Pushing the Boundaries of Vinylogous Reactivity: Catalytic Enantioselective Mukaiyama Aldol Reactions of Highly Unsaturated 2‐Silyloxyindoles

Abstract

The first example of catalytic, enantioselective hypervinylogous Mukaiyama aldol reaction (HVMAR) involving multiply unsaturated 2-silyloxyindoles is reported. The reaction utilizes a chiral Lewis base-catalyzed Lewis acid-mediated technology to deliver homoallylic 3-polyenylidene 2-oxindoles with extraordinary levels of regio-, enantio-, and geometrical selectivity. This work highlights a subtle yet decisive influence of the indole N-substituents on the propagation of the vinylogous reactivity space of the donor substrates up to ten bonds away from the origin of the vinylogy effect. Analysis of the (13) C NMR chemical shifts of the C-ω remote site within homologous silyloxyindole donors enabled rationalization of the results and easy qualitative prediction of the HVMAR reactivity/inertia toward a given aldehyde acceptor.

Enantioselective Vinylogous Reactions of 3-Alkylidene Oxindoles

“…In 2015, Zanardi, Curti, and co-workers extended the reaction to polyenyl-2-(siloxy)indoles with a high stereocontrol both of the E/Z geometry and of R/S configuration of the remote carbinol stereocenter (Scheme 3). 6 The reaction was performed in the dark, because the presence of light induced E/Z isomerization of the double bonds, leading to intractable mixtures of isomers. Moreover, it was found that the oxindole N-substituent influenced the vinylogous reac-tivity, and it had to be carefully chosen to obtain reactivity at the most remote reactive carbon site, which was up to ten bonds away from the oxindole moiety.…”

Enolizable Alkylidene Heterocyclic and Carbocyclic Carbonyl Systems­: Valuable Vinylogous Donor Substrates in Synthesis

“…In 2015, Curti, Zanardi and colleagues 31 reported the first example of a catalytic, enantioselective hypervinylogous Mukaiyama aldol reaction involving multiply unsaturated 2-silyloxyindoles (Scheme 18). The aldol reaction of silyl enolates 42 with diverse aldehydes was catalyzed by the same (R,R)-bisphosphoramide 40/SiCl 4 couple 30 used for the previously described vinylogous Mukaiyama aldol reaction.…”

“…Scheme 18 First example of a catalytic, enantioselective hypervinylogous Mukaiyama aldol addition of multiply unsaturated 2-silyloxyindoles 42 to aldehydes 31…”

Asymmetric Bisvinylogous Aldolation of Aldehydes via 2-Oxonia-Cope Rearrangement Enabling Total Stereochemical Control

“…Furthermore, as shown in Figure , mechanistic analysis reveals that the ABVMA reactions are intrinsically flawed to become a general solution for the direct asymmetric synthesis of ε-hydroxy-α,β,γ,δ-unsaturated esters: (1) the nucleophilicity of the terminal carbons of required silyl ketene acetals decreases as the degree of conjugation increases . As a result, activation of silyl ketene acetals by a furan and indole ring structure is sometimes needed . (2) Since the nucleophilicity differences among the α-, γ-, and ε-carbons are small, there will always be regioselectivity issues.…”