Manuel van Gemmeren

Disulfonimide-catalyzed asymmetric synthesis of β3-amino esters directly from N-Boc-amino sulfones.

An asymmetric Mannich reaction of silyl ketene acetals with N-Boc-amino sulfones has been developed. A chiral disulfonimide efficiently catalyzes both the in situ generation of the corresponding N-Boc imines and the asymmetric Mannich reaction with excellent yields and enantioselectivities. Kinetic studies confirm a proposed stepwise mechanism.

The Catalytic Asymmetric α-Benzylation of Aldehydes

The first aminocatalyzed α-alkylation of α-branched aldehydes with benzyl bromides as alkylating agents has been developed. Using a sterically demanding proline derived catalyst, racemic α-branched aldehydes are reacted with alkylating agents in a DYKAT process to give the corresponding α-alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities.

The Catalytic Asymmetric Abramov Reaction

The first catalytic enantioselective Abramov reaction is described. The process is based on the utilization of a chiral disulfonimide catalyst, which efficiently avoids the difficulties encountered with metal-based catalysts. Several functionalized α-hydroxy phosphonates were synthesized in good yields and with excellent enantiomeric ratios of up to >99:1. The process was shown to be scalable and up to 1 g of starting material could be employed under mild reaction conditions.

Asymmetric Disulfonimide-Catalyzed Synthesis of δ-Amino-β-Ketoester Derivatives by Vinylogous Mukaiyama–Mannich Reactions

An organocatalytic asymmetric synthesis of δ-amino-β-ketoester derivatives has been developed. A chiral disulfonimide (DSI) serves as a highly efficient precatalyst for a vinylogous Mukaiyama-Mannich reaction of readily available dioxinone-derived silyloxydienes with N-Boc-protected imines, delivering products in excellent yields and enantioselectivities. The synthetic utility of this reaction is illustrated in various transformations, including a new CC bond-forming reaction, which provide useful enantioenriched building blocks. The methodology is applied in a formal synthesis of (-)-lasubin.

Towards High-Performance Lewis Acid Organocatalysis†

The combination of Lewis acid organocatalysis and internal hydrogen-bond assistance was used to develop a new type of highly active disulfonimide catalyst. The increased Lewis acidity was documented by activity comparisons as well as theoretical investigations. Finally, the potential of the hydrogen-bond-assisted disulfonimide catalyst was demonstrated by its application in an enantioselective transformation.

Asymmetric counteranion-directed Lewis acid organocatalysis for the scalable cyanosilylation of aldehydes

Due to the high versatility of chiral cyanohydrins, the catalytic asymmetric cyanation reaction of carbonyl compounds has attracted widespread interest. However, efficient protocols that function at a preparative scale with low catalyst loading are still rare. Here, asymmetric counteranion-directed Lewis acid organocatalysis proves to be remarkably successful in addressing this problem and enabled a molar-scale cyanosilylation in quantitative yield and with excellent enantioselectivity. Also, the catalyst loading could be lowered to a part-per-million level (50 ppm: 0.005 mol%). A readily accessible chiral disulfonimide was used, which in combination with trimethylsilyl cyanide, turned into the active silylium Lewis acid organocatalyst. The nature of a peculiar phenomenon referred to as a “dormant period”, which is mainly induced by water, was systematically investigated by means of in situ Fourier transform infrared analysis.

Switchable Site-Selective Catalytic Carboxylation of Allylic Alcohols with CO2

A switchable site-selective catalytic carboxylation of allylic alcohols has been developed in which CO2 is used with dual roles, both facilitating C-OH cleavage and as a C1 source. This protocol is characterized by its mild reaction conditions, absence of stoichiometric amounts of organometallic reagents, broad scope, and exquisite regiodivergency which can be modulated by the type of ligand employed.

1,1,3,3-Tetratriflylpropene (TTP): A Strong, Allylic C–H Acid for Brønsted and Lewis Acid Catalysis

Tetratrifylpropene (TTP) has been developed as a highly acidic, allylic C-H acid for Brønsted and Lewis acid catalysis. It can readily be obtained in two steps and consistently shows exceptional catalytic activities for Mukaiyama aldol, Hosomi-Sakurai, and Friedel-Crafts acylation reactions. X-ray analyses of TTP and its salts confirm its designed, allylic structure, in which the negative charge is delocalized over four triflyl groups. NMR experiments, acidity measurements, and theoretical investigations provide further insights to rationalize the remarkable reactivity of TTP.

Pd-Catalyzed β-C(sp3)-H Arylation of Propionic Acid and Related Aliphatic Acids

A generally applicable Pd-catalyzed protocol for the β-C(sp3 )-H arylation of propionic acid and related α-branched aliphatic acids is reported. Enabled by the use of N-acetyl-β-alanine as ligand our protocol delivers a broad range of arylation products. Notably, the highly challenging substrate, propionic acid, which lacks any acceleration through the Thorpe-Ingold effect, can be employed as substrate with synthetically useful yields. Furthermore, the scalability and synthetic applicability of the protocol are demonstrated.

Dual Ligand‐Enabled Nondirected C−H Olefination of Arenes

The application of the Pd-catalyzed oxidative C-H olefination of arenes, also known as the Fujiwara-Moritani reaction, has traditionally been limited by the requirement for directing groups on the substrate or the need to use the arene in large excess, typically as a (co)solvent. Herein the development of a catalytic system is described that, through the combined action of two complementary ligands, makes it possible to use directing-group-free arenes as limiting reagents for the first time. The reactions proceed under a combination of both steric and electronic control and enable the application of this powerful reaction to valuable arenes, which cannot be utilized in excess.