Continuous Flow, Highly Enantioselective Michael Additions Catalyzed by a PS-Supported Squaramide

A polystyrene (PS) supported bifunctional squaramide organocatalyst promotes fast Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes with very high enantioselectivities at low catalyst loadings. The polystyrene supported catalyst can be recycled up to 10 times without any decrease in enantioselectivity (average 96% ee) and adapted to continuous flow operation (24 h). A single flow experiment involving six different nitroalkenes in a sequential manner highlights the applicability of this methodology for rapid access to chemical diversity

Polystyrene-Supported (2<i>S</i>)-(−)-3-<i>exo</i>-Piperazinoisoborneol: An Efficient Catalyst for the Batch and Continuous Flow Production of Enantiopure Alcohols

A polystyrene-supported analog (PS-PIB) of 3-<i>exo</i>-morpholinoisoborneol (MIB), designed for increased chemical stability, has been synthesized and used as a ligand in the asymmetric alkylation of aldehydes with Et₂Zn. The supported ligand turned out to be highly active and enantioselective for a broad scope of substrates (92–99% ee), allowing repeated recycling. A single-pass, continuous flow process implemented with PS-PIB shows only a marginal decrease in conversion after 30 h of operation

Photoswitchable Thioureas for the External Manipulation of Catalytic Activity

A series of azobenzene-based thiourea catalysts have been developed with the aim of achieving control over the catalytic activity by the use of light. The conceptual design of these systems relies on the inactivation by means of intramolecular hydrogen bonding, only likely to take place in one of their isomeric forms. After fine structure modulation of the catalyst a substantial difference in activity has been observed between the irradiated and the nonirradiated reaction. Furthermore, the system allowed in situ manipulation of the catalyst activity during the course of a given experiment

Organocatalytic Enantioselective Continuous-Flow Cyclopropanation

A set of six solid-supported diarylprolinol catalysts (varying on the anchoring strategy and the type of polymeric support) has been prepared and applied to the enantioselective cyclopropanation reaction. The selected candidate allows implementation of a long flow experiment (48 h) and generates a library of 12 cyclopropanes by sequential flow experiments. The mildness and utility of the method have enabled a telescoped process in which the outstream is directly used in a Wittig flow reaction

Asymmetric [4 + 2] Annulation Reactions Catalyzed by a Robust, Immobilized Isothiourea

A polystyrene-supported isothiourea (<b>1a</b>) behaves as a highly efficient organocatalyst in a variety of formal [4 + 2] cycloaddition reactions. The catalytic system has proven to be highly versatile, leading to six-membered heterocycles and spiro-heterocycles bearing an oxindole moiety in high yields and very high enantioselectivities (32 examples, including the previously unreported oxindole spiropyranopyrazolones <b>8</b>; 97% mean ee). The notable chemical stability of <b>1a</b> under operation conditions results in high recyclability (11 cycles, accumulated TON of 76.8) and allows the implementation of an extended-operation continuous flow process (no decrease in yield or ee after 18 h)

Asymmetric [4 + 2] Annulation Reactions Catalyzed by a Robust, Immobilized Isothiourea

A polystyrene-supported isothiourea (<b>1a</b>) behaves as a highly efficient organocatalyst in a variety of formal [4 + 2] cycloaddition reactions. The catalytic system has proven to be highly versatile, leading to six-membered heterocycles and spiro-heterocycles bearing an oxindole moiety in high yields and very high enantioselectivities (32 examples, including the previously unreported oxindole spiropyranopyrazolones <b>8</b>; 97% mean ee). The notable chemical stability of <b>1a</b> under operation conditions results in high recyclability (11 cycles, accumulated TON of 76.8) and allows the implementation of an extended-operation continuous flow process (no decrease in yield or ee after 18 h)

Polystyrene-Supported TRIP: A Highly Recyclable Catalyst for Batch and Flow Enantioselective Allylation of Aldehydes

The widely applicable TRIP phosphoric acid catalyst has been immobilized on polystyrene using a copolymerization-based strategy. The resin (<b>PS-TRIP</b>) has proven to be highly active and enantioselective in the asymmetric allylboration of aldehydes. Moreover, it has shown to be extremely robust, as it can be reused for 18 times, after which it still retained its activity. Lastly, to further prove the benefits of the immobilization, a continuous flow experiment spanning 28 h has been carried out with very high yields and ee’s

Translating the Enantioselective Michael Reaction to a Continuous Flow Paradigm with an Immobilized, Fluorinated Organocatalyst

A novel polymer-supported fluorinated organocatalyst has been prepared and benchmarked in the enantioselective Michael addition of aldehydes to nitroalkenes. The system has proven to be highly efficient and displays excellent selectivities (er and dr) with a wide variety of substrates. Detailed deactivation studies have given valuable insights, thus allowing the lifespan of this immobilized aminocatalyst to be significantly extended. These data have facilitated the implementation of enantioselective, continuous flow processes allowing either the multigram synthesis of a single Michael adduct over a 13 h period or the sequential generation of a library of enantiopure Michael adducts from different combinations of substrates (13 examples, 16 runs, 18.5 h total operation). A customized in-line aqueous workup, followed by liquid–liquid separation in flow, allows for product isolation without the need of chromatography or other separation techniques

Asymmetric Organocatalytic Formal [2 + 2]-Cycloadditions via Bifunctional H-Bond Directing Dienamine Catalysis

A new concept in organocatalysis allowing for the construction of cyclobutanes with four contiguous stereocenters with complete diastereo- and enantiomeric control by a formal [2 + 2]-cycloaddition is presented. The concept is based on simultaneous dual activation of α,β-unsaturated aldehydes and nitroolefins by amino- and hydrogen-bonding catalysis, respectively. A new bifunctional squaramide-based aminocatalyst has been designed and synthesized in order to enable such an activation strategy. The potential and scope of the reaction are demonstrated, and computational studies which account for the stereochemical outcome are presented