Enantiopure N-Boc piperidine-2-ethanol for the synthesis of (+)- and (−)-dumetorine, and (+)- and (−)-epidihydropinidine

The convenient synthesis of both enantiomers of the piperidine alkaloids such as dumetorine and epidihydropinidine is described. Pure enantiomers of 2-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester are used as a common starting material. The syntheses are based on a RCM reaction and on methylation of the piperidine ring according to Beak–Lee methodology, respectively.

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(S)-2-((R)-2-Hydroxy-4-methylpent-4-enyl)piperidine-1-carboxylic acid tert-butyl esterC16H29NO3[α]D=-34[α]D=-34 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′R)

(S)-2-((S)-2-Hydroxy-4-methylpent-4-enyl)piperidine-1-carboxylic acid tert-butyl esterC16H29NO3[α]D=-47[α]D=-47 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′S)

(S)-2-((R)-2-Acryloyloxy-4-methyl-pent-4-enyl)piperidine-1-carboxylic acid tert-butyl esterC19H31NO4[α]D=+44[α]D=+44 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′R)

(S)-2-((R)-4-Methyl-6-oxo-3,6-dihydro-2H-pyran-2-ylmethyl)piperidine-1-carboxylic acid tert-butyl esterC17H27NO4[α]D=+64[α]D=+64 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′R)

(S)-2-((R)-4-Methyl-6-oxo-3,6-dihydro-2H-pyran-2-ylmethyl)piperidineC12H19NO2[α]D=+54[α]D=+54 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′R)

(1R,7S,9S)-1-Methyl-10-oxa-2-azatricyclo[7.3.1.02,7]tridecan-11-oneC12H19NO2[α]D=+3[α]D=+3 (c 0.26, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (1R,7S,9S)

(+)-DumetorineC13H21NO2[α]D=+37[α]D=+37 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′R)

(S)-2-((S)-2-Acryloyloxy-4-methylpent-4-enyl)piperidine-1-carboxylic acid tert-butyl esterC19H31NO4[α]D=+51[α]D=+51 (c 0.9, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′S)

(S)-2-((S)-4-Methyl-6-oxo-3,6-dihydro-2H-pyran-2-ylmethyl)piperidine-1-carboxylic acid tert-butyl esterC17H27NO4[α]D=+58[α]D=+58 (c 0.8, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′S)

(S)-2-((R)-2-Hydroxy-4-methylpent-4-enyl)piperidine-1-methylC12H23NO[α]D=-27[α]D=-27 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′R)

(S)-2-((R)-2-Acryloyloxy-4-methylpent-4-enyl)piperidine-1-methylC15H25NO2[α]D=-26[α]D=-26 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,2′R)

(R)-2-[2-(tert-Butyldimethylsilanyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl esterC18H37NO3Si[α]D=+17.4[α]D=+17.4 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2R)

(2R,6S)-2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-6-methylpiperidine-1-carboxylic acid tert-butyl esterC19H39NO3Si[α]D=+14.8[α]D=+14.8 (c 1, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2R,6S)

(2R,6S)-2-(2-Hydroxyethyl)-6-methylpiperidine-1-carboxylic acid tert-butyl esterC13H25NO3Si[α]D=+32.7[α]D=+32.7 (c 1.15, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2R,6S)

(2R,6S)-2-(2-Oxoethyl)-6-methylpiperidine-1-carboxylic acid tert-butyl esterC13H23NO3[α]D=+17.5[α]D=+17.5 (c 1.15, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2R,6S)

(2R,6S)-2-Allyl-6-methylpiperidine-1-carboxylic acid tert-butyl esterC14H25NO2[α]D=+23.7[α]D=+23.7 (c 1.5, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2R,6S)

(2S,6S)-2-Propyl-6-methylpiperidine-1-carboxylic acid tert-butyl esterC14H27NO2[α]D=+40.4[α]D=+40.4 (c 0.25, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2S,6S)

(−)-EpidihydropinidineC9H19N[α]D=-2.7[α]D=-2.7 (c 0.2, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (2R,6S)