Asymmetric enamine catalysis.

In recent years, photoredox catalysis has come to the forefront in organic chemistry as a powerful strategy for the activation of small molecules. In a general sense, these approaches rely on the ability of metal complexes and organic dyes to convert visible light into chemical energy by engaging in single-electron transfer with organic substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon–carbon and carbon–heteroatom bonds.

http://pubs.acs.org/doi/pdf/10.1021/acs.joc.6b01449

Photoredox Catalysis in Organic Chemistry

After an initial period of validating asymmetric organocatalysis by using a wide range of important model reactions that constitute the essential tools of organic synthesis, the time has now been reached when organocatalysis can be used to address specific issues and solve pending problems of stereochemical relevance. This Review deals with selected studies reported in 2006 and the first half of 2007, and is intended to highlight four main aspects that may be taken as testimony of the present status and prospective of organocatalysis: a) chemical efficiency; b) discovery of new substrate combinations to give new asymmetric syntheses; c) development of new catalysts for specific purposes by using mechanistic findings; and d) applications of organocatalytic reactions in the asymmetric total synthesis of target natural products and known compounds of biological and pharmaceutical relevance.

Asymmetric Organocatalysis: From Infancy to Adolescence

Catalysis with chiral secondary amines (asymmetric aminocatalysis) has become a well-established and powerful synthetic tool for the chemo- and enantioselective functionalization of carbonyl compounds. In the last eight years alone, this field has grown at such an extraordinary pace that it is now recognized as an independent area of synthetic chemistry, where the goal is the preparation of any chiral molecule in an efficient, rapid, and stereoselective manner. This has been made possible by the impressive level of scientific competition and high quality research generated in this area. This Review describes this "Asymmetric Aminocatalysis Gold Rush" and charts the milestones in its development. As in all areas of science, progress depends on human effort.

Asymmetric aminocatalysis--gold rush in organic chemistry.

In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

The growing study of glycobiology has led to an increased focus upon carbohydrate architecture as an important platform for reaction design and methodological advancement. Application of the aldol reaction to the synthesis of carbohydrates is well-documented; however, the attendant need for protection-group manipulations and oxidation-state adjustments has thus far precluded a broadly utilizable protocol. Intriguingly, a highly expedient two-step carbohydrate synthesis can be envisioned based on an iterative aldol sequence using simple a-oxyaldehydes [Eq. (1)]. While attractive in theory, the practical execution of this carbohydrate strategy would require the invention of two new aldol technologies: a) an enantioselective aldol union of a-oxyaldehyde substrates (Aldol step 1) and b) a diastereoselective aldol coupling between tri-oxy substituted butanals and an a-oxyaldehyde enolate (Aldol step 2). Herein we report the successful development of the first enantioselective organocatalytic coupling of an a-oxyaldehyde (Aldol step 1). This new aldol reaction provides an operationally simple protocol for the stereocontrolled production of polyol architectures and sets the stage for a twostep enantioselective carbohydrate synthesis. The development of a direct, enantioselective catalytic aldol reaction between a-oxyaldehyde substrates (Aldol step 1) is dependent upon three key issues of chemical selectivity. In addition to the traditional requirements of absolute and relative stereocontrol comes the chemoselective constraint that the a-oxyaldehyde reagent A must readily participate as both a nucleophilic and electrophilic coupling partner while the a-oxyaldehyde product B must be inert to in situ enolization or carbonyl addition [Eq. (1)]. Recently,

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200453716

Enantioselective Organocatalytic Direct Aldol Reactions of α‐Oxyaldehydes: Step One in a Two‐Step Synthesis of Carbohydrates

The first total syntheses of littoralisone (1) and brasoside (2) have been achieved in 13 overall steps. Both natural products are forged from a common intermediate which is rapidly assembled using organocatalytic technology, including a proline-catalyzed α-aminoxylation and a contra-thermodynamic intramolecular Michael addition. Application of the two-step carbohydrate synthesis technology has enabled to access a selectively substituted glucose derivative for use as an intramolecular cycloaddition tether. This synthesis culminates with an intramolecular [2+2] photocycloaddition that serves to support the proposed biosynthetic origins of 1 from 2.

Total synthesis of brasoside and littoralisone.

In 1971, Hajos and Parrish and Eder, Sauer, and Wiechert independently described the first examples of enantioselective proline-catalyzed reactions in the form of an intramolecular aldol reaction. Almost three decades later, studies by the groups of Barbas and List revealed that proline catalysis could be extended to a variety of transformations, including the direct enantioselective aldol reaction between ketones and aldehydes. Recently, our group advanced this proline-catalysis concept to the first example of a direct enantioselective cross-coupling of aldehyde substrates (Scheme 1), a powerful yet elusive aldol variant that had previously only been carried out within the realm of enzymatic catalysis.

Ian Mangion

Papers

Enantioselective Organocatalytic Direct Aldol Reactions of α‐Oxyaldehydes: Step One in a Two‐Step Synthesis of Carbohydrates

Total synthesis of brasoside and littoralisone.

The Importance of Iminium Geometry Control in Enamine Catalysis: Identification of a New Catalyst Architecture for Aldehyde–Aldehyde Couplings

A concise synthesis of a β-lactamase inhibitor.

Iridium-Catalyzed X−H Insertions of Sulfoxonium Ylides