Stereodefined acyclic trisubstituted metal enolates towards the asymmetric formation of quaternary carbon stereocentres

Abstract

Reactions that involve metal enolate species are amongst the most versatile carbon-carbon bond forming processes available to synthetic chemists. Enolate species are involved in a multitude of powerful applications in asymmetric organic synthesis, but the generation of fully substituted enolates in a geometrically defined form is not easily achieved especially in acyclic systems. In this Feature Article we focus on the most prominent examples reported in the literature describing the formation of highly diastereo- and enantiomerically enriched quaternary stereocentres in acyclic molecules derived from stereodefined non-cyclic trisubstituted metal enolates.

Enabling the Cross-Coupling of Tertiary Organoboron Nucleophiles through Radical-Mediated Alkyl Transfer

“…1 Although methods have evolved dramatically, there are still relatively few ways to install these centers reliably across a broad array of functionalized partners. 2–4 Among the most commonly employed methods, three predominate: 1) alkylation of 1,1-disubstituted allylic leaving groups, 5a 2) conjugate addition to α,β-unsaturated carbonyls, 5b and 3) alkylation of substituted enolate equivalents. 5c In many cases, each of these subclasses can cleanly access the requisite quaternary center, but are constrained by the requirement and natural reactivity pattern for a particular structural element (e.g., α,β-unsaturated carbonyls, allyl, or carbonyl systems).…”

Enantioselective Construction of Acyclic Quaternary Carbon Stereocenters: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Amide Enolates

“…In this context, regioselective formation of functionalized and fully-substituted enolates is the center of renewed interest, 6 with several attractive strategies having been reported for the preparation of β,β-disubstituted enolates of esters 7 and amides 8 (albeit, largely using enantiomerically enriched α,α-disubstituted carbonyl derivatives) (Scheme 1A). …”

Stereoselective Formation of Fully Substituted Ketone Enolates

“…[3] Indeed, one structural element that invariably increases the difficulty of achemical synthesis is the presence of quaternary carbon stereocenters in the target molecule.…”

“…[11,12] Despite all these efforts,t he stereoselective formation of a,a-disubstituted enolate of ketones is still very challenging and remains in its complete infancy, as the regioselectivity and the E/Zselectivity of the enolization need to be concomitantly controlled (Scheme 1, Path A). [3] Theo nly report to date for the stereoselective preparation of af ully substituted ketone enolate originates from Seebach and co-workers through the in situ generation and trapping of ketene intermediates. [13] It was proposed that ketene or ketene-like intermediate species, produced by elimination reaction from BHT ester lithium enolates,w ere trapped by methyllithium to lead to the diastereoselective formation of ketone enolates (Scheme 1, Path D).…”

“…Taking into consideration the significance of enolates as valuable intermediates in asymmetric organic synthesis, [2] one can evaluate the consequence of developing efficient methods to the direct access of a,a-disubstituted metal enolates 1 as ar oute to the formation of challenging quaternary carbon stereocenters (Scheme 1, Path A). [3] Indeed, one structural element that invariably increases the difficulty of achemical synthesis is the presence of quaternary carbon stereocenters in the target molecule.[4] Thei mpediment to synthesis presented by such centers arises from the steric congestion imposed by the four attached carbons.I f such stereocenters could be prepared in asingle-pot operation through the formation of several CÀCb onds from common and easily accessible starting materials,i tw ould surely find numerous applications in organic synthesis. [5,6] However,t he generation of as tereodefined fully substituted enolate precursor as as ingle isomer in acyclic systems is not atrivial task, especially for ketone enolates,a nd therefore all the enolization reactions leading to stereodefined a,a-disubstituted enolates were restricted to esters and amides.F or instance, a,a-acyclic disubstituted esters require ap erfect conformational control for the abstraction of the a-hydrogen, [3] and this control can only be achieved by deprotonation of diastereomerically pure a,a-acyclic dialkylated amides, [7] enantiomerically pure a,a-acyclic dialkylated esters with chiral bases (Scheme 1, Path B), [8] or through conjugate additions.…”