Catalytic Asymmetric Synthesis of R207910

Abstract

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%.

Asymmetric Synthesis and Absolute Configuration Assignment of a New Type of Bedaquiline Analogue

“…After a thorough investigation into the asymmetric synthesis of bedaquiline, we found that only two asymmetric synthetic routes were available, reflecting the difficulty of building two vicinal chiral centers at sterically hindered positions surrounded by three bulky aryl groups [19]. Because we needed to obtain all four types of optical isomers, we proposed our asymmetric synthetic route based on the research of Chandrasekhar's group [20], starting with the synthesis of TM-05 as a starting material (Scheme 1).…”

Practical Syntheses of (2S)‐R207910 and (2R)‐R207910

“…There is no asymmetric synthesis reported on R207910 except a recent publication by Shibasaki et al which appeared during the completion of our work. [17] Herein, we report an efficient synthesis of (2S)-R207910 (3a) and (2R)-R207910 (3b) in 10 linear steps starting from a known compound with 12 % overall yield for each.…”

The Medicinal Chemistry of Novel Molecules in Clinical Trials for Tuberculosis Treatment

“…A alteração do anel piridínico com a adição de grupos que destitui a aromaticidade deste anel também diminui a atividade (Esquema 6). 35 38 O próton abstraído pelo ligante é então transferido para o carbono 1 pela face oposta à subunidade do complexo coordenada ao intermediário, determinando a configuração R deste centro em 88% de excesso enantiomérico. Este sofre purificação adicional para obtenção do composto de interesse.…”

“…Este sofre purificação adicional para obtenção do composto de interesse. 38 A etapa seguinte também é chave para a estereoquímica da molécula, pois determina a configuração do carbono 2. Esta reação consiste no acoplamento do grupo alil no carbono 2 de 36, o que é realizado a partir da coordenação das carbonilas com o ZnFCl , obtido in situ, seguido de acoplamento, pela face oposta à fenila, do grupo alila proveniente da transformação em alilcobre de intermediários da reação entre CuF e tBuOK com pinacol alilboronato (37), conforme é mostrado no mecanismo proposto no esquema 11.…”

“…Esta reação consiste no acoplamento do grupo alil no carbono 2 de 36, o que é realizado a partir da coordenação das carbonilas com o ZnFCl , obtido in situ, seguido de acoplamento, pela face oposta à fenila, do grupo alila proveniente da transformação em alilcobre de intermediários da reação entre CuF e tBuOK com pinacol alilboronato (37), conforme é mostrado no mecanismo proposto no esquema 11. 38 O produto de configuração desejada (38) Esta rota, embora seja complexa e utilize reagentes de maior custo que a primeira, representa um ganho considerável em eficiência, visto que o seu rendimento global é de 5%, ou seja, 25 vezes superior ao da anterior.…”