Straightforward synthesis of [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]methanol and [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl](diphenyl)methanol: novel chiral ligands for the catalytic addition of diethylzinc to benzaldehyde to give rise to an exten

Enantiopure [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]methanol 5a and [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]-(diphenyl)methanol 5b, new β-amino alcohols based on l-pipecolinic acid (homoproline), have been prepared straightforwardly from rac-alaninol and rac-2-amino-1,1-diphenylpropan-1-ol, respectively. The described route constitutes as a model procedure for the preparation of other related C(4) or/and C(3)-substituted 2-piperidinylmethanols.The new chiral ligands have shown a singular behaviour on the stereocontrol of the benchmark reaction of benzaldehyde and diethylzinc compared with other C(4)-unsubstituted analogues prepared by ourselves from l-pipecolinic acid (compounds 5c, 5d, 5e and 5f). The catalytic activity, the sense of asymmetric induction and the degree of the enantioselectivity depend on the appropriate combination of the substituents on the structural scaffold, but also on the metal-alkoxide involved in the catalysis (zinc or lithium alkoxides). The enantioselective addition of diethylzinc to benzaldehyde mediated by ligands 5a and 5c has been studied with DFT methods. The theoretical evaluation was performed in connection with a working hypothesis based on the different loadings of cis- and trans-catalysts in the reaction medium.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(Ss,7′R)-7′-Methyl-8′-[(4-methylphenyl)sulfinyl]-1′,1′-diphenyl-6′,7′-dihydrospiro[cyclohexane-1,3′-[1,3]oxazolo[3,4-a]pyridin]-5′(1′H)-oneC32H33NO3S[α]D = −367.0 (c 1.0, CHCl3)Absolute configuration: (SS,7′R)

(7′R)-7′-Methyl-1′,1′-diphenyl-6′,7′-dihydrospiro[cyclohexane-1,3′-[1,3]oxazolo[3,4a]pyridin]-5′(1′H)-oneC25H27NO2[α]D = +82.8 (c 1.0, CHCl3)Absolute configuration: (7′R)

[(2S,4R)-1-Cyclohexyl-4-methylpiperidin-2-yl]methanolC13H25NO[α]D = −27.8 (c 0.6, CHCl3)Absolute configuration: (2S,4R)

[(2S,4R)-1-Cyclohexyl-4-methylpiperidin-2-yl](diphenyl)methanolC25H33NO[α]D = −25.1 (c 0.4, CH2Cl2)Absolute configuration: (2S,4R)

[(2S)-1-Cyclohexylpiperidin-2-yl]methanolC12H23NO[α]D = −37.6 (c 0.25, MeOH)Absolute configuration: (2S)

[(2S)-1-Benzylpiperidin-2-yl]methanolC13H19NO[α]D = −31.4 (c 0.5, CHCl3)Absolute configuration: (2S)

[(2S)-1-Methylpiperidin-2-yl]methanolC7H15NO[α]D = +3.9 (c 0.25, MeOH)Absolute configuration: (2S)

[(2S)-1-Methylpiperidin-2-yl](diphenyl)methanolC19H23NO[α]D = −75.8 (c 1.0, CHCl3)Absolute configuration: (2S)

(2S)-1-Cyclohexylpiperidine-2-carboxylic acidC17H21NO2[α]D = −53.4 (c 0.71, MeOH)Absolute configuration: (2S)

(2S)-1-Benzylpiperidine-2-carboxylic acidC13H17NO2[α]D = −16.2 (c 0.5, EtOH)Absolute configuration: (2S)

(2S)-1-Methylpiperidine-2-carboxylic acidC7H13NO2[α]D = −62.2 (c 0.8, MeOH)Absolute configuration: (2S)

Diphenyl[(2S)-piperidin-2-y])methanolC18H21NO[α]D = −75.7 (c 0.75, CHCl3)Absolute configuration: (2S)