%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