EP1173397A1 - Stereospezifische herstellung von 4-hydroxy-1-alkenen - Google Patents
Stereospezifische herstellung von 4-hydroxy-1-alkenenInfo
- Publication number
- EP1173397A1 EP1173397A1 EP00927309A EP00927309A EP1173397A1 EP 1173397 A1 EP1173397 A1 EP 1173397A1 EP 00927309 A EP00927309 A EP 00927309A EP 00927309 A EP00927309 A EP 00927309A EP 1173397 A1 EP1173397 A1 EP 1173397A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- alkyl
- group
- configuration
- aryl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 17
- 230000000707 stereoselective effect Effects 0.000 title claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 125000003118 aryl group Chemical group 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- 150000004292 cyclic ethers Chemical class 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 39
- 229910052719 titanium Inorganic materials 0.000 claims description 14
- 239000010936 titanium Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000012429 reaction media Substances 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000746 allylic group Chemical group 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 4
- 150000001299 aldehydes Chemical class 0.000 abstract description 11
- 238000007075 allylic rearrangement reaction Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000005937 allylation reaction Methods 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- CYSFUFRXDOAOMP-UHFFFAOYSA-M magnesium;prop-1-ene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C=C CYSFUFRXDOAOMP-UHFFFAOYSA-M 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- -1 titanium carbohydrate Chemical class 0.000 description 2
- WWJMYJUXNLNOIP-QOMKKIOMSA-N (2R,3R)-1-benzo[a]anthracen-1-ylbutane-1,2,3,4-tetrol Chemical compound C1(=CC=CC2=CC=C3C=C4C=CC=CC4=CC3=C12)C([C@H]([C@@H](CO)O)O)O WWJMYJUXNLNOIP-QOMKKIOMSA-N 0.000 description 1
- HPCIROFWHAFUAW-XMMPIXPASA-N (3R)-1-trityloxyhex-5-en-3-ol Chemical compound O[C@@H](CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)CC=C HPCIROFWHAFUAW-XMMPIXPASA-N 0.000 description 1
- HPCIROFWHAFUAW-UHFFFAOYSA-N 1-trityloxyhex-5-en-3-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCCC(O)CC=C)C1=CC=CC=C1 HPCIROFWHAFUAW-UHFFFAOYSA-N 0.000 description 1
- KDYRNYXQEPYCTD-UHFFFAOYSA-N 1-trityloxypent-4-en-2-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(O)CC=C)C1=CC=CC=C1 KDYRNYXQEPYCTD-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DEPZGSLKTDSIDR-UHFFFAOYSA-N 2-trityloxyacetaldehyde Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC=O)C1=CC=CC=C1 DEPZGSLKTDSIDR-UHFFFAOYSA-N 0.000 description 1
- ZSUSDXCLKLOMNW-UHFFFAOYSA-M Cl[Ti]C1C=CC=C1 Chemical compound Cl[Ti]C1C=CC=C1 ZSUSDXCLKLOMNW-UHFFFAOYSA-M 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-threitol Chemical compound OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- AENCLWKVWIIOQH-UHFFFAOYSA-K cyclopentane;trichlorotitanium Chemical compound Cl[Ti](Cl)Cl.[CH]1C=CC=C1 AENCLWKVWIIOQH-UHFFFAOYSA-K 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003608 titanium Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/18—Preparation of optical isomers by stereospecific synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to the teresospec i f ic preparation of 4-hydroxyal c - 1 - ene compounds of configuration ⁇ R) or ⁇ S) of general formula (I):
- X represents an oxygen atom
- R is chosen from an alkyl, aryl, trityl, SiR 3 group [Si (Alkyl) 3 , • Si (Alkyl) 2 Ph], cyclic ether, tetrahydrofuryl, or a group of formula -CO-R '', where R '' represents an alkyl group or an aryl group, R 'represents the free oxygen doublet, and n is an integer greater than or equal to 1, or X represents an atom nitrogen, and in this case R is chosen from a hydrogen atom, an alkyl or aryl group, R 'is chosen from a group of formulas -C0 2 R'', -S0 2 R'',-COR''whereR''represents an alkyl group, an aryl group, or a group -CF 3 , and n is an integer greater than or equal to 1.
- titanium complexes derived from the trichloro-cyclopentadienyl-titanium complex (CpTiCl 3 ), to facilitate the enantioselective addition of the allylic group to aldehydes, is also described by Duthaler et al. (Pure & Applied Chemistry, 1990, vol. 62, n ° 4, pages 631-642, "Asymmetric CC bond formation ith titanium carbohydrate complexes").
- optically active compounds 4-hydroxyalkenes are very useful intermediates for the preparation of pharmaceutically active compounds.
- a more particular subject of the present invention is a process for the enantioselective preparation of 4-hydroxyalk-1-enes of configuration (R) or (S) of formula general (I) previously defined by an enantioselective allylation reaction of aldehydes of formula (II):
- R ' represents a group -C0 2 R''whereR''represents an alkyl or aryl group, or R' represents a group -S0 2 R '' where R '' represents an alkyl, CF 3 or aryl group, or alternatively
- R ' represents a group -COR''whereR''represents an alkyl or aryl group.
- High yields and high enantiomeric excesses are obtained by the use of an allyl-cyclopentadienyl-ti tane complex, having a bidentate ligand 2, 3-O-isopropylidene-l, 1, 4, 4-tetraphenylthreitol of configuration (2i ?, 3.) Of formula (Illa) or (25.35) of formula (Illb) below:
- This precursor can also be prepared according to the method described by Duthaler et al. (Pure & Applied Chemistry, 1990, vol. 62, n ° 4, pages 631-642, "Asymmetric C-C bond formation with titanium carbohydrate complexes").
- the present invention relates very particularly to a process for the enantioselective preparation of 4-hydroxyalkc-1-enes of general formula (I) comprising: a) the reaction of an aldehyde of formula (II) with ⁇ R, R) - cyclopentadienyl- [ ⁇ 4R, trans) -2, 2-dimethyl- ⁇ , ⁇ , ⁇ ', ⁇ ' - tetraphenyl-1, 3-dioxolane-4, 5-dimethanolato-O, 0 '-] -prop-2- enyl-titanium of formula (Illa), and b) hydrolysis of the product of reaction (a) to obtain the 4-hydroxyalk-1-ene compound of configuration (5) of formula (la).
- the allyl-cyclopentadienyl-titanium complex composed of formulas (Illa) or (Illb) in solution in ether is preferably cooled in step (a) to a temperature below about -70 ° C, preferably to -78 ° C.
- the aldehyde of formula (II), in an appropriate solvent, is then added to the compound of formula (III) by suitable means of addition. Generally, it is desirable to add the aldehyde solution slowly.
- step (b) After stirring the reaction medium, for a time sufficient to allow the formation of the compound of formulas (la) or (Ib), it is hydrolyzed in step (b) at the same temperature as in step (a) by slow addition of water.
- the reaction medium is then maintained at ambient temperature for a sufficient time, generally less than 10 to 20 hours approximately, preferably approximately 13 to 15 hours.
- reaction medium is filtered and washed with an appropriate solvent, for example diethyl ether.
- organic phase is separated and washed, preferably with ether, then dried over MgS0 4 .
- the residue is treated with an appropriate solvent (alkane), to precipitate the ligand.
- the filtrate is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel.
- Example 2 Preparation of (5) -1-benzyloxyhex-5-en-3-ol (compound of formula (I) in which R represents a benzyl group and n is 2).
- the mixture is hydrolyzed at this same temperature with water (15 ml) and the mixture is left to stir for 14 hours at room temperature.
- the content of the bicol is then filtered on Celite.
- the Celite is washed with ether (2X30 ml).
- the mixture is then washed with salt water and then extracted with ether.
- the organic phases are dried over MgSO 4 and evaporated in vacuo.
- the residue obtained is treated with hexane to precipitate the ligand, after filtration, the filtrate is evaporated and the residue is chromatographed on a column of silica gel (eluent AcOEt / Hexane 1: 9).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9905469A FR2793488B1 (fr) | 1999-04-29 | 1999-04-29 | Preparation stereospecifique de composes hydroxy-4-alcene-1 |
| FR9905469 | 1999-04-29 | ||
| PCT/FR2000/001167 WO2000066519A1 (fr) | 1999-04-29 | 2000-04-28 | Preparation stereospecifique de composes 4-hydroxyalc-1-ene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1173397A1 true EP1173397A1 (de) | 2002-01-23 |
Family
ID=9545046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00927309A Withdrawn EP1173397A1 (de) | 1999-04-29 | 2000-04-28 | Stereospezifische herstellung von 4-hydroxy-1-alkenen |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1173397A1 (de) |
| JP (1) | JP2002543167A (de) |
| AU (1) | AU4574000A (de) |
| FR (1) | FR2793488B1 (de) |
| WO (1) | WO2000066519A1 (de) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5047557A (en) * | 1989-03-08 | 1991-09-10 | Ciba-Geigy Corporation | Complexes having optically active ligands, a process for their preparation and their use |
-
1999
- 1999-04-29 FR FR9905469A patent/FR2793488B1/fr not_active Expired - Fee Related
-
2000
- 2000-04-28 EP EP00927309A patent/EP1173397A1/de not_active Withdrawn
- 2000-04-28 AU AU45740/00A patent/AU4574000A/en not_active Abandoned
- 2000-04-28 WO PCT/FR2000/001167 patent/WO2000066519A1/fr not_active Application Discontinuation
- 2000-04-28 JP JP2000615354A patent/JP2002543167A/ja not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0066519A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000066519A1 (fr) | 2000-11-09 |
| AU4574000A (en) | 2000-11-17 |
| JP2002543167A (ja) | 2002-12-17 |
| FR2793488A1 (fr) | 2000-11-17 |
| FR2793488B1 (fr) | 2001-08-24 |
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