DoE‐Driven Development of an Organocatalytic Enantioselective Addition of Acetaldehyde to Nitrostyrenes in Water**

Abstract

The development of an enantioselective enaminecatalysed addition of masked acetaldehyde to nitroalkenes via a rational approach helped to move away from the use of chloroform. The presented research allows the use of water as a reaction medium, therefore improving the industrial relevance of a protocol to access very important pharmaceut-ical intermediates. Critical to the success is the use of chemometrics-assisted 'Design of Experiments' (DoE) optimisation during the development of the presented new synthetic approach, which allows to investigate the chemical space in a rational way.

Catalysing (organo-) catalysis: Trends in the application of machine learning to enantioselective organocatalysis

“…While this shows the influence of the varied parameter on the observable, interaction effects between the parameters are significantly harder to capture with this approach. Design of experiments (DoE) is a more systematic approach where parameters are varied simultaneously to unravel their effect on the outcome [146,147]. Gaussian Process Regression (GPR) [161] to optimise the flow rate, the temperature as well as the stoichiometry of the reactant for the organocatalysed synthesis of spirooxindole analogues [162] (Figure 9).…”

Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

“…Recently, water-soluble diarylprolinol silyl ether containing the dimethylamine functionality was found to be very effective for the Michael additions of the acetaldehyde with nitroolefins. These reactions took place in brine with good yields and high enantioselectivities for a broad range of nitroolefins [33][34][35].…”

DoE‐Assisted Development of a 2H−MoS2‐Catalyzed Approach for the Production of Indole Derivatives

“…Rather than carrying out a trial-and-error approach, we relied on a rational use of Design of Experiments (DoE) method to optimize the catalysed reaction. [28][29][30] A commonly overlooked aspect in the optimization of a selected process is the proper understanding of how each variable (from now on, called factor) affects the desired response/s. A conventional method to optimize a process is based on the "One Factor at a Time" (OFAT) approach (Figure 2a).…”

“…The authors, by using a DoE supported rational approach, were able to transfer the enantioselective addition of masked acetaldehyde to nitroalkenes from chloroform to water. [28]…”

“…Additionally, another example of a successful DoE application has been reported by Carlone and co‐workers. The authors, by using a DoE supported rational approach, were able to transfer the enantioselective addition of masked acetaldehyde to nitroalkenes from chloroform to water [28] …”