Resolution, absolute configuration, and synthetic transformations of 7-amino-tetrahydroindazolones

The chiral resolution of 7-amino-1-aryl-4,5,6,7-tetrahydro-indazol-4-ones was achieved via salt formation with O,O′-dibenzoyl tartaric acid. The transformation of enantiomerically enriched 7-amino-THIs into their corresponding azides proceeds with no decrease in their ee’s. A comparison of the X-ray structures of the racemic and enantiopure forms of the title compounds explains the rather large melting point differences between both the series. The enantiopure azides obtained from the corresponding 7-amino-THIs were employed in copper-catalyzed Huisgen 1,3-dipolar cycloaddition reactions with various alkynes. The use of enantiomerically enriched THI scaffolds is demonstrated by the preparation of diastereomerically pure products when the former are conjugated with alkynes arising from natural sources.

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(+)-(7S)-7-Amino-6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-oneC15H17N3OEe 99.5%[α]D22=+26 (c 2.3, CHCl3)Source of chirality: (+)-(2S,3S)-O,O′-dibenzoyl tartaric acidAbsolute configuration: (7S)

(+)-(7S)-7-Amino-3,6,6-trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-oneC16H19N3OEe 92%[α]D20=+19.8 (c 6.8, CHCl3)Source of chirality: (+)-(2S,3S)-O,O′-dibenzoyl tartaric acidAbsolute configuration: (7S)

(−)-(7S)-7-Azido-6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-oneC15H15N5O[α]D20=-95 (c 1.8, CHCl3)Source of chirality: the precursorAbsolute configuration: (7S)

(−)-(7S)-7-Azido-3,6,6-trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-oneC16H17N5O[α]D20=-86 (c 2.2, CHCl3)Source of chirality: the precursorAbsolute configuration: (7S)

(−)-(1S)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid ((7S)-6,6-dimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-7-yl)-amideC25H29N3O4[α]D22=-27 (c 1.0, CHCl3)Source of chirality: the precursorsAbsolute configuration: (1S,7S)

(−)-(7S)-7-[(4-Bromo-benzylidene)-amino]-3,6,6-trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-oneC23H22BrN3O[α]D22=-54 (c 4.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (7S)

(−)-(7S)-6,6-Dimethyl-1-phenyl-7-(4-phenyl-[1,2,3]triazol-1-yl)-4,5,6,7-tetrahydro-1H-indazol-4-oneC23H21N5OEe 98%[α]D22=-39 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (7S)

(−)-(7S)-7-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-oneC18H19N5O2Ee >99%[α]D22=-54 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (7S)

(−)-(7S)-3,6,6-Trimethyl-1-phenyl-7-(4-phenyl-[1,2,3]triazol-1-yl)-4,5,6,7-tetrahydro-1H-indazol-4-oneC24H23N5OEe >99%[α]D22=-52 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (7S)

(+)-(7R,7′R)-7,7′-(4,4′-(Hexane-1,6-diyl)bis(1H-1,2,3-triazole-4,1-diyl))bis(6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-oneC40H44N10O2Ee 99%[α]D22=+56 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (7R,7′R)

(−)-(1-((7R)-6,6-Dimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-7-yl)-1H-[1,2,3]triazol-4-yl)methyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosideC32H37N5O11[α]D22=-1 (c 5.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (7R)

(−)-(1-((7S)-6,6-Dimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-7-yl)-1H-[1,2,3]triazol-4-yl)methyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosideC32H37N5O11[α]D22=-42 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (7S)

(−)-3-O-(1-((7S)-6,6-Dimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-7-yl)-1H-[1,2,3]triazol-4-yl)methyl 1,2:5,6-di-O-isopropylidene-α-d-glucofuranoseC30H37N5O7[α]D22=-41 (c 2.5, CHCl3)Source of chirality: the precursorAbsolute configuration: (7S)

(+)-(3aR,5S,6R,6aR)-(5-[(7S)-1-(6,6-Dimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-7-yl)-1H-[1,2,3]triazol-4-yl]-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yl)methyl methanesulfonateC26H31N5O7S[α]D22=+27 (c 1.0, CHCl3)Source of chirality: the precursorAbsolute configuration: (3aR,5S,6R,6aR,7S)