PROCESS FOR THE MANUFACTURE OF SPIROKETALS

Abstract: A process for the production of ambergris-type labdane spiroketals of general formulae (I) and (II), where R represents oxygen or sulphur, useful in the perfumery industry, the said process being characterized by the intramolecular cyclisation of the epoxyketone or its thio analog of general formula (III), where R1 represents COCH3 and R2 oxygen or sulphur. The starting materials are obtained by an oxidation step of labdane diterpenes of general formula (IV), where R is a tertiary allyl alcohol or vinyl acid, optionally esterified with an alkyl group, to form an intermediate methyl ketone of formula (V), where R = COCH3, with yields higher than 60 %, followed by an epoxidation step with peracid, with yields of the so-obtained epoxyketone III not below 80 %, and, finally, by treatment of III with various catalysts, in homogeneous or heterogeneous medium, the choice of catalyst depending on the desired selectivity, which can reach 100 % of I or 100 % of II, or lead to mixtures enriched in the odoriferous spiroketal II.

Description: Proce s s f or the man uf a cture of s p i ro ket a l s This invention describes a new process for the preparation of ambergris-type labdane spiroketals of the general formulae where R represents oxygen or sulphur. The labdane spiroketals of general formulae I and II, preferably II, where R • = 0 are highly valued in the perfumery industry because of their intense and lasting fragrance [G. Ohloff, in "Fragrance Chemistry: The Science of the Sense of Smell", E.T. Theimer (Ed.), Academic Press, N.Y., 1982, p.535-573] and are used as ingredients in the formulation of high quality perfumes [A. Boix Camps, Perfumer & Flavourist, 10, 15 (1985)]. However, it is known that the spiroketal I with R = 0 is odorless [E. Demole and H. West, Helv. Chim. Acta _5Q, 1314 (1967); IB. Bersuker et al., Nouv. J. Chemie, __), 211 (1985)] and that spiroketal II with R = 0 has a strong ambergris fragrance [G. Ohloff, C. Vial, H.R. Wolkf, K. Job, E. Jegou, J. Polonsky and E. Lederer, Helv. Chim. Acta, 62, 1932 (1980)]. The industrial processes for the production of these compounds generally start from sclareol and manool, and yield mixtures of the oxygenated spiroketals I and II (R = O). The preparation of I and II (R = 0) was first described by Schenk et al. [H.R. Schenk, H. Gutmann, 0. Jeger and L. Ruzicka, Helv. Chim. Acta, 35, 817 (1952)] and L. Ruzicka et al., U.S. P. 3,144,465 (1964) for the synthesis of a mixture of the oxygenated spiroketals I and IE (R • = O) starting from manool, by the expoxidation with peracetic, perbenzoic, monoperphthalic, percamphoric or performic acids, followed by oxidation, preferably with osmium tetroxide and sodium methaperiodate. A further process also described [E. Demole, Experientia, 2Q, 609 (1964)] the semi-industrial production of a mixture of the oxygenated spiroketals I and II (R =s 0) starting fro manool, which combines the epoxidation by perbenzoic acid with the ozonolysis of the resulting epoxide, the products thus obtained being then treated with p-toluenesulphonic acid. These methods lead to mixtures of the spiroketals I and II (R = O) in yields not higher than 30% and have the disadvantage of using toxic and/or expensive reagents, as well as the added disadvantage of producing mixtures of compounds in which one of the components is odorless, thereby reducing the commercial value of the final product for the application in the industry of perfumery. The process of the present invention allows the stereospecific and stereoselective production of compounds I and II and can use as starting material the labdane diterpenes of general formula where R is a allylic tertiary alcohol or a optionally alkyl esterfied vinyl acid residue, in particular R = C(CH 3 )=CHCOOR' or C(CH 3 XOH)CH=CH 2 with R' = C n H2n +l or H, and where n = 1-5, including thus the acids anticopalic (E-form) and copalic (Z-form) or its corresponding alkyl esters, or manool, or predecessors such as sclareol as starting materials, through the common intermediate III or preferably where Rl = COCH 3 and 2 represents oxygen or sulphur. This method allows producing from the compound of the general formula IV, with yields of 70-90%, exclusively the oxygenated compound of formula II or, if desired, mixtures enriched with said fragrant compound II. The oxidation of anticopalic acid IV (R = E-C(CH 3 )=CHCOOH) with an oxidizing agent, e.g. a permanganate, such as potassium permanganate, in the presence of a conventional phase-transfer catalyst, in particular of the quaternary ammonium salt type, leads to the 14, 15-dinorlabdan-8, 17-en-13- one where R = COCH3, in yields up to 90%, the same intermediate V being also obtained under similar conditions from manool, but in higher yields and with reaction times substantially shorter than those described in the literature [H.R. Schenk, H. Gutmann, O. Jeger and L. Ruzicka, Helv. Chim. Acta 3j>, 817-824 (1952); P.K. Grant and R. Hodges, J. Chem. Soc. 5274 (1960); P.K Grand and R.T. Weavers, Tetrahedron, 2386-2395 (1974); P.F. Vlad, Russian Chem. Rev. £1- 644 (1982)]. The epoxidation of V with a peracid, such as m-chloroperbenzoic acid, under reaction conditions compatible with the species III which is unstable in acid medium, leads to the epoxyketone 8α, 17-epoxy-14,15-dinorlabdan-13- one (III, R 2 = O) stereoselectively and in yields greater than 80%. The epoxyketone (HI, R2 = 0) can be converted in high yields into the thiirane (EH, R2 = S) by treatment with a sulphurating agent, such as triphenyl- phosphine sulfi.de or thiazolidine-2-thione. The treatment of the epoxyketone HI involving an intramolecular cyclisation or ketalisation can be generally effected a) with organic protonic acids, such as p-toluenesulphonic acid - which embodiment is not part of the invention, or a') with Lewis acids, such as zinc chloride, or its complexes, e.g. e therates, Mg salts, Cu 2+ salts, BF3 or its complexes, e.g. etherates, etc., in homogeneous medium, in catalytic or stoichiometric amounts, or b) with mineral or organic protonic acid or Lewis acid catalysts (such as listed above), such as oxalic acid, etc., in heterogeneous phase, i.e. on appropriate supports, e.g. on a microporous solid, e.g. a sheet or phyllosilicate, or a tectosilicate, e.g. a clay, e.g. on aluminosilicates of substantial magnesium oxide content, e.g. vermiculite, montmorillite, a HY zeoHte [a Y type zeoHte in acid form], siHcaHte, siHca, alumina or on another microporous solids with comparable cristaUographical characteristics, and also on supports such as sulphonic ion exchange resins, in the presence or absence of an organic solvent, e.g. an optionaUy halogenated aliphatic or aromatic hydrocarbon, such as hexane, methylene or ethylene chloride, preferably at room temperature or at elevated temperatures, e.g. up to the boiling point of the reaction mixture. When using Lewis acids, the use of a solvent is indicated. The activation of the support is well known per se; one usually prepares a suspension of the support in - any of the above mentioned - acids, then foHows a washing step, and then, preferably, a drying step. Optimum activity of the obtained material can be estabHshed by means of a few experiments. The same appHes when using the heat treatment for the activation, the preferred temperature range being ca. 100°C to ca. 240°C. To ensure the predominant formation of spiroketal II (e.g. R = O), the oxygen atoms of the carbonyl group and of the epoxide grouping of compound III have to be complexed to the same catalytic site (atom, ion) in order to fix (to complex) the desired conformation enabling the intended internal cycHsation. This prerequisite is alsways fulfilled by the inventive method described here. The process of the present invention is illustrated in the following Examples, where the process is described using as starting material anticopaHc acid, methyl anticopalate and manool. EXAMPLE 1 (IV > V) 14, 15-DINOELABDAN-8, 17-EN-13-ONE (V.R. = COCH 3 ) FROM ANTICOPALIC ACID OR METHYLANTICOPALATE To a solution of potassium permanganate (700 mg) in water (7.5 ml) was added benzene (4 ml) followed by ben_yltriethyla___monium chloride (180 mg). To this mixture was added with permanent stirring a suspension of anticopaHc acid (230 mg) in benzene (1 ml) and heated to 35-50°C for 1.5 hours. The excess permanganate was destroyed, the mixture acidified with diluted hydrochloric acid, the organic phase separated, washed and dried. Removal of the solvent at reduced pressure gave a colourless oil (368.8 mg) which was purified by chromatography on siHca to aford 14, 15- dinorlabdan-8, 17-en-13-one as an oil (203.4 mg; 88%). [α] D20+22 0 (c. 0.01 mg, CDCI 3 ), λmaxmo (C=0), 1635 (C=C) cm- 1 ; δ 1 H (CDCI 3 ); 0.67 (3H, s, 2O-CH3), 0.78 (3H, s, I9-CH3), 0.85 (3H, s, I8-CH 3 ), 2.09 (3H, s, COCH3), 4.81 and 4.42 ppm (2H, 2s, =CH2); m/z 262 (M+), 247 (M-15), 219, 137, 104, 69, 43. Under identical conditions the same product is obtained from methyl anticopolate. EXAMPLE 2 ( iv -^ v) 14.15-DINORLABDAN-8.17-EN-13-ONE (V, R = COCH3) FROM MANOOL To a solution of manool (2.9 g) in dichioromethane (20 ml) at 0-20°C was slowly added a suspension of potassium permanganat-e (3.1g) and benzyltriethyiammonium chloride (4.5 g) in dichioromethane (90 ml). The mixture was kept at 0-3°C for 8 hours, acidified with concentrated hydrochloric acid and the excess permanganate destroyed by addition of an aqueous solution of sodium sulphite. The organic phase was separated, washed with water, dried and concentrated at reduced pressure to afford an oil (2.72 g) containing 90% of 14,15-dinorlabdan-8,17-en-13-one, which was purified by chromatography and characterised by physical and spectroscopic data (see Example 1). EXAMPLE 3 ( v S> III ) 8α,17-EPOXY-14,15-DINORLABDAN-13-ONE (III, Rι-= COCH 3 , R 2 =0) A solution of 14,15-dinoriabdan-8,17-en-13-one (71.7 mg) in dichioromethane (18 ml) was added to a 0,5 M aqueous solution of sodium bicarbonate (8.0 ml) followed by slow addition of m-chloroperbeπzoic acid (79.0 mg) with stirrring at room temperature. After 24 h, the reaction mixture was washed successively with aqueous sodium sulphide, sodium bicarbonate and water, the organic phase separated, dried and concentrated at reduced pressure to afford 8α, 17-epoxy-14,15-dinorladban-13-one (III, R = COCH3) as an oil (86%), δ 1 H (CDCI3): 0.82 (3H, s, 2O-CH3), 0.82 (3H, s, 19-CH 3 ), 0.89 (3H, s, I8-CH3), 2.10 (3H, s, COCH3), 2.43-2.50 (2H, m, CH2COCH3), 2.81 (1H, d, J= 4.3 , CH 2 0), 2.82 ppm (1H, dd, J= 4.3 ;J=1.25 , CH2O), m z 278 (M+-). EXAMPLE 4 ( in > • 1 , n ) 8,13-EPITHIOEPOXY-13,17-OXIDO-14,15-DINORLABDANES (I and II, 8,13R - S and 13,17R = 0) To a solution of 8α, 17-epoxy-14, 15-dinorlabdan-13-one (39 mg) and triphenylphosphine sulphide (41 mg) in dry benzene (0.5 ml) was added trifluoroacetic acid (0.1ml) at 20-25°C with stirring. After 10 min anhydrous sodium carbonate was added and stirring was kept for a further 15 min, and the mixture was filtered to afford a crude product containing the oxygenated spiroketals II (R = O) (60%), δ 1 H: 0.80 (3H, s, 19-CH 3 ), 0.89 (6H. s, 20-CH 3 and I8-CH3), 1.41 (3H, s, I6-CH3), 3.35 (1H, d, =7.5, 17-CH 2 ), 4.30 ppm (1H, d, J=7.5, 17-CH 2 ); and I (R = 0) (5%) δ 1 H: 0.87 (3H, s, 20-CH 3 ), 0.88 (3H, s, 19-CH 3 ), 1.09 (3H, s, I6-CH3), 1.43 (3H, 5, I8-CH3), 3.32 (1H, d, J=6.6, 17-CH 2 >, 3.77 ppm (1H. d. J =6.6, 17-CH 2 ), the epithiospiroketal I (8.13R = S and 13.17R = O) (8%), δ 1 H (CDCI3): 3.76 (1H, d, =7.5, 17-CH 2 ), 3.33 (1H, d, J=7.2 , 17-CH 2 ), 1.41 (3H, s, I8-CH3), 1.09 (3H, s, I6-CH3), 0.88 ppm (6H, s, 17-CH 3 and 20-CH 3 ), m/z 294 (M+-) and epithiospiroketal II ( 8.13R = S and 13.17R = O ) (23.4%) δ 1 H (CDCI3): 0.80 (3H, s, 19-CH3 ), 0.88 (6H, s, 2O-CH3 and18-CH3), 1.4.1 (3H, s, I6-CH3), 3.37 (1H, d, J=7.5, 17-CH 2 ), 4.31 ppm (1H, d, J=7.5, 17-CH 2 ), m z 294 (M*--), 218 (100.0). EXAMPLE 5 ( m Hi) 8α,13; 13, 17-DIOXI-14.15-DINORLABDANE (II, R = 0) 5.1 IN HOMOGENEOUS PHASE WITH ACID Epoxyketone 111 (R-j = COCH3, R = O) (4.3 mg) was dissolved in dichioromethane (2 ml) and zinc chloride was added (8.8 mg). After 1 hour at room temperature, the mixture was washed with water, the organic phase separated, dried and concentrated at reduced pressure to afford spiroketal ll (R = O) (97%) as an oil, δ 1 H (CDCI3): 0.80 (3H, 5, 19-CH3), 0.89 (6H, s, 20-CH3and I8-CH3). 1.41 (3H, s, I6-CH3), 3.35 (1H, d, J=7.5, 17-CH ), 4.30 ppm (1H, d, =7.5, 17-CH 2 ), m z 278 5.2. INHETEROGENEOUSPHASEWITHASOLIDTHERMICALLY ACTIVATEDSUPPORTANDINTHEPRESENCEOFSOLVENT A solution of epoxyketone ill (R-* = COCH3, R 2 = 0) (10 mg) in dry n-hexane (5 was added at 18-25°C to a flask containing activated vermiculite. Aft transformation of the starting material, the solution was filtered and the residu vermiculite washed with n-hexane. The filtrate was dried and concentrated reduced pressure to afford the spiroketal II (R = 0) (90%), δ 1 H (CDCI3): 0.80 (3H, 19-CH3), 0.89 (6H, s, 2O-CH3 and I8-CH3), 1.41 (3H, s, 16-CH 3 ), 3.35 (1H, d, =7.5, 17-CH 2 ), 4.30 ppm (1H, d, J=7.5, 17-CH 2 ) and spiroketal I (R = O) (5%) δ 1 (CDCI 3 ): 0.87 (3H, s, 20-CH 3 ), 0.88 (3H, s, 19-CH 3 ), 1.09 (3H, s, 16-CH 3 ), 1-4 (3H, 5, I8-CH3), 3.32 (1H, α. J=6.6, 17-CH 2 ), 3.77 ppm (1H, d, J=6.6, 17-CH ). 5.3. The mode is as in 5.2. To a solution of epoxyketone III (Ri = COCH3, R2 = O) (1 g) in dry dichioromethane (50 ml) was added 1 g of montmorillonite (type K 10) at a temperature of 18 to 25° C and the mixture stirred. After complete transfor¬ mation of the starting material (GC control) the solid was filtered off and the filtrate evaporated to give 0,9 g of a product containing the spiro ketals II and I in a ratio of 90 : 10. EXAMPLE β (HI T) 8β, 13; 13, 17-DIEPOXI-14, 15-DMORLABDANE ((I, R = O) 6.1 IN HOMOGENEOUS PHASE WITH ACID To a solution of epoxyketone HI (Ri = COCH3, R2 = 0) (10 mg) in dry toluene (2-5ml) was added anhydrous p-toluenesulphonic acid (7 mg) and the mixture kept at room temperature with stirring for a few hours, or heated immediately to reflux until complete disappearance of the starting material, to produce quantitatively the spiroketal 8β, 13; 13, 17-diepo_d-14, 15- dinorlabdane I (R = O) identified by proton nuclear magnetic resonance and mass spectrometry (see 6.2). 6.2 IN HETEROGENEOUS PHASE WITH A SOLID SUPPORT (THERMICALLY ACTIVATED) AND IN THE ABSENCE OF SOLVENT The catalyst (siHca gel 230-400 mesh, 0.4g; neutral aluminium oxide, Brockmann, activity I, 150 mesh, 50 A, 0,4g; siHcaHte 0.5g; basic alumina, activity I, 230-400 mesh, 1 g; activated vermicuHte, 0.1 g) was added to a solution of epoxyketone III ((Ri = COCH3, R2 = O) (6 mg) in dry petroleum ether (3 ml), the solvent removed and the mixture heated to 150-200°C for 1-4 hours. Addition of solvent, filtration of the suspension and concentration of the filtrate produced the spiroketal I (R = O) as an oil (6.0 mg; 100%), δ X H (CDCI3): 0.87 (3H, s, 2O-CH3), 0.88 (3H, s, 19-CH 3 ), 1.09 (3H, s, I6-CH3), 1.43 (3H, s, I8-CH3), 3.32 (1H, d, J=6.6, 17-CH 2 ), 3.77 ppm (1H, d, J=6.6, 17-CH 2 ). EXAMPLE 7 8β, 13; 13, 17-DIEPOXI-14, 15-DINORLABDANE (I, R = O) and 8α, 13; 13, 17- DIEPOXI-14, lδ-DINORLABDANE (II, R = O) To a suspension of siHca gel 60 (230-400 mesh, O.llg) in dichlormethane (0.5 ml) was added a 10% aqueous solution of the acidic activator oxalic acid (0.8 ml) and a solution of epoxyketone HI (Ri = COCH3, R 2 = O) (2.4 mg) in dichioromethane (1 ml). After the reflux for 24 hours, the reaction mixture was treated with sodium bicarbonate, the organic phase separated, dried and concentrated to afford a mixture of spiroketals I (R = O) (25%) and II (R = O) (70%), identified by comparison with authentic samples.

Claims: CLAIMS A process for the manufacture of compoτmds of the general formulae I and II where R represents oxygen or sulphur, comprising the intramolecular cyclisation or ketalisation of the epoxyketone or its thio analog of general formula III III where RI = COCH3 and R2 represents oxygen or sulphur, effected by a solid catalyst activated by acid, or by heat treatment, preferably under vacuum, or by a Lewis acid catalyst, and in the presence or absence of an organic solvent, at room temperature or at elevated temperatures. 2. A process according to claim 1, where the solid catalyst is a microporous solid, e.g. a sheet or phyllosilicate, or a tectosilicate, e.g. a clay, vermiculite, montmorilHte, a HY zeolite, silicalite, silica, alumina or another microporous solid with comparable cristallographical characteristics. 3. A process according to claim 1, where the Lewis acid is zinc chloride. 4. A process according to claim 1 or 2, where the preferred solid catalyst is high in magnesium oxide content, e.g. vermiculite, and the solvent is n-hexane, to produce practically quantitatively II 5. A process according to claim 4, where the soHd catalyst is heat- activated under vacuum at ca.lOO - ca.250° C. 6. A process according to daims 1 or 2, where said soHd or Lewis add catalyst reacts in an organic solvent at room temperature to produce quantitatively II. 7. A process according to daim 1 and 2, where the soHd catalyst reacts in tiie absence of solvent at ca.100 - ca.200° C to produce quantitatively I. 8. A process according to daim 1 or 2, where the soHd catalyst is activated by an add and reacts in an organic solvent, preferably at reflux temperature, to produce mixtures rich in π (e.g. >60%). 9. A process according to claim 1, where the compound HI is prepared by epoxidation of the compound where R = COCH3 , using a peradd, preferably m-diloroperbenzoic acid, in buffered medium. 10. A process according to claim 9, where the preferred buffering agent is sodium bicarbonate. 11. A process according to daim 9, where V is obtained by permanganate oxidation with phase-transfer catalysis and with pH control from a labdane diterpene of general formula IV where R is an allylic tertiary alcohol or a optionaUy alkyl esterified viny add residue. 12. A process according to claim 11, where IV is anticopaHc acid, copalic add or one of their esters. 13. A process according to claim 12, where the ester is the methyl ester. AMEMDED CLAIMS [received by the International Bureau on 11 December 1992 (11.12.92); original claim 1 amended; remaining claims unchanged (1 page)] 1. A process for the manufacture of compounds of the general formulae I and π where R represents oxygen or sulphur, comprising the intramolecular cycHsation or ketaHsation of the epoxyketone or its thio analog of general formula HI III where RI = COCH3 and R2 represents oxygen or sulphur, effected by a soHd catalyst activated by add, or by heat treatment, preferably under vacuum, or by a Lewis add catalyst with the exception of BF 3 or its complexes, and in the presence or absence of an organic solvent, at room temperature or at elevated temperatures. 2. A process according to daim 1, where the soHd catalyst is a microporous soHd, e.g. a sheet or phyllosiHcate, or a tectosiHcate, e.g. a clay, vermicuHte, montmorilHte, a HY zeoHte, siHcaHte, siHca, alumina or another microporous soHd with comparable cristallographical characteristics. 3. A process according to claim 1, where the Lewis add is zinc chloride. 4. A process according to daim 1 or 2, where the preferred soHd catalyst is high in magnesium oxide content, e.g. vermicuHte, and the solvent is n-hexane, to produce practicaUy quantitatively H STATEMENT UNDER ARTICLE 19 In view of CH,A,428 765, more particularly in view of column 4, line 37 a disclaimer to the BF 3 type Lewis catalyst is necessary in claim 1. This disdaimer necessitates the deletion of the term "BF 3 or its complexes, e.g. etherates," on page 4, line 12 of the spedfication.

Inventors: DE LOUREIRO DA SILVA TAVARES D, GONCALVES DA COSTA MARIA DO CE, MOTHERWELL WILLIAM BRANKS, VIDAL DE OLIVEIRA BAPTISTA MAR, DE LOUREIRO DA SILVA TAVARES DA ROSA, MARIA, REGIN, GONCALVES DA COSTA, MARIA DO CEU, MOTHERWELL, WILLIAM, BRANKS, VIDAL DE OLIVEIRA BAPTISTA MARCELO CURTO, MARIA, J
Applicants: GIVAUDAN ROURE INT, GIVAUDAN-ROURE (INTERNATIONAL) S.A.
Application year: 1992
Main classification: C07D493
IPC codes: B01J21, B01J29, C07B61, C07C45, C07C49, C07D301, C07D303, C07D331, C07D493, C07D495, C07D497, C11B9