A Practical Chemo-enzymatic Approach to Highly Enantio-Enriched 10-Ethyl-7,8-dihydro-γ-ionone Isomers: A Method for the Synthesis of 4,5-Didehydro-α-Ionone

An efficient and convenient strategy for the enantioselective synthesis of enantiomerically enriched 10-ethyl-7,8-dihydro-γ-ionone isomers (R)-(+)-7, and (S)-(−)-7 are described utilizing a lipase mediated resolution protocol, and reductive elimination of the secondary allylic alcohol as the key step. The enantioselective and diastereoselective lipase kinetic acetylation of 4-hydroxy-γ-ionone derivatives 6a afforded the 4-acetyl-γ-ionone derivatives (−)-8, and the 4-hydrox-γ-ionone derivatives (+)-6a, which are suitable precursors of the desired products. Stereospecific palladium-mediated elimination of allylic acetate provides the target compounds with an excellent enantiomeric excess and yield. Additionally, the novel 4,5-didehydro-α-ionone 13 is obtained from readily prepared (2,6,6-trimethylcyclohexa-2,4-dien-1-yl) methanol 9. The structures of all newly synthesized compounds have been elucidated by 1H, 13C NMR, GC-MS, and IR spectrometry. These compounds represent a new class of odorants that may be of pivotal relevance in industrial perfumery.


Introduction
Timberol ® and Ionones are among the most important fragrance constituents due to their distinctive fine woody, amber, violet and rose scents [1,2]. The industrial creation of new perfumes [3,4] needs two essential lines of research: the discovery of new odorous molecules and the reinvestigation or chemical modification of older commercial products. Due to the unpredictable relationship between chemical structure and odor [5], the latter approach is particularly interesting from a chemical point of view. Indeed, many fragrances are sold as a mixture of isomers whose specific contribution to the perceived odor may be very different. Moreover, olfactory evaluation shows that the regioisomeric purity and the absolute stereochemistry of these compounds dramatically determines the fragrance properties, sometimes with amazingly pronounced differences between the notes and the odor thresholds of the isomers. Taking advantage of processes based on the enzyme-mediated resolution, Fuganti et al. [6] have reported a synthetic approach to the olfactory active components of the woody odorant timberol ® whereas Serra et al. [7,8] described the enantioselective synthesis of a number of natural odorants with the ionone skeleton. Furthermore, the exocyclic double bond confers particularly characteristic nuances to the fragrance, which can favorably complement other widely used compound from the same family [9][10][11][12][13][14][15].
In this context, we have focused our attention on the odorants in a combination of timberol and ionone framework ( Figure 1) that are of pivotal relevance in industrial perfumery.

Preparation of 10-Ethyl-7,8-dihydro-γ-ionone
We prepared compound 7 in racemic and enantiomer-enriched form starting from commercially available racemic α-ionone. It was introduced by Dragoco [16] as a synthetic fragrance with fixative properties with the brand name timberol ® . Funganti et al. have previously developed a stereoselective procedure that allows the conversion of α-ionone derivatives into γ-ionone derivatives [17,18]. The regioselective base-mediated isomerization of 4,5-epoxy-4,5-dihydro-α-ionone followed by reductive elimination of the obtained allylic alcohols were the key steps of our syntheses. Therefore, we decided to apply the latter synthetic pathway for the conversion of compounds 1 into 7. The synthesis began with the reaction of α-ionone 1 with Br 2 and NaOH as base in a mixture of H 2 O and dioxane, the resulting intermediate acid was treated with MeOH in the presence of a catalytic amount of H 2 SO 4 to afford the corresponding methyl ester. The later compound was reduced with LiAlH 4 to produce the allylic alcohol 2. The latter allylic alcohol was oxidized and the obtained aldehyde was treated with propyl magnesium bromide. The resulting ionol was then converted into pure 3 by an oxidation reaction using MnO 2 (Scheme 1).

Synthesis of 4,5-Didehydro-α-ionone
Aldol condensation of readily available aldehyde with acetone in the presence of base and Wittig reaction with phosphonate were not successful to reach the target compound because isomeric products are inseparable by the usual methodologies. It was found that the readily available alcohol 9 [19] is a good starting material for the synthesis. Tosylation of the free OH-group, followed by addition of thiophenol, deprotonated by NaH afforded the sulphide 10 in 95% yield. Oxidation of the latter compound with a mixture of (NH 4 ) 6 .Mo 7 O 24 and H 2 O 2 gives the sulphone 11 in moderate yield where the disulfide occurred as a by-product. Sulphone 11 was deprotonated by nBuLi at −78 °C , then epoxide in DMPU were added, followed by the addition of BF 3 .OEt 2 to the reaction mixture. The reaction mixture was stirred for a further 5 h at −78 °C and was left overnight to warm at RT to give 12 in 43% yield that was oxidized by Dess-Martin reagent to give the corresponding ketone in quantitative yield. Removal of PhSO 2 group by DBU regenerates the target compound 13 (Scheme 4) [20]. Scheme 4. Synthesis of 4,5-didehydro-α-ionone 13.

General Procedures and Instrumentation
All moisture-sensitive reactions were carried out under a static atmosphere of nitrogen. All reagents were of commercial quality. Lipase from Pseudomonas cepacia (PS), Amano Pharmaceuticals Co., Japan, 30 units/mg, was employed in this work. TLC: Merk silica gel 60 F 254 plates. Column chromatography (CC): silica gel. GC-MS analyses: HP-6890 gas chromatograph equipped with a 5973 mass detector, using a HP-5MS column (30 m × 0.25 mm, 0.25 μm firm thickness; Hewlett Packard). Chiral GC analyses: DANI-HT-86.10 gas chromatograph; enantiomer excesses determined on a CHIRASIL DEX CB-Column. Optical rotations: Jasco-DIP-181 digital polarimeter. 1 H and 13 C Spectra: CDCl 3 solution at room temperature; Bruker-AC-400 spectrometer at 400 and 100 MHz, respectively; chemical shifts in ppm relative to internal SiMe 4 (=0 ppm), J values in Hz. IR spectra were recorded on a Perkin-Elmer 2000 FT-IR spectrometer; films; ν in cm −1 . Melting points were measured on a Reichert apparatus, equipped with a Reichert microscope, and are uncorrected. Microanalyses were determined on an analyzer 1106 from Carlo Erba.

General Procedure for the Synthesis of Adducts 4a/4b
m-Chloroperbenzoic acid (7.4 g, of 75% wet acid, 32 mmol) was added to a solution of racemic α-ionone isomer 3 (7 g, 30 mmol) in methylene chloride (75 mL) at 0 °C . The reaction mixture was stirred at 0 °C for 2 h and then filtered in order to remove the m-clorobenzoic acid precipitate. The organic phase was washed with saturated Na 2 SO 3 solution (50 mL) and saturated NaHCO 3 solution (50 mL), respectively, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (hexane/Et 2 O 9:1) to give the corresponding α-epoxy-derivatives.

General Procedure for the Synthesis of Adducts 5a/5b
H 2 (360 mL, 1 equiv) was adsorbed of a solution of 4a or 4b (4.5 g, 19mmol, 1 equiv) in EtOAc (150 mL) and excess of Rany-Ni for 2 h. The reaction mixture was filtered off and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (hexane/ EtOAc 9:1) to give the corresponding product.

General Procedure for the Synthesis of Adducts 6a/6b
nBuLi (3.0 mL of a 10 M solution in hexane) was added dropwise to a cooled (−78 °C ) solution of iPr 2 NH (5.3 g, 50 mmol) in dry THF (90 mL) under nitrogen. The mixture was stirred at this temperature for 30 min. then a solution of the epoxide 5a or 5b (2.5 g, 10 mmol) in dry THF (20 mL) was added dropwise. The reaction was gradually warmed to r.t (1 h) and then was heated under reflux until no more starting epoxide was detected by TLC analysis (3 h). After cooling to room temperature, the mixture was poured into a mixture of crushed ice and 5% HCl solution. (80 mL) and extracted with Et 2 O (3 × 200 mL). The organic phase was successively washed with saturated aqueous NH 4 Cl solution (100 mL), brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by chromatography (eluting from hexane/AcOEt 9:1 to hexane/AcOEt 1:1) to give allylic alcohol.
In a round bottom flask, thiophenol (2.6 g, 23.54mmol, 1.2 equiv) was dissolved in DMF (30 mL), NaH (1.4 g 60%, 3 equiv) was added portion wise. After 15 min, TsCl (6.2 g, 19.62 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then at 60 o C for 2.5 h, then cooled to room temperature 0.1 N NaOH (30 mL) was added and extracted with Et 2 O, the organic phase was washed with water, brine, dried over Na 2 SO 4 , and concentrated under reduced pressure, and the crude was purified by CC using nhexane:EtOAc 100:2; 4.8 g, 95% yield.