Synthesis of enantiopure 1-azaspiro[4.5]dec-6-en-8-ones from l-proline derivatives

An enantioselective synthesis of protected 1-azaspiro[4.5]dec-6-en-8-one derivatives was achieved using an alkylidene carbene 1,5-CH insertion reaction as the key step.

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1-tert-Butyl 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylateC11H18N4O4[α]D23=-40.3(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4S

1-tert-Butyl 2-methyl (2S,4S)-4-(N-methoxycarbonyl)aminopyrrolidine-1,2-dicarboxylateC13H22N2O6[α]D23=-23.7(c0.85,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4S

tert-Butyl 2-methyl (2S,4S)-4-[(N-methoxycarbonyl)-N-methylamino]pyrrolidine-1,2-dicarboxylateC14H24N2O6[α]D23=-44.7(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4S

tert-Butyl (2S,4S)-2-(hydroxymethyl)-4-[(N-methoxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylateC13H24N2O5[α]D23=-43.7(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4S

tert-Butyl (2S,4S)-2-formyl-4-[(N-methoxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylateC13H22N2O5[α]D23=-70.7(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4S

tert-Butyl (2S,4S)-2-[(1E)-3-oxobut-1-enyl]-4-[(N- methoxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylateC16H26N2O5[α]D23=-31.8(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2S,4S

tert-Butyl (2S)-2-[(1E)-3-oxobut-1-enyl]pyrrolidine-1-carboxylateC13H21NO3[α]D23=-86.9(c1,CHCl3)Source of chirality: l-prolineAbsolute configuration: 2S

tert-Butyl (2R,4S)-2-(3-oxobutyl)-4-[(N-methoxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylateC16H28N2O5[α]D23=-47.3(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2R,4S

tert-Butyl (2S)-2-(3-oxobutyl)pyrrolidine-1-carboxylateC13H23NO3[α]D23=-51.8(c1,CHCl3)Source of chirality: l-prolineAbsolute configuration: 2S

tert-Butyl (3S,5R)-4-[(N-methoxycarbonyl)-N-methylamino]-7-methyl-1-azaspiro[4.4]non-6-ene-1-carboxylateC17H28N2O4[α]D23=-78.3(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 3S,5R

tert-Butyl (5R)-7-methyl-1-azaspiro[4.4]non-6-ene-1-carboxylateC14H23NO2[α]D23=-104.8(c1,CHCl3)Source of chirality: l-prolineAbsolute configuration: 5R

tert-Butyl (3S,5R,6R,7S)-6,7-dihydroxy-4-[(N-methoxycarbonyl)-N-methylamino]-7-methyl-1-azaspiro[4.4]nonane-1-carboxylateC17H30N2O6[α]D23=+11.8(c1.05,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 3S,5R,6R,7S

tert-Butyl (5S,6R,7S)-6,7-dihydroxy-7-methyl-1-azaspiro[4.4]nonane-1-carboxylateC14H25NO4[α]D23=+40.5(c1.05,CHCl3)Source of chirality: l-prolineAbsolute configuration: 5S,6R,7S

tert-Butyl (2R,4S)-2-formyl-4-[(N-methoxycarbonyl)-N-methylamino]-2-(3-oxobutyl)pyrrolidine-1-carboxylateC17H28N2O6[α]D23=+12.5(c1,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration: 2R,4S

tert-Butyl (2S)-2-formyl-2-(3-oxobutyl)pyrrolidine-1-carboxylateC14H23NO4[α]D23=+11.9(c1,CHCl3)Source of chirality: l-prolineAbsolute configuration: 2S

tert-Butyl (3S,5R)-4-[(N-methoxycarbonyl)-N-methylamino]-8-oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylateC17H26N2O5[α]D23=-18.3(c1.05,CHCl3)Source of chirality: trans-4-hydroxy-l-prolineAbsolute configuration:3S,5R

tert-Butyl (5S)-8-oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylateC14H21NO3Ee ⩾90% by HPLC on Chiralpak® AD column[α]D23=-111.5(c0.95,CHCl3)Source of chirality: l-prolineAbsolute configuration: 5S