Stereoselective syntheses of pinane-based 1,3-diamines and their application as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde

A library of 1,3-difunctionalized pinane derivatives was synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The key intermediate β-lactam 2 was prepared regio- and stereoselectively from (−)-apopinene 1. The treatment of 2 with di-tert-butyl dicarbonate afforded N-Boc β-lactam 3, while acid-catalyzed ring opening of 2 resulted in amino acid 4. Nucleophilic ring opening of 3 with dimethylamine, followed by deprotection and benzylation, furnished β-amino amides 5, 8, and 11, which were transformed in two steps into the corresponding N-tosyldiamines 7, 10, and 13, respectively. Since the use of other amines, such as diethylamine, to study the influence of dialkyl substitution was unsuccessful, an alternative synthetic route was applied. Amidation of tosylated β-amino acid 14 furnished amides 15–25. Reduction of 15, 16, 19, 20, and 24 resulted in N-tosyl diamines 26–30. The β-amino amides and N-tosylated diamines were used as chiral ligands in the enantioselective alkylation of benzaldehyde with diethylzinc, resulting in (R)- and (S)-1-phenyl-1-propanol. The (R)-enantiomer was predominant except when 17, 22, 23, and 25 were used as ligands, in which case the opposite stereochemistry was observed. The best ee values (up to 83%) were obtained when 17, 20, 23, and 25 were used as catalysts.

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tert-Butyl(1R,2R,3S,5R)-3-(dimethylcarbamoyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-ylcarbamateC17H30N2O3[α]D20=+31.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-3-((Dimethylamino)methyl)-N- 6,6-trimethylbicyclo[3.1.1]heptan-2-amineC13H26N2[α]D20=-132.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-3-((Dimethylamino)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC19H30N2O2S[α]D20=-5.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-3-((Diethylamino)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC21H34N2O2S[α]D20=-24.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-Benzyl-N-((1R,2R,3S,5R)-3-((dimethylamino)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC26H36N2O2S[α]D20=+37.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-6,6-Dimethyl-3-(pyrrolidin-1-ylmethyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC21H32N2O2S[α]D20=-20.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-3-((Benzyl(methyl)amino)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC25H34N2O2S[α]D20=+12.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-6,6-Dimethyl-3-((methyl(phenyl)amino)methyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC24H32N2O2S[α]D20=+17.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-6,6-Dimethyl-3-(piperidin-1-ylmethyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC22H34N2O2S[α]D20=-29.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-3-((Dimethylamino)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-N,4-dimethylbenzenesulfonamideC20H32N2O2S[α]D20=+121.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-N,N,6,6-Tetramethyl-2-(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxamideC19H28N2O3S[α]D20=+21.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-2-(N-Benzyl-4-methylphenylsulfonamido)-N,N,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamideC26H34N2O3S[α]D20=-69.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-6,6-Dimethyl-2-(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxylic acidC17H23NO4S[α]D20=-55.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-2-Amino-N,N,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamideC12H22N2O[α]D20=-12.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-2-(Benzylamino)-N,N,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamideC19H28N2O[α]D20=-29.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-N,N-Diethyl-6,6-dimethyl-2-(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxamideC21H32N2O3S[α]D20=+15.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-6,6-Dimethyl-3-(pyrrolidine-1-carbonyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC21H30N2O3S[α]D20=+12.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-N-Benzyl-6,6-dimethyl-2-(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxamideC24H30N2O3S[α]D20=+70.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-6,6-Dimethyl-2-(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxamideC17H24N2O3S[α]D20=+13.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-N-Benzyl-N,6,6-trimethyl-2-(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxamideC25H32N2O3S[α]D20=-3.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-6,6-Dimethyl-2-(4-methylphenylsulfonamido)-N-((R)-1-phenylethyl)bicyclo[3.1.1]heptane-3-carboxamideC25H32N2O3S[α]D20=+108.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-6,6-Dimethyl-2-(4-methylphenylsulfonamido)-N-((S)-1-phenylethyl)bicyclo[3.1.1]heptane-3-carboxamideC25H32N2O3S[α]D20=-6.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-N,6,6-Trimethyl-2-(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxamideC18H26N2O3S[α]D20=+67.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

N-((1R,2R,3S,5R)-6,6-Dimethyl-3-(piperidine-1-carbonyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzenesulfonamideC22H32N2O3S[α]D20=+21.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-N,6,6-Trimethyl-2-(4-methylphenylsulfonamido)-N-phenylbicyclo[3.1.1]heptane-3-carboxamideC24H30N2O3S[α]D20=-39.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)

(1R,2R,3S,5R)-6,6-Dimethyl-2-(4-methylphenylsulfonamido)-N-phenylbicyclo[3.1.1]heptane-3-carboxamideC23H28N2O3S[α]D20=+97.0 (c 0.125, MeOH)Source of chirality: (1R)-myrtenalAbsolute configuration: (1R,2R,3S,5R)