Stereoselective additions to the exocyclic CC bond of some α-alkylidene-(+)-camphor derivatives

Stereoselective additions to the exocyclic CC double bond of some (1R,3E,4S)-3-alkylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and (1R,4E,5S)-4-alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones were studied. All additions took place predominantly from the less hindered endo-face of the methylidene compounds to give the corresponding exo-adducts as the major isomers. Thus, catalytic hydrogenations afforded the α-alkylated (1R,3R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and (1R,4R,5R)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones in 28–100% de. Similarly, 1,3-dipolar cycloadditions of 2,4,6-trisubstituted benzonitrile oxides gave the corresponding spiro cycloadducts in 66–100% de. The structures were determined by 2D NMR techniques, NOESY spectroscopy and X–ray diffraction.

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(1S,3E,4R)-3-[(Dimethylamino)methylidene]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC13H21NODe = 100%[α]D21=-455.7 (c 0.19, CH2Cl2)Source of chirality: (1S)-(−)-camphorAbsolute configuration: (1S,3E,4R)

(E)-3-[(1R,4S)-1,7,7-Trimethyl-2-oxobicyclo[2.2.1]heptan-3-ylidene]acetonitrileC12H15NODe = 100%[α]D23=+183.7 (c 0.40, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,3E,4S)-1,7,7-Trimethyl-3-[(2-methyl-1H-indol-3-yl)methylidene]bicyclo[2.2.1]heptan-2-oneC20H23NODe = 100%[α]D22=+261.9 (c 0.26, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,3E,4S)-3-Ethylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC12H18ODe = 100%[α]D21=+185.1 (c 1.51, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,3E,4S)-3-Pentylidene-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-oneC15H24ODe = 100%[α]D21=+158.9 (c 0.53, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,3E,4S)-3-Cyclopentylmethylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC16H24ODe = 100%[α]D21=+162.6 (c 0.83, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,3E,4S)-3-Benzylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC17H20ODe = 100%[α]D21=+446.6 (c 0.30, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,3E,4S)-3-(2-Methylbenzylidene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC18H22ODe = 100%[α]D21=+397.1 (c 0.24, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,3E,4S)-3-(4-Methylbenzylidene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC18H22ODe = 100%[α]D21=+458.1 (c 0.28, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,3E,4S)-3-(4-Fluorobenzylidene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC17H19FODe = 100%[α]D21=+413.4 (c 0.19, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1S,3E,4R)-3-(4-Fluorobenzylidene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC17H19FODe = 100%[α]D21=-399.4 (c 0.34, CHCl3)Source of chirality: (1S)-(−)-camphorAbsolute configuration: (1S,3E,4R)

(1R,3E,4S)-3-[3,5-Bis(trifluoromethyl)benzylidene]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC19H18F6ODe = 100%[α]D21=+242.0 (c 0.27, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

N-Methyl-N-{[(1R,4E,5S)-1,8,8-trimethyl-3-oxo-2-oxabicyclo[3.2.1]octan-4-ylidene]methyl}nitrous amideC12H18N2O3De = 100%[α]D22=+462.3 (c 0.22, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)

(1R,4R,5R)-1,4,8,8-Tetramethyl-2-oxabicyclo[3.2.1]octan-3-oneC11H18O2De = 28%[α]D19=-31.4 (c 0.17, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,5R)

(1R,4R,5R)-4-Propyl-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC13H22O2De = 100%[α]D23=-11.9 (c 0.19, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,5R)

(1R,3R,4R)-3-[(2-Methyl-1H-indol-3-yl)methyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC20H25NODe = 100%[α]D23=+12.1 (c 0.78, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4R)

(1R,4E,5S)-4-[(Methylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC12H19NO2De = 100%;E:Z = 95:5[α]D22=+155.9 (c 0.26, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)

(1R,4R,4′S,5S)-3′-(2,4,6-Trimethoxyphenyl)-1,8,8-trimethyl-3-oxo-4′H-2-oxaspiro[bicyclo[3.2.1]octane-4,5′-isoxazole]-4′-carbonitrileC22H26N2O6De = 100%[α]D22=-338.3 (c 0.09, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,4′S,5S)

(1R,3E,4S)-3-{[3-(2,4,6-Trimethoxyphenyl)-1,2,4-oxadiazol-5-yl]methylidene}-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC22H26N2O5De = 100%[α]D21=-346.6 (c 0.32, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3E,4S)

(1R,4R,4′R,5S)-4′-Ethyl-3′-(2,4,6-trimethoxyphenyl)-1,8,8-trimethyl-4′H-2-oxaspiro[bicyclo[3.2.1]octane-4,5′-isoxazol]-3-oneC23H31NO6De = 100%[α]D23=-402.2 (c 0.09, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,4′R,5S)

(1R,4R,4′R,5S)-4′-Butyl-3′-(2,4,6-trimethoxyphenyl)-1,8,8-trimethyl-4′H-2-oxaspiro[bicyclo[3.2.1]octane-4,5′-isoxazol]-3-oneC25H35NO6De = 100%[α]D23=-358.7 (c 0.14, CHCl3)Source of chirality: natural (1R)-(+)- camphorAbsolute configuration: (1R,4R,4′R,5S)

(1R,4R,4′R,5S)-4′-(4-Fluorophenyl)-3′-(2,4,6-trimethoxyphenyl)-1,8,8-trimethyl-4′H-2-oxaspiro[bicyclo[3.2.1]octane-4,5′-isoxazol]-3-oneC27H30FNO6De = 94%[α]D21=-352.9 (c 0.14, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,4′R,5S)

(1R,3R,4S,4′R)-1,4′,7,7-Tetramethyl-3′-(2,4,6-trimethoxyphenyl)-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC22H29NO5De = 100%[α]D19=-421.3 (c 0.15, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1R,3R,4S,4′R)-4′-Butyl-3′-(2,4,6-trimethoxyphenyl)-1,7,7-trimethyl-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC25H35NO5De = 100%[α]D19=-470.5 (c 0.42, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1R,3R,4S,4′R)-4′-Phenyl-3′-(2,4,6-trimethoxyphenyl)-1,7,7-trimethyl-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC27H31NO5De = 100%[α]D21=-508.9 (c 0.09, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1R,3R,4S,4′R)-4′-(2-Methylphenyl)-3′-(2,4,6-trimethoxyphenyl)-1,7,7-trimethyl-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC28H33NO5De = 90%[α]D21=-533.6 (c 0.12, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1R,3R,4S,4′R)-4′-(4-Methylphenyl)-3′-(2,4,6-trimethoxyphenyl)-1,7,7-trimethyl-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC28H33NO5De = 100%[α]D19=-496.4 (c 0.14, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1R,3R,4S,4′R)-4′-(4-Fluorophenyl)-3′-(2,4,6-trimethoxyphenyl)-1,7,7-trimethyl-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC27H30FNO5De = 100%[α]D21=-469.9 (c 0.16, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1S,3S,4R,4′S)-4′-(4-Fluorophenyl)-3′-(2,4,6-trimethoxyphenyl)-1,7,7-trimethyl-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC27H30FNO5De = 100%[α]D21=+498.9 (c 0.09, CHCl3)Source of chirality: (1S)-(−)-camphorAbsolute configuration: (1S,3S,4R,4′S)

(1R,3R,4S,4′R)-4′-[3,5-Bis(trifluoromethyl)phenyl]-3′-(2,4,6-trimethoxyphenyl)-1,7,7-trimethyl-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC29H29F6NO5De = 86%[α]D21=-309.3 (c 0.16, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1R,3R,4S,4′R)-4′-(2-Methylphenyl)-1,7,7-trimethyl-3′-(2,4,6-trimethylphenyl)-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC28H33NO2De = 100%[α]D21=-534.4 (c 0.28, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1R,3R,4S,4′R)-4′-(4-Fluorophenyl)-1,7,7-trimethyl-3′-(2,4,6-trimethylphenyl)-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC27H30FNO2De = 100%[α]D21=-509.7 (c 0.06, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)

(1R,3R,4S,4′R)-4′-[3,5-Bis(trifluoromethyl)phenyl]-1,7,7-trimethyl-3′-(2,4,6-trimethylphenyl)-4′H-spiro[bicyclo[2.2.1]heptane-3,5′-isoxazol]-2-oneC29H29F6NO2De = 100%[α]D21=-401.1 (c 0.09, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S,4′R)