Synthesis of (1R,4E,5S)-4-{[(E)-(azinyl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones and (1R,4R,5R)-4-([1,2,4]triazolo[4,3-x]azin-3-yl)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones

4-[(Heteroaryldiazenyl)methylidene] and 4-([1,2,4]triazolo[4,3-x]azin-3-yl) substituted (1R,5R)-4-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones 6/6′ and 7/7′ were obtained in a one-pot transformation of the enamino lactone 2 with hydrazinoazines 3a–g followed by oxidation of the intermediate mixture of isomeric enehydrazines 4/4′ and hydrazones 5/5′ with lead tetraacetate. The oxidation selectivity was dependent on the ratio of isomeric intermediates 4/4′ and 5/5′. Treatment of 7b with lead tetraacetate led to α-acetoxylated compound 11, while bromination of 9b afforded a 1:1 mixture of α-bromination products 12 and 12′, which were separated by medium pressure liquid chromatography (MPLC). The structures of intermediates and products were confirmed by NMR and X-ray diffraction.

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(1R,4E,5S)-4-{[(2-Phthalazin-1-yl)hydrazino]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC19H22N4O2De = 100%[α]D25=-68.4(c0.234,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)E:Z = 87:13

(1R,4E,5S)-4{[(E)-(Pyridin-2-yl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC16H19N3O2De = 100%[α]D21=-17.4(c0.132,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)E:Z = 100:0

(1R,4E,5S)-4{[(E)-(6-Phenylpyridazin-3-yl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC21H22N4O2De = 100%[α]D21=+24.2(c0.124,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)E:Z = 100:0

(1R,4Z,5S)-4{[(E)-(6-Phenylpyridazin-3-yl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC21H22N4O2De = 100%[α]D24=+266.9(c0.130,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4Z,5S)E:Z = 0:100

(1R,4E,5S)-4{[(E)-(6-Chloropyridazin-3-yl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC15H17ClN4O2De = 100%[α]D21=-6.6(c0.198,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)E:Z = 100:0

(1R,4E,5S)-4{[(E)-(Phthalazin-1-yl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC19H20N4O2De = 100%[α]D21=-106.3(c0.025,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)E:Z = 100:0

(1R,4E,5S)-4{[(E)-(4-Chlorophthalazin-1-yl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC19H19ClN4O2De = 100%[α]D21=-215.9(c0.063,CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)E:Z = 100:0

(1R,4E,5S)-4{[(E)-(Pyrimidin-2-yl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC15H18N4O2De = 100%[α]D21=-28.2(c0.142,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)E:Z = 100:0

(1R,4E,5S)-4{[(E)-(Pyrazinyl)diazenyl]methylidene}-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC15H18N4O2De = 100%[α]D21=-35.7(c0.140,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4E,5S)E:Z = 100:0

(1R,4R,5R)-4-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC16H19N3O2De = 68%[α]D22=-81.8(c0.088,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,5R)

(1R,4R,5R)-4-(6-Phenyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC21H22N4O2De = 92%[α]D22=-18.7(c0.214,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,5R)

(1R,4R,5R)-4-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC15H17ClN4O2De = 100%[α]D22=-19.0(c0.252,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,5R)

(1R,4R,5R)-4-([1,2,4]Triazolo[4,3-a]pyrimidin-3-yl)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC15H18N4O2De = 54%[α]D22=-79.2(c0.130,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,5R)

(1R,4R,5R)-4-([1,2,4]Triazolo[4,3-a]pyrazin-3-yl)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-oneC15H18N4O2De = 100%[α]D22=-175.0(c0.112,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,4R,5R)

(1R,3Z,4S)-3-{[(E)-(6-Phenylpyridazin-3-yl)diazenyl]methylidene}-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC21H22N4ODe = 100%[α]D19=+497.4(c0.038,CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3Z,4S)E:Z = 30:70

(1R,3Z,4S)-3-{[(E)-(6-Chloropyridazin-3-yl)diazenyl]methylidene}-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC15H17ClN4ODe = 100%[α]D19=-11.2(c0.224,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3Z,4S)E:Z = 31:69

(1R,4R,5S)-3-Oxo-4-(6-phenyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]oct-4-yl acetateC23H24N4O4De = 100%[α]D21=-73.0(c0.200,CH2Cl2)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1′R,4′R,5′S)

(1R,3R,4S)-3-Bromo-3-(6-phenyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC21H21BrN4ODe = 100%[α]D22=+202.6(c0.350,CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3R,4S)

(1R,3S,4S)-3-Bromo-3-(6-phenyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-oneC21H21BrN4ODe = 100%[α]D22=-287.1(c0.132,CHCl3)Source of chirality: natural (1R)-(+)-camphorAbsolute configuration: (1R,3S,4S)