338 SCENT AND CHEMISTRY [229] KD. Groen RS de Simone, LG Hetn ta memati Flared Fane Ger, fen. 44041, 17) (Cham Abr IME a sey [23] Sot M. Winer, Gauci I Flame! Win, Chin. Asa 96230. (2311 A'F Thomas dpe Fon Ch 197321 988 [232 Demo. D Brie. Hee Can, ca 728. 8 [23] FW. Somme, der ch Chom Cer 9225, [23] FW, Sommer: er Dash Chon Gea 4 17218. 8. Mare pate communication Phe Rrat 3) Oc [E36 1. Obeeman, Drop Re (Ger) 1978293) [27] ease Pn Floor eRe 819, FS. Corona, Rit Tate 196129, 197 [29] T Kao. Yen Ujturn,¥ Racha, Che Lt Bs (200) E. Kin. HL Obeoman, Tato Le TT, [24] CH. Brskorn. P Not Pl Ma 9H 1,0 BAI KA, Whoa B.D, Mootheee, Characterize of Aroma Donating Componens of “My inProesedings ofthe IX trations Congres of Esenal Ota 1 7 acs 1 Sings, 98, VL 4p [261 C chateaus, Heh Chi, Aca 199, 7520 BH) C Nowboomer Re Calter Kray Iie Cm As 198, 8283. £265] 6 Maron A.P'S Prodi, RC, Pars Frm Pgnce J 24,1 $8 (246) 1. Kotinnstbeges.S Nz. F Drawer, 2 Lefemm-Unem Re Wk, on Se [20] 5: Derouwer M. Vez Omang St 19864, 98 [BAH BM. Laven, eon Flv 198,900). [26] K.A.GleiC 1 Hammond, A.C. Weg Pacino yin fs nck Pepper (Fiver a ation Vive OM (Weert ener Ya eee ene Favor oad Fragrance Resear, Ede Kral, K AD Suil, Vong Hahn eee ‘ea Zip FR0) Lovet, G Bucswsr MB Npisoum.M. Gc! Chroma 2, 975,265, Odorants of Animal Origin 8.1. Musk and Civet (Gest notions: Fe es in he proximity of Teach the size of “shicken‘SCENT AKD CHEMISTRY ar a cxsriotanioes — (eHPbeusecpne discovered by Envin Sack in 1915 [6], and structurally elucidated by Ruzicka (7) as (9Z)- US NW Aw ¢ 8 ODORANTS OF ANIMAL ORIGIN | fication of 8.32 with decarbos lecarboxylation. This bicyctofi0.3.0}pentadee-1(12)-en- Piel (12)-en-13.0ne Scheme RS Symes of Bye 420 pon 21 RH) by Sotho lL 3DIponate 112) 4n 13 one (4 12), by Sake Ops 12 Ve competes COTS CD cas a2 Sage azrmen? Te, anion 827 into + mono-uctinal macro onofusctonal ma brosedure has been developed whieh became Hace te Imoier-Ohlf tagmenai a} th fragmentation of.cpongs i & Bp z resence of weak bs the corresponding350 SCENT AND CHEMISTRY Schume 86 Sys of ee Macone (rc) and Exo (82) fram 827 by Esc The limiting factor of this reaction sequence is the WeitzScheffer epoxidation, because it competes with a Baeyer—Villger oxidation. This is the reason why the epoxidation of the bicyclic enone 8.27 is stopped after ea, $0% conversion, However, peracid epoxidation of the corresponding ally alcohol to 827, followed by CrO, oxidation to the «af-epoxy ketone 8.33 proceeds quantitatively. The epoxidation step can be entirely avoided as depicted in Sclieme 8.8 by N-bromination of the tosylhydrazone 8.40 [46]. Alternatively, the fragmentation ofthe bieycic a f-unsaturated tosyl hydrazone 8.40 can also be achieved by electro- ‘chemical oxidation (47. Both methods lead to the formation of Exalt-4- ynone (8.38, R=H) in ca. 80% yield. If, however, the substituent is methyl (R=Me), the yields of these reactions decrease dramatically. Consequently. a completely diferent synthetic route must be followed if muscone (rae-8.1) isthe desired product, 8 0B0RA OF ANIMAL ORIGIN 351 SehOME RE An Alemaive Exchemmee-ONot Epuriain ugmevinion Avoiding Wet Schter 6 ( oe V4 Lee Gh tae The route towards racmuscone (rn WOSdIpenadeei(a)enisone (ast iene elhbiods- Scheme 8.9 (42), Key res sare Sa ey reaction ithe Creasy te the bisele 34thydro2Hpyran a6 Coaney ot as ee acme (ac) from Hey Scheme RS. Smt of “ah ng eset epee 133382 SCENT AND CHEMISTRY a 4S ODORANTS OF ANIMAL ORIGIN: phosphoric acid to muscenone (8.47), and subsequent catalytic hydro- ed ‘genation lead to rac-muscone (rac-B1) in an acceptable yield. The ‘eye 846 can also be cleaved and hydrogenated in one step employing ‘Hyactivated Pt at 270°C as a catalyst, which circumvents one step and increases the total yield. However, the unintended by-product musce- noone (8.47) turned out to be itself avery potent musk odorant of desired nitro-musk tonality. For its (+)(3R,SZ)-somer, an odor threshold of 10.027 ng/l air was reported [23], i. 16 times lower than that of natural (©) R)-amuscone (8.1) [23 ‘The fragmentation of 8.46 is thus mainly used for the synthesis of ‘muscenone (847), and much effort has been made in recent years to increase the amount of the (5Z)isomer. Meanwhile the general strategy ‘of the muscone synthesis surprisingly changed towards aliphatic pre ‘cursors due to the implementation of a new process employing an OH- assisted Prins reaction [48] (Scheme 8.10). The two central C=C bonds increase the efficiency of this cyclization by favoring a reactive conformation, The (4E,82)-cosfigured dialdchyde 8.49, prepared by rreduetive workup of the mono-ozonide of cyclododcea-! 5 9riene 4848), is mono-acetalyzed prior to reaction with (methallyl)magnesium hoe oui. the bicyel om de ‘assisted Prins reaction of 8.1 provides ive 52 in 75% yield, while the ra Mucone (83) fom Clade 39 rene by OH. And ‘Scheme R10 Sykes Scheme 81. Sheds of 1-Ocahereoa ¥ W104 Ohesaic (2m: (838) from Cyclades. mc Ce ae Oe con or CO 13 8K |e |r wc N Loe Leo on cy wa CUS ass34 SCENT AND CHEMISTIOY ed 4 ODORANTS OF ANIMAL ORIGIN 355 (wt Show highest ental atvily and enanoseletviy, and provi (CR ymuscone (81) of > 98% ee [55] ‘83. Non-Natural Musks. "smn tg Path A a Perea te ste on the route to rac- |, does actual Frente La Trea gehts ina ne te yn (—)-(R)-muscone (8. lose to musceno = (04) 3 ‘Sac and etans charter Nati (8) with a wee Frets ce cece ODORANTS OF ANIMAL ORIGIN (eases sasonesr ——(omaee (HERZ }mimeSemane (138 10Z.Airvaoakde 4 configured C=C bond, which intl luences the folding of he ringal acts as an electronegative bi ling element, and a methyl group, which i placed insuch a way aso imitate a larger ring perimeter on the receptor withoot actually reducing the vapor pressure by incorporation of the respective Catoms in the ring, which would be required to fill the same volume {26]{58]. The C=C bond in Nirvanolide (8.67) can be replaced by an ©. tom as electronegative element without much change in the olfactory properties [59]. Again, only the (){)-enantiomer. which possesses a, Odor threshold of 0.09 ng/t air (57), is the odor vector of the enn macrolide 8.68. An S-alom can mimic the steric and electronie propertice of 2 (Z)conligured C=C bond even more closely than an Onatom, replacing both Cratoms of the respective CaC bond, ‘Thus, this: ambrettolide (8.69) resembles its natural lead structure ambrettolide (85) very closely in its tenacious musk note, while being ony slightly more green-mossy in its facets. Remarkably, the odor threshold of 8.69 (02 ng/l air) is about ten times tower than that of 85 (1.8 ng ait) (60) Introduction of heteroatoms into macrocyclic rings may also lead to more easily available building blocks and andlor shorter synthetic caences. The best example for this isthe dilactone [61] ethylene brassylate (8.7) [39] available from brassylic acid, which is obtained by Saponifcation of rape seed oil. Nippon Mining Corp., Tokyo. alee developed a biotechnological process to produce braslie acid frome tridecane. Ata price below 15 CHFikg, ethylene brassjlae (8.70) is the workhorse macrocyclic musk when price mattersSCENT AND CHEMISTRY 388 : a higher on a brief, high-impact a ee uchas muscnone (at) and Bivona Deployed in whieh Me prope sd C=C on ae placed y deen shor tha vy of stg materia Covmone (87K p. 357 of $id anthers geese musk [2] hha the wer homing mussenene (G4, The smaller menor Mgt ene A) kaso ies epee conan ih muse enone (GA), wile the binding moti and ites is Freed ho C=C ton han the16memberd marke 872 63) offer ane ynstrain the conformational ym of (oes aaa and thereby dein mre potent most. (EIZE)- raylonxnecain ane (RD) postr a Song and crop cu ey ar! mask ote (8). The pepe of satel acing feo ronal ried C-Ctonds anon Ne ou opti he Sitar propre msc mas have been emp se Silge a bbe) mats ioecoptdec dodo A: 2S nlc posses a pleasant powdery ms Tesi af 02 nt ae * coeneate hmong te te C=C bord tomers yee coon nye me! AGS) nor re (Faken), Mase TM Se ee ohne by Spe rer 8 (Scheme 10), marked 8 ors owing ene 6 ey rnin af elodaesnene (69) me prone fC ret aie eager stone AM wh 2 ego of i ss eo aa (96) by OnpCoe Rng 15 dil Sh of the Cyr Sano (8) Sens net arencn of Cpldodeone (829) 2xomy™ ea 8, ODORANTS OF ANIMAL ORIGIN ‘Shem 16 dnd Syme ofthe Conde enone es Cylons (7 OS CoO an (89) by Rog Opening Mew of the divinyleyclodadecanol 875 65]. Thereby, cyclododecanone (8.29) 5 ringenlarged by four C-atoms. As shown in Scheme 8.6, eyele hhexadee‘-enone (79) is industilly synthesized by ring-opening metathesis of eyslooctene (8.77), which i also industrially available by the Wilke method (40](41} fom butadiene. Employing dirheniury heptoside on alumina, 8.7 is transformed in flow reactors into cyclo. hexadeca-1.9-diene (8.78), which then is monohydroborated and oxi. clized by alkaline H,O, to afford cyclohexadec-8-enone (Globunone, 8.79) as the final product [66] ‘Almost 18 years prior tothe ‘solation of (~)4(R)-muscone,(8:1) from ‘musk glands by Heinrich Walbaum, Albert Baur [67] discovered a serien (of highly substituted nitro-arenes, which possess typical musk odors, The first ofthese so-called nitro musks, 2-(cr-butyl)-+methyl-135trinitres, benzene (880), sold as a 10% sclution in acetanilide at 500 USSIkg, was such an immediate commercial success that it became known as Wack. Baur (8.80). However, Baur discovered in short succession with Musk aplene (881), Musk ketone (882) [68], and Musk ambrene (883) [69] {three more potent nitro musks that became the epitome for musk till the 1960s Musk xylene (8.81) has an almost penetratingly sweet musk note and found use mainly in functional perfumery, especially for soaps and detergents Musk ketone (8.82) [68] is the nitro musk most closely resembling natural musk tincture with a powdery-warm slightly animalic ‘musk tonality, and the musk character of Musk ambrene (883) (61) is ‘accompanied by a dstinet floral tone in the direction of yellow freesia we wh, he ; on [ne 3x0 ast as ass meen hye ale gS360 SCENT AND CHEMISTRY “The floral-powdery aspects made 882 and 883 very popular in fine fragrances. and the original formula of “Chanel N'S" (Parfums Chanel 1921) contained, for instance, 3.5% of Musk ketone (882) and 25% of ‘Musk ambrete (883) (70), which was a typical dosage and ratio fr this era of perfumery. When Musk ambrerte (883) was shown to eause Photodermatts and persistent light reactions (71, its we was severely restricted in 1981, and subsequently, it was withdrawn from the market. “The same fate was shared in the meantime by Musk xylene (8.81) and ‘Musk ketone (B82) due to their similar phototoxicty, making it sometimes challenging to maintain the character of classical perfumes ‘when replacing these nitro musks. “The photochemical reactivity ofthe nitro musks and their instability in alkaline media initiated, already after World War Il, the search for aromatic musks without NO, groups. These research efforts led to the discovery of the third generation of musk odorants, that of polycyclic tomatic musks (PCM) with ils most prominent repreventatives TonalidelFixolide (rac-8.84), Versalide (885), Vuleanolide (rac8.86), Galaxolide (rac-881), Phantolide (8.88), and CelestolidelMusk DTI (8.90). Whenever known, the most powerful enantiomer was dravin for hon MY ~hn~ CL Cite AL: egies Asana ec > 2G te ODORANTS OF ANIMAL ORIGIN ANTS OF ANIMA 361 ach representative (57). Tonal och repre (57). TonalideiFixolide oustanding stably and good depenton ise we of Calaalide (ac) il Soe Ree aueonstenmenl nen ett aes Calasoite (48)889) (2h TOW sed in place of mete (AS). ir bioaccumulation, POMS are, however considered toute oe thalene? Sage a EI (5678etebydro5.388ttomethynaph Wigan ay ttn of et geo 1 frst polyeyctc musk intr (838, discovered y Ke rane | |362 ‘between a woody odorant and a musk. Cashmeran (891) is usually meant ‘when a perfume description lists the term ‘Cashmere wood’. Moxalone (1492), derived from a lead discovered by M. Klaus during his work on ‘aromatic retinoids [77], is on the other hand a true musk, rich and ‘Powerful, and is only accompanied by slightly fruity facets and woody aceents. It has been used in many fine fragrances, and is not only non- ‘but also the one and only epoxide musk to date. The most recent non-aromatie polycyclic musk is Nebulone (8.93) [78], which extends Cashimeran (8.91) structurally and olfactory to full-scale musk odorant. “The fourth generation of musks (58]{79] comprises aliphatic and alicyelic musks that are principally linear in structure, and thus are alse referred to as ‘linear musk’. While citronely! ethyl oxalate (8.84) and Rosamusk (895) possess discernible musky facets behind a dominant es SSR se a 896 ovate sami ap the as7 Ccolemslontsie vow calomatlop am 2 R&R Ade DE RE ALG ne a90 2.100 aot ons seatie spas 8 ODORANTS OF ANIMAL ORIGIN 368 Frees fly was Clomust (496) doer ea memes mann of BASF {80}. Only 15 years lat “ ee i family, Helvetolide (8.97), Glerch a ulte-Elte of Firmenich (81). It exhibits ret tl i be exened by Romandolide (8.98) with even, mn coor intensifies even mare shen Appelide (8.101) (83), block in the construction of an Althovgh no very intense 8.101 rear feeealy, even a fifth family of muck cane364 SCENT AND CHEMISTRY of8.102 exhibits a certain rigidity, seco-structures were designed, opening oth rings of 8.102 [85], oF just one of them [85]. The 1.2:2.3:5.6:6, vonnseee derivative 8103 pessesses a pleasant sweet musky, violet odo eth a thaeshold of 0.54 nga [85], the 5,6:6,7-diseco derivative 8.104 warn an lower threshold of 0.26 ng air with a very typical musk odor Mh aspects of dried fruits and a beetroot character, and the 12: iswco derivative 8.104 a musk odor with green, flora, lily-f-the-valley Hane and threshold of 090 ng air (86). The area of new non-natural seek odorants is sil being actively investigated, and further generations Tre likely to emerge, exhibiting improved biodegradation, substantivty, ‘Tttusivty lower thresholds or lower prices, and, most importantly, new GHaracteristic olfactory properties that provide new signatures in perfumery. 8, Ambergris ‘Ambergris played similarly important role in cultural history 8s ‘musket was used a5 9 pharmaceutical, asa spice in East Asian cuisine, ean aphrodisice, and fisally a5 an important perfumery ingredient ‘Ones, the possession of ambergris was synonymous with wealth, power, and prosperity. vPmbergrs is a pathological metabolite of the sperm whale (Physeter macrocephalus Le; Fig. 86), occurring in co. 1% ofall sperm whales. is Tiatoieal function i to cover lesions oftheir intestines as a result of eerrical injuries upon digestion of giant squids and octopuses. ‘Reabergrs chunks occur in pieces weighing as much as 100 ke (fag 82), The most aburdant component of ambergis i the odorless Ce ce alcohol (_rambrein (8.106) and variable amounts of (4 cpioprosterine (B07). Actually, as litle as 03% of the components of sElpergris contribute 10 the complex odor profile, which fas een seerited as exotic woody odor with incense-ike, earthy, camphora- cet fobaeco- and must-like facets surrounded by smells of the ocean (Fig. 88). See of these odor qualities are present in compounds 8.109 8.116, which are all metaboties of (~)-ambrein (8.106) [87]. Only very Wauently, the acetals 8.111 and 8112 were discovered in ambersts Tiooture (38), and these may very well be formed by reaction of the Conesponding 34-dihydro-2/1-pyran and 23-dihydrofuran precursors Soth alcohol, However, most of the components of ambergrs tincture eran irom a long maturation process commencing after the amberaris is ‘elieg by the whale. As is lighter than water, ambergis lots on the 8. ODORANTS OF ANIMAL ORIGIN Fig. 86. Sper 8.86. Sperm whale (Physcer macrocephalsL). Photo courtesy of Dou Perr. ip 87. Chant of amborgrs surface where its subj soe whee abe oi, samih, rd waves Sinlation of Singlet oxygen ae he formation af he yee ent her ia set an ed fhe ovmtion othe n he a Gm 114), anc }-ambra-aldehy : ther impact onthe or ofthe atl product (-) dbo376 Laudamiel feature overdoses of Galazolide (rac-8.87). Such concen- trations of musk odorants are almost unaffordable by using, macro- cyclic musks, but the bioaccumulation of PCM led to an increased use of macrocycles at the beginning of the 21st century. The new polycyclic musk Nebulone (893) was used in ‘Lovely’ (Sarah Jessica Parker, 2005) and‘Tom Ford For Men’ (Tom Ford, 2007) at 2.4% and, ‘Miracle Forever’ (Lancéme, 2006) at 5.7%. ‘To exploit synergistic effects and to circumvent anosmias that many people have towards one class of musk, the combination of different musk families is most common nowadays. The fragrance that pioneered this approach was ‘CK be’ (Calvin Klein, 1996) by René Morgenthaler, featuring amongst other musks also Moxafone (8.92) at 0.62%. In 2000, ‘Flower’ (Kenzo, 2000) with 3.8% of Helvetolide (897) and ‘Miracle (Lancéme, 2000) with 6.1% of 897, both composed by Alberio Morillas, initiated the recent trend for linear musks and ‘white musk’ accords, as exemplified in ‘Emporio ‘Armani White for Her’ (Armani, 2001) with 8.8% of Helvetolide (8.97). Its oxa analog Romandolide (8,98) was, for instance, used by Jacques Cavallier at 5.0% in ‘Absolu’ (Rochas, 2002) and at 1.0% in “Murmure’ (Van Cleef & Arples, 2002). Examples for the use of ‘Serenolide (8.99), which had its debut in ‘Polo Double Black’ (Ralf Lauren, 2006) by Ellen Molner, are ‘Unforgivable Woman’ (Sean John, 2008) by David Apel with 6% of 8.99, ‘7 Million’ (Paco ‘Rabanne, 2008), ‘John Galliano’ (John Galliano, 2008) and ‘CK free’ (Calvin Klein, 209). Massively en vogue currently are also ambery notes, a trend initiated by niche perfumes such as ‘Ambre Soie’ (Armani Pivé,2004) by Christine Nagel, and supported by decreasing prices for ‘Ambrox (8410) and Ceialox (rac-8.110). We find previously ‘unimaginable levels of 13.6% of 8.110 in ‘Bois d’Argent’ (Dior, 2004), 5.4% of 8.110 in “Mille er Une Roses! (Lancéme, 2006), 53% ‘of 8:110 in ‘Versace pour Homme’ (Versace, 2008), and 5.1% of 8.110 in ‘Alien’ (Thierry Mugler, 2005). Unprecedented amounts of ( ‘Ambroz (810) are claimed to have been incorporated in ‘ex Cenincl2" (escentnc molecules, 2008) by Geza Schon, and many ‘ambery main stream fragrances were also recently launched, such a “Bau des Merveilles’ (Hermes, 2004) by Ralf Schwieger and Nathalie Reisthauer with 12% of 8.110, ‘Baldessarini Ambré’ (Baldessarini, 2007), ‘Allure Homme Edition Blanche’ (Chanel, 2008) by Jacques Polge, and ‘L’Eau Ambrée' (Prada,2009) by Daniela Andrier. In this SL ODORANTS OF ANIMAL ORIGIN Tange of modern amber notes, (=)-Ambrox accom pated by the ete BISA Noe pct ane (137) was import in “Oul-Non" (Kook, 188) oat ee $Geglarel, 1998), Okoumal(rac8139) in “Escape for Men” (Cals ‘li 9%) and Huo (en, 199), and anal faa inn ih Rn ih gt ea 5) sls used in high concentration in? lon (Conner nt Garcons, 2004) by Mare Buxton, & ) by Mare Buxton, ‘Gucci pour homme’ (Gucci 2003), btn ro Christopher Sheldrate's ‘el de Bow (Sune Lana Salons du Palais Roya! Shiseido, : Palas Royal Shiseido, 2005) and “Coo! Hey" #5 nt a uerlain, 008) by Beatrice Piguet and Sylvaine Delcongn shine Grit (Pere Balmain, 208) by Gul Par te Fat ampery facets are cated by (~)-a-ambrinol (R114), backed ee 1um_benzoin-vanilla—tonka bean accord. um nies are tralitionallyasoiated with leathery chypre 1924) by EmetrBeaur, and Scr ce es recent animale chypres featuring casireum tecoriie oa oe ‘et tao acai rom emt ae Paso (Paloma Pica, 198) by Francs Boos Casoroun hers {ned popularity with ary niche perfume hoses), suchas Co) Ientons (Kian, 200) by Sidante Lancer tad 1A Ol ion, mo te pling they often convey a Pa Bats Da Anan aa) ‘nt by Christophe Laudaiel wich eadvertaed socolng ome rent of the genitalia of a. freshly shampooed beast’ as) REFERENCES 11 1 wat Ch 196 73, Da) Ranh fe Cnn ae ————————