CHEMISTRY & BIODIVERSITY – Vol.

11 (2014) 1629

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: anubhav.narula@iff.com)

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

1630 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)

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.

 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 1631

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 struc-

ture 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.
1632 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)

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

 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 1633

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 dimethylbuta-
diene) 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 campho-
lenic 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)

1634 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)

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 Pentamethy-
lindane 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 pentamethylin-
dane 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) 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.
 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 1635

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 struc-
ture odor relationship perspective, we envisaged the synthesis of methyl-Trisamber

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

1636 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)

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, dihydro-
Cashmeran (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 cis-
isomer 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.
 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 1637

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.
1638 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)

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).
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& 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