WO2002055470A1 - Method for the enantioselective preparation of adducts of $g(a)-substituted phenylethylamine-cycloalkanes and of 2-acetoxyacrylonitrile, intermediates in the enantioselective synthesis of the lateral chain of harringtonines - Google Patents

Abstract

The invention relates to a method for the enantioselective preparation of adducts of α-substituted phenylethylimino-cycloalkanes and of 2-acetoxyacrylonitrile with the formula (I), wherein the carbon atom in position 1' has the stereochemistry 1'S or 1'R; n = 0 to 3; Z is a protected alcohol radical having the formula OGP1; GP1 is a protective group such as a carbon-containing ether, a silylated ether or an ester; GP2 is a protective group of enols such as a silylated ether; and involving a Michael reaction between the methyl cyanoacetate and a chiral imine.

Description

          Process for the enantioselective preparation of a-substituted phenylethvliminocycloalkane and 2-acetoxvacrylonitrile adducts, intermediates in the enantioselective synthesis of the side chain of harringtonines and 2-acetoxyacrylonitrile, as well as various other synthetic intermediates useful in the preparation of harringtonines. More generally, the invention relates to the enantioselective synthesis of chiral compounds allowing access to the ester side chain of harringtonines, in particular of homoharringtonine. In the context of the present invention, the desired chirality is obtained depending on the chirality of the amine used in an asymmetric Michael reaction. It will be briefly recalled that harringtonines are alkaloids of great interest in anticancer chemotherapy, in particular on certain polyresistant hematosarcomas to existing therapies. The selectivity of harringtonines, which is based on an original mechanism of action at the level of protein synthesis, means that this series has a great future in cancer therapy (Kantarjian HM, et al., J Clin Oncol. 2000 Oct 15 18(20):3513-21). Harringtonines were extracted over 35 years ago from an exclusively Asian Cephalotaxaceae named Cephalotaxus harringtonia. In fact, Cephalotaxus alkaloids consist mainly (at least 50%) of cephalotaxine, a biosynthetic precursor of harringtonines, the latter individually representing only a few percent of total alkaloids. natural in the plant raw material, harringtonines are mixed with many congeners with very similar chemical structures.If we consider that: - on the one hand, as predicted by the flexibility of their side chains, generally branched and aliphatic , harringtonines are generally not very crystallogenic, - on the other hand, these esters, in particular harringtonine as well as homoharringtonine, are contaminated by congeners themselves endowed with biological activity and very difficult to separate even in analytical HPLC at high resolution, the current state of the art did not make it possible to produce these compounds profitably on an industrial scale at the level of purity required for active pharmaceutical ingredients. However, the teachings of WO 99/48894 provide a first decisive improvement in this regard. In addition, mastering the synthesis of the side chain of harringtonines constitutes a particularly interesting objective for the development of new structural analogues that are more active and less toxic than natural harringtonines. It has just been demonstrated that subtle variations in the side chain of harringtonines, sometimes of a single methylene group, could dramatically modify their therapeutic potential (Robin, JP, et al., Blood vol. 90 ( 11) part 1.2000 abstract #1322; Radosevic et al., Blood vol 90 (11) part 1.2000 abstract #1323). The object of the present invention is precisely to provide synthesis intermediates useful in the preparation of harringtonines by hemisynthesis, which allow implementation under good conditions of stereoselectivity, convergence, yield and chirality at the level of the functionalization and side chain construction of harringtonines. According to a first aspect of the invention, the present application relates to a process for the enantioseiective preparation of adducts of a-substituted phenylethylimino-cycloalkanes and of 2-acetoxyacrylonitrile of formula EMI2.1 in which: - the carbon atom in position 1 'has the stereochemistry 1'S or 1'R, n=0 to 3, Z is either a protected alcohol radical of formula OGP', or a protected thiol radical of formula SGP1, or a hydrocarbon radical comprising from 1 to 12 carbon atoms, bearing or non-heteroatom, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, Go1 being a protective group for alcohols such as a carbonaceous or silyl ether, an ester, GP2, a protective group for enols such a silyl ether corresponding to the formula SiR1R2R3, in which R1, R2 and R3 are, taken independently, hydrocarbon radicals comprising from 1 to 12 carbon atoms, bearing or not heteroatoms, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, or else a hydrocarbon-based ether of formula OR4, in which R4 is a hydrocarbon-based radical containing from 1 to 12 carbon atoms, bearing or not a heteroatom, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, and R4 is a hydrocarbon radical comprising from 1 to 12 carbon atoms, bearing or not a heteroatom, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, characterized in that it consists in protecting the tautomeric enol form of the ketoester corresponding to the following formula: EMI3.1 in which: n, Z and R5 are defined as above using protection reagents such as: - a halide or a trialkylsilane triflate in the presence of an alkylamine in a usual organic solvent or -an alcohol in the presence of an acid catalyst such as a Lewis acid or usual protonic acid, said ketoester above being obtained by deprotection of the corresponding acetal corresponding to the formula below EMI4.1 in which: - n, Z and R5 are defined as above - X and Y are, taken independently, oxygen, nitrogen or sulfur heteroatoms , R6 and R7 are, taken independently, hydrocarbon radicals containing from 1 to 12 carbon atoms, bearing or not heteroatoms, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, the said hydrocarbon radicals capable of forming between them a cyclic acetal bridge, By the action of a reagent such as an aqueous acid or else preferably cerium trichloride in a solvent such as acetonitrile, said acetal above being obtained from the protected cyanoacetate corresponding to the formula below: EMI4.2 in which n, Z, X, Y and R5, R6 and R7 are defined as above by oxidative degradation in the presence of activated manganese dioxide and an alkaline cyanide such as sodium cyanide, in a solvent such as an anhydrous alcohol, preferably methanol, at room temperature for 1 to 5 days, said cyanoacetate above being obtained by protection of the Michael adduct ketone corresponding to the formula below: EMI5.1 in which n, and Z are defined as above by action either of the free form of the corresponding alcohol corresponding to the formulas R6OH or R70H or of the diol HoR6R7OH, or of the masked form of rounding alcohol with the formulas R6OR8, R'OR8 or R8OR6R7OR8, in the presence of a proton or Lewis acid, more particularly by the action of bis-trimethylsilyloxyethane in the presence of trimethylsilyl triflate, said Michael adduct being obtained by simple presence of ethyl cyanoacetate and of the imine of chirality suitably chosen according to the desired stereochemistry in the 1' position, followed by in situ hydrolysis using an aqueous polar solvent and an acid such as acetic acid according to the following reaction scheme: EMI5.2 -in which n and Z are defined as above, A and A' are different from each other and, taken independently, hydrocarbon radicals comprising from 1 to 12 carbon atoms , bearing or not heteroatoms, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, said chiral imine being obtained by reaction between a chiral amine and a substituted racemic ketone according to the following reaction scheme: EMI6. 1 in which n, Z, A and A' are defined as above. According to a certain number of particular embodiments of the invention, the method relates to the compounds of general formulas mentioned above in which: - n = 1 or 2, Z = OGP1, Go1 being a protective group for alcohols and/or - the protective group of the alcohols is a benzyl radical, X and Y are oxygen atoms and Gp2 a trialkylsilyl and/or - n = 1 or 2, and Z is a C1 to C4 alkyl radical, linear or branched and/or - the alkyl radical is a methyl and, X and Y are oxygen atoms and Gp2 a trialkylsilyl and/or - A is a phenyl radical and A' is a methyl radical and/or - A' is a phenyl radical and A is a methyl radical. The present invention also relates to the compound and its enantiomer, in particular as a useful intermediate in the synthesis of harringtonines by oxidative cleavage followed by known chemical reactions of alkylation and other functionalizations, corresponding to the following formula: EMI7.1 in which n , Z, R5 and Gp2 are defined above, as are the intermediates of formulas: EMI7.2 in which n, Z, and R5 are defined above. EMI7.3 in which n, Z, X, Y, R5, R6 and R7 are previously defined. EMI8.1 in which n, Z, X, Y, R6 and R7 are previously defined. EMI8.2 in which n and Z are previously defined. Finally, the invention relates more particularly to the specific compounds of the following formulas: EMI8.3 EMI8.4 EMI9.1 EMI9.2 EMI9.3 EMI9.4 EMI10.1 EMI10.2 EMI10.3 The enantioselective preparation process according to the present The invention can be illustrated by the following reaction scheme: PLANCHEI: DESCRIPTION EMI11.1 EMI11.2 EMI11.3 The various aspects of the present invention will be illustrated by the few specific examples mentioned below by way of simple illustration. Example 1 Preparation of (1'R)-2-acetoxy-3-(1'-benzyloxy-2'-oxo-cyclohexylpropionitrile1 EMI12.1 In a 1 liter reactor placed under vacuum, a mixture of basic alumina (activity I; 20 g), silica (230-400 Mesh; 10 g) and 5 A molecular sieve (90 g). The assembly is placed under nitrogen then the mixture is suspended in 150 mL of dry cyclohexane. add 75 g (367.0 mmol) of 2-benzoxycyclohexanone 1A then 52.5 mL of (R)-(+)-phenylethylamine 1B (49.3 g; 403.7 mmol; 1.1 eq). After 4 hours stirring at room temperature, the reaction medium is filtered on frit and the solid is rinsed with 4 times 300 mL of dry ethyl ether. The filtrate is concentrated under reduced pressure and the imine thus obtained is reacted again without purification in a 500 mL reactor dried beforehand, under a stream of nitrogen At ambient temperature, 78 mL of 1D vinyl cyanoacetate (81.1 g; 734 mmol; 2.0 Eq) are added and the mixture is stirred for 36 hours. The intermediate alkylated imine IC is then hydrolyzed with 500 mL of a 20% THF/AcOH mixture: 1/1 for 4 hours at ambient temperature. The solvent is distilled off under reduced pressure and the oil obtained is taken up in 150 mL of 1M HCl and 750 mL of ethyl ether. The phases are decanted then the organic phase is extracted with 3 times 500 mL of ether. The combined organic phases are washed with 3 times 250 mL of a saturated NaHCO3 solution, then 2 times 300 mL of a saturated NaCl solution, dried over MgSO4, filtered and then concentrated under reduced pressure. The excess Michael acceptor (1D vinyl cyanoacetate) is distilled under partial vacuum. The oil obtained is chromatographed on silica gel (cyclohexane/AcOEt: 90/10) to give 78.7 g of the desired product 1, in the form of a crystalline solid, Mp=62 C (EtOH), exhibiting the characteristics following analytical data: [alD 20=+75.1 (c=2.13; EtOH). IR (KBr, v cm¯1): 3039, 2251,1756 and 1721. 1H NMR (400 MHz, CDCl3): 6 ppm 1.5-1.65 (m, 4H); 1.99 (s, 3Hk); 2.12 (m, 1H); 2.21 (dd, J=15.7; 7.1Hz, 1H); 2.27-2.40 (m, 2H); 2.67 (dd, J=15.7; 5.4Hz, 1H); 2.77 (td, J=12.2; 4.9Hz, 1H); 4.17 (d, J=11.1Hz, 1H); 4.53 (d, J=11.1Hz, 1H); 5.43 (dd, J=7.1; 5.4Hz, 1H); 7.28-7.44 (m, 5H-Ph). Example 2 Preparation of (1'S)-)-2-acetoxy-3-(1'-benzyloxy-2'-oxo-cyclohexyl) propionitrile 2 EMI13.1 In a 500 mL reactor placed under vacuum, a mixture consisting of basic alumina (activity l; 10g), silica (230-400 Mesh; 50 g) and 5 A molecular sieve (45 g). The assembly is placed under a nitrogen atmosphere then the mixture is suspended in 150 mL of dry cyclohexane. 75 g (367.0 mmol) of 2-benzoxycyclohexanone 1A are added then 25 mL of (R)-(-)-phenylethylamine 2B (23 g). After 4 hours of stirring at ambient temperature, the reaction medium is filtered on frit and the solid is rinsed with 4 times 150 mL of dry ethyl ether. The filtrate is concentrated under reduced pressure and the imine thus obtained is put back into reaction without purification in a 500 mL reactor dried beforehand, under a stream of nitrogen. At room temperature, 39 mL of 1D vinyl cyanoacetate are added and the mixture is stirred for 38 hours. The intermediate 2C alkylated imine is then hydrolyzed with 250 mL of a 20% THF/AcOH mixture: 1/1 for 4 hours at ambient temperature. The solvent is distilled off under reduced pressure and the oil obtained is taken up in 75 mL of 1M HCl and 375 mL of ethyl ether. The phases are decanted then the organic phase is extracted with 3 times 250 mL of ether. The combined organic phases are washed with 3 times 125 mL of a saturated NaHCO3 solution, then 2 times 150 mL of a saturated NaCl solution, dried over MgSO4, filtered and then concentrated under reduced pressure. The excess Michael acceptor (7D vinyl 1-cyanoacetate) is distilled under partial vacuum. The oil obtained is chromatographed on silica gel (cyclohexane/AcOEt: 90/10) to give 78.7 of the desired product 2, in the form of a crystalline solid, Mp = 62 C (EtOH), exhibiting the analytical characteristics following: [α]D 20=-74.7 (c=2.1; EtOH). IR (KBr, v cm¯1): 3039,2251,1756 and 1721. 1H NMR (400 MHz, CDCI3): 8 ppm 1.51-1.64 (m, 3Hd + 1Hc); 1.99 (s, 3Hk); 2.12 (m, 1Hd); 2.21 (dd, J=15.7; 7.1Hz, 1Hg); 2.27-2.40 (m, 1Hc+1He); 2.67 (dd, J=15.7; 5.4Hz, 1Hg); 2.77 (td, J=12.2; 4.9Hz, 1He); 4.17 (d, J=11.1Hz, 1Hf); 4.53 (d, J=11.1Hz, 1Hf); 5.43 (dd, J=7.1; 5.4Hz, 1Hh); 7.28-7.44 (m, 5HPh). 13C NMR (50 MHz, CDCI3): 6 ppm 20.2 (CH3, k); 20.4 (CH2, d); 27.7 (CH2, d); 34.3 (CH2, g); 37.5 (CH2, c); 39.1 (CH2, e); 57.3 (CH, h); 65.4 (CH2,f); 81.3 (C,b); 117.1 (C, i); 127.1 (2*CH, Ph); 127.7 (CH, Ph); 128.5 (2*CH, Ph); 136.8 (C, Ph); 169.0 (C, y); 211.0 (C, a). Example Preparation of (1'R)-2-acetoxv-3-benzeloxv-2'-oxo-cycloPentyl) propionitrile 3 EMI15.1 In a 1 liter flask placed under vacuum, a mixture consisting of alumina is calcined for 10 minutes basic (activity l; 20g), silica (230-400 Mesh; 10 g) and 5 A molecular sieve (90 g). The assembly is placed under a nitrogen atmosphere then the mixture is suspended in 150 mL of dry cyclohexane. 68 g of 2-benzoxycyclopentanone 3A are added then 52 mL of (R)-(+)-phenylethylamine 1B (49.3 g). After 4 hours of stirring at ambient temperature, the reaction medium is filtered through a frit and the solid is rinsed with 4 times 300 mL of dry ethyl ether. The filtrate is concentrated under reduced pressure and the imine thus obtained is put back into reaction without purification in a 500 mL reactor dried beforehand, under a stream of nitrogen. At room temperature, 78 mL of 1D vinyl cyanoacetate (81.1 g) are added and the mixture is stirred for 36 hours. The intermediate 3C alkylated imine is then hydrolyzed with 500 mL of a 20% THF/AcOH mixture: 1/1 for 4 hours at ambient temperature. The solvent is distilled off under reduced pressure and the oil obtained is taken up in 150 mL of 1M HCl and 750 mL of ethyl ether. The phases are decanted then the organic phase is extracted with 3 times 500 mL of ether. The combined organic phases are washed with 3 times 250 mL of a saturated NaHCO3 solution, then 2 times 300 mL of a saturated NaCl solution, dried over MgS04, filtered and then concentrated under reduced pressure. The excess Michael acceptor (1-D vinyl cyanoacetate) is distilled under partial vacuum. The oil obtained is chromatographed on silica gel (cyclohexane/AcOEt: 90/10) to give 52 g of the desired product 3, in the form of an amorphous solid, having the following analytical characteristics: [a] D 20 = F 46 (c=0.8; EtOH). IR (KBr, v cm-1): 3039, 2251,1756,1721. Example 4 Preparation of (1'R)-2-acetoxy-3-1'-methyl-2'-oxo-cyclopentyl-propionitrile 3 EMI16.1 In a 1 liter flask placed under vacuum, a mixture is calcined for 10 minutes consisting of basic alumina (activity l; 20g), silica (230-400 Mesh; 10 g) and 5 A molecular sieve (90 g). The assembly is placed under a nitrogen atmosphere then the mixture is suspended in 150 mL of dry cyclohexane. 72 g of 2-methylpentanone 4A are added then 52 mL of (R)-(+)-phenylethylamine 1B (49.3 g). After 4 hours of stirring at ambient temperature, the reaction medium is filtered through a frit and the solid is rinsed with 4 times 300 mL of dry ethyl ether. The filtrate is concentrated under reduced pressure and the imine thus obtained is put back into reaction without purification in a 500 mL reactor dried beforehand, under a stream of nitrogen. At room temperature, 78 mL of 1D vinyl cyanoacetate (81.1 g) are added and the mixture is stirred for 36 hours. The intermediate 4C alkylated imine is then hydrolyzed with 500 mL of a 20% THF/AcOH mixture: 1/1 for 4 hours at ambient temperature. The solvent is distilled off under reduced pressure and the oil obtained is taken up in 150 mL of IM HCl and 750 mL of ethyl ether. The phases are decanted then the organic phase is extracted with 3 times 500 mL of ether. The combined organic phases are washed with 3 times 250 mL of a saturated NaHCO3 solution, then 2 times 300 mL of a saturated NaCl solution, dried over MgSO4, filtered and then concentrated under reduced pressure. The excess Michael acceptor (1-D vinyl cyanoacetate) is distilled under partial vacuum. The oil obtained is chromatographed on silica gel (cyclohexane/AcOEt: 90/10) to give 57 of the desired product 4, in the form of an amorphous solid, having the following analytical characteristics: [a) p 2 ¯ + 31 (c=05.5; EtOH). Example 5 Preparation of methyl 2-[(1R)-1'-(benzyloxy)-2'-oxocylohexyl] acetate 5 and its protected derivative in the form of dioxolane 5B EMI17.1 Preparation of the protected derivative of Michael's adduct in the form of dioxolane 5A 130 mL of CH2Cl2, 5.1 mL of TMSOTf and 48 mL of bis-trimethylsilyloxyethane are successively introduced into a 1 liter reactor, under a nitrogen atmosphere and cooled to −78° C. A solution of 32 g of adduct 1 in 130 mL of CH2Cl2 is added dropwise, then the reaction medium is brought to ambient temperature. After stirring for 6 hours, 20 mL of distilled pyridine are added. The reaction medium is diluted by adding 250 mL of a saturated solution of NaHCO3 and 300 mL of CH2Cl2. The phases are decanted then the aqueous phase is extracted with 2 times 250 mL of CH2Cl2. The combined organic phases are dried over MgSO4, filtered and then concentrated under reduced pressure to give a white solid, which is taken up hot (40 C) in 200 mL of absolute ethanol and then recrystallized at -20 C to give 28.4 g of intermediate dioxolane, having the following analytical characteristics: [a] D = + 106.0 (c = 2.15; CHCl3). IR (film, v cm-1): 3035, 2250 and 1743. 1H NMR (400 MHz, CDCI3): # ppm 1.41-1.73 (m, 4Hd + 1Hc + 1He); 1.88 (m, 1Hc); 1.95 (s+m, 3Hk+1He); 2.16 (dd, J=15.9; 5.2Hz, 1Hg); 2.65 (dd, J=15.9; 5.2Hz, 1Hg); 4.01 (m, 3HI); 4.18 (m, 1HI); 4.49 (d, J=11.4Hz, 1Hf); 4.55 (d, J=11.4Hz, 1Hf); 5.72 (t, J=5.2Hz, 1Hh); 7.27 (m, 1HPh); 7.34 (m, 4HPh). 13C NMR (50 MHz, CDCl3): 6 ppm 20.1 (CH3, k); 20.4 (CH2, d); 22.5 (CH2, d); 29.8 (CH2, c); 32.2 (CH2, c); 34.8 (CH2, g); 58.1 (CH, h); 63.7 (CH2,f); 64.1 (CH2, I); 64.4 (CH2, I); 78.6 (C,b); 110.3 (C, a); 118.3 (C, i); 126.8 (2CH, Ph); 127.2 (CH, Ph); 128.3 (2CH, Ph); 138.4 (C, Ph); 168, 9 (C, j). Preparation of 2-[(1R)-1'-(benzyloxy)-2'-oxocylohexyl] protected methyl acetate 5B by oxidative degradation of the protected Michael adduct In a 5 liter reactor, 25 g of the 5A protected adduct in 1 liter of absolute methanol. 120 g of activated manganese dioxide then 17 g of sodium cyanide are added. The suspension is stirred vigorously at room temperature for 3 days. 2 liters of ether are then added, then the reaction medium is filtered through celite. The celite is rinsed with 3 times 0.5 liter of ether then the filtrate is concentrated. The solid obtained is chromatographed on silica gel (cyclohexane/AcOEt: 95/5) to give 13.5 of intermediate methyl ester 5B in the form of a colorless oil having the following analytical characteristics: IR (pure, v cm- 1): 3032 and 1733. 1H NMR (200 MHz, CDCl3): 8 ppm. 1.27-1.61 (m, 4Hd+1Hc); 1.67-1.88 (m, 2Hc); 1.96-2.12 (m, 1Hc); 2.52 (d, J=13.7Hz, 1Hf); 2.73(d, J=13.7Hz, 1H; 3.55(s, 3Hh); 3.75-3.98(m, 4Hi); 4.54(d, J=11.3Hz , 1 He), 4.64 (d, J = 11.3 Hz, 1 He), 7.11-7.38 (m, 5H Ph) 13c-NMR (50 MHz, CDCl3): 6 ppm 20.2 (CH2,d);22.9(CH2,d);30.5(CH2,c);32.6(CH2,c);35.8(CH2,f);51.3(CH3,h) 64.1 (CH2, i); 64.5 (CH2, i); 65.2 (CH2, e,); 79.9 (C, b); 110.9 (C, a); 126.9 (CH, Ph);127.3 (2 CH, Ph);128.1 (2 CH, Ph);139.4 (C, Ph);171.6 (C, g) Preparation of 2-[( 1R)-1′-(benzyloxy)-2′-oxocylohexyl] methyl acetate 5 by deprotection of its dioxolane derivative In a 1 liter reactor fitted with a condenser, 19 g of dioxolane 5B are placed in 0.60 liter of acetonitrile. 2.56 g of sodium iodide then 39.7 g of cerium trichloride heptahydrate are added to the solution. A yellow color appears rapidly and the reaction medium is refluxed with acetonitrile for 18 hours. After cooling , the reaction medium is poured into 1.45 title of a 0.5 M HCl/AcOEt mixture: 1/1. The phases are then separated and then the aqueous phase extracted with 3 times 375 mL of AcOEt. The combined organic phases are washed with 2 times 300 mL of a saturated NaHCO3 solution, 2 times 250 mL of a 0.4 M sodium thiosulfate solution, dried over MgSO4, filtered and then concentrated under reduced pressure. The oil obtained is chromatographed on a silica column (cyclohexane/AcOEt: 95/5) to give 14.0 g of ketoester 5 in the form of a colorless colorless oil having the following analytical characteristics: IR (pure, v cm- 1): 3032, 1735 and 1715. 1H NMR (200 MHz, CDCI3): 6 ppm. 1.44-2.08 (m, 4Hd+1Hc); 2.16-2.44 (m, 2Hc); 2.49-2.74 (m, 1Hc+1Hf); 2.92 (d, J=14.9Hz, 1Hf); 3.57 (s, 3Hh); 4.02 (d, J=10.8Hz, 1He); 4.57 (d, J=10.8Hz, 1He); 7.15-7.38 (m, 5H Ph). 13C NMR (50 MHz, CDCI3): 6 ppm 20.3 (CH2, d); 27.6 (CH2,d); 36.7 (CH2, f); 38.2 (CH2, c); 39.1 (CH2, c); 51.5 (CH3,h); 65.7 (CH2, e,); 81.2 (C,b); 127.4 (2CH, Ph); 127.5 (CH, Ph); 128.3 (2CH, Ph); 137.7 (C, Ph); 170.8 (C, g); 210.4 (C, a). Example 6 Preparation of methyl 2-[(1R)-1'-(benzyloxy)-2'-oxocylopentyl] acetate 6 and its protected derivative in the form of dioxolane 6B EMI20.1 Preparation of the protected derivative of Michael's adduct in the form of dioxolane 6A In a 0.5 liter reactor, under a nitrogen atmosphere and cooled to −78° C., 65 mL of CH2Cl2, 2.6 mL of TMSOTf and 24 mL of bis-trimethylsilyloxyethane are successively introduced. A solution of 15 g of cyclopentyl adduct 3 in 80 mL of CH2Cl2 is added dropwise, then the reaction medium is brought to ambient temperature. After stirring for 6 hours, 10 mL of distilled pyridine are added. The reaction medium is diluted by adding 125 mL of a saturated solution of NaHCO3 and 150 mL of CH2Cl2. The phases are decanted then the aqueous phase is extracted with 2 times 125 mL of CH2Cl2. The combined organic phases are dried over MgSO4, filtered and then concentrated under reduced pressure to give a white solid, which is taken up hot in 100 mL of absolute ethanol and then recrystallized at -20° C. to give 11.2 g of the intermediate dioxolane 6A, having the following analytical characteristics: IR (film, v cm¯1): 3036.2251.1744. 1H NMR (400 MHz, CDCl3): ?ppm 1.40-1.95 (m, 6H); 2.16 (dd, J=15.9; 5.2Hz, 1H); 2.65 (dd, J=16; 5Hz, 1H); 4.01 (m, 3H); 4.18 (m, 1H); 4.49 (d, J=11Hz, 1H); 4.55 (d, J=11Hz, 1H); 5.72 (t, J=5Hz, 1H); 7.27 (m, 1H-Ph); 7.34 (m, 4H-Ph). Preparation of 2-ji1 R)-1'-(benzyloxY-2'-oxocylopentvi, 6B protected methyl acetate by oxidative degradation of the protected Michael cyclopentyl adduct In a 2.5 liter flask, 11 g of the 6A-protected cyclopentyl adduct in 500 mL of absolute methanol 61 g of activated manganese dioxide then 8.5 g of sodium cyanide are added The suspension is stirred vigorously at room temperature for 3 days 1 liter of ether, then the reaction medium is filtered on celite. The celite is rinsed with 3 times 250 mL of ether then the filtrate is concentrated. The solid obtained is chromatographed on silica gel (cyclohexane/AcOEt: 95/5) to give 5 .6 g of intermediate methyl ester 6B in the form of a colorless oil having the following analytical characteristics: IR (pure, v cm¯1): 3030.1733 1 H-NMR (200 MHz, CDCI3): 5 ppm. 1.25-2.1(m,6H);2.52(d,J=14Hz,1H);2.73(d,J=14Hz,1H);3.55(s,3H) );3.75-3.97 (m, 4H); 4.55 (d, J=11Hz, 1H); 4.65 (d, J=11Hz, 1H); 7.11-7.39 (m, 5H-Ph). Preparation of methyl 2-[(1R)-1'-(benzyloxy)-2'-oxocyclopentyl acetate 6 by deprotection of its cyclic acetal derivative In a 125 mL flask fitted with a condenser, 1.7 g of cyclic acetal 6B in 60 mL of acetonitrile. 0.26 g of sodium iodide and then 4 g of cerium trichloride heptahydrate are added to the solution. A yellow color appears quickly and the reaction medium is brought to reflux of acetonitrile for 18 hours. After cooling, the reaction medium is poured into 200 mL of a 0.5 M HCl/AcOEt mixture: 1/1. The phases are then separated and then the aqueous phase extracted with 3 times 50 mL of AcOEt. The combined organic phases are washed with 2 times 30 mL of a saturated NaHCO3 solution, 2 times 25 mL of a 0.4 M sodium thiosulfate solution, dried over MgSO4, filtered and then concentrated under reduced pressure. The oil obtained is chromatographed on a silica column (cyclohexane/AcOEt: 95/5) to give 94 mg of cyclopentyl ketoester 6 in the form of a colorless colorless oil having the following analytical characteristics: IR (pure, v cm¯1 ): 3030,1735,1715. 1 H NMR (200 MHz, CDCl3): 6 ppm. 1.44-2.08 (m, 3H); 2.16-2.44 (m, 2H); 2.49-2.74 (m, 2H); 2.92 (d, J=15Hz, 1Hf); 3.58 (s, 3H); 4.02 (d, J=11Hz, 1H); 4.57 (d, J=11Hz, 1H); 7.16-7.40 (m, 5H-Ph). Example 7 Preparation of methyl 2-f(1S)-1'-(benzvioxy)-2'-oxocylohexyl]acetate 7 and its protected derivative as the dioxolane 78 EMI22.1 Preparation of the protected derivative of Michael's adduct in the form of dioxolane 7A Using a procedure identical to that of Example 5, 28.4 g of intermediate dioxolane 7A are obtained, having the following analytical characteristics: [α]D 20 = -104 (c = 2.0; CHCl3). IR (film, v cm-1): same as 5A. 1H NMR (400 MHz, CDCl3): identical to M Preparation of 2-[(1S)-1'-(benzyloxy)-2'-oxocylohexyl] protected methyl acetate 7B by oxidative degradation of the protected Michael adduct Using an operating mode identical to that of Example 5, 12.1 g of the intermediate dioxolane 7B are obtained, exhibiting spectroscopic characteristics identical to its 5B enantiomer obtained in Example 5. Preparation of 2-[(1S)-1 '-(Benzyloxy)-2'-oxocylohexyl] methyl acetate 7 by deprotection of its dioxolane derivative Using a procedure identical to that of Example 5, 14 g of the deprotected ketoester 7 is obtained, having identical spectroscopic characteristics to its enantiomer 5 obtained in Example 5. Example 8 Preparation of methyl 2-[(1R)-1'-methyl-2'-oxocylopentyii acetate 8 and its protected derivative in the form of dioxolane 8B EMI23.1 Preparation of the protected derivative of the methylcyclopentylic Michael adduct 8A In a 50 mL flask, under a nitrogen atmosphere and cooled to -78 C, are successively introduced 6.5 mL of CH2Cl2, 2.6 mL of TMSOTf and 2.4 mL of bis-trimethylsilyloxyethane. A solution of 1.5 g of methylcyclopentyl adduct 8 in 8.0 mL of CH2Cl2 is added drop by drop, then the reaction medium is brought to ambient temperature. After stirring for 6 hours, 1 mL of distilled pyridine is added. The reaction medium is diluted by adding 12.5 mL of a saturated solution of NaHCO3 and 15 mL of CH2Cl2. The phases are decanted then the aqueous phase is extracted with 2 times 12.5 mL of CH2Cl2. The combined organic phases are dried over MgSO4, filtered and then concentrated under reduced pressure to give a white solid, which is taken up hot in 10 mL of absolute ethanol and then recrystallized at -20° C. to give 1.32 g of the intermediate dioxolane 8A which is introduced without further purification, in the next step. Preparation of 2 d, 1 R)-1'-methyl-2'-oxocyclopentyl acetate 8B protected by oxidative degradation of the protected cyclopentyl adduct of Michael In a 250 mL flask, 1.1 g of the 8A protected methylcyclopentyl adduct in 50 mL of absolute methanol. 6.2 g of activated manganese dioxide then 0.85 g of sodium cyanide are added. The suspension is stirred vigorously at room temperature for 3 days. 100 mL of ether are then added, then the reaction medium is filtered through Celite, which is rinsed with 3 times 25 mL of ether and then the filtrate is concentrated. The solid obtained is chromatographed on silica gel (cyclohexane/AcOEt: 95/5) to give 520 mg of intermediate methyl ester 8B in the form of a colorless oil exhibiting the following characteristics in infrared spectroscopy: IR (film, v cm-1): 3030 and 1733. This ester is introduced in the raw state in the next step. Preparation of 2-f (1R)-1'-methvl-2'-oxoceloPentyl acetate of methvte 8 by deprotection of its cyclic acetal derivative In a 100 mL flask fitted with a condenser, 1.6 g of the cyclic acetal 8B in 55 mL of acetonitrile. 0.25 g of sodium iodide and then 8.8 g of cerium trichloride heptahydrate are added to the solution. A yellow color appears quickly and the reaction medium is brought to reflux of acetonitrile for 18 hours. After cooling, the reaction medium is poured into 250 mL of a 0.5 M HCl/AcOEt mixture: 1/1. The phases are then separated and then the aqueous phase extracted with 3 times 40 mL of AcOEt. The combined organic phases are washed with 2 times 25 mL of a saturated NaHCO3 solution, 2 times 25 mL of a 0.4 M sodium thiosulfate solution, dried over MgSO4, filtered and then concentrated under reduced pressure. The oil obtained is chromatographed on a silica column (cyclohexane/AcOEt: 95/5) to give 940 mg of methylcyclopentyl ketoester 8 in the form of a colorless colorless oil having the following analytical characteristics: IR (pure, v cm¯1 ): 3030, 1735 and 1715. 1H NMR (200 MHz, CDCl3): 8 ppm. 1.2-2.2 (m, 3H+6H); 2.40-2.60 (m, 2H); 3.60 (s, 3H); 3.70 (d, J=10.5Hz, 1H); 4.01 (d, J=10.5Hz, 1H). Example 9 Preparation of methyl 2-{(1R)-1-(benzyloxy)-2-[(trimethylsilyl)oxy]-2 cyclohèxenylTacetate 9 EMI25.1 In a 50 mL flask under a nitrogen atmosphere, a solution of 1.86 g of ketoester 5 in 20 mL of dry acetonitrile. 1.12 mL of dry triethylamine and 0.86 mL of chlorotrimethylsilane chloride are successively added. After stirring for 15 minutes at 40° C., a solution of 940 mg of anhydrous sodium iodide in 20 mL of dry acetonitrile is added dropwise and at room temperature. After 20 hours of stirring away from light, the reaction medium is diluted in 40 mL of ether and then hydrolyzed with 20 mL of an ice-cold 1% K2CO3 solution. The aqueous phase is then extracted with 3 times 40 mL of AcOEt. The combined organic phases are dried over K2CO3, filtered and then concentrated under reduced pressure to give 2 g of the crude silylated enol ether 9 in the form of a colorless oil used in the following stage without further purification. ! R (fitm, v cm¯1): 3032 and 1733. 1H NMR (200 MHz, CDCl3): # ppm. 0.11 (s, 9H); 1.40-2.06 (m, 6H); 2.61 (d, J=13.9Hz, 1H); 2.78 (d, J=13.9Hz, 1H); 3.56 (s; 3H); 4.39 (d, J=11.5Hz, 1H); 4.49 (d, J=11.5Hz, 1H); 4.91 (t, J=3.9Hz, 1H); 7.06-7.31 (m, 5H-Ph). 13C NMR (50 MHz, CDCl3): # ppm 0.1 (3CH3); 19.0 (CH2); 24.2 (CH2); 33.5 (CH2); 40.9 (CH2); 51.2 (CH3); 65.7 (CH2); 76.1 (C); 107.0 (CH); 126.3 (CH, Ph); 127.3 (2CH, Ph); 128.0 (2CH, Ph); 139.8 (C, Ph); 149.0 (C); 171.3 (C). Example 10 Preparation of methyl 2-{(1R)-1-(benzyloxy)-2-[(trimethylsilyl)oxy]-2 cyclopentenylTacetate 10 EMI26.1 6 10 Treated according to the method of Example 9.1.62 g of ketoester 6 gave 1.6 g of the crude enol silyl ether 10 as a colorless oil used in the next step without further purification. The enol ether has the following analytical characteristics: IR (film, v cm-1): 3033 and 1734. 1H NMR (200 MHz, CDCl3): 8 ppm. 0.12 (s, 9H); 1.40-2.10 (m, 4H); 2.61 (d, J=14Hz, 1H); 2.78 (d, J=14Hz, 1H); 3.58 (s; 3H); 4.40 (d, J=11.5Hz, 1H); 4.50 (d, J=11.5Hz, 1H); 4.93 (t, J=4Hz, 1H); 7.05-7.32 (m, 5H-Ph). 13C NMR (50 MHz, CDCl3): 8 ppm 0.1 (3CH3); 19.1 (CH2); 24.3 (CH2); 41.2 (CH2); 51.3 (CH3); 65.9 (CH2); 76.4 (C); 107.0 (CH); 126.3 (CH, Ph); 127.3 (2CH, Ph); 128.0 (2CH, Ph); 139.8 (C, Ph); 149.0 (C); 171.3 (C). Example 11 Preparation of methyl 2-{(1R)-1-(benzyloxy)-2-[(trimethylsilyl)oxy]-2 clohexanyllacetate 11 EMI27.1 Treated according to the method of Example 9.1.85 g of ketoester 7 gave 1.9 g of the crude enol silyl ether 11 as a colorless oil used in the next step without further purification. The enol ether has the following analytical characteristics: IR (film, v cm −1 ): 3032 and 1733. 1H NMR (200 MHz, CDCI3): 8 ppm. 0.11 (s, 9H); 1.40-2.06 (m, 6H); 2.61 (d, J=13.9Hz, 1H); 2.78 (d, J=13.9Hz, 1H); 3.56 (s; 3H); 4.39 (d, J=11.5Hz, 1H); 4.49 (d, J=11.5Hz, 1H); 4.91 (t, J=3.9Hz, 1H); 7.06-7.31 (m, 5H-Ph). 13C NMR (50 MHz, CDC13): 6 ppm 0.1 (3CH3); 19.0 (CH2); 24.2 (CH2); 33.5 (CH2); 40.9 (CH2); 51.2 (CH3); 65.7 (CH2); 76.1 (C); 107.0 (CH); 126.3 (CH, Ph); 127.3 (2CH, Ph); 128.0 (2CH, Ph); 139.8 (C, Ph); 149.0 (C); 171.3 (C). Example 2 Preparation of methyl 2-{(1R)-1-(benzyloxy)-2-[(trimethylsilyl)oxy]-2-clopentenylTacetate 12 EMI27.2 8 12 Treated according to the method of Example 9.150 mg of ketoester 8 gave 117 mg of the crude silylated enol ether 12 in the form of a colorless oil used in the next step without further purification. The enol ether has the following analytical characteristics:
    

Claims

IR (film, v cm¯1): 3033 and 1738.

1H NMR (200 MHz, CDCI3): 8 ppm. 0.12 (s, 9H); 1.40-2.10 (m, 7H); 2.32.5 (m, 2H); 4.91 (t, J=4Hz, 1H).

The reaction schemes below illustrate the possible applications of the adducts according to the invention to various syntheses of harringtonines.

The adduct of formula 1 is first subjected to one or more conventional reaction(s) of oxidative cleavage of the double bond to lead to the acid aldehyde of formula II which in turn undergoes a series of known chemical reactions. alkylation or other functionalizations.

The first oxidative cleavage operation can be carried out by ozonolysis in a dichloromethane/methanol mixture at low temperature (-78 C), followed by reduction of the intermediate ozonide by a reducing agent such as dimethyl sulphide, triphenylphosphine, etc. or by triethylamine, or by dihydroxylation followed by cleavage of the intermediate glycol either in two stages or by a "one pot" method such as: - catalytic OsO4 + TMNO (trimethylamine N-oxide) in a 2-methylpropan-2-ol mixture:

water in the presence of pyridine + Na104 (80 C, 2h), or - catalytic OsO4 + MNO (N-methylmorpholine N-oxide) in aqueous acetone, or - catalytic Os04 + a hydroperoxide such as hydrogen peroxide or peroxide tert-butyl in water or tert-butanol in the presence of hydroxytriethylamine, or -RuCl3, (H20) 2 catalytic (3.5 mol%) + Na104 in a 1,2-dichloroethane: water (1: 1) mixture at room temperature, or - RuCl3, (H20) 2 catalytic (3.5 mol%) + NalO4 in a mixture CCI4: CH3CN at room temperature for 14 h, or - RuC13, (H20) 3 catalytic + Nal04 in a mixture CCI4 :

CH3CN at room temperature for 2 h, or - catalytic RuCl3, (H20) 2 (3.5 mol%) + oxone in an acetonitrile: water (1: 1) and sodium bicarbonate mixture, or - cold aqueous KMn04 ( 0 C) in the presence of a base followed by a treatment with periodic acid in an alcohol or in ether.

The few following references illustrate these oxidative cleavage operations: JOC (2001), 66.4814; JOC (1990), 55.1217; Synthesis (1996), 281 and 702; Phytochemistry (1996), 42, (4) 1097; TetAsym (1997), 8 (23), 3921 and Org Lett (2000), 2, 3047.

PLATE II: APPLICATIONS TO DWARF SYNTHESES EMI29.1 <tb> <SEP> or <tb> <SEP> z <SEP> 0 <SEP> C02Me <SEP> OH <SEP> COMO <tb> <SEP> fX <SEP> Z <SEP> RCH <SEP> J <tb> <SEP> 10 <SEP> 1 <SEP> s <SEP> CO2R <tb> <SEP> 10 <SEP> t <SEP> H <SEP> Ht <SEP> <tb> 10 <SEP> '1. <SEP> ¯ <SEP> I <SEP> (I <tb> <SEP> 9 <SEP> Z <tb> <SEP> C02Me <SEP> R <tb> <SEP> COJ <SEP> s <SEP> <tb> <SEP> -GP <SEP> + <SEP> H+ <tb><SEP>.'t <tb> <SEP> 2n, <SEP> Z).

<SEP> n <tb> <SEP> IV <SEP> v <SEP> èoÊ'A <tb> <SEP> s <SEP> OH <SEP> 9 <SEP> pGp2 <tb> <SEP> zH <SEP> R9 <SEP> O <SEP> C02H <tb> <SEP> <SEP> Î <SEP> 2a <SEP> 1 <SEP> jZ8 <SEP> 'r'2 <SEP> q <SEP> 8 <SEP> %, <SEP> 5 <tb> <SEP> OGP <SEP> OGP <SEP> R <SEP> C02R <tb> <SEP> po <tb> <SEP> V <SEP> VIII <SEP> IX <tb> <SEP> CtXOH <SEP> CTXOH <SEP> CKOH <tb> <SEP> R9 <SEP> a'i <SEP> 9 <tb> <SEP> t <SEP> 0 <SEP> a <SEP> OGP <SEP> a <SEP>? <tb> <SEP> R9 <SEP> OH <SEP> 9 <SEP> OGP2 <SEP> 8 <SEP> 9 <SEP> t <tb> <SEP> 2) <SEP> n <SEP> C02 <SEP> ! <SEP> e <tb> R <SEP> (C2) <SEP> n <SEP> *\ <SEP> ogp1 <SEP> R8 <SEP> (CH2) <SEP> & } <SEP> GP1 <SEP> R8 <SEP> ( CH) <SEP> S <SEP> * <SEP> C02R5 <tb> <SEP> OGP <SEP> (CH2) <SEP> y <tb> <SEP> 5 <tb> <SEP> CpzR <tb> <SEP> Deprot <SEP> ions <tb> <SEP> SU’ONDINES <tb> Examples for CTX = CEPHALOTAXINYL, R5=R8=R9 = Me n = 0:

NORHARRINGTONINE (NATURAL) n=1: HARRINGTONINE (GLINICALLY ACTIVE) n=2: HOMOHWNGTONINE (CLINICALLY ACTIVE) n=3: BISHOMOPHARRINGTONINE (NATURAL) Claims 1) Process for the enantioselective preparation of a-substituted phenylethylimino-cycloalkane adducts and 2-acetoxyacrylonitrile of formula EMI30.1 in which :

- the carbon atom in position 1' has the stereochemistry 1'S or 1'R, - n=0 to 3, Z is either a protected alcohol radical of formula OGP1, or a protected thiol radical of formula SGP1, or a hydrocarbon radical containing from 1 to 12 carbon atoms, whether or not bearing a heteroatom, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, Go' being a protective group for alcohols such as a carbonaceous or silyl ether or else an ester, GP2, a protective group for enols such as a silyl ether corresponding to the formula SiR1R2R3, in which R1, R2 and R3 are, taken independently,

hydrocarbon radicals comprising from 1 to 12 carbon atoms, whether or not bearing heteroatoms, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, or alternatively a hydrocarbon ether of formula OR4, in which R4 is a hydrocarbon radical comprising from 1 to 12 carbon atoms, bearing or not heteroatoms, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, -and R4 is a hydrocarbon radical comprising from 1 to 12 atoms of carbon, whether or not bearing a heteroatom, saturated and/or unsaturated, linear,

branched and/or cyclic and/or aromatic, characterized in that it consists in protecting the tautomeric enolic form of the ketoester corresponding to the following formula: EMI31.1 in which: n, Z and R5 are defined as above using protection reagents such as:

-a halide or a trialkylsilane triflate in the presence of an alkylamine in a usual organic solvent or -an alcohol in the presence of an acid catalyst such as an acid of Lewis or usual protonic said ketoester above being obtained by deprotection of the corresponding acetal corresponding to the formula below EMI31.2 in which :

- n, Z and R5 are defined as above -X and Y are, taken independently, oxygen, nitrogen or sulfur heteroatoms, -R6 and R7 are, taken independently, hydrocarbon radicals containing from 1 to 12 carbon atoms, whether or not bearing heteroatoms, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, the said hydrocarbon radicals being able to form between them a cyclic acetal bridge, by the action of a reagent such as an aqueous acid or else preferably cerium trichloride in a solvent such as acetonitrile, said acetal above being obtained from the protected cyanoacetate corresponding to the formula below:

EMI32.1 wherein n, Z, X, Y and R5, R6 and R7 are defined as above by oxidative degradation in the presence of activated manganese dioxide and an alkali cyanide such as sodium cyanide, in a solvent such as an anhydrous alcohol, preferably methanol, at room temperature for 1 to 5 days, said cyanoacetate above being obtained by protection of the Michael adduct ketone corresponding to the formula below:

EMI32.2 in which n, and Z are defined as above by action either of the free form of the corresponding alcohol corresponding to the formulas R6OH or R70H or of the diol HOR6R7OH, or of the masked form of the rounding alcohol with the formulas R6OR8, R7OR8 or R8OR6R7OR8, in the presence of a proton or Lewis acid, more particularly by the action of bis-trimethylsilyloxyethane in the presence of trimethylsilyl trifluorosulfonate, said Michael adduct being obtained by simple bringing together ethyl cyanoacetate and 'imine of chirality suitably chosen according to the desired stereochemistry in position 1',

followed by in situ hydrolysis using an aqueous polar solvent and an acid such as acetic acid according to the following reaction scheme: EMI33.1 in which n and Z are defined as above, A and A' are different from each other and, taken independently, hydrocarbon radicals comprising from 1 to 12 carbon atoms, bearing or not heteroatoms, saturated and/or unsaturated, linear, branched and/or cyclic and/or aromatic, said chiral imine being obtained by reaction between a chiral amine and a substituted racemic ketone according to the following reaction scheme: EMI33.2 where n, Z, A and A' are defined as above.

2) Process according to claim 1, in which n=1 or 2, Z=C) GP′, Go1 being a protective group for alcohols.

3) Process according to claim 2, in which the protecting group of the alcohols is a benzyl radical, X and Y are oxygen atoms and Gp2 is a trialkylsilyl.

4) Process according to claim 1, in which n=1 or 2, and Z is a C1 to C4 alkyl radical, linear or branched.

5) Process according to claim 4, in which the alkyl radical is a methyl and, X and Y are oxygen atoms and Gp2 is a trialkylsilyl.

6) Method according to one of claims 1 to 5, wherein A is a phenyl radical and A'un methyl radical.

7) Process according to one of claims 1 to 5, in which A′ is a phenyl radical and A is a methyl radical.

8) Compound and its enantiomer, in particular as a useful intermediate in the synthesis of harringtonines by oxidative cleavage followed by known chemical reactions of alkylation and other functionalizations, corresponding to the following formula: EMI34.1 where n, Z, R5 and Gp2 are defined above.

9) Intermediate for preparing the compound of claim 8, corresponding to the following formula: EMI35.1 where n, Z, and R5 are defined above.

10) intermediate for preparing the compound of claim 9, corresponding to the following formula: EMI35.2 where n, Z, X, Y, R5, R6 and R7 are defined above.

11) intermediate for preparing the compound of claim 10, corresponding to the following formula: EMI35.3 where n, Z, X, Y, R6 and R7 are defined above.

12) Intermediate for preparing the compound of claim 11, corresponding to the following formula: EMI35.4 where n and Z are previously defined.

13) Compound according to claim 8, in which n=1 or 2, Z=OGP1, Go1 being a protective group for alcohols.

14) Compound according to claim 13, in which the protecting group of the alcohols is a benzyl radical, X and Y are oxygen atoms and Gp2 is a trialkylsilyl.

15) A compound according to claim 8, in which n=1 or 2, and Z is a C1 to C4 alkyl radical.

16) Compound according to claim 15, in which the alkyl radical is a methyl and, X and Y are oxygen atoms and Gp2 is a trialkylsilyl.

17) As synthesis intermediates necessary for carrying out the process according to claim 1, the chiral imines corresponding to the following formulas: EMI37.1 EMI37.2 EMI37.3 EMI37.4 18) As synthesis intermediates necessary for carrying out the process according to claim 1, the Michael adduct ketones corresponding to the following formulas: EMI38.1 NDE38.2 NDE38.3 NDE38.4 19) As synthesis intermediates necessary for carrying out the process according to claim 1, the protected cyanoacetates corresponding to the following formulas: EMI39.1 NDE39.2 NDE39.3 NDE39.4 20) As synthesis intermediates necessary for the implementation of the process according to claim 1, the acetols corresponding to the following formulas:

EMI40.1 21) As synthesis intermediates necessary for carrying out the process according to claim 1, the cito esters corresponding to the following formulas: EMI41.1 EMI41.2 EMI41.3 EMI41.4 22) As synthesis intermediates necessary for the implementation of the process according to claim 1, the protected enol forms of cito esters corresponding to the following formulas: EMI42.1 EMI42.2 EMI42.3 EMI42.4