A PROCESS FOR PREPARING A CYCLOADDITION COMPOUND

Abstract: A process for preparing a cycloaddition compound, which comprises reacting ketene with a carbonyl group-containing compound having formula (I), which contains a highly electron-attractant group in the alpha -position relative to the carbonyl group in the presence of a chiral tertiary amine as catalyst to form a cycloaddition compound having formula (II).

Description: A process for preparing a cycloaddition compound. The invention relates to a process for preparing a cyclo¬ addition compound. According to the invention ketene is reacted, for that purpose with a carbonyl group-containing compound having formula 1 of the sheet of formulae which contains a highly electron-attractant group in the α-position relative to the carbonyl group in the presence of a chiral tertiary amine as catalyst, to form a cycloaddition compound having formula 2 of the sheet of formulae. Surprisingly,it as.beenfoundthat, in the reaction of ketene with the compound having formula 1 of the sheet of formulae the use of a chiral ertiary amine is highly enantioselective with respect to the reaction product formed / aevalues as high as 90-95% and more being obtainable. Examples of compounds having formula.1 containing a carbonyl group and a highly electron-attractant group in the ct-position relative to the carbonyl group are chloral and in particular 1,1,1,-tricholoro- propanone-2. By means of the reaction product formed by using this last- mentioned compound cholecalciferol compoundsmay be readily and stereo- selectively prepared, such as both 25(S) . and 25(R)-lα, 25, 26- trihydrojcycholecalciferol and both 25(S) and 25(R)-dihydroxycholecal- ciferol which cholecalciferol compounds play their part in the human body, e.g. the 25(S), 26-dihydroxycholecalciferol which is an important vitamin D, metabolite. Examples of the catalyst employed according to the process according to the invention are the chiral tertiary amines listed in Table A contained hereinafter. A comparison of the correlated values given in columns II, III and IV of Table A shows in what sense and degree the enantioselectivity is effected by the selection of the catalyst on the basis of the reaction of ketene with chloral as the compound having formula 1. Table A; Relationship between absoluteconfiguration of the β-lactone formed and configuration of catalyst \ -ϊ- Explanation of the table. a Standard conditions: 4 mol % katalyst in toluene at -50 a C. b Configuration of carbon atom adjacent to nitrogen atom (C- for nos. 1-8; C_ for nos. 9 and 10). c Change in nomenclature because of change in substitution, d Reaction performed in CΞC1- because of solubility problems of catalyst e Chemical yields are lower in these cases (2:60%) because of intramolecular hydrogen bonding (epiquinine) and steric blocking of nitrogen by chlorine (epichlorocinchonidine) which causes reduced availability of nitrogen for catalysis. ΓRI OMPI The invention also relates to a cycloaddition compound having formula 2 of the sheet of formulae, in particular having formula 3 of the sheet of formulae, in which R represents H or CH_.Especially preferred are the cycloaddition compounds- aving formula 2 or formula 3 in the form of the R- or S-enantiomer. thereof. Such cycloaddition compounds having formula 2 or formula 3 are novel and very advantageous as a starting material for the asymetric synthesis of chiral. compounds, e.g., of a hydroxyalkanedicarboxylic acid such as malic acid. Moreover, these cycloaddition compounds are suitable as starting compounds for the preparation of novel acetonide compounds. The invention therefore also relates to a process for preparinganacetonide which is characterized in that a compound having formula 2 of the sheet of formulae is converted to an acetonide having formula 32 of the sheet of formulae, in a manner known per se, especially in that a compound having formula 3, in which R is CH_, is converted to an acetonide having fof ula 33. Preferably, X in formulae 32 and 33, respectively*of the sheet of formulae represents OTs, OH, Cl, Br or J, GTs being tosylate. It is further preferred to prepare the R- or S-enantiomer of the acetonide compound having formulae 32 or 33 by starting from the corresponding enantiomer of the compound having formula 2 orformula 3. As for the preparation of a compound having formula 32, e.g., a compound having formula 33, in which X is Cl, Br or J, it is effective to start from a compound having formula 3, e.g., the R-enantiomer of the compound having formula 3, in which R is CH,, and subjecting the same to the following chemical operations (equation 14, sheet of formulae) a) Acid hydrolysis of the oxetanone having formula 23 to 3-hydroxy-3-(trichloromethyl)butanoic acid (formula 8); . b) Basic hydrolysis of the compound having formula 8 to 2-methyl-2-hydrox3_-succinic acid (formula 9) (isolation by treating with ion exchanger) ; c) Esterification of the compound having formula 9 to the diester (e.g., diethyl- or dimethylester) (formula 10); d) Reduction of the diester to 2-methyl-l,2,4-butanetriol having formula 11; e) Formation of the 1,2-acetonide of 2-methyl-l,2,4-butane- triol to the compound having formula 12; OMPI f) Tosylation of this compound to 2-methy1-1,2,4-butane- trial-l,2-acetonide-4-tosyla e having formula 13; g) Substitution of the 4-tosyl group in the compound having formula 13 by a halogen (J, Br, Cl) gives a compound having formula 33 in which X is J, Br or Cl. The compounds having formula 32, substituted in the 4-position , in particular the 4-substituted 2-methyl-l,2-butanediol-l,2-acetonides or the R- or S-enantiomer thereof also belong to the invention. The Grignard compounds of the 4-halogen-2-methyl-l,2-butanediol- 2-acetonides are -mportant intermediates for a novel method of preparing lα, 25, 26-trihydroxycholecalciferols (formula 6) and 25, 26-dihydrσxy- cholecalciferols (formula 5) . This preparation method, with the use of the Grignard compounds of the acetonides having formula 33, has significant advantagesoyer the method employed thus far for synthesis of these cholecalciferols. (J.J. Partridge, M.R. Oskokovic et al. J. Am.Chem. Soc.,1981, 103, 1253; J.J. Partridge, M.R. ϋskokovic et al., Helv. Chem. Act. J54, 2138 (1981), disclosing an alk lation of the carbanion having formula 22 by the halogβicompound having formula 23 (sheet of formulae, equation 15). Moreover, the starting compound for the tosylate (formula 7) is accessible more readily than the starting compound for the carbanion having formula 22. The key compound for the preparation of a compound having formula 33 is the 4-methyl-4-(trichloromethyl)-2-oxetanone having formula 3, in which R is CH,. Of this compound both the (S) and the (R) enantiomer (resp. formulae 4a and 4b, sheet of formulae) can be prepared in pure form by cycloaddition of l,l,l-trichloropropanone-2 with ketene. Starting from either of the two enantiomer-pure oxetanones having formulae 4a and 4b, the two enantiomeric forms of compounds 8 through 11 (equation 14, sheet of formulae) as well as the compounds having formula 33 can be prepared, the Grignard compounds of which latter compounds can be used for the preparation of both 25(S)- and 25(R)-lct, 25 r 26-trihydroxycholecal- ciferol (formula 6) as well as for the preparation of both 25(S)- and 25 (R)-25,26-dihγdrσxycholecalciferol (formula 9) . The invention will be further elucidated by means of the examples given hereinbelow. OMPI Example I a) Preparation of (S)-g-(trichloromethyD-β-propiolactone (formula 16 of the sheet of formulae) . In a three-necked round-bottom flask (100 cm* )equipped with a thermometer, a ketene inlet under the surface of the toluene, and a dropping funnel was dissolved 83 mg (0.25 mmol) of purified quinidine in 50 cm 3 of toluene. The solution was cooled to -50°C. Then ketene was passed through the solution which was stirred by means of a magnetic stirrer, while 1.47 g (0.01 mol) of anhydrous chloral in 20 cm 3 of toluene was added dropwise during 0.75-1 h. Excess of ketene was avoided inαrcfertominimize formation of diketene. After the reaction was complete the mixture was warmed to room temperature and transferred to a separatory funnel. The catalyst was removed by repeated (2x) washing with 4N HC1. The toluene layer was washed with saturated NaCl solution and dried over MgSO . After removing MgSO. by filtration, toluene was removed under reduced pressure. The residuewas purified by distillation: 20 120°C (0.5 mm Hg) , yield 1.67 g (89%); [αj __„ - 15.3°C (cl, cyclohexane) corresponding to an ee of 98%; NMR 3.7(2 H, ) , 5.0 ppm (lH,t) . b) Preparation of optically pure (R)- and (S)-β-(trichloro- methyl)-β-propiolactone(formula 16 of the sheet of formulae). 18g of the lactone having formula 16 (ee 95%) was dissolved in 4.1 cm 3 of methylcyclohexane by warming. The solution was filtered and allowed to cool to rooin temperature. After filtration and washing with a little amount of methylcyclohexane, 15.5 g of (S)-lactone product 20 could be recovered (85% yield), [α] _„ - 15.6° (cl, cyclohexane), mp * . 51-52°C. The specific rotation did not change after another crystallisation. The same procedure starting with 19.7 g of lactone having formula 16 (72% ee) from 110 cm 3 of methylcyclohexane yielded 12.8 g 20 (R)-lactone (65% yield), [α] 15.4° (cl, cyclohexane), mp 51-52°C. Again it turnedout that the rotation did not change after another crystallisation. Racemic lactone having formula 16 had mp 36-37°C. Example II. By use of quinidine as catalyst in the reaction between ketene and l,l,l-trichloropropanone-2 an enantiomer-pure compound having formula 4a could be prepared as follows. Under an atmosphere of dried nitrogen 389 mg (1.2 mmol) of quinidine was dissolved in 35 cm 3 of toluene, in a three-necked flask, of 100 cm 3 , equipped with a thermometer and a ketene inlet. Then 10 g (63 mmol) of 1,1,l-thrichloropropanone-2 was added. The mixture was cooled to -25 β C. Ketene was passed for 5 hours with stirring (about 10 mmol/h) . After 5 hours about 50% of 1,1,l-trichloropropanone-2 was converted to the desired 2-oxetanone according to an NMR of the reaction mixture. The reaction was stopped byadding 25 cm 3 of 4N HCl. In a separatory funnel the reaction mixture was then washed three times with 10 cm 3 of 4 N HCl, further with 10 cm 3 of saturated NaCL solution and dried over MgSO . After filtration and evaporation of the solvent the residue was purified by bulb to bulb distillation (0.1 ππι_Hg/120 o C) . 20 Chemical yield 5.6 g (45%); [α] __ a + 6.0 (c=1.96% ethanol), corresponding to an ee of 95% S-enantiomer. By one recrystallisation fcάαmethylcyclohexane the 2-oxetanone enantiomer could be obtained in 20 pure form; [α] ___ + 6.35 (c=l, 96% ethanol) (S-enantiomer) mp 39.5-40.5°C. Starting from quinine, instead of quinidine, the (R)-enantiomer of the 2-oxetanone could be isolated in 86% ee; starting from cinchonidine, the (R)-enantiomer could be isolated in 86% ee; and startin from cinchonine, the (S)-enantiomer could be isolated in 92% ee. OMPI

Claims: C L A I M S . 1. A process for preparing a cycloaddition compound, characterized by reacting ketene with a carbonyl group-containing compound having formula 1 of the sheet of formulae which contains a highly electron- attractant group in the α-position relative to the carbonyl group, in the presence of a chiral tertiary amine as catalyst to form a cycloaddition compound having formula 2 of the sheet of formulae. 2. A process according to claim 1, characterized by reacting ketene and 1,1,l-trichloropropanone-2 in the presence of quinidine as. the chiral catalyst. 3. A process according to claim 1, characterized by reacting keten with chloral in the presence of quinidine as the chiral catalyst. 4. A cycloaddition compound, characterized by formula 2 of the sheet of formulae. 5. A compound according to claim 4, characterized by formula 3 of the sheet of formulae, in which R is H or CH,. 6. A compound according to claim 4, characterized in that the compound is the R-or S-enantiomer having formula 2. 7. A compound according to claim 5, characterized in that the compound is the R- or S-enantiomer having formula 3. 8. A process for preparing an acetonide, characterized by convertin a compound having formula 2 of the sheet of formulae to an acetonide having formula 32 of the sheet of formulae, in a manner known per se. 9. A process according to claim 8, characterized by converting a compound having formula 3, in which R is CH,, to an acetonide having having formula 33. 10. A process according to claims 8-9, characterized in that X is OTs, OH, Cl, Br or J and OTs is tosylate. 11. ' A process according to claims 8-10, characterized by preparing the R- or S-enantiomer of the acetonide compound having formula 32 or OMPI 33 by starting from the corresponding enantiomer of the compound having formula 2 or formula 3. 12. An acetonide compound, characterized, by formula 32 of the sheet of formulae. 13. A compound according to claim 12, characterized by formula 33, in which X is OTs,OH, Cl, Br of J and OTs is tosylate. 14. A compound according to claims 12-13, characterized in that the compound is the R- or S-enantiomer of the compound having formula 32 of formula 33. 15. A process for preparing a cholecalciferol compound, characteriz by.performing on the tosylate of a compound having formula 7 substitution by a Grignard compound of a compound having formula 33 of the sheet of formulae, in which X is Cl, Br or J. 16. A process according to claim 15, characterized in that the 25 (R)- or 25(S)-enantiomer of 25, 26-dihydroxycholecalciferol having formula 5 is prepared by starting from the corresponding enantiomer of the Grignard compound having formula 33. 17. A process according to claim 15,characterized in that the 25(R) or 25 (S)-enantiomer of lα, 25, 26-trihydrox^cholecalciferol having formula 6 is prepared by starting from the corresponding enantiomer of the Grignard compound having formula 33. CMPI

Inventors: STARING EMIEL GRADUS JOHANNES, WYNBERG HANS, STARING, EMIEL, GRADUS, JOHANNES, WYNBERG, HANS
Applicants: STARING EMIEL GRADUS JOHANNES, WYNBERG HANS, STARING, EMIEL, GRADUS, JOHANNES, WYNBERG, HANS
Application year: 1983
Main classification: C07D305
IPC codes: C07C29, C07C33, C07C401, C07D305, C07D317