Jørgensen’s Organocatalysts

Introduction

Professor Karl Anker Jørgensen and his group have developed (R)- and (S)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether which serve as excellent chiral organocatalysts in the direct asymmetric α-functionalization of aldehydes.

In the field of asymmetric synthesis this stereoselective functionalization certainly represents an important breakthrough. Jørgensen’s diarylprolinol silyl ether reagents were shown to catalyze a variety of bond-forming reactions such as C–C, C–N, C–O, C–S and C–Hal in high yields with excellent levels of enantiocontrol.

Figure 1. pyrrolidinemethanol trimethylsilyl

Representative Applications

α-Amination

Direct α-amination between aldehydes and azodicarboxylates at room temperature using Jørgensen’s organocatalyst was reported to match enantioselectivities achieved by using l-proline as a catalyst. Interestingly, the aminated products were of inverted absolute configuration even though the absolute configuration of the catalyst is the same, due to steric shielding.

Figure 2. α-Amination

Domino Conjugated Nucleophilic Addition-Electrophilic Amination

A simple approach to highly functionalized molecules is Jørgensen’s one-pot multicomponent domino conjugated nucleophilic addition-electrophilic amination protocol. This procedure gives access to 1,2-aminothiol derivatives with enantioselectivities >99% ee. The soft sulfur nucleophile first reacts with the iminium ion intermediate formed by the α,β-unsaturated aldehyde, followed by the addition of the electrophile (i.e. the azodicarboxylate) to the enamine intermediate, yielding nearly enantiopure products when 2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilanyloxy- methyl]pyrrolidine was used as the catalyst.

Figure 3. Domino Conjugated Nucleophilic Addition

Asymmetric Epoxidation

In addition to direct α-functionalization, Jørgensen also reported the first organocatalytic asymmetric epoxidation of α,β-unsaturated aldehydes using his sterically encumbered chiral pyrrolidine derivative under environmentally friendly reaction conditions (e.g. hydrogen peroxide as the oxidant). A series of differently substituted enals were transformed into the corresponding α,β-epoxy aldehydes with up to >90%, diastereoselectivities up to 98:2 and enantioselectivities up to 98%.

Figure 4. Asymmetric Epoxidation

Asymmetric Hydrophosphinylation

Very recently, Melchiorre and Córdova have simultaneously developed the first organocatalytic asymmetric hydrophosphinylation of α,β-unsaturated aldehydes, affording direct access to highly enantioenriched β-phosphine aldehydes. Advantageously, and in contrast to a metal-catalyzed process, the organocatalytic variant does not suffer from product inhibition arising from the coordination ability of the phosphorus atom. The chiral phosphines can provide, after simple manipulations, valuable bidentate P-ligands for metal-catalyzed enantioselective transformations.

Figure 5. Asymmetric Hydrophosphinylation