Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction

Abstract

The unimolecular nucleophilic substitution (SN1) mechanism figures prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate allows for the construction of highly congested carbon centers. However, the intrinsic instability and high reactivity of the carbocationic intermediates render it very difficult to control product distributions and stereoselectivity in reactions proceeding via SN1 pathways. Here we report asymmetric catalysis of an SN1-type reaction mechanism resulting in the enantioselective construction of quaternary stereocenters from racemic precursors. The new transformation relies on the synergistic action of a chiral hydrogen bond donor (HBD) catalyst with a strong Lewis acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and achieve high levels of control over reaction enantioselectivity and product distribution. The work presented here provides a foundation for the enantioconvergent synthesis of other fully-substituted carbon stereocenters.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…[28] In order to probe the possible involvement of cation-p substituent effect, we compared the corresponding quadrupole moment (Q zz ) values of the respective substituted aryl groups, often used as measureo fc ation-p interaction. [101][102][103] However there was no correlation between selectivity and Q zz (see Supporting Informationf or additional details) indicating that selectivity is independento fc ation-p substituent effects. Notably,t his finding is Figure 4.…”

“…Therefore, at the very onset, we set out to verify whether selectivity is only a manifestation of cation–π interaction, as alluded to by Sibi and co‐workers . In order to probe the possible involvement of cation–π substituent effect, we compared the corresponding quadrupole moment (Q zz ) values of the respective substituted aryl groups, often used as measure of cation–π interaction . However there was no correlation between selectivity and Q zz (see Supporting Information for additional details) indicating that selectivity is independent of cation–π substituent effects.…”

A Celebration of Science amidst Nature: The 54th Bürgenstock Conference

“…[19] Theg ained mechanistic understanding allowed the Jacobsen group to tackle challenging transformations like site-selective glycosidations [20] and to exploit the cooperative reactivity of H-bond donors and Lewis acids. [21] Tuesday 7thofM ay On Tuesday morning Jonathan Clayden (University of Bristol) gave an inspiring lecture about the biomimetic function from folded molecules.W eg ained deep insight in conformational challenges.H ed escribed how the conformational understanding can lead to the design and synthesis of molecular communication devices [22] with the capability to transfer information to remote reactive sites.Heenlightened the importance of foldamers [23] (conformationally defined molecules) ( Figure 4) towards their potential ability to mimic biological function. Moreover,h is group have designed and Angewandte Chemie Meeting Reviews discovered the function of synthetic molecules with conformational properties that allow them to mimic biological information-processing systems,i ncluding the first fully synthetic membrane-bound receptor mimics.…”

Ein Fest der Wissenschaft inmitten der Natur: Die 54. Bürgenstock‐Konferenz

“…[19] Das gewonnene mechanistische Verständnis ermçglichte es der Jacobsen-Gruppe, herausfordernde Tr ansformationen wie ortsselektive Glyko- Angewandte Chemie Tagungsberichte sidierungen [20] anzugehen und die kooperative Reaktivität von H-Brücken-Donoren und Lewis-Säuren zu nutzen. [21] Dienstag, 7. Mai Am Dienstagmorgen hielt Jonathan Clayden (University of Bristol) einen inspirierenden Vortrag über die biomimetische Funktion von gefalteten Molekülen.…”