WO2005056543A2 - Process for use in the preparation of oxiranes from alkenes, and catalysts for use therein - Google Patents

Abstract

There is provided a process for the preparation of oxiranes wherein an optionally substituted alkene is reacted in the presence of a chiral catalyst, an oxidant and an organic solvent characterised in that the oxidant is at least partially soluble in the organic solvent and the oxidant displays low reactivity towards the alkene in the absence of the catalyst. The optionally substituted alkene is preferably an alkene of formula (1): wherein: R1-4 each independently are hydrogen, an optionally substituted aromatic or is saturated hydrocarbyl, an optionally substituted hetrocyclyl, an optionally substituted aromatic or saturated hydrocarbyloxy, an optionally substituted aromatic or saturated hydrocarbylamino, an optionally substituted aromatic or saturated hydrocarbyloxycarbonyl, an optionally substituted aromatic or saturated hydrocarbylaminocarbonyl, nitrile, halide or one or more of R1 & R2, R2 & R3 , R3 & R4 , R1 & R4 optionally being linked in such a way as to form an optionally substituted ring(s). The oxidant is preferably an oxidant of formula (2): A+ HSO5- wherein A+ is a counterion capable of conferring organic solvent solubility. Preferred chiral catalysts of formula (4): wherein: R11 and R12 are each independently an optionally substituted hydrocarbyl group or R11 & R12 are linked in such a way as to form an optionally substituted ring(s); R13 is hydrogen or an optionally substituted hydrocarbyl group; R14 is an optionally substituted hydrocarbyl group; R17 is hydrogen or an optionally substituted hydrocarbyl group; R15 and R16 each independently are hydrogen or an optionally substituted hydrocarbyl group; and 30 X- is a counterion; * is a chiral centre; and *' is a chiral centre when R17 is not hydrogen are provided.

Description

PROCESS FOR USE IN THE PREPARATION OF OXIRANES FROM ALKENES, AND CATALYSTS FOR USE THEREIN

This invention relates to a process for the preparation of oxiranes from alkenes, preferably asymmetrically. There is provided a process for the preparation of oxiranes wherein an optionally substituted alkene is reacted in the presence of a chiral catalyst, an oxidant and an organic solvent characterised in that the oxidant is at least partially soluble in the organic solvent and the oxidant displays low reactivity towards the alkene in the absence of the catalyst. The optionally substituted alkene is preferably an alkene of formula (1):

(1) wherein: R^1"4 each independently are hydrogen, an optionally substituted aromatic or saturated hydrocarbyl, an optionally substituted hetrocyclyl, an optionally substituted aromatic or saturated hydrocarbyloxy, an optionally substituted aromatic or saturated hydrocarbylamino, an optionally substituted aromatic or saturated hydrocarbyloxycarbonyl, an optionally substituted aromatic or saturated hydrocarbylaminocarbonyl, nitrile, halide or one or more of R¹ & R², R² & R³, R³ & R⁴, R¹ & R⁴ optionally being linked in such a way as to form an optionally substituted ring(s). Preferably R^1"4 each independently are hydrogen, an optionally substituted aromatic or saturated hydrocarbyl, an optionally substituted hetrocyclyl, or one or more of R¹ & R², R² & R³, R³ & R⁴, R¹ & R⁴ optionally being linked in such a way as to form an optionally substituted ring(s). Preferably at least one of R\ R², R³ or R⁴ is selected to be different from the remaining groups, or one or more of R¹ & R², R² & R³, R³ & R⁴, R¹ & R⁴ are linked in such a way as to form an optionally substituted unsymmetrical ring(s). Preferably at least one of R\ R², R³ or R⁴ is hydrogen, with the remaining R^1"4 groups being the same or different. Preferably at least one of R\ R², R³ or R⁴ is an aryl group, with the remaining R^1"4 being the same or different. When one or more of R\ R², R³ and R⁴ are different, preferably the compound of formula (1 ) is a Z (or cis) isomer. Aromatic or saturated hydrocarbyl groups which may be represented by R^1"4 independently include alkyl and aryl groups and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups. Alkyl groups which may be represented by R^1"4 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprising up to 10 branch chain carbon atoms, preferably up to 4 branch chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R^1"4 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups. Aryl groups which may be represented by R^1"4 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R^1"4 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups. Aromatic or saturated heterocyclic groups which may be represented by R^1"4 independently include aromatic, saturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R ^"4 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups. Optionally substituted aromatic or saturated hydrocarbyloxy groups which may be represented by R^1"4 independently include alkyoxy and aryloxy groups and any combination thereof, such as aralkyloxyl and alkaryloxyl, for example benzyloxy groups. Optionally substituted aromatic or saturated hydrocarbylamino groups which may be represented by R^1"4 independently include mono and d-alkylamino and mono and di- arylamino groups and any combination thereof, such as aralkylamino and alkarylamino, for example benzylamino and benzylmethylamino groups. Optionally substituted aromatic or saturated hydrocarbyloxycarbonyl groups which may be represented by R^1"4 independently include alkyoxycarbonyl and aryloxycarbonyl groups and any combination thereof, such as aralkyloxycarbonyl and alkaryloxycarbonyl, for example benzyloxycarbonyl groups. Optionally substituted aromatic or saturated hydrocarbylaminocarbonyl groups which may be represented by R^1"4 independently include mono- and di-alkyaminocarbonyl and mono and di-arylaminocarbonyl groups and any combination thereof, such as aralkylaminocarbonyl and alkarylaminocarbonyl, for example benzylaminocarbonyl groups. Halides which may be represented by R ^"4 independently include fluorine, chlorine, bromine and iodine. When any of R^1"4 is a substituted aromatic or saturated hydrocarbyl, a substituted heterocyclic group, a substituted aromatic or saturated hydrocarbyloxy, a substituted aromatic or saturated hydrocarbylamino, a substituted aromatic or saturated hydrocarbyloxycarbonyl, a substituted aromatic or saturated hydrocarbylaminocarbonyl, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivety of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R¹ above. One or more substituents may be present. Where the substituted aromatic or saturated hydrocarbyl group is fully substituted by halogen substituents, the group is referred to as a perhalogenated aromatic or saturated hydrocarbyl group. Perhalogenated aromatic or saturated hydrocarbyl groups which may be represented by R^1"4 independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R^1"4 include -CF₃ and -C₂F₅. When any of R¹ & R², R² & R³, R³ & R\ R¹ & R⁴ are linked in such a way that when taken together with the carbon atoms to which they are attached that an optionally substituted ring is formed, the ring atoms may in addition to carbon atoms may optionally comprise one or more heteroatoms, preferably selected from N, O, S or P. Preferably, when any of R¹ & R², R² & R³, R³ & R⁴, R¹ & R⁴ are linked in such a way that when taken together with the carbon atoms to which they are attached that an optionally substituted ring is formed, the rings atoms are carbon atoms. Preferably, when any of R¹ & R², R² & R³, R³ & R⁴, R¹ & R⁴ are linked in such a way that when taken together with the carbon atoms to which they are attached that an optionally substituted ring is formed, that the ring is a 5, 6 or 7 membered rings. When any of R¹ & R², R² & R³, R³ & R⁴, R¹ & R⁴ are linked in such a way that when taken together with the carbon atoms to which they are attached that an optionally substituted ring is formed, the optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R¹ above. One or more substituents may be present. Examples of such compounds of formula (1 ) include:

Although ozone is not considered to show the required level of solubility in organic solvents, there are many oxidants which show appropriate levels of solubility in organic solvents. However, only those oxidants which also do not display high levels of background epoxidation of the alkene in the absence of the catalyst find use in the process of the present invention. Oxidants which show appropriate levels of solubility in organic solvents and which show no appreciable levels of epoxidation of the alkene in the absence of the catalyst in the range 0°C to -78°C are preferred. Preferred oxidants include oxidants of formula (2):

A⁺ HSO₅ ^" (2)

wherein A⁺ is a counterion capable of conferring organic solvent solubility. Preferred counterions which are represented by A⁺ include (PR⁶R⁷R⁸R⁹)⁺ wherein R^6"9 are optionally substituted aryl groups. Optionally substituted aryl groups are as described above for R^1"4. More preferably the oxidants are compounds of formula (3):

(3) wherein: R¹⁰ is hydrogen, a polyfluorinated alkyl, a resin or a linker bound to a resin. Polyfluorinated alkyl groups which may be represented by R¹⁰ include partial and fully halogenated alkyl groups, preferably fully halogenated alkyl group. Examples of polyfluorinated alkyl groups include CF₃. Most preferably, R ⁰ is hydrogen. The chiral catalyst is often a chiral iminium salt. The chiral catalyst is preferably a chiral iminium salt of formula (4):

wherein: R¹¹ and R¹² are each independently an optionally substituted hydrocarbyl group or R¹¹ & R¹² are linked in such a way as to form an optionally substituted ring(s); R¹³ is hydrogen or an optionally substituted hydrocarbyl group; R¹⁴ is an optionally substituted hydrocarbyl group; R¹⁷ is hydrogen or an optionally substituted hydrocarbyl group; R¹⁵ and R¹⁶ each independently are hydrogen or an optionally substituted hydrocarbyl group; and X^" is a counterion; * is a chiral centre; and ^*' is a chiral centre when R¹⁷ is not hydrogen. Preferably, R¹¹ & R¹² are linked in such a way as to form an optionally substituted ring(s); R¹³ is hydrogen; R¹⁴ is an optionally substituted hydrocarbyl group; R¹⁷ is hydrogen or an optionally substituted hydrocarbyl group; R¹⁵ and R¹⁶ each independently are hydrogen or an optionally substituted hydrocarbyl group; and * is a chiral centre Hydrocarbyl groups which may be represented by R^11"17 independently include alky and aryl groups and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups. Alkyl groups which may be represented by R^11"17 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprising up to 10 branch chain carbon atoms, preferably up to 4 branch chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R^{1 "17} include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups. Aryl groups which may be represented by R^11"17 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R^11"17 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups. Aromatic or saturated heterocyclic groups which may be represented by R^11"17 independently include aromatic, saturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R ^1"17 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups. When any of R^11"17 is a substituted aromatic or saturated hydrocarbyl or a substituted heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivety of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R¹ above. One or more substituents may be present. Where the substituted aromatic or saturated hydrocarbyl group is fully substituted by halogen substituents, the group is referred to as a perhalogenated aromatic or saturated hydrocarbyl group. Perhalogenated aromatic or saturated hydrocarbyl groups which may be represented by R^11"17 independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R^11"17 include -CF₃ and -C₂F₅. When R¹¹& R¹² are linked in such a way that when taken together with the nitrogen and carbon atoms to which they are attached that an optionally substituted ring is formed, it is preferred that these be 5, 6 or 7 membered rings. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R¹ above. One or more substituents may be present. Catalysts of Formula (4) may optionally be attached to a resin. Preferably attachment to a resin via an optional linker may suitably achieved by substitution on one or more of R¹¹, R¹², R¹⁴ or R¹⁷. Counterions which may be represented by X^" include anions which confer organic solubility, preferably delocalised anions, more preferably[BPh₄]\ Examples of counterions which may be represented by X include [BF₄]^', [CF₃SO₃]-, [BPh₄]-, [PF₆]^' and [CIO₄]-. Preferred catalysts are compounds of formula (4a), (4b), (4c) and (4d):

(4a) (4b) (4c) (4d)

wherein: R¹⁴ is an optionally substituted aryl group, preferably an optionally substituted phenyl group; R ⁵ is hydrogen or C_1-4 alkyl group, preferably hydrogen or a methyl group, most preferably a methyl group; R¹⁶ is hydrogen or C_1-4 alkyl group, preferably hydrogen or a methyl group, most preferably a methyl group; R¹⁸ and R¹⁹ are each independently hydrogen or a C_1-4 alkyl group, preferably hydrogen or a methyl group, most preferably both are methyl groups; R²⁰ is preferably an electron donating group, more preferably dihydrocarbylamino; and is a counterion, preferably [BF₄]^_, [CF₃SO₃]-, [BPh₄]^", [PF₆]^_ and [CIO₄]\ Preferred are catalysts of compound of formula (4a), (4b), (4c) or (4d) wherein R¹⁴ is an optionally substituted phenyl group; R¹⁵ is hydrogen or a methyl group; R¹⁶ is hydrogen or a methyl group; R¹⁸ and R¹⁹ are each independently hydrogen or a methyl group; R²⁰ is a dihydrocarbylamino group; and X^" is [BPh₄]^", [PF₆]^" or [CIO₄]^". Highly preferred are catalysts of Formula (4a) wherein R¹⁴ is an unsubstituted phenyl group and R¹⁵ and R¹⁶ are methyl groups, and catalysts of Formula (4c) wherein R¹⁴ is a C₆H₄SO₂CH₃ group and R¹⁵ and R¹⁶ are methyl groups. Organic solvents suitable for use in the process of present invention include polar and non-polar organic solvents, especially hydrocarbons, for example benzene, toluene and xylene, halogented hydrocarbons, for example choloroform and methylene chloride, ethers, for example tetrahydrofuran, t-butyl methyl ether and diglyme, alcohols, such as C₄.₈ aliphatic alcohols, especially pentanol and hexanol and isomers thereof, cyclohexanol, acetonitrile, and polar aprotic solvents, for example N-methyl pyrrolidone, dimethylformamide, N,N-dimethylacetamide or dimethyl sulphoxide, and mixtures thereof. Preferred organic solvents are acetonitrile, methylene chloride and chloroform. The choice of organic solvent or organic solvent mixtures is typically influenced by the solubility of the substrate, the catalyst and the oxidant. Unusually, for certain substrates, it has been found that the choice of solvent may influence the stereospecificity of the reaction. For example, when the substrate is a trans tri-substituted alkene, chlorinated solvents leads to a predominance of one enatiomeric 5 product, whereas acetonitrile leads to a predominance of the other enantiomeric product. Usually it is preferred to operate in substantial absence of water, but water does not appear to inhibit the reaction. Although the use of base is not required in the substantial absence of water, the process of the present invention may optionally be carried out in the presence of a base.0 Suitably the process is carried out at temperatures in the range of from minus 85 to plus 50°C, preferably from minus 78 to plus 35°C and more preferably from minus 40 to plus 25°C. The initial concentration of the alkene, a compound of formula (1 ), is suitably in the range 0.1 to 100 %wt/v and, for convenient larger scale operation, can be for example up5 to 20%wt/v more especially 0.5 to 10% wt v. The molar ratio of the substrate to catalyst is suitably no less than 10:1 and can be up to 1000:1 , preferably between 10:1 and 100:1 and more preferably between 20:1 and 1 :1. The oxidant is preferably employed in a molar excess over the substrate, especially about a 2 fold excess. Reaction times are typically in the range of from 3 min to 24h, especially up to 24h and conveniently about0 4h. After the reaction is complete, the resulting mixture is worked up by standard procedures. Typically, addition of diethyl ether results in precipitation of the oxidant which is removed by filtration leaving the product in solution. The invention will now be described, without limitation, by the following examples.5 EXPERIMENTAL

PREPARATION OF AMINE INTERMEDIATES: General procedure for the formation of the formate protected 5-amino-1,3-dioxanes o from commercially available amino diols:

The amino diol (1.0 equiv.) was dissolved in methanol (10 ml/g) and methyl formate (1.1 equiv.) was added with sodium methoxide (10 mol%). The reaction was left to stir for 3.5h and the solvent removed under reduced pressure. The crude yellow oil was 5 dissolved with CSA (10 mol%) in acetone (50 ml/g) and 2,2-dimethoxypropane (10.0 equiv.). The reaction was left to stir for up to 4h and monitored by thin layer chromatography (TLC). Solvents were removed under reduced pressure and the residue re-dissolved in ethyl acetate, which was washed with sat. aq. sodium hydrogen carbonate. The organics were dried (MgSO₄) and solvents removed under reduced pressure.

N-[(4S,5S)-2,2-Dimethyl-4-[4-nitro-phenyl]-1,3-dioxan-5-yl]formamide:

Prepared according to the general procedure from (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)- 1 ,3-propandiol (1.00 g, 4.71 mmol). Colourless oil (1.12 g, 85%); [α]_D +3.5° (c 1.02, CHCI₃); v_max(film) /cm^"1 1674, 1520, 1346, 856; δ_H (250 MHz; CDCI₃) 1.55 (3H, s), 1.59 (3H, s), 3.83 (1 H, dd, J 12.1 , 1.7 Hz), 4.24 (1 H, dd, J 12.1 , 1.8 Hz), 4.40 (1 H, m,), 5.26 (1 H, d, J 1.0 Hz), 7.50 (2H, d, J 8.9 Hz), 7.91 (1H, s), 8.15 (2H, d, J 8.9 Hz); δ_c (62.5 MHz; CDCI₃) 18.81 , 29.29, 45.38, 64.86, 71.91 , 100.70, 123.72, 126.79, 145.80, 147.80, 160.62. m/z 298.1399; C₁₃H₁₆N₂O₅ (M⁺NH₄) requires 298.1403.

Λ/-[(4S,5S)-2,2-Dimethyl-4-[4-(methylsulfanyl)-phenyl]-1,3-dioxan-5-yl]formamide:

Prepared according to the general procedure from (1 S,2S)-(+)-2-amino-1-(4- methylthiophenyl)-1 ,3-propandiol (5.00 g, 23.4 mmol). Colourless oil (5.50 g, 84%); m/z 281.1081 ; C₁₄H₁₉NO₃S (M⁺) requires 281.1085.

Λ -[(4S,5S)-2,2-Dimethyl-4-[4-(methylsulfonyI)-phenyl]-1,3-dioxan-5-yl]formamide:

Λ/-[(4S,5S)-2,2-Dimethyl-4-[4-(methylsulfanyl)-phenyl]-1 ,3-dioxan-5-yl]formamide (4.0 g, 14.2 mmol) was dissolved in dichloromethane (100 ml) and cooled to 0°C. To this solution was added m-CPBA (2.2 eq, 7.03 g, 31.0 mmol) as a solution in chloroform (20 ml), dropwise over 10 min. The reaction was then left to stir for 2 h. The reaction mixture was transferred to a separating funnel and washed with sat. aq. sodium hydrogen carbonate (2 x 40 ml), brine (2 x 40 ml) and dried (MgSO₄). Solvents were removed under reduced pressure to yield a colourless oil. Crystallized from chloroform/diethyl ether, colourless crystals (3.80 g, 85%); m.p. 146-147°C; m/z 314.1058; C₁₄H₁₉NO₅S (M⁺H) requires 314.1062.

(2S)-terf-ButoxycarbonyIamino-3-(4-methoxy-phenyl)-propionic acid methyl ester:

A solution of (2S)-terf-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid (8.00 g, 28.5 mmol) in dimethylformamide (80 ml) was treated with ground potassium hydroxide (1.72 g, 31.3 mmol) and iodomethane (1.95 ml, 31.3 mmol) (in 20 ml dimethylformamide) was added dropwise over 5 min at 0°C. The reaction was stirred at room temperature for 30 min and, after this time period, additional ground potassium hydroxide (1.72 g, 31.3 mmol) and iodomethane (1.95 ml, 31.3 mmol) (in 20 ml dimethylformamide) were added at 0°C. The reaction was then left to stir for 3 h. The solution was poured onto ice (150 ml) and extracted with ethyl acetate (3 x 75 ml). The organic layers were washed with water (3 x 50 ml), brine (2 x 50 ml) and dried (MgSO₄). The solvent was removed under reduced pressure to yield a colourless oil. Crystallization was achieved from ethyl acetate/light petroleum, to give colourless crystals (6.5 g, 74%); m.p. 52-53 °C; m/z 309; C₁₆H₂₃NO₅ requires 309.15762.

Methyl (4S,5/?)-5-[4-(methyloxy)phenyI]-2-oxo-1 ,3-oxazolane-4-carboxylate :

(2S)-fert-Butoxycarbonylamino-3-(4-methoxy-phenyl)-propionic acid methyl ester (5.0 g, 16.2 mmol) was dissolved in CH₃CN (200 ml). To this was added K₂S₂O₈ (8.75 g, 32.4 mmol) as a solution in water (210 ml) and CuSO₄ (0.52 g, 3.2 mmol) also as a solution in water (50 ml). The reaction mixture was then heated to 70°C, under a blanket of N₂, for 3 h. The solution was allowed to cool and extracted with ethyl acetate (3 x 150 ml), dried (MgSO₄), concentrated under reduced pressure to yield a crude dark yellow oil. Column chromatography eluting with ethyl acetate/light petroleum (1:10-1:1) afforded a colourless solid, which was recrystallized from ethyl acetate/light petroleum to afford colourless crystals (2.10g, 52%); m.p. 94-96°C; m/z 251.0794; C₁₂H₁₃NO₅ (M⁺) requires 251.0794.

(4R,5/?)-4-(hydroxymethyl)-5-[4-(methyloxy)phenyl]-1,3-oxazolan-2-one: Methyl (4S,5R)-5-[4-(methyloxy)phenyl]-2-oxo-1 ,3oxazolane-4-carboxylate (2.20 g, 8.8 mmol) was dissolved in ethanol (25 ml) and cooled to 0°C. To this was added dropwise NaBH₄ (0.70 g, 19.3 mmol) as a solution in ethanol (8 ml). After the addition was complete the ice bath was removed and the reaction stirred at room temperature for 45 min. The reaction was cooled down to 0°C and cone. HCI (1.5 ml) was added, followed by water (15 ml). The ethanol was evaporated under reduced pressure and the remaining aqueous solution extracted with ethyl acetate (3 x 50 ml). The organics were dried (MgSO₄) and solvents removed to afford a crude off white solid, which was recrystallized from ethyl acetate/light petroleum, to afford colourless crystals (1.75 g, 90%); m.p. 140-142°C; C₁₁H₁₃NO₄ (M⁺) requires 223.0845.

(1 f?,2R)-(-)-2-Amino-1 -(4-methyloxy-phenyl)-1 ,3-propanediol:

4-Hydroxymethyl-5-(4-methoxy-phenyl)-oxazolidin-2-one (1.65 g, 7.4 mmol) was suspended in 1 M NaOH (40 ml) and heated at reflux for 30 min. The reaction was allowed to cool to room temperature and extracted with ethyl acetate (8 x 30 ml). The organics were dried (MgSO₄) and solvents removed to afford a colourless solid, recrystallized from methanol/diethyl ether (1.33 g, 91%); m.p. 132-134°C; m/z 198.1125; C₁₀H₁₅NO₃ (M⁺H) requires 198.1130.

Λ/-{(4R,5R)-2,2-Dimethyl-4-[4-(methyloxy)-phenyl]-1,3-dioxan-5-yl}formamide: (1R,2ft)-(-)-2-Amino-1-(4-methyloxy-phenyl)-1 ,3-propanediol (1.2 g, 6.1 mmol) was dissolved in methanol (25 ml) and methyl formate (0.45 ml, 7.3 mmol) was added with sodium methoxide (0.1 ml). The reaction was left to stir for 3.5 h and the solvent removed under reduced pressure. The crude yellow oil was then dissolved in acetone (60 ml), 2,2-dimethoxypropane (10 equiv.) and boron-trifluoride-diethyletherate was added until pale yellow colour persisted (ca 0.2 ml). The reaction was then left to stir for 45 min. Solvents were again removed under reduced pressure and the residue re-dissolved in ethyl acetate, which was washed with sat. aq. sodium hydrogen carbonate. The organics were dried (MgSO₄) and solvents removed to yield a pale yellow oil (1.21 g, 75%); m/z 266.1390; C₁₄H₁₉NO₄ (M⁺H) requires 266.1392.

General procedure for the deprotection of formamides with hydrazine hydrate:

The formate protected acetonide was dissolved in aq. hydrazine hydrate (85%) (20 ml/g) and the solution heated under reflux for 2.5 h. The solution was allowed to cool to room temperature and extracted with ethyl acetate (3 x 20 ml/g). The organic layers were washed with water (2 x 20 ml/g), dried (MgSO₄) and solvents removed under reduced pressure.

(4S,5S)-2,2-dimethyl-4-[4-nitro-phenyl]-1,3-dioxan-5-amine: Prepared according to the general procedure from Λ/-[(4S,5S)-2,2-Dimethyl-4-[4-nitro- phenyl]-1 ,3-dioxan-5-yl]formamide (4.00 g, 14.9 mmol), except reaction heated under reflux for 1 h. Chromatography performed eluting with ethylacetate. Pale yellow plates. (2.80 g, 78%); mp 117-119°C; [α]_D ²⁰ +66.2° (c 1.13, CHCI₃); Found: C, 57.05; H, 6.51 ; N, 10.77. C₁₂H₁₆N₂O₄ requires C, 57.13; H, 6.39; N, 11.10.; v_max(film) /cm^"1 1605, 1520, 1350, 1196, 1080, 941 , 856; δ_H (250 MHz; CDCI₃) 1.56 (6H, s), 2.84 (1 H, q, J 1.9 Hz), 3.86 (1 H, dd, J 11.8, 1.9 Hz), 4.31 (1 H, dd, J 11.8, 2.3 Hz), 5.17 (1 H, d, J 0.7 Hz), 7.49 (2H, d, J 7.5 Hz), 8.22 (2H, d); δ_c (100 MHz; CDCI₃) 18.59, 29.66, 49.42, 66.32, 73.42, 99.57, 123.63, 126.66, 147.17, 147.29; m/z 253.1191 ; C₁₂H₁₆N₂O₄ (M⁺H) requires 253.1188.

(4S,5S)-2,2-dimethyl-4-[4-(methylsulfanyl)-phenyl]-1 ,3-dioxan-5-amine:

Prepared according to the general procedure from Λ/-[(4S,5S)-2,2-Dimethyl-4-[4- (methylsulfanyl)-phenyl]-1 ,3-dioxan-5-yl]formamide (1.50 g, 5.34 mmol). Colourless oil (1.28 g, 95%); m/z 253.1137; C₁₃H₁₉NO₂S (M⁺) requires 253.1137.

(4S,5S)-2,2-dimethyl-4-[4-(methylsulfonyl)-phenyl]-1 ,3-dioxan-5-amine:

Prepared according to the general procedure from Λ/-[(4S,5S)-2,2-Dimethyl-4-[4- (methylsulfonyl)-phenyl]-1 ,3-dioxan-5-yl]formamide (1.80 g, 5.8 mmol). Product isolated as a colourless oil, crystallized from diethyl ether/ethylacetate. Colourless crystals (1.59 g, 96%); m.p. 120-122 °C; m/z 285.1028; C₁₃H₁₉NO₄S (M⁺) requires 285.1035.

(4R,5/?)-2,2-dimethyI-4-[4-(methyloxy)-phenyI]-1,3-dioxan-5-amine:

Prepared according to the general procedure from Λ/-[(4R,5R)-2,2-Dimethyl-4-[4- (methyloxy)-phenyl]-1 ,3-dioxan-5-yl]formamide (0.70 g, 2.6 mmol). Colourless oil. (0.59 g, 95%); m/z 238.1443; C₁₃H₁₉NO₃ (M⁺H) requires 238.1443. PREPARATION OF CATALYSTS:

General procedure for the synthesis of dihydroisoquinolinium salts from 2-(2- bromoethyl) benzaldehyde and primary amines: A solution of the amine in ethanol, (10 ml per g of amine, 1 equivalent), was added dropwise via a stoppered, pressure equalising, dropping funnel, to an ice cooled, one- neck flask, containing 2-(2-bromoethyl) benzaldehyde, (1.60 equivalents, 1.10 if distilled previously). After the addition was complete the dropping funnel was removed and replaced by a stopper to contain the hydrogen bromide generated temporarily in the reaction. The reaction mixture was stirred overnight while attaining ambient temperature. Sodium tetraphenylborate, (or any other anion exchanging salt, 1.10 equivalents), in the minimum amount of acetonitrile, was added in one portion to the reaction mixture and after 5 minutes of stirring, the organic solvents are removed under reduced pressure. Ethanol was added to the residue, followed by water. The resulting solid was collected by filtration and washed with additional ethanol followed by diethyl ether. If no solid materialises after the addition of the water the suspension was allowed to settle and the ethanol/water phase was decanted off. The gummy residue which may be obtained, was macerated in hot ethanol or methanol. The organic salt may then precipitate but in some rare cases it does so upon slow cooling of the hot alcoholic solution. If solubility problems do arise, small amounts of acetonitrile may be added during this process.

(+)-2-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yI]-3,4-dihydroisoquinolinium tetraphenylborate:'

Prepared according to the general procedure. Yield 75%, recrystallized from acetone/diethyl ether, yellow solid, m.p. 169-170°C; δ_H (250 MHz; CD₃CN), 1.65 (3H, s), 1.94 (3H, s), 2.39-2.48 (1 H, m), 2.70-2.82 (1 H, m) 3.25-3.40 (1 H, m), 3.81-3.97 (1 H, m), 4.06 (1H, m), 4.30 (1 H, d, J 13.7 Hz), 4.58 (1 H, dd, J 13.7, 3.1 Hz), 5.70 (1 H, d, J 2.8 Hz), 6.81 (4H, t, J 7.2 Hz), 7.35-7.40 (6H, m), 7.46 (1 H, t, J 7.3 Hz), 7.65-7.74 (2H, m), 8.92 (1H, s); δ_c (62.50 MHz; CD₃CN) 17.98, 24.06, 28.68, 51.55, 61.44, 65.46, 70.72, 104.88, 121.85, 124.29, 125.44, 125.72, 128.14, 128.46, 128.62, 128.04, 134.39, 135.79, 136.97,

137.68, 138.72, 163.51 , 167.48; m/z 322.1809; C₂₁H₂₄NO₂ (cation) requires 322.1807.

(-)-2-[(4R,5 ?)-2,2,4-Trimethyl-1,3-dioxan-5-yI]-3,4-dihydroisoquinolinium tetraphenylborate: Prepared according to the general procedure from (1R,2R)-2,2,4-Trimethyl-[1,3]dioxan-5- yl-amine (0.75 g, 2.96 mmol). Recrystallized from DCM/hexane, yellow plates (1.13 g, 66%); Recrystallized from acetone/ethyl acetate. Yield (0.149 g, 66%); mp 164-165°C (dec); m/z 260.1655; C₁₆H₂₂NO₂ (cation) requires 260.1651. (+)-2-[(4S,5S)-2,2-dimethyl-4-(1-methylethyl)-1,3-dioxan-5-yl]-3_J4- dihydroisoquinolinium tetraphenylborate: Prepared according to the general procedure from (4S,5S)-2,2-dimethyl-4-(1- methylethyl)-1 ,3-dioxan-5-amine (0.05 g, 0.29 mmol). Recrystallized from acetone/diethyl 5 ether, yellow plates (0.120 g, 70%); mp 166-167°C (dec); m/z 288.1959; C₁₈H₂₆NO₂ (cation) requires 288.1964.

(+)-[(4S,5S)-2,2-dimethyl-4-[4-(nitro)-phenyl]-1,3-dioxan-5-yl]-dihydroisoquinolinium tetraphenylborate:0 Prepared according to the general procedure from (+)-(4S,5S)-2,2-dimethyl-4-[4-(nitro)- phenyl]-1 ,3-dioxan-5-amine (0.19 g, 0.8 mmol). Recrystallized from DCM/hexane, yellow plates (0.36 g, 74%); m.p. 176-178 °C (dec); Found C, 77.73; H, 6.23; N, 4.00; C₄₅H₄₃BN₂O₄-0.5H₂O requires: C, 77.66; H, 6.38; N, 4.03.; m/z 367.1658; C₂₁H₂₃N₂O₄ (cation) requires 367.1658.5 (+)-[(4S,5S)-2,2-dimethyl-4-[4-(methylsulfanyl)-phenyl]-1,3-dioxan-5-yI]- dihydroisoquinolinium tetraphenylborate: Prepared according to the general procedure from (4S,5S)-2,2-dimethyl-4-[4- (methylsulfanyl)-phenyl]-1 ,3-dioxan-5-amine (0.50 g, 2.0 mmol). Recrystallized from0 DCM/hexane, yellow plates (1.00 g, 73%); m.p. 146-148°C (dec); Found: C, 79.05; H, 6.59; N, 1.93. C₄₆H₄₆BNO₂S-0.5H₂O requires C, 79.27; H, 6.66; N, 2.01.; m/z 368.1682; C₂₂H₂₆NO₂S (cation) requires 368.1684.

(+)-[(4S,5S)-2,2-dimethyl-4-[4-(methylsulfonyl)-phenyl]-1,3-dioxan-5-yl]-3,4-5 dihydroisoquinolinium tetraphenylborate: Prepared according to the general procedure from (4S,5S)-2,2-dimethyl-4-[4- (methylsulfonyl)-phenyl]-1 ,3-dioxan-5-amine (0.75 g, 2.96 mmol). Recrystallized from DCM/hexane, yellow plates (1.55 g, 73%); m.p. 199-201°C (dec); Found: C, 75.62; H, 6.32; N, 1.84. C₄₆H₄₆BNO₄S-0.5H₂O requires C, 75.79; H, 6.50; N, 1.92.; m/z 400.1586; o C₂₂H₂₆NO₄S (cation) requires 400.1583.

H-[(4/?,5 ?)-2,2-dimethyl-4-[4-(methyIoxy)-phenyl]-1,3-dioxan-5-yl]- dihydroisoquinolinium tetraphenylborate: Prepared according to the general procedure (-)-(4R,5R)-2,2-dimethyl-4-[4-(methyloxy)-5 phenyl]-1 ,3-dioxan-5-amine (0.40 g, 1.7 mmol). Recrystallized from DCM/hexane, yellow plates (0.83 g, 74%); m.p. 171-173°C (dec); m/z 352.1915; C₂₂H₂₆NO₃ (cation) requires 352.1913.

General procedure for the synthesis of 5H-dibenzo[c,e]azepinium salts from 2-[2- (bromomethyl)phenyljbenzene carbaldehyde and primary amines:

A solution of the amine in ethanol, (10 ml per g of amine, 1 equivalent), was added dropwise via a stoppered, pressure equalising, dropping funnel, to an ice cooled, one- neck flask, containing a solution of 2-[2-(bromomethyl)phenyl]benzene carbaldehyde, (1.10 equiv.) in ethanol (10 ml/g carbaldehyde). After the addition was complete the dropping funnel was removed and replaced by a stopper to contain the hydrogen bromide generated temporarily in the reaction. The reaction mixture was stirred overnight while attaining ambient temperature. Sodium tetraphenylborate, (or any other anion exchanging salt, 1.10 equivalents), in the minimum amount of acetonitrile, was added in one portion to the reaction mixture and after 5 minutes of stirring, the organic solvents are removed under reduced pressure. Ethanol was added to the residue, followed by water. The resulting solid was collected by filtration and washed with additional ethanol followed by diethyl ether. If no solid materialises after the addition of the water the suspension is allowed to settle and the ethanol/water phase is decanted off. The gummy residue which may be obtained, is macerated in hot ethanol or methanol. The organic salt may then precipitate but in some rare cases it does so upon slow cooling of the hot alcoholic solution. If solubility problems do arise, small amounts of acetonitrile may be added during this process.

5,7-dihydrodibenzo[c,e]oxepine:

A suspension of 2,2'-biphenyl dimethanol, (4.22 g, 19.5 mmol), in hydrobromic acid (60 ml, 24% in water), was heated to 100°C for 40 min. The cloudy solution was then allowed to cool and the aqueous phase extracted with diethyl ether (3 x 50 ml). The organic layers are then washed with brine (50 ml), sat. aq. Sodium hydrogen carbonate and dried (MgSO₄). Solvent was removed to yield a colourless solid. Recrystallized from ethyl acetate/light petroleumto give colourless crystals, (3.25 g, 85%); m.p. 71°C; v_max(film) /cm^{" 1} 1567, 1197, 1073, 1042, 903, 891 , 754, 602; δ_H (400 MHz; CDCI₃) 4.35 (4H, s), 7.23- 7.56 (8H, m); δ_c (100 MHz; CDCI₃) 67.53, 127.46, 128.24, 128.91 , 129.69, 135.16, 141.19; m/z 196.0887; C₁₄H₁₂O (M⁺) requires 196.0888.

2-[2-(bromomethyl)phenyl]benzene carbaldehyde:

To an ice cooled solution of 5,7-dihydrodibenzo[c,e]oxepine (2.00 g, 10.2 mmol), in carbon tetrachloride (50 ml), in a round bottom flask equipped with a reflux condenser was added molecular bromine (1.76 g, 11.0 mmol), in carbon tetrachloride (6 ml), dropwise over 5 min (the reaction turns deep red). The cooling bath was removed and the reaction mixture irradiated with ultra violet light for 5 h (after 20 min solution turns pale yellow, indicative of complete consumption of bromine). The resultant solution was evaporated under reduced pressure, then diluted with diethyl ether, washed with sat. aq. Sodium carbonate, brine and dried (MgSO₄). Solvents were removed under reduced pressure to yield a orange oil. Crystallized from ethyl acetate/light petroleum as colourless crystal. (1.80 g, 64%); m.p. 56-58°C; v_max(nujol) /cm^"1 1694, 1594, 1255, 1221 , 1197, 761 ; δ_H (400 MHz; CDCI₃) 4.21 (2H, dd, J 40.0, 10.1 Hz), 7.12-7.98 (8H, m), 9.65 (1 H, s); δ_c (100 MHz; CDCIs), 33.83, 129.96, 130.88, 131.02, 131.40, 133.00, 133.05, 133.39, 5 135.95, 136.41 , 138.28, 140.16, 145.63, 194.08; m/z 275.9977 (⁸¹Br isotope); C^HnBrO (M⁺) requires 275.9974.

(+)-6-[(1R,2R,3/?,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yI]-5H- dibenzo[c,e]azepinium tetraphenylborate :0 Prepared according to the general procedure from (-)-i^s°pi^nocamPhenylamine (3.12 g, 20.5 mmol). The product was isolated as yellow plates (8.00 g, 60%); m.p. 212°C (dec); [α]²⁰ _D +22.4 (c 1.00, CH₃CN); Found: C, 87.81 ; H, 7.20; N, 1.95. C₄₈H₄₈BN«0.3H₂O requires C, 87.79; H, 7.37; N, 1.95.; v_max(nujol) /cm^'1 1630, 1599, 1580, 1557, 1209, 756, 705, 612; δ_H (400 MHz; DMSO-d₆, 80°C) 1.02 (3H, d, J 11.28 Hz), 1.14 (3H, s), 1.35 (3H,5 s), 1.48 (1H, d, J 16.8 Hz), 2.02 (1 H, td, J 9.3, 2.6 Hz), 2.10-2.31 (2H, m), 2.55-2.74 (3H, m), 4.84-5.12 (3 H, m), 6.80 (4H, t, J 11.4 Hz), 6.93 (8H, t, J 11.8 Hz), 7.20-7.29 (8H, m), 7.61-7.92 (6H, m), 8.02 (1 H, td, J 11.64, 2.24 Hz), 8.07-8.16 (1 H, m), 9.69 (1 H, s); δ_c (100 MHz; DMSO-d₆, 80°C) 19.92, 23.76, 28.97, 33.69, 34.80, 40.00, 41.12, 42.15, 48.36, 53.99, 74.28, 122.23, 125.96, 127.77, 129.41 , 129.65, 129.94, 130.31 , 130.69, 131.08,0 131.12, 135.41 , 135.74, 136.55, 137.93, 141.90, 164.50, 171.15; m/z 330.2228; C₂₄H₂₈N (cation) requires 330.2222.

(-)-2-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]-5H-dibenzo[c,e]azepinium tetraphenylborate:5 Prepared according to the general procedure from (+)-(4S,5S)-2,2-Dimethyl-4-phenyl-1 ,3- dioxan-5-amine (3.85 g, 18.8 mmol). The product was isolated as yellow plates (9.00 g, 68%); m.p. 187-188°C (dec); Found C, 85.23; H, 6.52; N, 1.96. C₅₀H₄₆BNO₂ requires C, 85.34; H, 6.59; N, 1.99.; m/z 384.1968; C₂₆H₂₆NO₂ (cation) requires 384.1964.

o (-)-2-[(4S,5S)-2,2-Dimethyl-4-[4-(nitro)-phenyI]-1 ,3-dioxan-5-yl]-5H- dibenzo[c,e]azepinium tetraphenylborate: Prepared according to the general procedure from (+)-(4S,5S)-2,2-Dimethyl-4-[4-(nitro)- phenyl]-1 ,3-dioxan-5-amine (0.30 g, 1.19 mmol). The product was isolated as yellow plates (0.57 g, 64%); m.p. 209-210°C (dec); Found: C, 85.23; H, 6.52; N, 1.96.5 C₅₀H₄₆BNO₂ requires C, 85.34; H, 6.59; N, 1.99.; m/z 429.1815; C₂₆H₂₅N₂O₄ (cation) requires 429.1814.

(-)-2-[(4S,5S)-2,2-Dimethyl-4-[4-(methylsulfonyl)-phenyl]-1,3-dioxan-5-yI]-5H- dibenzo[c,e]azepinium tetraphenylborate: Prepared according to the general procedure from (+)-(4S,5S)-2,2-dimethyl-4-[4- (methylsulfonyl)-phenyl]-1 ,3-dioxan-5-amine (0.30 g, 1.05 mmol). The product was isolated as yellow plates (0.54 g, 66%); m.p. 162-165°C (dec); Found: C, 75.14; H, 5.89; N, 1.75. C₅₁H₄₈BNO₄S»2.0H₂O requires C, 74.87; H, 6.29; N, 1.71.; m/z 462.1739; C₂₇H₂₈NO₄S (cation) requires 462.1739.

(+)-2-[(4S,5S)-2,2-Dimethyl-4-[4-(methyloxy)-phenyl]-1,3-dioxan-5-yl]-5H- dibenzo[c,e]azepinium tetraphenylborate:

Prepared according to the general procedure from (-)-(4R,5R)-2,2-dimethyl-4-[4- (methyloxy)-phenyl]-1 ,3-dioxan-5-amine (0.13 g, 0.48 mmol). The product was isolated as yellow plates (0.23 g, 64%); m.p. 207-209°C (dec); Found: C, 76.58; H, 6.02; N, 1.84. C₅₁H₄₈BNO₃«3.5H₂O requires C, 76.84; H, 6.52; N, 1.76.; m/z 414.2063; C₂₇H₂₈NO₃ (cation) requires 414.2069.

General procedure for the synthesis of 3H-4-azapinium-cyclohepta[2,1-a;3,4- a']dinaphthalene salts from (R) or (S)-2'-Bromomethyl-[1,1']binaphthalenyl-2- carbaldehyde and primary amines:

A solution of the amine in ethanol, (10 ml per g of amine, 1 equivalent), was added dropwise via a stoppered, pressure equalising, dropping funnel, to a one-neck flask, containing a solution of (R) or (S)-2'-Bromomethyl-[1,1']binaphthalenyl-2-carbaldehyde,

(1.10 equiv.) in ethanol (10 ml/g carbaldehyde) warmed at 35°C. After the addition was complete the dropping funnel was removed and replaced by a stopper to contain the hydrogen bromide generated temporarily in the reaction. The reaction mixture was stirred overnight while attaining ambient temperature. Sodium tetraphenylborate, (or any other anion exchanging salt, 1.10 equivalents), in the minimum amount of acetonitrile, was added in one portion to the reaction mixture and after 5 minutes of stirring, the organic solvents are removed under reduced pressure. Ethanol was added to the residue, followed by water. The resulting solid was collected by filtration and washed with additional ethanol followed by hexane. If no solid materialises after the addition of the water the suspension is allowed to settle and the ethanol/water phase is decanted off.

The gummy residue which may be obtained, is macerated in hot ethanol or methanol. The organic salt may then precipitate but in some rare cases it does so upon slow cooling of the hot alcoholic solution. If solubility problems do arise, small amounts of acetonitrile may be added during this process.

(R)-Trifluoro-methanesulfonic acid 2'-trifluoromethanesulfonyloxy [1,1']binaphthalenyl-2-yl ester:

(R)-[1 ,1']Binaphιhalenyl-2,2'-diol (1.70 g, 5.9 mmol) was dissolved in dichloromethane (40 ml) and cooled to -30°C. To this was added 4-dimethylaminopyridine (0.289 g, 2.4 mmol), 2,6-lutidine (2.06 ml, 17.7 mmol) and triflic anhydride (2.98 ml, 17.7 mmol). The solution was allowed to warm to room temperature and stirred for 4 h. Silica gel was added to the solution and the solvent evaporated under reduced pressure. The compound adsorbed on silica was transferred to a fritted glass funnel and washed with ethyl acetate/light petroleum until the title compound had eluted. Solvents were removed under reduced pressure to yield a crude colourless solid, which was recrystallized from hexane to give colourless crystals (3.20 g, 99%), m.p. 68-70°C; [α]²⁰ _D -145.3° (c 1.08, CHCI₃); v_max(film) /cm^"1 3062, 1508, 1424, 1246, 1140, 1065, 963, 865; δ_H (250 MHz; CDCI₃) 7.25 (2H, m), 7.40 (2H, m), 7.59 (4H, m), 8.00 (2H, d, J 8.2 Hz), 8.13 (2H, d, J 9.0 Hz); δ_c (100 MHz; CDCI₃) 118.12, 119.33, 123.46, 126.76, 127.33, 127.99, 128.36, 132.00, 132.37, 133.17,

145.41 ; m/z 549.9974; C₂₂H₁₂F₆O₆S₂ (M⁺) requires 549.9980.

(S)-Trifluoro-methanesulfonic acid 2"-trifluoromethanesulfonyloxy [1,1']binaphthalenyl-2-yl ester: Prepared in an identical manner to the (R)-enantiomer above, from (S)- [1 ,1']binaphthalenyl-2,2'-diol (6.76 g, 24.0 mmol). Colourless crystals (13.0 g, 99%); m.p. 65-67°C; [α]²⁰ _D +140.6 (c 1.09, CHCI₃).

(RJ^'-Dimethyl-Il.ribinaphthalenyl : (f?)-Trifluoro~methanesulfonic acid 2'-trifluoromethanesulfonyloxy [1 ,1']binaphthalenyl-2-yl ester (13.0 g, 23.6 mmol) and 1 ,3-bis(diphenylphosphino)propane nickel(ll)chloride (1.10 g, 1.7 mmol) were dissolved in anhydrous diethyl ether (100 ml). The reaction was cooled to -10°C in a ice/salt bath and methylmagnesium bromide (3 M in Et₂O, 31.5 ml, 94.4 mmol) was added dropwise over 30 min. The reaction was allowed to attain ambient temperature and stirred over night. The dark green/brown solution was diluted with diethyl ether (150 ml) and filtered through celite (to remove the nickel catalyst). The filtrate was washed with 0.5 M hydrochloric acid (2 x 50 ml) and brine (50 ml). Removal of solvent under reduced pressure yielded a red/orange crude oil, which was purified by column chromatography eluting with hexane to give a pale yellow oil. Crystallization from methanol afforded the product as colourless crystals (6.00 g, 90%); m.p. 68-72°C (Lit 67-

71 °C); [α]²⁰ _D -39.0° (c 1.12, CHCI₃); v_max(film) /cm^"1 3053, 2246, 1594, 1506, 1421 , 1379, 1351 , 1221 , 1143, 1027, 913, 865; δ_H (250 MHz; CDCI₃) 2.03 (6H, s), 7.04 (2H, d, J 8.4Hz), 7.19 (2H, m), 7.35 (2H, m), 7.37 (2H, d, J 8.3 Hz), 7.86 (2H, d, J 8.4 Hz), 7.88 (2H, d, J 8.4 Hz); δ_c (100 MHz; CDCI₃) 20.01 , 124.87, 125.62, 126.06, 127.41 , 127.90, 128.70, 132.20, 132.75, 134.25, 135.11 ; m/z 300.1747; C₂₂H₂₂N (M⁺NH₄) requires

300.1752.

(SJ^^'-Dimethyl-ϊl.rjbinaphthalenyl:

Prepared in an identical manner to the (R)-enantiomer above, from (S)-trifluoro- methanesulfonic acid -trifluoromethanesulfonyloxy [1 ,1']binaphthalenyl-2-yl ester (5.00g, 9.0 mmol). Colourless crystals (2.33 g, 92%); m.p. 71-73°C; [α]²⁰ _D +37.0°(c 1.01 , CHCI₈).

(R)-2,2'-DibromomethyI-[1,1']binaphthalenyl:

Method 1 :

(R)-2,2'-Dimethyl-[1 ,1']binaphthalenyl (5.00 g, 17.7 mmol) was dissolved in carbon tetrachloride (70 ml) and Λ/-bromosuccinamide (6.63 g, 37.2 mmol), benzoyl peroxide (0.057 g, 0.2 mmol) were added. The mixture was heated under reflux for 24 h and upon cooling the solvent was removed under reduced pressure. The red/brown residue which remained, was diluted with chloroform and washed with water and brine. The organics were dried (MgSO₄) and solvent removed under reduced pressure. Recrystallization from chloroform/hexane afforded the product as colourless crystals (3.5 g, 45%). The remaining filtrate was concentrated and subjected to column chromatography eluting with light petroleum/ethyl acetate (97:3). Giving 0.18 g of starting material and a further 1.50 g of product (after recrystallization from chloroform/hexane), a total of 5.0 g, 64%.

Method 2:

(R^^'-DimethyHl .rjbinaphthalenyl (3.00 g, 10.6 mmol), Λ/-bromosuccinamide (3.78 g, 21.3 mmol) and AIBN (10 mol%, 0.174 g, 1.1 mmol) were stirred in carbon tetrachloride (35 ml). The solution was irradiated with visible light (150 Watt Philips tungsten bulb) for 5 h. The reaction mixture was filtered through a fritted glass funnel and a scoop of silica added. The solvent was removed under reduced pressure to give the reaction mixture adsorbed onto silica. Immediately chromatographed eluting with light petroleum/ethyl acetate (97:3) to afford a colourless solid, recrystallized from chloroform/hexane. Colourless crystals (4.10 g, 88%).

Method 3:

Prepared as Method 2, from (R)-2,2'-Dimethyl-[1 ,1']binaphthalenyl (4.00 g, 14.2 mmol), using cyclohexane as reaction solvent (60 ml). Colourless crystals (5.50 g, 88%). m.p. 185-187°C; [α]²⁰ _D -164.4° (c 1.04, benzene); v_max(film) /cm^"1 3049, 2360, 1506, 1431 , 1210, 818, 749, 684; δ_H (400 MHz; CDCI₃) 4.25 (4H, s), 7.07 (2H, d, J 8.0 Hz), 7.25 (2H, m), 7.46 (2H, m), 7.74 (2H, d, J 8.0 Hz), 7.91 (2H, d, J 8.0 Hz), 8.00 (2 H, d, J 8.0 Hz); δ_c (100 MHz; CDCI₃) 32.61 , 126.78, 126.80, 127.61 , 127.74, 128.02, 129.35, 132.50, 133.25, 134.07, 134.17; m/z 437.9614; C₂₂H₁₆Br₂ (M⁺) requires 437.9619.

(S)-2,2'-Dibromomethyl-[1,1']binaphthalenyl:

Prepared in an identical manner to the (R)-enantiomer above (method 1), from (S)-2,2'- dimethyl-[1 ,1']binaphthalenyl (2.00 g, 7.1 mmol). Colourless crystals (1.87 g, 60%); m.p. 181-183°C; [α]²⁰ _D -159.0° (c 1.17, benzene).

(R)-3,5-Dihydro-4-oxa-cyclohepta[2,1-a;3,4-a']dinaphthalene: (R)-2,2'-Dibromomethyl-[1 ,1']binaphthalenyl (0.50 g, 1.1 mmol) was suspended in a mixture of sat. aq. sodium carbonate solution and 1 ,4-dioxane (1 :1 , 60 ml). The solution was heated under reflux for 12 h. Upon cooling the mixture was extracted with diethyl ether (3 x 30 ml), washed with brine (2 x 20 ml) and dried. Removal of the solvent under reduced pressure afforded a yellow oil (TLC visualised using UV shows product as bright blue spot). Column chromatography eluting with ethyl acetate/light petroleum (0:100- 10:90) gave a colourless solid, recrystallized from chloroform/hexane, (0.21 g 65%); m.p. 187-188°C; [α]²⁰ _D -551.2° (c 1.12, CHCI₃); v_max(film) /cm^"1 3052, 2983, 2926, 1594, 1508, 1465, 1420, 1368, 1265, 1158, 1056, 895; δ_H (250 MHz; CDCI₃) 4.18 (2H, d, 11.33 Hz), 4.64 (2H, d, J 11.33 Hz), 7.29 (2H, m), 7.50 (4H, m), 7.61 (2H, d, J 8.33 Hz), 7.97 (4H, dd, J 7.99 Hz); δ_c (100 MHz; CDCI₃) 67.44, 125.85, 125.94, 127.35, 127.59, 128.35, 129.15, 131.16, 133.55, 133.64, 135.46; m/z 296.1205; C₂₂H₁₆O (M⁺) requires 296.1201.

(S)-3,5-Dihydro-4-oxa-cyclohepta[2,1-a;3,4-a']dinaphthalene:

Prepared in an identical manner to the (R)-enantiomer above, from (S)-2,2'- dibromomethyl-[1 ,1']binaphthalenyl (7.00 g, 15.9 mmol). Colourless crystals (3.10 g, 66%); m.p. 186-188°C; [α]²⁰ _D +572.6° (c 1.04, CHCI₃).

(R)-2'-Bromomethyl-[1 ,1 ']binaphthalenyl-2-carbaldehyde:

To an ice-cooled solution of (R)-3,5-dihydro-4-oxa-cyclohepta[2,1-a;3,4-a']dinaphthalene (3.0 g, 9.6 mmol) in carbon tetrachloride (50 ml), molecular bromine (1.24 g, 7.8 mmol) as a solution in carbon tetrachloride (5 ml) was added over a period of 5 min (solution turned dark red). After a further 5 min the ice bath was removed and the reaction mixture heated under reflux until it became pale yellow (ca 1 h). The solvent was removed under reduced pressure and the residue obtained dissolved in diethyl ether. The organic solvents were washed with sat. aq. sodium hydrogen carbonate (2 x 50 ml) and brine (2 x 30 ml). The organic solution was dried (MgSO₄) and solvents were removed under reduced pressure to yield a orange oil. Crystallization from ethyl acetate afforded the product as colourless crystals (2.33 g, 65%); m.p. 151-153°C; [α]²⁰ _D +144.7° (c 1.02, CHCI₃); Found: C, 70.04; H, 3.78. C₂₂H₁₅BrO requires C, 70.41 ; H, 4.03.; v_max(film) /cπr¹ 3058, 1688, 1594, 1430, 1324, 1212, 1027, 821 , 749; δ_H (250 MHz; CDCI₃) 4.07 (1 H, d, J 10.2 Hz), 4.27 (1 H, d, J 10.2 Hz), 7.01 (1 H, dq, J 8.4, 2.0 Hz) 7.22-7.38 (3H, m), 7.50

(1 H, m), 7.63 (1 H, m), 7.72 (1 H, d, J 8.6 Hz), 7.93-8.12 (4H, m), 8.22 (1 H, d, J 8.6 Hz), 9.56 (1 H, d, J 0.9 Hz); δ_c (100 MHz; CDCI₃) 31.92, 122.38, 126.56, 126.94, 127.03, 127.39, 127.40, 128.17, 128.48, 129.20, 129.34, 129.85, 132.41 , 132.42, 132.53, 132.97, 133.56, 134.63, 136.29, 141.59, 191.81 ; m/z 374.0310; C₂₂H₁₅BrO (M⁺) requires 374.0306.

(S)-2"-Bromomethyl-[1 ,1 ']binaphthalenyl-2-carbaldehyde:

Prepared in an identical manner to the (R)-enantiomer above, from (S)-3,5-dihydro-4-oxa- cyclohepta[2,1-a;3,4-a']dinaphthalene (2.30 g, 7.8 mmol). Colourless crystals (1.87 g, 64%); m.p. 154-155°C; [α]²⁰ _D -140.3° (c 1.13, CHCI₃).

(R)-[(4S,5S)-2,2-dimethyI-4-phenyl-1,3-dioxan-5-yl]-3H-4-azapinium-cycIohepta[2,1- a;3,4-a']dinaphthalene tetraphenylborate: Prepared according to the general procedure from (+)-(4S,5S)-2,2-Dimethyl-4-phenyl-1 ,3- dioxan-5-amine (0.15 g, 0.72 mmol). The product was isolated as yellow plates (0.39 g, 66%); m.p. 111-113°C (dec); [α]²⁰ _D -98.5° (c 1.04, acetone); Found: C, 84.44; H, 5.97; N, 1.71. C₅₈H₅₀BNO₂«1.0H₂O requires C, 84.73; H, 6.13; N, 1.71.; v_max(film) /cm^"1 3055, 2986, 1626, 1610, 1593, 1548, 1478, 1450, 1382, 1266, 1203, 1110, 846, 817, 735, 704; δ_H(400 MHz; acetone-d₆) 1.79 (3H, s), 1.85 (3H, s), 4.43 (1 H, d, J 13.2 Hz), 4.51 (1H, d, J 13.6

Hz), 4.86 (2H, m), 5.98 (2H, m), 6.76 (4H, t, J 7.2 Hz), 6.93 (8H, t, J 7.6 Hz), 6.95-7.10 (5H, m), 7.18-7.32 (2H, m), 7.34 (8H, m), 7.45 (3H, m), 7.45-7.65 (2H, m), 7.78 (1 H, m), 7.88 (1 H, d, J 8.4 Hz), 8.10 (1 H, d, J 8.4 Hz), 8.17 (1 H, d, J 8.4 Hz), 8.23 (1 H, dd, J 8.4, 2.4 Hz), 9.29 (1 H, s); δ_H(400 MHz; acetone-d₆) 19.34, 29.69, 57.00, 62.26, 68.42, 72.94, 102.06, 120.51 , 122.67, 126.33, 126.40, 126.58, 127.30, 128.11 , 128.15, 128.38, 129.05,

129.19, 129.88, 130.04, 130.12, 130.57, 130.65, 131.70, 132.16, 132.57, 132.92, 133.25, 135.25, 136.61 , 137.43, 142.75, 165.25, 171.37; m/z 484.2275; C₃₄H₃₀NO₂ (cation) requires 484.2277.

(S)-[(4R,5R)-2,2-dimethyl-4-phenyl-1 ,3-dioxan-5-yl]-3H-4-azapinium-cyclohepta[2,1 - a;3,4-a']dinaphthalene tetraphenylborate:

Prepared according to the general procedure from (-)-(4R,5R)-2,2-Dimethyl-4-phenyl-1 ,3- dioxan-5-amine (0.16 g, 0.77 mmol). The product was isolated as yellow plates (0.40 g, 64%), having almost identical spectroscopic data to its enantiomer above: m.p. 109- 112°C (dec); [α]²⁰ _D +95.3° (c 1.01 , acetone).

(S)-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]-3H-4-azapinium-cyclohepta[2,1- a;3,4-a']dinaphthalene tetraphenylborate:

Prepared according to the general procedure from (+)-(4S,5S)-2,2-Dimethyl-4-phenyl-1 ,3- dioxan-5-amine (0.20 g, 0.97 mmol). The product was isolated as yellow plates (0.50 g, 64%); m.p. 218°C (dec); Found: C, 84.33; H, 6.06; N, 1.64. C₅₈H₅₀BNO₂«1.0H₂O requires C, 84.73; H, 6.13; N, 1.71.; m/z 484.2282; C₃₄H₃₀NO₂ (cation) requires 484.2277.

H-(R)-6-[(1R,2R_>3R,5S)-2,6_J6-trimethylbicyclo[3.1.1]hept-3-yl]- 3H-4-azapinium-cyclohepta[2,1-a;3,4-a']dinaphthalene tetraphenylborate:

Prepared according to the general procedure from (-)-isopinocampheylamine (0.25 g, 1.6 mmol). The product was isolated as yellow plates (0.82 g, 73%), mp 219-221 °C (dec); Found: C, 88.22; H, 6.81 ; N, 1.79%. C₄₈H₄₈BN«0.5H₂O requires C, 88.61 ; H, 6.91 ; N, 1.85%.; m/z 430.2540; C₃₂H₃₂N (cation) requires 430.2535.

(+)-(S)-6-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]- 3H-4-azapinium-cyclohepta[2,1-a;3,4-a']dinaphthalene tetraphenylborate:

Prepared according to the general procedure from (-)-isopinocampheylamine (0.25 g, 1.6 mmol). The product was isolated as yellow plates (0.82 g, 73%), mp 225-227°C (dec); Found: C, 88.38; H, 6.86; N, 1.80%. C₄₈H₄₈BN«0.5H₂O requires C, 88.61 ; H, 6.91 ; N, 1.85%.; m/z 430.2536; C₃₂H₃₂N (cation) requires 430.2535.

General procedure for catalytic asymmetric epoxidation of simple alkenes mediated by iminium salts using Tetraphenylphosphonium monoperoxysulfate:

Tetraphenylphosphonium monoperoxysulfate (2 eq with respect to the substrate) was dissolved in the desired solvent (2 ml per 0.1 g oxidant) and cooled to the required temperature. To this was added the iminium salt as a solution in the solvent (0.5 ml per 0.1 g oxidant). This iminium salt solution was cooled to the same temperature as the solution containing the oxidant and added dropwise over 15-20 min, the temperature of the reaction vessel was monitored to minimize increase in temperature during the addition. The substrate (100 mol%) was also added as a solution in the reaction solvent (0.5 ml per 0.1 g oxidant) in the same manner as the catalyst. The reaction was stirred at the same temperature until the substrate was completely consumed by TLC. Diethyl ether (pre-cooled to the reaction temperature) (20 ml per 0.1 g oxidant) was then added to precipitate the remaining oxidant. The solution was then filtered through Celite. Solvents are removed. Diethyl ether (40 ml) was then added to the brown residue obtained and the solution passed through a short pad of silica (to remove catalyst residues). Solvent was again removed to yield the pure epoxide. If the reaction did not go to completion the epoxide can be separated from the alkene through the use of column chromatography eluting with ethyl acetate/light petroleum 1 :99.

Tetraphenylphosphonium monoperoxysulfate: Ph₄P⁺ cr + Oxone™(2 KHSO₅:KHSO₄: K₂SO₄) → Ph₄P⁺(HSO₅)-

Oxone™ triple salt (2 KHSO₅:KHSO₄:K₂SO₄) (15.0 g, 48.8 mmol, w.r.t. KHSO₅) was dissolved in deionised water (300 ml) in a conical flask (1 L) and kept under magnetic stirring at 10-15°C (water bath). To this solution tetraphenylphosphonium chloride (15.0 g, 40.0mmol) in distilled dichloromethane (300 ml) was gradually added over 5 min. After an additional 30 min, stirring was interrupted, the organic layer was separated and solvent was removed under vacuum at room temperature. The crude white salt was then transferred to a fritted glass funnel and washed with distilled water (2 x 75 ml). The solid was dissolved in dichloromethane (180 ml), dried (MgSO₄) and hexane was added until cloudiness develops and the flask was placed in the freezer (-20°C) overnight, producing a solid white precipitate. Ca 85% pure in peroxide, yield 15.4 g, 70%. δ_H (250 MHz; CDCI₃) 7.64 (8 H, m, 8 x CH arom.), 7.78 (8 H, m, 8 x CH arom.), 7.89 (4 H, m, 4 x CH arom., para to P), 8.92 (1 H, s, OH).

EPOXIDATIONS USING TPPP AND ORGANIC SOLVENT CONDITIONS:

(-)-3S,4S-2,2-Dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6- carbonitrile : Tetraphenylphosphonium monoperoxysulfate (2 eq, 4.90 g, 10.8 mmol) was dissolved in chloroform (98 ml) and cooled to -40°C. To this was added the iminium salt, (+)-[(4S,5S)- 2,2-dimethyl-4-[4-(methylsulfonyl)-phenyl]-1 ,3-dioxan-5-yl]-3,4-dihydroisoquinolinium tetraphenylborate, (0.39g, 0.54 mmol) as a solution in chloroform (24.5 ml). This iminium salt solution was cooled to the same temperature as the solution containing the oxidant and added dropwise over 15-20 min, the temperature of the reaction vessel was monitored to minimize increase in temperature during the addition. The substrate (1.0 g, 5.4 mmol) was also added as a solution in chloroform (24.5 ml) in the same manner as the catalyst. The reaction was stirred at 40°C for 24 h. Diethyl ether (pre-cooled to -40 °C) was then added to precipitate the remaining oxidant. The solution was filtered through Celite. Solvents were removed under reduced pressure to afford a pale yellow oil. Column chromatography eluting with ethyl acetate/light petroleum 1 :99 gave the product as a colourless oil which solidified (0.64 g, 59% yield, 97% ee): [α]²⁰ _D -59.5° (c 1.09, CHCI₃), [lit +62.7° (c 0.71 , CHCI₃) for (+)-3R,4R enantiomer]; v_max(film)/crrr¹ 3089, 3038, 2979, 2934, 2226, 1615, 1579, 1490, 1346, 1279, 1157, 1107, 1046, 955; δ_H(400 MHz; CDCI₃) 1 -22 (3 H, s, CH₃, C11), 1.52 (3H, s), 3.47 (1 H, d, J 4.4 Hz), 3.86 (1 H, d, J

4.4 Hz), 6.79 (1 H, d, J 8.4 Hz), 7.45 (1 H, dd, J 2.0, 8.4 Hz), 7.58 (1 H, d, J 2.4 Hz); δ_c(100 MHz; CDCI₃) 23.41 , 25.88, 50.26, 62.69, 75.07, 104.65, 118.97, 119.15, 121.51, 134.21, 134.80, 156.87; m/z 219.1132; C^H^NO, (M⁺NH₄) requires 219.1134.

Cis-β-methylstyrene oxide:

Tetraphenylphosphonium monoperoxysulfate (2 eq, 0.768 g, 1.70 mmol) was dissolved in chloroform (16 ml) and cooled to -40°C. To this was added the iminium salt, (+)-[(4S,5S)- 2,2-dimethyl-4-[4-(methylsulfonyl)-phenyl]-1 ,3-dioxan-5-yl]-3,4-dihydroisoquinolinium tetraphenylborate, (10 ol %, 0.061 g, 0.09 mmol) as a solution in chloroform (4 ml). This iminium salt solution was cooled to the same temperature as the solution containing the oxidant and added dropwise over 15-20 min, the temperature of the reaction vessel was monitored to minimize increase in temperature during the addition. The substrate (0.10 g, 0.85 mmol) was also added as a solution in chloroform (4 ml) in the same manner as the catalyst. The reaction was stirred at -40°C for 24 h. Diethyl ether (20 ml) (pre-cooled to -40°C) was then added to precipitate the remaining oxidant. The solution was filtered through Celite. Solvents were removed under reduced pressure to afford a pale yellow oil. Column chromatography eluting with ethyl acetate/light petroleum 1 :99 gave the product as a colourless oil (0.97 g, 85% yield, 70% ee, (+)-1S,2R). v_max(neat)/cm^'1 3061 , 2994, 1604, 1496, 1450, 1258, 1149, 9563, 853, 742, 700, 619; δ_H(250 MHz; CDCI₃) 1.12, (3H, d, J 5.4 Hz), 3.32-3.40 (1 H, m), 4.08 (1 H, d, J 4.3 Hz), 7.24-7.39 (5H, m); δ_c(62.5 MHz; CDCI₃) 12.84, 55.37, 57.78, 126.85, 127.74, 128.26, 135.84.

Epoxidation of simple tri-substituted alkenes using (R)-[(4S,5S)-2,2-dimethyl-4- phenyl-1,3-dioxan-5-yl]-3H-4-azapinium-cycIohepta[2,1-a;3,4-a']dinaphthalene tetraphenylborate³:

^a Epoxidation conditions: Iminium salt (10 mol %), Tetraphenylphosphonium monoperoxysulfate (2 eq), MeCN, -40 C.

" Isolated yield. ^c Enantiomeric excess determined by ¹H-NMR with (+)-Eu(hfc)₃ (0.1 mol eq) as chiral shift reagent. ^d The absolute configuration of the major enantiomer was determined by comparison to those reported in the literature. ^e Numbers in brackets refer to the corresponding reaction carried out in chloroform. EPOXIDATIONS USING SPECIFIC CATALYSTS UNDER OXONE / WATER CONDITIONS:

General procedure for catalytic asymmetric epoxidation of simple alkenes mediated by iminium salts using Oxone:

To an ice cooled solution of sodium carbonate, (4 equivalents), in water (12 ml per 1.50 g of sodium carbonate), Oxone™ (2 equivalents), was added with stirring and the resulting foaming solution was left to stir for 5-10 minutes, so that most of the initial effervescence subsides. The iminium salt, (10 mol% with respect to the substrate), was then added as a solution in acetonitrile, (6 ml per 1.50 g of sodium carbonate used), followed by the alkene substrate, (1 equivalent, 100 mol%), also as a solution in acetonitrile of the same volume as the solution of the catalyst. The suspension was stirred at the same temperature until the substrate was completely consumed by TLC. The reaction mixture was then diluted with ice cooled diethyl ether (20 ml per 100 mg substrate) and was immediately followed by the addition of the same volume of water. The aqueous phase was washed 4 times with diethyl ether and the organics are combined, washed with brine and dried. Filtration and evapouration of the solvents furnishes a yellow or light brown residue. Column chromatography was then performed typically using ethyl acetate : Light petroleum 1 :99 to produce the pure epoxide.

Study of Catalyst loading on the epoxidation of 1-phenylcyclohexene^a

To an ice cooled solution of sodium carbonate (0.26 g, 2.52 mmol), in water (2.1 ml), Oxone™ (0.77 g, 1.26 mmol), was added with stirring and the resulting foaming solution was left to stir for 5-10 minutes, so that most of the initial effervescence subsided. The iminium salt, (0.5 mol %, 0.0025g, 0.0032 mmol), was then added as a solution in acetonitrile, (1.05 ml), followed by the alkene substrate, (1 equivalent, 0.10 g, 0.63 mmol), also as a solution in acetonitrile (1.05 ml). The suspension was stirred at the same temperature until the substrate was completely consumed by TLC (2.0 h). The reaction mixture was then diluted with ice cooled diethyl ether (20 ml) and immediately followed by the addition of water (20 ml). The aqueous phase was washed with diethyl ether (4 x 20 ml) and the organics were combined, washed with brine and dried (MgSO₄). Filtration and evaporation of the solvents furnished a light brown residue. Column chromatography eluting with ethyl acetate : light petroleum (1 :99) afforded the pure epoxide as a colourless oil (0.071 g, 65 %, 91 % ee, (-)-1S,2S). Colourless oil; v_max(neat)/cm^"1 3084, 1602, 1495, 1446, 1359, 1249, 1173, 1132, 1079, 1030, 993, 974; δ_H(250 MHz; CDCI₃) 1.22-1.35 (1 H, m), 1.53-1.64 (3H m), 1.99-2.06 (2H, m) 2.16-2.18 (1 H, m), 2.26-2.32 (1 H, m), 3.10 (1 H, t, J 2.0 Hz), 7.28-7.44 (5 H, m); δ_c (62.5 MHz; CDCI₃) 19.8, 20.1 , 24.7, 28.2, 60.1 , 61.8, 125.3, 127.1 , 128.2, 142.8. The experiment was repeated with varying levels of catalyst.

^a Conditions: Cat = (R)-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]-3H-4-azapinium- cyclohepta[2,1-a;3,4-a']dinaphthalene tetraphenylborate, Oxone (2 eq), Na₂CO₃ (4 eq),

MeCN/H₂O (1:1), 0 °C. ^b Isolated yields.

⁰ Enantiomeric excesses were determined by ¹H NMR spectroscopy in the presence of

(+)-Eu(hfc)₃ (0.1 mol eq). ^d The absolute configurations of the major enantiomers were determined by comparison of the optical rotation with those reported in the literature.

Comparison of literature methods for the asymmetric epoxidation of 1- phenylcyclohexene

Ref 1. Aggarwal, V. K.; Wang, M. F. J. Chem. Soc, Chem. Commun., 1996, 191. Ref 2. Bohe, L.; Lusinchi, M.; Lusinchi, X. Tetrahedron, 1999, 55, 141. Ref 3. Wong, M-K.; Ho, L-M.; Zheng, Y-S.; Ho, C-Y.; Yang, D. Org. Lett., 2001 , 16, 2587. Ref 4. Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A.; Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin, A. M. Z. J. Org. Chem. 2001 , 66, 6926. Ref 5. Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A.; Bethell, D.; Merifield, E. Synlett, 2002, 4, 580.

Conclusion: Catalyst of the present invention is highly effective, resulting in higher ee's. High ee's are achievable even at very low loading of catalyst.

Asymmetric epoxidation of alkenes mediated by an iminium salt catalyst ^a 1-Phenyl-3,4-dihydronaphthalene oxide: To an ice cooled solution of sodium carbonate (0.20 g, 1.96 mmol), in water (1.6 ml), Oxone™ (0.60 g, 0.98 mmol), was added with stirring and the resulting foaming solution was left to stir for 5-10 minutes, so that most of the initial effervescence subsided. The iminium salt, (5 mol %, 0.020 g, 0.025 mmol), was then added as a solution in acetonitrile, (0.8 ml), followed by the alkene substrate, (1 equivalent, 0.10 g, 0.49 mmol), also as a solution in acetonitrile (0.8 ml). The suspension was stirred at the same temperature until the substrate was completely consumed by TLC (0.35 h). The reaction mixture was then diluted with ice cooled diethyl ether (20 ml) and immediately followed by the addition of water (20 ml). The aqueous phase was washed with diethyl ether (4 x 20 ml) and the organics were combined, washed with brine and dried (MgSO₄). Filtration and evaporation of the solvents furnished a light brown residue. Column chromatography eluting with ethyl acetate : light petroleum (1 :99) afforded the pure epoxide as a colourless oil which solidified (0.072 g, 66 %, 95 % ee, (-)-1 S,2R). mp 104-106 °C; v_max(nujol)/cm^"1 1602, 1486, 1307, 1155, 1074, 1042, 953; δ_H(250 MHz; CDCI₃) 2.10 (1 H, td, J 5.8 and 13.7 Hz), 2.49-2.60 (1 H, m), 2.77 (1 H, dd, J 5.6 and 15.5 Hz), 2.98-3.06 (1 H, m), 3.71 (1 H, d, 3.1 Hz), 7.11-7.31 (4H, m), 7.45-7.61 (5H, m); δ_c(62.5 MHz; CDCI₃) 22.1 , 25.4, 60.9, 63.0, 126.0, 127.7, 127.9, 128.1 , 128.2, 128.6, 129.8, 135.0, 137.5, 138.8.

^a Conditions: (R)-[(4S,5S)-2,2-dimethyl-4-phenyl-1 ,3-dioxan-5-yl]-3H-4-azapinium- cyclohepta[2,1-a;3,4-a']dinaphthalene tetraphenylborate (5 mol%), oxone (2 eq), Na₂CO₃ (4 eq), MeCN/H₂O (1 :1 ), 0 °C. ^b Isolated yields. ^c Enantiomeric excesses were determined by ¹H NMR spectroscopy in the presence of (+)-Eu(hfc)₃ (0.1 mol eq) or by chiral HPLC using a Chiracel OD column. ^d The absolute configurations of the major enantiomers were determined by comparison of the optical rotation with those reported in the literature.

Conclusion: Catalyst shows good ee even with terminal olefins

Comparison of the Oxone/MeCN-H₂O and TPPP reaction conditions: 1, 2-Dihydronapthylene oxide - Oxone/Water:

To an ice cooled solution of sodium carbonate (0.32 g, 3.08 mmol), in water (2.6 ml), Oxone™ (0.95 g, 1.54 mmol), was added with stirring and the resulting foaming solution was left to stir for 5-10 minutes, so that most of the initial effervescence subsided. The iminium salt, (10 mol %, 0.055 g, 0.08 mmol), was then added as a solution in acetonitrile, (1.3 ml), followed by the alkene substrate, (1 equivalent, 0.10 g, 0.77 mmol), also as a solution in acetonitrile (1.3 ml). The suspension was stirred at the same temperature until the substrate was completely consumed by TLC (2.0 h). The reaction mixture was then diluted with ice cooled diethyl ether (20 ml) and immediately followed by the addition of water (20 ml). The aqueous phase was washed with diethyl ether (4 x 20 ml) and the organics were combined, washed with brine and dried (MgSO₄). Filtration and evaporation of the solvents furnished a light brown residue. Column chromatography eluting with ethyl acetate : light petroleum (1 :99) afforded the pure epoxide as a colourless oil (61 % conversion, 45 % ee, (-)-1S,2R). v_max(neat)/cm^"1 3059, 3028, 2930, 2850, 1602, 1493, 1316, 1129, 1088, 1030, 964; δ_H(400 MHz; CDCI₃) 1.67 (1 H, m), 2.33 (1 H, m), 2.45 (1 H, dd, J 15.6, 5.6 Hz), 2.67 (1 H, m), 3.65 (1 H, t, J 4.0 Hz), 3.78 (1 H, d, J 4.4 Hz), 7.01 (1 H, d, J 7.2 Hz), 7.17 (2H, m), 7.33 (1 H, d, J 7.2 Hz); δ_c(100 MHz; CDCI₃) 22.19, 24.78, 55.16, 55.52, 126.51 , 128.80, 128.83, 129.94, 132.91 , 137.07.

1 ,2-Dihydronapthylene oxide - Tetraphenylphosphonium monoperoxysulfate/Organic

Solvent :

Tetraphenylphosphonium monoperoxysulfate (2 eq, 0.696 g, 1.54 mmol) was dissolved in chloroform (14 ml) and cooled to -40°C. To this was added the iminium salt (10 mol %,

0.055 g, 0.08 mmol) as a solution in chloroform (3.5 ml). This iminium salt solution was cooled to the same temperature as the solution containing the oxidant and added dropwise over 15-20 min, the temperature of the reaction vessel was monitored to minimize increase in temperature during the addition. The substrate (0.10 g, 0.77 mmol) was also added as a solution in chloroform (3.5 ml) in the same manner as the catalyst. The reaction was stirred at -40°C for 17 h. Diethyl ether (20 ml) (pre-cooled to -40°C) was then added to precipitate the remaining oxidant. The solution was filtered through Celite. Solvents were removed under reduced pressure to afford a pale yellow oil. Column chromatography eluting with ethyl acetate/light petroleum 1 :99 gave the product as a colourless oil (0.10 g, 89% yield, 82% ee, (-)-1 S,2R).

The following alkenes were compared according to the above conditions.

^a Conditions: (+)-[(4S,5S)-2,2-dimethyl-4-[4-(methylsulfonyl)-phenyl]-1 ,3-dioxan-5-yl]-3,4- dihydroisoquinolinium tetraphenylborate (10 mol%), oxone (2 eq), Na₂CO₃ (4 eq), MeCN/H₂O (1 :1 ), 0°C. ^b Conditions: (+)-[(4S,5S)-2,2-dimethyl-4-[4-(methylsulfonyl)-phenyl]-1 ,3-dioxan-5-yl]-3,4- dihydroisoquinolinium tetraphenylborate (10 mol%), TPPP (2 eq), CHCI₃, -40°C. ^c Conversion evaluated from the ¹H-NMR by integration of alkene versus epoxide. ^d Enantiomeric excesses were determined by ¹H NMR spectroscopy in the presence of (+)-Eu(hfc)₃ (0.1 mol eq) or by chiral HPLC using a Chiracel OD column. ^e The absolute configurations of the major enantiomers were determined by comparison of the optical rotation with those reported in the literature. ^f Isolated yields. Stereospecificity under the TPPP conditions: Effect of reaction solvent: Catalytic asymmetric epoxidation of various alkenes using TPPP and (+)-[(4S,5S)-2,2- dimethyl-4-[4-(methylsulfonyl)-phenyl]-1 ,3-dioxan-5-yl]-3,4-dihydroisoquinolinium tetraphenylborate³

^a Conditions: (+)-[(4S,5S)-2,2-dimethyl-4-[4-(methylsulfonyl)-phenyl]-1 ,3-dioxan-5-yl]-3,4- dihydroisoquinolinium tetraphenylborate (10 mol %), TPPP (2 eq), Solvent, -40 C, 24 h.

" Isolated yield.

⁰ Enantiomeric excess determined by H-NMR with (+)-Eu(hfc)₃ (0.1 mol eq) as chiral shift reagent or by Chiral HPLC on a Chiracel OD column. ^d The absolute configuration of the major enantiomer was determined by comparison of the optical rotation with those reported in the literature. ^e Conversion evaluated from the ¹H-NMR by integration alkene versus epoxide.

Claims

1. A process for the preparation of oxiranes wherein an optionally substituted alkene is reacted in the presence of a chiral catalyst, an oxidant and an organic solvent characterised in that the oxidant is at least partially soluble in the organic solvent and the oxidant displays low reactivity towards the alkene in the absence of the catalyst.

2. A process according to Claim 1 wherein the oxidant is a compound of formula (2): A⁺ HSO₅- (2)

wherein A⁺ is a counterion capable of conferring organic solvent solubility.

3. A process according to Claim 2 wherein the counterions A⁺ is (PR⁶R⁷R⁸R⁹)⁺ wherein R^6"9 are optionally substituted aryl groups.

4. A process according to Claim 2 or 3 wherein the oxidants are compounds of formula (3):

(3) wherein: R¹⁰ is hydrogen, a polyfluorinated alkyl, a resin or a linker bound to a resin.

5. A process according to Claim 4 wherein R¹⁰ is hydrogen.

6. A process according to any one of Claims 1 to 5 wherein the chiral catalyst is a chiral iminium salt of formula (4):

wherein: R¹¹ and R¹² are each independently an optionally substituted hydrocarbyl group or R¹¹ & R¹² are linked in such a way as to form an optionally substituted ring(s); R¹³ is hydrogen or an optionally substituted hydrocarbyl group; R¹⁴ is an optionally substituted hydrocarbyl group; R¹⁷ is hydrogen or an optionally substituted hydrocarbyl group; R¹⁵ and R¹⁶ each independently are hydrogen or an optionally substituted hydrocarbyl group; and X^" is a counterion; * is a chiral centre; and *' is a chiral centre when R¹⁷ is not hydrogen.

7. A process according to Claim 6 wherein the catalyst is a compound of formula (4a), (4b), (4c) or (4d):

wherein: R¹⁴ is an optionally substituted aryl group; R¹⁵ is hydrogen or C_1-4 alkyl group; R¹⁶ is hydrogen or C_1-4 alkyl group; R¹⁸ and R¹⁹ are each independently hydrogen or a C,^ alkyl group; R²⁰ is preferably an electron donating group; and X^" is a counterion.

A process according to Claim 7 wherein the catalyst is a compound of formula (4a), (4b), (4c) or (4d) wherein R¹⁴ is an optionally substituted phenyl group; R ⁵ is hydrogen or a methyl group; R¹⁶ is hydrogen or a methyl group; R¹⁸ and R¹⁹ are each independently hydrogen or a methyl group; R²⁰ is a dihydrocarbylamino group; and X is [BFJ-, [CF₃SO3]-, [BPhJ^", [PF₆]- or [CIO₄]\

9. A process according to Claim 8 wherein the catalyst is a compound of formula (4a), (4b), (4c) or (4d) wherein R¹⁴ is an optionally substituted phenyl group; R¹⁵ is a methyl group; R¹⁶ is a methyl group; R¹⁸ and R¹⁹ are methyl groups; R²⁰ is a dihydrocarbylamino group; and X is [BPh₄]^', [PFJ- or [CIO₄]\

10. A process according to any one of Claims 7, 8 or 9 wherein the catalyst is a compound of formula (4a) wherein R¹⁴ is a phenyl group; R¹⁵ is a methyl group; and R¹⁶ is a methyl group; or the catalyst is a compound of formula (4c) wherein R¹⁴ is a C₆H₄SO₂Me group; R¹⁵ is a methyl group; and R¹⁶ is a methyl group.

11. A process according to any proceeding claim wherein the optionally substituted alkene is compound of formula (1):

(1) wherein: R^1"4 each independently are hydrogen, an optionally substituted aromatic or saturated hydrocarbyl, an optionally substituted hetrocyclyl, an optionally substituted aromatic or saturated hydrocarbyloxy, an optionally substituted aromatic or saturated hydrocarbylamino, an optionally substituted aromatic or saturated hydrocarbyloxycarbonyl, an optionally substituted aromatic or saturated hydrocarbylaminocarbonyl, nitrile, halide or one or more of R¹&R², R²&R³, R³&R⁴, R¹&R⁴ optionally being linked in such a way as to form an optionally substituted ring(s).

12. A catalyst of formula (4a), (4b), (4c) or (4d):

(4a) (4b) (4c) (4d)

wherein: R¹⁴ is an optionally substituted aryl group; R¹⁵ is hydrogen or C_1-4 alkyl group; R¹⁶ is hydrogen or C_1-4 alkyl group; R¹⁸ and R¹⁹ are each independently hydrogen or a C_1-4 alkyl group; R²⁰ is preferably an electron donating group; and X^" is a counterion.

13. A catalyst according to Claim 12 wherein R¹⁴ is an optionally substituted phenyl group; R¹⁵ is hydrogen or a methyl group; R¹⁶ is hydrogen or a methyl group; R¹⁸ and R¹⁹ are each independently hydrogen or a methyl group; R²⁰ is a dihydrocarbylamino group; and X is [BF₄]-, [CF₃SO₃]-, [BPh₄]^", [PF₆]^" or [CIO₄]^".

14. A catalyst according to Claim 13 wherein R¹⁴ is an optionally substituted phenyl group; R¹⁵ is a methyl group; R¹⁶ is a methyl group; R¹⁸ and R¹⁹ are methyl groups; R²⁰ is a dihydrocarbylamino group; and X is [BPh₄]^", [PF₆]- or [CIO₄]^".

15. A catalyst according to any one of Claims 12, 13 or 14 wherein the catalyst is a compound of formula (4a) wherein R¹⁴ is a phenyl group; R¹⁵ is a methyl group; and R¹⁶ is a methyl group, or the catalyst is a compound of formula (4c) wherein R¹⁴ is a C₆H₄SO₂Me group; R¹⁵ is a methyl group; and R¹⁶ is a methyl group.