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An efficient and general strategy for the highly stereoselective synthesis of HR22C16-like mitotic kinesin Eg5 inhibitors 1 from both l - and d -tryptophan methyl ester hydrohalides is described. (1R,3S)-trans-1,3-Disubstituted 1,2,3,4-tetrahydro-β-carbolines (1R,3S)-trans-2 could be obtained in high yields and with high stereoselectivities from the Pictet–Spengler reaction of l -tryptophan methyl ester hydrohalide with some 3-acyloxyl benzaldehydes via a CIAT (crystal induced asymmetric transformation) process, whereas (1R,3R)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines (1R,3R)-cis-2 could also be obtained in high yields and with high stereoselectivities from a Pictet–Spengler reaction of d -tryptophan methyl ester hydrohalide with some other 3-acyloxyl benzaldehydes via a CIAT process. Both compounds (1R,3S)-trans-2 and (1R,3R)-cis-2 were efficiently converted into HR22C16-like mitotic kinesin Eg5 inhibitors 1 by the same one-pot procedure through tandem reactions. A total of eighteen target compounds 1 were obtained from six intermediate compounds 2 in 87–95% yields. |
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