Marcel Sickert

Brønsted Acid-Catalyzed, Enantioselective, Vinylogous Mannich Reaction of Vinylketene Silyl N,O-Acetals

Vinylketene silyl N, O-acetals undergo chiral phosphoric acid-catalyzed, vinylogous Mukaiyama-Mannich reactions with imines and afford delta-amino-alpha,beta-unsaturated amides in typically good yields, complete gamma-regioselectivity, and up to 92% ee with catalyst loadings of as low as 1 mol %. The Mannich products can be readily manipulated to furnish valuable synthetic intermediates.

Asymmetric organocatalysis and analysis on a single microfluidic nanospray chip.

The miniaturization of chemical processes onto so-called labon-a-chip devices has gained significant importance in different fields of chemistry. Besides the advantages of enhanced portability, reduced reagent consumption, and improved safety, a characteristic feature of miniaturized platforms is the possibility to achieve higher reaction and analysis rates. From their roots in analytical sciences, microfluidic systems have received much attention over the past decade. At present, microfluidics is becoming increasingly popular in inorganic and organic chemistry, as syntheses are performed on chip-based microreactors or capillary-based microflow reactors. While diverse reactions have been performed in microfluidic chip devices with impressive results, the analytical characterization is, however, usually carried out off-chip by conventional macroscopic instruments. However, this approach does not exploit the promise and the full potential of chip technology, namely, the integration of different functionalities such as chemical synthesis and analysis on one single device. Thus, it is desirable to develop, in analogy to microelectronics, integrated chemical circuits as new chemical tools, for example, for catalyst screening or for online monitoring of biological processes. In previous work we demonstrated a first approach for integrating chemical reactions and analysis on a single microchip for the screening of enantioselective biocatalysts. Nevertheless, this system was limited to aqueous media and native fluorescent molecules. Therefore we intended to develop an advanced chip system with a wider applicability in synthetic chemistry, including the utilization of non-aqueous reaction media and a more general detection system. In this context, the coupling to mass spectrometry appears to be very attractive, as it provides additional structural information for substance identification. To demonstrate our concept, we focused on organocatalysis, which has been one of the most innovative research fields in synthetic chemistry over the past years. Recently, Odedra and Seeberger described a first miniaturized approach, performing organocatalysis in a microfluidic flow reactor chip. The reaction products were, however, analyzed offline by traditional HPLC. Herein we present the, to our knowledge, first asymmetric organocatalytic reaction on a single chip with integrated analysis. As a model system we chose the enantioselective vinylogous Mannich reaction published in 2008, which is catalyzed by chiral phosphoric acid. The alcoholic solvent mixture and the nonfluorescent reaction products in this synthesis are quite challenging for chip integration. Thus, it was necessary to adapt the reaction media to the aqueous separation electrolyte on-chip to enable an undistorted electrophoretic analysis of the reaction products. Therefore, we developed a new microfluidic chip design containing different functionalities, including a reaction structure for the organic synthesis, a structure for aqueous dilution of the reaction mixture, a cross section for injection, and a separation channel for chip electrophoresis. Furthermore, the chip layout includes an integrated nanoelectrospray emitter with makeup-flow channels for dead-volume free coupling to mass spectrometry at the end of the separation channel. A schematic drawing of the chip with 50 mm wide channels and a photo is shown in Figure 1. Reaction and analysis processes on the single chip were carried out as follows: initially, the reaction structure was filled with the alcoholic solvent mixture for synthesis; then the remaining structure was replenished with the aqueous separation electrolyte. Afterwards, each reactant solution

The Bronsted Acid-Catalyzed, Enantioselective Aza-Diels-Alder Reaction for the Direct Synthesis of Chiral Piperidones

We disclose herein the first enantioselective aza-Diels-Alder reaction of β-alkyl-substituted vinylketene silyl-O,O-acetals and imines furnishing a broad range of optically highly enriched 4-alkyl-substituted 2-piperidones. As a catalyst for this one-pot reaction we employed a chiral phosphoric acid which effects a vinylogous Mannich reaction directly followed by ring-closure to the lactam. Subsequent fully diastereoselective transformations including hydrogenation, enolate alkylation, and lactam alkylation/reduction processes converted the cycloadducts into various highly substituted piperidines of great utility for the synthesis of natural products and medicinally active compounds.