METHOD AND CATALYST FOR SYNTHESISING AZIRIDINE

Abstract

The present invention relates to methods of synthesising aziridines including isotopically labelled aziridines, said methods comprising contacting an imine or one or more precursors thereof with a diazo compound in the presence of a phosphoramide or a phosphoramide-derived catalyst. The present invention also relates to aziridines, modified aziridines and aziridine-derived compounds preparable by the aforementioned methods, and to phosphoramide or phosphoramide-derived catalysts suitable for use in such methods.

Claims

1-38. (canceled)

39. A method of synthesising aziridine (III) or a salt thereof, said method comprising contacting imine (I), or a salt or one or more precursors thereof, with a diazo compound (II) or a salt thereof in the presence of a catalyst: ##STR00043## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each independently represent any atom or group, and wherein the catalyst is a compound of formula (IV) or a salt thereof, or a compound of formula (V) or a salt thereof: ##STR00044## wherein X is O, S or NR.sup.9, and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 each independently represent any atom or group.

40. A method as claimed in claim 39, wherein: (i) the imine (I), one or more precursors thereof, and/or the diazo compound (II) are isotopically labelled such that the resultant aziridine (III) is also isotopically labelled; and/or (ii) the imine (I) or the salt or the one or more precursors thereof are contacted with the diazo compound (II) or the salt thereof in a solvent comprising a mixture of halocarbons.

41. A method as claimed in claim 39, wherein the catalyst is: (i) a chiral compound of formula (IV) or a salt thereof, or a chiral compound of formula (V) or a salt thereof; and/or (ii) a compound of formula (IV) or a salt thereof.

42. A method as claimed in claim 39, wherein: the method comprises contacting the imine (I) or the salt thereof with the diazo compound (II) or the salt thereof; or (ii) the method comprises contacting the imine (I) or the salt thereof with the diazo compound (II) or the salt thereof, and wherein the method further comprises the step of synthesising the imine (I) or the salt thereof from an amine H.sub.2NR.sup.3 or a salt or protected derivative thereof, and a carbonyl compound R.sup.1COR.sup.2 or a salt or protected derivative thereof; or (iii) the method comprises contacting the imine (I) or the salt thereof with the diazo compound (II) or the salt thereof, and wherein the method further comprises the step of synthesising the imine (I) or the salt thereof from an amine H.sub.2NR.sup.3 or a salt or protected derivative thereof, and a carbonyl compound R.sup.1COR.sup.2 or a salt or protected derivative thereof, wherein the imine (I) or the salt thereof is not isolated; or (iv) the method comprises contacting one or more precursors of the imine (I) with the diazo compound (II) or the salt thereof; or (v) the method comprises contacting one or more precursors of the imine (I) with the diazo compound (II) or the salt thereof, wherein the one or more precursors comprise an amine H.sub.2NR.sup.3 or a salt or protected derivative thereof, and a carbonyl compound R.sup.1COR.sup.2 or a salt or protected derivative thereof.

43. A method as claimed in claim 39, wherein: (i) R.sup.1, R.sup.2 and R.sup.3 are each independently hydrogen, halogen or a hydrocarbyl group, wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton, and wherein any two or more of R.sup.1, R.sup.2 and R.sup.3 together with the atom or atoms to which they are attached may form a cyclic hydrocarbyl group which may optionally be substituted and which may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and/or (ii) R.sup.1 is hydrogen, R.sup.2 is a substituted or unsubstituted alkyl, acyl, aryl, arylalkyl or alkylaryl group which optionally includes one or more heteroatoms in its carbon skeleton, and R.sup.3 is a substituted or unsubstituted alkyl, alkenyl, aryl, arylalkyl or alkylaryl group which optionally includes one or more heteroatoms in its carbon skeleton; and/or (iii) R.sup.4 and R.sup.5 are each independently hydrogen, halogen or a hydrocarbyl group, wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton, and wherein R.sup.4 and R.sup.5 together with the atom or atoms to which they are attached may form a cyclic hydrocarbyl group which may optionally be substituted and which may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and/or (iv) at least one of R.sup.4 and R.sup.5 is a COOR.sup.d group, wherein R.sup.d is an unsubstituted alkyl or alkenyl group comprising from 1 to 6 carbon atoms or an unsubstituted arylalkyl group comprising from 7 to 12 carbon atoms; and/or (v) R.sup.4 is hydrogen and R.sup.5 is a COOR.sup.d group, wherein R.sup.d is an unsubstituted alkyl or alkenyl group comprising from 1 to 6 carbon atoms or an unsubstituted arylalkyl group comprising from 7 to 12 carbon atoms.

44. A method as claimed in claim 39, wherein: (i) at least one of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is chiral; and/or (ii) R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are each independently hydrogen, halogen or a hydrocarbyl group, wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, alkylaryl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton, and wherein any two or more of R.sup.6, R.sup.7, R.sup.8 and R.sup.9 together with the atom or atoms to which they are attached may form a cyclic hydrocarbyl group which may optionally be substituted and which may optionally include one or more heteroatoms N, O or S in its carbon skeleton; and/or (iii) X is O; and/or (iv) R.sup.6 is SO.sub.2CF.sub.3.

45. A method as claimed in claim 39, wherein: (i) R.sup.7 and R.sup.8 together form a chiral bidentate ligand of formula (VI): ##STR00045## wherein each Z is independently selected from O, S or NR.sup.f, wherein each R.sup.f is independently hydrogen, halogen or a hydrocarbyl group, wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton, and wherein Ar.sup.1 and Ar.sup.2 are each independently a substituted or unsubstituted arylene group which optionally includes one or more heteroatoms in its carbon skeleton; or (ii) R.sup.7 and R.sup.8 together form a chiral bidentate ligand of formula (VIb): ##STR00046## wherein Y.sup.6 and Y.sup.7 are the same and are selected from hydrogen, ##STR00047## or (iii) R.sup.7 and R.sup.8 together form a chiral bidentate ligand of formula (VIb), (VIb) or (VIb): ##STR00048## wherein Y.sup.6 and Y.sup.7 are each independently selected from a substituted or unsubstituted fused aryl group, which optionally includes one or more heteroatoms in its carbon skeleton.

46. A method as claimed in claim 39, wherein: (i) at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is .sup.2H or .sup.3H; and/or (ii) R.sup.1 and/or R.sup.4 are .sup.2H or .sup.3H; and/or (iii) the nitrogen atom of the CN group of the imine (I) and/or the nitrogen atom of the amine H.sub.2NR.sup.3 or the protected derivative thereof is .sup.15N, such that the nitrogen atom in the aziridine ring of (III) is .sup.15N; and/or (iv) the carbon atom of the CN group of the imine (I) and/or the carbon atom of the CO group of the carbonyl compound R.sup.1COR.sup.2 or the protected derivative thereof, and/or the carbon atom of the CN.sub.2 group of the diazo compound (II) is .sup.13C or .sup.14C, such that one or both of the carbon atoms in the aziridine ring of (III) is .sup.13C or .sup.14C.

47. A method as claimed in claim 39, wherein: (i) R.sup.1 and R.sup.4 in the aziridine (III) are mostly cis- or mostly trans; and/or (ii) the synthesis of the aziridine (III) is enantioselective.

48. A method as claimed in claim 39, wherein the method further comprises the steps of: (a) chemically modifying or cleaving any of R.sup.1, R.sup.2, R.sup.3, R.sup.4 or R.sup.5 to give a modified aziridine or a salt thereof; and/or (b) ring-opening or ring-expanding the aziridine (III) or the modified aziridine to give an aziridine-derived compound or a salt thereof.

49. An aziridine or a salt thereof, preparable by a method as claimed in claim 39.

50. A modified aziridine or a salt thereof or an aziridine-derived compound or a salt thereof, preparable by a method as claimed in claim 48.

51. An isotopically labelled aziridine or a salt thereof, wherein the isotopically labelled aziridine is not a meso compound, but would be a meso compound if it were not isotopically labelled.

52. An isotopically labelled aziridine or a salt thereof as claimed in claim 51, wherein: (i) the isotopically labelled aziridine is a compound of formula (IIIa): ##STR00049## wherein R.sup.1 and R.sup.4 are different and are selected from .sup.1H, .sup.2H and .sup.3H; R.sup.2 and R.sup.5 are the same and are selected from any atom or group other than hydrogen; and R.sup.3 is independently selected from any atom or group; and/or (ii) the isotopically labelled aziridine or the salt thereof has a stereochemical purity of 75%.

53. An isotopically labelled modified aziridine or a salt thereof or an isotopically labelled aziridine-derived compound or a salt thereof, preparable by chemically modifying, ring-opening or ring-expanding the isotopically labelled aziridine or salt thereof as claimed in claim 51.

54. A compound of formula (IV) or a salt thereof, or a compound of formula (V) or a salt thereof: ##STR00050## wherein X is O, S or NR.sup.9, and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 each independently represent any atom or group, with the proviso that when X is O, R.sup.6 is SO.sub.2CF.sub.3, and R.sup.7 and R.sup.8 together form a chiral bidentate ligand of formula (VIb): ##STR00051## wherein Y.sup.6 and Y.sup.7 are the same and are selected from hydrogen, ##STR00052## the compound is not a compound of formula (IV) or a salt thereof.

55. A compound as claimed in claim 54, wherein: (i) the compound of formula (IV) or (V) is chiral; and/or (ii) R.sup.7 and R.sup.8 together form a chiral bidentate ligand of formula (VI): ##STR00053## wherein each Z is independently selected from O, S or NR.sup.f, wherein each R.sup.f is independently hydrogen, halogen or a hydrocarbyl group, wherein each hydrocarbyl group independently is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkenylaryl or alkynylaryl group which optionally includes one or more heteroatoms in its carbon skeleton, and wherein Ar.sup.1 and Ar.sup.2 are each independently arylene groups which optionally include one or more heteroatoms in their carbon skeleton and which are substituted with a heterocyclic aryl group; and/or (iii) R.sup.7 and R.sup.8 together form a chiral bidentate ligand of formula (VIb): ##STR00054## wherein Y.sup.6 and Y.sup.7 are the same and are heterocyclic aryl groups; and/or (iv) the compound is a compound of formula (IV) or a salt thereof, wherein X is O, R.sup.6 is SO.sub.2CF.sub.3 and R.sup.7 and R.sup.8 together form a chiral bidentate ligand of formula (VIb): ##STR00055## wherein Y.sup.6 and Y.sup.7 are the same and are selected from: ##STR00056##

56. A compound of formula (IV) or a salt thereof, or a compound of formula (V) or a salt thereof: ##STR00057## wherein X is O, S or NR.sup.9, and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 each independently represent any atom or group, and wherein the compound is attached to a solid support.

57. A compound of formula (IV) as claimed in claim 56, or a salt thereof, wherein X is O, R.sup.6 is SO.sub.2CF.sub.3 and R.sup.7 and R.sup.8 together form a chiral bidentate ligand of formula (VIb): ##STR00058## wherein Y.sup.6 and Y.sup.7 are the same and are selected from: ##STR00059##

58. Use of a compound of formula (IV) or a salt thereof, or a compound of formula (V) or a salt thereof: ##STR00060## wherein X is O, S or NR.sup.9, and R.sup.6, R.sup.7, R.sup.8 and R.sup.9 each independently represent any atom or group, in a method as claimed in claim 39.

Description

EXAMPLES

Example 1

[0183] ##STR00030##

[0184] Pyridine-2-carboxaldehyde (25 L, 0.26 mmol,), o-tert-butoxy aniline (43 mg, 0.26 mmol), and catalyst (S)-3,3-bis(9-anthracenyl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide (2.2 mg, 0.0026 mmol, 1 mol %) were added to a flame dried biotage 2 mL microwave vial under nitrogen. 1 mL of chloroform was added (pre-dried over 4 molecular sieves), followed by 40 mg of powdered 4 molecular sieves, and the vial was sealed with a PTFE crimp cap. After stirring at room temperature for 6 hours, the reaction mixture was cooled to 60 C. After 30 minutes, tert-butyl diazoacetate (40 L, 0.286 mmol) was added via syringe, and the reaction mixture was stirred at 60 C., monitoring by .sup.1H-NMR until the reaction was deemed complete (24 hours). At this point the reaction mixture was passed through a short plug of silica, eluted with diethyl ether. The solvents were removed under reduced pressure, and the residue was purified by flash chromatography (14% diethyl ether in PET ether). A sample was submitted to chiral analytical HPLC analysis [Chiralpak AD, iso-hexane/iso-propanol: 8/2, 1 mL/min, 5.25 min (1.sup.st peak), 7.43 min (2.sup.nd peak), 99% e.e., absolute configuration not determined]. The chiral reaction product cis-tert-butyl 1-(2-tert-butoxyphenyl)-3-(pyridin-2-yl)aziridine-2-carboxylate was afforded as a colourless oil in a 82% yield. The trans-product was not detectable by NMR.

Example 2

[0185] ##STR00031##

[0186] Pentafluorobenzaldehyde (40 mg, 0.26 mmol,), O-tert-butoxy aniline (43 mg, 0.26 mmol), and catalyst (S)-3,3-bis(9-anthracenyl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide (21.6 mg, 0.026 mmol, 10 mol %) were added to a flame dried biotage 2 mL microwave vial under nitrogen. 800 L of deuterated chloroform was added (pre-dried over 4 molecular sieves), followed by 40 mg of powdered 4 molecular sieves, and the vial was sealed with a PTFE crimp cap. 200 L of anhydrous DCM was added via syringe through the septum, and the reaction mixture was cooled to 80 C. After 30 minutes, >95% -deuterated tert-butyl diazoacetate (40 L, 0.286 mmol) was added via syringe, and the reaction mixture was stirred at 80 C., monitoring by .sup.1H-NMR until the reaction was deemed complete (72 hours). At this point the reaction mixture was passed through a short plug of silica, eluting with diethyl ether. The solvents were removed under reduced pressure, and the residue was purified by flash chromatography (14% diethyl ether in PET ether). The product was a yellow oil afforded in an 82% yield. This was added to 1 mL acetonitrile and 500 L of water was added, followed by para-toluene sulphonic acid (17 mg, 0.087 mmol). The resulting mixture was heated to 65 C. in a biotage creator microwave synthesiser, with stirring for 5 hours. After this time, the reaction mixture was neutralised by addition of a saturated aqueous solution of NaHCO.sub.3. This was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with MgSO.sub.4, filtered and the solvent removed under reduced pressure. The crude material was purified via column chromatography (30% diethyl ether in PET ether). The product cis-tert-butyl 1-(2-hydroxyphenyl)-3-(perfluorophenyl)aziridine-2-deutero-2-carboxylate was a slightly brown oil afforded in a 67% yield. A sample was submitted to chiral analytical HPLC analysis [Chiralpak IA, CO.sub.2/iso-propanol: 5%-50% over 9 min, 0.7 mL/min, 3.78 min (1.sup.st peak), 4.23 min (2.sup.nd peak), 92% e.e., absolute configuration not determined]. The trans-product was not detectable by NMR.

Example 3

[0187] ##STR00032##

[0188] (E)-2-tert-Butoxy-N-(2-napthylmethylene)phenylamine (79 mg, 0.26 mmol), and catalyst (S)-3,3-bis(9-anthracenyl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide (21.6 mg, 0.026 mmol, 10 mol %) were added to a flame dried Biotage 2 mL microwave vial under nitrogen. 800 L of deuterated chloroform was added (pre-dried over 4 molecular sieves), and the vial was sealed with a PTFE crimp cap. 200 L of anhydrous DCM was added via syringe through the septum, and the reaction mixture was cooled to 80 C. After 30 minutes, >95% -deuterated tert-butyl diazoacetate (40 L, 0.286 mmol) was added via syringe, and the reaction mixture was stirred at 80 C., monitoring by .sup.1H-NMR until the reaction was deemed complete. At this point the reaction mixture was passed through a short plug of silica and eluted with diethyl ether. The solvents were removed under reduced pressure, and the residue was purified by flash chromatography (14% diethyl ether in PET). A sample was submitted to chiral analytical HPLC analysis [Chiralpak AD, iso-hexane/iso-propanol: 95/5, 1 mL/min, 4.61 min (1.sup.st peak), 11.01 min (2.sup.nd peak), 90% e.e., absolute configuration not determined]. 2-Deutero-cis-tert-butyl-1-(2-tert-butoxyphenyl)-3-(naphthalen-2-yl)aziridine-2-carboxylate was afforded as a yellow oil in an 85% yield. The trans-product was not detectable by NMR.

Example 4

[0189] ##STR00033##

[0190] (E)-2-tert-Butoxy-N-(4-bromophenylmethylene)phenylamine (85 mg, 0.26 mmol), and catalyst (S)-3,3-bis(9-anthracenyl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide (21.6 mg, 0.026 mmol, 10 mol %) were added to a flame dried Biotage 2 mL microwave vial under nitrogen. 800 L of deuterated chloroform was added (pre-dried over 4 molecular sieves), and the vial was sealed with a PTFE crimp cap. 200 L of anhydrous DCM was added via syringe through the septum, and the reaction mixture was cooled to 80 C. After 30 minutes, >95% -deuterated tert-butyl diazoacetate (40 L, 0.286 mmol) was added via syringe, and the reaction mixture was stirred at 80 C., monitoring by .sup.1H-NMR until the reaction was deemed complete. At this point the reaction mixture was passed through a short plug of silica and eluted with diethyl ether. The solvents were removed under reduced pressure, and the residue was purified by flash chromatography (14% diethyl ether in PET). A sample was submitted to chiral analytical HPLC analysis [Chiralpak AD, iso-hexane/iso-propanol: 95/5, 1 mL/min, 4.12 min (1.sup.st peak), 7.27 min (2.sup.nd peak), 95% e.e., absolute configuration not determined]. 2-Deutero-cis-tert-butyl-1-(2-tert-butoxyphenyl)-3-(4-bromophenyl)aziridine-2-carboxylate was afforded as a yellow oil in an 87% yield. The trans-product was not detectable by NMR.

Example 5

[0191] ##STR00034##

[0192] (E)-2-tert-Butoxy-N-(4-cyanophenylmethylene)phenylamine (72 mg, 0.26 mmol), and catalyst (S)-3,3-bis(9-anthracenyl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide (21.6 mg, 0.026 mmol, 10 mol %) were added to a flame dried Biotage 2 mL microwave vial under nitrogen. 800 L of deuterated chloroform was added (pre-dried over 4 molecular sieves), and the vial was sealed with a PTFE crimp cap. 200 L of anhydrous DCM was added via syringe through the septum, and the reaction mixture was cooled to 80 C. After 30 minutes, >95% -deuterated tert-butyl diazoacetate (40 L, 0.286 mmol) was added via syringe, and the reaction mixture was stirred at 80 C., monitoring by .sup.1H-NMR until the reaction was deemed complete. At this point the reaction mixture was passed through a short plug of silica and eluted with diethyl ether. The solvents were removed under reduced pressure, and the residue was purified by flash chromatography (14% diethyl ether in PET). A sample was submitted to chiral analytical HPLC analysis [Chiralpak AD, iso-hexane/iso-propanol: 95/5, 1 mL/min, 6.19 min (1.sup.st peak), 8.75 min (2.sup.nd peak), 99% e.e., absolute configuration not determined]. The 2-deutero-cis-tert-butyl-1-(2-tert-butoxyphenyl)-3-(4-cyanophenyl) aziridine-2-carboxylate was afforded as a yellow oil in a 65% yield. The trans-product was not detectable by NMR.

Example 6

[0193] ##STR00035##

[0194] (E)-2-tert-Butoxy-N-(4-cyanophenylmethylene)phenylamine (74 mg, 0.26 mmol), and catalyst (S)-3,3-bis(9-anthracenyl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide (21.6 mg, 0.026 mmol, 10 mol %) were added to a flame dried Biotage 2 mL microwave vial under nitrogen. 800 L of deuterated chloroform was added (pre-dried over 4 molecular sieves), and the vial was sealed with a PTFE crimp cap. 200 L of anhydrous DCM was added via syringe through the septum, and the reaction mixture was cooled to 80 C. After 30 minutes, >95% deuterated allyl diazoacetate (35 L, 0.286 mmol) was added via syringe, and the reaction mixture was stirred at 80 C., monitoring by .sup.1H-NMR until the reaction was deemed complete. At this point the reaction mixture was passed through a short plug of silica and eluted with diethyl ether. The solvents were removed under reduced pressure, and the residue was purified by flash chromatography (14% diethyl ether in PET ether). A sample was submitted to chiral analytical HPLC analysis [Chiralpak AD, iso-hexane/iso-propanol: 95/5, 1 mL/min, 12.20 min (1.sup.st peak), 20.40 min (2.sup.nd peak), 87% e.e., absolute configuration not determined]. The 2-deutero-cis-allyl-1-(2-tert-butoxyphenyl)-3-(4-cyanophenyl)aziridine-2-carboxylate was afforded as a yellow oil in a 68% yield. The trans-product was not detectable by NMR.

Example 7

[0195] ##STR00036##

[0196] >95% Deuterated benzaldehyde (28 L, 0.26 mmol,), O-tert-butoxyaniline (43 mg, 0.26 mmol), and catalyst (R)-3,3-bis(9-anthracenyl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide (21.6 mg, 0.026 mmol, 10 mol %) were added to a flame dried Biotage 2 mL microwave vial under nitrogen. 800 L of deuterated chloroform was added (pre-dried over 4 molecular sieves), followed by 40 mg powdered 4 molecular sieves, and the vial was sealed with a PTFE crimp cap. 200 L of anhydrous DCM was added via syringe through the septum, and the reaction mixture was cooled to 80 C. After 30 minutes, tert-butyl diazoacetate (40 L, 0.286 mmol) was added via syringe, and the reaction mixture was stirred at 80 C., monitoring by .sup.1H-NMR until the reaction was deemed complete. At this point the reaction mixture was passed through a short plug of silica and eluted with diethyl ether. The solvents were removed under reduced pressure, and the residue was purified by flash chromatography (14% diethyl ether in PET ether). A sample was submitted to chiral analytical HPLC analysis [Chiralpak AD, iso-hexane/iso-propanol: 95/5, 1 mL/min, 3.77 min (1.sup.st peak), 7.10 min (2.sup.nd peak), 88% e.e., absolute configuration not determined]. 3-Deutero-cis-tert-butyl-1-(2-tert-butoxyphenyl)-3-phenylaziridine-2-carboxylate was afforded as a colourless oil in a 65% yield. The trans-product was not detectable by NMR.

[0197] From the above, it can be seen that the aziridination protocol disclosed herein has the following benefits: [0198] 1. It is extremely straightforward; the reagents are simply mixed and stirred. [0199] 2. In general there is no need to utilise dry solvents or inert atmospheres (unless either one of the starting materials is water sensitive), meaning that the system is cost efficient. Thus the process has a lower environmental/carbon footprint than conventional metal based protocols. [0200] 3. The starting materials are readily and cheaply available. [0201] 4. The asymmetric organocatalysts are highly efficient/active and can be utilised at low concentrations, even down to 0.1 mol %. [0202] 5. The catalysts should be recyclable, for instance by transferring them to a solid-support system allowing for facile removal after use. Immobilisation of the catalyst would also allow the synthesis of aziridines using flow technology or bed reactors. [0203] 6. The reaction conditions are extremely mild and the majority of commonly used functional and protecting groups are tolerated. [0204] 7. The aziridination protocol affords in many cases exceptionally high yields of product in exceptionally high stereoselectivities with no by-product formation. [0205] 8. The reaction process is environmentally benign, generating only nitrogen and water. Furthermore due to the high yields, the fact that no enamine or by-products are observed, and the fact that all of the starting materials are completely consumed, purification of the product is straightforward and uncomplicated. [0206] 9. The organocatalysts are easily generated and can be stored and used straight out of the bottle. [0207] 10. The procedure/catalysts are widely applicable to the transformation of structurally diverse starting materials into the corresponding aziridines; this contrasts with the relatively poor substrate specificity displayed by other reported catalysts.

Example 8

[0208] To compare the catalytic activity of the phosphoramide catalysts of the present invention to the catalytic activity of the equivalent phosphoric acid catalysts used by Akiyama et al. and Zeng et al. in the prior art as discussed above, the following experiment was performed:

##STR00037##

[0209] The aziridine formation outlined above was attempted using phosphoric acid based catalysts A, B and C, and also using phosphoramide catalyst D, all at 10 mol % in DCM at room temperature.

##STR00038##

[0210] Using phosphoric acid catalyst A, the desired cis-aziridine was isolated in 16% yield, although the product was racemic by chiral HPLC analysis. Only trace amounts (<5% yield) of the desired cis-aziridine were found in the .sup.1H-NMR spectra of the crude reaction mixtures when B or C was used as the catalyst.

[0211] In contrast, when the phosphoramide catalyst (S)-3,3-bis(9-anthracenyl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide D was used, the reaction afforded the desired cis-aziridine in an 85% yield. Moreover, careful scrutinization of the .sup.1H-NMR crude spectra proved that complete consumption of the starting imine had taken place and no traces of the trans-azirdine were found in the crude reaction mixture. Analysis of the cis-aziridine produced using analytical chiral HPLC column confirmed that catalyst D had afforded the cis-aziridine in a 47% e.e.

[0212] Thus, it can be seen that under like-for-like conditions, the phosphoramide catalysts employed in the present invention afford superior yields and greater stereoselectivity than the equivalent phosphoric acid catalysts of the prior art.

Example 9

[0213] To compare the effect of the solvents utilised in the preferred embodiments of the present invention with those used by Hashimoto et al. in the journal article discussed above, the following experiment was performed:

##STR00039##

[0214] The aziridine formation outlined above was attempted using phosphoramide catalyst D at 10 mol % concentration at 78 C. in a range of solvents. Each solvent study was repeated to confirm reproducibility. The results are shown in the table below.

TABLE-US-00001 e.e. Molar yield Solvent Study 1 Study 2 Study 1 Study 2 DCM 39% 47% 81% 82% DCM:hexane (1:1) 25% 17% 83% 68% Toluene 19% 22% 87% 80% CHCl.sub.3:DCM (8:2) 84% 90% 87% 74%

[0215] Thus it can be seen that, under like-for-like conditions, the use of a reaction solvent comprising a mixture of halocarbons results in a marked increase in the stereoselectivity of the reaction versus the use of the solvent systems suggested in Hashimoto et al.

Example 10

[0216] To compare the effect of the reaction conditions utilised in the preferred embodiments of the present invention with those used by Hashimoto et al. in the journal article discussed above, the following experiment was performed:

##STR00040##

[0217] To a stirred solution of 3-(2-diazopropanoyl)oxazolidin-2-one (0.12 mmol, 20.0 mg) and benzaldehyde N-Boc imine (0.15 mmol, 31.6 mg) in CDCl.sub.3/CD.sub.2Cl.sub.2 8:2 mixture (0.8 mL) was added (S)-3,3-bis(anthracen-9-yl)-[1,1]-binaphthalen-2,2-yl-N-triflyl-phosphoramide (5.9 mol, 4.9 mg, 5 mol %) in CDCl.sub.3/CD.sub.2Cl.sub.2 8:2 mixture (0.2 mL) at 78 C. under argon. The reaction mixture was stirred at the same temperature for 1 hour and then treated with triethylamine (20 L). The mixture was poured into aqueous NaHCO.sub.3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO.sub.4 and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (eluting with hexane/ethyl acetate/triethylamine, 4:1:0.05) to give tert-butyl 2-methyl-2-(2-oxooxazolidine-3-carbonyl)-3-phenylaziridine-1-carboxylate (29.7 mg, 72% yield) as a white solid. A single isomer was detectable by NMR. Enantiomeric purity was determined by HPLC analysis to be 90.7% e.e. (Column Cellulose-1, iso-hexane/iso-propanol=85:15, flow rate=1.0 ml/min, retention time=12.9 min (minor) and 22.4 min (major), column oven at 30 C.). The absolute configuration was not determined.

[0218] By comparison with entries 4 and 5 of Table 1 of Hashimoto et al., it can be seen that the reaction conditions of the present invention result in a substantial improvement in the enantiomeric excess of the aziridine obtained.

Example 11

[0219] To investigate the influence of solvent choice in the synthesis of isotopically labelled aziridines, the following experiment was performed:

##STR00041##

[0220] The aziridine formation outlined above was attempted using phosphoramide catalyst D at 10 mol % concentration at 78 C. in a range of solvents. Each solvent study was repeated to confirm reproducibility. The results are shown in the table below.

TABLE-US-00002 e.e. Molar yield Solvent Study 1 Study 2 Study 1 Study 2 DCM 61% 53% 68% 86% DCM:hexane (1:1) 59% 59% 88% 71% Toluene 79% 69% 86% 79% CHCl.sub.3:DCM (8:2) 88% 82% 91% 91%

[0221] Again, using a mixture of halocarbons a marked increase in the stereoselectivity of the reaction versus the use of the solvent systems suggested in Hashimoto et al. was observed.

Example 12

[0222] To further investigate the influence of solvent choice in the synthesis of isotopically labelled aziridines, the following experiment was performed:

##STR00042##

[0223] The aziridine formation outlined above was attempted using phosphoramide catalyst D at 10 mol % concentration in a range of solvents at various temperatures. The results are shown in the table below.

TABLE-US-00003 Solvent Temperature e.e. Molar yield DCM 70 C. 79% 80% CHCl.sub.3:toluene (1:1) 80 C. 83% 73% CHCl.sub.3 63 C. 82% 87% CHCl.sub.3:DCM (8:2) 80 C. 92% 85%

[0224] Once again, it can be seen that by using a mixture of halocarbons as the reaction solvent, a marked increase in the stereoselectivity of the reaction is observed.

[0225] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the present invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.