Organocatalysis by Networks of Cooperative Hydrogen Bonds: Enantioselective Direct Mannich Addition to Preformed Arylideneureas

The concept of noncovalent organocatalysis by means of networks of cooperative hydrogen bonds (NCHB organocatalysis) has been explored. Arylideneureas were chosen as ideal substrates because of their powerful donor–acceptor properties. We have examined their uncatalyzed, direct Mannich reaction with acetoacetates in comparison with that catalyzed by a number of salan derivatives capable of providing a network of cooperative hydrogen bonds. Catalyst D [(R,R)‐N,N′‐bis(salicyl)cyclohexane‐1,2‐diamine] was found to drive the above direct Mannich reaction in an enantioselective manner, thereby allowing the synthesis of several Biginelli dihydropyrimidinones with high enantioselectivity. DFT calculations (B3LYP‐D‐PCM/6‐31+G*//B3LYP/6‐31+G*) revealed that the NCHB organocatalyst lowers the energy barrier of the reaction. The NCHB organocatalysts appear to function as biomimetic catalysts.     

Diversity‐Oriented Synthesis of Drug‐Like Macrocyclic Scaffolds Using an Orthogonal Organo‐ and Metal Catalysis Strategy

Small‐molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity‐oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three‐dimensionality, to target a broad area of biological space. In this study, an organocatalysis‐derived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. The orthogonal combination of multiple diversity‐generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only two to four steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a one‐pot protocol facilitated the synthesis of drug‐like macrocycles with natural‐product‐like levels of shape diversity in a single step.     

The enantioselective Morita-Baylis-Hillman reaction and its aza counterpart

The development of asymmetric Morita-Baylis-Hillman (MBH) reactions has evolved dramatically over the past few years, parallel to the emerging concept of bifunctional organocatalysis. Whereas organocatalysis is starting to compete with metal-based catalysis in several important organic transformations, the MBH reaction belongs to a group of prototypical reactions in which organocatalysts already display superiority over their metal-based counterparts. This Minireview summarizes recent mechanistic insights and advances in the design and synthesis of small organic molecules for enantioselective MBH and aza-MBH reactions.     

Enantioselective Synthesis of Spiro Heterocyclic Compounds Using a Combination of Organocatalysis and Transition-Metal Catalysis

Over the last ten years, the combination of organocatalysis with transition metal (TM) catalysis has become one of the most important toolboxes used for synthesizing optically pure compounds containing chiral quaternary centers, including spiro heterocyclic molecules. The dominant method in the enantioselective synthesis of spiro heterocyclic compounds based on synergistic catalysis includes chiral aminocatalysis and NHC catalysis, as already established covalent organocatalytic strategies. Another area of organocatalysis widely combined with TM catalysis producing enantiomerically enriched spiro heterocyclic compounds is non-covalent catalysis, dominated by chiral phosphoric acids, thiourea, and squaramide derivatives. This review article aims to summarize enantioselective methods used for constructing spirocyclic heterocycles based on a combination of organocatalysis and transition metal catalysis.     

Activation of Carboxylic Acids in Asymmetric Organocatalysis

Organocatalysis, catalysis using small organic molecules, has recently evolved into a general approach for asymmetric synthesis, complementing both metal catalysis and biocatalysis. 1 Its success relies to a large extent upon the introduction of novel and generic activation modes. 2 Remarkably though, while carboxylic acids have been used as catalyst directing groups in supramolecular transition‐metal catalysis, 3 a general and well‐defined activation mode for this useful and abundant substance class is still lacking. Herein we propose the heterodimeric association of carboxylic acids with chiral phosphoric acid catalysts as a new activation principle for organocatalysis. This self‐assembly increases both the acidity of the phosphoric acid catalyst and the reactivity of the carboxylic acid. To illustrate this principle, we apply our concept in a general and highly enantioselective catalytic aziridine‐opening reaction with carboxylic acids as nucleophiles.     

One‐Pot Sequential Organocatalysis: Highly Stereoselective Synthesis of Trisubstituted Cyclohexanols

A highly diastereoselective (d.r. >99:1) and enantioselective (ee value up to 96 %) synthesis of trisubstituted cyclohexanols was achieved by using a one‐pot sequential organocatalysis that involved a quinidine thiourea‐catalyzed tandem Henry–Michael reaction between nitromethane and 7‐oxo‐hept‐5‐en‐1‐als followed by a tetramethyl guanidine (TMG)‐catalyzed tandem retro‐Henry–Henry reaction on the reaction products of the tandem Henry–Michael reaction. Through a mechanistic study, it has also been demonstrated that similar results may also be achieved with this one‐pot sequential organocatalysis by using the racemic Henry product as the substrate.     

Chiral Tertiary Sulfonium Salts as Effective Catalysts for Asymmetric Base‐Free Neutral Phase‐Transfer Reactions

Although chiral quaternary ammonium and phosphonium salts are commonly used for asymmetric organocatalysis, the catalytic ability of chiral tertiary sulfonium salts has yet to be demonstrated in asymmetric synthesis. Herein, we show that chiral bifunctional trialkylsulfonium salts catalyze highly enantioselective conjugate additions of 3‐substituted oxindoles to maleimides under base‐free neutral phase‐transfer conditions.     

Chemistry of quinuclidines as nitrogen bicyclic bridged‐ring structures

This review summarises the structure, basicity, asymmetric organocatalysis, synthesis and reactions of quinuclidines. Quinuclidines are bicyclic saturated pyridin‐containing compounds with rigid structures and a ring‐juncture nitrogen atom. This review covers the period from 1984–2005.     

Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes

Pyrrolidines are important heterocyclic compounds with endless applications in organic synthesis, metal catalysis, and organocatalysis. Their potential as ligands for first‐row transition‐metal catalysts inspired a new method to access complex poly‐heterocyclic pyrrolidines in one step from available materials. This fundamental step forward is based on the discovery of an essential organoaluminum promoter that engages unactivated and electron‐rich olefins in intermolecular [3+2] cycloadditions.     

Rationalization of an Unusual Solvent‐Induced Inversion of Enantiomeric Excess in Organocatalytic Selenylation of Aldehydes

An unusual solvent‐induced inversion of the sense of enantioselectivity observed in the α‐selenylation of aldehydes catalyzed by a diphenylprolinol silyl ether catalyst is correlated to the presence of intermediates formed subsequent to the highly selective C? Se bond‐forming step in the catalytic cycle. This work provides support for a mechanistic concept for enamine catalysis and includes a general role for “downstream intermediates” in selectivity outcomes in organocatalysis.     

Catalytic Asymmetric Oxidative γ‐Coupling of α,β‐Unsaturated Aldehydes with Air as the Terminal Oxidant

A novel concept for catalytic asymmetric coupling reactions is presented. Merging organocatalysis with single‐electron oxidation by using a catalytic amount of a copper(II) salt and air as the terminal oxidant, we have developed a highly stereoselective carbon–carbon oxidative coupling reaction of α,β‐unsaturated aldehydes. The concept relies on the generation of a dienamine intermediate, which is oxidized to an open‐shell activated species that undergoes highly selective γ‐homo‐ and γ‐heterocoupling reactions. In the majority of examples presented, only a single stereoisomer was formed.     

A theoretical study of imine hydrocyanation catalyzed by halogen‐bonding

A detailed theoretical study of the mechanism and energetics of an organocatalysis based on C?N activation by halogen‐bonding is presented for the hydrocyanation of N‐benzylidenemethylamine. The calculations at the level of scalar‐relativistic gradient‐corrected density functional theory give an insight in this catalytic concept and provide information on the characteristics of four different monodentate catalyst candidates acting as halogen‐bond donors during the reaction. © 2015 Wiley Periodicals, Inc.     

Combining Organocatalysis and Lanthanide Catalysis: A Sequential One‐Pot Quadruple Reaction Sequence/Hetero‐Diels–Alder Asymmetric Synthesis of Functionalized Tricycles

A stereoselective one‐pot synthesis of functionalized complex tricyclic polyethers has been achieved using the combination of secondary amine and lanthanide catalysis. This one‐pot quadruple reaction/Hetero‐Diels–Alder sequence gave good yields (per step) as well as excellent diastereo‐ and enantioselectivities. Furthermore, the particular combination of lanthanide complexes with organocatalysis is one of the first examples described for sequential catalysis.     

Atroposelective Arene Formation by Carbene‐Catalyzed Formal [4+2] Cycloaddition

Atroposelective arene formation is an efficient method to build axially chiral molecules with multi‐substituted arenes. Reported here is an organocatalyzed atroposelective arene formation reaction by an N‐heterocyclic carbene (NHC) catalyzed formal [4+2] cycloaddition of conjugated dienals and α‐aryl ketones. This study expands the synthetic potential of NHC organocatalysis and provides a competitive pathway for the synthesis of axially chiral ligands, catalysts, and other functional molecules.     

Recent efforts directed to the development of more sustainable asymmetric organocatalysis

In line with the principles of "green" chemistry, organocatalysis seeks to reduce energy consumption and to optimize the use of the available resources, aiming to become a sustainable strategy in chemical transformations. Nevertheless, during the last decade diverse experimental protocols have made organocatalysis an even "greener" alternative by the use of friendlier reaction conditions, or via the application of solvent-free methodologies, or through the design and synthesis of more selective catalysts, or via the development of multicomponent one-pot organocatalytic reactions, or by the recycling and reuse of organocatalysts, or by means of the application of more energy-efficient activation techniques, among other approaches. In this feature article we review some of the remarkable advancements that have made it possible to develop even more sustainable asymmetric organocatalyzed methodologies.     

Asymmetric organocatalysis: from infancy to adolescence

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.     

Enantioselective Organocatalytic Addition of Oxazolones to 1,1‐Bis(phenylsulfonyl)ethylene: A Convenient Asymmetric Synthesis of Quaternary α‐Amino Acids

A new, easy, and highly enantioselective method for the synthesis of quaternary α‐alkyl‐α‐amino acids based on organocatalysis is reported. The addition of oxazolones to 1,1‐bis(phenylsulfonyl)ethylene is efficiently catalyzed by simple chiral bases or thioureas. The reaction affords α,α‐disubstituted α‐amino acid derivatives with complete C4 regioselectivity and with excellent yields and enantioselectivities. This methodology is complementary to previously reported enantioselective approaches to quaternary α‐amino acids and allows the synthesis of α‐phenyl‐α‐alkyl‐α‐amino acids and α‐tert‐butyl‐α‐alkyl‐α‐amino acids. It has distinct advantages in terms of operational simplicity, enviromentally friendly conditions, and suitability for large‐scale reactions.     

Enantioenriched Methylene‐Bridged Benzazocanes Synthesis by Organocatalytic and Superacid Activations

Achieving in a straightforward way the synthesis of enantioenriched elaborated three‐dimensional molecules related to bioactive natural products remains a long‐standing quest in organic synthesis. Enantioselective organocatalysis potentially offers a unique opportunity to solve this problem, especially when combined with complementary modes of activation. Here, we report the sequential association of organocatalytic and superacid activations of simple linear achiral readily available precursors to promote the formation of unique highly elaborated chiral methylene‐bridged benzazocanes exhibiting three to five fully‐controlled stereocenters. This peculiar backbone, difficult to assemble by standard synthetic approaches, is closely related to bioactive natural and synthetic morphinans and benzomorphans. The formation of a highly reactive chiral 7‐membered ring N‐acyl iminium superelectrophilic ion, evidenced by low‐temperature in situ NMR experiments, triggers a challenging stereoselective Friedel–Crafts‐type cyclization.     

Functional Mechanically Interlocked Molecules: Asymmetric Organocatalysis with a Catenated Bifunctional Brønsted Acid

Interlocked molecules, such as catenanes, rotaxanes, and molecular knots, have become interesting candidates for the development of sophisticated chemical catalysts. Herein, we report the first application of a catenane‐based catalyst in asymmetric organocatalysis, revealing that the catenated catalyst shows dramatically increased stereoselectivities (up to 98 % ee ) in comparison to its non‐interlocked analogues. A mechanistic rationale for the observed differences was developed by DFT studies, suggesting that the involvement of two catalytically active groups in the stereodetermining reaction step is responsible for the superior selectivity of the interlocked catalyst.     

Halogen Bonding in Organic Synthesis and Organocatalysis

Halogen bonding is a noncovalent interaction similar to hydrogen bonding, which is based on electrophilic halogen substituents. Hydrogen‐bonding‐based organocatalysis is a well‐established strategy which has found numerous applications in recent years. In light of this, halogen bonding has recently been introduced as a key interaction for the design of activators or organocatalysts that is complementary to hydrogen bonding. This Concept features a discussion on the history and electronic origin of halogen bonding, summarizes all relevant examples of its application in organocatalysis, and provides an overview on the use of cationic or polyfluorinated halogen‐bond donors in halide abstraction reactions or in the activation of neutral organic substrates.