Stereoselective synthesis of optically active cyclopenta[c]pyridines and tetrahydropyridines

The intramolecular Pauson–Khand and ring closing metathesis (RCM) reactions of nitrogen containing chiral enynes and dienes are described. The enyne and diene systems comprised of N-propargylated and N-allylated units are constructed on chiral homoallylic or homopropargylic alcohol backbones, respectively, via SN2 and/or modified Mitsunobu reactions. The racemic homoallylic and homopropargylic alcohol derivatives were successfully resolved in high ee (93–99%) by applying chemoenzymatic methods using various lipases such as PS-C II, Lipozyme, and CAL-B. Each enantiomerically enriched enyne afforded the most conformationally stable diastereomeric cyclopenta[c]pyridine ring system as the sole product, whereas enantiomerically enriched dienes gave tetrahydropyridine derivatives as a result of intramolecular Pauson–Khand and RCM reactions, respectively.

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(R)-(+)-N-(Prop-2-yn-1-yl)-1-(pyridin-2-yl)but-3-en-1-amineC12H14N2Ee = 98%[α]D31=+79.2 (c 1, EtOH)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-(+)-4-Methyl-N-(prop-2-yn-1-yl)-N-(1-(pyridin-2-yl)but-3-en-1-yl)benzenesulfonamideC19H20N2O2SEe = 98%[α]D31=+83.7 (c 1, CH2Cl2)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-(+)-N-(1-(Furan-2-yl)but-3-en-1-yl)-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamideC18H19NO3SEe = 99%[α]D35=+10.1 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-(+)-4-Methyl-N-(prop-2-yn-1-yl)-N-(1-(thiophen-2-yl)but-3-en-1-yl)benzenesulfonamideC18H19NO2S2Ee = 99%[α]D31=+9.9 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-(+)-N-Allyl-N-(1-(furan-2-yl)but-3-en-1-yl)-4-methylbenzenesulfonamideC18H21NO3SEe = 99%[α]D26=+4.5 (c 1, CH2Cl2)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-(+)-N-Allyl-4-methyl-N-(1-(thiophen-2-yl)but-3-en-1-yl)benzenesulfonamideC18H21NO2S2Ee = 99%[α]D26=+11.6 (c 1, CH2Cl2)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-(+)-N-Allyl-1-(pyridin-2-yl)but-3-yn-1-amineC12H14N2Ee = 95%[α]D24=+25.9 (c 1, CHC3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-(+)-N-Allyl-4-methyl-N-(1-(pyridin-2-yl)but-3-yn-1-yl)benzenesulfonamideC19H20N2O2SEe = 95%[α]D25=+41.4 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(3R,4aS)-(+)-3-(Pyridin-2-yl)-2-tosyl-3,4,4a,5-tetrahydro-1H-cyclopenta[c]pyridin-6(2H)-oneC20H20N2O3SEe = 98%[α]D25=+55.4 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4aS)

(3R,4aS)-(+)-3-(Furan-2-yl)-2-tosyl-3,4,4a,5-tetrahydro-1H-cyclopenta[c]pyridin-6(2H)-oneC19H19NO4SEe = 99%[α]D32=+13.5 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4aS)

(3R,4aS)-(+)-3-(Thiophen-2-yl)-2-tosyl-3,4,4a,5-tetrahydro-1H-cyclopenta[c]pyridin-6(2H)-oneC19H19NO3S2Ee = 99%[α]D32=+10.6 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3R,4aS)

(3R)-(+)-3-(Pyridin-2-yl)-2-tosyl-3,4,7,7a-tetrahydro-1H-cyclopenta[c]pyridin-6(2H)-oneC20H20N2O3SEe = 95%[α]D25=+124.3 (c 1, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3R)

(R)-(+)-2-(Furan-2-yl)-1-tosyl-1,2,3,6-tetrahydropyridineC16H17NO3SEe = 99%[α]D20=+4.8 (c 1, CH2Cl2)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)

(R)-(+)-2-(Thiophen-2-yl)-1-tosyl-1,2,3,6-tetrahydropyridineC16H17NO2S2Ee = 99%[α]D18=+4.1 (c 1, CH2Cl2)Source of chirality: enzymatic resolutionAbsolute configuration: (1R)