Chiral brØnsted acid-catalyzed enentioselective synthesis of α-quaternary (triaryl)methanamines

U sklopu ove disertacije pripravljena je serija α-(diaril) izoindolinonskih alkohola 1–24 koja je poslužila kao polazni supstrat za razvoj metodologije priprave kiralnih α-(3-indolil)(diaril)metanamina 26–60 i α-(triaril)metanamina 61–91. Provedeno je detaljno ispitivanje priprave 3-supstituiranih 3-hidroksiizoindolinona upotrebom organometalnih reagensa. Fenilni supstituenti s elektron-donirajućim skupinama reagirali su s ftalimidom u Grignardovoj reakciji, dok su elektron-odvlačeće skupine i heteroaromatske jezgre zahtijevale litij-brom izmjenu ili strategiju izravne litijacije. Protokoli su tolerantni prema različitim funkcionalnim skupinama, a širok raspon 3-hidroksiizindolinona 1–24 dobiven je u dobrim i izvrsnim prinosima. Razrađena je studija razvoja aza-Friedel-Craftsove asimetrične adicije indola na cikličke α-(diaril) supstituirane N-(acil)ketimine, generiranih in situ iz 3-aril-3-hidroksiizoindolinona. Enantioselektivna transformacija katalizirana kiralnim Brønstedovim kiselinama SPINOL-ne okosnice tolerira širok spektar različito supstituiranih indola i izoindolinonskih alkohola. Reakcijom su dobiveni α-kvaterni (3-indolil)(diaril)metanamini 26–60 u odličnim prinosima i razinama enantioselektivnosti (do 98 % prinosa, >99:1 e.r.). Izvor stereokemijske indukcije potkrijepljen je računalnim (DFT) i eksperimentalnim metodama. Opisano je i istraživanje razvoja asimetrične Bettijeve reakcije fenola s α-(diaril) izoindolinonskim alkoholima 1–24 katalizirane kiralnim fosfornim kiselinama BINOL-ne strukture u svrhu dobivanja α-kvaternog (triaril) stereogenog centra. Reakcija je tolerantna na širok raspon supstituiranih 3-arilnih prstena izoindolinona 1–24, te na različite supstituente u para-položaju fenolnog nukleofila. Dobiveni α-(triaril)metanamini 61–91 izolirani su u dobrim do izvrsnim prinosima i umjerenim razinama enantioselektivnosti.Within this Thesis, a series of α-(diaryl) isoindolinone alcohols 1–24 were prepared which served as the starting materials for the development of a methodology for the preparation of chiral α-(3-indolyl)(diaryl) methanamines 26–60 and α-(triaryl) methanamines 61–91. A detailed investigation of the synthesis of 3–substituted 3-hydroxyisoindolinones with organometallic reagents is described. Phenyl groups with electron-donating substituents are easily introduced by employing Grignard reaction, while aryls with electron-withdrawing groups and heteroaromatic cores require lithium exchange or direct lithiation strategy. The protocols are tolerant of various functional groups, and a wide range of 3-hydroxyisoindolinones 1–24 were afforded in good to excellent yields. The study of asymmetric aza-Friedel-Crafts reaction between indoles and cyclic α-diaryl-substituted N-acyl imines, generated in situ from 3-aryl 3-hydroxyisoindolinones, is described. The enantioselective transformation proceeds smoothly with a broad range of indoles and isoindolinone alcohols using a SPINOL-derived chiral Brønsted acid catalyst to afford α-quaternary (3-indolyl)(diaryl)methanamines 26–60 in excellent yields and enantioselectivities (up to 98% yield, up to >99:1 e.r.). The origin of stereochemical induction is supported by DFT calculations and experimental data. The study of asymmetric Betti reaction between phenol derivatives and α-(diaryl) isoindolinone alcohols 1–24 catalyzed by chiral phosphoric acids for the construction of α-quaternary (triaryl) stereogenic centre is developed. The reaction is tolerant to a wide range of 3-aryl substituents on 3-hydroxyisoisoindolinones 1–24, as well as in the para-position of the phenol nucleophiles. The resulting α-(triaryl) methanamines 61–91 were isolated in good yields and moderate levels of enantioselectivity