Stereochemistry of C-6 nucleophilic displacements on 1,1-difluorocyclopropyldibenzosuberanyl substrates. An improved synthesis of multidrug resistance modulator LY335979 trihydrochloride.
Studies of the displacement chemistry of 1,1-difluorocyclopropyldibenzosuberanyl alcohol 4 and its activated bromide derivative 6 have led to an improved approach to anti-2, a key precursor to LY335979 3HCl (1). Bromination of either syn-4 or anti-4 gave anti-oriented 6, indicating thermodynamically controlled product stereochemistry via a stabilized 1,1-difluorohomotropylium ion intermediate. Reaction of 6 with piperazine proceeded irreversibly to provide an isomeric mixture of piperazine products, with the syn:anti product ratio increased by solvent effects. Reaction of 6 with pyridine and pyrazine, on the other hand, gave anti-pyridinium and pyrazinium salts, respectively, apparently via equilibration of initially formed syn products. Reduction of pyrazinium salt 11 with lithium borohydride/TFA provided anti-2 unaccompanied by its syn isomer. A practical and expeditious approach to 1 was derived from these new results.
Barnett
Charles J
CJ
Chemical Product Research and Development Division, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana, 46285, USA. cjbarnett@comcast.net
Huff
Bret
B
Kobierski
Michael E
ME
Letourneau
Michael
M
Wilson
Thomas M
TM
D020650:Combinatorial Chemistry Techniques; D003986:Dibenzocycloheptenes / Q000138:chemical synthesis* / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D003986:Dibenzocycloheptenes; D006845:Hydrocarbons, Fluorinated; D006877:Hydroxamic Acids; D011804:Quinolines; C095179:zosuquidar trihydrochloride