FI105684B - Enantioselective chiral sulfide catalysts, process for their preparation and their use in stereoselective epoxidation, cyclopropanization and aziridination reactions - Google Patents

Description

105684

Enantioselective Chiral Sulfide Catalysts, Process for their Preparation and their Use in Stereoselective Epoxidation, Cyclopropanization, and Acididation Reactions

The present invention relates to enantioselective chiral sulfide catalysts for stereoselective epoxidation, cyclopropanation and aziridination and to a process for their preparation from amino acids.

Non-racemic epoxides can be prepared from the corresponding alkenes by catalytic asymmetric oxidation, or alternatively epoxides, cyclopropanes and aziridines can also be obtained by reaction of sulfur ylides with aldehydes and ketones. In the Corey-Chaykovs-ky reaction, the preparation of epoxides from carbonyl compounds, acting as mediators of homochiral sulfur bonds, comprises two steps, the first of which involves the alkylation of the sulfide and the isolation of the sulfonium salt in the second step; :; the phonium salt is treated with a strong base in the presence of aldehyde. Deprotonation of the sulphonium salt under basic conditions then results in the formation of sulfur ylide; which then reacts with the carbonyl to form the epoxide. A stoichiometric *: * ·: amount of chiral sulfide relative to the amount of aldehyde is usually required.

: X: 25 · Later, a Corey-Chaykovsky reaction catalytic stereoselective cycle has been developed that requires only catalytic amounts of about 0.2 eq of sulfide. This «· · -: ..

. '* Cycle is based on the production of sulfuride from the chiral sulfide while the carbene acts as a mediator. . __--- -. .

* · V, for reaction and recycling in the presence of a carbonyl compound under neutral conditions. The catalytic cycle is illustrated in Scheme 1 below.

«41« I

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I I I I

I I 11 «I II · 2 105684

Scheme 1: s. | _mt Λ ”i -" '7 \ ^ y a [RjS] Rh = CHff 10

The highest enantioselectivities have been achieved when the metal catalyst is a copper catalyst and the structure of [R2S] is as follows (I): 15!;! ·! ® • · 20 [r2si • «« · • · «· ·

However, using only the sulfide catalyst of formula (I), only the (R, R) -trcms form of, for example, stilbene oxide can be prepared.

In the reaction indicated by the cycle, sulfuride formation occurs as a result of sulfide. · * ·. nucleophilic attack on metal carbene, again formed by the metal salt • · · * ·. ···. and the diazo compound reacting with one another. The ylide is thus formed by the regeneration of the metal. in this context. The sulfuride then reacts with the carbonyl compound to form the epoxide and • t; regenerates sulfidine. As a result, catalytic amounts of metal salts and sulfide are * * f 30 sufficient to provide satisfactory epoxy yields. Typically, the metal catalyst used in the cycle is copper acetylacetonate Cu (acac) 2 or rhodium acetate Rh2 (OAc> 4, 105684) of which the copper carboxylic acid is apparently less sterically hindered than the corresponding rhodium carbenoid and can react with the sulfuric acid non-racemic epoxides.

5

Catalyst (I) used in the Corey-Chaykovsky catalytic reaction has also been used in the corresponding catalytic sulfuride-based cyclopropanation and aziridination reactions, which have produced high enantioselectivity of cyclopropanes and aziridines.

10

In order to improve the enantioselectivity of the epoxidation reaction, various chiral sulfides have been developed, depending on the kind of products being made. Problems with these processes have been variations in enantioselectivity, slow reactions, poor yields, and numerous undesirable side reactions, on the one hand, and multistep, long processes for the preparation of sulfide catalysts, on the other. In addition, the known catalysts are generally not available as both enantiomers, which means that the product can only be prepared as one enantiomer. enantiomers.

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.! The object of the invention are chiral sulfide catalysts suitable for epoxidation, cyclopropanization and aziridination, processes for their preparation, use of sulfide catalysts, and processes for the preparation of epoxides, aziridines and cyclopropanes.

Ill • · • · · · · ·

The chiral sulfide catalysts of the invention, the process for their preparation, their use and the processes are characterized by what is stated in the patent claims.

The above mentioned disadvantages of the prior art applications can be eliminated and «· a '. the objectives defined above are achieved by a solution according to the invention. In the following • i. the invention will be explained in more detail. Surprisingly, it has been found that novel highly α---30 stereoselective chiral sulfide catalysts can be prepared by an amino acid-based strategy that harnesses the benefits of molecular modeling.

105684 4

The chiral sulfides of the invention have the structure of formula (II) wherein R 1 is a hydrogen atom, an aryl, heteroaryl or haloaryl group substituted with an alkyl, aryl, alkylaryl, nitro or cyano group and R 2 is a hydrogen atom, an aryl, heteroaryl or haloaryl group substituted by an alkyl, aryl, alkylaryl, nitro or cyano group or R 1 and R 2 together form a ring comprising from 2 to 10 carbon atoms and / or heteroatoms, preferably R 1 and / or R 2 is a hydrogen atom or a methyl group or R 1 and R 2 together form a cyclohexyl group;

I I I I

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I I I

X is an alkyl, alkoxy, aryl or alkylaryl group or a dialkyl nitrogen and preferably X. , is a methyl or tert-butoxy group; and 20 Y is the formula (III)

B

·: · * I

Y - C - COOH (III): · · · · · · · · · · · · · · · · · · · · I · · · · · · · · · · · side chain of amino acids in natural proteins, other non-protein amino acids or non-naturally occurring amino acids, and preferably Y is isopropyl- , a tert-butyl or triphenylmethyl group.

5, 105684

The chiral sulfides of the invention may be prepared starting from amino acids present in natural proteins, other non-protein amino acids or non-naturally occurring amino acids such as, for example, L-valine or L-terleucine. By converting the ketal protecting R 1 and R 2 and the amino acid side chain Y, the steric environment of the sulfur atom suitable for the epoxidation, cyclopropanation or aziridination reaction can be optimized and affect the aldehyde approach direction.

The process for the preparation of chiral sulfide catalysts of the invention comprises the following steps: a) reduction of the amino acid to amino alcohol and preferably reduction with LiAlH4, b) protection of the amino group and conversion of the hydroxy group to thioacetate, preferably by Mitsunobu reaction, c) d) deprotecting the aminothiol j) · (e) forming a thiazolidine ring by ketalization • · • · f) protecting the amino group to yield the desired sulfide catalyst and

M1 · · · *. * * 25 is preferably carried out as tert-butoxycarbamate.

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f · «« · • · «· · · · · 105684 6

The preparation of amino acid-based sulfide families is illustrated in Scheme 2 below, which exemplifies the preparation of chiral sulfide (8) based on L-valine (1), η 5 -, 5-tert-butoxycarbonyl-2,2-dimethyl-4-isopropyl-thiazolidine.

5 Scheme 2: HOOC ^ J ^ i THF HO Y ^ CH2CI2 HO i (Qh2 F) h2 nh 10 (1) (2) BOC ^

DIAD

(PH) 3P

CH3COSH

THF

I 1: 1 MeOHxonc. HCl JL KOH

15 ÄH2HCI ίΗ Me0H

/ g \ 600 BOO

(5) (4)

Iff

III

'' '5: 2 Acetone: 2,2-DMP

f f r 1 1 f 1 r r r 1 1: V; 20 I 1

: '; ': (BOCfeO

^ NH-HCl - S &

'BOC

0.: (7) (8) • · · · 25 · * • · · · ...: L-valine sulphide (8) ('S,? - 5 -? - butoxycarbonyl -2,2-dimethyl-4-isopropyl ·, ··· pyl-thiazolidine can be prepared from (S, S) -trans-trans-stilbene oxide from benzaldehyde in the presence of rhodium acetate and phenyldiazomethane using dichloromethane and tert-butylmethyl ether as the solvents, shown in Scheme 3 below: 7 105684

Scheme 3: N2CHPh, 1.5eq.

PhCHO + S jq + Rh 2 (OAc) 4 -—— A ^ Ph 'boc mtbe / dcm Phx 5 (1 eq.) (0.2 eq.) (0.01 eq.)

The reaction can produce (S, SJ-trans -stilbene oxide with 90% aeration in an enantiomeric excess. The reaction can also be carried out using 10 Cu (acac) 2 as the metal catalyst.

Similarly, Scheme 4 below shows the preparation of (S) -3-tert-butoxycarbonyl-4-tert-butyl-thiazolidine chiral sulfide (16) starting from L-tert-butyl leucine.

15 Scheme 4: • · t · ·

H00CA ho ^ V H0AC

• · - THF - ΟΠ2ν »2 · i: · nh2 nh2 nh

(9) (1 °) BOC

(11)

20 DIAD

(PH) 3P

·. · CH3COSH

THF

• · '· * · 1: 1 MeOH: conc.HCI ___ KOH ^; ·, ^ H3 + cr Sh Me0H Sh 25 M4, · ··· · boc boc (14) (13) (12) • i * · ·

paraformaldehyde E tO H

- vi 30 (BOC) 20 ^

S \ ^ NH2 + C | - DIPEA S N

acetonitrile - ^ BOC

(15) (16) 105684 8

The sulfide suitable for the stereoselective epoxidation, cyclopropanization and azidation reaction is required to be able to produce the desired product such as epoxide in a highly enantioselective manner, without undesirable side reactions, in a rapid and good yield.

5

The major advantages of the sulfide catalysts according to the invention are the high enantioselectivity and wide variability that can solve the problems of yields and side reactions. The catalyst can easily be optimized for specific reactions and, if necessary, fine-tuned for a particular substrate in each reaction.

10

The amino acid-based chiral sulfide catalysts of the invention can be prepared in excellent yields and with good enantiomeric excess (% ee) of epoxides, cyclopropanes and aziridines. The amino acid-based chiral sulfide catalysts of the invention can be prepared from any amino acid.

15 Because different amino acids contain different side chains, this enables: fine-tuning of the catalyst structure and hence the reaction itself for different applications. Modification of the ketal function also provides another opportunity to fine-tune the properties of the catalyst: '· ... A number of amino acids are available in both the L and D form, allowing both the catalyst and the two enantiomers of the products to be prepared. Further, amino acids are readily available commercially and are inexpensive, so production of the sulfide catalyst does not entail high manufacturing costs. The chiral sulfides of the invention may be used for epoxidation of carbonyls, azididines of imines, and cyclopropanation reactions of alkenes.

Preferred imines include N-tosylbenzaldimine, N- (diphenylphosphinyl) benzaldimine • (DPP) and N - [[3- (trimethylsilyl) ethanesulfonyl] benzaldimine (SES), and preferred · · · alkenes are enones. In these reactions, it is preferable to use a metal catalyst such as *: ·: copper acetylacetonate or rhodium acetate, and any diazo compound can be used as the diazo compound, however preferably phenyldiazomethane, diazomethane or trimethylsilyldiazomethane and most preferably phenyldiazomethane. Carbonyl compounds such as aromatic aldehydes, aliphatic aldehydes, ketones and imines are suitable for the subtraction-30 reaction. The chiral sulfide catalysts of the invention can also be used in epoxidation reactions under the Simmons-Smith conditions where sulfuride is formed in the reaction between sulfide and zinc carbenoid. Generally, in a process for preparing epoxides, the aldehyde is reacted with a sulfide catalyst of a sulfide catalyst and a metal carboxide, preferably rhodium, copper, rhenium or zinc, as a solvent or mixture of solvents to give the desired epoxide. The intermediate metal carbenoid may be formed in various ways, such as in the reaction of the diazo compound with Rh 2 (OAc) 4 or Cu (acac) 2 or in the reaction between dihalomethane and dialkyl zinc.

The fact that catalysts can be used to prepare products in high enantiomeric excess (% ee value) is due to several favorable synergies between the structural and energetic properties of the catalysts. The ring structure of the catalyst is rigid, i.e. fully defined, which is a prerequisite only for the reactivity of the second sulfur electron pair and for its still high enantioselectivity. The stiffness is due to the combination of the sp2 nitrogen and its 15a substituent with which a normally flexible: five ring is frozen in one conformation. The catalyst has such essential properties that the ylide produced therefrom has only one favorable conformation in the transition state of the reaction. Moreover, the catalyst protect the other side of the ylide aldehyde Approaches "·" · wherein the aldehyde may approach the ylide a sterically more favorable side of these i ·. V. 20 because of the combined effect of the factors of the catalyst-mediated reaction produces only one, of the desired I I * 'of the final product.

The invention will now be illustrated by a description of some preferred embodiments. however, the invention is not intended to be limited to details.

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·. ·. · 25 • · · * · * »• · · t • t • · l f · i · ·. · I __ 10 105684

Example 1 Preparation of (S) -3-tert-butoxycarbonyl-2,2-dimethyl-4-isopropyl-thiazolidine (8) according to Scheme 2. use. The acetone was dried over the sycon. Reactions were carried out under argon, unless otherwise stated, the organic extracts were dried over 28 28 (4 4) and the evaporations were performed on a vacuum rotary evaporator.

LlAlH 4 (4.81 g, 126.75 mmol) was stirred in THF (110 mL). The mixture was cooled (10) and L-valine (1) (9.92 g, 84.5 mmol) was added over 15 min. The reaction mixture was allowed to warm to room temperature and then refluxed for 16 h. To diethyl ether (80 mL) and water (2 mL) was added to the mixture 15 and stirred for 2 h. The resulting light gray precipitate was filtered, the filtrate evaporated and the resulting crude product purified Kugelrohrdistillation. The product was obtained as a waxy L-valinol (2) (6.103 g, 70%).

L-Valinol (2) (5.00 g, 48.47 mmol) was dissolved in dichloromethane (18 mL). The solution • · 20 was cooled (10 ° C). Di-tert-butyl dicarbonate (10.07 g, 46.16 mmol) was dissolved in dichloromethane (7 mL) and the resulting solution was carefully added to the L-valinol solution.

The reaction mixture was allowed to warm to room temperature where it was stirred for 45 min.

• · ·

The reaction mixture was washed with citric acid solution (20% aqueous solution, 3x30 mL) and sodium chloride. dilute solution (saturated aqueous solution, 40 ml). The organic layer was dried. Evaporation of solvent 9,999,999 '· * ·' gave oily BOC-L-valinol (3) in quantitative yield (9.85 g).

• 9 9 9 999 9 * · “· Triphenylphosphine (17.69 g, 67.40 mmol) was dissolved in THF (100 mL) and the resulting solution 9 9 Ύ ′! was cooled (0 ° C). Diisopropyl azodicarboxylate (14.04 mL, 67.40 mmol) was added to the solution. The mixture was stirred for 30 min, during which time a solid light brown adduct 30 was formed. To this mixture was added BOC-L-valinol (3) (6.85 g, 33.70 mmol) and thioacetic acid (5.02 mL, 67.40 mmol) dissolved in THF (50 mL) over 10 min. The resulting 11 105684 mixture was stirred for 1 h (0 ° C) and 4 h at room temperature. The mixture was evaporated and the residue was dissolved in diethyl ether, from which both triphenylphosphine oxide and the remaining adduct were precipitated several times by cooling. The filtrates were evaporated and the residue was purified by MPLC purification (MTBE: hexane, 1: 7) to give an oily thioacetate (4) (7.13 g, 5%).

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 stirred for 30 min at room temperature. Citric acid solution (50% aqueous solution, 25 mL) was added quickly, followed by dichloromethane 10 (30 mL). The organic layer was washed with citric acid solution (20% aqueous solution, 2 x 30 ml) and brine (saturated aqueous solution, 30 ml). Drying of the organic layer and evaporation of the solvent gave the solid thiol (5) in quantitative yield (1.26 g).

The thiol (5) (1.32 g, 6.02 mmol) was dissolved in methanol (10 mL). To the solution was added concentrated «- --------- j; hydrochloric acid (37% aqueous solution, 10 mL) and the mixture was refluxed for 8 h. Evaporation of the mixture i * V '* and vacuum drying (24 h) afforded the solid thiol hydrochloride salt (6) (915 mg, Γ' * 98%).

The thiol hydrochloride salt (6) (915 mg, 5.88 mmol) was dissolved in acetone (25 mL) and 2,2-dimethoxypropane (10 mL) was added to the III ______________ mL). The mixture was refluxed for 12 h. The resulting precipitate was filtered to give the solid thiazolidine hydrochloride salt (7) (802 mg, :: 70%).

• · ·

• · I

• ___ _______ I t • · · · '· * 25 Thiazolidine hydrochloride salt (7) (673 mg, 3.44 mmol) and di-ie / t-butyl dicarbonate • 9 ----------' '· '(998 mg, 4.57 mmol) was dissolved in acetonitrile (10 mL). To the solution was added diisopropyl * -ethylamine (611 μΐ, 3.51 mmol) and the resulting mixture was stirred for 14 d (50 ° C). Evaporation of the mixture and purification of the residue by MPLC gave liquid sulfide (8) (625 mg, 70%).

Λ: 105.894 δ NMR (CDCl3) δ: 0.89 (dd, J = 6.9 Hz, 2.2 Hz, 6H) 1.41 (s, 9H) 1.69 (s, 3H) δ, 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).

13CNMR (CDCl3) δ: 19.4, 19.9, 28.4, 29.4, 30.6, 31.6, 69.3, 70.0, 79.8, 153.3.

HRMS (M + 1); measured 260.1696, calculated 260.1684.

15

R t = 0.61 (1: 3 MTBE: hexane, vanillin).

EXAMPLE 2 Preparation of II («20 (S) -3-tert-butoxycarbonyl-4-tert-butyl-thiazolidine (16) · '·' According to Scheme 4 * * * <«· THF was distilled over sodium / benzophenone ketyl, dichloromethane calcium hydride · · M, methanol over magnesium methoxide and acetonitrile over phosphorous pentoxide before use. otherwise, the organic extracts were dried over Na 2 SO 4 and evaporated on a vacuum rotary evaporator.

L1AIH4 (9.80 g, 258.20 mmol) was dissolved in THF (250 mL). The mixture was cooled to? (10 ° C) and L-tert -Leucine (9) (22.17 g, 169.04 mmol) was added over 25 min. The reaction mixture was allowed to warm to room temperature, then refluxed for 16 h. Diethyl ether (160 mL) and water (3 mL) were added to the mixture and stirred for 2 h.

13 105684

The resulting light gray precipitate was filtered, the filtrate evaporated and the resulting crude product was purified by Kugelrohr distillation. The product was obtained as solid L-terf leucinol (10) (11.98 g, 61%).

5-L-terilucleolol (10) (5.72 g, 48.81 mmol) was dissolved in dichloromethane (20 mL). The mixture was cooled (10) and a solution of di- tert -butyl dicarbonate (10.15 g, 46.49 mmol) in dichloromethane (15 mL) was carefully added. The reaction mixture was allowed to warm to room temperature where it was stirred for 2 h. The reaction mixture was washed with citric acid solution (20% aqueous solution, 3x30 ml) and brine (saturated aqueous solution, 40 ml). The organic layer was dried. Evaporation of the solvent gave BOC-L-terf-leucinol solid (11) in quantitative yield (10.59 g).

Triphenylphosphine (17.68 g, 67.40 mmol) was dissolved in THF (100 mL) and the solution was cooled (0 ° C). Diisopropyl azodicarboxylate (DIAD) (14.04 mL, 67.40 mmol) was added to the solution. The mixture was stirred for 30 min during which time a solid, light brown adduct was formed. To this mixture was added BOC-L-tert-leucinol (11) (6.85 g, 33.70 µmol) and thioacetic acid (5.02 mL, 67.40 mmol) dissolved in THF (10 min). 50 ml). The resultant

III

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The mixture was stirred for 1 h (0 ° C) and for 4 h at room temperature. The mixture was evaporated and the residue was dissolved in diethyl ether, which was cooled several times by precipitation and triphenyl

I I I I I

j 20 phosphine oxide and the remaining adduct. The filtrates were evaporated, and the residue

• € I

Purification by MPLC (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 Me. 25 tananol (20 mL) and the mixture was stirred for 30 min at room temperature. Citric acid solution (50% aqueous solution, 30 ml) was rapidly added followed by dichloromethane (35 ml). The organic layer was washed with citric acid solution (20% aqueous solution, 2 x 30 ml) and brine (saturated aqueous solution, 30 ml). Drying of the organic layer and evaporation of the solvent gave thiol (13) in quantitative yield (2.103 g).

30 105684 14

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 was refluxed for 8 h. Evaporation of the mixture and vacuum drying (10 h) gave the crude solid thiol hydrochloride salt (14) (1.59 g, 108%).

5

The thiol hydrochloride salt (14) (200 mg, 1.18 mmol) was dissolved in ethanol (2.5 mL) and formaldehyde solution (35% aqueous solution, 101 µL, 1.18 mmol) was added. After stirring for 30 min at room temperature, the mixture was heated (70 ° C) for 30 min. Evaporation of the mixture gave the solid thiazolidine hydrochloride salt (15) (202 mg, 10 94%).

The thiazolidine hydrochloride salt (15) (202 mg, 1.11 mmol) and di-tert-butyl dicarbonate (322 mg, 1.49 mmol) were dissolved in acetonitrile (5 mL). Diisopropylethylamine (198 μΐ, 1.13 mmol) was added to the solution and the resulting mixture was stirred for 48 h (50 ° C). Evaporation of the mixture and purification of the residue by MPLC gave liquid sulfide (16) (240 mg, 88%).

· • • · • 0 0:: ΧΗ NMR (CDCl)) δ: 0.93 (s, 9H) δ 1.46 (s, 9H) ′ l!; , 2H) 4.02 (d, J = 10.0 Hz, 1H) 4.29 (broad, s, 1H)? 10.02 (broad, s, 1H).

13 C NMR (CDCl 3) δ: 27.5, 28.9, 36.9, 50.9, 67.8, 81.2, 155.7. · HRMS (M + 1); measured 246.1535, calculated 246.1528.

30

R f = 0.65 (1: 3 MTBE: hexane, vanillin)

Example 3 Use of 105684 (5) -3-tert-Butoxycarbonyl-4-tert-butyl-thiazolidine (16) as Mediator 5 Dichloromethane was distilled over calcium hydride. Reactions were carried out under argon unless otherwise noted. The organic extracts were dried over Na 2 SO 4. Evaporations were performed on a vacuum rotary evaporator. Enantiomeric excess was determined by HPLC. Chiralcell OD column, 5% isopropanol in hexane, was used as column for HPLC measurements.

10

Sulfide (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 μl, 1.0 mmol) was added to this solution. . To the resulting reaction mixture was added phenyl diazomethane (0.18 g / mL, 1.5 mmol) dissolved in MTBE (1 mL) via a syringe pump for 3 h at room temperature. After evaporation of the solvents and purification by MPLC (2: 3 dichloromethane: hexane), 118 mg (60.12%) of Ia / w -stilbene oxide and 9 mg of cis -stilbene oxide (4.6%) were obtained; «·«: <! : (cis.-trans 7:93). (S, 5) -? -,? - Stilbene oxide was formed in an enantiomeric excess of 26%.

Ill 'on. Retention times 8.48 min (S, S) and 13.16 min (R, R); flow rate 0.9 ml / min.

• <,, 20 Example 4 Use of 4 '1', 3 ', 3', 3 ', 4' - (5) -3-tert-butoxycarbonyl-2,2-dimethyl-4-isopropyl-thiazolidine (8) * · * • »· • • • • - - • •» * *. ·. The sulfide (8) (30 mg, 0.12 mmol) and rhodium acetate (2.6 mg, 0.006 mmol) were dissolved in · · · ____ • · ---------.

M dichloromethane (0.5 mL), and to this solution benzaldehyde (59 μΐ, 0.58 mmol) was added.

• ·

To the resulting reaction mixture was added phenyl diazomethane (0.1 g / mL, 0.87 mmol) dissolved in · · · · ·]] MTBE (1 mL) was added via syringe pump over 3 h at room temperature. The reaction • (· · · · · · ** yielded (S.S, β-rra / γ-still benzene oxide in 90% enantiomeric excess. Retention times 30 7.79 min (5.5) and 13.83 min (R, R)) , flow rate 1.0 ml / min.

Example 5 16 105684 Preparation of (S) -3-tert-butoxycarbonyl-4-isopropyl-thiazolidine (18) according to Scheme 5

Figure 5.

10 HS '/ * sV ^ s> Ä ______ paraformaldehyde Jz ^ NH2HC Sy mu + ρ.ι ·

EtOH 'Cl (6> (17)

15 (BO0) 2O

DIPEA

acetonitrile, τΑ

\ ^ N

BOC

: 20 (10) • at · a • «• • • • • • • e

The thiol hydrochloride salt (6) was prepared as described in Example 1. The thiol · 999 ′ 25 hydrochloride salt (6) (258 mg, 1.66 mmol) was then added to ethanol (2.5 mL) and formaldehyde solution (35%, aqueous solution, 1.66 mmol) was added to the solution. The mixture was stirred for 30 min at room temperature followed by heating (70 ° C) for 30 min. The mixture was evaporated. and the crude product was washed several times with acetone to give the solid thiazolidine hydrochloride salt (17) (194 mg, 70%).

• «· 30 * a a •

I I I I

taa • a a a * 17 105684

The thiazolidine hydrochloride salt (17) (99 mg, 0.59 mmol) and di-tert-butyl carbonate (255 mg, 1.18 mmol) were dissolved in acetonitrile. To the solution was added diisopropylethylamine (105 µL, 0.60 mmol) and the resulting mixture was stirred for 24 h at room temperature.

Evaporation of the mixture and purification of the residue by MPLC gave liquid sulfide (18) (134 mg, 98%).

1 H NMR (CDCl 3) δ: 0.91 (d, 3H, J = 6.8 Hz) δ 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) 15 4.06 (d, 1H, J = 9.0 Hz) 4.13 (bs, 1H) 4.83 (bd, J = 9.0 Hz) 13 C NMR (CDCl 3) δ:? 9 19.1 28.3 30.3, 47.5 65.0 80.3 153.9 • · «« ai • «f • * ·· HRMS (M + 1); measured 232.1339, calculated 232.1371 Rt = 0.56 (1: 3 MTBE; hexane, vanillin).

··· 1 a 9 · 25 • aa • · · · · · · • • • • • • • • • • • • • • • • • • •. ~ "" ----- ~ «· -” T ~ 7L —---- 'a · • a · a • a a a a a a a 18 105684

Example 6 Use of (S) -3-tert-Butoxycarbonyl-4-isopropyl-thiazolidine (18) as Mediator 5 Sulfide (18) (46 mg, 0.20 mmol) and rhodium acetate (4 mg, 0.01 mmol) were dissolved in dichloromethane ( 1.0 mL) and benzaldehyde (102 μΐ, 1.00 mmol) was added to this solution.

To the resulting reaction mixture was added phenyldiazomethane (0.17 g / mL, 1.50 mmol) dissolved in 10 MTBE (1 mL) via a syringe pump for 3 h at room temperature. After evaporation of the solvent and purification by MPLC (2,3-dichloromethane: hexane), 44 mg (22%) of m / w -stilbene oxide and 6 mg of cis -stilbene oxide (3%) were obtained (cis.trans 12:88). (S, S) -iran-5-stilbene oxide was formed in an enantiomeric excess of 19%.

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Claims (9)

1. Chiral sulfide catalyst, characterized in that the sulfide catalyst has a structure according to formula (II) 5 / Y ΓΛ n J Vr / P (Π) Is a hydrogen atom, one substituted with an alkyl, aryl, alkylaryl, nitro or cyano group, aryl, heteroaryl or haloaryl group and is a hydrogen atom, one having an alkyl, aryl -, alkylaryl, nitro or cyano group substituted aryl, heteroaryl or haloyl group or R 1 and R together form a ring comprising 2-10 carbon atoms and / or heteroatoms; «(« <I *: “X is an alkyl, alkoxy, aryl or alkylaryl group or a dialkyl type; and • · • ♦ • · · Y is a side chain of amino acids found in natural proteins, in other non-« ii • · Protein amino acids or amino acids non-existent in nature according to ... Formula (III) • * • * • · • · · • · * · 'H Y - C - COOH (III) nh2 • · 23 105684 Sulfide catalyst according to claim 1, characterized in that R1 and / or R2 are a hydrogen atom or a methyl group, or R1 and R2 together form a cyclohexyl group, X is a methyl or tert-butoxy group and Y is an isopropyl group. tert-butyl or triphenylmethyl group. Sulfide catalyst according to claim 1 or 2, characterized in that the catalyst is (S) -3- / m-butoxycarbonyl-2,2-dimethyl-4-isopropylthiazolidine, (S) -3- [e] t -butoxycarbonyl - 4-Teri-butyl-thiazolidine or (S) -3-ie-t-butoxycarbonyl-4-isopropylthiazolidine. 10 A process for producing chiral sulfide catalysts, characterized in that the process comprises the steps of: a) an amino acid is reduced to an amino alcohol b) an amino group is protected and a hydroxy group is converted to a thioacetate c) d) the protection of the aminothiol is removed e) a thiazolidine ring is formed by ketalization f) an amino group is protected, whereby a desired sulfide catalyst is obtained as a product. ;. A process according to claim 4, characterized in that in step a) the reduction 4'1 4 is carried out with LiAlH4, in step b) the hydroxy group is converted to a thioacetate with 4L; By means of a Mitsunobu reaction, in step c) the base hydrolysis is carried out with KOH in methanol and ice step f) the protection of the amino group is carried out as a tert-butoxycaric acid. carbamate. Use of a sulfide catalyst according to claims 1-3 or prepared 4 · · s * ··, according to claims 4 or 5 for stereoselective epoxidation, cyclopropanation and • · * _____ aziridineringsreaktioner. A process for the preparation of epoxides, characterized in that an aldehyde is allowed to react with a sulfuric acid formed by a sulfide catalytic converter. according to any one of claims 1-3 or prepared according to claim 4 or 5 and a metal carbenoid, advantageously rhodium, copper, rhenium or zinc carbenoid, in a solvent or in a mixture of solvents, as a result of to obtain a desired epoxide. Process for the preparation of aziridines, characterized in that an imine is allowed to react with a diazo compound in the presence of a sulfide catalyst according to any of claims 1-3 or prepared according to claims 4 or 5 and a metal catalyst, advantageously a rhodium catalyst. , rhenium or copper catalytic acid, in a solvent or in a mixture of solvents, as a result of which a desired aziridine is obtained. 10 9. A process for the preparation of cyclopropanes, characterized in that an alkene is allowed to react with a diazo compound in the presence of a sulfide catalyst according to any one of claims 1-3 or prepared according to claim 4 or 5 and a metal catalyst, preferably a rhodium, rhenium or copper catalytic acid, in a solvent or in a mixture of solvents, as a result of which a desired cyclopropane is obtained. <<<«I tf Γ t '*« • »• · • I · • ·» • • M • I l • * * «« · • * • · • · · ♦ ♦ · • · ♦ ♦ · «' «·« <<<«I (« * * * «f