A general strategy for the highly stereoselective synthesis of HR22C16-like mitotic kinesin Eg5 inhibitors from both l- and d-tryptophans

Abstract

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. (1 R,3 S)- trans-1,3-Disubstituted 1,2,3,4-tetrahydro-β-carbolines (1 R,3 S)- 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 (1 R,3 R)- cis-1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines (1 R,3 R)- 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 (1 R,3 S)- trans- 2 and (1 R,3 R)- 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.