Tertiary amine-promoted enone aziridination: investigations into factors influencing enantioselective induction

trans-N-Unsubstituted aziridines were synthesised (up to 77% ee) via a chiral tertiary amine-promoted nucleophilic aziridination of α,β-unsaturated ketones utilising in situ generated N–N ylides (aminimines). A wide range of chiral tertiary amines were synthesised and evaluated, allowing structure–activity relationships to be drawn. The most efficient promoter for asymmetric aziridination, quinine, was assessed with several enones to ascertain the effect of substrate structure on product ee, while the intermediate hydrazinium salt was characterised by X-ray crystallography.

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(2S,5S)-2,5-Bis(methoxymethyl)-1-methylpyrrolidineC9H19NO2[α]D28=-51.4 (c 0.55, CHCl3)Source of chirality: chiral poolAbsolute configuration: (2S,5S)

(S)-2-((S)-1-Isopropylpyrrolidin-2-yl)-1-methylpyrrolidineC12H24N2[α]D20=-62.8 (c 0.51, CHCl3)Source of chirality: chiral poolAbsolute configuration: (2S,2S)

4-Methyl-(3R,5R)-3,5-bis(tert-butyldiphenylsiloxymethyl)morpholineC39H51NO3Si2[α]D18=+37.2 (c 0.86, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,5R)

(3S,5S)-3,5-Bis(hydroxymethyl)-4-methylmorpholineC7H15NO3[α]D22=+30.4 (c 1.25, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3S,5S)

(S)-2-Morpholin-4-yl-propan-1-olC7H15NO2[α]D22=+40.4 (c 0.94, CHCl3)Source of chirality: chiral poolAbsolute configuration: (2S)

(2S)-1,2-Dimethyl-4-(para-toluenesulfonyl)piperazineC13H20N2O2S[α]D23=+38.9 (c 0.93, CHCl3)Source of chirality: chiral poolAbsolute configuration: (2S)

(3S)-3-Phenyl-N-methylmorpholineC11H15NO[α]D24=+36.8 (c 0.87, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3S)

9-Fluoro(9-deoxy)-quinineC20H23FN2O[α]D23=-31.1 (c 0.9, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S,8S,9R)

9-Fluoro(9-deoxy)-epiquinineC20H23FN2O[α]D23=+25.3 (c 1.19, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S,8S,9S)

9-Amino(9-deoxy)-quinineC20H25N3O[α]D19=-55.1 (c 0.65, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S,8S,9R)

9-N-Acetamido-(9-deoxy)-9-quinineC22H27N3O2[α]D22=-35.3 (c 1.4, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S,8S,9R)

9-N-Acetamido-(9-deoxy)-9-epiquinineC22H27N3O2[α]D22=+16.6 (c 0.7, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S,8S,9S)

N-(p-Toluenesulfonyl)-9-amino(9-deoxy)-quinineC27H31N3O3S[α]D22=+96.6 (c 0.58, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S,8S,9R)

N-(p-Toluenesulfonyl)-9-amino(9-deoxy)-epiquinineC27H31N3O3S[α]D22=+49.1 (c 1.43, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S,8S,9S)

(3R,4S)-8-[(6-Methoxyquinolin-4-yl)methylene]-5-vinylquinuclidineC20H22N2O[α]D22=+55.2 (c 0.58, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S)

O-Benzyl-β-isocupreidineC26H28N2O2[α]D22=+10.3 (c 0.58, CHCl3)Source of chirality: chiral poolAbsolute configuration: (3R,4S,8R,9S)

(2R,3S)-Phenyl-(3-phenylaziridin-2-yl)methanoneC15H13NOee = 56%[α]D22=-139 (c 0.66, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (determined by comparison to the literature (J. Am. Chem. Soc. 2003, 125, 16178.))

((2R,3S)-3-(4-Methoxyphenyl)aziridin-2-yl)phenyl methanoneC16H15NO2ee = 55%[α]D22=-379.3 (c 0.12, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)

((2R,3S)-3-(4-Methylphenyl)aziridin-2-yl)phenyl methanoneC16H15NOee = 52%[α]D22=-99.4 (c 0.9, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)

((2R,3S)-3-(4-Chlorophenyl)aziridin-2-yl)phenyl methanoneC15H12ClNOee = 48%[α]D22=-147.5 (c 0.8, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)

((2R,3S)-3-(4-Nitrophenyl)aziridin-2-yl)phenyl methanoneC15H12N2O3ee = 37%[α]D22=-103.3 (c 0.8, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)

((2R,3S)-3-Phenylaziridin-2-yl)-4-methoxyphenyl methanoneC16H15NO2ee = 66%[α]D22=-138.9 (c 0.36, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)

((2R,3S)-3-Phenylaziridin-2-yl)-4-methylphenyl methanoneC16H15NOee = 59%[α]D22=-169.6 (c 0.63, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)

((2R,3S)-3-Phenylaziridin-2-yl)-4-chlorophenyl methanoneC15H12ClNOee = 46%[α]D22=-128.0 (c 0.63, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin- 2-yl)methanone)

((2R,3S)-3-Phenylaziridin-2-yl)(furan-2-yl) methanoneC13H11NO2ee = 71%[α]D22=-395.3 (c 0.4, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-Phenyl-(3-phenylaziridin-2-yl)methanone)

((2R,3S)-3-Phenylaziridin-2-yl)(thiophen-2-yl) methanoneC13H11NOSee = 72%[α]D26=-319.0 (c 0.79, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)

((2R,3S)-3-Phenylaziridin-2-yl)(4-methylthiophen-2-yl) methanoneC14H13NOSee = 77%[α]D23=-536.4 (c 0.22, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)

(2R,3S)-3-Phenylaziridin-2-yl)(5-chlorothiophen-2-yl) methanoneC13H10ClNOSee = 64%[α]D22=-311.1 (c 0.52, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S) (assigned in analogy to (2R,3S)-phenyl-(3-phenylaziridin-2-yl)methanone)