Process for the production of macrocyclic MUSK compounds

Abstract

The present invention is concerned with a new process for the production of macrocyclic musk compounds utilizing renewable starting materials and practical reaction conditions that allow easy scale up. The invention is also concerned with novel macrocyclic musk ketones having unique organoleptic properties which can be obtained by the new process.

Description

[0001] Case 09302(2) 1PROCESS FOR THE PRODUCTION OF MACROCYCLIC MUSK COMPOUNDS FIELD OF THE INVENTION The present invention is concerned with a new process for the production of macrocyclic musk compounds utilizing renewable starting materials and practical reaction conditions that allow easy scale up. The invention is also concerned with novelmacrocyclic musk ketones having unique organoleptic properties which can be obtained bythe new process. BACKGROUND OF THE INVENTION The efficient synthesis of saturated or unsaturated macrocyclic ketones (ring sizes of14 to 18 carbon atoms) has been explored a lot since these compounds are used quiteextensively as musk odorants in the field of perfumery. For example, fully saturated 15 membered macrocyclic ketones, exaltone and muscone are among the first macrocyclic musks that were discovered in the first half of the last century by Ruzica et al, Helv. Chim. Acta, 9, (1926), 230. Several macrocyclic musk compounds possess a double bond and exhibit cis-trans stereoisomerism leading to a mixture of diastereoisomers and / orregioisomers; for example (Z)-4-Cyclopentadecen-1-one reported by G. Ohloff et al., Helv.Chim. Acta 50 (1967) 705, ambretone (cyclohexadec-5- en-l-one), reported by T. Kato etal., “Bull. Chem. Soc. Jpn.,” vol.53 p.2958 (1980), 3-methylcyclopentadec-5-en-l-one as disclosed by E. Demole et al., U.S. Pat. No.5,354,735 and cycloheptadec-9-en-l-one(civetone) reported in by Ruzica et al, Helv. Chim. Acta, 9, (1926), 230. Such unsaturatedmacrocyclic compounds with mixture of isomers possess superior olfactory qualities.Main products from the unsaturated musk category Exaltenone®, Muscenone® and Ambretone® or Velvione® were reportedly synthesized from cyclododecanone.Cyclododecanone is industrially accessed via trimerization of 1,3-butadiene tocyclodecatriene which is then converted into cyclododecanone in 2 steps. Cyclododecanone is an important intermediate for the synthesis of dodecanedioic acid andlaurolactam which in turn are extensively used in industrial synthesis of polymers.Exaltenone® and muscenone® are synthesized from cyclododecanone by enlarging thering with three carbon atoms to afford a 15-membered carbocycle.Scheme 1 illustrates synthesis of muscenone from cyclododecanone.Case 09302(2) 2 On the other hand, Ambretone® or Velvione® (5-Cyclohexadecen-1-one) is synthesized asshown in Scheme 2. As originally patented in JPS-524787B1, chlorination of cyclododecanone with gaseous chlorine or CuCl2-DMF affords 2-chlorocyclododecanonewhich is then reacted with 2 equivalents of vinyl magnesium chloride to yield 1,2-divinylcyclododecanol. This alcohol is subjected to thermal oxy-cope rearrangement at180-250 °C to produce 5-Cyclohexadecen-1-one. Availability of cyclododecanone is limited and more importantly 1,3-butadiene is apetroleum product. Many reported syntheses macrocyclic musk compounds utilizecyclododecanone as the starting material. However, there is an urgent need in the field ofmacrocyclic musk compounds for the development of a process that utilizes renewablestarting materials. EP1264594B1 describes use of macrocyclic compounds for inhibition of melaninsynthesis. The synthesis of novel macrocyclic diene ketones as well as other macrocycliccompounds mentioned in EP1264594 was originally described in US6200254B1. However, the raw materials used in US6200254B1 are also derived from petroleumproducts. Further, use of Grignard reagents as listed in all claims demands that anhydrousconditions are maintained in the reaction medium. Use of Claisen condensation that isemployed in these two inventions ensured that the double bond in the final macrocyclicCase 09302(2) 3ketones was always at positions 4 or 5 from carbonyl carbon. This is another limitation ofthis process. On the other hand, the process disclosed in this invention is very broad in itsscope and allows synthesis of macrocyclic enones with double bond at any of the position from 4thto 8thcarbon from the carbonyl group. US8642814B1 describes a contemplated synthesis of macrocyclic compoundsstarting from a mixture of palmitoleic acid (C16:1) and oleic acid (C18:1). For example,Omega-7 rich oil is subjected to transesterification and distillation to afford Omega-7 richfraction of esters. This fraction is subjected to metathesis and subsequent Dieckmanncyclization to eventually afford Civetone. A major limitation of this method is that only17-membered macrocycles are produced by this process. A common and practical synthetic route that easily enables synthesis of various unsaturated and substituted macrocyclic ketones, that vary in the position of the double bond and methyl group, by use of different starting materials, will be a welcome addition to the existing arsenal of synthetic methods of macrocyclic ketones. Surprisingly, the inventors were able to design and optimize such awaited process.The sequence of reactions claimed here is novel and additionally uses renewable startingmaterials in synthesis of multiple macrocyclic ketones which represents a salient feature of this invention. SUMMARY OF THE INVENTION The invention relates to a novel process that allows preparation of unsaturatedmacrocycles of formula (I) by using a sequence of common organic reactions. Thesequence of reactions utilizes low cost reagents. More importantly, the key startingmaterials used in the present invention are renewable raw materials.A first object of the present invention is a process for the preparation of the followingunsaturated macrocycle ketone of formula (I) or the mixture of its regioisomers and / or stereoisomers thereof;Case 09302(2) 4wherein m is an integer selected from 0, 1, 2, 3 and 4,R1, R2 R3, R4, R5, R6 and R7 represent a hydrogen atom or a methyl group, andthe dotted lines represent alternate positions of double bonds, wherein the double bond isbetween carbon atoms 4 and 5, or 5 and 6, or 6 and 7, or 7 and 8, or 8 and 9.A second object of the invention is to provide a novel unsaturated macrocycle ketone of formula (I). A third object of the invention is to provide a novel mixture of regioisomers and / orstereoisomers of the unsaturated macrocyclic ketone of formula (I).A fourth object of the present invention is to provide fragrance compositionscomprising the compounds represented by general formula (I).

[0002] Case 09302(2) 5DETAILED DESCRIPTION OF THE EMBODIMENTS Furfural which can be obtained from biomass can be converted into cyclopentanone using Ru / C with Al11.6PO23.7 catalyst in 84% yield in aqueous medium (Shen, T. et a., RSCAdv. 2018, 8, 37993). Anisole which is available naturally can be converted intocyclohexanone using bromide salt-modified Pd / C in H2O / CH2Cl2 [Meng, Q. et al., Nature Communications, 8, Article number: 14190 (2017)].3-Methylcyclohexanone can be obtained from Mentha pulegium, a flowering plant. Similarly, many long chain ω-alkenyl alcohols such as 10-undecen-1-ol and 9- Decen-1-ol are produced commercially from raw materials that are available from natural resources. As exemplified in the experimental section, our processes use renewable starting materials detailed above.The first embodiment of this invention is Process-1 which is given below. The first step involves free radical coupling reaction between a substituted cyclicketone 2 and an ω-alkenyl alkyl carboxylic ester 1. The resulting substituted ketone 3 isconverted into a lactone 4 in step-2. In step-3, the lactone is hydrolyzed to thecorresponding hydroxy-substituted 1,ω-dicarboxylate 5 which is then dehydrated to thecorresponding unsaturated 1,ω-dicarboxylate 6 in step-4. In step-5, intramolecularDieckmann reaction of diester 6 followed by hydrolytic decarboxylation affords desiredmixtures of macrocyclic ketones of general formula (I).Case 09302(2) 6Conversion of lactone to a corresponding hydroxy-substituted 1,ω-dicarboxylate has not been exemplified in any literature. This hydroxy derivative is dehydrated to the corresponding unsaturated 1,ω-dicarboxylate. Taken together, steps 3 and 4 are key to our invention for the introduction of unsaturation. Another embodiment of this invention is Process-2 as outlined below. In Process-2, the first step involves free radical coupling reaction between a substitutedcyclic ketone 2 and an ω-alkenyl alkyl carboxylic ester 1. The resulting substituted ketone3 is converted into a lactone 4 in step-2. In step-3, the lactone is heated with thionylchloride to convert it into the corresponding chloro-substituted 1,ω-dicarboxylate 5. Inmethod-A, compound 5 is then dehydrochlorinated to the corresponding unsaturated 1,ω-dicarboxylate 6 in step-4. In step-5, intramolecular Dieckmann reaction of diester 6followed by hydrolytic decarboxylation affords desired mixtures of macrocyclic ketones of general formula (I). As shown in method-B, compound of general formula (I) were prepared byintramolecular Dieckmann reaction of compound 5 followed by hydrolytic decarboxylationto afford compound 6-B, which on base-mediated elimination afforded desired macrocyclic ketones of general formula (I). Conversion of lactone to a corresponding chloro-substituted 1,ω-dicarboxylate has not been exemplified in any literature. This chloro derivative is dehydrochlorinated to thecorresponding unsaturated 1,ω-dicarboxylate. Taken together, steps 3 and 4 are key to ourinvention for the introduction of unsaturation.Case 09302(2) 7Another embodiment of this invention is Process-3 as outlined below. In Process-3, the first step involves free radical coupling reaction between a substituted cyclic ketone 2 and an ω-alkenyl alkyl carboxylic ester 1. The resultingsubstituted ketone 3 is converted into a lactone 4 in step-2. In step-3, the lactone ishydrolyzed to the corresponding hydroxy-substituted 1,ω-dicarboxylate 5 which is thendehydrated to the corresponding unsaturated 1,ω-dicarboxylate 6 in step-4. In steps-5 / 6,acyloin condensation of diester 6 affords α-hydroxyester 7 which on dehydroxylation (e.g.by using zinc / acetic acid / concentrated HCl) affords desired mixtures of macrocyclicketones of general formula (I). Conversion of lactone to a corresponding hydroxy-substituted 1,ω-dicarboxylate has not been exemplified in any literature. This hydroxy derivative is dehydrated to the corresponding unsaturated 1,ω-dicarboxylate. Taken together, steps 3 and 4 are key to our invention for the introduction of unsaturation. Another embodiment of this invention is Process-4 as outlined below.Case 09302(2) 8 In Process-4, the first step involves free radical coupling reaction between asubstituted cyclic ketone 1 and an ω-alkenyl alkyl carboxylic ester 2. The resultingsubstituted ketone 3 is converted into a lactone 4 in step-2. In step-3, the lactone is heatedwith thionyl chloride to convert it into the corresponding chloro-substituted 1,ω-dicarboxylate 5 which is then dehydrochlorinated to the corresponding unsaturated 1,ω-dicarboxylate 6 in step-4. In steps-5 / 6, acyloin condensation of diester 6 affords α-hydroxyester 7 which on dehydroxylation (e.g. by using zinc / acetic acid / concentrated HCl) affords desired mixtures of macrocyclic ketones of general formula (I). Conversion of lactone to a corresponding chloro-substituted 1,ω-dicarboxylate has not been exemplified in any literature. This chloro derivative is dehydrochlorinated to thecorresponding unsaturated 1,ω-dicarboxylate. Taken together, steps 3 and 4 are key to ourinvention for the introduction of unsaturation. As described before, there are many salient features of this invention: use of renewable starting materials, formation of single novel compounds or mixtures ofunsaturated macrocyclic ketones, a common synthetic pathway with a novel sequence ofreactions that acts as a divergent synthetic route such that the same unsaturated 1,ω-dicarboxylate 6 can be converted into different sized macrocyclic ketones either byemploying intramolecular Dieckmann reaction or Acyloin condensation.Case 09302(2) 9It is a very salient feature of this invention that the synthetic pathways described in this invention allow one to synthesize novel macrocyclic ketones in a crowded research area where lot of macrocyclic ketones are already reported. In an embodiment, compounds of general formula (I) wherein m is an integer / whole number selected from 0, 1, 2, 3 and 4,R1, R2R3, R4, R5, R6and R7represent a hydrogen atom or a methyl group, the dotted lines represent alternate positions of double bonds, the double bond may bebetween carbon atoms 4 and 5, 5 and 6, 6 and 7, 7 and 8, or 8 and 9, or a mixture ofregioisomers and / or stereoisomers thereof can advantageously be prepared by the claimedprocess. In a preferred embodiment, the compounds of general formula (I) are selected from(i) (Z)-4-methylcyclopentadec-5-en-1-one(ii) (E)-4-methylcyclopentadec-5-en-1-one(iii)(Z)-5-methylcyclohexadec-6-en-1-one (iv)(E)-5-methylcyclohexadec-6-en-1-one(v) (Z)-4-methylcyclohexadec-6-en-1-one(vi)(E)-4-methylcyclohexadec-6-en-1-one(vii) (Z)-3-methylcycloheptadec-5-en-1-one(viii) (E)-3-methylcycloheptadec-5-en-1-one(ix)(Z)-3-methylcycloheptadec-6-en-1-one(x) (E)-3-methylcycloheptadec-6-en-1-one(xi)(Z)-5-methylcycloheptadec-5-en-1-one(xii) (E)-5-methylcycloheptadec-5-en-1-one(xiii) (Z)-5-methylcycloheptadec-6-en-1-one(xiv) (E)-5-methylcycloheptadec-6-en-1-one(xv) (Z)-4-methylcycloheptadec-5-en-1-oneCase 09302(2) 10(xvi) (E)-4-methylcycloheptadec-5-en-1-one(xvii) (Z)-4-methylcycloheptadec-6-en-1-one(xviii) (E)-4-methylcycloheptadec-6-en-1-one(xix) (Z)-cyclooctadec-6-en-1-one(xx) (E)-cyclooctadec-6-en-1-one(xxi) (Z)-cyclooctadec-7-en-1-one, or(xxii) (E)-cyclooctadec-7-en-1-one,or a mixture of regioisomers and / or stereoisomers thereof. In another embodiment, a mixture of regioisomers and / or stereoisomers ofcompounds of formula (I) can advantageously be prepared by the claimed process; saidmixture may advantageously be characterized by a weight ratio between regioisomers and / or stereoisomers which is between 95:5 and 5:95. In an embodiment, an odorant consisting of a compound or mixture as defined hereinabove is provided. In an embodiment, a fragrance, flavor and / or deodorizing / masking composition comprising a compound or a mixture as defined hereinabove is provided. The invention is now further described with reference to the following non-limiting examples. These examples are for the purpose of illustration only and it is understood that variations and modifications can be made by one skilled in the art. Example 1: Preparation of mixture of isomers of (E&Z)-cyclopentadec-4-en-1-one and (E&Z)-cyclopentadec-5-en-1-one Step 1: Methyl 11-(2-oxocyclopentyl)undecanoate: A 3-neck 500 mL round bottom flask equipped with a magnetic stirer, addition funnel and reflux condenser was charged with di-tert-butyl peroxide (0.66 g, 0.004. mol), and cyclopentanone (212 g, 2.52 mol). The solution was slowly heated to 110-120 °C and then carefully charged with a solution of methyl 10-undecenoate (50 g, 0.252 mol) and di- tert-butyl peroxide (5.3 g, 0.034.mol) via additional funnel over a period of 20 min. The reaction mixture was refluxed at 120 °C for 4 hr. After cooling to room temperature, water (50 mL) was added and the layers were separated. The organic layer was washed with aqueous saturated sodium carbonate (50 mL), 5% aqueous acetic acid (50 mL) and saturated brine (50 mL). The organic layer was concentrated under reduced pressure andCase 09302(2) 11excess cyclopentanone was removed. The resulting material was purified by fractional distillation to give methyl 11-(2-oxocyclopentyl)undecanoate (57 g, 80% yield) as a colorless liquid.1H-NMR (400 MHz, CDCl3) δ (ppm): 3.63 (s, 3H), 2.32-2.28 (m, 1H), 2.8-2.23 (t, J = 7.2Hz, 2H), 2.2-1.994 (m, 6H), 1.787-1.741 (m, 2H), 1.61-1.53 (m, 2H), 1.26 (s, 14H).13C-NMR (100.6 MHz, CDCl3) δ (ppm): 221.4, 174.8, 51.2, 48.9, 37.9, 33.9, 29.5, 29.4, 29.3, 29.2, 29.02, 28.9, 27.3, 24.7, 20.5 GCMS: 282.2 (M+), 251.2, 222.2, 198.2, 167.1, 149.1, 129.1, 111.1, 84.1, 55.1IR (Neat): 2925, 2854, 1735 (s) cm-1Step 2: Methyl 11-(6-oxotetrahydro-2H-pyran-2-yl)undecanoate: A 3-neck 500 mL round bottom flask equipped with an overhead stirrer, addition funnel and reflux condenser was charged with methyl 11-(2-oxocyclopentyl)undecanoate (57 g, 0.20 mol), sodium carbonate (23 g, 0.21 mol) under nitrogen atmosphere and cooled to 0 °C in an ice bath. To this reaction mixture, peracetic acid (17 g, 0.27 mol) was added over a period of 1 h. The solution was then allowed to warm to room temperature and stirred for 8 h. The reaction was quenched with ice water (200 mL) and to it was added ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous FeSO4, hot water and then dried over anhydrous Na2SO4. The organic layer was concentrated to afford a white solid (58 g, 90% yield) which was used as such for the next step.1H-NMR (400 MHz, CDCI3) δ (ppm): 4.30-4.24 (m, 1H), 3.66 (s, 3H), 2.62-2.46 (m, 2H), 2.44-2.42 (t, J= 7.2 Hz, 2H), 1.93-1.81 (m, 4H), 1.69-1.47 (m, 4H), 1.26 (s, 14H)13C-NMR (100.6 MHz, CDCl3) δ (ppm): 174.35, 172.02, 80.60, 51.4, 35.8, 34.1, 29.4,29.4, 29.2, 29.1, 27.8, 24.9, 18.5 GCMS: 299.1 (M+), 280.1, 249.1, 227.2, 207.2, 185.2, 151.1, 123.1, 99.0, 74.1, 55.1IR (Neat): 2919, 1720 cm-1Step 3: Dimethyl 5-chlorohexadecanedioate: A3-neck 500 mL round bottom flask equipped with a magnetic stirrer, additionfunnel and reflux condenser was placed under nitrogen atmosphere and chargedCase 09302(2) 12successively methyl cyclohexane (100 mL), methyl 11-(6-oxotetrahydro-2H-pyran-2- yl)undecanoate (58 g, 0.19 mol) and 0.526 g of zinc chloride (0.003mol). The reaction mixture was then cooled to 0 °C and then dropwise addition of thionyl chloride (45.8 g,0.39 mol) via addition funnel was done over a period of 1.5 h. The reaction mixture wasthen warmed up to room temperature and then refluxed at 80 °C for 5 hours. The darkreaction mixture was cooled to 0 °C and quenched with methanol (100 mL) which was slowly added to the reaction mixture. The reaction mixture was allowed to stir for 1h. Then methanol was evaporated and the dark crude was quenched with aqueous saturated sodium carbonate (100 mL) and extracted with ethyl acetate (2 x 200 mL) and then organic layers were separated. The organic layer was finally washed with brine (200 mL) and dried over anhydrous Na2SO4and concentrated to afford crude product (65 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate inhexane, to afford dimethyl 5-chlorohexadecanedioate (40.9 g, 60% yield), as a pale yellowliquid which was used in the following step.1H-NMR (400 MHz, CDCI3) δ (ppm): 3.92-3.85 (m, 1H), 3.68-3.667 (2s, 6H), 2.35-2.29 (m, 4H), 1.93-1.59 (m, 8H), 1.55-1.39 (m, 2H), 1.275 (m,12H)13C-NMR (100.6 MHz, CDCl3) δ (ppm): 174.2-173.6, 63.3, 51.3, 38.3, 37.6, 33.9, 33.3, 29.3, 29.1, 28.9, 26.3, 24.8, 21.8. GCMS: 349.2 (M+), 313.2281.2, 249.2 , 207.2 , 165.1 , 123.1 , 98.1 , 98.1 , 74.1 , 41.1 IR (Neat): 2927, 1737 cm-1Step 4: Dimethyl (E&Z)-hexadec-4-enedioate and dimethyl (E&Z)-hexadec-5-enedioate: A 3-neck 250 mL round bottom flask equipped with a magnetic stirrer andreflux condenser was charged with dimethyl 5-chlorohexadecanedioate (40.9 g, 0.12 mol)and cooled to 10 °C. Using addition funnel, 1,8-Diazabicyclo(5.4.0)undec-7-ene (35.3 g, 0.23 mol) was added very slowly over a period of 1 h to control the exotherm generated. The reaction mixture was slowly heated to 125 °C and maintained at that temperature for 6 h. The dark colored reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous saturated sodium carbonate (100 mL) followed by saturated brine (100 mL). The organic layer wasCase 09302(2) 13then dried over anhydrous Na2SO4and concentrated under reduced pressure to give crude product (30 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give a mixture of dimethyl (E&Z)-hexadec-4-enedioate and dimethyl (E&Z)-hexadec-5-enedioate (21.7 g, 60% yield), as apale yellow liquid which was used in the next step.1H-NMR (400 MHz, CDCI3) δ (ppm): 5.46-5.35 (m, 2H), 3.66 (s,6H), 2.36-2.28 (t, 2H J=7.6Hz), 2.02-1.95 (m, 4H), 1.70-1.67 (m,2H), 1.634-1.634(m, 2H) , 1.28-1.26 (m, 14H)13C-NMR (100.6 MHz, CDCl3) δ (ppm): 174.1-173.5, 131.7, 128.7-127.7, 51.3, 33.9, 33.2, 32.3, 31.8, 29.3, 29.1, 28.9, 27.6, 24.8 GCMS: 312.2 (M+), 280.1, 248.2, 220.2, 178.2, 150.1IR (Neat): 2925, 1738 cm-1Step 5: Mixture of methyl (E&Z) -2-oxocyclopentadec-5-ene-1-carboxylate, methyl(E&Z) -2-oxocyclopentadec-6-ene-1-carboxylate, methyl (E&Z) -15-oxocyclopentadec-3-ene-1-carboxylate and methyl (E&Z) -15-oxocyclopentadec-4-ene-1-carboxylate: Asolution of dimethyl (E&Z) -hexadec-4-enedioate and dimethyl (E&Z) -hexadec-5-enedioate (10 g, 0.03 mol) in THF (600 ml) was slowly added to a refluxing mixture of LiHMDS (Lithium hexamethyldisilazide) (192 mL, 1M in THF, 0.19 mol) and THF (350 mL) under nitrogen atmosphere. After completion of the addition, the mixture was further stirred for 15 min at reflux. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4~5) and then extracted with ethyl acetate (3x 200 mL). The combined organic layer was washed with water (200 mL), saturated brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude liquid was purified by column chromatography on silica gel, eluting with a gradient of ethylacetate in hexane to afford a mixture of methyl (E&Z) -2-oxocyclopentadec-5-ene-1-carboxylate, methyl (E&Z) -2-oxocyclopentadec-6-ene-1-carboxylate, methyl (E&Z) -15-oxocyclopentadec-3-ene-1-carboxylate and methyl (E&Z) -15-oxocyclopentadec-4-ene-1-carboxylate (4.5 g, 55% yield) as a light yellow oil.1H-NMR (400 MHz, CDCI3) δ (ppm): 5.33-5.17 (m, 2H), 3.63-3.49 (m, 4H), 2.51-2.39(m, 4H), 1.94-1.56 (m, 4H), 1.31-1.07 (m,14H)Case 09302(2) 1413C-NMR (100.6 MHz, CDCl3) δ (ppm): 205.8, 170.2-169.7, 133.8, 133.1, 132.4, , 131.9, 129.9, 128.9, 126.2, 58.1, 57.7, 56.9, 56.6, 52.2, 42.7, 42.5, 41.8, 40.4, 31.4, 31.2, 31.0, 30.8, 30.2, 29.55, 29.2, 28.5, 28.1, 27.9, 27.4, 27.1, 26.9 GCMS: 280.1 (M+), 248.1, 220.1, 179.1, 135.1, 95.1, 55.1IR (Neat): 2926, 1746, 1714, 1645 cm-1Step 6: Mixture of E&Z isomers of cyclopentadec-4-en-1-one and cyclopentadec-5-en-1-one: A solution of mixture of compounds from step-5 (4 g, 0.01 mol) in MeOH (20 mL) was treated with aqueous NaOH (1.68 g, 0.04 mol in 10 mL water) and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature, acidified to pH 1 by dropwise addition of 10% H2SO4 and then heated to reflux for 30 min. The reaction mixture was then cooled to room temperature and MeOH was evaporated. The crude solution was extracted with MTBE (2x 30 mL) and thecombined organic layer was washed with water (100 mL) and saturated brine (100 mL).The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give a mixture of E Z isomers of cyclopentadec-4-en-1-one and cyclopentadec-5-en-1-one (2.5 g, 0.011 mol, 80% yield) as a colorless liquid.1H-NMR (400 MHz, CDCI3) δ (ppm): 5.42-5.26 (m,2H), 2.50-2.41 (m, 4H), 2.39-2.32 (m, 2H), 2.06-2.00 (m, 2H), 1.67-1.60 (m, 2H), 1.38-1.19 (m, 14H)13C-NMR (100.6 MHz, CDCl3) δ (ppm): 212.75-211.51, 132.25-128.09, 42.49, 42.35, 41.65, 41.26, 31.38, 31.01, 30.62, 27.93, 27.31, 27.18, 27.00, 26.90, 26.74, 26.31, 26.15, 26.08, 25.79 GCMS: 222.2 (M+), 207.2 , 193.2IR (Neat): 2925, 1712, 1645 cm-1Odour: Creamy musky and animalic Example 2: Preparation of mixture of isomers of 3-methylcyclopentadec-5-en-1-one, 3-methylcyclopentadec-6-en-1-one, 5-methylcyclopentadec-5-en-1-one and 5- methylcyclopentadec-6-en-1-oneCase 09302(2) 15Step 1: methyl 10-(4-methyl-2-oxocyclohexyl)decanoate and methyl 10-(2-methyl-6- oxocyclohexyl)decanoate: A 3-neck 500 mL round bottom flask equipped with a magnetic stirrer, addition funnel and reflux condenser was charged with di-tert-butyl peroxide (0.674 g, 0.004mol), and 3-methylcyclohexan-1-one (147 g, 1.31 mol). The solution was slowly heated to 110- 120 °C and then carefully charged with a solution of methyl dec-9-enoate (50 g, 0.27 mol) and di-tert-butyl peroxide (6.67 g, 0.04mol) via additional funnel over a period of 20 min. The reaction mixture was refluxed at 120 °C for 16 hr. After cooling to room temperature, water (50 mL) was added and the layers were separated. The organic layer was washedwith aqueous saturated sodium carbonate (50 mL), 5% aqueous acetic acid (50 mL) andsaturated brine (50 mL). The organic layer was concentrated under reduced pressure and excess cyclopentanone was removed. The resulting material was purified by fractional distillation to give methyl 10-(4-methyl-2-oxocyclohexyl)decanoate and methyl 10-(2- methyl-6-oxocyclohexyl)decanoate (70 g, 87 % yield) as a colorless liquid.1H-NMR (400 MHz, CDCl3) δ (ppm): 3.63 (s, 3H), 2.34-2.28 (m, 4H), 2.25 -1.56 (m, 8H), 1.32 -1.27 (m, 14H), 0.99-0.97 (m, 3H). Step 2: methyl 10-(5-methyl-7-oxooxepan-2-yl)decanoate and methyl 10-(3-methyl-7-oxooxepan-2-yl)decanoate: A 3-neck 500 mL round bottom flask equipped with an overhead stirrer, addition funnel and reflux condenser was charged with methyl 10-(4-methyl-2- oxocyclohexyl)decanoate and methyl 10-(2-methyl-6-oxocyclohexyl)decanoate (45 g, 0.15 mol), sodium carbonate (16.05 g, 0.15 mol) under nitrogen atmosphere and cooled to 0 °Cin an ice bath. To this reaction mixture, peracetic acid (115 g, 0.30 mol) was added over aperiod of 1 h. The solution was then allowed to warm to room temperature and stirred for 8 h. The reaction was quenched with ice water (200 mL) and to it was added ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous FeSO4, hot water and then dried over anhydrous Na2SO4. The organic layer was concentrated to afford a thick liquid (40 g, 84% yield) which was used as such for the next step.1H-NMR (400 MHz, CDCl3) δ (ppm): 4.22 – 4.05 (m, 1H), 3.59 (s, 3H), 2.54 -2.37 (m,4H), 2.25-2.21 (m, 2H), 1.82 – 1.39 (m, 7H), 1.38 -1.20 (m, 12H), 0.98 – 0.96 (m, 3H).Case 09302(2) 16Step 3: dimethyl 6-chloro-3-methylhexadecanedioate and dimethyl 6-chloro-5- methylhexadecanedioate: A3-neck 250 mL round bottom flask equipped with a magnetic stirrer, additionfunnel and reflux condenser was placed under nitrogen atmosphere and chargedsuccessively methyl 10-(5-methyl-7-oxooxepan-2-yl)decanoate and methyl 10-(3-methyl-7-oxooxepan-2-yl)decanoate (60 g, 0.18 mol) and 0.52 mg of zinc chloride (0.004 mol).The reaction mixture was then cooled to 0 °C and then dropwise addition of thionylchloride (45.7 g, 0.38 mol) via addition funnel was done over a period of 1.5 h. Thereaction mixture was then warmed up to room temperature and then refluxed at 80 °C for 5hours. The dark reaction mixture was cooled to 0 °C and quenched with methanol (100 mL) which was slowly added to the reaction mixture. The reaction mixture was allowed to stir for 1h. Then methanol was evaporated and the dark crude was quenched with aqueoussaturated sodium carbonate (100 mL) and extracted with ethyl acetate (2 x 200 mL) andthen organic layers were separated. The pH of organic layer was maintained between 7-8. The organic layer was finally washed with brine (200 mL) and dried over anhydrous Na2SO4and concentrated to afford crude product (60 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane, to afford dimethyl 6-chloro-3-methylhexadecanedioate and dimethyl 6-chloro-5-methylhexadecanedioate (16.5 g, 24% yield), as a pale yellow liquid which was used in thefollowing step.1H-NMR (400 MHz, CDCl3) δ (ppm): 3.85-3.850 (m, 1H), 3.68-3.667 (2s, 6H), 2.35-2.29 (m, 4H), 1.93-1.59 (m, 8H), 1.55-1.39 (m, 2H), 1.275 (m,12H) Step 4: Dimethyl (E&Z) 3-methylhexadec-5-enedioate, dimethyl(E&Z) 3- methylhexadec-6-enedioate, dimethyl(E&Z) 5-methylhexadec-5-enedioateand dimethyl(E&Z)5-methylhexadec-6-enedioate: A 3-neck 250 mL round bottom flask equipped with a magnetic stirrer and reflux condenser was charged with dimethyl 6-chloro- 3-methylhexadecanedioate and dimethyl 6-chloro-5-methylhexadecanedioate (40.0 g, 0.11 mol) and cooled to 10 °C. Using addition funnel, 1,8-Diazabicyclo(5.4.0)undec-7-ene (33.5 g, 0.22 mol) was added very slowly over a period of 1 h to control the exotherm generated. The reaction mixture was slowly heated to 125 °C and maintained at that temperature for 6Case 09302(2) 17h. The dark colored reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous saturated sodium carbonate (100 mL) followed by saturated brine (100 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product (30 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give a mixture of dimethyl (E, Z) 3- methylhexadec-5-enedioate, dimethyl(E, Z) 3-methylhexadec-6-enedioate, dimethyl(E, Z)5-methylhexadec-5-enedioateand dimethyl(E, Z)5-methylhexadec-6-enedioate (14.4 g,40% yield), as a pale yellow liquid which was used in the next step.1H-NMR (400 MHz, CDCl3) δ (ppm): 5.40-5.29 (m, 2H), 3.64 (s, 6H), 2.29-2.25 (m, 4H), 1.98-1.91 (m, 3H), 1.61-1.55 (m, 4H), 1.32 -1.24 (m, 12H), 0.93-0.89 (m, 3H). Step 5: Mixture of methyl (E&Z) -4-methyl-2-oxocyclopentadec-5-ene-1-carboxylate, methyl (E&Z) -4-methyl-15-oxocyclopentadec-3-ene-1-carboxylate, methyl(E&Z) - 4-methyl-2-oxocyclopentadec-6-ene-1-carboxylate and methyl (E&Z) - 4-methyl-15-oxocyclopentadec-4-ene-1-carboxylate: Asolution of dimethyl (E&Z) 3-methylhexadec-5-enedioate, dimethyl(E&Z) 3-methylhexadec-6-enedioate, dimethyl(E&Z) 5-methylhexadec-5-enedioateanddimethyl(E&Z) -5-methylhexadec-6-enedioate (10 g, 0.03 mol) in THF (600 ml) wasslowly added to a refluxing mixture of LiHMDS (Lithium hexamethyldisilazide) (180 mL, 1M in THF, 0.18 mol) and THF (350 mL) under nitrogen atmosphere. After completion of the addition, the mixture was further stirred for 15 min at reflux. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4~5) and then extracted with ethyl acetate (3x 200 mL). The combined organic layer was washed with water (200 mL), saturated brine (200 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The resulting crude liquid was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to afford a mixture of mixture of methyl(E&Z) -4-methyl-2-oxocyclopentadec-5-ene-1-carboxylate, methyl (E&Z) -4-methyl-15-oxocyclopentadec-3-ene-1-carboxylate, methyl (E&Z) - 4-methyl-2-oxocyclopentadec-6-Case 09302(2) 18ene-1-carboxylate and methyl(E&Z) - 4-methyl-15-oxocyclopentadec-4-ene-1-carboxylate(3.78 g, 42% yield) as a light yellow oil.1H-NMR (400 MHz, CDCl3) δ (ppm): 5.39-5.30 (m, 2H), 3.70-3.67 (m, 3H), 3.55-3.42 (m, 1H), 2.45-1.99 (m, 6H), 1.39-1.18 (m, 15 H), 0.99-0.88 (m,3 H)IR (Neat): 2926, 2855, 1748, 1713, 1644 cm-1Step 6: Mixture of E&Z isomers of 3-methylcyclopentadec-5-en-1-one, 3-methylcyclopentadec-6-en-1-one, 5-methylcyclopentadec-5-en-1-one and 5- methylcyclopentadec-6-en-1-one: A solution of mixture of compounds from step-5 (4 g, 0.01 mol) in MeOH (20 mL) was treated with aqueous NaOH (1.68 g, 0.04 mol in 10 mL water) and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature, acidified to pH 1 by dropwise addition of 10% H2SO4 and then heated to reflux for 30 min. The reaction mixture was then cooled to room temperature and MeOH was evaporated. The crude solution was extracted with MTBE (2x 30 mL) and the combined organic layer was washed with water (100 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give a mixture of Mixture ofE&Z isomers of 3-methylcyclopentadec-5-en-1-one, 3-methylcyclopentadec-6-en-1-one, 5-methylcyclopentadec-5-en-1-one and 5-methylcyclopentadec-6-en-1-one (1.9 g, 0.008 mol, 60% yield) as a colorless liquid.1H-NMR (400 MHz, CDCl3) δ (ppm): 5.40-5.32 (m, 2H), 2.70-2.62 (m, 1H), 2.43-2.25(m, 2H), 2.18-2.03 (m, 4H), 1.72-1.55 (m, 4H), 1.37-1.19 (m, 12 H), 0.96 – 0.90 (m, 3H).IR (Neat): 2925 (s), 2854, 1709 (s) cm-1Odor: Animalic, powdery, musky Example 3: Preparation of mixture of isomers of cyclohexadec-5-en-1-one and cyclohexadec-6-en-1-one Step 1: Methyl 11-(2-oxocyclohexyl)undecanoate: A 3-neck 100 mL round bottom flask equipped with a magnetic stirrer, addition funnel and reflux condenser was charged with di-tert-butyl peroxide (0.125 g, 0.85 mmol), and cyclohexanone (47.8 g, 0.48 mol). The solution was slowly heated to 110-120 °C andCase 09302(2) 19then carefully charged with a solution of methyl 10-undecenoate (10 g, 0.05 mol) and di- tert-butyl peroxide (1.12 g, 0.007mol) via additional funnel over a period of 20 min. The reaction mixture was refluxed at 120 °C for 4 hr. After cooling to room temperature, water (30 mL) was added and the layers were separated. The organic layer was washed with aqueous saturated sodium carbonate (30 mL), 5% aqueous acetic acid (20 mL) and saturated brine (20 mL). The organic layer was concentrated under reduced pressure and excess cyclohexanone was removed. The resulting material was purified by fractional distillation to give methyl 11-(2-oxocyclohexyl)undecanoate (7.3 g, 49% yield) as a colorless liquid.1H NMR (400 MHz, CDCl3) δ (ppm): 3.64 (s, 3H), 2.39-2.33 (m, 1H), 2.30-2.19 (m, 2H),2.2-1.99 (m, 8H), 1.78-1.71 (m, 2H), 1.61-1.53 (m, 2H), 1.23-0.85 (m, 14H)GCMS : 296.45 (M+), 265.2, 236.2, 198.2, 168.1, 149.1, 121.1, 98.1, 74.1, 55.1 IR (Neat): 2925, 2854, 1739, 1709, 1248 cm-1Step 2: methyl 11-(7-oxooxepan-2-yl)undecanoate: A 3-neck 500 mL round bottom flask equipped with an overhead stirrer, addition funnel and reflux condenser was charged with methyl-11-(2-oxocyclohexyl)undecanoate (55 g, 0.18 mol), sodium carbonate (19.6 g, 0.18 mol) under nitrogen atmosphere and cooled to 0 °C in an ice bath. To this reaction mixture, peracetic acid (212 g, 0.55 mol) wasadded over a period of 1 h. The solution was then allowed to warm to room temperatureand stirred for 8 h. The reaction was quenched with ice water (200 mL) and to it was added ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous FeSO4, hot water and then dried over anhydrous Na2SO4. The organic layer was concentrated to afford a white solid (45 g, 81% yield) which was used as such for the next step.1H NMR (400 MHz, CDCl3) δ (ppm): 4.30-4.23 (m, 1H), 3.66 (s, 3H), 2.619-2.45 (m, 2H), 2.43-2.41 (m, 2H), 1.93-1.81 (m, 6H), 1.69-1.47 (m, 4H), 1.26-0.85 (m, 14H) GCMS: 312.45(M+), 294.2, 263.1, 200.2, 143.1, 113.1, 84.1, 55.1 IR (Neat): 2925, 2855, 1731, 1251, 1172 cm-1Step 3: dimethyl 6-chloroheptadecanedioate: A3-neck 250 mL round bottom flask equipped with a magnetic stirrer, additionfunnel and reflux condenser was placed under nitrogen atmosphere and chargedCase 09302(2) 20successively methyl cyclohexane (100 mL), methyl 11-(7-oxooxepan-2-yl)undecanoate (50g, 0.16 mol) and 0.43g of zinc chloride (0.003mol). The reaction mixture was then cooled to 0 °C and then dropwise addition of thionyl chloride (38 g, 0.32 mol) via addition funnel was done over a period of 1.5 h. The reaction mixture was then warmed up to roomtemperature and then refluxed at 80 °C for 5 hours. The dark reaction mixture was cooledto 0 °C and quenched with methanol (100 mL) which was slowly added to the reaction mixture. The reaction mixture was allowed to stir for 1h. Then methanol was evaporated and the dark crude was quenched with aqueous saturated sodium carbonate (100 mL) and extracted with ethyl acetate (2 x 200 mL) and then organic layers were separated. The pH of organic layer was maintained between 7-8. The organic layer was finally washed with brine (200 mL) and dried over anhydrous Na2SO4and concentrated to afford crude product (55 g). The crude was purified by flash column chromatography on silica gel, eluting witha gradient of ethyl acetate in hexane, to afford dimethyl 6-chloroheptadecanedioate (18 g,31% yield), as a pale yellow liquid which was used in the following step.1H-NMR (400 MHz, CDCl3) δ (ppm): 3.92-3.84 (m, 1H), 3.67-3.66 (s, 6H), 2.34-2.28 (m, 4H), 1.93-1.59 (m, 8H), 1.54-1.39 (m, 2H), 1.27-0.86 (m,15H) IR (Neat): 2925, 2855, 1731, 1251, 1172 cm-1Method-A: Step 4: Dimethyl (E&Z) -heptadec-5-enedioate and dimethyl (E&Z) -heptadec-6-enedioate: A 3-neck 250 mL round bottom flask equipped with a magnetic stirrer andreflux condenser was charged with 6-chloroheptadecanedioate (45 g, 0.14 mol) and cooledto 10 °C. Using addition funnel, 1,8-Diazabicyclo(5.4.0)undec-7-ene (42.6 g, 0.28 mol) was added very slowly over a period of 1 h to control the exotherm generated. The reaction mixture was slowly heated to 125 °C and maintained at that temperature for 6 h. The dark colored reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous saturated sodium carbonate (100 mL) followed by saturated brine (100 mL). The organic layer was then dried over anhydrous Na2SO4and concentrated under reduced pressure to give crude product (25 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethylCase 09302(2) 21acetate in hexane to give a mixture of dimethyl (E&Z) -heptadec-5-enedioate and dimethyl(E&Z) -heptadec-6-enedioate (18 g, 44% yield), as a pale yellow liquid which was used inthe next step.1H-NMR (400 MHz, CDCl3) δ (ppm): 5.45-5.34 (m, 2H), 3.66 (s, 6H), 2.32-2.28 (m, 4H ), 2.02-1.95 (m, 4H), 1.70-1.66 (m, 2H), 1.63-1.63 (m, 2H) ,1.28-1.25 (s, 14H)GCMS: 326.2 (M+), 294.2, 262.2, 234.2, 192.2, 150.1, 121.1, 81.1, 55.1IR (Neat): 2925, 2854, 1738, 1195, 1167 cm-1Method-A: Step 5: Mixture of methyl (E&Z) -2-oxocyclopentadec-5-ene-1-carboxylate, methyl(E&Z) -2-oxocyclopentadec-6-ene-1-carboxylate, methyl (E&Z) -15-oxocyclopentadec-3-ene-1-carboxylate and methyl (E&Z) -15-oxocyclopentadec-4-ene-1-carboxylate:A solution of dimethyl (E&Z) -heptadec-5-enedioate and dimethyl (E&Z) -heptadec-6-enedioate (10 g, 0.03 mol) in THF (600 ml) was slowly added to a refluxing mixture of LiHMDS (Lithium hexamethyldisilazide) (183 mL, 1M in THF, 0.18 mol) and THF (350 mL) under nitrogen atmosphere. After completion of the addition, the mixture was further stirred for 15 min at reflux. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4~5) and then extracted with ethyl acetate (3x 200 mL). The combined organic layer was washed with water (200 mL), saturated brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude liquid was purified by column chromatography on silica gel, eluting with a gradient of ethylacetate in hexane to afford a mixture of methyl (E&Z) -2-oxocyclopentadec-5-ene-1-carboxylate, methyl (E&Z) -2-oxocyclopentadec-6-ene-1-carboxylate, methyl (E&Z) -15-oxocyclopentadec-3-ene-1-carboxylate and methyl (E&Z) -15-oxocyclopentadec-4-ene-1-carboxylate (3.5 g, 39% yield) as a light yellow oil.1H-NMR (400 MHz, CDCl3) δ (ppm): 5.32 - 5.17 (m, 2H), 3.63-3.57 (s, 3H), 3.55-3.49(m, 1H), 2.51-2.38 (m, 2H), 1.94-1.56 (m, 4H), 1.30-1.07 (s,18H)GCMS: 294.2(M+), 262.2, 234.2, 192.2, 150.1, 121.1, 81.1, 55.1IR (Neat): 2925, 2854, 1747, 1714, 1646, 1437, 1235 cm-1Step 6: Mixture of (E&Z)cyclohexadec-5-en-1-one and cyclohexadec-6-en-1-one:Method ACase 09302(2) 22A solution of mixture of compounds from step-5 (4.0 g, 0.014 mol) in MeOH (20 mL) was treated with aqueous NaOH (1.68 g, 0.04 mol in 10 mL water) and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature, acidified to pH 1 by dropwise addition of 10% H2SO4and then heated to reflux for 30 min. The reaction mixture was then cooled to room temperature and MeOH was evaporated. The crude solution was extracted with MTBE (2x 30 mL) and the combined organic layer was washed with water (100 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography onsilica gel, eluting with a gradient of ethyl acetate in hexane to give a mixture of E & Zisomers of cyclopentadec-4-en-1-one and cyclopentadec-5-en-1-one (2.2 g, 66% yield) as a colorless liquid.1H-NMR (400 MHz, CDCl3) δ (ppm): 5.41-5.25 (m, 2H), 2.45-2.30 (m, 4H), 2.09-2.01 (m, 4H), 1.70-1.64 (m, 2H), 1.39-1.20 (m, 16 H)GCMS: 236.2(M+), 218.2, 193.2, 175.2, 152.1, 133.1, 109.1, 81.1, 55.1IR (Neat): 2925, 2854, 1711, 1459, 967 cm-1Odor: Musky, creamy, powdery Method-B: Step 4: Methyl 13-chloro-2-oxocyclohexadecane-1-carboxylate and methyl 7-chloro- 2-oxocyclohexadecane-1-carboxylate: A solution of dimethyl 6-chloroheptadecanedioate (5.0 g, 0.014 mol) in THF (300 ml) was slowly added to a refluxing mixture of LiHMDS (Lithium hexamethyldisilazide) (85 mL, 1M in THF, 0.084 mol) and THF (300 mL) under nitrogen atmosphere. After completion of the addition, the mixture was further stirred for 15 min at reflux. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4~5) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with water (100 mL), saturated brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The resulting crude liquid was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to afford a mixture of methyl 13-chloro-2-oxocyclohexadecane-1-carboxylate and methyl 7-chloro-2-oxocyclohexadecane-1-carboxylate (2.5 g, 55 % yield) as a light-yellow oil.Case 09302(2) 231H NMR (400 MHz, CDCl3) δ 4.09 – 3.87 (m, 1H), 3.70 (s, 3H), 3.58 – 3.41 (m, 1H), 2.61– 2.54 (m,1H), 2.05 – 1.94 (m, 1H), 1.88 – 1.61 (m, 7H), 1.40 – 1.18 (m, 17H).GCMS: 330.2 (M+) , 295.2, 263.2, 234.2, 202.2,165.1,132.0IR (Neat): 2928, 2858, 1744, 1713 cm-1Step 5: Synthesis of 6-chlorocyclohexadecan-1-one: A solution of mixture of compounds from step-4 (4.5 g, 0.014 mol) in MeOH (30 mL) was treated with aqueous NaOH (1.63 g, 0.04 mol in 30 mL water) and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature, acidified to pH 1 by dropwise addition of 10% H2SO4and then heated to reflux for 30 min. The reaction mixture was then cooled to room temperature and MeOH was evaporated. The crude solution was extracted with MTBE (2x 30 mL) and the combined organic layer was washed with water (100 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give 6-chlorocyclohexadecan-1-one (1.7 g, 46% yield) as a colorless liquid.1H-NMR (400 MHz, CDCl3) δ (ppm): 3.99 -3.96 (m, 1H), 2.52 – 2.31 (m, 4H), 1.81 – 1.55(m, 10 H), 1.45 –1.39 (m, 3H), 1.32 – 1.23 (m, 11H).GCMS: 272.2(M+), 236.2, 207.2, 178.2 IR (Neat) : 2927, 2857, 1709, 1458 cm-1Step 6: Mixture of (E&Z)cyclohexadec-5-en-1-one and cyclohexadec-6-en-1-one:A 3-neck 50 mL round bottom flask equipped with a magnetic stirrer and reflux condenserwas charged with 6-chloroheptadecanedioate (1.5 g, 0.006 mol) and cooled to 10 °C. Then,1,8-Diazabicyclo(5.4.0)undec-7-ene (1.67 g, 0.011 mol) was added very slowly over a period of 10 min to control the exotherm generated. The reaction mixture was slowly heated to 125 °C and maintained at that temperature for 6 h. The dark colored reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with aqueous saturated sodium carbonate (10 mL) followed byCase 09302(2) 24saturated brine (10 mL). The organic layer was then dried over anhydrous Na2SO4and concentrated under reduced pressure to give crude product (1.7 g). The resulting crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethylacetate in hexane to give a mixture of E & Z isomers of cyclopentadec-4-en-1-one andcyclopentadec-5-en-1-one (0.5 g, 38% yield) as a colorless liquid.1H-NMR (400 MHz, CDCl3) δ (ppm): δ 5.41 – 5.22 (m, 2H), 2.46 – 2.30 (m, 4H), 2.08 –1.98 (m, 4H), 1.70 – 1.52 (m, 2H), 1.28 – 0.57 (m, 16H).GCMS: 236.2 (M+), 221.2, 195.1, 179.2 IR (Neat): 2925, 2854, 1710, 1440 cm-1Odor: Musky, creamy, powdery Example 4: Preparation of mixture of isomers of 3-methylcyclohexadec-5-en-1-one, 3-methylcyclohexadec-6-en-1-one, 5-methylcyclohexadec-5-en-1-one and 5- methylcyclohexadec-6-en-1-one Step-1: Methyl 11-(4-methyl-2-oxocyclohexyl)undecanoate and methyl 11-(2- methyl-6-oxocyclohexyl)undecanoate: A 3-neck 500 mL round bottom flask equipped with a magnetic stirrer, addition funnel and reflux condenser was charged with di-tert-butyl peroxide (0.62g, 0.004mol), and 3-methylcyclohexan-1-one (156 g, 1.38 mol). The solution was slowly heated to 110- 120 °C and then carefully charged with a solution of methyl 10-undecenoate (50 g, 0.25 mol) and di-tert-butyl peroxide (5.63 g, 0.038mol) via additional funnel over a period of 20 min. The reaction mixture was refluxed at 120 °C for 16 hr. After cooling to room temperature, water (50 mL) was added and the layers were separated. The organic layer was washed with aqueous saturated sodium carbonate (50 mL), 5% aqueous acetic acid (50 mL) and saturated brine (50 mL). The organic layer was concentrated under reduced pressure and excess cyclopentanone was removed. The resulting material was purified by fractional distillation to give Methyl 11-(4-methyl-2-oxocyclohexyl)undecanoate and methyl 11-(2-methyl-6-oxocyclohexyl)undecanoate (40.5 g, 58 % yield) as a colorless liquid.1H-NMR (400 MHz, CDCl3) δ (ppm): 3.63 (s, 3 H), 2.32-2.09 (m, 4 H), 2.08-2.01 (m, 2 H), 1.86-1.55 (m, 4 H), 1.63-1.53 (m, 2 H), 1.54-1.44 (m, 1 H), 1.22-1.03 (m, 15 H).1.02- 0.91 (m, 3 H). GCMS: 310.3 (M+), 279.2, 263.2, 237.2, 219.2, 198.2, 176.1Case 09302(2) 25IR (Neat): 2926, 2856, 1739, 1710 cm-1Step 2: methyl 11-(5-methyl-7-oxooxepan-2-yl)undecanoate and methyl 11-(3- methyl-7-oxooxepan-2-yl)undecanoate: A 3-neck 500 mL round bottom flask equipped with an overhead stirrer, addition funnel and reflux condenser was charged with Methyl 11-(4-methyl-2- oxocyclohexyl)undecanoate and methyl 11-(2-methyl-6-oxocyclohexyl)undecanoate (50 g, 0.16 mol), sodium carbonate (17.05 g, 0.16 mol) under nitrogen atmosphere and cooled to 0 °C in an ice bath. To this reaction mixture, peracetic acid (110 g, 0.29 mol) was added over a period of 1 h. The solution was then allowed to warm to room temperature and stirred for 8 h. The reaction was quenched with ice water (200 mL) and to it was added ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous FeSO4, hot water and then dried over anhydrous Na2SO4. The organic layer was concentrated to afford a thick liquid (47.5 g, 90% yield) which was used as such for the next step.1H-NMR (400 MHz, CDCl3) δ (ppm): 4.22- 4.15 (m, 1H), 3.66 (s, 3H), 2.92-2.83 (dd, J =13.2, 2.8 Hz, 1H), 2.59-2.46 (m, 1H), 2.30-2.06 (t, J = 7.2 Hz, 2H), 1.87-1.65 (m, 5H),1.61-1.43 (m, 4H), 1.25-1.04 (s, 14H).1.02-0.90 (m, 3 H). GCMS: 326.7 (M+), 308.2, 277.2, 235.2, 200.2, 157.1, 127.1, 98.169.1, 41.0 IR (Neat): 2926, 2856, 1730 cm-1Step 3: Dimethyl 6-chloro-3-methylheptadecanedioate and dimethyl 6-chloro-5- methylheptadecanedioate: A3-neck 250 mL round bottom flask equipped with a magnetic stirrer, additionfunnel and reflux condenser was placed under nitrogen atmosphere and chargedsuccessively methyl cyclohexane (100 mL), methyl 11-(5-methyl-7-oxooxepan-2-yl)undecanoate and methyl 11-(3-methyl-7-oxooxepan-2-yl)undecanoate (50 g, 0.15 mol)and 0.42g of zinc chloride (0.003mol). The reaction mixture was then cooled to 0 °C andthen dropwise addition of thionyl chloride (36 g, 0.31 mol) via addition funnel was doneover a period of 1.5 h. The reaction mixture was then warmed up to room temperature andthen refluxed at 80 °C for 5 hours. The dark reaction mixture was cooled to 0 °C andquenched with methanol (100 mL) which was slowly added to the reaction mixture. TheCase 09302(2) 26reaction mixture was allowed to stir for 1h. Then methanol was evaporated and the dark crude was quenched with aqueous saturated sodium carbonate (100 mL) and extracted with ethyl acetate (2 x 200 mL) and then organic layers were separated. The pH of organic layer was maintained between 7-8. The organic layer was finally washed with brine (200 mL) and dried over anhydrous Na2SO4 and concentrated to afford crude product (52 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane, to afford dimethyl 6-chloro-3-methylheptadecanedioate anddimethyl 6-chloro-5-methylheptadecanedioate (20 g, 35% yield), as a pale-yellow liquidwhich was used in the following step. 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.86-3.82 (m, 1H), 3.64 (s, 6H), 2.35-2.23 (m, 4H),2.16-2.08 (m, 1H), 1.72-1.55 (m, 7H), 1.25 (bs, 15H), 0.92 (t, J = 6.8 Hz, 3H)GCMS: 377.2 (M+), 308.1, 276.2, 235.3, 193.2, 146.1, 98.0IR (Neat): 2926, 2855, 1737 cm-1Step 4: Dimethyl ((E&Z) 3-methylheptadec-5-enedioate and dimethyl (E&Z) 3-methylheptadec-6-enedioate: A3-neck 250 mL round bottom flask equipped with a magnetic stirrer and refluxcondenser was charged with dimethyl 6-chloro-3-methylheptadecanedioate and dimethyl 6-chloro-5-methylheptadecanedioate (40 g, 0.11 mol) and cooled to 10 °C. Using addition funnel, 1,8-Diazabicyclo(5.4.0)undec-7-ene (30.4 g, 0.22 mol) was added very slowly over a period of 1 h to control the exotherm generated. The reaction mixture was slowly heated to 125 °C and maintained at that temperature for 6 h. The dark colored reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous saturated sodium carbonate (100 mL) followed by saturated brine (100 mL). The organic layer was then dried over anhydrous Na2SO4and concentrated under reduced pressure to give crude product (34 g). The crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give a mixture of dimethyl (E&Z) 3-methylheptadec-5-enedioate and dimethyl(E&Z) 3-methylheptadec-6-enedioate (12.3 g, 34% yield), as a pale yellow liquid whichwas used in the next step.Case 09302(2) 271H-NMR (400 MHz, CDCl3) δ (ppm): 5.43-5.30 (m, 2H), 3.65 (s, 6H), 3.35-3.23 (m, 4H), 2.01-1.89 (m, 4H), 1.63-1.56 (m, 3H), 1.29 (bs, 14H).0.95-0.86 (m, 3H). GCMS: 340.2 (M+), 308.2, 290.2, 276.2, 262.1, 248.2, 234.2 IR (Neat): 3521, 2925, 2854, 1736 cm-1Step 5: Mixture of methyl (E&Z) 4-methyl-2-oxocyclohexadec-6-ene-1-carboxylate,methyl (E&Z) 4-methyl-2-oxocyclohexadec-7-ene-1-carboxylate, methyl (E&Z) 4-methyl-2-oxocyclohexadec-7-ene-1-carboxylate and methyl (E&Z) 6-methyl-2-oxocyclohexadec-7-ene-1-carboxylate: Asolution of dimethyl (E&Z) 3-methylheptadec-5-enedioate and dimethyl (E&Z)3-methylheptadec-6-enedioate (9 g, 0.026 mol) in THF (600 ml) was slowly added to a refluxing mixture of LiHMDS (Lithium hexamethyldisilazide) (162 mL, 1M in THF, 0.16 mol) and THF (350 mL) under nitrogen atmosphere. After completion of the addition, the mixture was further stirred for 15 min at reflux. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4~5) and then extracted with ethyl acetate (3x 200 mL). The combined organic layer was washed with water (200 mL), saturated brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude liquid was purified by column chromatography on silica gel, eluting with a gradientof ethyl acetate in hexane to afford a mixture of methyl (E&Z) 4-methyl-2-oxocyclohexadec-6-ene-1-carboxylate, methyl (E&Z) 4-methyl-2-oxocyclohexadec-7-ene-1-carboxylate, methyl (E&Z) 4-methyl-2-oxocyclohexadec-7-ene-1-carboxylate andmethyl (E&Z) 6-methyl-2-oxocyclohexadec-7-ene-1-carboxylate (3.0 g, 37% yield) as alight yellow oil.1H-NMR (400 MHz, CDCl3) δ (ppm): 5.34-5.28 (m, 1H), 3.74-3.66 (m, 3H), 3.53-3.46 (m, 1H), 2.01-1.84 (m, 9 H), 1.29 (bs, 15H).0.97-0.86 (m, 3H). GCMS: 308.0 (M+), 275.3, 231.2, 179.1, 135.195.1, 55.1IR (Neat): 2926, 2855, 1746, 1713 cm-1Step 6: Mixture of (E&Z) 3-methylcyclohexadec-5-en-1-one, (E&Z) 3-methylcyclohexadec-6-en-1-one, (E&Z) 5-methylcyclohexadec-5-en-1-one and (E&Z) 5- methylcyclohexadec-6-en-1-one: A solution of mixture of compounds from step-5 (3.0 g, 0.01 mol) in MeOH (20 mL) was treated with aqueous NaOH (1.2 g, 0.04 mol in 10 mL water) and the resulting mixtureCase 09302(2) 28was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature, acidified to pH 1 by dropwise addition of 10% H2SO4 and then heated to reflux for 30 min. The reaction mixture was then cooled to room temperature and MeOH was evaporated. The crude solution was extracted with MTBE (2x 30 mL) and the combined organic layerwas washed with water (100 mL) and saturated brine (100 mL). The organic layer wasdried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography on silica gel, eluting with agradient of ethyl acetate in hexane to give a mixture of Mixture of (E & Z) 3-methylcyclohexadec-5-en-1-one, (E & Z) 3-methylcyclohexadec-6-en-1-one, (E & Z) 5-methylcyclohexadec-5-en-1-one and (E & Z) 5-methylcyclohexadec-6-en-1-one (1.8 g,74% yield) as a colorless liquid.1H-NMR (400 MHz, CDCl3) δ (ppm): 5.38-5.34 (m, 1H), 2.40-2.29 (m, 3H), 2.11-1.97 (m, 5H), 1.69-1.54 (m, 4H), 1.29 (bs, 14H), 0.95-0.86 (m, 3H). GCMS: 250.2 (M+), 221.2, 192.2, 165.1, 135.1, 109.1, 81.1IR (Neat): 2924, 2854, 1710 cm-1Odor: Creamy, powdery, musky, very diffusive Example 5: Preparation of mixture of isomers of 4-methylcyclohexadec-5-en-1-oneand 4-methylcyclohexadec-6-en-1-oneStep-1: methyl 11-(5-methyl-2-oxocyclohexyl)undecanoate: A 3-neck 500 mL round bottom flask equipped with a magnetic stirrer, additionfunnel and reflux condenser was charged with di-tert-butyl peroxide (0.69 g, 4.7 mmol),and 4-methylcyclohexan-1-one (198 g, 1.77 mol). The solution was slowly heated to 110-120 °C and then carefully charged with a solution of methyl 10-undecenoate (50 g, 0.252mol) and di-tert-butyl peroxide (6.23 g, 0.042mol) via additional funnel over a period of 20min. The reaction mixture was refluxed at 120 °C for 16 hr. After cooling to room temperature, water (50 mL) was added and the layers were separated. The organic layer was washed with aqueous saturated sodium carbonate (50 mL), 5% aqueous acetic acid (50 mL) and saturated brine (50 mL). The organic layer was concentrated under reduced pressure and excess cyclopentanone was removed. The resulting material was purified byfractional distillation to give methyl 11-(5-methyl-2-oxocyclohexyl)undecanoate (64.5 g,82 % yield) as a colorless liquid.Case 09302(2) 291H NMR (400 MHz, CDCl3): δ 3.67 (s, 3H), 2.52 – 2.22 (m, 5H), 2.16 – 1.86 (m, 3H),1.81 – 1.54 (m, 5H), 1.25 (s, 15H), 1.01 (dd, J = 20.5, 6.6 Hz, 3H).13C (400MHz, CDCl3): 215.2, 213.4, 174.2, 51.3, 49.5, 48.5, 42.2, 41.6, 39.6, 37.8, 35.9, 34.5, 34.0, 32.0, 31.0, 29.7, 29.54, 29.4, 29.4, 29.3, 29.3, 29.1, 29.0, 29.0, 27.2, 27.0, 26.4, 25.0, 21.2, 20.3 IR (Neat): 2926, 2856, 1738, 1711 cm-1Step 2: Methyl 11-(4-methyl-7-oxooxepan-2-yl)undecanoate: A 3-neck 500 mL round bottom flask equipped with an overhead stirrer, addition funnel and reflux condenser was charged methyl 11-(5-methyl-2-oxocyclohexyl)undecanoate (50 g, 0.16 mol), sodium carbonate (60 g, 0.19 mol) undernitrogen atmosphere and cooled to 0 °C in an ice bath. To this reaction mixture, peraceticacid (136 g, 0.30 mol) was added over a period of 1 h. The solution was then allowed towarm to room temperature and stirred for 8 h. The reaction was quenched with ice water (200 mL) and to it was added ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous FeSO4, hot water and then dried over anhydrous Na2SO4. Theorganic layer was concentrated to afford a liquid (70 g, 91% yield) which was used as suchfor the next step.1H NMR (400 MHz, CDCl3) δ 4.46 – 4.34 (m, 1H), 3.66 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H),2.13 – 1.97 (m, 1H), 1.93 – 1.77 (m, 2H), 1.74 – 1.54 (m, 4H), 1.27 (s, 16H), 1.01 (dd, J =29.7, 6.7 Hz, 3H).13C (400MHz, CDCl3): 175.3, 174.0, 79.3, 75.4, 51.12, 43.0, 41.0, 36.2, 36.0, 35.1, 34.0, 31.0, 30.1, 29.2, 29.1, 29.0, 28.1, 28.0, 25.2, 24.7, 22.4IR (Neat): 2925, 2855, 1731 cm-1Step 3: Dimethyl 6-chloro-4-methylheptadecanedioate: A3-neck 250 mL round bottom flask equipped with a magnetic stirrer, additionfunnel and reflux condenser was placed under nitrogen atmosphere and chargedsuccessively methyl 11-(4-methyl-7-oxooxepan-2-yl)undecanoate (67 g, 0.20 mol) and0.56 g of zinc chloride (0.004mol). The reaction mixture was then cooled to 0 °C and thendropwise addition of thionyl chloride (61 g, 0.51 mol) via addition funnel was done over aperiod of 1.5 h. The reaction mixture was then warmed up to room temperature and thenrefluxed at 80 °C for 5 hours. The dark reaction mixture was cooled to 0 °C and quenchedCase 09302(2) 30with methanol (100 mL) which was slowly added to the reaction mixture. The reaction mixture was allowed to stir for 1h. Then methanol was evaporated and the dark crude was quenched with aqueous saturated sodium carbonate (100 mL) and extracted with ethyl acetate (2 x 200 mL) and then organic layers were separated. The pH of organic layer was maintained between 7-8. The organic layer was finally washed with brine (200 mL) anddried over anhydrous Na2SO4 and concentrated to afford crude product (70 g). The crudewas purified by flash column chromatography on silica gel, eluting with a gradient of ethylacetate in hexane, to afford dimethyl 6-chloro-4-methylheptadecanedioate (33 g, 43%yield), as a pale-yellow liquid which was used in the following step.1H NMR (400 MHz, CDCl3) δ 4.06 – 3.88 (m, 1H), 3.73 – 3.59 (m, 6H), 2.46 – 2.23 (m,4H), 1.83 – 1.45 (m, 9H), 1.28 (s, 14H), 0.91 (t, J = 6.7 Hz, 3H).13C (400MHz, CDCl3): 174.1, 61.7, 51.2, 45.7, 45.2, 39.1, 38.4, 33.8, 32.1, 30.4, 29.6, 29.3, 29.2, 29.1, 28.9, 26.3, 24.8, 19.4, 18.1 IR (Neat): 2926, 2855, 1737 cm-1Step 4: dimethyl (E&Z) -4-methylheptadec-5-enedioate and dimethyl (E&Z) -4-methylheptadec-6-enedioate: A3-neck 250 mL round bottom flask equipped with a magnetic stirrer and refluxcondenser was charged with dimethyl 6-chloro-4-methylheptadecanedioate (30 g, 95% GCpurity, 0.08 mol) and cooled to 10 °C. Using addition funnel, 1,8-Diazabicyclo(5.4.0)undec-7-ene (46 g, 0.32 mol) was added very slowly over a period of 1h to control the exotherm generated. The reaction mixture was slowly heated to 125 °C and maintained at that temperature for 6 h. The dark colored reaction mixture was then cooled to room temperature and quenched with 6N HCl until the pH of the solution became acidic. The solution was diluted with ethyl acetate, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with aqueous saturated sodium carbonate (100 mL) followed by saturated brine (100 mL). The organic layer was then dried over anhydrous Na2SO4and concentrated under reducedpressure to give crude product (30 g). The crude was purified by flash columnchromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give amixture of dimethyl (E&Z) -4-methylheptadec-5-enedioate and dimethyl-4-Case 09302(2) 31methylheptadec-6-enedioate (15 g, 58% yield), as a pale yellow liquid which was used inthe next step.1H NMR (400 MHz, CDCl3) δ 5.45 – 5.10 (m, 2H), 3.63 (s, 6H), 2.27 (t, J = 7.6 Hz, 4H),2.05 – 1.73 (m, 4H), 1.69 – 1.35 (m, 5H), 1.23 (s, 14H), 0.89 (dd, J = 45.0, 6.6 Hz, 3H).13C (400MHz, CDCl3) : 174.3, 134.6, 132.1, 129.8, 127.9, 51.3, 39.6, 36.4, 34.0, 32.6, 32.5, 32.4, 32.0, 31.8, 31.3, 29.4, 29.3, 29.2, 29.1, 24.9, 20.8, 19.0IR (Neat): 2925, 2854, 1738 cm-1Step 5: Mixture of methyl (E&Z) -3-methyl-16-oxocyclohexadec-4-ene-1-carboxylate, methyl (E&Z) -3-methyl-16-oxocyclohexadec-5-ene-1-carboxylate, methyl(E&Z) )-5-methyl-2-oxocyclohexadec-6-ene-1-carboxylate and methyl (E&Z) -5-methyl-2-oxocyclohexadec-7-ene-1-carboxylate: Asolution of dimethyl (E&Z) -4-methylheptadec-5-enedioate and dimethyl (E&Z) -4-methylheptadec-6-enedioate (5 g, 0.014 mol) in THF (88 ml) was slowly added to arefluxing mixture of LiHMDS (Lithium hexamethyldisilazide) (58 mL, 1M in THF, 0.058mol) and THF (176 mL) under nitrogen atmosphere. After completion of the addition, themixture was further stirred for 15 min at reflux. The mixture was then cooled to room temperature, treated with 1N HCl (pH = 4~5) and then extracted with ethyl acetate (3x 100 mL). The combined organic layer was washed with water (100 mL), saturated brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude liquid was purified by column chromatography on silica gel, eluting with a gradientof ethyl acetate in hexane to afford a mixture of methyl (E&Z) -3-methyl-16-oxocyclohexadec-4-ene-1-carboxylate, methyl (E&Z) -3-methyl-16-oxocyclohexadec-5-ene-1-carboxylate, methyl (E&Z) -5-methyl-2-oxocyclohexadec-6-ene-1-carboxylate andmethyl (E&Z) -5-methyl-2-oxocyclohexadec-7-ene-1-carboxylate (2.5 g, 55% yield) as acolorless liquid. 1H NMR (400 MHz, CDCl3): 5.4-5.0 (m,2H), 3.7-3.4 (m,3H), 2.6-2.4(m,2H), 2.1-2.0 (m,5H), 1.7-1.3(m,14H), 0.9-0.95 (m,3H) 13C (400MHz, CDCl3) : 206.6, 205.8, 170.4, 135.7, 134.9, 133.1, 132.4, 131.2, 130.4, 128.9, 127.9, 71.8, 57.79, 57.2, 55.4, 52.4, 41.4, 40.7, 40.0, 39.5, 37.0, 36.5, 36.0, 35.1, 34.9, 33.8, 32.2, 30.9, 30.3, ,29.3, 28.5, 28.0, 27.5, 27.1, 26.9, 26.6, 26.4, 25.9, 25.7, 25.6, 25.3, 24.9, 23.4, 21.7, 20.0, 19.1IR (Neat): 2926, 2855, 1746, 1714 cm-1Case 09302(2) 32Step 6: Mixture of isomers of (E&Z)-4-methylcyclohexadec-5-en-1-one and 4- methylcyclohexadec-6-en-1-one: Asolution of mixture of compounds from step-5 (2.1 g, 0.006 mol) in MeOH (20mL) was treated with aqueous KOH (1.1 g, 0.02 mol in 10 mL water) and the resulting mixture was heated to reflux for 1.5 h. The resulting mixture was then cooled to room temperature, acidified to pH 1 by dropwise addition of 10% H2SO4 and then heated to reflux for 30 min. The reaction mixture was then cooled to room temperature and MeOH was evaporated. The crude solution was extracted with MTBE (2x 30 mL) and thecombined organic layer was washed with water (100 mL) and saturated brine (100 mL).The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane to give a mixture of Mixture of(E&Z) 3-methylcyclohexadec-5-en-1-one, (E&Z) 3-methylcyclohexadec-6-en-1-one,(E&Z) 5-methylcyclohexadec-5-en-1-one and (E&Z) 5-methylcyclohexadec-6-en-1-one(1.2 g, 70% yield) as a colorless liquid.1H NMR (400 MHz, CDCl3): 5.3-5.1 (m,2H), 2.5-2.3 (m,4H), 2.1-1.7 (m, 6H), 1.3(s,12H), 1.0-0.9 (dd, 3H)13C (400MHz, CDCl3) : 212.6, 136.0, 132.3, 130.1, 128.8, 42.1, 41.0, 40.3, 36.8, 32.7, 32.2, 32.1, 30.3, 30.1, 28.6, 28.5, 27.7, 27.5, 27.2, 27.0, 26.8, 26.7, 26.6, 26.3, 25.7, 25.5 GCMS: 250.2 (M+), 221.2, 192.2, 165.1, 135.1, 109.1, 81.1IR (Neat): 2924, 2854, 1711 cm-1Odor: Very fine and premium musk Example 6: Preparation of mixture of isomers of (E&Z)cyclotetradec-4-en-1-one and (Z)-cyclotetradec-5-en-1-one Step 1: Methyl 10-(2-oxocyclopentyl)decanoate: Synthesis of Methyl 10-(2-oxocyclopentyl)decanoate was done following the protocol of Example 1 step 1 with cyclopentanone and methyl 9-decenoate.1H (400 MHz, CDCl3) δ (ppm): 3.63 (s, 3H), 2.32-2.28 (m, 1H), 2.8-2.23 (m, 2H), 2.21- 1.99 (m, 4H), 1.787-1.741 (m, 2H), 1.61-1.53 (m, 2H), 1.26 (s, 14H).Case 09302(2) 3313C (100.6 MHz, CDCl3) δ (ppm) : 221.4(s), 174.8, 51.2, 48.9, 37.9, 33.9, 29.5, 29.4, 29.3,29.2, 29.0, 28.9, 27.3, 24.7, 20.6. GCMS : 268.2 (M+), 251.2, 222.2, 203.1, 184.1 IR (cm-1) : 2926, 2855, 1735 Step 2: Methyl 10-(6-oxotetrahydro-2H-pyran-2-yl)decanoate Methyl 10-(2-oxocyclopentyl)decanoate was converted to methyl 10-(6- oxotetrahydro-2H-pyran-2-yl)decanoate following the protocol as mentioned in the Example 1 step 2.1H (400 MHz, CDCl3) δ (ppm): 4.30-4.24 (m, 1H), 3.66 (s, 3H), 2.62-2.45 (m, 2H), 2.44- 2.42 (m, 2H), 1.93-1.81 (m, 4H), 1.69-1.47 (m, 2H), 1.26 (s, 14H).13C (100.6 MHz, CDCl3) δ (ppm): 174.3, 172.1, 80.6, 51.4, 35.8, 34.1, 29.4, 29.4, 29.2, 29.1, 27.8, 24.9, 18.5. GCMS: 284.1 (M+), 266.1, 235.2, 193.2 IR (cm-1): 2926, 2855, 1733 Step 3: Dimethyl 5-chloropentadecanedioate Dimethyl 5-chloropentadecanedioate was synthesized using methyl 10-(6- oxotetrahydro-2H-pyran-2-yl)decanoate following the protocol in Example 1 step 3.1H (400 MHz, CDCl3) δ (ppm): 3.92-3.85 (m, 1H), 3.68-3.67 (s, 6H), 2.35-2.29 (m, 4H), 1.93-1.59 (m, 8H), 1.549-1.397 (m, 2H), 1.275 (s,10H)13C (100.6 MHz, CDCl3) δ (ppm): 174.2,173.6, 63.3, 51.3, 38.3, 37.5, 33.9, 33.2, 29.3, 29.1, 28.9, 26.3, 24.8, 21.8 GCMS: 334.1 (M+), 299.2, 267.2, 235.2, 193.2 IR (cm-): 2928, 2855, 1736 Step 4: Dimethyl (E&Z)-pentadec-4-enedioate and Dimethyl (E&Z)-pentadec-5- enedioate Mixture of Dimethyl (E&Z)-pentadec-4-enedioate and Dimethyl (E&Z)-pentadec-5- enedioate was synthesized using dimethyl 5-chloropentadecanedioate following the protocol in Example 1 step 4.1H (400 MHz, CDCl3) δ (ppm): 5.46-5.35 (m, 2H), 3.66 (s,6H), 2.32-2.28 (m, 2H), 2.02- 1.95 (m, 4H), 1.70-1.67 (m,2H), 1.63 (m, 2H), 1.28-1.26 (s, 12H)Case 09302(2) 3413C (100.6 MHz, CDCl3) δ (ppm): 174.1,173.5, 131.7, 128.6,127.7, 51.2, 33.9, 33.2, 32.3, 31.8, 29.3, 29.1, 28.9, 27.8, 24.8 GCMS: 298.2 (M+), 266.1, 234.2, 193.2 IR (cm-1): 2926, 2854, 1737 Step 5: Mixture of methyl (E&Z)-2-oxocyclotetradec-6-ene-1-carboxylate, methyl (E&Z)-2-oxocyclotetradec-5-ene-1-carboxylate, methyl (E&Z)(14-oxocyclotetradec-3-ene- 1-carboxylate and methyl (E&Z)14-oxocyclotetradec-4-ene-1-carboxylate Mixture of Dimethyl (E&Z)-pentadec-4-enedioate and Dimethyl (E&Z)-pentadec-5- enedioate was converted to mixture of methyl (E&Z)-2-oxocyclotetradec-6-ene-1- carboxylate, methyl (E&Z)-2-oxocyclotetradec-5-ene-1-carboxylate, methyl (E&Z)-14- oxocyclotetradec-3-ene-1-carboxylate and methyl (E&Z)-14-oxocyclotetradec-4-ene-1- carboxylate following the protocol mentioned in Example 1 step 5.1H (400 MHz, CDCl3) δ (ppm): 5.33 - 5.17 (m, 2H), 3.63-3.57 (s, 3H), 3.56-3.49 (m, 1H),2.51-2.39 (m, 4H), 1.94-1.56 (m, 6H), 1.31-1.07 (s,14H)13C (100.6 MHz, CDCl3) δ (ppm): 205.80 (d), 170.15-169.68 (d), 133.80, 133.10, 132.36, , 131.95, 129.90, 128.93, 126.22, 58.13, 57.67, 56.93, 56.65, 52.19, 42.66, 42.50, 41.82, 40.41, 31.40, 31.24, 31.05, 30.76, 30.19, 29.55, 29.20, 28.46, 28.06, 27.88, 27.41, 27.10, 26.96 GCMS: 266.2 (M+) IR (cm-1) : 2927, 2854, 1738 Step 6: Mixture of (E&Z)-cyclotetradec-4-en-1-one and (E&Z)-cyclotetradec-5-en-1-one: Mixture of (E&Z)-cyclotetradec-4-en-1-one and (E&Z)-cyclotetradec-5-en-1-onewas synthesized using mixture of methyl (E / Z)-2-oxocyclotetradec-6-ene-1-carboxylate, methyl (E&Z)-2-oxocyclotetradec-5-ene-1-carboxylate, methyl (E&Z)-14- oxocyclotetradec-3-ene-1-carboxylate and methyl (E&Z)-14-oxocyclotetradec-4-ene-1- carboxylate following the protocol in Example 1 step 6.1H (400 MHz, CDCl3) δ (ppm): 5.42-5.26 (m, 2H), 2.50-2.41 (m, 4H), 2.39-2.32 (m, 2H), 2.06-2.00 (m, 2H), 1.672-1.604 (m, 2H), 1.38-1.19 (m, 12H)Case 09302(2) 3513C (100.6 MHz, CDCl3) δ (ppm): 212.75-211.5, 132.3-128.1, 42.5, 42.4, 41.7, 41.3, 31.38, 31.0, 30.6, 27.9, 27.3, 27.2, 27.0, 26.9, 26.7, 26.3, 26.2, 26.1, 25.8 GCMS: 208.2 (M+) IR (cm-1): 2927, 2854, 1708Odour: Musky, Smoky ,leatheryExample 7: Preparation of mixture of isomers of (E&Z)cyclohexadec-4-en-1-one and cyclohexadec-5-en-1-one following process 3: A 250ml three neck RBF equipped with a magnetic stirrer and reflux condenser wascharged was charged with anhydrous Toluene (44.8 ml) under nitrogen atmosphere. TheRBF was then heated upto reflux to remove residual moisture from the solvent. Then the temperature was brought to about 70-80 degrees and freshly fine cut shiny sodium pieces was added piece by piece to the reaction mixture. The temperature was raised to 110 ℃ until the sodium metal turn into shiny grey beads. Then Dimethyl (E&Z)-hexadec-4-enedioate and dimethyl (E&Z)-hexadec-5-enedioate (intermediate of Example 1, step 4) (10 g, 32.0 mmol) dissolved in Toluene (44.8 ml) was added dropwise using addition funnel in a period of 3 h under reflux condition. After complete addition, the RM was allowed to reflux foradditional 1h. The reaction mass was cooled to rt and then to -5 °C. Then 1:1 mixture ofglacial acetic acid and toluene (30ml) was added dropwise, keeping temperature below 5 °C.The reaction mixture was diluted with ethyl acetate (100ml) and then the binary layer wasallowed to stir for 1h, until sodium was fully quenched. The layers were separated, theaqueous layer was extracted twice with ethyl acetate and combined organic layers werewashed with water followed by brine. Organic layers was concentrated to give 9 g cruderesidue. The compound was purified using column chromatography to afford 3.6 g a mixtureof (E&Z)-2-hydroxycyclohexadec-4-en-1-one and (E&Z)-2-hydroxycyclohexadec-5-en-1- one which was used in the next step.1H NMR (400 MHz, CDCl3): δ 5.36-5.32 (m, 2H), 4.26-4.03 (m, 1H), 3.64-3.46 (bs, 1H),2.55-2.26 (m, 2H), 2.11-1.94 (m, 4H), 1.831.74 (m, 2H), 1.65-1.49 (m, 4H), 1.34-1.17 (m, 16H), 0.99-0.87 (m, 2H).13C NMR (100 MHz, CDCl3): δ 212.8, 136.0, 135.3, 132.0, 130.4, 128.6, 75.9, 39.7, 37.3,36.3, 35.5, 33.5, 32.1, 31.4, 30.7, 28.8, 27.9, 27.0, 26.8, 22.6, 22.0, 20.2.IR ν (neat, cm-1): 3483, 1709Case 09302(2) 36A 50 ml two neck RBF equipped with a magnetic stirrer and reflux condenser wascharged with acyloin product (0.5 g, 1.981 mmol) from the above reaction along with 10 mlof acetic acid. Then to the reaction mixture sieved zinc powder followed by conc. HCl was added dropwise, with vigorous stirring. The mixture was heated to 120 ℃ and further portion of hydrochloric acid were added twice at the interval of 30 minutes. The reaction mixturewas then decanted from unchanged zinc. It was cooled to 25 ℃ and 50 mL of water wasadded. The organic layer was extraxted twice with diethyl ether. The combined organic layer was washed with aqueous saturated sodium carbonate (50 mL) followed by saturated brine (50 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel toafford 0.2 g (yield 43%) of mixture of (E&Z) cyclohexadec-4-en-1-one and cyclohexadec-5-en-1-one.1H NMR (400 MHz, CDCl3): δ 5.39-5.27 (m, 2H), 2.45-2.30 (m, 4H), 2.20-2.03 (bs, 4H),1.65-1.61 (m, 4H), 1.36-1.28 (m, 14H)13C NMR (100 MHz, CDCl3): δ 212.6, 212.3, 132.1, 131.7, 130.8, 129.8, 43.0, 42.1, 41.0,40.5, 32.1 ,31.9, 31.1, 28.4, 27.9, 27.5, 27.1, 26.9, 26.8, 26.7, 26.6, 25.8, 25.6, 24.0, 23.2IR ν (neat, cm-1): 1712Odor: Clean, white musk Example 8: Preparation of mixture of isomers of (E&Z)-cycloheptadec-5-en-1- one and cycloheptadec-6-en-1-one : Mixture of isomers of (E&Z)-cycloheptadec-5-en-1-one and cycloheptadec-6-en-1- one was prepared using mixture of dimethyl (E / Z)-heptadec-5-enedioate and dimethyl (E / Z)-heptadec-6-enedioate (intermediate of example 3, step 4) following reaction protocolsmentioned in example 7 in two steps.1H NMR (400 MHz, CDCl3): δ 5.37-5.35 (m, 2H), 2.42-2.38 (m, 4H), 2.04-2.02 (bs, 4H),1.88-1.58 (m, 4H), 1.37-1.30 (m, 16H)13C NMR (100 MHz, CDCl3): δ 212.8, 211.9, 131.1, 130.4, 42.9, 42.2, 32.1, 32.0, 31.8,31.8, 31.8, 31.4, 29.4, 28.9, 28.7, 28.6, 28.5, 28.3, 28.2, 28.1, 28.1, 28.0, 27.9, 27.8, 27.7, 27.6, 27.5, 27.4, 27.3, 27.2, 27.2Case 09302(2) 37IR ν (Neat, cm-1): 2923, 2853, 1711Odor: Musky, powdery, very diffusiveExample 9: Preparation of mixture of isomers of (E&Z)-3-methylcycloheptadec-5-en-1-one, (E&Z)-3-methylcycloheptadec-6-en-1-one, (E&Z)-5-methylcycloheptadec-5-en-1-one and (E&Z)-5-methylcycloheptadec-6-en-1-one, Mixture of dimethyl (E&Z)-3-methylheptadec-5-enedioate and dimethyl (E&Z) 3-methylheptadec-6-enedioate (intermediate of example 4, step 4) was used for the synthesis of mixture of isomers of (E&Z)-3-methylcycloheptadec-5-en-1-one, (E&Z)-3-methylcycloheptadec-6-en-1-one, (E&Z)-5-methylcycloheptadec-5-en-1-one and (E&Z)-5-methylcycloheptadec-6-en-1-one following the protocol mentioned in example 7 viaacyloin condensation.1H NMR (400 MHz, CDCl3): δ 5.38-5.33 (m, 2H), 2.43-2.35 (m, 4H), 2.08-1.97 (m, 4H), 1.70-1.58 (m, 4H), 1.56-1.33 (m, 14H), 1.00-0.80 (m, 4H)13C NMR (100 MHz, CDCl3): δ 212.9, 212.2, 132.6, 132.0, 130.8, 128.6, 51.0, 48.7, 42.8,41.9, 40.9, 39.8, 36.6, 33.0, 31.9, 30.3, 29.7, 29.2, 28.6, 27.9, 27.5, 27.2,27.0, 26.3, 23.7, 23.3. IR(Neat, cm-1): 2924, 2855, 1712 Odor: Musky, powdery Example 10. Alternative synthetic protocol of mixture of isomers of 3- methylcyclohexadec-5-en-1-one, 3-methylcyclohexadec-6-en-1-one, 5- methylcyclohexadec-5-en-1-one and 5-methylcyclohexadec-6-en-1-one (Example 4) Dimethyl (E&Z) 3-methylhexadec-5-enedioate, dimethyl(E&Z) 3-methylhexadec-6- enedioate, dimethyl(E&Z) 5-methylhexadec-5-enedioateand dimethyl(E&Z)5- methylhexadec-6-enedioate (intermediate of example 2, step 4) was used for the synthesisof mixture of isomers of (E / Z) 3-methylcyclohexadec-5-en-1-one, (E / Z) 3-methylcyclohexadec-6-en-1-one, (E / Z) 5-methylcyclohexadec-5-en-1-one and (E / Z) 5-methylcyclohexadec-6-en-1-one following the protocol mentioned in example 7 via acyloincondensation. The spectrochemical data is aligned with the Example 4.Case 09302(2) 38COMPOSITION EVALUATION EXAMPLES: In the following invention, as shown in Table-1: Composition (C) containing the compoundfrom Example-1 was compared with compositions of commercially available materials like3,7-dimethyloct-6-en-1-yl ethyl oxalate (citronellyl ethoxylate, composition G), Ethylene brassylate (composition B) and Exaltolide (Composition I) respectively. (Composition A = blank), DPG = Dipropylene glycol. Table -1: Example-1 in Shampoo: Composition A B C G IRaw Materials (parts by weight) Geranyl acetate 250 250 250 250 250Citronellyl acetate 180 180 180 180 180Kflorol 98 20 20 20 20 20Cis-3-hexenyl acetate 12 12 12 12 12Manzanate 10 10 10 10 10Linalool 10 10 10 10 10Vertolal® 7 7 7 7 7Damascenone4 4 4 4 4Exavanilla® 4 4 4 4 4Noirenone® 10% IPM 5 5 5 5 5Doremox 6 6 6 6 6DPG 242 92 167 92 92Ethylene brassylate 0 150 0 0 0Example-1 0 0 75 0 03,7-dimethyloct-6- en-1-yl ethyl oxalate (Citronellyl ethoxylate) 0 0 0 150 0Case 09302(2) 39Exaltolide 0 0 0 0 150Total 750 750 750 750 750When Example-1 was dosed at 10% w / w in shampoo, a powerful and substantial musky character was imparted to the composition C. Compared to other compositions B, G and I which contained commercial compounds ethylene brassylate, 3,7-dimethyloct-6-en-1-yl ethyl oxalate (citronellyl ethoxylate) and Exaltolide respectively, the character of composition C was stronger, very rounded and comprehensive. On an odor strip, compound from Example-1 was found to be much stronger and longer-lasting than ethylene brassylate, citronellyl ethoxylate and Exaltolide In the following invention, as shown in Table-2: Composition (A) containing the compound from Example-5 was compared with composition of commercially available Exaltolide, composition B) with Composition C serving as Blank (Isopropyl myristate IPM).Table -2-: Example-5 in Shampoo:Compositions A B CRaw Materials (Parts by Weights) Phenyl Ethyl Alcohol 5 5 5Example-5 1 0 03-((2-1 1 1methylenehexyl)oxy)propanenitrile Rhubafuran 0.1 0.1 0.1Tropicate 1 1 1Noirenone® 10% IPM 0.2 0.2 0.2Exaltolide 0 1 0Javanol 0.25 0.25 0.25Patchouli oil iron free 0.5 0.5 0.5Case 09302(2) 40Fruitate 4.8 4.8 4.8Amberone 10 10 10Aldehyde cycloflor 10% IPM 1 1 1Cassis oxime 1% IPM 1 1 15 Dimethyl octanol 5 5 5Hedione 15 15 15IPM 0 0 1Majantol 5 5 5OTBCHA 7 7 710 PTBCHA 9 9 9Hexyl Cinnamic Aldehyde 12 12 12Kflorol 8 8 8Dipropylyne Glycol 8.25 8.25 8.25Total 95.1 95.1 95.1In the above floral fruity musky accord, comparison of composition A containing Example-5 with composition B containing commercial compound Exaltolide, indicated that comparedto Exaltolide, the addition of Example-1 imparted more natural volume and grantedsubstantial richness and creaminess to this accord.The foregoing description of the invention has been set merely to illustrate the invention and is not intended to be limiting. Since modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to person skilled in the art, the invention should be construed to include everything within the scope of the disclosure.

Claims

AMENDED CLAIMS received by the International Bureau on June 4, 2025 (04.06.2025)CLAIMS1. Process for the preparation of an unsaturated macrocycle ketone of formula(I) or a mixture of the regioisomers and / or stereoisomers thereofwherein m is an integer selected from 0, 1, 2, 3 and 4,Ri, R2 R3, R4, R5, Re and R7 represents either a hydrogen atom or a methyl group, and the dotted lines represent alternate positions of double bonds, wherein the double bond is between carbon atoms 4 and 5, or 5 and 6, or 6 and 7, or 7 and 8, or 8 and 9, comprising the following steps: reacting a substituted cyclic ketone yl carboxylic esterto prepare a substituted ketone 3wherein R = H or methyl and n is 0, 1, 2 or 3, and reacting the substituted ketone 3 with an acid selected from peracetic acid, perbenzoic acid or 3-Chloroperbenoic acid to prepare lactone 4,wherein R = H or methyl and n is 0, 1, 2 or 3, and either (A) hydrolyzing the lactone 4 to form the hydroxy-substituted l,co- di carb oxy lateand dehydrating the hydroxy-substituted l,co-dicarboxylate 5 to form the unsaturated l,co-dicarboxylate 6,wherein R = H or methyl and n is 0, 1, 2 or 3, or (B) converting the lactone 4 to form the chloro- substituted l,co-dicarboxylateand either dehydrochlorinating the chi oro-substituted l,co-dicarboxylate 5 to form the unsaturated l,co-dicarboxylate 6wherein R = H or methyl and n is 0, 1, 2 or 3, orIntramolecular Dieckmann condensation of compound 5 followed by hydrolytic decarboxylation to the compound 6B wherein R = H or methyl and n is 0, 1, 2 or 3,and either (C) subjecting compound 6B to elimination to form the unsaturated macrocycle ketone of formula (I) or the mixture of the regioisomers and / or stereoisomers thereof; or(D) subjecting the unsaturated l,co-dicarboxylate 6 to intramolecular Dieckmann reaction followed by hydrolytic decarboxylation to form the unsaturated macrocycle ketone of formula (I) or the mixture of the regioisomers and / or stereoisomers thereof: or (E) subjecting the unsaturated l,co-dicarboxylate 6 to Acyloin condensationm = 0,1 ,2,3,4Ri to R7= H or Me to form an a-hydroxyester 7 and dehydroxylating the a-hydroxyester 7 to form the unsaturated macrocycle ketone of formula (I) or the mixture of the regioisomers and / or stereoisomers thereof.

2. A process for preparation of the unsaturated macrocyclic ketones of general formula (I) according to claim 1 comprising the following steps: hydrolyzing the lactone 4 to the corresponding hydroxy-substituted l,co- dicarboxylate 5,wherein, R = H or Me and n is 0, 1, 2 or 3; dehydrating the hydroxy-substituted l,co-dicarboxylate 5 to unsaturated 1, co- dicarb oxy late 6,wherein, R = H or Me and n is 0, 1, 2 or 3, subjecting the unsaturated l,co-dicarboxylate 6 to intramolecular Dieckmann reaction followed by hydrolytic decarboxylation to afford the macrocyclic ketones of general formula (I) or the mixture of the regioisomers and / or stereoisomers thereof3. A process for preparation of the unsaturated macrocyclic ketones of general formula (I) according to claim 1 comprising the following steps: converting the lactone 4 to the corresponding chi oro-substituted l,co-dicarboxylate5,wherein, R = H or Me and n is 0, 1, 2 or 3; dehydrochlorinating the chloro-substituted 1, co -di carboxyl ate 5 to unsaturated 1, co- dicarb oxy late 6,wherein R = H or methyl and n is 0, 1, 2 or 3, subjecting the unsaturated l,co-dicarboxylate 6 to intramolecular Dieckmann reaction followed by hydrolytic decarboxylation to afford the macrocyclic ketones of general formula (I) or the mixture of the regioisomers and / or stereoisomers thereofm 0,1 , 2, 3, 4(I)4. A process for preparation of the unsaturated macrocyclic ketones of general formula (I) according to claim 1 comprising the following steps: converting the lactone 4 to the corresponding chloro-substituted l,co-dicarboxylate5,wherein, R = H or Me and n is 0, 1, 2 or 3;subjecting the chi oro-substituted l,co-dicarboxylate 5 to Dieckmann condensation followed by hydrolytic decarboxylation to afford unsaturated macrocycle 6-B,subjecting the unsaturated macrocycle 6-B to base-mediated dehydrochlorination to afford the macrocyclic ketones of general formula (I) or the mixture of the regioisomers and / or stereoisomers thereof5. A process for preparation of the unsaturated macrocyclic ketones of general formula (I) according to claim 1 comprising the following steps: hydrolyzing the lactone 4 to the corresponding hydroxy-substituted l,co- dicarboxylate 5,wherein, R = H or Me and n is 0, 1, 2 or 3; dehydrating the hydroxy-substituted l,co-dicarboxylate 5 to unsaturated 1, co- dicarb oxy late 6,wherein R = H or methyl and n is 0, 1, 2 or 3, subjecting the unsaturated l,co-dicarboxylate 6 to Acyloin condensation to afford an a-hydroxyester 7,m = 0,1 , 2, 3, 4 R-i to R7= H or Me and finally dehydroxylation of a-hydroxyester 7 to afford the macrocyclic ketones of general formula (I) or the mixture of the regioisomers and / or stereoisomers thereof6. A process for preparation of the unsaturated macrocyclic ketones of general formula (I) according to claim 1 comprising the following steps: converting the lactone 4 to the corresponding chi oro-substituted l,co-dicarboxylate5,wherein, R = H or Me and n is 0, 1, 2 or 3; dehydrochlorinating the chloro-substituted 1, co -di carboxyl ate 5 to unsaturated 1, co- dicarb oxy late 6,wherein, R = H or Me and n is 0, 1, 2 or 3, subjecting the unsaturated l,co-dicarboxylate 6 to Acyloin condensation to afford an a-hydroxyester 7,m = 0,1 , 2, 3, 4 R-i to R7= H or Me and finally dehydroxylation of a-hydroxyester 7 to afford the macrocyclic ketones of general formula (I) or the mixture of the regioisomers and / or stereoisomers thereof7. Compound of general formula (I)wherein m is an integer / whole number selected from 0, 1, 2, 3 and 4,Ri, R2 R3, R4, R5, Re and R7 represent a hydrogen atom or a methyl group, the dotted lines represent alternate positions of double bonds, the double bond may be between carbon atoms 4 and 5, 5 and 6, 6 and 7, 7 and 8, or 8 and 9, and selected from(i) (Z)-5-methylcyclohexadec-6-en-l-one(ii) (E S-methylcyclohexadec-b-en-l-one(iii)(Z)-4-methylcyclohexadec-6-en-l-one(iv)(E')-4-methylcyclohexadec-6-en-l-one(v) (Z)-3-methylcycloheptadec-5-en-l-one(vi)(E')-3-methylcycloheptadec-5-en-l-one(vii) (Z)-3-methylcycloheptadec-6-en-l-one(viii) (E S-methylcycloheptadec-b-en-l-one(ix)(Z)-5-methylcycloheptadec-5-en-l-one(x) (E S-methylcycloheptadec-S-en-l-one(xi)(Z)-5-methylcycloheptadec-6-en-l-one(xii) (E S-methylcycloheptadec-b-en-l-one(xiii) (Z)-4-methylcycloheptadec-5-en-l-one(xiv) (E d-methylcycloheptadec-S-en-l-one(xv) (Z)-4-methylcycloheptadec-6-en-l-one(xvi) (^-d-methylcycloheptadec-b-en- 1 -one(xvii) (Z)-cyclooctadec-6-en- 1 -one(xviii) (.E)-cyclooctadec-6-en-l -one(xix) (Z)-cyclooctadec-7-en-l-one, or(xx) (E')-cyclooctadec-7-en-l -one,or a mixture of regioisomers and / or stereoisomers thereof.

8. Mixture of regioisomers and / or stereoisomers of compounds according to claim 7.

9. Mixture according to claim 8 wherein the weight ratio between regioisomers and / or stereoisomers is between 95:5 and 5:95 .

10. Odorant consisting of a compound or mixture according to any of claims 7 to 9.

11. Fragrance, flavor and / or deodorizing / masking compositions comprising a compound or a mixture according to any of claims 7 to 9.

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