title: Noncovalent bifunctional organocatalysts: powerful tools for contiguous quaternary-tertiary stereogenic carbon formation, scope, and origin of enantioselectivity.
abstract: Relying on the assembly of commercially available catalyst building blocks, highly stereocontrolled quaternary carbon (all carbon substituted) formation has been achieved with unmatched substrate diversity. For example, the in situ assembly of a tricomponent catalyst system allows α-branched aldehyde addition to nitroalkene or maleimide electrophiles (Michael products), while addition to an α-iminoester affords Mannich reaction products. Very good yields are observed and for fifteen of the eighteen examples 96-99 % ee is observed. Using racemic α-branched aldehydes, two contiguous (quaternary-tertiary) stereogenic centers can be formed in high diastereo- and enantiomeric excess (eight examples) via an efficient in situ dynamic kinetic resolution, solving a known shortcoming for maleimide electrophiles in particular. The method is of practical value, requiring only 1.2 equiv of the aldehyde, a 5.0 mol % loading of each catalyst component, for example, O-tBu-L-threonine (O-tBu-L-Thr), sulfamide, DMAP or O-tBu-L-Thr, KOH, and room temperature reactions. As a highlight, the first demonstration of ethylisovaleraldehyde (7) addition is disclosed, providing the most congested quaternary stereogenic carbon containing succinimide product (8) known to date. Finally, mechanistic insight, via DFT calculations, support a noncovalent assembly of the catalyst components into a bifunctional catalyst, correctly predict two levels of product stereoselectivity, and suggest the origin of the tricomponent catalyst system's exceptionality: an alternative hydrogen bond motif for the donor-acceptor pair than currently suggested for non-assembled catalysts.
authors.affiliation: School of Engineering & Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany. t.nugent@jacobs-university.de
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Nugent
authors.forename: Abdul
authors.initials: A
authors.lastname: Sadiq
authors.forename: Ahtaram
authors.initials: A
authors.lastname: Bibi
authors.forename: Thomas
authors.initials: T
authors.lastname: Heine
authors.forename: Lei Liu
authors.initials: LL
authors.lastname: Zeonjuk
authors.forename: Nina
authors.initials: N
authors.lastname: Vankova
authors.forename: Bassem S
authors.initials: BS
authors.lastname: Bassil
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000475:Alkenes / Q000737:chemistry*; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D006860:Hydrogen Bonding; D008301:Maleimides / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D000475:Alkenes; D008301:Maleimides; D009574:Nitro Compounds; C043592:maleimide; D002244:Carbon