Synthesis of spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-amines via stereoselective cycloadditions of trimethylenemethane to (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones

Stereoselective [3+2] cycloadditions of trimethylenemethane (TMM) to the exocyclic CO and CN double bonds of (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones gave the corresponding spiro[bicyclo[2.2.1]heptane-2,2′-furan] and spiro[bicyclo[2.2.1]heptane-3,2′-pyrrolidine] derivatives. Further stereoselective reductions of the CN or CO bond in these cycloadducts furnished new chiral amines, diamines, and a new aminoalcohol. All cycloadditions and reductions of the CN double bonds took place from the less hindered endo-face of the (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones, exclusively, thus giving the corresponding products in 100% de. The structures were determined by NMR, NOESY spectroscopy, and by X-ray diffraction.

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(1S,3E,4R)-1,7,7-Trimethyl-3-(phenylimino)bicyclo[2.2.1]heptan-2-oneC16H19NODe = 100%[α]D23=-652.1 (c 0.14, CHCl3)Source of chirality: (1S)-(+)-camphorquinoneAbsolute configuration: (1S,3E,4R)E:Z = 96:4

(1S,3E,4R)-1,7,7-Trimethyl-3-[(1-naphthyl)imino]bicyclo[2.2.1]heptan-2-oneC20H21NODe = 100%[α]D23=-620.8 (c 0.11, CHCl3)Source of chirality: (1S)-(+)-camphorquinoneAbsolute configuration: (1S,3E,4R)E:Z = 97:3

(1S,3E,4R)-1,7,7-Trimethyl-3-[(2-nitrophenyl)imino]bicyclo[2.2.1]heptan-2-oneC16H18N2O3De = 100%[α]D23=-94.6 (c 0.11, CHCl3)Source of chirality: (1S)-(+)-camphorquinoneAbsolute configuration: (1S,3E,4R)E:Z = 75:25

(1S,3E,4R)-1,7,7-Trimethyl-3-[(4-nitrophenyl)imino]bicyclo[2.2.1]heptan-2-oneC16H18N2O3De = 100%[α]D23=-358.2 (c 0.17, CHCl3)Source of chirality: (1S)-(+)-camphorquinoneAbsolute configuration: (1S,3E,4R)E:Z = 90:10

(1S,3E,4R)-1,7,7-Trimethyl-3-[(3-nitrophenyl)imino]bicyclo[2.2.1]heptan-2-oneC16H18N2O3De = 100%[α]D23=-377.3 (c 0.11, CHCl3)Source of chirality: (1S)-(+)-camphorquinoneAbsolute configuration: (1S,3E,4R)E:Z = 89:11

(3E)-N-{(1S,2R,4R)-1,7,7-Trimethyl-4′-methylenedihydro-3′H- spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-ylidene}anilineC20H25NODe = 100%[α]D26=-18.0 (c 0.16, CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,4R)

(3E)-N-{(1S,2R,4R)-1,7,7-Trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-ylidene}naphthalen-1-amineC24H27NODe = 100%[α]D26=-36.8 (c 0.19, CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,4R)

(3E)-2-Nitro-N-{(1S,2R,4R)-1,7,7-trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-ylidene}anilineC20H24N2O3De = 100%[α]D23=+133.9 (c 0.24, CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,4R)

(3E)-4-Nitro-N-{(1S,2R,4R)-1,7,7-trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-ylidene}anilineC20H24N2O3De = 100%[α]D23=+32.8 (c 0.19, CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,4R)

(1S,3S,4R)-1,7,7-Trimethyl-4′-methylene-1′-(4-nitrophenyl)spiro[bicyclo[2.2.1]heptane-3,2′-pyrrolidin]-2-oneC20H24N2O3De = 100%[α]D23=-237.5 (c 0.12, CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,3S,4R)

(1S,2R,4R)-1,7,7-Trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-oneC14H20O2De = 100%[α]D27=+122.8 (c 0.23,CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,4R)

(1S,2R,3S,4R)-1,7,7-Trimethyl-4′-methylene-N-phenyldihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-amineC20H27NODe = 100%[α]58927=+141.5 (c 0.27,CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,3S,4R)

(1S,2R,3S,4R)-1,7,7-Trimethyl-4′-methylene-N-(naphthalen-1-yl)dihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-amineC24H29NODe = 100%[α]58925=+211.6 (c 0.07,CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,3S,4R)

N1-{(1S,2R,3S,4R)-1,7,7-Trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-yl}benzene-1,2-diamineC20H28N2ODe = 100%[α]58925=+150.0 (c 0.09,CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,3S,4R)

N1-{(1S,2R,3S,4R)-1,7,7-Trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-yl}benzene-1,4-diamineC20H28N2ODe = 100%[α]58925=+417.2 (c 0.06,CHCl3)Source of chirality:(1S)-(+)-camphorquinoneAbsolute configuration:(1S,2R,3S,4R)

(E)-1,2-Bis(4-{(1S,2R,3S,4R)-1,7,7-trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3- ylamino}phenyl)diazeneC40H52N4O2De = 100%[α]58925=+100.0 (c 0.04, CHCl3)Source of chirality: (1S)-(+)-camphorquinoneAbsolute configuration: (1S,2R,3S,4R)

(E)-1,2-Bis(4-{(1S,2R,3S,4R)-1,7,7-trimethyl-4′-methylenedihydro-3′H-spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-ylamino}phenyl)diazene oxideC40H52N4O3De = 100%[α]58925=+85.3 (c 0.03, CHCl3)Source of chirality: (1S)-(+)-camphorquinoneAbsolute configuration: (1S,2R,3S,4R)

(1R,2S,3R,4S)-1′-(4-Aminophenyl)-4,7,7-trimethyl-4′-methylenespiro[bicyclo[2.2.1]heptane-2,2′-pyrrolidin]-3-olC20H28N2ODe = 76%[α]58926=-80.2 (c 0.17, CHCl3)Source of chirality: (1S)-(+)-camphorquinoneAbsolute configuration: (1R,2S,3R,4S)