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A direct and simple activation of quinolines, without isolating unstable intermediates, or using isolated N,O-acetals in the presence of Lewis or Bronsted acids, is described. The procedure is quite straightforward and allows the addition in a stereoselective manner of different aldehydes to various differently substituted quinolines. The desired products were obtained in 28–76 % yields, with dr values up to 83:17 in favor of the syn isomer, and up to 99 % ee. Studies towards the use of acetaldehyde were also performed with different catalysts and the addition was promoted affording the desired product in 62 % yield with 46 % ee. Finally, deprotection and chemical transformations of the enantioenriched adducts were performed.

What do quantum cellular automata (QCA), "on water" reactions, and SN 1-type organocatalytic transformations have in common? The link between these distant arguments is the practical access to useful intermediates and key products through the use of stabilized carbenium ions. Over 10 years, starting with a carbenium ion bearing a ferrocenyl group, to the 1,3-benzodithiolylium carbenium ion, our group has exploited the use of these intermediates in useful and practical synthetic transformations. In particular, we have applied the use of carbenium ions to stereoselective organocatalytic alkylation reactions, showing a possible solution for the "holy grail of organocatalysis". Examples of the use of these quite stabilized intermediates are now also considered in organometallic chemistry. On the other hand, the stable carbenium ions are also applied to tailored molecules adapted to quantum cellular automata, a new possible paradigm for computation. Carbenium ions are not a problem, they can be a/the solution!

The first catalytic asymmetric addition of TosMIC to unactivated ketones is presented. A combination of Me2Zn and aminoalcohol catalyst promoted the aldol addition/cyclization reaction to render oxazolines possessing a fully substituted stereocenter with excellent yields (up to 92%), high enantioselectivities (up to 96%), and complete diastereoselectivity. The chiral oxazolines were then used to give, after a straightforward acid hydrolysis, enantioenriched building blocks bearing tertiary alcohol motifs such as hydroxylaldehydes, hydroxylacids, and hydroxylesters without racemization.

The title reaction between aryl substituted thioesters and aryl or hetaryl esters provides the corresponding β-hydroxy thioesters in moderate yield, with no to excellent diastereomeric and moderate to high enantioselectivity.

Recently, the direct substitution of allylic, benzylic, and tertiary alcohols has been achieved via SN1-type reactions with catalytic amounts of Bronsted or Lewis acids. When a new stereogenic center is formed most of these transformations produce the desired product as a racemate, as these reactions proceed through carbenium ions. The arsenal of activation modes available in organocatalysis can be used to set up suitable reaction conditions in which chiral nucleophiles (enamine catalysis) or chiral electrophiles (iminium catalysis, chiral counterion catalysis) can easily be generated. Recently, we have used stabilized carbenium ions, directly available or obtained from the corresponding alcohols, in new organocatalytic stereoselective SN1-type reactions. The commercially available carbenium ion benzodithiolylium tetrafluoroborate 1 can be used for the straightforward organocatalytic stereoselective alkylation of aldehydes. In this account we will illustrate the application of this methodology in the total synthesis of natural products and the preparation of valuable starting materials. Chirality 26:607–613, 2014. © 2014 Wiley Periodicals, Inc.

This gives exclusively the E isomers of the arylidene-hetarylium tetrafluoroborates, which can be easily reduced to the corresponding aryl-hetaryl-methanes.

In recent years there has been an accelerated rate of development in the field of organocatalysis, with asymmetric organocatalysis now reaching full maturity. The invention of new organocatalytic reactions and the exploration of new concepts now appear in tandem with the application of organocatalytic techniques in the synthesis of natural products and active pharmaceutical ingredients (APIs). After a “golden rush” in organocatalysis, researchers are now starting to combine different methods, thereby taking advantage of the significant benefits of synergy. Metals are used in combination with organocatalytic processes, thus reaching complexity that is found in nature, where enzymes take advantage of the presence of certain metals to increase the arsenal of organic transformations available. In this Focus review, we illustrate the possibility of a “happy marriage” between Lewis acids and organocatalytic stereoselective processes. Questions have been raised about the combination of Lewis acids and organocatalysis owing to the presence of water and/or strong bases in these processes. Some Lewis acids have been shown to be compatible with organocatalysis and concepts relating to their use will be illustrated herein. To summarize the fruitful use of Lewis acids in stereoselective organocatalytic processes, we will draw attention to the advantages and selectivity achieved using this method. I principi di attivazione dell′organocatalisi, amminocatalisi, catalisi via legame idrogeno, catalisi via acidi di Bronsted solo per citarne alcuni, hanno contribuito in anni recenti allo sviluppo esponenziale del′organocatalisi stereoselettiva. La nuova frontiera di sviluppo dell′organocatalisi e pero rappresentata dalla sinergia con altri sistemi catalitici, in particolare, con sistemi contenenti metalli. Tra metalli di transizione e non, l′impiego di acidi di Lewis nelle reazioni organocatalitiche rappresenta un fertile campo di innovazione, dove concetti quali sinergia e compatibilita sono sapientemente adoperati nell′invenzione di nuove reazioni.

The general applicability and the recyclability of the novel heterogeneous catalyst are demonstrated by batch reactions between carbonyl compounds and nitroolefins.

1-Vinyl tetrahydroisoquinoline ((R)-II) is synthesized through a metal-free strategy for a stereoselective Friedel—Crafts-type cyclization reaction using an axial-chiral phosphoric acid as catalyst.

A series of chiral alcohols (III), (V), and (VII) is prepared by a reaction of cationic electrophiles with aldehydes in a packed-bed reactor filled with a polymer-supported enantiopure imidazolidinone catalyst.

The frequent occurrence of chiral 1-substituted-1,2,3,4-tetrahydroisoquinoline ring systems in a large number of alkaloids, possessing a broad spectrum of biological and pharmaceutical properties, has prompted out a considerable interest in their synthesis. Economical and valuable stereoselective processes based on organocatalytic transformations represent a new avenue for approaching isoquinoline alkaloids with efficiency and creativity.

The new method affords alkylated isoquinolines as diastereomeric mixtures with high enantioselectivities.

Chiral α-thioaldehydes 2–6 undergo chelation or non-chelation controlled addition of silylketene acetal 1 , depending on the nature of the Lewis acid catalyst and of the ligands at the stereocenter.

Treatment of 2-pyridylthioesters with triethylamine in the presence of titanium tetrachloride affords titanium enolates that add to imines to give β-lactams in fair to excellent yields with moderate to good stereoselectivity.

Simply generated (TiCl 4 , Et 3 N, −78°C) titanium enolates of some thioesters and α-thio substituted esters undergo aldol condensations with achiral and chiral aldehydes with low to high stereoselectivity. An 1 H-NMR study of the TiCl 4 /ester complexation and of the enolization process is presented. The relation between the enolate structure and the aldol product stereochemistry is discussed.

Addition of titanium enolates of 2-pyridyl thioesters to chiral imines derived from alkoxy aldehydes occurs with good diastereofacial control, and opens a simple access to important carbapenem antibiotics.

The Lewis acid-promoted cyclocondensation between two electron-rich dienes with a series of racemic α- and β-thio-substituted aldehydes has been studied. Boron trifluoride etherate proved to be the catalyst of choice, affording satisfactory chemical yields and generally good diastereoselectivities. Other Lewis acidic catalysts gave lower yields and in some cases reversed the sense of the diastereoselection. A rationalization of the stereochemical results is presented

Several organocatalytic SN1-type reactions from allylic, benzylic and benzhydrylic alcohols are promoted by In(III) salts.

Macmillan′s catalyst is employed in the enantioselective α-methylation of 2-arylacetaldehydes.

The title reaction is accomplished from the commercially available carbenium ionic compound (II) without the use of transition metals.

A catalytic titanium mediated Reformatsky reaction is presented. The technique employs cyclopentadienyltitaniumdichloride(IV) (10 mol%) in conjunction with Mn (2 equiv.), as the stoichiometric reductant, and (CF3CO)2O (1.5 equiv.), as the scavenger, and it is based on the formation of titanocene(III) chloride as a mild and homogeneous single-electron reductant. The reaction gives moderate yields of the desired Reformatsky adduct, and it works well with aromatic and aliphatic aldehydes.

The Reformatsky reaction is the well-recognized carbon-carbon bond-forming reaction of α-halo esters with aldehydes or ketones in the presence of Zn metal to give β-hydroxy esters. Recently, it has been reported that Rh- and Ni-catalyzed Reformatsky reaction, in which R2Zn (R = Me, Et) acts as the Zn source, reacted smoothly with carbonyl compounds and imines. Taking advantage of N-methylephedrine as a cheap and recoverable chiral ligand, we have discovered the first homogeneous enantioselective Ni-catalyzed imino Reformatsky reaction. The process is a one-pot, three-component reaction, in which Me2Zn plays multiple roles as dehydrating agent, reductant, and coordinating metal. Broad scope, high enantiomeric excess, and a simple procedure are adding value to our findings.

The Reformatsky reaction is the well-recognized carbon-carbon bond-forming re- action of α-halo esters with aldehydes or ketones in the presence of Zn metal to give β-hydroxy esters. Recently, it has been reported that Rh- and Ni-catalyzed Reformatsky re- action, in which R 2 Zn (R = Me, Et) acts as the Zn source, reacted smoothly with carbonyl compounds and imines. Taking advantage of N-methylephedrine as a cheap and recoverable chiral ligand, we have discovered the first homogeneous enantioselective Ni-catalyzed imino Reformatsky reaction. The process is a one-pot, three-component reaction, in which Me 2 Zn plays multiple roles as dehydrating agent, reductant, and coordinating metal. Broad scope, high enantiomeric excess, and a simple procedure are adding value to our findings.

Schiff base ligands are considered "privileged ligands" because they are easily prepared by the condensation between aldehydes and imines. Stereogenic centres or other elements of chirality (planes, axes) can be introduced in the synthetic design. Schiff base ligands are able to coordinate many different metals, and to stabilize them in various oxidation states, enabling the use of Schiff base metal complexes for a large variety of useful catalytic transformations. Practical guidelines for the preparation and use of different Schiff base metal complexes in the field of catalytic transformations are discussed in this tutorial review.

Functionalised allyl halides, useful starting materials for the preparation of substituted organometallic reagents can be simply obtained by a straightforward approach. Hoveyda's ruthenium carbene catalyst 3, used in catalytic amount (2 mol%), is able to promote the cross metathesis of allyl bromide and chloride with a variety of different substituted olefins giving the corresponding functionalised allyl halides in satisfactory yields. trans-Olefins are obtained as major diastereoisomers reaching 90:10 (trans:cis) ratio when allyl chloride is used as the metathesis partner. This reaction represents a simple and accessible way for the preparation of valuable precursors for functionalised organometallic reagents. In particular, the use of functionalised allyl bromides (lOb and 13) in the enantioselective Nozaki-Hiyama reaction promoted by [Cr(Salen)Cl] is presented.

Continuous-flow organocatalyzed Diels-Alder reactions have been performed with excellent enantioselectivity for the first time in a chiral "homemade" HPLC column, packed with silica on which a MacMillan catalyst has been supported by a straightforward immobilization procedure. The versatility of the system was also proven by running with the same column continuous-flow stereoselective reactions with three different substrates, showing that the catalytic reactor may efficiently work in continuo for more than 150 h; the regeneration of the HPLC column was also demonstrated, allowing to further extend the activity of the reactor to more than 300 operating hours.

A new ferrocene-based catalyst is designed in which the ferrocenyl group in connection with the geminal dialkylmethyl-linker impose the preferred conformation of the pyrrolidine moiety for intermediary enamine formation.

The first example of the addition of various nitro compounds to alcohols performed in TFE is described.

Diastereoselective SN1-type reactions have been known for many years and have been used in the synthesis of many natural products. It has recently been shown that chiral nucleophiles, obtained using organocatalytic methodologies, can react with highly reactive carbenium ions in a stereoselective fashion. Based on this, carbenium ions can be applied in asymmetric catalytic reactions. 1 Introduction 1.1 Reaction of Ferrocenyl Alcohols with Lewis Acids 2 Reaction of Alcohols ‘on Water’ 2.1 Stability of Carbenium Ions and the Mayr Scale 3 Organocatalytic Stereoselective SN1-Type Reactions of Aldehydes and Isolated Carbenium Ions 3.1 Attempts at the Related Asymmetric SN1-Type α-Alkylation of Ketones 3.2 Organocatalytic Stereoselective SN1-Type Reactions under Oxidative Conditions 4 Organocatalytic SN1-Type Reactions Involving Lewis Acids 5 Alkylation of Aldehydes Made Simple with the Benzodithiolylium Ion 6 Organocatalytic SN1-Type Reactions Involving Bronsted Acids 7 SN1-Type Reactions Promoted by Chiral Thioureas 8 Conclusion and Perspectives

The bisphosphine oxide catalyst PPO is optimal as catalyst in aldol reactions of thioesters (I) with aromatic aldehydes.

Synergetic Au(I)- and amine organo-catalysis promotes intramolecular stereo- and enantioselective α-allylic alkylations of aldehydes with simple primary and secondary alcohols.

A simple and general methodology for the enamine-mediated α-alkylation of α-substituted aldehydes is presented.

The first organocatalytic stereoselective α-addition of a formyl group to aldehydes (I) or (X) is described to give the alcohols (III) or (XII), respectively.

Stereoselective addition of aldehydes (II) towards α-substituted propargylic alcohols, e.g. (I), (V) and (VIII), is efficiently catalyzed by a combination of indium triflate and a spirocyclic imidazolidinone organocatalyst.

The first organocatalytic, stereoselective and direct aldol reaction of activated thioesters with aldehydes has been accomplished. The trichlorosilyl ketene thioacetal generated in situ by adding a tertiary amine to a trifluoroethyl thioester in the presence of tetrachlorosilane is activated by catalytic amounts of an enantiomerically pure biheteroaromatic phosphine oxide to react with different aldehydes, coordinated to as well as activated by the chiral cationic hypervalent silicon species. Starting from a variety of readily available thioesters, this Lewis acid-mediated Lewis base-catalyzed transformation allows the direct synthesis of syn-β-hydroxy thioesters in up to 95% ee.

In 2005, the ACS Green Chemistry Institute (GCI) and the global pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage the development of green chemistry and green engineering in the pharmaceutical industry. The Roundtable has established a list of key research areas including the direct nucleophilic reactions of alcohols. The substitution of activated alcohols is a frequently used approach for the preparation of active pharmaceutical ingredients. Alcohols are transformed into the reactive halides or sulfonate esters, thereby allowing their reaction with nucleophiles. Although the direct nucleophilic substitution of an alcohol should be an attractive process, as one of the byproducts from the reaction yields water, hydroxide is a poor leaving group that hinders the reaction. Recently, the direct substitution of allylic, benzylic, and tertiary alcohols has been achieved through an S N 1 reaction with catalytic amounts of Bronsted or Lewis acids. In this review, the approaches leading to a greener process are examined in detail, and the advances achieved to date in this important transformation are presented.

Stereoselective α-alkylation of aldehydes is achieved in the presence of MacMillan catalyst salts and lutidine as base.

Controlled living polymerization of a broad range of monomers is a radical process known as ATRP (atom transfer radical polymerization) and is mediated by a variety of metals. A complex of copper has been found to be the most efficient catalyst, with a copper(I)/copper(II) catalytic cycle. The radical, enantioselective catalytic Reformatsky reaction mediated by Me2Zn can be efficiently promoted by copper(I) complexes avoiding the use of other promoters such as air and oxidant, giving more reproducible and affordable conditions. The CuCN-mediated enantioselective addition of ethyliodoacetate to functionalized ketones is described in this paper.

Enantiomerically pure (E)-γ-alkoxy-α,β-unsaturated esters were reacted with azomethine ylides obtained from glycine imines in the presence of LiBr and diazabicycloundecene (DBU), to afford tetrasubstituted pyrrolidines with complete regiocontrol and fair to excellent diastereoselectivity (only two diastereoisomers formed in up to 96: 4 diastereoisomeric ratio). The results are compared with those of other 1,3-dipolar cycloadditions, and the origin of stereocontrol is discussed.