%0 Journal Article %A Keen, Stephen P. %A Cowden, Cameron J. %A Bishop, Brian C. %A M. J. Brands, Karel %A Davies, Antony J. %A Dolling, Ulf H. %A Lieberman, David R. %A Stewart, Gavin W. %D 2005 %T Practical Asymmetric Synthesis of a Non-Peptidic αvβ3 Antagonist %U https://acs.figshare.com/articles/journal_contribution/Practical_Asymmetric_Synthesis_of_a_Non_Peptidic_sub_v_sub_sub_3_sub_Antagonist/3298189 %R 10.1021/jo048082n.s001 %2 https://ndownloader.figshare.com/files/5135923 %K methanolysi %K azepine ring system %K keto %K metalation %K Wittig reaction %K tetrahydropyrido %K acid moiety %K cyclization %K kilogram quantities %K α v β 3 antagonist %K propionaldehyde %K Antagonist %K elaboration %K aryl %K fragment %K pyridoazepine moiety %K chloro %K compound %K phosphorane %K Boc %K chiral %K Practical Asymmetric Synthesis %K drug candidate %K Suzuki reaction %K ortho %K convergent synthesis %K anhydride %K quantity %X The development of a practical and highly convergent synthesis of an αvβ3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite β-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared. %I ACS Publications