Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity

Abstract

Aldol reaction chemoselectivity, racemic or enantioselective, has not been previously demonstrated in the presence of Knoevenagel active functional groups. Here, we show that unhindered β-diketones remain unreacted while a ketone moiety undergoes a highly enantioselective aldol desymmetrization resulting in three new stereogenic centers using in water reaction conditions. A mechanistic hypothesis for the chemoselective formation of either aldol or Knoevenagel products is presented. It elucidates how these amino acid catalyzed reactions completely suppress formation of the expected Knoevenagel product under in water (heterogeneous) reaction conditions, but not when water is present as a dissolved cosolvent (homogeneous). Finally, the developed hypothesis reinforces and expands the role of water at an organic-water interface.

A 2000 to 2020 Practitioner's Guide to Chiral Amine‐Based Enantioselective Aldol Reactions: Ketone Substrates, Best Methods, in Water Reaction Environments, and Defining Nuances.

“… [48c,68,69] In a similar vein of research, it was recently shown that triketones consisting of a cyclohexanone carbonyl moiety and an unhindered β‐diketone, can chemoselectively undergo an aldol reaction (Scheme 8). [21] This is the first example of aldol reactivity superseding Knoevenagel reactivity.…”

“…Low yield generally implies the limiting reagent has not been fully consumed, i. e ., by‐product formation is uncommon. In theory this can be solved by increasing the catalyst loading, but our observations have shown that a catalyst loading plateau is commonly reached [21,48] . For example, repetition of an optimized reaction, in which the limiting substrate is only 85 % consumed, with, e. g ., double or even quadruple the catalyst loading, often provides only incremental increases in yield (<5%).…”

“… (2S,4R)‐ trans‐ 4‐hydroxyproline based catalysts for cyclohexanone reactions with aldehydes [19,20,21,26,67] …”

“…[19] In particular Gruttadauria's benzhydryl-substituted catalyst is shown in Scheme 3, it is a top performing aldol catalyst for cyclohexanone, 4-substituted cyclohexanones, and cyclopentanone. [20,21] Enamines are the nucleophilic intermediates in these reactions, and formed in situ, in low concentrations, under equilibrium conditions. They are notably less reactive than their enolate counterparts and are sterically much more hindered.…”

“…Among them, a set of esters, based on the (2 S ,4 R )‐ trans‐ 4‐hydroxyproline template, were developed by Gruttadauria [19] . In particular Gruttadauria's benzhydryl‐substituted catalyst is shown in Scheme 3, it is a top performing aldol catalyst for cyclohexanone, 4‐substituted cyclohexanones, and cyclopentanone [20,21] …”