Organocatalyzed Enantioselective Direct Mannich Reaction of α-Styrylacetates

Abstract

An organocatalyzed direct Mannich reaction of unactivated α-styrylacetates was realized for the first time. By using a quinidine-derived C6'-urea catalyst, the direct Mannich reaction of α-styrylacetates and N-tosylimines gave the desired β-amino esters in high yields, diastereoselectivities, and ee values. The reaction provides a highly stereoselective (up to 96:4 dr and 97% ee) and the most straightforward synthesis of functionalized N-tosylated β-amino esters. The products can be used as precursors for the highly selective synthesis of tetrahydrofuran derivatives.

Controlling the α/γ‐Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions

“…Under similar catalytic conditions, b,g-unsaturated (thio)esters showed inferior a/g-site as well as stereoselectivity,but the use of b',g'-unsaturated ketols as superb equivalents can remedy this limitation. This study complements previous efforts [9][10][11] to switch from the innate g-reactivity of most vinylogous enolate equivalents (conjugation preserved) to areactivity (conjugation disrupted), and sets the basis for further developments.…”

“…On the other hand, g,g-disubstituted enals have been found to react through the a-carbon atom of the dienamine intermediate [7] because the disubstituted g-carbon atom is sterically shielded (Scheme 1c). [8] Af ew Brønsted base catalyzed a-site functionalizations of vinylogous enolate intermediates have also been reported, [9] but these examples featured moderate enantioselectivities [9a] or were restricted to specific substrates. [9b-d] Notably,r eadily available b,g-unsaturated alkyl ketones,with three potentially reactive sites (a, g, and a'), have remained undeveloped pronucleophiles in this context.…”

Controlling the α/γ‐Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions

“…This study complements previous efforts [9][10][11] to switch from the innate g-reactivity of most vinylogous enolate equivalents (conjugation preserved) to areactivity (conjugation disrupted), and sets the basis for further developments. Under similar catalytic conditions, b,g-unsaturated (thio)esters showed inferior a/g-site as well as stereoselectivity,but the use of b',g'-unsaturated ketols as superb equivalents can remedy this limitation.…”

“…On the other hand, γ,γ‐disubstituted enals have been found to react through the α‐carbon atom of the dienamine intermediate because the disubstituted γ‐carbon atom is sterically shielded (Scheme c) . A few Brønsted base catalyzed α‐site functionalizations of vinylogous enolate intermediates have also been reported, but these examples featured moderate enantioselectivities or were restricted to specific substrates –. Notably, readily available β,γ‐unsaturated alkyl ketones, with three potentially reactive sites (α, γ, and α′), have remained undeveloped pronucleophiles in this context .…”

“…Shibasaki and co-workers described abarium alkoxide catalyzed Mannich reaction of b,g-unsaturated benzyl esters that provided the corresponding Morita-Baylis-Hillman-type adducts [6] upon C=Ci somerization (Scheme 1b). [8] Af ew Brønsted base catalyzed a-site functionalizations of vinylogous enolate intermediates have also been reported, [9] but these examples featured moderate enantioselectivities [9a] or were restricted to specific substrates. [8] Af ew Brønsted base catalyzed a-site functionalizations of vinylogous enolate intermediates have also been reported, [9] but these examples featured moderate enantioselectivities [9a] or were restricted to specific substrates.…”