Synthesis of Glutamic Acid and Highly Functionalized Pyrrolidine Derivatives by Utilizing Tunable Calcium Catalysts for Chemoselective Asymmetric 1,4‐Addition and [3+2] Cycloaddition Reactions

Abstract

A current trend in organic chemistry is the development of highly efficient, environmentally friendly and inexpensive catalysts for asymmetric transformations. Alkaline earth metals, due to their specific chemical properties and abundance in nature, provide promising and challenging catalysts in organic synthesis. This article describes the utilization of alkaline earth metals in the development of an effective catalytic system based on calcium salts in combination with Box-type ligands. We disclose asymmetric 1,4-addition and [3+2] cycloaddition reactions using simple catalytic systems consisting of calcium chloride dihydrate, chiral ligands and tetramethylguanidine. Various Box ligands were synthesized and the most effective proved to be that bearing an indane chiral backbone and a cyano group. Depending on the structure of both glycine Schiff bases and a,b-unsaturated compounds, the corresponding Michael adducts or pyrrolidine derivatives were obtained in moderate to high yields with high enantioselectivities. Modification of the catalytic system by using more Lewis acidic calcium salts such as calcium triflate and neutral Pybox-type ligands allows a tuning of the chemoselectivity and leads to suppression of the [3+2] cycloadition reactions. Various b-substituted acrylates provided 1,4-addition adducts exclusively in high yields with moderate to high diastereo-and enantioselectivities. This methodology has broadened a synthetic route to b-branched glutamic acid derivatives and established calcium salts as useful and attractive catalysts for asymmetric catalysis.

Enantioselective Main Group Catalysis: Modern Catalysts for Organic Transformations

“…Very good yields as well as excellent enantioselectivities were recorded, 87% and 98% ee respectively, when using optimized conditions involving the indane functionalized BOX ligand (38, Schemes 10 and 11) [68]. Further to this, a tandem 1,4-addition/[3+2] cycloaddition could occur depending on the enolate that was employed.…”

“…Further to this, a tandem 1,4-addition/[3+2] cycloaddition could occur depending on the enolate that was employed. The less nucleophilic enolate proceeded through the proposed addition process followed by protonation to yield the Schiff base functionalized glutamic acid 37, whereas in the case where a more nucleophilic enolate was used, the intermediate could undergo a [3+2] cycloaddition followed by protonation to give the functionalized pyrrolidine 46 (Scheme 11) with enantioselectivities routinely exceeding 90% ee [68]. Supplementary organic transformations have been effected by similar Ca-BOX systems such as the installation of chiral tertiary and quaternary centers on 3-tetrasubstituted oxindoles further displaying the increased versatility of these calcium catalysts in contrast to previous assertions that such systems were incapable of effecting a wide selection of reactions in such good enantioselectivity [69,70].…”

Humboldt and Bessel Research Awards

“…Kobayashi’s research program includes the development of new synthetic methods and novel catalysts, organic reactions in water, solid‐phase and flow synthesis, total synthesis of biologically interesting compounds, and organometallic chemistry. He has reported in Advanced Synthesis & Catalysis on the applications of tunable calcium catalysts,4a and in Angewandte Chemie on asymmetric carbon–carbon bond formation under continuous‐flow conditions 4b. Kobayashi is on the editorial or advisory board of Advanced Synthesis & Catalysis , the Asian Journal of Organic Chemistry , and Chemistry—An Asian Journal…”

Humboldt‐ und Bessel‐Forschungspreise

“…In seiner Forschung geht es um die Entwicklung neuer Synthesemethoden und neuartiger Katalysatoren, organische Reaktionen in Wasser, Synthesen an fester Phase und in Durchflusssystemen, Totalsynthesen biologisch interessanter Verbindungen und die Organometallchemie. In Advanced Synthesis & Catalysis erschien eine Arbeit von ihm über abstimmbare Calciumkatalysatoren4a und in der Angewandten Chemie eine über asymmetrische C‐C‐Kupplungen in Durchflusssystemen 4b. Kobayashi gehört den Editorial oder Advisory Boards von Advanced Synthesis & Catalysis , dem Asian Journal of Organic Chemistry und Chemistry—An Asian Journal an…”