A new synthetic approach to biaryls of the rhazinilam type. Application to synthesis of three novel phenylpyridine-carbamate analogues.
The synthesis of three novel racemic phenylpyridine-carbamate analogues of rhazinilam and their biological evaluation as inhibitors of microtubule assembly and disassembly by interaction with tubulin are described. The sterically hindered ortho-disubstituted biaryl unit as the challenging key structural element is first obtained by a sequential regiocontrolled nucleophilic addition of a lithium ortho-lithiohomobenzylic alkoxide species to 3-bromo-5-oxazolyl pyridine as the electrophile and a subsequent oxidation step. The incorporation of the amino group by replacement of the bromide has been achieved using a Buchwald-Hartwig amination coupling. Ultimate deprotection steps furnished free-amino and free-hydroxyl appendages which were connected by phosgenation to furnish the nine-membered median carbamate ring.
Bonneau
Anne-Laure
AL
Laboratoire de Chimie Organique Fine et Hétérocyclique UMR 6014, Université et INSA de Rouen, Place E. Blondel, 76131, Mont Saint Aignan, France.
Robert
Nicolas
N
Hoarau
Christophe
C
Baudoin
Olivier
O
Marsais
Francis
F
D000470:Alkaloids / Q000737:chemistry* / Q000145:classification / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007212:Indolizines / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use; D015394:Molecular Structure; D048448:Phenylcarbamates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D014404:Tubulin / Q000187:drug effects*
D000470:Alkaloids; D007212:Indolizines; D007769:Lactams; D048448:Phenylcarbamates; D011725:Pyridines; D014404:Tubulin; C009170:rhazinilam