Philip Kraft

Optically Active Ionones and Derivatives: Preparation and Olfactory Properties

The isomeric ionones 1−3 are of both academic and commercial interest. Since their first preparation at the end of the 19th century they have been widely used as fragrances and as starting materials or building blocks in the synthesis of many relevant products. The regioselective and/or enantioselective preparation of ionones has therefore been investigated with growing interest over the last decades. In this Microreview, we summarize the syntheses of optically active α- and γ-ionones (1, 3) and the epoxy and dihydro ionones 4−7. In addition, the olfactory properties of most of them are reported comprehensively.

Preparation and Olfactory Characterization of the Enantiomerically Pure Isomers of the Perfumery Synthetic Galaxolide

The commercially important isochromane musk odorant Galaxolide® (=1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran; HHCB; 3) was separated into its diastereoisomers via the tricarbonyl(η6-cyclopenta[g]-2-benzopyran)chromium complexes 10. Since GC/olfactometry indicated that only one enantiomer of each diastereoisomer (4RS,7RS)-3 and (4RS,7SR)-3 determines the odor characteristics of the commercial product, all four stereoisomers (4S,7R)-, (4S,7S)-, (4R,7S)-, and (4R,7R)-3 were synthesized by Friedel-Crafts alkylation of 1,1,2,3,3-pentamethylindane (11) with (S)- and (R)-methyloxirane ((S)- and (R)-12, resp.), acid-catalyzed reaction of the resulting products with paraformaldehyde, and separation of the formed diastereoisomer pairs via the tricarbonyl(η6-cyclopenta[g]-2-benzopyran)chromium complexes 10. The powerful musk odor of Galaxolide ® (3) was thus attributed to its (−)-(4S)-isomers (4S,7R)- and (4S,7S)-3, while the (+)-(4R)-isomers (4R,7S)- and (4R,7R)-3 were weak to almost odorless.

Conception, Characterization and Correlation of New Marine Odorants

Via a synthetic sequence consisting of PPA-mediated Friedel−Crafts acylation of veratrol (8), Clemmensen reduction, demethylation with TMSI, Williamson ether synthesis employing 3-chloro-2-(chloromethyl)prop-1-ene and in-situ ruthenium tetroxide oxidation, numerous substituted benzo[b][1,4]dioxepinones 15−27 and 2,3-dihydro-1H-5,9-dioxacyclohepta[f]indenones 7, 13 and 14 were prepared to study their odor−structure correlation. In the course of these studies, we discovered the extremely powerful new marine odorant 7-(3′-methylbutyl)benzo[b][1,4]dioxepin-3-one (16). On the basis of the measured odor threshold data, an olfactophore model was constructed that rationalizes the observed odor intensities, and indicates an aliphatic hydrophobe at a distance of 6.3 A from the centre of the aromatic-ring binding site. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

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.

Cassis Odor through Microwave Eyes: Olfactory Properties and Gas‐Phase Structures of all the Cassyrane Stereoisomers and its Dihydro Derivatives

Blackcurrant is arguably the most sophisticated and elegant fruity top note in perfumery, with an extreme 18 % of “Cassis base 345B” in “Le monde est beau” (Kenzo, 1997) by Daniela Andrier and 2.2% in “DKNY Be Delicious” (Donna Karan, 2004) by Maurice Roucel, in the latter perfume juxtaposed to 7.7 % undecavertol. “Cassis base 345B” contains the 1,3-oxathiane Oxane, the odor of which is due mainly to the (+)-2S,4R stereoisomer 1 and Isospirene (2), a less-volatile synthetic theaspirane derivative. Theaspiranes occur in different enantiomeric ratios in a variety of natural products, but the blackcurrant odor originates predominantly from the (+)-2R,5S stereoisomer 3. More potent derivatives such as Isospirene (2), Neocaspirene (4), and Etaspirene (6) have been introduced to perfumery, but these are less volatile and diffusive than 3. For top notes, only the sulfur-containing rac-1 and Corps Cassis (5) were available, until the recent introduction of Cassyrane (7), which can be regarded as a seco-Etaspirene (Scheme 1) and is devoid of sulfur off-odors. For the related vitispiranes, such as the 5S-configured diastereomers 8 that occur in vanilla oleoresin, the more intense cis compounds possess a green chrysanthemum note, while the trans isomers resemble exotic flowers with earthywoody undertones. Since the cassis odor of 1 and 3 was also critically dependent upon the stereochemistry, it was highly interesting to investigate the olfactory properties of the stereoisomers of Cassyrane (7) and its dihydro derivatives. A combination of microwave spectroscopy and quantum chemistry seemed ideal to determine the relative stereochemistry and their gas-phase structures, since microwave spectroscopy has recently been applied to solving the structures of sizeable molecules where energy differences are small and conformational distinction is not possible by quantum chemical calculations alone. Here we report on the gas-phase structures of the Cassyrane stereoisomers 7 and its dihydro derivatives 15 calculated by quantum chemical methods and validated by molecular beam Fourier transform microwave (MB-FTMW) spectroscopy. The synthesis of the stereoisomers 7 and its dihydro derivatives 15 started with the commercially available (R)and (S)-butynol 9 ( 99 % ee), as shown in Scheme 2 for the 5R-configured isomers. In analogy to the preparation of the racemic material, (S)-alkyne 9 was transformed into its Grignard reagent and treated with ketone 10 in the presence of cerium(III) chloride to afford diol 11 as a 5R/5S diastereoisomeric mixture of 56:44. Lindlar reduction, acetylation, and chromatographic separation furnished the acetates 13 a and 14a in good overall yield and with retained absolute stereochemistry (99 % ee). The most apparent strategy would have been hydrolysis of the acetates and subsequent cyclization of the diols 13b and 14 b via the corresponding tosylates or mesylates. However, under a variety of conditions, 1–10% of the C-5 epimers (5S)-7 were formed, together with other side products. Diol 14b was more prone to side reactions than 13b, and experiments with the latter indicated that mesylation/cyclization at various temperatures was inferior to tosylation/cyclization (94.8 % de versus 98.2 % de, see the Supporting Information). Therefore, a cyclization route in which the acetate function was used as a leaving group was envisaged. Treatment of 14 a with 1.5 equivalents of NaH in THF at reflux indeed furnished (2S,5R)-7 in 73% yield (85% Scheme 1. Important blackcurrant and theaspirane odorants.

(±)-1-[(1R*,2R*,8aS*)-1,2,3,5,6,7,8,8a-Octahydro-1,2,8,8-tetramethylnaphthalen-2-yl]ethan-1-one: Isolation and Stereoselective Synthesis of a Powerful Minor Constituent of the Perfumery SyntheticIso E Super®

(±)-1-[(1R*,2R*,8aS*)-1,2,3,5,6,7,8,8a-Octahydro-1,2,8,8-tetramethylnaphthalen-2-yl]ethan-1-one (5) was identified as a minor (ca. 5%) but very powerful (5 pg/l (air)) constituent of the important perfumery synthetic Iso E Super®. Its structure was assigned by NMR spectroscopy and established by a stereoselective synthesis starting from α-ionone (10). Diastereoselective conjugate addition of Me2CuLi to 10 was followed by a haloform reaction, esterification, and isomerization of the C=C bond by treatment with NaOCl (Schemes 3 and 4). The resulting allyl chloride 17 was ozonized and transformed into the trimethyl(vinyl)octahydrocoumarin 20 by diastereoselective Grignard reaction with ethynylmagnesium chloride, and subsequent Lindlar hydrogenation. Ireland-Claisen rearrangement of 20 followed by methylation with MeLi afforded the target molecule 5 that was identical with the material isolated from commercial Iso E Super®.

Efficient Macrocyclization by a Novel Oxy‐Oxonia‐Cope Reaction: Synthesis and Olfactory Properties of New Macrocyclic Musks

Musk odorants are indispensable in perfumery to lend sensuality to fine fragrances, a nourishing effect to cosmetics, and a comforting feeling to laundry. Due to a certain phototoxicity of nitro musks, and the lack of biodegradation of polycyclic musks, the two most important musk families at present are macrocycles 1–5 (Figure 1), derived from the natural lead muscone (1), and linear alicyclic musks such as 6–7, the odor of which has been attributed to horseshoeshaped conformers that mimic macrocyclic rings on the odorant receptors. Both musk families, linear as well as macrocyclic, comprise highly flexible structures, which make double bonds and methyl groups ideal design elements to rigidify and conformationally constrain them. The two most powerful macrocyclic musks, (+)-(3R,5Z)-5-muscenone (2) and (13R,10Z)-Nirvanolide (3) both feature a double bond and a methyl substituent, and Cosmone (4) can be regarded as a “nor-muscenone”. By introduction of two double bonds such as in 5, the conformational freedom can be further restricted, enabling a targeted design of potent musk odorants. Methyl substituents determine the conformational space of linear musks to a great extend; yet, as apparent from the two dehydro-derivatives 6 and 7 of Serenolide (Figure 1), a shift of a double bond can change the odor threshold by a factor of over 150. The synthesis of further unsaturated macrocyclic musks can shed light upon similarities in the structure–odor correlation of these two musk families, and to this purpose we herein report on the intramolecular application of a new reaction of b,g-unsaturated aldehydes with different aldehydes in the presence of Lewis acids. The projected macrocyclization can be regarded as an oxy-version of the established 2-oxonia Cope rearrangement, but as illustrated in Scheme 1, could as well proceed through compound 11 in a Prins-type manner by coordination of the Lewis acid to the opposite formyl function. Both pathways would however lead to the same macrocyclic alk-3-en-1-yl formates 10. Hydride reduction and subsequent oxidation of 10 should provide b,g-unsaturated macrocyclic ketones, which could then be hydrogenated to the saturated macrocycles; thus, could then also open up a new route to ( )-muscone (1). As delineated in Scheme 2, the dicarbonyl substrates 8 a–g were prepared from commercial bromo alcohols 12 a–g by protection as tert-butyldiphenylsilyl (TBDPS) ethers 13 a–g, and subsequent Finkelstein reaction with KI in acetone to afford iodides 14 a–g in excellent yields. Deconjugated a-alkylation of the Weinreb amide 15 with 14 a–g afforded alkylated amides 16 a–g in 39–60 % yield, with unreacted 14 a–g being recovered. Deprotection of the Weinreb amides 16 a–g with tetrabutylammonium fluoride (TBAF) in THF [a] Dr. Y. Zou, Prof. Dr. Q. Wang Department of Chemistry, Fudan University 220 Handan Road, Shanghai, 200433 (P.R. China) Fax: (+86) 216-564-1740 E-mail : qrwang@fudan.edu.cn [b] Dr. Y. Zou, Dr. A. Goeke Givaudan Fragrances (Shanghai) Ltd 298 Li Shi Zhen Road, Shanghai, 201203 (P.R. China) [c] Dr. H. Mouhib, Prof. Dr. W. Stahl RWTH Aachen University, 52056 Aachen (Germany) Institute of Physical Chemistry [d] Dr. P. Kraft Givaudan Schweiz AG, Fragrance Research berlandstrasse 138, 8600 D bendorf (Switzerland) Fax: (+41) 44-8242926 E-mail : philip.kraft@givaudan.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201200882. Figure 1. Macrocyclic musks 1–5, and linear musk structures 6 and 7.

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.

NATURE-LIKE ODORANTS BY STEREOSELECTIVE RING ENLARGEMENT OF CYCLOHEXANONE AND CYCLODODECANONE

Abstract Both enantiomers of muscolide ( 3a b ), (R)-(−)-phoracantholide I [ (R)- 3c ] and the homologous (9R)-(−)-9-tetradecanolide [ (R)- 3d ] were synthesized by ring enlargement of cyclohexanone (6c) and cyclododecanone (6a). The ring-enlargement sequence was improved by oxidation of 9 10 with ruthenium tetroxide and reduction of 8 using catecholborane.

Ring enlargement by alkylated 3-hydroxybutyrates: A synthesis of (12s, 13r)-(−)-12-methyl-13-tetradecanolide 1

TBS-protected iodo alkohols 6 were prepared via Frater alkylation and applied hi the synthesis of optically active macrohdes 5 and 10. By ring enlargement of cyclodecanone (7) the superposition molecule 5 of two macrocyclic odorants was synthesized and a conformationally fixed tricyclic macrolide11 constructed.