Synthesis of enantiopure 5.7-spirodiamines: (S)-1,7-diaza[4.6]undecane and related compounds

The efficient synthesis of enantiomerically pure (S)-1,7-diaza[4.6]undecane and (S)-7-methyl-1,7-diaza[4.6]undecane and related compounds is reported. These novel diamines are obtained from (S)-proline, which is reacted with chloral to give an enantiomerically pure oxazolidinone, which is alkylated at the α-position using cis-1,4-dibromobutene. The resulting allylbromide is then reacted with ammonia or methylamine to yield, as intermediates, allylamines, which ring close to give the corresponding spirolactams. The parent and the 7-methyl (S)-5.7-spirodiamines are obtained via reduction in two steps of the spirolactams. The expected absolute configuration was confirmed by X-ray structural analysis. Enantiomeric excess (>99.8% ee) was determined using the Mosher amides of the spirodiamines and gas chromatography.

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(2R,5R)-5-(4-Bromo-2-butenyl)-2-trichloromethyl-1-aza-3-oxabicyclo[3.3.0]octan-4-oneC11H13BrCl3NO2[α]D25=-7.5 (c 4.552, CHCl3)

(5R)-1,7-Diaza-spiro[4.6]undec-9-en-6-oneC9H14NO2[α]D25=-133.9 (c 0.85, CHCl3)

(5R)-7-Methyl-1,7-diaza-spiro[4.6]undec-9-en-6-oneC10H16NO2[α]D25=-113.5 (c 1.36, CHCl3)

(5R)-7-Methyl-1,7-diaza-spiro[4.6]undec-9-eneC10H19N2[α]D25=-37.2 (c 0.395, CHCl3)

Bis-(4-[(2R,5R)-2-trichloromethyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one-5-yl]-2-butenyl)-methylamineC23H29Cl6N3O4[α]D25=-5.9 (c 0.17, CHCl3)

(5S)-1,7-Diaza-spiro[4.6]undecaneC9H18N2[α]D25=-1.6 (c 2.12, CHCl3)

(5S)-7-Methyl-1,7-diaza-spiro[4.6]undecaneC10H20N2[α]D25=-9.9 (c 3.25, CHCl3)

(5S)-1,7-Dimethyl-1,7-diaza-spiro[4.6]undecaneC11H22N2[α]D25=-2.9 (c 0.58, CHCl3)

(5S)-1,7-Diaza-spiro[4.6]undecan-6-oneC9H16N2O[α]D25=-45.9 (c 0.58, CHCl3)

(5S)-7-Methyl-1,7-diaza-spiro[4.6]undecan-6-oneC10H18N2O[α]D25=-45.0 (c 2.77, CHCl3)