Group-assisted purification (GAP) chemistry for the synthesis of Velcade via asymmetric borylation of N-phosphinylimines
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A new approach to the anticancer drug Velcade was developed by performing asymmetric borylation of an imine anchored with a chiral N-phosphinyl auxiliary. Throughout the 7-step synthesis, especially in the imine's synthesis and in the asymmetric borylation reactions, operations and work-up were conducted in simple and easy ways without any column chromatographic purification, which defines the GAP (group-assisted purification) chemistry concept. It was found that the optically pure isomer (dr > 99: 1) can be readily obtained by washing the crude mixture of the asymmetric borylation reaction with hexane; the chiral N-phosphinyl auxiliary can be easily recovered after deprotection is finished. Several other N-phosphinylimines were also investigated for the asymmetric borylation reaction. The absolute configuration of the borylation product was confirmed by single crystal X-ray diffraction analysis.
Xie , J , Luo , J , Winn , T R , Cordes , D B & Li , G 2014 , ' Group-assisted purification (GAP) chemistry for the synthesis of Velcade via asymmetric borylation of N-phosphinylimines ' Beilstein Journal of Organic Chemistry , vol 10 , pp. 746-751 . DOI: 10.3762/bjoc.10.69
Beilstein Journal of Organic Chemistry
© 2014 Xie et al; licensee Beilstein-Institut. This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)
The authors acknowledge the financial support from the NIH (R33DA031860), the Robert A. Welch Foundation (D-1361) and the Jiangsu Innovation Team Program (P. R. China) for their support of this research. They also thank NSF Grant CHE-1048553 and the CRIF program for supporting their NMR facility.
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