domain: chim phys

text:
Pauline Chaumont-Olive

Jorge Sánchez-Quesada

Ana María Collado Pérez

Janine Cossy

Synthetic approaches to the Damascone and Damascenone isomers

Keywords:

Introduction

The essence of the Bulgarian rose, the Damask rose (Rosa Damascena mill.), has been one of the oldest essence explored as it contains different organoleptic compounds with a large diversity of flavors and fragrances. [START_REF] Ohloff | [END_REF][2][3][4][5][6][START_REF] Mannschreck | [END_REF][START_REF] Schaefer | Natural Products in the Chemical Industry[END_REF][START_REF] Dunkel | [END_REF] With a low threshold concentration, some of these constituents stand for an important source of odors for flavor and fragrance companies such as plum, cooked apple-like, rose, tobacco, black tea, wood, honey, etc. This essence has been used since the 80's in the composition of fragrances, soaps, cosmetic powders and detergents. 10,11 The complex composition of the essential oil of the Bulgarian rose has been elucidated in part by Kováts between 1962 and 1967, who identified 127 constituents using two-dimensional preparative gas chromatography for the isolation and spectroscopic analytical methods, this study being of "enormous economic importance". 12 Since then, the number of identified constituents has more than doubled. [START_REF] Ohloff | [END_REF] During these studies, -damascenone has been identified as a 0.1% constituent of the extract of the Bulgarian rose. This compound possesses a powerful floral rose odor, which can be detected at very low concentration and represents 70% of the relative proportion of the rose oil in scent units.

In 1970, the structure and the first synthesis of -damascone, -damascone and -damascenone were reported by Demole et al. at Firmenich and Kováts from the Chemical Laboratory, ETH Zürich. 13,14 The origin of the names, damascone and damascenone, is damascene coming from the Damask rose "damasc" and "one" or "enone" related to their chemical functionalities, and the -, -,and -nomenclature of damascones is related to ionones as damascones are finally isoionones (Fig. 1). [START_REF] Kraft | Designing Damascone-and Ionone-like Odorants[END_REF] The biosynthesis of natural products can be highly useful to understand the origin of compounds and to design suitable and efficient synthetic routes. Following the identification of the chemical structure of damascones, in 1973 Ohloff et al. in their initial research at Firminich as well as Isoe et al., reported their discoveries on the biosynthesis of these natural products. [START_REF] Ohloff | [END_REF]17 Based on results published in 1968 on the origin of -ionone from carotene, [18][19][20][21][22][23] the authors reported that damascones were formed through the same biosynthetic pathway. This metabolic pathway was mainly confirmed by mimicking the in vivo degradation of damascones with in vitro model reactions applied to -ionone or other carotenoids metabolites, which lead to -damascenone. This work was then completed by numerous experiments affording the complete damascone biosynthetic route, which is finally part of C13-norisoprenoids: a class of volatile carotenoid metabolites. [START_REF] Schaefer | Natural Products in the Chemical Industry[END_REF][START_REF] Fleischmann | Carotenoid Cleavage Enzymes in Animals and Plants[END_REF][START_REF] Suzuki | Identification of β-Damascenone Progenitors and Their Biogenesis in Rose Flowers (Rosa Damascena Mill.)[END_REF][START_REF] Waché | Production of Aroma Compounds by Enzymatic Cooxidation of Carotenoids[END_REF][START_REF] Bezman | [END_REF][28] Fig. 1. Damask rose: Structure of damascones and damascenones and their fragrances.

Considering the biosynthetic pathway, allowing the formation of -ionone from -carotene, the first step is an enzymatic oxidative bond cleavage of the C9-C10 double bond of -carotene by -carotene-dioxygenase. This enzyme produces singlet oxygen, a highly reactive entity towards double bonds. After the oxidative cleavage of -carotene, the resulting -ionone undergoes another oxidation step giving the allenic intermediate 1, followed by a Meyer-Shuster rearrangement to afford intermediate 2. 29 -Damascone is then formed by dehydration under acidic conditions (Scheme 1, Pathway A).

Another biosynthetic pathway to damascones can be considered from-carotene as this latter can be enzymatically degraded to neoxanthin after several oxidation steps. The cleavage of neoxanthin by carotenoid enzymes, mainly xanthine oxidase, leads to the Grasshopper ketone, an allenic carotenoid. This ketone is then enzymatically reduced to Grasshopper alcohol which undergoes a Meyer-Shuster rearrangement affording the enolized hydroxy ketone 3. After several dehydration steps under acidic conditions, -damascenone is produced. It is worth mentioning that this biosynthetic route can also lead to -damascone via deoxyneoxanthin which is also a metabolite issued from the enzymatic oxidation of-carotene (Scheme 1, Pathway B). Scheme 1. Biosynthesis of -damascone and -damascenone from -carotene and derivatives.

The biosynthesis of damascones from -carotene explains the variety of odors and their ubiquitous presence in other natural sources than Damask rose. Their close structure to ionones is also enlightened as the ionones are also issued from -carotene. [30][31][32][33][34][START_REF] Roberts | Developments in the Isolation and Characterization of β-Damascenone Precursors from Apples[END_REF][START_REF] Skouroumounis | The Formation of β-Damascenone in Wine[END_REF][START_REF] Winterhalter | Carotenoid-Derived Aroma Compounds: An Introduction[END_REF][START_REF] Crupi | [END_REF][39][40] Since their early discovery, damascones and damascenones are of high interest for fragrance companies. Due to the number of reported syntheses, 4,41 we will only focus on the most important syntheses. Three main strategies have been used to access damascones and damascenones:

-From ionones by 1,3-carbonyl migration (Scheme 2, eq 1).

-From or via cyclohexenyl aldehydes, esters and acids, such as I, by attack of a nucleophile on the carbonyl group. To access the cyclohexenyl derivatives, from linear starting materials, the cyclization step can be at early or at late stage (Scheme 2, eq 2).

-From cyclohexenyl methylketones, such as II, by using an aldolization/crotonization sequence (Scheme 2, eq 3).

Scheme 2. General synthetic routes to access damascones and damascenones.

In this review, the synthesis of damascones and damascenones will be classified according to the starting cyclic substrates (ionone, cyclocitral, cyclogeranate and cyclohexenyl methylketones) and subdivided according to the starting materials used to produce the cyclic substrate. The multigram scale syntheses will be highlighted by notifying the number of grams or kilograms obtained.

-Damascone

The first syntheses of -damascone were realized in a racemic form and efforts have been made to access selectively the two enantiomers.

Racemic syntheses

Syntheses of -damascone from cheap starting materials were realized. One of the most evident starting material to access -damascone is -ionone. As -damascone possesses the -ionone carbon skeleton, only a 1,3-carbonyl transposition is necessary to obtain -damascone.

. 1 . 1 . Fr o m i o n o n e

To realize the 1,3-transposition of the -ionone carbonyl, several rearrangements were used: a Wharton rearrangement, a Büchi-Vederas rearrangement and a Meisenheimer rearrangement.

Wharton rearrangement

To transform -ionone to -damascone, Luche et al. applied a Wharton rearrangement to an epoxy-hydrazone. 42 This compound was obtained from -ionone (epoxidation/hydrazone formation) via epoxy-ionone 4 and, epoxy-hydrazone 5 was converted to -iso-ionol under basic conditions (t-BuOK, THF/pentane, -100 °C to -85 °C). It is worth mentioning that the use of t-BuOK is necessary to realize the deprotonation of the diazene intermediate A to avoid the formation of bicyclic side-products. 43 -iso-Ionol was then oxidized to -damascone by using the Dess-Martin periodinane (4 steps, overall yield = 58%) (Scheme 3).

We have to mention that an alternative to the Wharton rearrangement was applied to an -bromo-epoxyde. 44 Epoxyionone 4 was reduced to epoxy-ionol 6 (NaBH 4 , CeCl 3 , MeOH, 0 °C) and this latter was transformed to the corresponding -bromo-epoxide 7 (CBr 4 , PPh 3 , Py). The bromide intermediate underwent a reductive debromination/ring-opening of the epoxide, via a radical intermediate or an anion generated by zinc (Zn, CuI, EtOH, H 2 O), and -iso-ionol was isolated in high yield (91%) as an equimolar mixture of (Z)-and (E)-stereoisomers. (eq 2) (eq 3)

I

II

Aldolization/ crotonization

Scheme 3. Synthesis of -damascone using a Wharton rearrangement.

After oxidation of the resulting (E)-and (Z)-allylic alcohols (MnO 2 , pentane), the isomerization of the double bond to the (E)isomer was achieved under acidic conditions (p-TsOH, refluxing THF). -Damascone was produced in 6 steps from -ionone with an overall yield similar to the one obtained by applying a Wharton rearrangement to 5 (59% versus 58%), however with two more steps (6 steps versus 4 steps) (Scheme 4). Scheme 4. Synthesis of -damascone by reductive ring-opening of an -bromo epoxide.

Büchi-Vederas rearrangement

Büchi and Vederas took advantage of the Crabbé et al. work 45 to synthesize -damascone from -ionone by rearrangement of an isoxazole. 46 -Ionone was treated with hydroxylamine hydrochloride to produce an -ionone-oxime intermediate, which after an iodocyclization/elimination sequence (KI, I 2 , NaHCO 3 , refluxing THF/H 2 O), led to isoxazole 8. A Birch reduction (NH 3(l) , t-BuOH, THF) applied to 8 produced the amino-ketone intermediate B which after an acidic treatment (p-TsOH, refluxing toluene), was converted to -damascone. If only 4 steps were necessary to access -damascone from -ionone, the overall yield is modest (38%) (Scheme 5).

An improvement of the Büchi-Vederas rearrangement was reported by Xu et al. via an isoxazole intermediate obtained in 3 steps from -ionone. 47 At first, -ionone was converted to an -ionone-oxime (NaOAc, NH 2 OH.HCl, EtOH/H 2 O) and, after an epoxidation [H 2 O 2 , cetyltrimethylammonium hydroperoxide (CTAOH), LiOH, H 2 O], the resulting epoxy-oxime 9 was converted to isoxazole 8 under acidic conditions (HCl, refluxing cyclohexane). Scheme 5. Synthesis of-damascone from -ionone using a Büchi-Vederas rearrangement.

The transformation of isoxazole 8 to -damascone was achieved in one step using sodium in EtOH (refluxing cyclohexane). This straightforward synthesis of -damascone from -ionone is competitive with the Luche et al. synthesis (4 steps, overall yield = 55%) (Scheme 6). Scheme 6. Synthesis of -damascone from -ionone via an epoxy-oxime intermediate.

It is worth mentioning that a less effective Büchi-Vederas rearrangement was reported by Schulte-Elte et al. 48,49 [2,3]-Meisenheimer rearrangement Rautenstrauch et al. took advantage of the [2,3]-Meisenheimer rearrangement 50 to synthetize -damascone. 51 After reduction of -ionone to -ionol (NaBH 4 , THF, 50 °C), this latter was transformed to the corresponding bromide (PBr 3 , pentane), which after treatment with N,N-dimethylamine, afforded -N-ionyl-N,N-dimethylamine 10. This tertiary amine was oxidized to the key N-amine-oxide intermediate which was rearranged to O-damascyl-N,N-dimethylhydroxyl-amine 11 according to a Meisenheimer rearrangement (35 °C, 0.05 Torr). Compound 11 was then N-alkylated (FSO 2 OMe, Et 2 O, 5 °C) to intermediate C and, after treatment under basic conditions (NaOH, 80 °C), a Hoffman elimination took place to afford -damascone (6 steps, overall yield = 14%) (Scheme 7).

The two most efficient syntheses of -damascone from -ionone were the Luche et al. synthesis, using a Wharton rearrangement, and the Xu et al. synthesis, using a Büchi-Vederas rearrangement. Scheme 7. Synthesis of -damascone from -ionol using a Meisenheimer rearrangement.

. 1 . . Via c yc l o c i t r a l

The synthesis of -damascone from different starting materials, precursors of -cyclocitral, were developed as -cyclocitral can be transformed easily to -iso-ionol.

From citral

The first synthesis of -damascone from -cyclocitral, prepared from citral by an intramolecular cyclization, 52,53 was reported by Demole et al. 14 Treatment of citral with aniline led to the corresponding Schiff base which was cyclized under acidic conditions (H 2 SO 4 , H 2 O/Et 2 O, -20 °C) to produce a mixture of and -cyclocitrals in a ratio of 2 to 1 (70%). 54,55 These cyclocitrals were separated by distillation yielding α-cyclocitral in 47% yield. Addition of 1-propenyllithium to -cyclocitral led to the corresponding -iso-ionol which was then oxidized by the Sarrett reagent (CrO 3 , Py) to afford the expected -damascone (3 steps, overall yield = 16%) (Scheme 8). Scheme 8. Synthesis of -damascone from citral.

Kovàts et al. and Ruedenauer et al. reported the synthesis of -damascone from citral with a late stage cyclization. 56,57,58 Citral was transformed to trienone 13 via the allylic alcohol 12 (propenylMgBr, THF then MnO 2 , CH 2 Cl 2 ) which was then cyclized under acidic conditions (BF 3 .OEt 2 , refluxing benzene) to produce -damascone with an overall yield of 26% (Scheme 9, eq 1). The overall yield of -damascone was increased to 32% by replacing the vinyl Grignard reagent by the allyl Grignard reagent (Scheme 9, eq 2). After oxidation of the obtained homo-allylic alcohol 12' [Fe(NO 3 ) 3 .9H 2 O, TEMPO, NaCl, O 2 , toluene], the obtained linear non-conjugated enone 13 was cyclized under acidic conditions (H 3 PO 4 , toluene, 80 °C) to produce -damascone (Scheme 9). Scheme 9. Synthesis of -damascone from citral.

From -pyronene

Another starting material than citral was used by Delmond et al. to access -damascone: the -pyronene, a terpenic compound easily accessible by pyrolysis of -pinene via myrcene. 59 A chemoselective epoxidation of the exo cyclic double bond of -pyronene (m-CPBA, Et 2 O, 0 °C) led to epoxy-pyronene 14 (30%). After treatment with allylmagnesium bromide, epoxypyronene 14 was converted to homo-allylic alcohol 15 via -cyclocitral, formed in situ by rearrangement of the epoxide induced by the Grignard reagent acting as a Lewis acid. After a one-pot oxidation/isomerization sequence using PCC (CH 2 Cl 2 , rt), -damascone was isolated (3 steps, overall yield = 25%) (Scheme 10). Scheme 10. Synthesis of -damascone from -pyronene.

Even if citral or -pyronene can be transformed to -damascone in 3 to 4 steps, the overall yields are always very modest (16% to 32%).

. 1 . 3 . Fr o m cy cl o g e r a n i c a ci d a n d d er i va t i v es

-Cyclogeranic acid and derivatives were transformed to -damascone. It is worth mentioning that -cyclogeranic acid and derivatives can be prepared by cyclization of -geranic acid.

From -cyclogeranic acid After the generation of ketene D from -cyclogeranic acid [(COCl) 2 , benzene, then Et 3 N], 60 the addition of allylmagnesium bromide afforded a non-conjugated enone which was isomerized under acidic conditions (p-TsOH, rt, 28 h) to produce -damascone 61 (3 steps, overall yield = 25%) (Scheme 11). Scheme 11. Synthesis of -damascone from -cyclogeranic acid via a ketene intermediate.

The overall yield in -damascone was doubled by Chen et al. who synthesized the Weinreb amide 16 from cyclogeranic acid. After addition of allylmagnesium bromide to 16 and isomerization of the double bond, -damascone was isolated (4 steps, overall yield = 43%). 62 By using this sequence of reactions, the synthesis of 50 g of -damascone was possible (Scheme 12). Scheme 12. Synthesis of -damascone from -cylogeranic acid via Weinreb amide 16.

From methyl-cyclogeranate

Snowden et al., in collaboration with Schulte-Elte, synthesized -damascone from methyl -cyclogeranate. [63][64][65] After a double addition of allylmagnesium bromide on methyl cyclogeranate, the obtained tertiary alcohol 17 was deprotonated (KH, HMPA, rt to 80 °C), generating a non-conjugated enone which was then transformed to -damascone under acidic conditions (p-TsOH, refluxing THF) (3 steps, overall yield = 35%). The overall yield in -damascone was improved to 85% by Fehr et al. 66 The main improvement consists of the treatment of methyl -cyclogeranate with an equimolecular mixture of allylmagnesium bromide and LDA. Under these conditions, the addition of allylmagnesium bromide to the enone intermediate cannot happen as enolate E-Li is formed. After workup and acidic treatment, -damascone was obtained with an excellent yield (85%). Multigram of -damascone were obtained by generating the E-Li intermediate (18 g) (Scheme 13). Scheme 13. Synthesis of -damascone from -cyclogeranate.

From a functionalized -cyclogeranate derivative -Damascone was also synthesized from a functionalized -cyclogeranate derivative obtained from ethyl acetoacetate. 67 Ethyl acetoacetate was condensed with acetone (BF 3 .OEt 2 , Et 2 O) to produce a mixture of two regio-isomers 18 and 18' in a 2 to 1 ratio. The difficult separation of these two isomers was avoided by treatment of the mixture with 1,2-ethanedithiol, as only isomer 18 was reacting to produce thioketal 19 (28% over two steps). The latter was then converted to allylic alcohol 21 after a reduction/oxidation sequence and treatment with propenyl magnesium bromide. Allylic alcohol 21 was isolated in 93% yield as a mixture of (E)-and (Z)-isomers in an equimolar ratio. After separation of these two stereoisomers, by preparative thinlayer chromatography on silica, the (E)-isomer was isolated and, after a two-step sequence (oxidation/reduction of the thioketal), -damascone was obtained in a very low overall yield (7 steps, overall yield = 8%) (Scheme 14). Scheme 14. Synthesis of -damascone from a functionalized -cyclogeranate.

. 1 . 4 . Fr o m cy cl o h e xen yl m e t h y l ke t o n e

Cyclohexenyl methylketones can be prepared by a Diels-Alder reaction and then transformed to -damascone by an aldolization/crotonization sequence.

From isoprene

Cookson et al. reported the synthesis of -cyclohexenyl methylketone 23 through a Lewis acid-catalyzed inverse electron-demand Diels-Alder reaction. 68,69 At first, the electronpoor diene, dienone 22, was synthesized from isoprene and acetyl chloride as a mixture of (E)-and (Z)-isomers in a 1 to 4 ratio (SnCl 4 , PhNEt 2 ). This dienone 22 was then involved in an inverse electron-demand Diels-Alder reaction with isobutene (AlCl 3 , CH 2 Cl 2 ) affording -cyclohexenyl methylketone 23 in very low yield (12%) due to the formation of numerous side products. However, the transformation of 23 to -damascone was efficiently achieved by using an aldolization/crotonization sequence under the Zimmerman's conditions [PhN(Me)MgBr, CH 3 CHO, benzene then NaOAc, (AcO) 2 , 100 °C]. 70 It is worth mentioning that the use of N-methyl aniline magnesium bromide is very important to obtain a good yield in the aldol product (4 steps, overall yield = 3%) (Scheme 15). Scheme 15. Synthesis of -damascone from -cyclohexene methylketone by an aldolization/crotonization sequence.

From penta-1,3-diene

Yamamoto et al. reported an industrial process for the synthesis of -damascone by replacing the low yielding inverse electron-demand Diels-Alder reaction by a normal electrondemand Diels-Alder reaction between pentan-1,3-diene and mesityl oxide, which afforded -cyclohexenyl methylketone 24 (63%). 71 The isomerization of the double bond in 24 (RhCl 3 .3H 2 O, refluxing EtOH) led to 23, which was then converted to -damascone through an aldolization/crotonization sequence [PhN(Me)MgBr, CH 3 CHO, benzene then NaOAc, (AcO) 2 , 100 °C]. According to this sequence of reactions, the synthesis of -damascone was realized on multigram scale (31 g) with an overall yield of 32% (4 steps). It is worth pointing out that this process was highlighted in Org. Process Res. Dev. as ''a novel route to useful intermediates that may be cheaper than alternative processes" (Scheme 16). 72 Scheme 16. Synthesis of -damascone from -cyclohexenyl methylketone 24.

. 1 . 5 . M i s c el l a n eo u s From cyclohexenyl borane

Another strategy to access -damascone from cyclohexenyl derivatives was reported by Zaidlewicz et al. as these authors used a cyclohexenylborane, prepared from 2,4,4-trimethyl 2-cyclohexenone 25, to prepare -damascone. 73 Cyclohexenone 25 was transformed to allylborane F via diene 26, using a Shapiro reaction (TsNHNH 2 then MeLi), followed by a regioselective hydroboration (9-BBN, THF, rt then reflux). The allylboration of crotonaldehyde using F led to -iso-ionol which was then oxidized (PDC, DMF, rt) to produce -damascone, however with a low overall yield (6 steps, overall yield = 8%) (Scheme 17). Scheme 17. Synthesis of -damascone by allylboration of crotonaldehyde.

From a -hydroxy-sulfide

Starting from -hydroxy-sulfide 27, the six-membered ring of -damascone was built at a late stage. 74 -Hydroxy-sulfide 27 was converted to 32 (6 steps), precursor of the cyclized product 33. At first, -hydroxy-sulfide 27 was transformed to dienic sulfone 28 in 3 steps (chlorination/oxidation/nucleophilic substitution), which was then alkylated with allylbromide (n-BuLi, allylbromide, HMPA, -78 °C) to produce sulfone 30. After conversion of this sulfone to ketone 31 (LDA then MoOPH, -78 °C), an isomerization/1,4-addition of methylate (MeONa, MeOH, rt) sequence led to the methoxy ketone 32, which was then cyclized to 33 (SnCl 4 , CH 2 Cl 2 , 0 °C to rt). After treatment of 33 under acidic conditions (p-TsOH), -damascone was isolated (8 steps, overall yield = 13%) (Scheme 18). SO

From methyl heptenone

A three-step synthesis of -damascone was reported by Wei et al. from dehydrolinalool with an a excellent overall yield (70%). 75 Dehydrolinalool was obtained from 6-methyl-hept-5-en-2-one and then converted to dienylol 34 by allylation under basic conditions (allylbromide, K 2 CO 3 , KOH, CuCl, MeOH, toluene). After a Meyer-Schuster rearrangement/ isomerization sequence (pentan-2,4-dione, anisic acid, DMSO/ toluene, 100 °C), trienone 13 was isolated with an excellent yield (92%). -Damascone was obtained from 13 after treatment under acidic conditions (H 3 PO 4 , toluene, 60 °C). This synthesis of -damascone is very efficient and was run on multigram scale (62 g) with an overall yield of 70% (Scheme 19). If the syntheses -damascone from-ionone and citral using a rearrangement as a key step are efficient, the most efficient synthesis is the one implying a Meyer-Schuster rearrangement.

Enantioselective syntheses

Due to the importance of chirality for organoleptic compounds, [START_REF] Pickenhagen | Enantioselectivity in Odor Perception[END_REF][START_REF] Wetzel | [END_REF][78] the two enantiomers of -damascone were separated by chiral chromatography 79 to evaluate their distinctive odor and olfactive power. As a continuum, the syntheses of these two enantiomers were explored from enantio-enriched starting materials such as ionones, cyclocitrals and cyclohexenyl methylketones, or from racemic starting materials by realizing an enantioselective protonation of an enolate, an enantioselective reduction of a ketone, or an enzymatic resolution of a diol. 80,81

. . 1 . Fr o m i o n o n e From (±)--ionone by enzymatic resolution of a diol

By using an enzymatic resolution of a 1,3-diol synthesized from (±)--ionone, (R)-()--damascone and (S)-(-)-damascone were synthesized by Serra and Fuganti. 82 At first, (±)--ionone was transformed to epoxide (±)-4 (NaOH, H 2 O 2 , MeOH) and this latter was converted to the anti-1,3-diol 35 (ring-opening of the epoxide by generating a ketyl radical by Al/Hg, THF/EtOH/H 2 O), followed by a diastereoselective reduction of the obtained 1,3-hydroxyketone [Me 4 NHB(OAc) 2 , MeCN/AcOH, -20 °C to -10 °C]. An enzymatic resolution of this diol (Lipase PS, vinyl acetate/t-BuOMe) led to 1,3-diol (+)-35 (48%, ee = 94%) and to hydroxyacetate (-)-36 (44%, ee > 99%). Diol (+)-35 was transformed to (R)-(+)--damascone in 3 steps (acetylation/oxidation/elimination) with an overall yield of 13%, and to (S)-(-)--damascone in 2 steps (oxidation/ elimination) with an overall yield of 24%. The synthesis of (S)-(-)-damascone was patented by Tianyi et al. and it is worth mentioning that the only modification of the procedure developed by Serra et al. was the replacement of DBU by KOH to realize the final elimination step. 83 Under these conditions, (-)-36 was transformed to (S)-(-)--damascone in 95% yield and 5 g of (S)-(-)--damascone were obtained (Scheme 20). Scheme 20. Synthesis of (R)-(+)-and (S)-(-)--damascone by enzymatic resolution of 1,3-diol.

From (R)-(+)--ionone by chemical resolution

As (R)-and (S)--ionones can be obtained from (±)--ionone by chemical resolution, the (R)-and (S)--damascones were synthesized using the same synthetic scheme than the one used to syntesize (±)--damascone.

(±)--Ionone was condensed with (R)-menthylhydrazone (AcOH cat., NaOAc cat.) to furnish -ionone-(R)-(-)-menthylhydrazone 37. [84][85][86] As in EtOH (S)-(-)--ionone-(R)-(-)-menthylhydrazone (S,R)-37 is crystalline and (R,R)-37 soluble, the two diastereomers were separated. After an acidic treatment (phthalic anhydride, H 2 O reflux), (S)-(+)--ionone and (R)-(-)--ionone were respectively obtained and converted to enantio-enriched -damascones (Scheme 21). Scheme 21. Resolution of (±)--ionone using (R)-(-)menthylhydrazone.

Wharton rearrangement

As for the racemic synthesis, a Wharton rearrangement was used by Ohloff et al. to transform (R)-(+)--ionone to (R)-(+)-damascone (cf Scheme 4) however, the use of slightly different conditions was detrimental to the overall yield of -damascone. 13 A highly diastereomeric epoxidation of (R)-(+)--ionone (NaOH, H 2 O 2 , MeOH, 4 °C) was achieved and the Wharton rearrangement was applied to epoxy ketone (+)-4 without any additional base (NH 2 NH 2 , MeOH) affording (R)-(+)--iso-ionol in low yield (20%). After oxidation (MnO 2 , acetone, rt then 105 °C), (R)-(+)--damascone was produced. It is worth mentioning that the overall yield was not reported as (R)-(+)-damascone was contaminated by side-products (Scheme 22). Scheme 22. Synthesis of (R)-(+)--damascone from (R)-(+)-ionone using a Wharton rearrangement.

Dihydroxylation/Peterson elimination sequence

Taddei et al. reported the synthesis of (R)-(+)--damascone from (R)-(+)--ionone by using a Peterson elimination as the key step. 87 (R)-(+)--Ionone was converted to allylsilane 38 in 3 steps (reduction/acylation/silylation) and, after a dihydroxylation (OsO 4 , Me 3 NO.3H 2 O, THF/H 2 O, 0 °C) and treatment of the resulting silyl diol 39 with KH (THF, rt), -iso-ionol was formed. After oxidation, (R)-(+)--damascone (MnO 2 , acetone, rt) was isolated with a low overall yield of 22% (6 steps). It is worth mentioning that the ee of the obtained (R)-(+)-damascone was not reported and only the [] D was indicated. Compared to the [] D reported by Oloff et al., it seems that by using this sequence of reactions, (R)-(+)-damascone is also contaminated by side-products (Scheme 23). Scheme 23. Synthesis of (R)-(+)--damascone from (R)-(+)-ionone using a Peterson elimination.

. . . Via o p t i ca l l y a ct i ve cy cl o c i t r a l From citral

Yamada et al. reported a non-efficient synthesis of (R)-(+)-damascone from citral. 88 When citral was treated with the optically active 2-isopropylpyrrolidine under acidic conditions (H 2 SO 4 , H 2 O, 0 °C), the yield in (R)-(+)--cyclocitral was low (26%) as well as the enantiomeric excess (ee = 27%). However, the synthesis of enantio-enriched (R)-(+)--damascone was completed from the enantio-enriched -cyclocitral by treatment with 1-propenyllithium (Et 2 O, rt) and the resulting allylic alcohol was oxidized to (R)-(+)--damascone (CrO 3 , Py). Even if a good transfer of chirality from (R)-(+)--cyclocitral to (R)-(+)-damascone took place, the enantiomeric excess of (R)-(+)-damascone is low (ee = 27%) as well as the overall yield (3 steps, overall yield = 17%) (Scheme 24).

From neryl acetate

Vidari et al. achieved the synthesis of (S)-(-)--damascone from neryl acetate. 89 Taking advantage of their studies on the regioselective asymmetric Sharpless hydroxylation of nonconjugated dienes using AD-mix- (t-BuOH/H 2 O, 0 °C) 90 the optically active epoxide 41 was synthesized via diol 40, and then transformed to (S)-(-)--cyclocitral in 7 steps (cyclization/ protection/mesylation/elimination/hydrogenation/deprotection/ oxidation). It is worth mentioning that the hydrogenation of diene, present in the 6-membered ring of 43, is chemoselective [H 2 , (Rh/Al 2 O 3 ), AcOEt] and a good transfer of chirality from 40 to (S)-(-)--cyclocitral was observed (ee = 97%). After treatment of (S)-(-)--cyclocitral with allyltributyltin (AllylSnBu 3 , BF 3 .OEt 2 , CH 2 Cl 2 ), the resulting homo-allylic alcohol was oxidized (DMP, CH 2 Cl 2 , rt) and the non-conjugated enone was isomerized to (S)-(-)--damascone (DBU, CH 2 Cl 2 , rt). If the ee is excellent (99%), the overall yield of the synthesis is low (8%). Noting that the Sharpless dihydroxylation could also produce the (R)-(+)--damascone from neryl acetate using AD-mix-(Scheme 25). Scheme 25. Synthesis of (S)-(-)--damascone from neryl acetate via (S)-(-)--cyclocitral.

. . 3 . Fr o m ( ± ) -cy cl o g er a n i c a c i d b y en a n t i o s e l e ct i ve p r o t o n a t i o n

The enantio-enriched (R)-(+)-and (S)-(-)--damascones were efficiently obtained by the enantioselective protonation of enolates. In 1988, Fehr et al. reported the enantioselective protonation of enolates to access optically active ketones, esters and thio-esters, [91][92][93][94][95][96] and this method was applied to the synthesis of optically active damascones.

Protonation of a keto-enolate

The nucleophilic attack of ketene D, generated from (±)-cyclogeranic acid, by allylmagnesium bromide led to a magnesium enolate intermediate E'-MgCl which was then enantioselectively protonated by N-isopropylephedrine to produce either (R)-(+)-or (S)-(-)--damascone. 97 The best conditions to induce a good enantiomeric excess revealed to be the in situ generation of 1 equivalent of lithium N-isopropylephedrine alkoxide, as this alkoxide generates an equimolar enolate/alkoxide complex and, after addition of 2 equivalents of N-isopropyl-ephedrine, the enantioselective protonation of a mixed lithium-magnesium aggregate took place, affording the expected enantio-enriched non-conjugated enone. After isomerization of the enone (Al 2 O 3 or p-TsOH, toluene, rt), the expected optically active damascones were isolated. The use of (S,R)-N-isopropylephedrine led to (R)-(+)--damascone (34% yield, ee = 98% after recrystallization) and the use of (R,S)-Nisopropylephedrine led to (S)-(-)--damascone with an identical yield and enantiomeric excess. This enantioselective protonation of the enolate intermediate E'-MgCl allowed the preparation of 6 g of each enantiomer of -damascone (Scheme 26a).

A catalytic enantioselective protonation is possible due to the presence of the acidic proton H1 in the non-conjugated enone 44. 98 When the lithium enolate E'-Li was treated with only 0.3 equivalent of (R,S)-N-isopropylephedrine, (S)-(-)--damascone was obtained in 86% yield and 93% ee. By performing a control reaction, the authors demonstrated that ketone 44 did not enantioselectively protonate enolate E'-Li in the absence of a chiral proton source. It is worth mentioning that, in the case of the lithium enolate, it is not necessary to form an organometallic aggregate to obtain a high ee for -damascone, as in the case of the magnesium enolate (Scheme 26b). Scheme 26. Enantioselective protonation. Synthesis of (R)-(+)and (S)-(-)--damascones from -cyclogeranic acid.

When the enol intermediate E'-H, obtained by addition of allylmagnesium bromide on ketene D, was deprotonated/ reprotonated with a catalytic amount of lithium (R,S)-N-isopropylephedrine alkoxide (0.33 equiv), ketone 44 was isolated with a good ee of 76% and in 77% yield and then converted to -damascone (Scheme 27). 99 Scheme 27. Catalytic enantioselective protonation.

Enantioselective protonation of lithium thio-ester enolate

Fehr et al. compared the enantio-discrimination of the protonation of a lithium keto-enolate with a lithium thio-ester enolate using the same chiral inductor: N-isopropylephedrine. 100 The lithium thio-ester enolate was generated from (±)--thiocyclogeranate (n-BuLi, THF, -100 °C), and then protonated either with (S,R)-(+)-N-isopropylephedrine, leading to (R)-(+)-thio-cyclogeranate (ee = 99%, yield = 87%), or by the (R,S)-(-)-N-isopropylephedrine, producing (S)-(-)--thio-cyclogeranate (ee = 99%, yield = 87%). By addition of allylmagnesium bromide followed by an acidic treatment, (S)-(-)--thio-cyclogeranate was transformed to (S)-(-)--damascone (ee = 99%, overall yield = 67%) and 27 g of this compound were prepared (Scheme 28). Scheme 28. Synthesis of (S)-(-)--damascone from -cyclogeranic acid via -thio-cyclogeranate enolate.

The optically active (S)-(-)--thio-cyclogeranate was generated from ketene D, obtained -cyclogeranic acid, by addition of lithium thiophenolate followed by an enantioselective protonation of the enolate, using 1 equivalent of (R,S)-(-)-Nisopropylephedrine. (S)-(-)--Thio-cyclogeranate was isolated with a high ee (ee = 95%, yield = 84%) (Scheme 29). 101 A catalytic procedure was also set up, consisting of the treatment of ketene D with a catalytic amount of lithium (R,S)-(-)-Nisopropylephedrine alkoxide (5 mol %) in the presence of 4 mol % of thiophenol, followed by a slow addition of 0.96 equivalent of thiophenol at -28 °C. This second procedure led to (S)-(-)--thio-cyclogeranate with an ee of 89%. These transformations were achieved on gram scale (around 3 g). (S)-(-)--Thio-cyclogeranate was then converted to the corresponding enantio-enriched (S)-(-)--damascone (3 steps, overall yield = 67%) (Scheme 29). Scheme 29. Synthesis of enantio-enriched (S)-(-)--thiocyclogeranate from ketene intermediate.

. . 4 . Fr o m a cy cl o h exen o n e d e r i va t i ve b y a n en a n t i o s e l e ct i ve r ea r r a n g emen t

Mori et al. achieved the synthesis of (S)-(-)--damascone by using a [2,3]-Wittig rearrangement. 102 To access the precursors of the Wittig rearrangement, 2,4,4-trimethylcyclohex-2-en-1-one 25 was enantioselectively reduced (BH 3 .THF, CBS, ee = 96%) and the resulting alcohol 45 was converted either to stannyl ether 46 or to propargyl ether 47. Both of these ethers were rearranged to propargyl alcohol 49 (n-Buli with or without TMEDA, -85 °C, -78 °C) and then transformed to (S)-(-)--damascone after a reduction/oxidation sequence (LiAlH 4 , NaOMe, THF then MnO 2 , acetone, rt). It is worth mentioning that the access to (S)-(-)-damascone from propargylic ester 47 is more straightforward than from stannyl ether 46. However, the yield in (S)-(-)-damascone from 49 depends on the synthetic route used to produce this latter intermediate. The synthesis of 49 by Route B affords by-products during the Wittig rearrangement, which could not be separated from 49, and dramatically affects the yield of (S)-(-)--damascone during the last reduction/oxidation sequence (Scheme 30).

Scheme 30. Synthesis of (S)-(-)--damascone by a [2,3]-Wittig rearrangement.

Among all the reported methods to access the optically (R)-(+)-and (S)-(-)--damascones, the asymmetric protonation of a lithium thio-enolate synthesized from (±)--cyclogeranic acid, reported by Fehr et al., seems to be the most powerful method in terms of enantioselectivity. In addition, (±)--cyclogeranic acid, is a cheap and commercially available compound and the enantioselective protonation can be performed on gram scale.

-Damascone

-Damascone was synthesized from -ionone, -cyclocitral and -cyclogeranates using the strategies developed to produce -damascone. However, some more specific strategies were developed to produce -damascone by using, for example, an Overman rearrangement. It is worth pointing out thatdamascone can also be synthesized in good yield by selective hydrogenation of -damascenone (Lindlar cat., H 2 , AcOEt, 90%) (Scheme 31). [START_REF][END_REF]104 Scheme 31. Synthesis of -damascone from -damascenone.

From -ionone

Wharton rearrangement

As for the formation of -ionone to -damascone by using a Wharton rearrangement, -ionone was transformed to -damascone by using also a Wharton rearrangement 42 applied to an epoxy-hydrazone or an epoxy-bromide intermediate 44 (Scheme 32, eq 1-2). Scheme 32. Synthesis of -damascone from -ionone using a Wharton rearrangement.

Büchi-Vederas rearrangement

Similarly to the transformation of -ionone to -damascone (cf Scheme 6 and Scheme 7), -ionone was transformed to damascone by using a Büchi-Vederas rearrangement. 46,47 This rearrangement allowed the synthesis of 6 g of -damascone (Scheme 33). 105 Scheme 33. Synthesis of -damascone from -ionone via a Büchi-Vederas rearrangement.

The most efficient synthesis of -damascone from -ionone is the synthesis reported in 2019 by Guanqun et al., allowing the synthesis of 169 g of -damascone. 106 Treatment of -iononeoxime 53 with a mixture of iodine and tert-butyl hydroperoxide led to -isoxazole 52, which was converted to -damascone in a one-step process using the rhodium catalyst H under an atmosphere of hydrogen (Scheme 34). Scheme 34. Synthesis of -damascone from -ionone oxime on multi-gram scale using a the Büchi-Vederas rearrangement.

Overman rearrangement

An efficient synthesis of -damascone was realized from -ionone by Zhixun et al. using an Overman rearrangement as the key step.

Epoxidation/ring-opening

Similarly to their synthesis of enantio-enriched -damascone (cf Scheme 20), Taddei et al. have synthesized -damascone from -ionone via an epoxy-silane intermediate. 87 Starting from -ionone, the enone was selectively reduced to the corresponding allylic alcohol. After acylation (Ac 2 O, Et 3 N, DMAP) and a S N2 reaction using TMS 2 CuLi.LiCN, the silyl derivative 55 was isolated. Epoxidation of the double bond of the allylic silane was achieved (m-CPBA, CH 2 Cl 2 ), and the resulting epoxy-silane was opened by treatment with tetra-n-butylammonium fluoride (TBAF, THF, rt), due to the generation of an anion to the epoxide which induces the epoxide ring-opening. The obtained -iso-ionol was oxidized (PDC, DMF, rt) to -damascone (6 steps, overall yield = 28%) (Scheme 36). Scheme 36. Synthesis of -damascone and -damascenone from -ionone via an allylsilane.

via Cyclocitral From citral

As reported previously,-cyclocitral can be synthesized from citral by condensation with aniline followed by an acidic treatment and distillation to separate-cyclocitral from -cyclocitral. -Cyclocitral was then converted to -iso-ionol in similar yields by addition of either 1-propenyllithium or 1-propenylmagnesium bromide (68%-65%). After oxidation of -iso-ionol (MnO 2 , pentane) followed by an acidic treatment (p-TsOH, benzene, rt), -damascone was isolated with a very low overall yield (4 steps, overall yield = 10%) (Scheme 37). 14 Scheme 37. Synthesis of -damascone from-cyclocitral.

Pelliciari et al. used another nucleophile than prop-1-enyl lihium or magnesium bromide to introduce the enone side chain of -damascone, i.e. the lithium anion of diazoacetone. 108,109 Addition of 1-diazo-1-lithioacetone, generated in situ, to -cyclocitral afforded diazo hydroxy-ketone 56 and, the metallacarbene generated with the rhodium(II) catalyst Rh(OAc) 2 (DME, 45 °C), led to the enolized 1,3-diketone 57. After treatment with oxalyl chloride (CHCl 3 , rt to reflux), chloro-enone 58 was isolated as a 1:5 mixture of (Z)-and (E)-isomers. After separation by chromatography of these two stereoisomers and treatment of the (E)-isomer with a Zn-Ag alloy (MeOH, rt), -damascone was isolated with a low overall yield (5 steps, overall yield = 9%) (Scheme 38). Scheme 38. Synthesis of -damascone from -cyclocitral via diazo hydroxy-ketone 56.

From a cyclohexenone derivative

An umpolung reactivity of -cyclocitral, due to its conversion to an thioacetal, allowed the access to -damascone. 110 Thioacetal 59 was synthesized from 2,6,6-trimethyl-cyclohexen-2-one 25 in 4 steps. After epoxidation of 25 (NaH, Me 3 SI, DMSO/THF, 0 °C) to 14 and rearrangement to -cyclocitral under Lewis acidic conditions (MgBr 2 , Et 2 O), -cyclocitral was quantitatively isomerized to -cyclocitral under basic conditions (KOH, MeOH) and then converted to thioacetal 59 (1,2-ethanedithiol, BF 3 .OEt 2 ).-Cyclocitral thioacetal 59 was then converted to -damascone by an allylation/thioketal cleavage/isomerization sequence (7 steps, overall yield = 43%) (Scheme 39).

From methyl -cyclogeranate

Similarly to -damascone (cf Scheme 13), -damascone was synthesized from -cyclogeranate by Snowden et al. by double allylation using allylmagnesium bromide followed by a fragmentation under basic conditions (KH, HMPA) and an isomerization of the resulting non-conjugated enone which produces -damascone (3 steps, overall yield = 53%). [63][64][65] Fehr et al., by using the conditions that they had developed for the synthesis of -damascone from -cyclogeranate (allylMgBr/ LDA) (cf Scheme 13), were able to produced 8 g -damascone from -cyclogeranate in 2 steps (2 steps, overall yield = 80%) (Scheme 41). 66 Scheme 41. Synthesis of -damascone from methyl -cyclogeranate.

From cyclohexenyl methylketone

As previously reported for the synthesis of -damascone (cf Scheme 16), Yamamoto et al. synthesized -damascone from mesityl oxide. 71 A normal Diels-Alder reaction followed by an isomerization of the obtained cyclic methylketone under basic conditions (t-BuOK, DMSO, 100 °C) and an aldolization/ crotonization sequence, produced -damascone. This sequence of reactions allowed the preparation of 13.7 g of -damascone (4 steps, overall yield = 12%) (Scheme 42). Scheme 42. Synthesis of -damascone from cyclohexenyl methylketone.

The most efficient synthesis of -damascone was achieved by Guanqun et al. from -ionone by using a Büchi-Vederas rearrangement, which allowed the preparation of 169 g of -damascone with an overall yield of 93%.

-Damascone

As -ionone, -cyclocitral and -cyclogeranates are accessible, -damascone was synthesized from these compounds by using similar strategies and conditions to the ones used to produce and -damascones.

Racemic syntheses of -damascone

. 1 . 1 . Fr o m  -i o n o n e

The two rearrangements previously reported, e.g. the Wharton and the Büchi-Vederas rearrangements, were used to synthesize -damascone from -ionone.

Wharton rearrangement

When the Wharton rearrangement was applied to -ionone epoxides 62 and 62', the yield in -iso-ionone was very low from 62 (4.5%) and very modest from 62' (30%) (Scheme 43). 43 Thus, the overall yield of -damascone from -ionone is very low (2-7%). Scheme 43. Synthesis of -damascone using the Wharton rearrangement.

Büchi-Vederas rearrangement

-Damascone was also synthesized by Schulte-Elte et al. from -ionone using a Büchi-Vederas rearrangement (4 steps, overall yield = 42%) (Scheme 44). 48,49 Scheme 44. Synthesis of -damascone from -ionone through the Büchi-Vederas rearrangement.

. 1 . 2 . Via  -c ycl o ci t r a l

Epoxidation of -pyronene by epoxidation (m-CPBA, Et 2 O, 0 °C) and rearrangement of the obtained epoxide 66 by allylmagnesium bromide, acting as a Lewis acid, led to -cyclocitral which reacts with a second equivalent of allylmagnesium bromide to form the non-conjugated alcohol 67. After oxidation by PCC (CH 2 Cl 2 , rt), -damascone was isolated in 80% yield (3 steps, overall yield = 36%) (Scheme 45). 59 Scheme 45. Synthesis of -damascone from -pyronene.

. 1 . 3 . Fr o m cy cl o g e r a n a t e

In a one-pot reaction, by treatment of methyl -cyclogeranate with n-BuLi followed by the addition of allylmagnesium bromide to enolate L-Li, the non-conjugated dienol M-Li was formed and, after work-up and a basic treatment (Al 2 O 3 , Et 2 O), -damascone was produced with an overall yield of 76% (2 steps) (Scheme 46). 112 Scheme 46. Synthesis of -damascone from methyl -cyclogeranate. -Methyl di-thio-cyclogeranate 69, prepared from allylic bromide 68, 113 was transformed to -damascone in three steps. 114,115 After addition of allylmagnesium bromide (THF/HMPT then MeI), the conjugated thio-enol 70 (Z/E = 96:4) was obtained and transformed to -damascone by two consecutive acidic treatments (HCl, H 2 O/MeOH then p-TsOH, refluxing benzene) (3 steps, overall yield = 40%) (Scheme 47).

. 1 . . Vi a c yc l o h e xen y l m et h yl k et o n e d er i va t i ve

Starting from 3-methyl cyclohexen-2-one, 4 steps (1,4addition/acetylation/1,2-addition/dehydration) were necessary to synthesize the non-conjugated enone 73, precursor of -damascone. 116 When methylketone 73 was submitted to an aldolization/crotonization sequence [PhN(Me)MgBr, CH 3 CHO then p-TsOH], -damascone was isolated with a low overall yield of 9% ( 5

. 1 . 5 . M i s c el l a n eo u s

As for the synthesis of -damascone (cf Scheme 17), the allylboration of crotonaldehyde with 75 led to -damascol, which after oxidation (PDC, DMF), furnished 3.1 g of -damascone (7 steps, overall yield = 18%) (Scheme 49).

Enantioselective syntheses of -damascone

Similarly to the synthesis of optically active -damascone, enantio-enriched (R)-(-)-and (S)-(+)--damascones were synthesized either from (±)--ionone using either an enzymatic resolution as the key step, or an enantioselective protonation of an enolate.

. 2 . 1 . Fr o m ( ± )-i o n o n e by a n en z y m a t i c r es o l u t i o n o f a d i o l

The synthesis of (R)-(-)-and (S)-(+)--damascones was realized from (±)--ionone. 82 At first, (±)--ionone was converted to 1,3-diol (±)-35, as previously reported for the synthesis of enantio-enriched -damascones (cf Scheme 20). After an acetylation (Ac 2 O, Py), a photochemical isomerization of the endo cyclic double bond to the exo cyclic double (h, high pressure mercury lamp, iPrOH/xylene) and a saponification (KOH, MeOH), diol 76 was obtained. An enzymatic resolution of 76 using Lipase PS (Pseudomonas cepacia) followed by a separation, afforded diol (-)-76 (43% yield, ee = 98%) and hydroxy-acetate (+)-77 (49% yield, ee >99%). Diol (-)-76 was converted to (R)-(-)--damascone in three steps (regioselective acylation/oxidation/elimination) and hydroxyl-acetate (+)-77 was converted to (S)-(+)--damascone in 2 steps (oxidation/ elimination). The two enantiomers were obtained with high ees (>99%) but with low overall yields (9 steps, overall yield for (R)-(-)--damascone = 12%; 8 steps, overall yield for (S)-(+)-damascone = 17%) (Scheme 50). Scheme 50. Synthesis of (R)-(-)-and (S)-(+)--damascones involving an enzymatic resolution.

. 2 . 2 . Vi a e n a n t i o -en r i ch ed  -c ycl o ci t r a l

Similarly to the synthesis of enantio-enriched -damascones (cf Scheme 25), Vidari et al. synthesized (S)-(+)--damascone from methyl acetoacetate via (S)-(+)--cyclocitral. 117 Methyl acetoacetate was converted to the non-conjugated diene 78 in a three-step one-pot sequence (alkylation/enol phosphonylation/ cross-coupling). Diene 78 was then subjected to a Sharpless dihydroxylation (AD-mix-, MeSO 2 NH 2 , t-BuOH/H 2 O and the 1,2-diol was transformed to epoxide 79 (mesylation/S Ni ). After cyclization of 79 to 80 (BF 3 .OEt 2 , CH 2 Cl 2 ), 6 steps were necessary to transform 80 to (S)-(+)--cyclocitral (reduction/ protection/thio-esterification/Barton deoxygenation/deprotection/ oxidation). (S)-(+)--Cyclocitral was then involved in an alkylation/oxidation/isomerization sequence to produce -damascone (ee = 88%, 13 steps, overall yield = 7%) (Scheme 51). Scheme 51. Synthesis of (S)-(+)--damascone from methyl acetoacetate via (S)-(+)--cyclocitral.

. 2 . 3 . Fr o m  -c yc l o g er a n i c a c i d a n d d er i va t i v es

By chemical resolution of -cyclogeranic acid Fehr et al. have explored the synthesis of optically active -damascones from (±)--cyclogeranic acid after separation of the two enantiomers by preferential crystallization with (R)-phenylethylamine. 118 (S)-(+)--Cyclogeranic acid was recovered in 52% yield with a high ee (>96%) and, after esterification (K 2 CO 3 , MeI), (S)-(+)-methyl--cyclogeranate was converted to (S)-(+)-damascone in a two-step sequence (allylation/isomerization) with an ee of 96% (4 steps, overall yield = 28%). Around 1 g of (S)-(+)--damascone was obtained (Scheme 52). Scheme 52. Synthesis of (S)-(+)--damascone by resolution of (±)--cyclogeranic acid using (R)-(+)-1-phenylethylamine.

By enantioselective protonation of enolates

Enantioselective protonation of an enolate was also used to access (S)-(+)--damascone from methyl -cyclogeranate. 118 The non-conjugated magnesium enolate M-MgCl was generated from methyl -cyclogeranate (n-BuLi, allylMgCl) and then transformed to lithium enolate M-Li in 2 steps (TMSCl then MeLi). An inverse addition of lithium enolate M-Li to a 1:2 mixture of (R,S)-(-)-N-isopropylephedrine/(R,S)-(-)-N-isopropylephedrine lithium alkoxide, led to the non-conjugated enone 82 with an ee of 75% (87% yield). After isomerization of the double bond (Al 2 O 3 , Et 2 O), (S)-(+)--damascone was isolated (3 steps, overall yield = 76%) (Scheme 53). Scheme 53. Synthesis of (S)-(+)--damascone from methyl -cyclogeranate by enantioselective protonation of an enolate.

Based on an enantioselective protonation of lithium thioenolate O-Li, the synthesis of (S)-(+)--damascone was realized from -thio-cyclogeranate prepared from methyl -cyclogeranate. 118 By treating -thio-cyclogeranate with LDA, the lithium thio-enolate intermediate O-Li was generated and, after addition of 4 equivalents of (R,S)-N-isopropylephedrine, an enantioselective protonation occurred to produce the expected (S)--thio-cyclogeranate with a good enantiomeric excess (ee = >96%) however with a low yield (37%). After addition of allylmagnesium bromide in the presence of LDA, the obtained homo-allylic ketone was isomerized to (S)-(+)--damascone (Al 2 O 3 , Et 2 O, rt) (ee = >96%, 3 steps, overall yield = 23%) (Scheme 54).

The most efficient synthesis of (±)--damascone was realized by Fehr et al. starting from (±)-methyl -cyclogeranate and by adding allylmagnesium bromide to a lithium ester (cf Scheme 46). This method was also the best method to synthesize 1 g (S)-(+)--damascone with an ee of 96% starting from (±)--cyclogeranic acid (cf Scheme 52). 118 Scheme 54. Synthesis of (S)-(+)--damascone from -thiocyclogeranate.

-Damascone

Two main strategies were reported to synthesize -damascone: one starting from a cyclohexenyl methylketone and the other one from Meldrum's acid.

From -cyclohexenyl methylketone

To synthesize -cyclohexenyl methylketone 85, a normal Diels-Alder reaction between bromo-mesityl oxide and penta-1,3-diene (AlCl 3 , CH 2 Cl 2 , 40 °C) was achieved by Cookson et al. followed by a dehalogenation (Zn dust, AcOH, Et 2 O) (2 steps, overall yield = 57%). 119,120 After an aldolization/crotonization sequence [PhN(Me)MgBr, CH 3 CHO then p-TsOH], -cyclohexenyl methylketone 85 was converted to a mixture of cis-and trans--damascones in 2.8 g quantity (4 steps, overall yield = 29%) (Scheme 55, eq 1).

Scheme 55. Synthesis of -damascone and trans--damascone from bromo-mesityl oxide using a Diels-Alder reaction. Mookherjee et al. improved the yield of the conversion of cyclohexenyl methylketone 85 to -damascone from 50% to 88% by realizing the crotonization step over 8 h, instead of 15 min, in refluxing benzene as an azeotrope to remove the formed water instead of refluxing CH 2 Cl 2 . 121 In addition, they submitted -cyclohexenyl methylketone 85 to a diastereo-convergent epimerization under basic conditions (KOH, EtOH) to obtain only the trans--cyclohexenyl methylketone 85. The authors were able to obtain 20.1 g of trans--damascone (5 steps, overall yield = 37%) (Scheme 55, eq 2).

From Meldrum's acid

A cheap commercially available starting material, Meldrum's acid (synthesized from malonic acid in 50% yield), 122 was considered by Dauben et al. to access -damascone. 123 Meldrum's acid was condensed with acetone (Knoevenagel condensation) to produce dienophile 86 and this latter was then engaged in a Diels-Alder reaction with penta-1,3-diene to afford the spirocyclic derivative 87. After treatment with allyllithium, the keto-acid intermediate was decarboxylated by heating at 165 °C to produce -damascone (3 steps, overall yield = 24%) (Scheme 56). Scheme 56. Synthesis of -damascone from Meldrum's acid.

The best synthesis of -damascone was reported by Mookherjee et al. from mesityl oxide and penta-1,3-diene to form -cyclohexenyl methylketone by a Diels-Alder reaction and then 3 steps were necessary to obtained the trans--damascone (epimerization/aldolization/crotonization sequence, overall yield = 37%) (cf Scheme 55). 119,120,121

Damascenones

Different syntheses of -damascenone were reported. As there is only one synthesis of -damascenone and one synthesis of -damascenone, their synthesis will be concomitantly described. It is worth mentioning that -damascone can be transformed to -damascenone in two steps e.g. by an allylic bromination followed by an elimination. Depending on the conditions, the overall yield varies from 44% to 88% (Scheme 57). 14,87,105 Scheme 57. Synthesis of -damascenone from -damascone.

From -ionone (-damascenone)

-Damascenone was synthesized from -ionone via isoxazole 52 prepared in two steps from -ionone. 48

via Cyclocitral and functionalized cyclocitral 6 . 2 . 1 . Fr o m ci t r a l (  -d a ma s c en o n e)

-Cyclocitral was transformed to -damascenone via -isoionol. 125 -iso-Ionol was photo-oxidized (NaOAc, O 2 , Bengal rose, h) to produce the key epoxy-ketone 90 and the unsaturated 1,2-diols 97 and 98 (90/97/98 = 55:40:5). After separation of keto-epoxide 90 from 97 and 98, the epoxide was opened under acidic conditions (HCl, dioxane, 65 °C) affording a 1:9 mixture of hydroxy-ketones 99 and 100, which were not separated but transformed to -damascenone after treatment with filtrol (acidic clay, dioxane, 105 °C). It is worth mentioning that the unsaturated 1,2-diols 97 and 98, obtained during the photooxidation, were also transformed to -damascenone (oxidation with MnO 2 and acidic treatment with filtrol, 85% yield). -Damascenone was obtained on multi-gram scale (5.8 g) in 3 steps from -iso-ionol with an overall yield of 32% (Scheme 60). The synthesis of -damascenone from -cyclocitral was patented in 1976 and 1980. 56,57 Scheme 60. Synthesis of -damascenone by photo-oxidation of -iso-ionol.

. 2 . 2 . Fr o m p yr o n en e (  -d a m a s cen o n e )

-Damascenone was synthesized from -epoxy-pyronene 14 via cyclocitral derivative 101, however with a poor overall yield (6 steps, overall yield = 5%) (Scheme 61). 59 Scheme 61. Synthesis of-damascenone from -epoxy-pyronene 14.

. 2 . 3 . Fr o m cy cl o g e r a n a t e / s a f r a n a t e ( -,  -and d a m a s c eno n es )

Methyl -cyclogeranate was transformed to -damascenone in 5 steps via methyl -safranate. [63][64][65] After epoxidation of methyl -cyclogeranate (H 2 O 2 , maleic anhydride, CH 2 Cl 2 ) and treatment of the resulting epoxide 103 with acidic silica (refluxing dioxane). Methyl -safranate was obtained and transformed to -damascenone by a double addition of allylmagnesium bromide to the ester, followed by a fragmentation (KH, HMPA) and an isomerization (p-TsOH, THF, reflux) (5 steps, overall yield = 11%) (Scheme 62). Scheme 62. Synthesis of -damascenone from methyl -cyclogeranate via methyl -safranate.

Ethyl -safranate can be synthesized from keto-ester 105 via ethyl -safranate by using a Wittig reaction followed by an acidic treatment (p-TsOH, refluxing benzene) (Scheme 63, eq 1). [START_REF][END_REF]104 It is worth mentioning that a mixture of ethyl and -safranates was obtained in a 3:1 ratio with a yield of 80% in the presence of 20% of unreacted ethyl Ethyl and -safranates were isolated and converted to and -damascenones respectively (Scheme 63, eq 2 and 3). [START_REF][END_REF]104 At first, ethyl and -safranates were respectively transformed to the corresponding damascenone derivatives 106 and 107 by addition of allyllithium and, after treatment under basic conditions (K, t-BuOH), 1.8 g and 1.7 g of and -damascenones were respectively obtained (overall yield from 105 = 36% and 31%, respectively). It is worth mentioning that the use of allyllithium at -60 °C is sufficient to prevent the second addition of allyllithium to 106 and 107. Scheme 63. Synthesis of -and-damascenones from keto-ester 102 via ethyl and -safranates. A linear starting material, the allylic sulfone 108, was transformed to -methyl safranate in 3 steps (alkylation with 109/cyclization/elimination). 126 After addition of allylithium (4 equiv, at -20 °C, THF) to methyl -safranate and isomerization of the non-conjugated double-bond of the obtained enone, -damascenone was synthesized (4 steps, overall yield = 60%) (Scheme 66). Scheme 66. Synthesis of -damascenone from allylic sulfone derivative via methyl -safranate.

. 2 . 4 . Vi a c yc l o h e xa d i en yl m et h yl k et o n e ( -d a ma s c en o n e)

A normal Diels-Alder reaction between bromo-mesityl oxide and penta-1,3-diene was realized by Cookson et al. leading to bromo-cyclohexenyl methylketone 84 (as reported for -damascone, cf Scheme 55). After dehalogenation (LiF, Li 2 CO 3 , DMF, 120 °C), the resulting dienyl methylketone 112 was submitted to an aldolization/crotonization sequence producing -damascenone with an overall yield of 22% (4 steps) (Scheme 67). 119,120 Penta An improvement of the aldolization/crotonization sequence was realized by Mookherjee et al. by using methylmagnesium bromide to generate the enolate which reacted with acetaldehyde and after an oxidation/crotonization sequence induced by PCC (PCC, NaOAc, CH 2 Cl 2 ) -damascenone was isolated (7 g were obtained by using this method) (Scheme 68).

. 3 . 2 . Fr o m d i m ed o n e (  -d a ma s c enone)

Torri et al. reported the synthesis of -damascenone from dimedone using an as the key step. 130,131 After the mono protection of dimedone (LDA, EtBr), 116 was involved in an aldol condensation with crotonaldehyde (LDA) and the resulting aldol product 117 was protected to produce 118 (PPTS, ethoxyethylene) which was then converted to enone 119 (MeLi, hexane, 3-4 °C). After a 4-step sequence (reduction/acetylation/ deprotection/oxidation), enone 121 was isolated and treated with DBU (reflux, 20 s) to produce -damascenone (9 steps, overall yield = 33%) (Scheme 70).

Even though the syntheses of -, and -damascenones from safranate are efficient (2 steps, overall yields = 61% to 81%, Scheme 62 to 66), the synthesis of -damascenone from 2,6,6trimethyl-cyclohexen-2-one, involving a Meyer-Shuster rearrangement, is also efficient and can produce 34 g of -damascenone (3 steps, overall yield = 57%) (cf Scheme 69). 128,129 It is worth mentioning that to the best of our knowledge, no enantio-enriched synthesis of and -damascenones were reported. Scheme 70. Synthesis of -damascenone from dimedone.

Conclusion

Due to the highly powerful organoleptic properties of damascones and damascenones and their importance for fragrance companies, many syntheses of the isomers and enantiomers of damascones, as well as the different isomers of damascenones, were developed since their discovery. Starting from academic syntheses, the syntheses were improved for industry to access efficient and low-cost synthetic routes which can be performed on gram and even kilogram scale.

Scheme 19 .

 19 Scheme 19. Synthesis of -damascone from dehydrolinalool.

Scheme 24 .

 24 Scheme 24. Synthesis of (R)-(+)--damascone from citral via (R)-(+)--cyclocitral.

Scheme 35 .

 35 Scheme 35. Synthesis of -damascone on a kg scale using an Overman rearrangement.

Scheme 39 .

 39 Scheme 39. Synthesis of -damascone from 2,6,6-trimethylcyclohexen-2-one 25.

62% 1 )Scheme 40 .

 140 Scheme 40. Synthesis of -damascone from methyl and ethyl -cyclogeranates.

Scheme 47 .

 47 Scheme 47. Synthesis of -damascone from -methyl thiocyclogeranate 69.

Scheme 48 .

 48 Scheme 48. Synthesis of -damascone from 3-methyl cyclohexen-2-one.

73

 73

Scheme 49 .

 49 Scheme 49. Synthesis of -damascone from 3-methyl 2cyclohexenone.

Fehr 66 Scheme 64 .Scheme 65 .

 666465 Scheme 64. Synthesis of -damascenone from methyl -cyclogeranate. According to the Fehr et al. procedure (cf Scheme 46), when methyl -safranate was treated with 1 equivalent of n-BuLi followed by the addition of allylmagnesium bromide, lithium enolate R-Li was formed and, after an acidic work-up and an isomerization (Al 2 O 3 , Et 2 O), -damascenone was isolated (2 steps, overall yield = 81%) (Scheme 65).112

Scheme 67 .

 67 Scheme 67. Synthesis of -damascenone via -cyclohexadienyl methylketone 112.

  127

Scheme 68 . 1 .Scheme 69 .

 68169 Scheme 68. Synthesis of -damascenone via -cyclohexadiene methylketone.6.3. Miscellaneous6 . 3 . 1 . Fr o m 2 , 6 , 6 -t r i m et h yl -c yc l o h ex en -2 -o n e ( -d a ma s c en o n e)2,6,6-Trimethyl-cyclohexen-2-one 25 was used to efficiently produce -damascenone using a Meyer-Shuster rearrangement. 128,129 2,6,6-Trimethyl-cyclohexen-2-one 25 was deconjugated to enone 113 [(AlOiPr) 4 , 190 °C] and then treated with propargylic magnesium bromide S-MgBr (prepared in 2 steps from the corresponding propargylic alcohol 114). The

59). Scheme 59. Synthesis

  Isoxazole 52 was treated with peracetic acid (CH 3 CO 3 H, CH 3 CO 2 Na, H 2 O/CH 2 Cl 2 ) to produce epoxy-isoxazole 88, which after hydrogenolysis under hydrogen pressure (H 2 , Raney Ni, KOH), was transformed to epoxy enamino-ketone 89. After a Birch reduction (Na/NH 3(l) , t-BuOH), the resulting epoxy dihydro -damascone 90, was treated under acidic conditions (HCl then filtrol, dioxane, 105 °C), to produce -damascenone (7 steps, overall yield = 33%) (Scheme 58). Synthesis of -damascenone from -ionone via an epoxy-isoxazole.Another strategy was developed by Campagnole et al. to synthesize -damascenone from -ionone via a methoxy-ionol derivative 91 synthesized in 3 steps (deconjugation/reduction/ methylation).124 After epoxidation of 91 (m-CPBA, Na 2 CO 3 , CH 2 Cl 2 ), treatment of the obtained epoxides 92 and 93 under acidic conditions (H 2 SO 4 ) led to 94 and 95. Fortunately, 94 could be transformed to 95 (3 steps) and, after a selective acylation of the allylic alcohol and oxidation (AcCl, Py then PCC, CH 2 Cl 2 ), 96 was produced and converted to -damascenone under acidic conditions (p-TsOH, benzene, 50 °C) (8 steps, overall yield = 26%) (Scheme of -damascenone from -ionone via a methoxy-ionol derivative 91.

	Scheme 58.

Acknowledgments

IFF is acknowledged for financial support

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Synthetic approaches to the Damascone and Damascenone isomers