The first highly stereoselective approach to the mitotic kinesin Eg5 inhibitor HR22C16 and its analogues

A general method for the synthesis of the mitotic kinesin Eg5 inhibitor HR22C16 1 and its analogues based on protecting group (PG)-modulated highly diastereoselective Pictet–Spengler reaction of l-tryptophan methyl ester hydrochloride with meta-(RO)-benzaldehyde is described. By using the enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-β-carboline trans-4c as a common chiral synthon, HR22C16 1 and its analogues 2 and 3 were synthesized in 90.1%, 90.2%, and 86.5% overall yields, respectively.

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(5R,11aS)-2-(5-Azido-pentyl)-5-(3-benzoyloxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC31H28N6O4[α]D20=-168.4 (c 0.9, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)

(5R,11aS)-2-(5-Azido-pentyl)-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC24H24N6O3[α]D20=-204.8 (c 0.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)

(5R,11aS)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC23H23N3O3[α]D20=-162.2 (c 0.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)

(5R,11aS)-2-Benzyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC26H21N3O3[α]D20=-162.6 (c 0.9, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)

(5R,11aS)-2-(5-Amino-pentyl)-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC24H26N4O3[α]D20=-151.5 (c 0.4, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)

(1S,3S)-Methyl 1-(3-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O3[α]D20=-45.1 (c 1.5, DMF)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)

(1R,3S)-Methyl 1-(3-benzoyloxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC26H22N2O4[α]D20=-33.5 (c 0.9, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1R,3S)

(1S,3S)-Methyl 1-(3-acetoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H20N2O4[α]D20=-7.2 (c 3.3, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)

(1R,3S)-Methyl 1-(3-allyloxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H22N2O3[α]D20=-34.5 (c 1.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1R,3S)

(5R,11aS)-2-Benzyl-5-(3-benzoyloxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC33H25N3O4[α]D20=-146.8 (c 1.7, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)