WO2000010985A1

WO2000010985A1 - Enantioselective chiral sulphide catalysts and a method for the manufacture thereof

Info

Publication number: WO2000010985A1
Application number: PCT/FI1999/000688
Authority: WO
Inventors: Vesa MYLLYMÄKI; Mika Lindvall; Ari Koskinen
Original assignee: Neste Chemicals Oy
Priority date: 1998-08-21
Filing date: 1999-08-20
Publication date: 2000-03-02
Also published as: FI105684B; AU5375399A; FI981795A; FI981795A0

Abstract

The invention relates to a chiral sulphide catalyst, having the structure of formula (IIa) or (IIb) or (IIc) or (IId), wherein X represents a hydrogen atom, alkyl, alkoxy, aryl or alkylaryl group, or a dialkyl nitrogen; Y is a side chain present in amino acids of naturally occurring proteins, in other non-protein amino acids, or in amino acids not occuring naturally, having formula (III), or Y forms with the nitrogen atom a ring having 4 to 10 carbon and/or hereto atoms. Further, the invention is directed to a method for producting such a catalyst, and the use of said catalyst.

Description

Enantioselective chiral sulphide catalysts and a method for the manufacture thereof

The present invention relates to enantioselective chiral sulphide catalysts useful in stereoselective epoxidations, cyclopropanizations and aziridizations, and to a method for producing them from amino acids.

Non-rasemic epoxides may be prepared from corresponding alkenes by catalytic asymmetric oxidation, or alternatively, epoxides, cyclopropanes and aziridines are also obtained in reactions of sulphur ylides with aldehydes and ketones. The Corey - Chaykovsky-reaction to produce epoxides from carbonyl compounds, wherein homochiral sulphur ylides act as mediators, comprises two steps. In the first step, the sulphide is alkylated and the sulphonium salt is separated, and then in the second step, the sulphonium salt is treated with a strong base in the presence of an aldehyde. The sulphonium salt is thus deprotonated in a basic environment to form a sulphur ylide that thereafter reacts with a carbonyl to produce an epoxide. Relative to the amount of the aldehyde, a stoichiometric amount of the chiral sulphide is normally required.

More recently, based on this Corey-Chaykovsky-reaction, a catalytic stereoselective cycle has been worked out requiring only catalytic amounts, that is, about 0.2 eq of sulphide. This cycle is based on the production of a sulphur ylide from a chiral sulphide, using a carbene as a mediator, as well as the reaction and recycling thereof in the presence of a carbonyl compound in a neutral environment. This catalytic cycle is presented in Scheme 1 below. Scheme 1:

Highest enantioselectivities are attained by using a copper catalyst as the metal catalyst, and as [R₂S] a moiety with the structure shown below:

[R₂S]

However, by using a sulphide catalyst of formula (I), only for instance the (R,R)- trans- form of stilbene oxide may be produced.

In the reaction shown by the cycle, sulphur ylide is formed as a result of the nucleophilic attack of a sulphide on a metal carbene. As for the metal carbene, it is formed in the reaction of a metal salt with a diazo compound. An ylide is thus formed as the metal is regenerated. The sulphur ylide then reacts with a carbonyl compound to form an epoxide, thus regenerating the sulphide. Accordingly, catalytic amounts of metal salts and sulphide are sufficient to provide satisfactory epoxide yields. Typically, copper acetyl acetonate, Cu(acac)₂, or rhodium acetate, Rh₂(OAc)₄, is used as the metal catalyst in the cycle, copper carbenoid being obviously sterically less hindered than the rhodium carbenoid, respectively formed, and may thus react with relatively hindered sulphides. As for the catalyst, the use of a chiral sulphide determining the stereomeric structure of the product results in the formation of non-rasemic epoxides.

The catalyst (I) used in the catalytic Corey-Chaykovsky-reaction is also employed in corresponding catalytic cyclopropanization and aziridization reactions based on sulphur ylides, allowing the production of cyclopropanes and aziridines with high enantioselecitivity .

To improve the enantioselectivity of the epoxidation reaction, several chiral sulphides have been developed according to the type of the compound being produced. Some of the disadvantages of these methods are variable enantioselectivities, time consuming reactions, low yields, as well as numerous undesired side reactions, not to mention the inconvenient multistep processes for the preparation of the sulphide catalysts. In addition, known catalysts are usually not available in both enantiomeric forms, and accordingly, only a single enantiomeric form of the product may be obtained.

The object of the invention is to provide chiral sulphide catalysts applicable to epoxidations, cyclopropanizations and aziridizations, methods for the production thereof, the use of the sulphide catalysts, as well as methods for the production of epoxides, aziridines, and cyclopropanes.

The chiral sulphide catalysts, the methods for the production and uses thereof, as well as the methods are characterized in the appended claims.

Said disadvantages of the applications of prior art may be eliminated, and the above objects may be attained with the solution of the invention. The invention is now explained in more detail. Surprisingly, it has been found that novel, highly stereo- selective chiral sulphide catalysts may be produced by using a strategy based on amino acids that takes advantage of molecular modeling. The chiral sulphides of the invention have the structure of formula (II)

(H)

wherein R , 1¹ represents a hydrogen atom, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, and R² represents a hydrogen atom, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, or R¹ and R², taken together, form a ring with 2 to 10 carbon and/or hetero atoms, and preferably, R¹ and/or R represent(s) a hydrogen atom or a methyl group, or R¹ and R² form together a cyclohexyl group; and

Z represents a hydrogen atom, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, and Z^~ represents a hydrogen atom, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, or Z¹ and Z², taken together, form a ring with 2 to 10 carbon and/or hetero atoms, and preferably, Z and/or Z~ rep- resent(s) a hydrogen atom or a methyl group; with the proviso that R¹ and/or R- each represent(s) a hydrogen atom if Z and/or Z~ represent(s) other than a hydro- gen atom, and Z and/or Z² each represent(s) a hydrogen atom if R and/or R² represent(s) other than a hydrogen atom; and

X represents a hydrogen atom, alkyl, alkoxy, aryl or alkylaryl group, or a dialkyl nitrogen, X being preferably a hydrogen atom, methyl or a tert-butoxy group; and

Y is a side chain present in amino acids of naturally occuring proteins, in other non- protein amino acids, or in amino acids not occuring naturally, having the formula (HI)

H

I Y - C - COOH (III)

I NH₂

or Y forms with the nitrogen atom a ring having 4 to 10 carbon and/or hetero atoms, the ring being preferably a cyclic lactone, and Y preferably represents an isopropyl, tert-butyl, triphenylmethyl, methylenethio or a isopropylthiol group, or Y forms with the oxygen atom a cyclic 5-membered lactone.

Chiral sulphides of the invention may be produced from amino acids present in natural proteins, other non-protein amino acids, or amino acids not occuring naturally, for instance from L-valine, L-tert-leucine ot D-penicillinamine. The steric environment of the sulphur atom suitable for the epoxidation, cyclopropanization and aziridization reactions respectively, may be optimized by altering the ketal protection R¹ and R², the substituents Z¹ and Z², and the side chain Y of the amino acid, being thus able to influence the direction of the aldehyde approach.

The method of the invention for producing chiral sulphide catalysts comprises the following steps: a) amino acid is reduced to an amino alcohol, preferably by using LiAlH , b) amino group is protected and hydroxy group is converted to thioacetate, preferably with the Mitsunobu reaction, c) thioacetate is subjected to basic hydrolysis, preferably by using KOH in methanol, to produce a protected amino thiol, d) aminothiol is deprotected, e) thiazolidine ring is formed by ketalization, f) amino group is protected to obtain the sulphide catalyst as the desired product, preferably protecting as tert-butoxy carbamate.

The production of sulphide families based on amino acids is shown in Scheme 2 below, wherein an exemplary chiral sulphide (8), rø-5-tert-butoxycarbony 1-2,2- dimethyl-4-isopropyl thiazolidine is produced on the basis of L-valine (1).

Scheme 2:

HCOC

(3)

DIAD (PH)₂? CHnCCSr Th'F

IS' '4

(8) (S,S)-rr- s^,-stilbene oxide may be produced from benzaldehyde by using the chiral sulphide(8), (S)-3-tert-butoxycarbonyl-2,2-dimethyl-4-isopropylthiazolidineprepared from L-valine, in the presence of rhodium acetate and phenyldiazomethane in dichloromethane and tert-butylmethylether as solvents, according to the Corey- Chaykovsky reaction presented in Scheme 3 below:

Scheme 3:

P CHO - o» .-

'0.2 eς.) (0,01 eq)

(S,S) -trans- stilbene oxide may be produced by this reaction with 90 % enantiomeric excess. The reaction may also be carried out by using Cu(acac)₂ as the metal catalyst.

Respectively, the preparation of the chiral sulphide (16), (S)-3-tert-butoxycarbonyl-4- tert-butyl thiazolidine using L-tert-leucine as the starting material is presented in Scheme 4 below.

Scheme 4:

LlAlH (BOC^C

HOOC . v

HC Cn^CI-

N-- h

1 1 >

DIAD >' PH)₂P

THF

2araιorrπaιcs~vαe Ξ:OH

(1 ! (16)

Further, Scheme 5 shows the preparation of the sulphide catalyst (18), (S)-3-tert- butoxycarbonyl-4-isopropyl thiazolidine, on the basis of L-valine. This Scheme is identical with Scheme 2 till compoud (6). Thereafter, the production of the sulphide (18) is carried out as follows: Scheme 5:

^πo

0 itrile

(18)

Scheme 6 below shows the preparation of the bicyclic sulphide catalyst (20), (S)-l- aza-3-oxa-7-thiabicyclo[3.3.0]-6-dimethyloctan-4-one with a known method, by using D-penicillinamine (19) as the starting material.

Scheme 6:

anhydrous MgS0₄

H₂C1₂, room temperature

' -.9) (20)

A sulphide is suitable for stereoselective epoxidation, cyclopropanization and aziridization reactions, if it allows a rapid and very enantioselective production of the desired product such as an epoxide with a high yield, without undesired side reactions. Main advantages of the sulphide catalysts of the invention include the high enan- tioselectivity and broad applicability thereof, thus making possible to solve the problems connected to yields and side reactions. The catalyst may easily be optimized for specific reactions, and if necessary, tuned for a certain substrate in a reaction.

Epoxides, cyclopropanes and aziridines may be produced with excellent yields and in high enantiomeric excess (% ee) by using the chiral sulphide catalysts based on amino acids according to the invention. The chiral sulphide catalysts based on amino acids of the invention may be produced from any amino acids. The fact that unlike amino acids contain different side chains allows the catalyst to be tuned, and thus to adjust the reaction itself for various applications. Modification of the ketal function is another possibility to tune the properties of the catalyst. There are several amino acids available both in L- and in D-form, and thus both enantiomers of the catalyst, and accordingly, of the product may be prepared. Further, amino acids are easily commercially available with low prices, and thus the production of the sulphide catalyst is not costly. The chiral sulphides of the invention may be used for the epoxidation of carbonyls, aziridization of imines, and cyclopropanization of alkenes. Preferable imines are N-tosylbenzaldimine, N-(diphenylphosphinyl)benzaldimine (DPP), and N-[/3 (trimethyl-silyl)ethanesulphonyl]benzaldimine (SES), enones being preferable alkenes. In these reactions, it is preferable to use a metal catalyst such as copper acetylacetonate, or rhodium acetate, whereas the diazo compound used may be any diazo compound, preferably, however, phenyl diazomethane, diazomethane or trimethylsilyl diazomethane, the phenyl diazomethane being most preferable. Carbonyl compounds such as aromatic aldehydes, aliphatic aldehydes, ketones, and imines are suitable substrates in this reaction. The chiral catalysts of the invention may also be used in epoxidation reactions in Simmons-Smith environment wherein sulphur ylide is formed in the reaction of sulphide with zinc carbenoid. Generally, in the method for producing epoxides, an aldehyde is reacted with a sulphur ylide formed by a sulphide catalyst and metal carbenoid, preferably rhodium, copper, rhenium or zinc carbenoid, in a solvent or solvent mixture, thus giving the desired epoxide. The metal carbenoid intermediate may be formed in different ways, for instance with a reaction of a diazo compound and Rh₂(OAc)₄ or Cu(acac)₂, or with a reaction of a dihalogen methane and dialkyl zinc.

The fact that products are obtained in high enantiomeric excess (% ee value) by using these catalysts, results from the favourable actions of several structural and energetic properties thereof. The ring structure of the catalyst is rigid, i.e. completely fixed, which is a requirement for the reactivity of only one electron pair of sulphur, and thus for high enantiomeric selectivity. The rigidity is due to the combination of the sp² nitrogen and the substituent in α-position relative thereto, allowing a normally flexible five-membered ring to be freezed into a single conformation. The steric properties of the catalyst are such that the ylide prepared therefrom has only one favourable conformation in the transition state of the reaction. Moreover, the catalyst protects one side of the ylide against the approaching aldehyde, and accordingly, the aldehyde may reach the ylide only from the other, sterically more favourable side. Owing to these factors, the reaction mediated by the catalyst produces a singe compound, i.e. the desired product.

The invention will now be illustrated with the following examples directed to some preferable embodiments thereof, without, however, wishing to limit the invention to the details presented.

Example 1

Preparation of CS)-3- ert-butoxycarbonyl-2,2-dimethyl-4-isopropylthiazolidine (8) according to Scheme 2

THF over sodium/benzophenone ketyl, dichloromethane over calcium hydride, methanol over magnesium methoxide, and acetonitrile over phosphorus pentoxide were respectively destilled before use. Acetone was dehydrated over siccone. Unless otherwise mentioned, the reactions were carried out in argon atmosphere, organic extracts were dried with Na₂SO , and solvents were evaporated with a vacuum rotary evaporator. LiAlH₄ (4.81 g, 126.75 mmol) was mixed with THF (110 ml). The mixture was cooled (10 °C), and L-valine (1) (9.92 g, 84.5 mmol) was added during 15 minutes. The reaction mixture was allowed to warm up to room temperature, and then it was refluxed for 16 hours. Diethyl ether (80 ml) and water (2 ml) were added to the mixture, and it was agitated for 2 hours. The pale gray precipitate formed was filtered, the filtrate was evaporated and the crude product obtained was purified with Kugelrohr-distillation. Waxy L-valinol (2) was obtained as the product (6.103 g, 70 %).

L-valinol (2) (5.00 g, 48.47 mmol) was dissolved in dichloromethane (18 ml). The solution was cooled down (10 °C). Di-tert-butyldicarbonate (10.07 g, 46.16 mmol) was dissolved in dichloromethane (7 ml), and the solution thus obtained was carefully added to the L-valinol solution. The reaction mixture was allowed to warm to room temperature, and mixed at that temperature for 45 minutes. The reaction mixture was washed with citric acid solution (20 % aqueous solution, 3 x 30 ml), and with sodium chloride solution (saturated aqueous solution, 40 ml). The organic layer was dried. The evaporation of the solvent gave oily BOC-L-valinol (3) with a quantitative yield (9.85 g).

Triphenyl phosphine (17.69 g, 67.40 mmol) was dissolved in THF (100 ml), and the solution obtained was cooled down (0 °C). Diisopropylazodicarboxylate (14.04 ml, 67.40 mmol) was added to this solution. The mixture was agitated for 30 minutes, during which a solid, pale brown adduct was formed. To the mixture was added the BOC-L-valinol (3) (6.85 g, 33.70 mmol) during 10 minutes, and thioacetic acid (5.02 ml, 67.40 mmol) dissolved in THF (50 ml). The mixture obtained was agitated for 1 hour (0 °C), and 4 hours at room temperature. The mixture was concentrated, the residue was dissolved in diethyl ether, and then, by cooling the solution, several batches of both triphenyl phosphine oxide and the remaining adduct were precipitated. The filtrates were evaporated, and the MPLC purification of the residue (MTBE:hexane, 1:7) gave oily thioacetate (4) (7.13 g, 81 %). Thioacetate (4) (1.50 g, 5.74 mmol), and KOH (644 mg, 11.48 mmol) were dissolved in methanol (10 ml), and the mixture was agitated for 30 minutes in room temperature. To the mixture was quickly added citric acid solution (50 % aqueous solution, 25 ml), and then dichloromethane (30 ml). The organic layer was washed with citric acid solution (20 % aqueous solution, 2x30 ml), and with sodium chloride solution (saturated aqueous solution, 30 ml). Drying of the organic layer, and evaporation of the solvent gave solid thiol (5) with a quantitative yield (1.26 g).

The thiol (5) (1.32 g, 6.02 mmol) was dissolved in methanol (10 ml). Concentrated hydrochloric acid (37 % aqueous solution, 10 ml) was added to the solution, and the mixture obtained was refluxed for 8 hours. The mixture was evaporated, and vacuum dried (24 hours), giving hydrochloride salt (6) (915 mg, 98 %) of the thiol as a solid material.

The hydrochloride salt (6) (915 mg, 5.88 mol) of the thiol was dissolved in acetone (25 ml), and 2,2-dimefhoxypropane (10 ml) was added to the solution. The reaction mixture was refluxed for 12 hours. The precipitate formed was filtered, giving solid hydrochloride salt (7) of thiazolidine (802 mg, 70 %).

The hydrochloride salt (7) of thiazolidine (673 mg, 3.44 mmol), and di-tert-butyldi- carbonate (998 mg, 4.57 mmol) were dissolved in acetonitrile (10 ml). Diisopropy- lethylamine (611 μl, 3.51 mmol) were added to the solution, and the mixture obtained was agitated for 14 days (50 °C). The mixture was evaporated, and the residue was MPLC purified, giving liquid sulphide (8) (625 mg, 70 %).

1H NMR (CDC1₃) δ:

0.89 (dd, J = 6.9 Hz, 2.2 Hz, 6H)

1.41 (s, 9H)

1.69 (s, 3H) 1.72 (s, 3H) 2.11 (m, 1H) 2.61 (dd, J = 11.8 Hz, 1.2 Hz, 1H) 3.04 (dd, J = 11.8 Hz, 5.9 Hz, 1H) 4.13 (M, 1H).

¹³C NMR (CDC1₃) δ: 19.4, 19.9, 28.4, 29.4, 30.6, 31.6, 69.3, 70.0, 79.8, 153.3.

HRMS (M + l): found 260.1696, calculated 260.1684.

R_f = 0.61 (1:3 MTBE:hexane, vanillin)

Example 2

Preparation of (S)-3-tert-butoxycarbonyl-4-tert-butyl thiazolidine (16) according to Scheme 4

THF over sodium/benzophenone ketyl, dichloromethane over calcium hydride, methanol over magnesium methoxide, and acetonitrile over phosphorus pentoxide were respectively destilled before use. Unless otherwise mentioned, the reactions were carried out in argon atmosphere, organic extracts were dried with Na₂SO₄, and solvents were evaporated with a vacuum rotary evaporator.

LiAlH₄ (9.80 g, 258.20 mmol) was dissolved THF (250 ml). The mixture was cooled (10 °C), and L-tert-leucine (9) (22.17 g, 169.04 mmol) was added during 25 minutes. The reaction mixture was allowed to warm up to room temperature, and it was then refluxed for 16 hours. Diethyl ether (160 ml) and water (3 ml) were added to the mixture, and it was agitated for 2 hours. The pale gray precipitate formed was filtered, the filtrate was evaporated and the crude product obtained was purified with Kugelrohr-distillation. Solid L-tert-leucinol (10) was obtained as the product (11.98 g, 61 %).

L-tert-leucinol (10) (5.72 g, 48.81 mmol) was dissolved in dichloromethane (20 ml). The solution was cooled down (10 °C) and a solution of di-tert-butyldicarbonate (10.15 g, 46.49 mmol) in dichloromethane (15 ml) was carefully added thereto. The reaction mixture was allowed to warm to room temperature, and mixed at that temperature for 2 hours. The reaction mixture was washed with citric acid solution (20% aqueous solution, 3x30 ml), and with sodium chloride solution (saturated aqueous solution, 40 ml). The organic layer was dried. The evaporation of the solvent gave solid BOC-L-tert-leucinol (11) with a quantitative yield (10.59 g).

Triphenyl phosphine (17.68 g, 67.40 mmol) was dissolved in THF (100 ml), and the solution obtained was cooled down (0 °C). Diisopropylazodicarboxylate (14.04 ml, 67.40 mmol) was added to this solution. The mixture was agitated for 30 minutes, during which a solid, pale brown adduct was formed. To the mixture was added the BOC-L-tert-leucinol (11) (6.85 g, 33.70 mmol) during 10 minutes, and thioacetic acid (5.02 ml, 67.40 mmol) dissolved in THF (50 ml). The mixture obtained was agitated for 1 hour (0 °C), and 4 hours at room temperature. The mixture was concentrated, the residue was dissolved in diethyl ether, and then, by cooling the solution, several batches of both triphenyl phosphine oxide and the remaining adduct were precipitated. The filtrates were evaporated, and the MPLC purification of the residue (MTBE:hexane, 1:7) gave oily thioacetate (12) (7.43 g, 80 %).

Thioacetate (12) (2.50 g, 9.08 mmol), and KOH (1.02 g, 18.16 mmol) were dissolved in methanol (20 ml), and the mixture was agitated for 30 minutes in room temperature. To the mixture was quickly added citric acid solution (50 % aqueous solution, 30 ml), and then dichloromethane (35 ml). The organic layer was washed with citric acid solution (20 % aqueous solution, 2x30 ml), and with sodium chloride solution (saturated aqueous solution, 30 ml). Drying of the organic layer, and evaporation of the solvent gave thiol (13) with a quantitative yield (2.103 g).

The thiol (13) (2.02 g, 8.66 mmol) was dissolved in methanol (15 ml). Concentrated hydrochloric acid (37 % aqueous solution, 15 ml) was added to the solution, and the mixture obtained was refluxed for 8 hours. The mixture was evaporated, and vacuum dried (10 hours), giving solid hydrochloride salt (14) of the thiol (1.59 g, 108 %) as a crude product. The hydrochloride salt (14) (200 mg, 1.18 mol) of the thiol was dissolved in ethanol (2.5 ml), and formaldehyde solution (35 % aqueous solution, 101 μl, 1, 18 mmol)) was added to the solution. The reaction mixture was agitated for 30 minutes at room temperature, and the the mixture was heated (70 °C). The mixture was evaporated, giving solid hydrochloride salt (15) (202 mg, 94 %) of thiazolidine.

The hydrochloride salt (15) (202 mg, 1.11 mmol) of thiazolidine and di-tert-butyldicarbonate (322 mg, 1.49 mmol) were dissolved in acetonitrile (5 ml). Diisopropylet- hylamine (198 μl, 1.13 mmol) were added to the solution, and the mixture obtained was agitated for 48 hours (50 °C). The mixture was evaporated, and the residue was MPLC purified, giving liquid sulphide (16) (240 mg, 88 %).

1H NMR (CDC1₃) δ: 0.93 (s, 9H) 1.46 (s, 9H)

2.96-3.12 (m, 2H) 4.02 (d, J = 10.0 Hz, 1H) 4.29 (broad, s, 1H) 5.02 (broad, s, 1H).

¹³C NMR (CDCI3) δ:

27.5, 28.9, 36.9, 50.9, 67.8, 81.2, 155.7

HRMS (M + l): found 246.1535, calculated 246.1528.

Rf = 0.65 (1:3 MTBE:hexane, vanillin) Example 3

Preparation of (S 3-tert-butoxycarbonyl-4-isopropyl thiazolidine (18) according to Scheme 5

The hydrochloride salt (6) of the thiol was prepared according to example 1. The hydrochloride salt (6) (258 mg, 1.6 mmol) of the thiol was dissolved in ethanol (2.5 ml), and formaldehyde solution (35 % aqueous solution, 1.66 mmol) was added to the solution. The mixture was agitated for 30 minutes in room temperature, and thereafter, the mixture was heated (70 °C) for 30 minutes. The mixture was evaporated and the crude product was washed several times with acetone, giving solid hydrochloride salt (17) (194 mg, 70 %) of thiazolidine.

The hydrochloride salt (17) (99 mg, 0,59 mmol) of thiazolidine and di-tert-butylcar- bonate (255 mg, 1.18 mmol) were dissolved in acetonitrile. Diisopropylethylamme (105 μl, 0.60 mmol) were added to the solution, and the mixture obtained was agitated for 24 hours at room temperature. The mixture was evaporated, and the residue was MPLC purified, giving liquid sulphide (18) (134 mg, 98 %).

1H NMR (CDC1₃) δ:

0.91 (d, 3H, J = 6.8 Hz)

0.92 (d, 3H, J = 6.7 Hz)

1.45 (s, 9H)

1.94 (septet, 1H, J = 6.8 Hz) 2.86 (dd, 1H, J = 11.0 Hz, 3.4 Hz)

2.99 (dd, 1H, J = 11.0 Hz, 6.5 Hz)

4.06 (d, 1H, J = 9.0 Hz)

4.13 (b s, 1H)

4.83 (b d, J = 9.0 Hz)

¹³C NMR (CDCL₃) δ:

18.9, 19.1, 28.3, 30.3, 47.5, 65.0, 80.3, 153.9 HRMS (M + l): found 232.1339, calculated 232.1371.

R = 0.56 (1:3 MTBE:hexane, vanillin)

Example 4

Use of (S)-3-te/?-butoxycarbonyI-4-ter/-butyl thiazolidine (16) as a mediator

Dichloromethane was distilled over calcium hydride. Unless otherwise mentioned, the reactions were carried out in argon atmosphere. Organic extracts were dried with Na₂SO . Solvents were evaporated with a vacuum rotary evaporator. Enantiomeric excesses were determined with HPLC method. In these HPLC determinations, Chiralcell OD column was used, the eluent being 5% isopropanol in hexane.

The sulphide (16) (49 mg, 0.2 mmol), and rhodium acetate (4.4 mg, 0.01 mmol) were dissolved in dichloromethane (0.5 ml), and benzaldehyde (102 l, 1.0 mmol) was added to this solution. To the reaction mixture was added phenyl diazomethane (0.18 g/ml, 1.5 mmol) dissolved in MTBE (1 ml) with an injection pump during 3 hours at room temperature. Evaporation of the solvents and MPLC-purification (dichloromethane: hexane 2:3) gave 118 mg (60.12 %) of trarø-stilbene oxide as well as 9 mg of cw-stilbene oxide (4.6 %) (cis:trans 7:93). fS,S)-trαπ5-stilbene oxide was obtained in 26 % enantiomeric excess. Retention times were 8.48 minutes for the (S,S) form, and 13.16 minutes for the (R,R) form; flow rate was 0.9 ml/min.

Example 5

Use of (S)-3-te/ϊ-butoxycarbonyl-2,2-dimethyl-4-isopropyl thiazolidine (8) as a mediator

The sulphide (8) (30 mg, 0.12 mmol), and rhodium acetate (2.6 mg, 0.006 mmol) were dissolved in dichloromethane (0.5 ml), and benzaldehyde (59 μl, 0.58 mmol) was added to this solution. To the reaction mixture was added phenyl diazomethane (0.1 g/ml, 0.87 mmol) dissolved in MTBE (1 ml) with an injection pump during 3 hours at room temperature. The reaction gave (S,S)-tr< 5'-stilbene oxide with 90 % enantiomeric excess. Retention times were 7.79 minutes for the (S,S) form, and 13.83 minutes for the (R,R) form; flow rate was 1.0 ml/min.

Example 6

Use of (S 3-tert-butoxycarbonyl-4-isopropyI thiazolidine (18) as a mediator

The sulphide (18) (46 mg, 0.20 mmol), and rhodium acetate (4 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 ml), and benzaldehyde (102 μl, 1.0 mmol) was added to this solution.

To the reaction mixture obtained was added phenyl diazomethane (0.17 g/ml, 1.50 mmol) dissolved in MTBE (1 ml) with an injection pump during 3 hours at room temperature. Evaporation of the solvents and MPLC -purification (dichloromethane: hexane 2:3) gave 44 mg (22 %) of trα/u-stilbene oxide as well as 6 mg of cw-stilbene oxide (3 %) (cis:trans 12:88). (S,S)-trα/w- stilbene oxide was obtained in 19 % enantiomeric excess.

Example 7

Preparation of ( S)- 1 -aza-3-oxa-7-thiabicyclo [3.3.0] -6- dimethyloctan-4-one

The sulphide (20) was prepared with the known method of Scheme 6.

D-penicillinamine (19) (4.55 g, 30.5 mmol) was dissolved in dichloromethane (250 ml), and dry MgSO₄ (4.0 g, 33.0 mmol) and paraformaldehyde (2.0 g, 66.6 mmol) were added thereto. The mixture was agitated at room temperature for 4 days, and thereafter, paraformaldehyde (2.0 g, 66.6 mmol) was again added thereto. Agitation was continued for 3 days, and then the reaction mixture was filtered through a silica column, eluting with dichloromethane. Purification gave pure, oily sulphide (20) (5.28 g, 99.9 %). Spectral data are consistent with those previously published (Trentman, W. , Mehler, T. , Martens, J. Tetrahedron Asymmetry, 1997, 8, 2033-2043).

Example 8

Use of (S)-l-aza-3-oxa-7-thiabicyclo[3.3.0]-6-dimethyloctan-4-one (20) as a mediator

The sulphide (20) [(S)-l-aza-3-oxa-7-thiabicyclo[3.3.0]-6-dimethyloctan-4-one] was used as a catalyst (mediator) in the Corey-Chaykovsky-epoxidation as follows:

The sulphide (20) (35 mg, 0.20 mmol), and rhodium acetate (4 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 ml), and benzaldehyde (102 μl, 1.00 mmol) was added to this solution. To the reaction mixture was added phenyl diazomethane (0.17 g/ml, 1.50 mmol) dissolved in MTBE (1 ml) with an injection pump during 3 hours at room temperature. Evaporation of the solvents and MPLC-purification (dichloromethane: hexane 2:3) gave 80 mg (40,76 %) of tr zw-stilbene oxide. (S,S)- trαns-stilbene oxide was obtained in 34 % enantiomeric excess.

Claims

1. Chiral sulphide catalyst, characterized in that said sulphide catalyst has the structure of formula (II)

(ID

wherein R¹ represents a hydrogen atom, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, and R² represents a hydrogen atom, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, or R¹ and R², taken together, form a ring with 2 to 10 carbon and/or hetero atoms; and

Z¹ represents a hydrogen atom, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, and Z² represents a hydrogen atom, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, or Z¹ and Z², taken together, form a ring with 2 to 10 carbon and/or hetero atoms; with the proviso that R¹ and/or R² each represent(s) a hydrogen atom if Z¹ and/or Z² represent(s) other than a hydrogen atom, and Z¹ and/or Z² each represent(s) a hydrogen atom if R¹ and/or R² represent(s) other than a hydrogen atom; X represents a hydrogen atom, alkyl, alkoxy, aryl or alkylaryl group, or a dialkyl nitrogen;

H

I Y - C - COOH (III)

I

NH₂

or Y forms with the nitrogen atom a ring having 4 to 10 carbon and/or hetero atoms.

2. Sulphide catalyst of claim 1, characterized in that R¹ and/or R² represent(s) a hydrogen atom or a methyl group, or R¹ and R² form together a cyclohexyl group, Z¹ and/ or Z² represent(s) a hydrogen atom or a methyl group, X is a hydrogen atom, methyl or a tert-butoxy group; and Y is an isopropyl, tert-butyl, triphenylmet- hyl, methylenethio or a isopropylthio group, or Y forms with the nitrogen atom a cyclic lactone, preferably a cyclic 5-membered lactone.

3. Sulphide catalyst of claim 1 or 2, characterized in that said catalyst is (S)-3-tert- butoxycarbonyl-2,2-dimethyl-4-isopropylthiazolidine,or(S)-3-tert-butoxycarbonyl-4- tert-butyl thiazolidine , or (S) -3-tert-butoxycarbonyl-4-isopropyl thiazolidine , or (S)- 1 - aza-3-oxa-7-thiabicyclo[3.3.0]-6-dimethyloctan-4-one.

4. Method for producing chiral sulphide catalysts, characterized in that said method comprises the following steps: a) amino acid is reduced to an amino alcohol, b) amino group is protected and hydroxy group is converted to thioacetate, c) thioacetate is subjected to basic hydrolysis to produce a protected aminothiol, d) aminothiol is deprotected, e) thiazolidine ring is formed by ketalization, f) amino group is protected to obtain the sulphide catalyst as the desired product.

5. Method of claim 4, characterized in that in step a), the reduction is carried out with LiAlH₄, in step b), the hydroxy group is converted to thioacetate by using the

Mitsunobu reaction, in step c), the basic hydrolysis is carried out with KOH in methanol, and in step f), the amino group is protected as tert-butoxy carbamate.

6. Use of the sulphide catalyst of any of claims 1—3, or prepared according to the method of claim 4 or 5 for stereoselective epoxidation, cyclopropanization and aziridization reactions.

7. Method for producing epoxides, characterized in that an aldehyde is reacted with a sulphur ylide formed by the sulphide catalyst of any of claims 1—3, or prepared according to the method of claim 4 or 5, and a metal carbenoid, preferably rhodium, copper, rhenium or zinc carbenoid, in a solvent or solvent mixture, thus giving the desired epoxide.

8. Method for producing aziridines, characterized in that an imine is reacted with a diazo compound in the presence of the sulphide catalyst of any of claims 1—3, or prepared according to the method of claim 4 or 5, and a metal catalyst, preferably a rhodium, rhenium or copper catalyst, in a solvent or solvent mixture, thus giving the desired aziridine.

9. Method for producing cyclopropanes, characterized in that an alkene is reacted with a diazo compound in the presence of the sulphide catalyst of any of claims 1—3, or prepared according to the method of claim 4 or 5, and a metal catalyst, preferably a rhodium, rhenium or copper catalyst, in a solvent or solvent mixture, thus giving the desired cyclopropane. AMENDED CLAIMS

[received by the International Bureau on 20 January 2000 (20.01.00); original claims 1-9 replaced by new claims 1-11 (5 pages)]

1. Chiral sulphide catalyst, characterized in that said sulphide catalyst has the structure of formula (Ila) or (lib)

(Ila) (lib)

wherein R ,ι¹ represents a hydrogen atom, an alkyl. an aryl, heteroaryl or halogenated aryl group substituted with an alkyl. aryl, alkylaryl, nitro or cyano group, and R~ represents a hydrogen atom, an alkyl, an aryl, heteroaryl or halogenated aryl group substimted with an alkyl, aryl. alkylaryl, nitro or cyano group, or R¹ and R-, taken together, form a ring with 2 to 10 carbon and/or hetero atoms; and

Z represents a hydrogen atom, an alkyl, an aryl or a heteroaryl group, and Z~ represents a hydrogen atom, an alkyl, an aryl, or a heteroaryl group, with the proviso that R 1 and/or R each represent(s) a hydrogen atom if Z 1 and/or Z~ represent(s) other than a hydrogen atom, and Z¹ and/or Z² each represent(s) a hydrogen atom if R¹ and/or R- represent(s) other than a hydrogen atom;

X represents an alkyl, alkoxy, aryl or alkylaryl group, or a dialkyl nitrogen;

Y is a side chain present in an amino acid selected from L-valine, L-tert-leucine or D-penicillinamine having the formula (III) H

I Y - C - COOH (III)

I NH₂

2. Sulphide catalyst of claim 1 , characterized in that R¹ and/or R² represent(s) a hydrogen atom or a methyl group, or R¹ and R² form together a cyclohexyl group, Z¹ and/or Z² represent(s) a hydrogen atom or a methyl group, X is a methyl or a tert-butoxy group; and Y is an isopropyl, tert-butyl, triphenylmethyl, methylenethio or a isopropylthio group.

3. Sulphide catalyst of claim 1 or 2, characterized in that said catalyst is S)-3-tert- butoxycarbonyl-2,2-dimethyl-4-isopropylthiazolidine,or(S)-3-tert-butoxycarbonyl-4- tert-butyl thiazolidine, or (S)-3-tert-butoxycarbonyl-4-isopropyl thiazolidine, or(S)-l- aza-3-oxa-7-thiabicyclo[3.3.0]-6-dimethyloctan-4-one.

4. Method for producing chiral sulphide catalysts, characterized in that said method comprises the following steps: a) amino acid is reduced to an amino alcohol, b) amino group is protected and hydro xy group is converted to thioacetate, c) thioacetate is subjected to basic hydrolysis to produce a protected aminothiol, d) aminothiol is deprotected, e) thiazolidine ring is formed by ketalization, f) amino group is protected to obtain the sulphide catalyst as the desired product.

5. Method of claim 4, characterized in that in step a), the reduction is carried out with LiAlH₄, in step b), the hydro xy group is converted to thioacetate by using the Mitsunobu reaction, in step c), the basic hydrolysis is carried out with KOH in methanol, and in step f), the amino group is protected as tert-butoxy carbamate.

6. Use of a chiral sulphide catalyst for stereoselective epoxidation, for cyclopro- panation and for aziridization reactions, characterized in that the chiral sulphide catalyst has the structure of formula (Ila), (lib), (lie) or (lid)

wherein R l l represents a hydrogen atom, an alkyl, an aryl, heteroaryl or a halo- genated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, and R" represents a hydrogen atom, an alkyl, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, or R¹ and R², taken together form a ring with 2 to 10 carbon and/or hetero atoms; and

Z represents a hydrogen atom, an alkyl, an aryl, heteroaryl or a halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, and Z² represents a hydrogen atom, an alkyl, an aryl, heteroaryl or halogenated aryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, or Z¹ and Z², taken together, form a ring with 2 to 10 carbon and/or heteroatoms; with the proviso that R¹ and/or R² each represent(s) a hydrogen atom if Z¹ and/or Z~ represent(s) other than a hydrogen atom, and Z¹ and/or Z~ each represent(s) a hydrogen atom if R¹ and/or R" represent(s) other than a hydrogen atom; X represents a hydrogen atom, alkyl, alkoxy, aryl or alkylaryl group, or a dialkyl nitrogen;

Y is a side chain in amino acids of naturally occurring proteins, in other non-protein amino acids, or in amino acids not occurring naturally, having the formula (III)

H

I Y - C - COOH (III) I

NH₂

7. Use of claim 6, characterized in that R¹ and/or R² represent(s) a hydrogen atom or a methyl group, or R¹ and R² form together a cyclohexyl group, Z¹ and/or Z² represent(s) a hydrogen atom or a methyl group, X is a methyl or a tert-butoxy group; and Y is an isopropyl, tert-butyl, triphenylmethyl, methylenethio or a isopropylthio group.

8. Use of claim 6 or 7, characterized in that said catalyst is (SJ-3-tert-butoxycar- bonyl-2, 2-dimethyl-4-isopropyl thiazolidine, or S -3-tert-butoxycarbonyl-4-tert-butyl thiazolidine, or (S)-3-tert-butoxycarbonyl-4-isopropyl thiazolidine, or (S)-l-aza-3- oxa-7-thiabicyclo[3.3.0] -6-dimethy loctan-4-one .

9. Method for producing epoxides, characterized in that an aldehyde is reacted with a sulphur ylide formed by the sulphide catalyst of any of claims 1—3, or prepared according to the method of claim 4 or 5, and a metal carbenoid, preferably rhodium, copper, rhenium or zinc carbenoid, in a solvent or solvent mixture, thus giving the desired epoxide.

10. Method for producing aziridines, characterized in that an imine is reacted with a diazo compound in the presence of the sulphide catalyst of any of claims 1—3, or prepared according to the method of claim 4 or 5, and a metal catalyst, preferably a rhodium, rhenium or copper catalyst, in a solvent or solvent mixture, thus giving the desired aziridine.

11. Method for producing cyclopropanes, characterized in that an alkene is reacted with a diazo compound in the presence of the sulphide catalyst of any of claims 1—3, or prepared according to the method of claim 4 or 5, and a metal catalyst, preferably a rhodium, rhenium or copper catalyst, in a solvent or solvent mixture, thus giving the desired cyclopropane.