Pd-catalyzed aryl amination mediated by well defined, N-heterocyclic carbene (NHC)-Pd precatalysts, PEPPSI

Pd-N-heterocyclic carbene (NHC)-catalyzed Buchwald-Hartwig amination protocols mediated by Pd-PEPPSI precatalysts is described. These protocols provide access to a range of hindered and functionalized drug-like aryl amines in high yield with both electron-deficient and electron-rich aryl- and heteroaryl chlorides and bromides. Variations in solvent polarity, base and temperature are tolerated, enhancing the scope and utility of this protocol. A mechanistic rationalization for base strength (pKb) requirements is also provided.     

Dependence of enantioselectivity on the ligand/metal ratio in the asymmetric Michael addition of indole to benzylidene malonates: electronic influence of substrates

Simple bis(oxazoline) ligands, especially azabis(oxazolines), can promote the copper(II)-catalyzed Michael addition of indoles to benzylidene malonates with up to >99 % ee (ee=enantiomeric excess), provided that the ligand/metal ratio is tuned meticulously with particular regard to the electronic properties of the substrate. Despite a common paradigm followed in many asymmetric catalyses, an excess of chiral ligand is not always beneficial. In fact any excess of ligand has to be avoided to reach excellent enantioselectivities when electron-rich benzylidene malonates are used. On the contrary, malonates carrying an electron-withdrawing group require an excess of ligand for an optimum ee value. A correlation of optical yields versus the sigma(I) values of several para substituents shows a sigmoid trajectory. In the presence of an additive, such as triflate, the significance of the ligand/metal ratio vanishes and very good enantioselectivities are achieved at any rate--no matter whether electron-donating or withdrawing substituents are present.     

One-pot catalytic enantioselective domino nitro-michael/michael synthesis of cyclopentanes with four stereocenters

A highly enantioselective organocatalytic one-pot synthesis of nitro-, formyl-, and ester-functionalized cyclopentanes with four stereocenters is presented. The cyclopentanes were formed as a predominant diasteroisomer and isolated in high yields with 97-99 % ee.     

Synthetic Studies on Camptothecins. Part 1

A six‐step asymmetric total synthesis of (20S)‐camptothecin ( 1 ) has been accomplished in 25% overall yield starting from the known pyridone 3 . The key steps in this synthesis are the chemoselective Ni‐catalyzed hydrogenation of 3‐cyanopyridone 6 to 3‐formylpyridone 7 in AcOH/pyridine/H₂O and the Davis asymmetric hydroxylation of tricyclic lactone 4 utilizing a chiral N‐sulfonyloxaziridine into (4′S)‐tricyclic hydroxylactone 2 .     

Ruthenium-Catalyzed Direct Reductive Amination of Carbonyl Compounds for the Synthesis of Amines: An Overview

Reductive amination is a valuable method for amine synthesis that has been the topic of a century‘s worth of in-depth study in both academia and industry. Amines and their derivatives serve as incredibly adaptable building blocks for a broad array of organic substrates and are significant precursors for a myriad of advanced chemicals, physiologically active compounds, agrochemicals, biomolecules, pharmaceuticals, and polymers. The creation of innovative catalytic processes for the long-term and selective synthesis of amines from readily accessible and environmentally benign reagents remains a top priority in chemical research. Both heterogeneous and homogeneous catalysts have been designed with success to enable these reactions to explore new amines. Ruthenium catalysts are employed in reductive amination owing to their stability, selectivity, versatility, low toxicity, and high efficiency. This review comprehensively overviews the Ru-catalyzed reductive amination processes and includes the literature from 2009 to 2022.     

Palladium-Catalyzed Asymmetric Trifluoromethylated Allylic Alkylation of N-Substituted Glycine Ethyl Esters with α-(Trifluoromethyl)alkenyl Acetates

An efficient strategy for asymmetric trifluoromethylated allylic alkylation of easily available N-substituted glycine ethyl esters with α-(trifluoromethyl)alkenyl acetates has been developed. Catalyzed by a [Pd(C₃H₅)Cl]₂/(R)-BINAP, various trifluoromethyl-containing N-substituted glycine ethyl ester derivatives are afforded with good yields and excellent enantioselectivities. The product can be readily converted into diverse fluoro-substituted species, which shows the practicability of this method.     

Phosphine-Catalyzed [3+2] Cycloaddition of Aza-Aurones and Allenoates: Enantioselective Synthesis of 2-Spirocyclopentyl-Indolin-3-Ones

An enantioselective phosphine-catalyzed [3+2] cycloaddition between aza-aurones and allenoates is here described. The reaction proceeded under mild reaction conditions to afford 2-spirocyclopentyl indolin-3-one derivatives as single γ-isomer and with high levels of stereocontrol.     

Diarylprolinol as an Effective Organocatalyst in Asymmetric Cross-Aldol Reactions of Two Different Aldehydes

The aldol reaction is one of the most important carbon-carbon bond-forming reactions in organic chemistry. Asymmetric direct cross-aldol reaction of two different aldehydes has been regarded as a difficult reaction because of the side reactions such as self-aldol reaction and over reaction. We found that trifluoromethyl-substituted diarylprolinol, α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol ( 1 ), is an effective organocatalyst that promotes several cross-aldol reactions of aldehydes with excellent diastereo- and enantioselectivities. Acetaldehyde can be employed as a suitable nucleophilic aldehyde. Successful electrophilic aldehydes are ethyl glyoxylate, chloroacetaldehyde, dichloroacetaldehyde, chloral, α-alkyl-α-oxo aldehyde, trifluoroacetaldehyde, glyoxal, alkenyl aldehyde, alkynyl aldehyde, and formaldehyde. Some of the aldehydes are commercially available as a polymer solution, an aqueous solution, or in the hydrated form. They can be used directly in the asymmetric aldol reaction as a commercially available form, which is a synthetic advantage. Given that the obtained aldol products possess several functional groups along with a formyl moiety, they are synthetically useful chiral building blocks.     

Cover Picture: Axis-Unfixed Biphenylphosphine-Oxazoline Ligands: Design and Applications in Asymmetric Catalytic Reactions (Chem. Rec. 10/2023)

The design and synthesis of chiral ligands plays an important role in asymmetric catalytic reactions. Over the past decades, various types of chiral phosphine-oxazolines (PHOX ligands) have been developed and have greatly advanced the field of asymmetric catalysis. Novel chiral PHOX ligand with an axis-unfixed biphenyl backbone, developed by our group, have shown interesting coordination behavior and excellent chiral inducing ability in various transition-metal-catalyzed asymmetric reactions. This personal account focuses on our developed axis-unfixed biphenylphosphine-oxazoline ligand (BiphPHOX), including an overview of its design and applications, which will provide inspiration for the exploration of novel ligands and related reactions.