Catalytic asymmetric synthesis of R207910.
The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate alpha-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)(3) and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu(4)NCl, alpha-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the gamma-position of 4, followed by regio- and enantioselective protonation at the alpha-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu(4)NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone 3 was promoted by CuF.3PPh(3).2EtOH (10 mol %) in the presence of KO(t)Bu (15 mol %), ZnCl(2) (1 equiv), and Bu(4)PBF(4) (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the alpha-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic alpha-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.
Saga
Yutaka
Y
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Motoki
Rie
R
Makino
Sae
S
Shimizu
Yohei
Y
Kanai
Motomu
M
Shibasaki
Masakatsu
M
D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D064687:Diarylquinolines; D011522:Protons; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity
D000995:Antitubercular Agents; D064687:Diarylquinolines; D011522:Protons; D011804:Quinolines; C493870:bedaquiline