Development of Non-C2-symmetric ProPhenol Ligands. The Asymmetric Vinylation of N-Boc Imines

Abstract

The development and application of a new generation of non-C2-symmetric ProPhenol ligands is reported herein. Rational design of the ProPhenol ligand paved the way to the first catalytic and asymmetric vinylation of N-Boc imines via hydrozirconation giving rise to valuable allylic amines in excellent yields and enantioselectivities. The utility of this method was demonstrated by developing the shortest reported asymmetric synthesis of the selective serotonine reuptake inhibitor (SSRI) (-)-dapoxetine.

Dinuclear Metal‐ProPhenol Catalysts: Development and Synthetic Applications

“…Unlike typical ProPhenol‐mediated processes that initiate with the catalytic deprotonation of pronucleophiles, this method utilizes in situ generated vinylzirconocenes 153 (from acetylenes) as donors. These donors were shown to undergo transmetallation to Zn‐ProPhenol for subsequent vinylation of N ‐Boc imines 124 b (Scheme ) . This process also led to the development of pseudo‐ C 2 ‐symmetric ligands, and L‐5 a was optimal for enantioselectivity.…”

“…The second category of ligands involves non‐ C 2 ‐symmetric molecules (Scheme ). In 2015, the Trost group disclosed a library of pseudo‐ C 2 symmetric ProPhenol ligands ( L‐5 ) by varying the electronic properties of the two biarylprolinol moieties . This modification was inspired by the crystal structure of 2 , where substrates in the chiral pocket should be proximal to the pseudo‐axial aryl groups of the catalyst, allowing for potential electrostatic interactions.…”

Zweikernige Metall‐ProPhenol‐Katalysatoren: Entwicklung und Anwendungen in der Synthese

“…Im Unterschied zu typischen ProPhenol‐vermittelten Prozessen, die mit der Deprotonierung von Pronukleophilen einsetzen, nutzt diese Methode in situ generierte Vinylzirconocene 153 (aus Acetylen) als Donoren. Diese Donoren unterliegen einer Transmetallierung zu Zn‐ProPhenol für die nachfolgende Vinylierung der N ‐Boc‐Imine 124 b (Schema ) . Dieser Prozess führte auch zur Entwicklung pseudo‐ C 2 ‐symmetrischer Liganden, und von diesen erwies sich L‐5 a als optimal für die Enantioselektivität.…”

“…Die zweite Kategorie Liganden betrifft nicht‐ C 2 ‐symmetrische Moleküle (Schema ). 2015 hat die Trost‐Gruppe eine Sammlung pseudo‐ C 2 ‐symmetrischer ProPhenol‐Liganden ( L‐5 ) mit variierten elektronischen Eigenschaften der beiden Biarylprolinol‐Einheiten vorgestellt . Deren Modifizierung war durch die Kristallstruktur von 2 inspiriert worden; diese legte nahe, dass sich die Substrate in der chiralen Reaktionstasche nahe zu den pseudo‐axialen Arylgruppen des Katalysators befinden sollten, um potentielle elektrostatische Wechselwirkungen zu ermöglichen.…”

Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza‐Darzens Reactions

“…We then investigated the use of non-C 2 -symmetric ProPhenol ligands L2 – L4 which proved to be differential for the enantioselective vinylation of N -Boc imines. [15] L2 and L3 did not surpass the standard ProPhenol ligand L1 (entries 7–8). However, the use of the more polarized donor-acceptor ligand L4 significantly improved the diastereoselectivity of the reaction and provided compound 3da with 96% ee (entry 9).…”