EP1173397A1

EP1173397A1 - Stereospecific method for preparing 4-hydoxyalk-1-ene compounds

Info

Publication number: EP1173397A1
Application number: EP00927309A
Authority: EP
Inventors: Janine Cossy; Samir Bouzbouz; Jean-Claude Caille
Original assignee: PPG Sipsy SAS
Current assignee: Zach System SA
Priority date: 1999-04-29
Filing date: 2000-04-28
Publication date: 2002-01-23
Also published as: FR2793488B1; AU4574000A; WO2000066519A1; FR2793488A1; JP2002543167A

Abstract

The invention concerns a method for stereospecific preparation of 4-hydroxyalk-1-ene compounds of configuration (R) or (S) of general formula (I) wherein: X represents an oxygen atom, and in such case R is selected among an alkyl, aryl, trityl, SiR, [Si(Alkyl)3; Si(Alkyl)2Ph], cyclic ether, tetrahydrofuryl group, or a group of formula -CO-R'', wherein R'' represents an alkyl group or an aryl group; R' represents the lone pair of oxygen; and n is a whole number not less than 1; or X represents a nitrogen atom, and in such case, R is selected among a hydrogen atom, an alkyl, aryl group; R' is selected among the groups of formulae -CO2R'', -SO2R'', -COR'', wherein R'' represents a alkyl group, an aryl group, or a -CF2 group, and n is a whole number not less than 1; by enantioselective allylic rearrangement reaction of aldehydes of formula (II) wherein X, R, R' and n are as defined in formula (I).

Description

STEREOSPECIFIC PREPARATION OF 4 - HYDROXYA C - 1 -ENE COMPOUNDS.

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):

(I) in which:

X represents an oxygen atom, and in this case 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.

The 4-hydroxyalk-l-ene compounds of configuration

(S) or {R) of general formula (I) can be represented respectively by the formulas (la) and (Ib) below, in which R, R 'and n have the same meaning as in formula (I) above:

[Ia): ib)

It has been described, in the prior art for example in US patent No. 5,047,557, asymmetric addition of the allylic group to aldehydes, using various organo-titanium complexes.

The use of 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"). These authors report more particularly the synthesis of the threitol (base) -titanium cycle, derived from the CpTiCl ₃ complex and of tartaric esters, and the use of corresponding allyl reagents, to add the allyl group to designated aldehydes.

The optically active compounds 4-hydroxyalkenes are very useful intermediates for the preparation of pharmaceutically active compounds.

The Applicant has now developed a new process for the preparation of these 4-hydroxyalkyl-1-enes compounds, by a particularly effective enantioselective allylic titanation reaction which is not known or suggested in the prior art.

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):

(II)

in which X, R, R 'and n have the same meaning as in formula (I).

A first embodiment of the process of the invention relates to the preparation of compounds of formula

(I) from compounds of formula (II) in which X represents an oxygen atom and R is chosen from an alkyl, aryl, trityl, SiR _{3 group} [Si (Alkyl) ₃ ; Si (Alkyl) ₂ Ph], cyclic ether, tetrahydrofuryl, or a group -CO-R '' where R '' represents an alkyl or aryl group, and R 'represents the free oxygen doublet and n is an integer greater than or equal to 1.

A second embodiment of the process of the invention relates to the preparation of compounds of formula

(I) from compounds of formula (II) in which X represents a nitrogen atom, n is an integer greater than or equal to 1, and R is chosen from a hydrogen atom, an alkyl or aryl group, and

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:

(He a) (Illb)

The precursor of the allyl-cyclopentadienyl titanium complex, the chloro-cyclopentadienyl titanium complex, or the compound {R, R) or {S, S) cyclopentadienyl- (4, 5-trans) -dimethyl- 2, 2-tetraphenyl-oc, α, α ', oc' -dixolane-1, 3-dimethanaloto-4, 5- 0.0 '] - chloro-titanium, is available from FLUKA, ALDRICH, SIGMA. 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").

“Allylation” is understood to mean the actual allylation reaction followed by an aqueous hydrolysis reaction.

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-α, α, α ', α' - 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 same reaction can be carried out with (5, S) -cyclopentadienyl- [(45, trans) -2, 2-dimethyl-α, α, α ', α' - tetraphenyl-1, 3-dioxolane-4, 5-dimethanolato-O, 0 '-] -prop-2- enyl-titanium, compound (IIIb), for preparing 4-hydroxyalk-1-enes compounds of configuration (R) of formula (Ib).

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.

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.

To isolate the 4-hydroxyalkyl-enes compounds of configuration (R) or (5) of general formula (I), the reaction medium is filtered and washed with an appropriate solvent, for example diethyl ether. The 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. After filtration, the filtrate is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel.

These steps can be represented by the following reaction schemes:

s

(the)

(Illa) configuration {R, R)

(Illb) configuration {S, S)

Other advantages and characteristics of the invention will appear in the description which follows and which relates to examples of implementation, it being understood that the person skilled in the art is able to transpose this teaching other examples, adapting products, quantities, ratios, temperatures, reaction conditions, etc., depending on the reagents involved.

Example 1: Preparation of (S) - 1 -

(triphenylmethoxy) pent-4-en-2-ol (compound of form (I) in which R represents a triphenylmethyl group and n is 1).

In a flask (bicol of 50 ml) under argon, (1.22 g, 2 mmol) of the {R, R) -chlorocyclopentadienyl titanium complex (Novartis) is placed and then dry ether (20 ml) is added ( c = 0.1 M), after cooling the flask to -20 ° C, a 2 M solution of allylmagnesium chloride (purchased from Aldrich) in ether is added (0.85 ml, 1.7 mmol). After the end of the addition, the mixture is left to stir at 0 ° C.

(ice bath) an orange solution is then formed, the mixture is then cooled to -78 ° C. The aldehyde, trityloxyacetaldehyde (0.453 g, 1.5 mmol) dissolved in (3 ml) of dry ether, is added over a period of 10 minutes, the mixture is then stirred for 4 hours at -78 ° C.

After 4 hours, 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 (2 × 30 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).

0.472 g of alcohol (5) - 1 - (triphenylmethoxy) pent-4-en-2-ol (colorless oil) is obtained. YId: 91% [] _D ²² = -8.13 (c 1.5 MeOH). The enantiomeric excess (ee) of the configuration compound (5) is determined by HPLC (ODH Chiracel Hexane / Ethanol: 85/15) and is 95%.

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).

In a flask (50 ml two-necked) under argon, (1.22 g, 2 mmol) of the complex (ϋ, i?) -C lorocyclopentadienyl-titanium (Novartis) is placed and then added (20 ml) of ether dry (c = 0.1 M), after cooling the flask to -20 ° C, a 2 M solution in allyl magnesium chloride ether (0.85 ml, 1.7 mmol) is added ( purchased from Aldrich). After the end of the addition, the mixture is allowed to stir at 0 ° C (ice bath) an orange solution is then formed, the mixture is then cooled to -78 ° C. The aldehyde 3- (benzyloxy) propanai (0.246 g, 1.5 mmol) dissolved in (3 ml) of dry ether is added over a period of 10 minutes, the mixture is then stirred for 4 hours at -78 ° vs.

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).

0.281 g of alcohol (5) -1-benzyloxyhex-5-en-3-ol (colorless oil) is obtained.

Yield: 91% [CX] _D ²² = -3.6 (c 0.87, CHCl ₃ ); ee> 96% 1 H-NMR: 7.3-7.2 (m, 5H); 5.91-5.78 (m, 1H); 5.13-5.08 (m, 2H); 4.52 (s, 2H); 3.91-3.84 (m, 1H); 3.76-3.60 (m, 2H); 2.87

(broad s, 1H); 2.25 (t, J = 7.2, 2H); 1.81 (m, 2H). ¹³ C NMR: 35.7 (t); 41.8 (t); 68.8 (t); 70.2 (d);

73.2 (t), 117.4 (t), 127.5 (2d, Ph); 127.6 (d, Ph), 128.3 (2d, Ph); 134.7 (d); 137.8 (s).

Example 3: Preparation of {R) - 1 - Triphenylmethoxyhex-5-en-3-ol (compound of forume (I) in which R represents a triphenylmethyl group and n is 2).

(1.22 g, 2 mmol) of the complex (5, 5) -chloro-cyclopentadienyl titanium is placed in a flask (50 ml two-necked flask) under argon and then (20 ml) of dry ether (c = 0, 1 M), after cooling the flask to -20 ° C., a 2 M solution in allylmagnesium chloride ether (purchased from Aldrich) is added (0.85 ml, 1.7 mmol). After the end of the addition, the mixture is allowed to stir at 0 ° C (ice bath) an orange solution is formed, then the mixture is cooled to -78 ° C. Aldehyde

3- (trityloxy) propanai (0.474 g, 1.5 mmol) dissolved in (3 ml) of dry ether is added over a period of 10 minutes, the mixture is then stirred for 4 hours at -78 ° C.

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). We obtain 0.477 g of alcohol (R) - 1 -

(Triphenylmethoxy) hex-5-en-3-ol (colorless oil).

YId: 89% [α] _D ²² = +20.7 (c 0.94; CHC1 ₃ ); ee> 96% ^X H NMR: 7.4-7.1 (m, 15H); 5.90-5.72 (m, 1H);

5.11-5.02 (m, 2H); 3.87-3.74 (m, 1H); 3.46-3.34 (m, 1H; CH ₂ - OTr); 3.24-3.15 (m, 2H; CH ₂ -OTr); 2.88 (br s, 1H); 2.23 (t, J = 7.0, 2H); 1.85-1.70 (m, 2H). ¹³ C NMR: 36.1 (t); 47.7 (t); 62.3 (t); 70.2 (d);

80.9 (s), 117.4 (t), 127.0-127.4-127.8 (15d, 3Ph); 123.8 (d), 143.2 (3s, 3Ph).

Claims

1) Process for the stereospecific preparation of 4-hydroxyalk-1-ene compounds of configuration {R) or (5) of general formula (I):

(D in which:

X represents an oxygen atom, and in this case R is chosen from an alkyl, aryl, trityl, SiR _{3 group} [Si (Alkyl) ₃ ; If (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 a nitrogen atom, 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'A -S0 ₂ R '', -COR '' where R '' represents an alkyl group, an aryl group, or a group -CF ₃ , and n is an integer greater than or equal to 1, by a enantioselective alylation reaction of aldehydes of formula (II):

(II)

in which the X, R, R 'and n have the same meaning as in formula (I). 2) Process for the stereospecific preparation of 4-hydroxyalk-1-ene compounds of configuration {R) or (5) of general formula (I) from compounds of formula (II) according to claim 1, in which X represents an atom of oxygen and R is chosen from an alkyl, aryl, trityl, SiR ₃ [Si (Alkyl) _{3 group} ; Si (Alkyl) ₂ Ph], cyclic ether, tetrahydrofuryl, or a group -CO-R '' where R '' represents an alkyl or aryl group, and R 'represents the free oxygen doublet and n is an integer greater than or equal to 1.

3) Process for the stereospecific preparation of 4-hydroxyalk-1-ene compounds of configuration {R) or (5) of general formula (I) from compound of formula (II) according to claim 1, in which X represents an atom nitrogen, n is an integer greater than or equal to 1, and R is chosen from a hydrogen atom, an alkyl or aryl group, and

R 'represents a group -C0 ₂ R''whereR''represents an alkyl or aryl group, or

R 'represents a group -S0 ₂ R''whereR''represents an alkyl, CF ₃ or aryl group, or alternatively

R 'represents a group -COR' 'where R' 'represents an alkyl or aryl group.

4) Process for the stereospecific preparation of 4-hydroxyalk-1-ene compounds of configuration {R) or (5) of general formula (I) from compounds of formula (II) according to one of claims 1 to 3 by a enantioselective allylic titanation reaction.

5) Method according to claim 4, characterized in that an allyl-cyclopentadienyl-titanium complex is used, having a bidentate ligand 2, 3 -O-isopropylidene- 1, 1, 4, 4-tetraphenylthreitol of configuration (2i?, 3J?) Of formula (Illa) or (25.35) of formula (Illb) below:

(Illa) (Illb)

6) Method according to any one of claims 1 to 5 characterized in that it comprises the following steps: a) the reaction of an aldehyde of formula (II) with the {R, R) -cyclopentadienyl- [{ AR, trans) -2, 2-dimethyl-α, α, α ', α' - tetraphenyl-1, 3-dioxolane-4, 5-dimethanolato-O, O '-] -prop-2- enyl-titanium formula (Illa), and b) hydrolysis of the product of reaction (a) to obtain the 4-hydroxyalk-1-ene compound of configuration (S).

7) Method according to any one of claims 1 to 5 characterized in that it comprises the following stages: a) the reaction of an aldehyde of formula (II) with the {S, S) -cyclopentadienyl- [( 45, trans) -2, 2-dimethyl-α, α, α ', α' - tetraphenyl-1, 3-dioxolane-4, 5-dimethanolato-O, 0 '-] -prop-2- enyl-titanium, compound (Illb), and b) hydrolysis of the product of reaction (a) to obtain the 4-hydroxyalk-1-ene compound of configuration (R).

8) Pro c edé sel on une une lc onque s of claims 6 or 7, characterized in that in step (a) the allyl-cyclopentadienyl-titanium complex of formulas (Illa) or (Illb) in solution in ether is preferably cooled to a temperature below about -70 ° C, preferably to -78 ° C.

9) Method according to any one of claims 6 to 8, characterized in that in step (a) the aldehyde of formula (II), in a suitable solvent, is slowly added to the compound of formula (III) by appropriate means of addition.

10) Method according to any one of claims 6 to 8, characterized in that after stirring the reaction medium, for a time sufficient to allow the formation of the compound of formula (I) of configuration {R) or (5), this is hydrolyzed in step (b) at the same temperature as in step (a) by a slow addition of water to the reaction medium, then maintained at room temperature for a sufficient time, around 10 to 20 hours, preferably around 13 to 15 hours.