyclopenta[b]furan derivatives [11] from campho-lenic aldehyde as delineated in Scheme 5. These THF derivatives were prepared in twosteps by the addition of appropriately substituted Grignard reagent, derived frommethyl, propyl, phenyl, benzyl, and 2-phenylethyl bromide, respectively, to 25 to affordthe corresponding alcohols [12] , followed by cyclization with MsOH to the substitutedcyclopenta[b]furan derivatives 37, 38, and 39 (cf. Scheme 5 for odor descriptions).


Scheme 4. Dihydro-Cassiffix by Hydrogenation of Cassiffix�

Scheme 5. Novel (Arylalkyl)- and Alkyl-cyclopenta[b]furans from Campholenic Aldehyde (25)

Unfortunately, this type of substituted cyclopenta[b]furan compounds did not possessany amber odor qualities; therefore, we turned our attention to building THFderivatives from isolongifolane, cedrane, and pentamethylindane skeletons.

THF Derivatives from the Isolongifolane Skeleton. Several amber molecules4) usedin perfumery are based on the isolongifolene (40) skeleton. In particular Piconia� 41and the recently discovered Ambermax� [13] stand out for their hedonics. Therefore,we extended our standard methodology of THF-derivatives formation to Piconia� andprepared 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 fragranceingredients5) such as Cedramber�, Vertofix�, Cedryl Methyl Ketone, Andrane�, andAmbrocenide� feature a cedrane backbone, we turned our efforts next to THP ethers46 starting with cedrone (48), which is available from Andrane (49). Cedrone (48) wasalkylated with allyl and methallyl bromide using NaH to give allyl cedrone (50) andmethallyl cedrone (51), which, on reduction with LiAlH4 (LAH) followed bycyclization with MsOH, gave the desired cedrane THF derivatives 46 and 47 asdepicted 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 Pentamethy-lindane Skeleton. Having gained insight and inspiration from our structure�odorrelationship studies thus far, we targeted the design of the THF derivative 2(Trisamber�) with a Cashmeran� backbone. This effort was based on severalconsiderations with regard to pentamethylindane skeleton. First, the pentamethylin-dane skeleton was the basis for the invention of such iconic and widely used fragranceingredients6) as Cashmeran� (52) and Galaxolide�, and, second, our modeling studiescarried out for 2 in comparison to Ambrox� (3) revealed a nearly perfect fit. Hence, byusing our standard methodology, dihydro-Cashmeran (53) was subjected to Claisenrearrangement with allylic alcohol which to provide allyl-dihydro-Cashmeran (54) ingood yield. This, on reduction with LiAlH4, furnished g,d-unsaturated alcohol 55 in


Scheme 6

4) Piconia is a registered fragrance ingredient of International Flavors and Fragrances Inc.5) Cedramber, Vertofix, and Andrane are registered fragrance ingredients of International Flavors and

Fragrances Inc., while Ambrocenide is a registered fragrance ingredient of Symrise.6) Galaxolide and Cashmeran is a registered fragrance ingredient of International Flavors and

Fragrances Inc.

high yield. Cyclization of 55 gave 2 (Scheme 8). On perfumery evaluation, compound 2was found to have a very strong, ambery, woody odor. The performance and hedonics of2 in many functional and fine fragrance applications was superior to several existingamber ingredients in the IFF perfumery catalog. Therefore, compound 2 wasrecommended for commercialization and subsequently trademarked as Trisamber� [5].

Discovery of Amber Xtreme� or Methyl Trisamber (1). A few years after thecommercialization of Trisamber� (2), just as a curiosity motivated by the struc-ture�odor relationship perspective, we envisaged the synthesis of methyl-Trisamber�


Scheme 7

Scheme 8. Route to Trisamber� (2) from Cashmeran (52)

(1), enouraged by the fact that there are many examples7) in the literature [15] whereincorporation of an additional Me group increases the intensity and performance 2– 3times over the parent compounds. Hence, by applying the same methodology describedbefore, methyl-Trisamber� was prepared as outlined in Scheme 9. First, dihydro-Cashmeran (53) was converted to dihydro-methallyl-Cashmeran (56) by Claisenrearrangement with methallyl alcohol, followed by reduction with LiAlH4 to thecorresponding dihydro-methally-Cashmeran alcohol (57), which, on cyclization withMsOH, 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 andfine fragrance perfumery applications was even superior to that of Trisamber� (2). Inconsequence, it was introduced to perfumery as Amber Xtreme� (1). Lastly, it is worthmentioning here that Amber Xtreme� is primarily a mixture of two isomers: the cis-isomer 58 and the trans-isomer 59 (Fig. 3). Subsequently, based on in-depth perfumery


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

Fig. 3. Odor differences of the Amber Xtreme� isomers

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

experiments, it was uncovered that the most powerful and major odor-donating ambercomponent in Amber Xtreme� [4] is the cis-isomer 58.

Miscellaneous Structures Obtained in Search for Novel Amber Odorants. Beforeconcluding this article, we would point out that, in our quest for new amber odorants wealso 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 methylethers such as 67, starting from well-known fragrance ingredients with carbonylfunctions like dihydro-Cashmeran (53), Piconia� (41), and Iso E Super� 8). This part ofour research efforts was also presented at the Leipzig meeting. The majority of thesenew compounds were found to have woody, ambery smells as delineated in Fig. 4. It isworth mentioning here that the best known tertiary alcohol with amber, ambergris odoris the naturally occurring Ambrinol (68).

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


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

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

reasoning and modeling approach applied in the successful quest of new, differentiatingmolecules.

The author wishes to acknowledge his colleagues at IFF, whose names are cited in the followingreferences, for their dedicated synthetic work, and several renowned perfumers for their expert fragranceevaluations of the new chemicals disclosed in this article. IFF�s commitment to introduce newdifferentiating fragrance molecules for sensorial pleasure of perfumers, customers, and consumerseverywhere 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, Z�rich, 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, Z�rich, 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, toInternational 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
