Synthesis and reductions of (1R,4E,5S)-4-oximino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one

(1R,4E,5S)-4-Oximino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one 9 was prepared in three steps from (1R)-(+)-camphor 1 via nitrosation of (1R,4E,5S)-4-[(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one 8. Catalytic hydrogenation of 9 under various reaction conditions afforded (1R,4S,5S)-4-amino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one derivatives 11, 13, and 15b. On the other hand, reduction of 9 with Grignard reagents led to two types of products, (1R,4S,5S)-4-dialkylamino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones 15b and 15c and/or 2-substituted (1E)-1-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]ethane-1,2-dione 1-oximes 16a,b and 15d–f. The structures of compounds 9, 10′, 15b, and 16b were determined by X-ray diffraction.

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(1R,4E,5S)-4-Oximino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC10H15NO3De = 100%[α]D22=+59.8 (c 0.39, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)

(1R,4Z,5S)-1,8,8-Trimethyl-2-oxabicyclo[3.2.1]octan-3,4-dione 4-(O-methyloxime)C11H17NO3De = 100%[α]D21=+142.5 (c 0.24, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4Z,5S)

(1R,4E,5S)-1,8,8-Trimethyl-2-oxabicyclo[3.2.1]octan-3,4-dione 4-(O-methyloxime)C11H17NO3De = 100%[α]D21=+61.4 (c 0.09, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)

(1R,4S,5S)-4-Amino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one hydrochlorideC10H18ClNO2De = 18%[α]D22=-21.6 (c 0.12, DMSO)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4S,5S)

Ethyl 3,5-dihydro-3-oxo-2-phenyl-5-[(1R,4S,5S)-3-oxo-1,8,8-trimethyl-2-oxabicyclo[3.2.1]oct-4-yl]-2H-pyrazolo[4,3-c]pyridin-7-carboxylateC25H27N3O5De = 100%[α]D21=+12.5 (c 0.12, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4S,5S)

Ethyl 3,5-dihydro-3-oxo-2-phenyl-5-[(1R,4R,5S)-3-oxo-1,8,8-trimethyl-2-oxabicyclo[3.2.1]oct-4-yl]-2H-pyrazolo[4,3-c]pyridin-7-carboxylateC25H27N3O5De = 100%[α]D23=+74.3 (c 0.07, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,5S)

(1R,4S,5S)-4-Diethylamino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC14H25NO2De = 100%[α]D21=-117.6 (c 0.31, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4S,5S)

(1R,4S,5S)-4-Di(n-butyl)amino-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC18H33NO2De = 100%[α]D28=-120.6 (c 0.23, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4S,5S)

(1E)-1-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]propane-1,2-dione 1-oximeC11H19NO3De = 100%[α]D21=-44.2 (c 0.16, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1E)-(1′S,3′R)

(1E)-1-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]butane-1,2-dione 1-oximeC12H21NO3De = 100%[α]D21=-32.9 (c 0.08, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1E)-(1′S,3′R)

(1E)-1-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]-2-phenylethane-1,2-dione 1-oximeC16H21NO3De = 100%[α]D21=-209.6 (c 0.19, CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1E)-(1′S,3′R)

(1E)-1-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]-2-(4-fluorophenyl)ethane-1,2-dione 1-oximeC16H20FNO3De = 100%[α]D23=-198.7 (c 0.22, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1E)-(1′S,3′R)

(1E)-1-[(1S,3R)-3-Hydroxy-2,2,3-trimethylcyclopentyl]-2-(4-methylphenyl)ethane-1,2-dione 1-oximeC17H23NO3De = 100%[α]D21=-210.5 (c 0.11, CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1E)-(1′S,3′R)