WO2003087075A1

WO2003087075A1 - Asymmetric synthesis of glycidic amides

Info

Publication number: WO2003087075A1
Application number: PCT/GB2003/001436
Authority: WO
Inventors: Varinder K. Aggarwal
Original assignee: University Of Bristol
Priority date: 2002-04-04
Filing date: 2003-04-04
Publication date: 2003-10-23
Also published as: AU2003222958A1; GB0207770D0

Abstract

Enantiomerically enriched trans-2,3-epoxyamides of the formula (I) in which R1 is a 1-18C aliphatic hydrocarbyl optionally substituted by one or more substituent groups selected from halo, nitro, phenyl and -ORW, where RW is H, 1-6C alkyl, benzyl or phenyl, or is aryl containing from 6-12 ring carbon atoms which is optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -ORW, where RW is as defined above, or is a monocyclic or fused bicyclic heterocyclic group containing at least one heteroatom selected from N, O and S which group is optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -ORW, where RW is as defined above; R2 and R3 are the same or different group selected from H, 1-6C alkyl optionally substituted with one or more substituent groups selected from halo, nitro, phenyl and -ORW, where RW is as defined above, 2-6C alkenyl optionally substituted with one or more substituent groups selected from halo, nitro, phenyl and -ORW, where RW is as defined above, phenyl optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -ORW, where RW is as defined above, and monocyclic heterocyclic groups containing one or more heteroatoms selected from O, S and N, optionally substituted with one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -ORW, where RW is as defined above or R2 or R3, or R2 or R3, together with the nitrogen atom to which they are attached, form a heterocyclic ring, are made by a method comprising reacting a sulfonium salt of the formula (II) wherein R2 and R3 are as defined above, R4 is a group selected from 1-12C alkyl, 6-12C aryl and 7-13C aralkyl and -SiMe3, R5 is 1-4C alkyl group and X- is a counterion, with an aldehyde of the formula R1CHO, where R1 is as defined above, in a solvent in the presence of a base. The use of this method gives excellent yields of the trans epoxides. Sulfonium salts of the formula (II), as defined above, are also disclosed.

Description

ASYMMETRIC SYNTHESIS OF GLYCID1C AMIDES

The present invention relates to asymmetric synthesis of glycidic amides. In particular, it relates to a method of making enantiomerically enriched frat7s-2,3-epoxyamides and to sulfonium ylides used in the method.

Epoxides are important intermediates in organic synthesis. Glycidic esters and amides are particularly useful as they can be further elaborated with a high degree of regio- and stereocontrol and as a result are key intermediates in the synthesis of several pharmaceutical products. For example, they have been employed in the synthesis of Diltiazem and the side chain of Taxol. However, there are very few efficient methods for the preparation of enantiomerically enriched glycidic acid derivatives. One method that has been used involves the asymmetric epoxidation of cinnamates with a chiral manganese-salen complex as catalyst.^1,2 However, only poorly accessible cis alkenes can be employed and these are often derived from Wittig type reactions of the corresponding aldehyde. Alternatively, the aldehyde can be converted to the glycidic compound directly by employing either a Darzens reaction^3"14 or a sulphur ylide mediated approach.^15"16 The asymmetric Darzens reaction is generally a diastereoselective condensation using a stoichiometric amount of chiral auxiliary^13"14 or chiral reagent^3"12 and in all but a few cases^3"5 enantioselectivities are still rather poor.^6"12 Furthermore, the asymmetric Darzens reaction is generally carried out in two steps: formation of the hydroxy-halide aldol followed by ring closure. The only one-step asymmetric Darzens reaction employs a chiral phase transfer catalyst and the enantioselectivities are moderate (42-79% ee).¹⁷ Furthermore, only ketone substrates, rather than esters or amides, have been employed.

The sulphur ylide mediated synthesis of glycidic amides was first reported by Ratts¹⁸ and, recently, Valpuesta-Ferήandez¹⁹ has reported that amide-stabilized sulfonium ylides react with chiral aldehydes in excellent yields and stereoselectivities. Dai²⁰ recently reported an efficient method for preparing (2 ^:?,3S)-epoxyamides through chiral camphor derived hydroxy- containing sulfonium ylides (Scheme 1).

R = Ar, yield 80-94%, ee 57-70% R = Alkyl, yield 70-80%, ee 1-11%

Scheme 1

Dai found that aryl, heteroaryl and aliphatic aldehydes reacted with the chiral sulfonium salt 2 to afford the desired epoxides 1 in good to excellent yields. However, the asymmetric induction was poor to moderate, with aromatic aldehydes giving the highest enantioselectivities and only low enantioselectivities being obtained for aliphatic aldehydes.

The present invention is based on our discovery that by using certain ethers of the camphor-derived sulfonium ylide used by Dai significant improvements can be achieved in asymmetric synthesis of glycidic amides.

Accordingly, the present invention provides a method of making enantiomerically enriched -rat?s-2,3-epoxyamides of the formula I

in which R ¹ is a 1-18C aliphatic hydrocarbyl optionally substituted by one or more substituent groups selected from halo, nitro, phenyl and -OR^w , where R^w is H, 1-6C alkyl, benzyl or phenyl, or is aryl containing from 6-12 ring carbon atoms which is optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -OR^w, where R^w is as defined above, or is a monocyclic or fused bicyclic heterocyclic group containing at least one heteroatom selected from N, O and S which group is optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -OR^w, where R^w is as defined above; R² and R³ are the same or different group selected from H, 1-6C alkyl optionally substituted with one or more substituent groups selected from halo, nitro, phenyl and -OR , where R^w is as defined above, 2-6C alkenyl optionally substituted with one or more substituent groups selected from halo, nitro, phenyl and -OR^w, where R^w is as defined above, phenyl optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -OR , where R^w is as defined above, and monocyclic heterocyclic groups containing one or more heteroatoms selected from O, S and N, optionally substituted with one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -OR^w, where R^w is as defined above or R² or R³, together with the nitrogen atom to which they are attached, form a heterocyclic ring, which method comprises reacting a salt of the formula II

wherein R² and R³ are as defined above, R⁴ is a group selected from 1-12C alkyl, 6-12C aryl and 7-13C aralkyl and -SiMe₃, R⁵ is 1-4C alkyl and X^" is a counterion, with an aldehyde of the formula R¹CHO, where R¹ is as defined above, in a solvent in the presence of a base.

We have found that by the method of the present invention only trans epoxides are obtained in excellent yields and that high enantioselectivities are observed for aromatic and heteroaromatic aldehydes. While aliphatic aldehydes, in general, give lower enantioselectivities compared to aromatic aldehydes, substantial improvements in enantioselectivities are obtained for aromatic, heteroaromatic and aliphatic aldehydes compared to that reported by Dai. Furthermore, the precursors can be recovered after chromatography in yields higher than 70% without loss of optical purity and so can be re-used.

The method of the present invention comprises reacting a salt having the structural formula II

wherein R², R³, R⁴, R⁵ and X^" have the definitions given above with an aldehyde of the formula

R¹CHO

where R¹ is defined above, in a solvent in the presence of a base.

According to one preferred embodiment, the group R¹ is an optionally- substituted straight chain, branched chain or cyclic alkyl group containing up to 12 carbon atoms in the alkyl moiety. Examples of such R¹ groups include t-butyl and dodecyl. The alkyl group may be substituted by an aryl group. An example of such an aralkyl group is a straight chain 1 to 12C alkylene substituted by a phenyl group.

According to another preferred embodiment, the group R¹ is an optionally-substituted aryl group containing from 6 to 12 ring carbon atoms, such as optionally-substituted phenyl. Examples of substituents that may be present on the aryl group include 1 to 6C alkyl, halo, 1 to 6C alkoxy, 1- 6C haloalkyl and nitro. By way of example of such R¹ groups, according to this embodiment, mention may be made of phenyl, p-methoxyphenyl, p- chlorophenyl, p-fluorophenyl, p-methyl phenyl, p-trifluoromethylphenyl, and p-nitrophenyl.

According to a further preferred embodiment, the group R¹ in the aldehyde may be an optionally-substituted heterocyclic group, preferably an aromatic heterocyclic group, such as pyridyl.

The sulfonium salt used in the method of the invention contains substituents R² and R³ attached to the N atom of the amide group. Typically, R² and R³, which may be the same or different, are selected from H, 1 to 6C alkyl and phenyl. Preferably both R² and R³ are ethyl. Alternatively, R² and R³, together with the N-atom to which they are both attached, form a heterocyclic group. In the case where R² and R³ are joined together to form a 4 to 6C alkylene group, the group -NR²R³ will be a nitrogen-containing heterocycle. For instance, in the case where R² and R³ together form the group -(CH₂)₄- the heterocycle -NR²R³ is 1-pyrrolidinyl. R² and R³ may, however, form a chain which is substituted in the chain by a hetero atom, for example O,N or S. An example of this is when R² and R³ together form the chain -(CH₂)₂-0-(CH₂)₂- such that the heterocycle -NR²R³ is 1-morpholinyl.

The sulfonium salt used in the invention contains an ether group - OR⁴. R⁴ is a group selected from 1-12C alkyl, 6-12C aryl, 7-13C aralkyl and -SiMe₃. Examples of the R⁴ group when it is alkyl include methyl, ethyl and butyl. When R⁴ is aralkyl a typical example is benzyl. Preferably, R⁴ is methyl.

The group R⁵ in the sulfonium salt is a 1 to 4C alkyl group. Preferably, R⁵ is a methyl group.

The group X^" is a counterion and examples of suitable counterions include Br^", CI^", BF₄ ^", PF₆ ^", CIO ^" and CF₃S0₃ ^". Preferably, X^" is Br^".

Sulfonium salts in which X^" is Br^" may be prepared by reacting a chiral sulfide III with the bromoamide ^R

^Br at room temperature in acetone. The sulfonium salt is obtained as a mixture of diastereoisomers and can then be recrystallized to give a single diastereoisomer. Although the sulfonium salt may be used, in the present invention, as a mixture of diastereoisomers, better results are, in general, obtained by using a single diastereoisomer.

The reaction of the sulfonium salt and the aldehyde is carried out in a solvent in the presence of a base. Examples of suitable solvents include acetone, acetonitrile, t-butyl methyl ether, diethyl ether, dichloromethane, 1 ,4-dioxane, ethanol, methanol, ethyl acetate, hexane, pentane, tetrahydrofuran, toluene, α, ,α-trifluorotoluene and water. Preferably, the solvent is selected from dichloromethane, n-hexane, ethanol, tetrahydrofuran, 1 ,4-dioxane, acetonitrile, toluene, ,α,α-trifluorotoluene and water.

The base is typically one selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, Λ/,Λ/-diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tet -butoxide, triethylamine, 4- methylmorpholine, Λ/,Λ/-dimethylaminopyridine, 1-methylpiperidine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene and N,N,N',N'-tetramethyl-/V"-

[tris(dimethylamino)phosphoranylidene]phosphoric triamide ethylamine (EtP₂)⁹. We have found that good results were obtained using ethanol as the solvent for the reaction and powdered potassium hydroxide, as the base. In general, the reaction may typically be carried out at a temperature in the range of from -78° to +50°C. Preferably, however, the temperature will be in the range of from -50°C to 0°C. We have found that for the reaction involving an aldehyde wherein R¹ is an optionally-substituted aryl or aralkyl group, the reaction temperature is preferably maintained within the range of from -20°C to -50°C. However, for aldehydes wherein R¹ is an optionally-substituted aliphatic group, the reaction temperature is preferably about -20°C.

EXAMPLES

In the following examples, the sulfonium salt II was prepared from sulfide III according to the reaction scheme

III

The epoxide I was prepared using the salt II according to the scheme:-

Example 1

(Diethylcarbamoyl)methyl-[(1 R, 2S, 3R)-2-benzyloxy-1 ,7,7-trimethyl blcyclo[2.2.1]hept-3-yl]methylsulfonium bromide (II, R₂, R₃ = Et, R = Benzyl, R₅ = Me)

A 5.6/1 mixture of diastereomeric sulfonium salt was prepared by alkylation of sulfide III (R = Benzyl, R₅ = Me) (1 eq) with Λ/,Λ/-diethyl-bromoacetamide (1 eq) in a small amount of acetone for 24 hours. After washing with hexane and removal of the volatiles, the crude oil obtained was used in the epoxidation process without further purification. Major isomer: 5H (270 MHz, CDCIs) 0.91 (s, 3H), 0.96 (t, J 7.1 , 3H), 1.03 (t, J 7.1 , 3H), 1.10-1.70 (m, 3H), 1.12 (s, 3H), 1.29 (s, 3H) 1.80-2.00 (m, 1 H), 2.08 (d, J 4.3, 1H), 2.85- 3.50 (m, 4H), 3.22 (s, 3H), 3.85 (d, J 15.8, 1 H), 4.06 (d, J 7.6, 1 H), 4.52 (d, J 12.2, 1 H), 5.05 (d, J 12.2, 1 H), 5.46 (d, J 7.6, 1 H), 6.26 (d, J 15.8, 1 H), 7.10- 7.50 (m, 5H).

Example 2

(Diethylcarbamoyl)methyl-[(1 R, 2S, 3R)-2-tιϊethylsilyloxy-1 ,7,7- trimethylbicyclo [2.2.1]hept-3-yl]-n-propylsulfonϊum tetrafluoroborate (11, R₂, R₃ = Et, R₄ = SiEt₃, R₅ = n-Pr)

A 10/1 mixture of diastereomeric sulfonium salt was prepared by alkylation of sulfide III (R₄ = SiEt₃, R₅ = n-Pr) (0.5 mmol) with Λ/,Λ/-diethyl- bromoacetamide (0.5 mmol) in acetone (1 ml_) in the presence of silver tetrafluoroborate (0.5 mmol) for 48 hours at room temperature. The mixture was then filtered on Celite and concentrated. The crude oil was purified by chromatography on silica gel with a mixture of light petroleum ether and ethyl acetate (1/1), then a mixture of dichloromethane and methanol (2.5% to 7%) as the eluant to give a colorless oil in 35% yield. Major isomer: 5H (270 MHz, CDCIs) 0.79 (s, 3H), 0.97 (s, 3H), 1.08 (t, J 7.9, 3H), 1.10 (t, J 7.2, 3H), 1.11 (s, 3H), 1.12-1.54 (m, 4H), 1.18 (t, J 7.2, 3H), 1.85 (q, J 7.9, 2H), 1.91 (d, J 4.6, 1H), 3.10 (m, 2H), 3.20-3.60 (m, 4H), 3.45 (s, 3H), 3.75 (d, J 7.6,1 H), 4.21 (d, J 16.5.1H), 4.24 (d, J 7.6, 1 H), 4.76 (d, J 16.5, 1 H); MS (El) m/z 356 ([M+1]-BF₄ ^", 51), 312 (40), 115 (100); MS (CI) m/z 356 ([M+1]-BF₄ ^",26) 314 (68), 190 (100).

Example 3 fran-s-iV-Phenyl-3-(4-chlorophenyl)-2,3-epoxypropionamide

To a solution of p-chlorobenzaldehyde (0.42 mmol) and chiral sulfonium salt (II, R₂ = Ph, R₃ = H, R₄ = Me, R₅ = Me) (2/1 diastereoisomeric ratio, 0.50 mmol) in dichloromethane (2.0 mL) at 0°C was added 10% aqueous NaOH (500 μl_). The reaction mixture was stirred overnight, during which the temperature was allowed to warm to RT. After dilution with dichloromethane and water, the aqueous phase was extracted with dichloromethane several times. The combined organic phases were dried over MgSO and concentrated, and the crude product was purified by column chromatography on silica gel with a mixture of light petroleum ether and ethyl acetate (9/1 to 2/1) as the eluant to give a white solid in 82% yield and 19% ee. mp 158-161 °C (hexane/ethyl acetate), δ_H (400 MHz, CDCI₃) 3.61 (d, J 2.0, 1H), 4.00 (d, J 2.0, 1H), 7.10-7.40 (m, 5H), 7.25 (d, J 8.3, 2H), 7.56 (d, J 8.3, 2H), 7.95 (brs, 1 H). Chiracel OJ, hexane-/-PrOH (80 : 20) 0.7 mL/min, 21.8 min (2S, 3R), 27.9 min (2R, 3S).

Example 4 frans-/V-Morpholine-3-(4-chlorophenyl)-2,3-epoxyprop[onamide

To a solution of p-chlorobenzaldehyde (0.42 mmol) and chiral sulfonium salt (ii, R₂ + R₃ = -(CH₂)₂ 0(CH₂)₂-, R4 = Me, R₅ = Me) (3/1 diastereoisomeric ratio, 0.50 mmol) in dichloromethane (2.0 mL) at 0°C was added 10% aqueous NaOH (500 μL). The reaction mixture was stirred overnight, during which the temperature was allowed to warm to RT. After dilution with dichloromethane and water, the aqueous phase was extracted with dichloromethane several times. The combined organic phases were dried over MgSO₄ and concentrated, and the crude product was purified by column chromatography on silica gel with a mixture of light petroleum ether and ethyl acetate (3/1) as the eluant to give the -ra/?s-epoxide as a white solid in 76% yield and 39% ee. δ_H (400 MHz, CDCI₃) 3.59 (d, J 1.7, 1 H), 3.60-3.82 (m, 8H), 4.09 (d, J 1.7, 1H), 7.25 (d, J 8.5, 2H), 7.35 (d, J 8.5, 2H); Chiracel OJ, hexane-/- PrOH (80 : 20) 0.7 mL/min, 27.3 min (2S,3R), 33.9 min (2R,3S).

Example 5 frans->V-Pyrrolidine-3-(4-chlorophenyl)-2,3-epoxypropionamide

To a solution of p-chlorobenzaldehyde (0.42 mmol) and chiral sulfonium salt (11, R₂ + R₃ = -(CH₂)₄-, R = Me, R₅ = Me) (14/1 diastereoisomeric ratio, 0.50 mmol) in dichloromethane (2.0 mL) at 0°C was added 10% aqueous NaOH (500 μL). The reaction mixture was stirred for 3 hours at this temperature. After dilution with dichloromethane and water, the aqueous phase was extracted with dichloromethane several times. The combined organic phases were dried over MgS0 and concentrated, and the crude product was purified by column chromatography on silica gel with a mixture of light petroleum ether and ethyl acetate (9/1 to 1/1) as the eluant to give the trans- epoxide as a white solid in 84% yield and 90% ee. δ_H (400 MHz, CDCI₃) 1.90 (m, 2H), 1.99 (m, 2H), 3.48-3.70 (m, 4H), 3.51 (d, J 2.0, 1 H), 4.11 (d, J 2.0, 1H), 7.27 (d, J 8.3, 2H), 7.33 (d, J 8.3, 2H); δ_c (100 MHz, CDCI₃) 24.0 (2), 26.2 (2), 46.1 (2), 46.5 (2), 57.0 (1), 57.7 (1), 127.1 (1), 128.9 (1), 134.5 (0), 134.6 (0), 164.7 (0); Chiracel OJ, hexane-/-PrOH (80 : 20) 0.7 mL/min, 13.9 min (2S.3R), 18.2 min (2R,3S).

Example 6 frai7s-/V,/V-Diethyl-3-te/t-butyl-2,3-epoxypropionamide

To a solution of 2,2-dimethylpropionaldehyde (0.5 mmol) and chiral sulfonium salt (N, R₂,R3 = Et, R₄ = Me, R₅ = Me) (0.25 mmol) in ethanol (0.9 mL) at -20°C was added powdered potassium hydroxide (0.5 mmol). The reaction mixture was stirred at this temperature for 72 hours. After removal of the solvent under reduced pressure, the crude mixture was purified by flash chromatography on silica gel with a mixture of light petroleum ether and ethyl acetate (3/1) as the eluant to give a colorless oil in 84% yield and 93% ee. IR (film) 2960, 2872, 1648, 1380, 1364 cm^"1; δ_H (400 MHz, CDCI₃) 0.98 (s, 9H), 1.14 (t, J 7.3, 3H), 1.25 (t, J 7.0, 3H), 2.94 (d, J 2.2, 1H), 3.31- 3.54 (m, 4H), 3.44 (d, J 2.2, 1H); δ_c (100 MHz, CDCI₃) 12.9 (3), 14.8 (3), 25.7 (3), 30.8 (0), 40.6 (2), 41.3 (2), 50.8 (1), 65.6 (1), 167.0 (0); MS (CI) m/z 200 (M+H⁺, 7), 182 (28), 142 (10), 130 (38), 59 (100); HRMS (El) calcd for CnH₂ιN0₂ 199.1572, found 199.1578; Chiracel OJ, hexane-t-PrOH (99 : 1) 0.7 mL/min, 17.2 min (2S,3R), 18.6 min (2R,3S).

Example 7 traπs-iV, V-Diethyl-3-[2-(8-phenyloctyl)phenyl]-2,3-epoxypropionamide

To a solution of 2-(8-phenyloctyl)benzaldehyde (0.2 mmol) and chiral sulfonium salt ( , R₂,R₃ = Et, R₄ = Me, R₅ = Me) (0.25 mmol) in ethanol (0.9 mL) at -30°C was added powdered potassium hydroxide (0.5 mmol). The reaction mixture was stirred at this temperature for 48 hours. After removal of the solvent under reduced pressure, the crude mixture was purified by flash chromatography on silica gel with a mixture of petroleum ether and ethyl acetate (10/1 to 3/1) as the eluant, a colorless oil was obtained in 77% yield and 90% ee. δ_H (400 MHz, CDCI₃) 1.15 (t, J 6.9, 3H), 1.20 (t, J 7.2, 3H), 1.29 (m, 8H), 1.4-1.65 (m, 4H), 2.50 (t, J 7.7, 2H), 2.64 (m, 2H), 3.35 (m, 4H), 3.40 (d, J 2, 1 H), 4.2 (d, J 2, 1 H), 7,05-7.35 (m, 9H); δ_c (100 MHz, CDCI3) 13.0 (3), 15.0 (3), 29.3 (2), 29.4 (2), 29.5 (2), 29.6 (2), 31.6 (2), 31.7 (2), 32.7 (2), 36.0 (2), 55.8 (1), 56.7 (1), 124.3 (1), 125.6 (1), 126.2 (1), 128.2 (1), 128.4 (1), 129.5 (1), 133.9 (0), 141.4 (0), 142.9 (0), 165.9 (0); MS (El) m/z 407 (M⁺, 11), 389 (35), 160 (34), 131 (45), 115 (68), 105 (50), 100 (100), 91 (92), 72 (78); Chiracel OD, hexane-/-PrOH (95 : 5) 0.7 mL/min, 18.1 min (2S,3R), 25.1 min (2R,3S).

Example 8

(1 ?,2S,3/?)-2-Methoxy-3-(/7-propylthio)-1,7,7-trimethylbJcyclo[2.2.1]- heptane (HI, R₄ = Me, R₅ = n-Pr)

Sodium hydride (169 mg, 7.06 mmol) was added under nitrogen to a solution of (1R,2S,3 )-3-(π-Propylthio)-1,7,7-trimethylbicyclo[2.2.1]-heptan- 2-ol⁸ (1.075 g, 4.706 mmol) in THF (15 mL) at room temperature. After stirring for 15 minutes, methyl iodide (880 μL, 14.11 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction was then quenched with saturated aqueous NH₄CI (5 mL) and water (5 mL). The aqueous phase was extracted with ether (3x20 mL) and the combined ethereal phases were washed with saturated aqueous NaCI, dried over MgS0₄ and concentrated. The crude product was purified by column chromatography with a mixture of light petroleum ether and ethyl acetate (100/0 to 9/1) as the eluant to give a colorless oil in 71% yield. [α]_D -74.2° (c 1.15, dichloromethane) IR (film) 2951 , 2873, 2827, 1604, 1455, 1391 , 1370, 1105 cm^"1; δ_H (400 MHz, CDCI₃) 0.77 (s, 3H), 0.90 (s, 3H), 1.00 (t, J 7.3, 3H), 0.99-1.09 (m, 2H), 1.11 (s, 3H), 1.47 (m, 1 H), 1.62 (m, 2H), 1.74 (m, 1 H), 1.81 (d, J 4.4 1H), 2.51 (t, J 7.4, 2H), 2.91 (d, J 7.7, 1H), 3.18 (d, J 7.7, 1 H), 3.43 (s, 3H); δ_c (100 MHz, CDCI3) 11.8 (3), 13.7 (3), 21.3 (3) (2 signals), 23.3 (2), 28.7 (2), 33.8 (2), 36.0 (2), 47.1 (0), 50.2 (0), 52.3 (1), 56.1 (1), 61.3 (3), 91.6 (1); MS (El) m/z 242 (M⁺, 44), 199 (41), 167 (46), 132 (53), 84 (100); MS (CI) m/z 242 (27), 211 (77), 84 (78), 55 (100); HRMS (El) calcd for C₁₄H₂₆OS 242.1704, found 242.1706; Anal. Calcd for C₁₄H₂₆OS: C, 69.36; H, 10.81. Found: C, 69.62; H, 10.90.

Example 9

(1R,2S,3R)-3-(i7-Methylthio)-2-triethylsilyloxy-1,7,7-trimethylbicyclo [2.2.1]-heptane (III, R₄ = -SiEt₃, R₅ = Me)

To a solution of the alcohol, exo-(methylthio)isoborneol,²¹ (290 mg, 1.45 mmol) in dichloromethane (1.5 mL) at 0°C under nitrogen was added dropwise 2,6-lutidine (421 μL, 3.61 mmol). This mixture was stirred at 0°C for 5 minutes, then triethylsilyltrifluoromethanesulfonate (491 μL, 2.17 mmol) was added dropwise. After stirring overnight at room temperature, saturated aqueous NaHCO₃ was added to the reaction mixture diluted with ether. The aqueous phase was extracted with ether and the combined ethereal phases were washed with saturated aqueous NaCI, dried over MgS0₄ and concentrated. The crude product was purified by column chromatography with 97/3 petroleum ether/ether as the eluant to give a colorless oil in quantititave yield. IR (film) 2951 , 2911, 2875, 1457, 1237, 1077cm^"1; δ_H (400 MHz CDCI₃) 0.51 (q, J 8.0, 2H), 0.64 (q, J 8.0, 2H), 0.65 (q, J 8.0, 2H), 0.78 (s, 3H), 0.84 (s, 3H), 0.93 (t, J 8, 3H), 0.95-1.01 (m, 2H), 0.98 (t, J 8 6H), 1.18 (s, 3H), 1.48 (m, 1 H), 1.75 (m, 1H), 1.86 (d, J 4.0, 1 H), 2.08 (s, 3H), 2.8 (d, J 7.7, 1H), 3.8 (d, 7.7, 1H); δ_c (100 MHz, CDCIs) 5.1 (2) (2 signals), 6.49 (2), 6.83 (3), 7.1 (3) (2 signals), 12.3 (3), 16.8 (3), 21.1 (3), 22.0 (3), 28.8 (2), 33.3 (2), 47.2 (0), 50.0 (1), 50.3(0), 60.3 (1), 81.7 (1). MS (CI) m/z 313 (MH⁺ -2,11), 285 (43), 183 (23), 57 (100).

Example 10

(Diethylcarbamoyl)methyl-[(1 ?,2S,3f?)-2-methoxy-1,7,7-trimethyI- bicyclo-[2.2.1]hept-3-yl]methylsu.fonium bromide (JJ, R2, R3 = Et, R₄ = Me, R₅ - Me)

A 10/1 mixture of diastereomeric sulfonium salt was prepared by quantitative alkylation of the sulfide III (R , R₅ = Me) (1 eq) with Λ/,Λ/-diethyl- bromoacetamide (1 eq) in a small amount of acetone for 24 hours. The crude solid obtained was washed with hexane, filtrated, then recrystallized in hexane/acetone to give diastereopure sulfonium ylide as a white crystal, mp 105-106°C, [α]_D + 111.2° (c 0.17, dichloromethane); IR (film) 3055, 1422, 1266, 896, 738, 704cm^"1; δ_H (250 MHz, CDCI3) 6.52 (d, J_AB 15.9, 1 H), 5.50 (d, J 7.6, 1 H), 4.12 (d, J_AB 15.9, 1H), 3.76 (d, J 7.6, 1 H), 3.65 (m., 1 H), 3.53 (s, 3H), 3.51 (m., 1H), 3.34 (m., 2H), 3.23 (s, 3H), 2.02 (d, J 4.3, 1 H), 2.00-1.80 (m, 1H), 1.60-1.10 (m, 3H), 1.28 (t, J 7.3, 3H), 1.17 (t, J 7.3, 3H), 1.17 (s, 3H), 1.06 (s, 3H), 0.87 (s, 3H); δ_c (63 MHz, CDCI₃) 162.2 (0), 88.4 (1), 61.4 (1), 59.6 (1), 51.4 (0), 48.0 (0), 47.7 (2), 47.4 (3), 43.0 (2), 41.0 (2), 32.1 (2), 27.4 (2), 23.2 (3), 21.0 (3), 20.5 (3), 14.3 (3), 12.3 (3), 11.7 (3); MS (El) m/z 281 (84), 167 (50), 115 (100), 100 (62), 86 (51), 72 (60), 58 (64); MS (CI) m/z 328 (76), 194 (62), 135 (72), 116 (100); Anal, calcd for C₁₈H₃₄N0₂ BrS: C, 52.93; H, 8.39; N, 3.43. Found: C, 52.86; H, 8.41; N, 3.39. HRMS calcd for Cι₈H₃₄NO₂S⁺ 328.2310, found 328.2311.

Example 11

(Phenylcarbamoy methyl-KlfJ^S.SRJ^-methoxy-l^^-trimethylblcyclo [2.2.1]hept-3-yl]methylsulfonium bromide (U, R₂ = H, R₃ = Ph, R₄ = Me, R₅ = Me)

A 2/1 mixture of diastereomeric sulfonium salt was prepared by alkylation of sulfide III (R₄, R₅ = Me) (2.33 mmol) with 2-bromo-Λ/-phenylacetamide (2.8 mmol) in acetone (0.5 mL) for 24 hours at room temperature. After washing with hexane and removal of the volatiles, the crude oil obtained was purified by chromatography on silica gel with a mixture of light petroleum ether and ethyl acetate (1/1), then a mixture of chloroform and methanol (9/1) as the eluant to give a pale yellow oil. Major isomer (selected signals): δ_H (270 MHz, CDCIs) 0.85 (s, 3H), 0.90-1.60 (m, 3H), 0.98 (s, 3H), 1.17 (s, 3H), 1.88 (m, 1H), 2.03 (d, J 4.3, 1H), 3.28 (s, 3H), 3.59 (s, 3H), 3.65 (d, J 7.6, 1H), 4.85 (d, J 7.6, 1H), 4.95 (d, J 14.8, 1 H), 5.35 (d, J 14.8, 1H), 7.12 (m, 1 H), 7.27 (m, 2H), 7.77 ( , 2H), 8.6 (brs,1H).

Example 12

(Morpholinecarbamoyl)methyl-[(1 R, 2S, 3R)-2-methoxy-1 ,7,7trimethyl bicyclo[2.2.1]hept-3-yl]methylsulfonium bromide (JJ, R₂ + ₃ = -(CH₂)₂- O-(CH₂)₂, R4 = Me, R₅ - Me)

A 3/1 mixture of diastereomeric sulfonium salt was prepared by alkylation of sulfide III (R₄, R₅ = Me) (2.33 mmol) with 2-bromo-1-morpholin-4-yl- ethanone (2.8 mmol) in acetone (0.5 mL) for 24 hours at room temperature. After washing with hexane and removal of the volatile, the crude oil obtained was used in the epoxidation process without further purification Major isomer (selected signals): δ_H (270 MHz, CDCI3) 0.87 (s, 3H), 0.90-1.70 (m, 3H), 1.06 (s, 3H), 1.17 (s, 3H), 1.88 (m, 1 H), 2.03 (d, J 4.6, 1 H), 3.20 (s, 3H), 3.32-4.00 (m, 9H), 3.54 (s, 3H), 4.18 (d, J 15.6, 1 H)), 5.25 (d, J 7.6, 1H), 6.63 (d, J 15.6, 1H). Example 13

(Pyrrolidinecarbamoyl)methyl-[(1R,2S,3R)-2-methoxy-1,7,7trimethyl bicyclo[2.2.1]hept-3-yl]methylsulfoniumbromide (Jl, R2 + 3 = -(CH₂)4^"' R₄ = Me, R₅ = Me)

A 14/1 mixture of diastereomeric sulfonium salt was prepared by alkylation of sulfide III (R₄, R₅ = Me) (2.33 mmol) with 2-bromo-1-pyrrolidin-1-yl- ethanone (2.8 mmol) in acetone (0.5 mL) for 24 hours at room temperature. After washing with hexane and filtration, the white solid obtained was used in the epoxidation process without further purification. Major isomer δ_H (400 MHz, CDCI₃) 0.86 (s, 3H), 1.05 (s, 3H), 1.06 (m, 1 H), 1.16 (s, 3H), 1.26 (m, 1 H), 1.56 (m, 1H), 1.80-1.22 (m, 2H), 2.02 (d, J 4.4, 1 H), 3.24 (s, 3H), 3.35- 3.62 (m, 4H), 3.52 (s, 3H), 3.71 (d, J 7.8, 1 H), 4.05 (d, J 15.8, 1 H), 5.44 (d, J 7.8, 1 H), 6.35 (d, J 15.8, 1 H).

Example 14 -fra/7S-Λ/,/V-Diallyl-3-(4-chlorophenyl)-2,3-epoxypropionamide

To a solution of p-chlorobenzaldehyde (0.15 mmol) and chiral sulfonium salt (U, R₂ + R₃ = -CH₂-CH=CH₂, R₄ = Me, R₅ = Me) (100/0 diastereoisomeric ratio, 0.19 mmol) in ethanol (0.70 mL) at 25°C was added powdered potassium hydroxide (0.39 mmol). The reaction mixture was stirred at this temperature for 2 hours and then washed with water. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and the solvents were removed under reduced pressure. The resulting residue was purified by flash chromatography on silica gel with a mixture of hexane and ethyl acetate (5/1) as the eluant to give the pure epoxide in 98% yield and 90% ee. δ_H (400 MHz, CDCI₃) 3.54 (d, J 1.5, 1 H), 3.93-4.10 (m, 4H), 4.06 (d, J 1.8, 1H), 5.13-5.23 (m, 4H), 5.73-5.82 (m, 2H), 7.23 (d, J 8.1, 2H), 7.33 (d, J 8.1 , 2H); δ_c (100 MHz, CDCI₃) 48.6 (2), 48.7 (2), 57.3 (1), 57.3 (1), 117.4 (2), 118.3 (2), 127.1 (1), 128.9 (1), 132.5 (1), 132.7 (1), 134.2 (0), 134.7 (0), 166.5 (0); Chiracel OJ, hexane-/-PrOH (90:10) 1 mL/min, 10.0 min (2S, 3R), 11.8 min (2 3S). EXPERIMENTAL SECTION

Sulfonium salt Ha (R₂, R₃ = Et, R₄ = Me, R₅ = Me) obtained as a single diastereoisomer after recrystallisation, was tested with a range of aldehyes (Table 1). It was found that only trans epoxides were obtained in excellent yields, and that high enantioselectivities were observed for aromatic and heteroaromatic aldehydes. Except in the case of pivaldehyde (entry 12), aliphatic aldehydes gave lower enantioselectivites compared to aromatic aldehydes. However, substantial improvements in enantioselectivities were obtained for aromatic, heteroaromatic and aliphatic aldehydes compared to that reported by Dai. Depending on the aldehyde, the ylide precursor (sulfide III, R , R₅ = Me) could be recovered after chromatography in higher than 70%) yield without loss of optical purity, and could be re-used.

lla

Table 1 Asymmetric synthesis of (2R,3S)-2,3-epoxyamides

0.25 mmol salt, 0.20 mmol aldehyde, 0.9 mL, EtOH, 0.50 mmol KOH, -50°C, 48 h; ^b 0.25 mmol salt, 0.20 mmol aldehyde, 0.9 L EtOH, 0.50 mmol KOH, -30°C, 24 h; ^c 0.25 mmol salt, 0.50 mmol aldehyde, 0.9 mL EtOH, 0.50 mmol KOH, -20°C, 72 .

In general, the optimum conditions found required the addition of powdered KOH to a solution of aldehyde and salt in EtOH at a) -50°C for the aromatic aldehydes or b) -20°C for the aliphatic aldehydes. The reactions were completed after stirring at those temperatures for 48 or 72 hours, respectively. Alternative sulfonium salts, prepared from the chiral sulfide HI (R₄, R5 = Me) and the corresponding α-bromo acetamide, were also tested using non-optimized conditions (Table 2). Although effective, it was found that the selectivities obtained were lower than in reactions starting from lla, in particular because it was not possible to isolate and use diastereopure sulfonium salts.

mixture of diastereoisomers Table 2 Asymmetric synthesis of (2R,3S)-2,3-epoxyamides with different sulfonium salts

after recrystallisation

To examine the effect of different substitutents on sulfur or oxygen, chiral sulfides 1Mb and 111c were also synthesized (Table 3). The corresponding sulfonium salts, obtained as a mixture of non-separable diastereoisomers, were used in the epoxidation process and moderate to good selectivities were obtained.

111

Table 3

Asymmetric synthesis effect of different substituents on the chiral sulfide

¹ The unpurified salt was directly used in the epoxidation. Tetrafluoroborate salt Solvent effect

lla

Table 4 : solvent effect⁸

^a Typical procedure: To a solution of pivaldehyde (0.5 mmol) and chiral sulfonium salt Ha (0.6 mmol) in the appropriate solvent (2.0 mL) at 0°C was added 10% aqueous NaOH (500 μL). The reaction mixture was stirred overnight, during which the temperature was allowed to warm to RT. After dilution with dichloromethane and water, the aqueous phase was extracted with dichloromethane several times. The combined organic phases were dried over MgSO and concentrated, and the crude product was purified by column chromatography on silica gel with a mixture of light petroleum ether and ethyl acetate (3/1) as the eluant to give the pure -rans-epoxide as a colorless oil. Base effect

lla

Table 5: effect of base

mmol) and chiral sulfonium salt lla (0.42 mmol) in DCM or EtOH (1.5 mL) at 0°C was added the appropriate base (2.5 eq). The reaction mixture was stirred 24 hours, during which the temperature was allowed to warm to RT. After dilution with dichloromethane and water, the aqueous phase was extracted with dichloromethane several times. The combined organic phases were dried over MgS0₄ and concentrated, and the crude product was purified by column chromatography on silica gel with a mixture of petroleum ether and ethyl acetate (10/1 to 3/i) as the eluant to give the pure trans-epoxide as a colorless oil (yields non-optimized). Temperature effect

Table 6

Asymmetric synthesis of (2f?,3S)-2,3-epoxyamides: temperature effect

Salt ratio effect

NEt₂

Table 7

Effect of the diastereoisomeric ratio of the sulfonium salt lla on enantioselectivity ^a

mmol) and chiral sulfonium salt lla (245 mg, 0.6 mmol) in dichloromethane (2.0 mL) at 0 or 40°C was added 10% aqueous NaOH (500 μL). The reaction mixture was stirred for 2 hours. After dilution with dichloromethane and water, the aqueous phase was extracted with dichloromethane several times. The combined organic phases were dried over MgS0 and concentrated, and the crude product was purified by column chromatography on silica gel with a mixture of light petroleum ether and ethyl acetate (3/1) as the eluant to give the pure -rans-epoxide.

References

1. E.N. Jacobsen, L. Deng, Y. Furukawa, and L.E. Martinez, Tetrahedron, 1994, 50, 4323.

2. L. Deng, and E.N. Jacobsen, J. Org. Chem., 1992, 57, 4320.

3. E.J. Corey, and S. Choi, Tetrahedron Lett, 1991, 32, 2857.

4. E.J. Corey, D.H. Lee, and S. Choi, Tetrahedron Lett, 1992, 33, 6735.

5. S.-l. Kiyooka, and K.A. Shahid, Tetrahedron: Asymmetry, 2000, 11, 1537.

6. S. Julia, J. Guixer, J. Masana, J. Rocas, S. Colonna, R. Annuziata, and H. Molinari, J. Chem. Soc, Perkin Trans. 1, 1982, 1317.

7. R. Annunziata, S.Banfi, and S. Colonna, Tetrahedron Lett, 1985, 26, 2471.

8. B.M. Adger, J.V. Barkley, S. Bergeron, M.W. Cappi, B.E. Flowerdew, M.P. Jackson, R. McCague, T.C. Nugent, and S.M. Roberts, J. Chem. Soc, Perkin Trans. 1, 1997, 3501.

9. S. Ebrahim, and M. Wills, Tetrahedron: Asymmetry, 1997, 8, 3163.

10. L Pu, Tetrahedron: Asymmetry, 1998, 9, 1457.

11. P. Bako, A. Szollosy, P. Bombicz, and L. Toke, Synlett, 1997, 291.

12. S. Arai, and T. Shioiri, Tetrahedron Lett., 1998, 39, 2145. 13. 0. Meth-Cohn, and Y. Chen, Tetrahedron Lett. 1999, 40, 6069.

14. O.Meth-Cohn, Y. Chen, and D.J. Williams, Chem. Commun., 2000, 495.

15. Y.-G. Zhou, X.-L. Hou, L.-X. Dai, L.-J. Xia, and M.-H. Tang, J. Chem. Soc, Perkin Trans. 7, 1999, 77.

16. R. Imashiro, T. Yamanaka, and M. Seki, Tetrahedron: Asymmetry, 1999, 10, 2845.

17. S. Arai, Y. Shirai, T. Ishida, and T. Shioiri, Tetrahedron, 1999, 55, 6375.

18. K.W. Ratts, and A.N. Yao, J. Org. Chem., 1966, 31, 1689.

19. M. Valpuesta-Fernandez, P. Durante-Lanes, and F.J. Lopez-Herrera, Tetrahedron, 1990, 46, 7911.

20. Y.-G. Zhou, X.-L. Hou, L.-X. Dai, L.-J. Xia, and M.-H. Tang, J. Chem. Soc, Perkins Trans. 1, 1999, 77.

21. R.J. Goodridge, T.W. Hambely, R.K. Haynes, and D.D. Ridley, J. Org. Chem., 1988, 53, 2318.

Claims

1. A method of making enantiomerically enriched trans-2,3- epoxyamides of the formula

in which R ¹ is a 1-18C aliphatic hydrocarbyl optionally substituted by one or more substituent groups selected from halo, nitro, phenyl and -OR , where R is H, 1-6C alkyl, benzyl or phenyl, or is aryl containing from 6-12 ring carbon atoms which is optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -OR^w, where R^w is as defined above, or is a monocyclic or fused bicyclic heterocyclic group containing at least one heteroatom selected from N, O and S which group is optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -OR^w, where R^w is as defined above; R² and R³ are the same or different group selected from H, 1-6C alkyl optionally substituted with one or more substituent groups selected from halo, nitro, phenyl and -OR^w, where R is as defined above, 2-6C alkenyl optionally substituted with one or more substituent groups selected from halo, nitro, phenyl and -OR^w, where R^w is as defined above, phenyl optionally substituted by one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -OR^w, where R^w is as defined above, and monocyclic heterocyclic groups containing one or more heteroatoms selected from O, S and N, optionally substituted with one or more substituent groups selected from 1-6C alkyl, halo, nitro, phenyl, benzyl and -OR , where R^w is as defined above or R² or R³, together with the nitrogen atom to which they are attached, form a heterocyclic ring, which method comprises reacting a sulfonium salt of the formula II

wherein R² and R³ are as defined above, R⁴ is a group selected from 1-12C alkyl, 6-12C aryl and 7-13C ^"aralkyl and -SiMe₃, R⁵ is 1-4C alkyl group and X^" is a counterion, with an aldehyde of the formula R¹CHO, where R¹ is as defined above, in a solvent in the presence of a base.

A method according to claim 1 , wherein R¹ is an optionally- substituted straight chain, branched chain or cyclic alkyl group containing up to 12 carbon atoms in the alkyl moiety.

A method according to claim 1, wherein R¹ is an optionally- substituted aryl group containing from 6 to 12 ring carbon atoms.

A method according to claim 3, wherein R¹ is phenyl, optionally- substituted by 1-6C alkyl, halo, 1-6C alkoxy, 1-6C haloalkyl and nitro.

A method according to claim 1 , wherein R¹ is an optionally- substituted monocyclic or fused bicyclic hetero aromatic group.

6. A method according to any one of claims 1 to 5, wherein R² and R³ are the same or different group selected from H, 1-6C alkyl and phenyl.

7. A method according to claim 6, wherein R² and R³ are both ethyl.

8. A method according to any one of claims 1 to 5, wherein R² and R³ together form a 4 to 6C alkylene group which is optionally-substituted in the chain by a heteroatom selected from O, N or S.

9. A method according to claim 8, wherein R² and R³ together form a group selected form -(CH₂)₄- and -(CH₂)₂-0-(CH₂)₂-.

10. A method according to any one of claims 1 to 9, wherein R⁴ is selected from methyl, ethyl, butyl, benzyl and trimethylsilyl.

11. A method according to any one of claims 1 to 10, wherein X^" is selected from Br^", CI^", BF₄ ^", PF₆ ^", CIO₄ ^" and CF₃SO₃ ^".

12. A method according to claim 11 , wherein X^" is Br^".

13. A method according to any one of claims 1 to 12, wherein the solvent is selected from dichloromethane, n-hexane, ethanol, tetrahydrofuran, 1 ,4-dioxane, acetonitrile, toluene, α,α,α- trifluorotoluene and water.

14. A method according to any one of claims 1 to 13, wherein the reaction is carried out in the presence of a base selected from alkali metal hydroxides and alkali metal alkoxides.

15. A method according to any one of claims 1 to 14, wherein the reaction is carried out at a temperature in the range of from -78°C to 50°C.

16. A method according to claim 15, wherein the reaction is carried out at a temperature in the range of from -50°C to 0°C.

17. A method according to claim 1 , wherein R¹ is an optionally- substituted aryl or aralkyl group, the solvent is ethanol, the base is potassium hydroxide and the reaction is carried out at a temperature in the range of from -30°C to -50°C.

18. A method according to claim 1 , wherein R¹ is an optionally- substituted aliphatic hydrocarbyl group, the solvent is ethanol, the base is potassium hydroxide and the reaction is carried out at a temperature of about -20°C .

19. A compound of the formula II

wherein R², R³, R , R⁵ and X^" are as defined in claim 1 and individual enantiomers and diastereoisomers thereof.