Noncovalent bifunctional organocatalysts: Powerful tools for contiguous quaternary-tertiary stereogenic carbon formation, scope, and origin of enantioselectivity

Thomas C. Nugent, Abdul Sadiq, Ahtaram Bibi, Thomas Heine, Lei Liu Zeonjuk, Nina Vankova, Bassem S. Bassil

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)

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. Noncovalent by nature: Commercially available building blocks allow in situ formation of bifunctional organocatalysts for the enantioselective formation of quaternary carbons (see scheme). This new catalyst approach is general in nature and the catalyst platform is readily adaptable.

Original languageEnglish
Pages (from-to)4088-4098
Number of pages11
JournalChemistry - A European Journal
Volume18
Issue number13
DOIs
Publication statusPublished - 2012 Mar 26

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Noncovalent bifunctional organocatalysts: Powerful tools for contiguous quaternary-tertiary stereogenic carbon formation, scope, and origin of enantioselectivity'. Together they form a unique fingerprint.

Cite this