Stereoselective synthesis and application of tridentate aminodiols derived from (+)-pulegone

A library of tridentate aminodiols, derived from naturally occurring (R)-(+)-pulegone, was synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The reduction of pulegone furnished pulegol, which was transformed into allylic trichloroacetamide via Overman rearrangement of the corresponding trichloroacetimidate. The protected enamine was subjected to dihydroxylation with OsO4/NMO system resulting in a 1:1 mixture of (1R,2R,4R)- and (1S,2S,4R)-aminodiol diastereomers. After the removal of the trichloroacetyl protecting groups, the obtained primary aminodiols were transformed into secondary ones. The regioselectivity of the ring closure of the N-benzyl substituted aminodiols with formaldehyde was investigated resulting in both the 1,3-oxazine and oxazolidine rings. The tautomerism of the spiro and fused ring systems was observed and its mechanism was studied by detailed DFT analysis by employing an IEFPCM solvent model to provide a more realistic representation of the experimental conditions. The obtained potential catalysts were applied to the reaction of benzaldehyde and diethylzinc with moderate to good enantioselectivity (up to 90% ee).

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(4R)-2,2,2-Trichloro-N-[1-methyl-1-(4-methyl-cyclohex-1-enyl)-ethyl]-acetamideC12H29Cl3NO[α]D20 = +39 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (4R)

(1R,2R,4R)-2,2,2-Trichloro-N-[1-(1,2-dihydroxy-4-methylcyclohexyl)-1-methyl-ethyl]-acetamideC12H20Cl3NO3[α]D20 = +27 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (1R,2R,4R)

(1S,2S,4R)-2,2,2-Trichloro-N-[1-(1,2-dihydroxy-4-methylcyclohexyl)-1-methyl-ethyl]-acetamideC12H20Cl3NO3[α]D20 = −18 (c 0.250, MeOH)Source of chirality (+)-pulegoneAbsolute configuration: (1S,2S,4R)

(1R,2R,4R)-1-(1-Amino-1-methylethyl)-4-methylcyclohexane-1,2-diolC10H21NO2[α]D20 = +26 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (1R,2R,4R)

(1S,2S,4R)-1-(1-Amino-1-methylethyl)-4-methylcyclohexane-1,2-diolC10H21NO2[α]D20 = −36 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (1S,2S,4R)

(1R,2R,4R)-1-(1-Benzylamino-1-methyl-ethyl)-4-methylcyclohexane-1,2-diolC17H27NO2[α]D20 = +27 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (1R,2R,4R)

(1S,2S,4R)-1-(1-Benzylamino-1-methyl-ethyl)-4-methylcyclohexane-1,2-diolC17H27NO2[α]D20 = −26 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (1S,2S,4R)

(1R,2R,4R)-1-[1-(3,5-Di-tert-butyl-benzylamino)-1-methylethyl]-4-methyl-cyclohexane-1,2-diolC25H43NO2[α]D20 = +15 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (1R,2R,4R)

(1S,2S,4R)-1-[1-(3,5-Di-tert-butylbenzylamino)-1-methylethyl]-4-methylcyclohexane-1,2-diolC25H43NO2[α]D20 = −20 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (1S,2S,4R)

(5R,6R,8R)-3-Benzyl-4,4,8-trimethyl-1-oxa-3-azaspiro[4.5]decan-6-olC18H27NO2[α]D20 = −56 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (5R,6R,8R)

(4aR,7R,8aR)-3-Benzyl-4,4,7-trimethyl-hexahydrobenzo[e][1,3]oxazin-4a-olC18H27NO2[α]D20 = −73 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (4aR,7R,8aR)

(5S,6S,8R)-3-Benzyl-4,4,8-trimethyl-1-oxa-3-azaspiro[4.5]decan-6-olC18H27NO2[α]D20 = −28 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (5S,6S,8R)

(4aS,7R,8aS)-3-Benzyl-4,4,7-trimethyl-hexahydrobenzo[e][1,3]oxazin-4a-olC18H27NO2[α]D20 = +57 (c 0.250, MeOH)Source of chirality: (+)-pulegoneAbsolute configuration: (4aS,7R,8aS)