Stereoselective synthesis of pinane-based β- and γ-amino acids via conjugate addition of lithium amides and nitromethane

Michael addition of dibenzylamine to (−)- and (+)-tert-butyl myrtenate, (−)-2 and (+)-2, derived from (−)- and (+)-myrtenal, furnished monoterpene-based β-amino acid derivatives in highly stereospecific reactions. The resultant amino esters (−)-3 and (+)-3 were transformed to unsubstituted, mono- and disubstituted and Fmoc-protected amino acids (−)-6-11 and (+)-6-11, which are promising building blocks for the synthesis of β-peptides and 1,3-heterocycles. The microwave-assisted conjugate addition of nitromethane to α,β-unsaturated esters (−)-12 and (+)-12 likewise resulted in nitro esters (−)-13 and (+)-13 in highly stereospecific reactions. Compounds (−)-13 and (+)-13 were successfully transformed into γ-amino acids (−)-16 and (+)-16 in two steps.

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(1S,2S,3S,5R)-tert-Butyl 3-(dibenzylamino)-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylateC28H37NO2[α]D20+46.0 (c 0.265, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3S,5R)-tert-Butyl 3-(benzyl((R)-1′-phenylethyl)amino)-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylateC29H39NO2[α]D20+56.0 (c 0.125, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1R,2S,3S,5R,1′R)

(1S,2S,3S,5R)-tert-Butyl 3-(benzyl((S)-1′-phenylethyl)amino)-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylateC29H39NO2[α]D20+86.0 (c 0.25, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1R,2S,3S,5R,1′S)

(1S,2S,3S,5R)-3-(Dibenzylamino)-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylic acid hydrochlorideC24H30ClNO2[α]D20+22.0 (c 0.125, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3S,5R)-tert-Butyl 3-amino-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylateC14H25NO2[α]D20+21.0 (c 0.25, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3S,5R)-tert-Butyl 3-benzylamino-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylateC21H31NO2[α]D20+39.0 (c 0.155, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3S,5R)-3-Benzylamino-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylic acid hydrochlorideC17H24ClNO2[α]D20+28.0 (c 0.125, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3S,5R)-3-Amino-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylic acid hydrochlorideC10H18ClNO2[α]D20+19.0 (c 0.125, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3S,5R)-3-[((9H-Fluoren-9-yl)methoxy)carbonylamino]-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylic acidC25H27NO4[α]D20+21.0 (c 0.125, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3S,5R)-Methyl 6,6-dimethyl-3-(nitromethyl)bicyclo[3.1.1]heptane-2-carboxylateC12H19NO4[α]D20-0.4 (c 0.25, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3R,5R)-Methyl 6,6-dimethyl-3-(nitromethyl)bicyclo[3.1.1]heptane-2-carboxylateC12H19NO4[α]D20-0.8 (c 0.25, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3R,5R)

(1S,2S,3S,5R) 6,6-Dimethyl-3-(nitromethyl)bicyclo[3.1.1]heptane-2-carboxylic acidC11H17NO4[α]D20-0.6 (c 0.25, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)

(1S,2S,3S,5R)-3-(Aminomethyl)-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylic acid hydrochlorideC11H20ClNO2[α]D20+1.4 (c 0.25, MeOH)Source of chirality: (−)-(1R,5S)-myrtenalAbsolute configuration: (1S,2S,3S,5R)