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Transannular reactions have shown a remarkable performance for the construction of polycyclic scaffolds from medium- or large-sized cyclic molecules in an unconventional manner. Recent examples of transannular reactions reported from 2011 have been reviewed, emphasizing the excellent performance of this approach when accessing the target compounds. This review also highlights how this methodology provides an alternative approach to other commonly used strategies for the construction of cyclic entities such as cyclization or cycloaddition reactions.1 Introduction2 Transannular Cycloadditions and Electrocyclizations3 Transannular Conjugate Additions4 Transannular 1,2-Addition to Ketones, Imines, Esters, and Amides5 Transannular Reactions via Electrophilic Activation of Olefins6 Transannular Ring-Opening of Epoxides7 Transannular Alkylations of Enolates and Related Species8 Miscellaneous Transannular Reactions9 Concluding Remarks

We have demonstrated that the catalytic and enantioselective vinylcyclopropane-cyclopentene rearrangement can be carried out on (vinylcyclopropyl)acetaldehydes through activation via enamine intermediates. The reaction makes use of racemic starting materials that, upon ring opening facilitated by the catalytic generation of a donor-acceptor cyclopropane, deliver an acyclic iminium ion/dienolate intermediate in which all stereochemical information has been deleted. The final cyclization step forms the rearrangement product, showing that chirality transfer from the catalyst to the final compound is highly effective and leads to the stereocontrolled formation of a variety of structurally different cyclopentenes. Grants PID2019-104090RB-100 and PID2020-118422GB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” are gratefully acknowledged together with the Basque Government (Grupos IT1558-22) and the Government of Aragón (Grupos Consolidados, E34-20R and a fellowship to M. P.). G. G. also thanks the Spanish Ministerio de Universidades for an FPU grant. The authors thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo”, technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain).

A palladium-catalyzed asymmeric conjugate addition of aryl boronic acids to medium-sized cycloalkenones followed by intramolecular aldol trapping is reported.

[EN]Hydrazones derived from cycloalkenones undergo an enantioselective transannular formal (3 + 2) cycloaddition catalyzed by a chiral phosphoric acid. The reaction provides high yields and excellent stereocontrol in the formation of complex adducts with one or two α-tertiary amine moieties at the ring fusion, and these can be converted into very versatile stereodefined decalin- or octahydro-1H-indene-derived 1,3-diamines through simple reductive N–N cleavage. This research was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) through projects FEDER-PID2020-118422-GB-I00, FEDER-PID2019-109674-GB-I00 and FPI fellowship to J.S. and by the Basque Government (IT908-16). J.S. acknowledges the Spanish MCIU for an FPI fellowship.

The ability of cyclooctatetraene oxide to undergo two sequential ring contraction events under mild conditions, using Brønsted acid catalysis, has been studied in detail. We have found that the selectivity can be controlled by the acidity of the catalyst and by the temperature, being able to obtain selectively either the cycloheptatriene carbaldehyde product, arising from a single ring-contraction event, or phenylacetaldehyde that is formed after a second ring contraction process. A complete mechanistic picture of the reaction and a rationale behind the influence of the catalyst is provided based on both experimental and computational data. Finally, this acid-catalyzed ring contraction has been coupled with an in situ enantioselective allylation reaction, delivering enantioenriched cycloheptatrienyl-substituted homoallylic alcohols when it is carried out in the presence of a chiral phosphoric acid catalyst. These homoallylic alcohols have also been converted into enantioenriched oxaborinanes through copper-catalyzed nucleophilic borylation/cyclization protocol. Grants PID2019-104090RB-100, PID2019-109674GB−I00 and PID2020-118422GB−I00 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” are gratefully acknowledged together with the Basque Government (Grupos IT1558-22) and the Government of Aragón (Grupos Consolidados, E34_20R and a fellowship to M. P.). O. S. thanks MF-URV for a predoctoral grant and J. S. thanks Grant PRE2018-083532 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” for an FPI fellowship. The authors thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo” and technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain).

Prozesu biokimikoen behaketak eta ulerkuntzak ikertzailea inspiratu du entzimen jarrera antzeratzen duten molekula organiko bakunak aurkitzeko. 2021eko Kimikako Nobel Sariak biomimetikan oinarritutako organokatalisian egin den garapena nabarmendu du; gainera, organokatalizatzaileek zenbait abantaila ditzute jatorrizko aitzindari entzimatikoekin alderatuta, hautakortasun eta espezifikotasun hobetua erakusten baitute, besteak beste.; Observation and understanding of biochemical processes has inspired the researcher to find simple organic molecules that resemble the mechanism of action of certain enzymes. The 2021 Nobel Prize in Chemistry recognizes the development of organocatalysis which is based on biomimetics, but in comparison with enzime precur-sors organocatalysts have advantages, showing improved selectivity and specificity.

The Prins reaction is a very convenient synthetic platform for the preparation of oxygen-containing heterocyclic compounds, especially tetrahydropyrans and tetrahydrofurans. While this reaction has been extensively used by synthetic chemists since its discovery, the last years have witnessed impressive improvements in its performance and scope and especially in the development of new catalytic and enantioselective versions. This mini-review presents these recent advances through selected representative examples. The authors thank the Spanish Agencia Estatal de Investigacion (FEDER-PID2020-118422-GB-I00) and the Basque Government (Grupos IT1558-22) for financial support.

Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming ever more important to prepare these compounds in a safe, economic, and environmentally sustainable fashion. Asymmetric organocatalysis has a long history, but it began its renaissance era only during the first years of the millennium. Since then, this field has reached an extraordinary level, as confirmed by the awarding of the 2021 Chemistry Nobel Prize. In the present review, we wish to highlight the application of organocatalysis in the synthesis of enantio-enriched molecules that may be of interest to the pharmaceutical industry and the medicinal chemistry community. We aim to discuss the different activation modes observed for organocatalysts, examining, for each of them, the generally accepted mechanisms and the most important and developed reactions, that may be useful to medicinal chemists. For each of these types of organocatalytic activations, select examples from academic and industrial applications will be disclosed during the synthesis of drugs and natural products. The authors acknowledge the Spanish Agencia Estatal de Investigación (FEDER-PID2020-118422-GB-I00), the Basque Government (Grupos IT1558-22), and the University of Bologna for financial support.

Acylcyclopropanes are employed as useful donor–acceptor cyclopropanes that undergo formal (4 + 2) cyclocondensation with N-unprotected 3-substituted indoles in the presence of a Brønsted acid catalyst. The reaction involves the simultaneous alkylation of both the N and C-2 positions of the indole and provides access to the 8,9-dihydropyrido[1,2-a]indole scaffold that is the central core of several biologically relevant indole alkaloids in excellent yields and good selectivities., This research was supported by the Spanish MINECO (PID2019-104090RB-100 and FEDER-CTQ2016-76155-R), Basque Government (IT908-16), UPV/EHU (fellowship to A.O.), and Government of Aragón (Grupos Consolidados, E34_20R).

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst., The authors thank the Spanish Ministerio de Ciencia, Innovación y Universidades (FEDER PID2020-118422GB−I00 and FEDER PID2019-104090RB-100), the Basque Government (Grupos IT1558-22 and postdoctoral contract to J.L.-B.) and the Regional Government of Aragon (Grupos 17R-34) for financial support. Predoctoral FPU fellowship to S.R. from the Spanish Ministry of Education and to M.P. from Government of Aragon are also acknowledged. The authors thankfully acknowledge the resources from the super-computers “Memento” and “Cierzo”, technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain).

The direct reaction between Cu(CH3COO)2 and uracil-1-acetic acid in water gives rise to the formation of a hydrogel consisting of entangled nanometric ribbons of a crystalline antiferromagnetic 1D Cu(ii) coordination polymer (CP) decorated with biocompatible uracil nucleobases. This hydrogel is the precursor for the preparation of a meso/macroporous ultralight aerogel that shows a remarkable Young's modulus. As a proof-of-concept of the molecular recognition capability of the terminal uracil moieties anchored at Cu(ii) CP chains, this material has been tested as the selective stationary phase for the separation of nucleobase derivatives in HPLC columns.

The 8-azabicyclo[3.2.1]octane scaffold is the central core of the family of tropane alkaloids, which display a wide array of interesting biological activities. As a consequence, research directed towards the preparation of this basic structure in a stereoselective manner has attracted attention from many research groups worldwide across the years. Despite this, most of the approaches rely on the enantioselective construction of an acyclic starting material that contains all the required stereochemical information to allow the stereocontrolled formation of the bicyclic scaffold. As an alternative, there are a number of important methodologies reported in which the stereochemical control is achieved directly in the same transformation that generates the 8-azabicyclo[3.2.1]octane architecture or in a desymmetrization process starting from achiral tropinone derivatives. This review compiles the most relevant achievements in these areas.

We have optimized a synthetic approach to (±)-Ferrugine in 8 steps starting from 5-aminocyclohept-1-ene and using the Brønsted acid-catalyzed pseudotransannular ring-opening of the epoxide derived from this cycloheptene as the key step for the construction of the 8-azabicyclo[3.2.1]octane central core. While attempting the enantioselective synthesis of this natural product from enantiopure 2-hydroxy-8-azabicyclo[3.2.1]octane we have found that this compound shows a pronounced tendency to racemize via an achiral symmetric aziridinium intermediate. This racemization side process has been studied in detail using both experimental and computational methods., This research was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) through projects PID2019-104090RB-100 and FEDER-CTQ2017-83633P, the Basque Government (Grupos IT908-16) and the Government of Aragón (Grupos Consolidados, E34_20R). S.R. acknowledges the Spanish MEC for an FPU fellowship and M. R.-R.. acknowledges the University of the Basque Country (UPV/EHU) for a postdoctoral contract.

The enantioselective Michael reaction catalyzed by a bifunctional tertiary amine/squaramide has been used to trigger a Michael/transannular aldol cascade process that leads to densely substituted bicyclo[5.4.0]undecanes and in which three contiguous stereogenic centres, one of them a tertiary alcohol moiety, have been formed in a fully stereocontrolled fashion.

Racemic γ-substituted allenes undergo enantioselective higher order [8 + 2]-cycloaddition with azaheptafulvenes using a chiral amino acid derived amidophosphine as catalyst, providing the corresponding azaazulenoid cycloadducts with excellent levels of regio-, diastereo-, and enantioselectivities. In this reaction, the activated allylic phosphonium ylide intermediate participates as the C2-component of the reaction, in contrast to the conventional reactivity of this type of zwitterionic intermediates as C3-components in cycloaddition reactions.

Racemic cyclopropyl ketones undergo enantioselective rearrangement to deliver the corresponding dihydrofurans in the presence of a chiral phosphoric acid as the catalyst. The reaction involves activation of the donor‐acceptor cyclopropane substrate by the chiral Brønsted acid catalyst to promote the ring‐opening event, thus generating a carbocationic intermediate that subsequently undergoes cyclization. Computational studies and control experiments support this mechanistic pathway., This research was supported by the Spanish MINECO (FEDER‐CTQ2017‐83633‐P and FEDER‐CTQ2016‐76155‐R), Basque Government (IT908‐16), UPV/EHU (fellowship to A.O.), and Government of Aragón (Grupos de Referencia, E34‐R17).

A diastereodivergent approach to highly substituted bicyclo[3.1.0]hexanes has been developed through a transannular alkylation reaction that builds up the bicyclic core employing asymmetric organocatalysis as the tool for the installation of all stereocenters. On one hand, a Michael/Michael cascade process between enals and 4-alkenyl sulfamidate imines under the iminium/enamine activation manifold provides an oxathiazole-2,2-dioxide-fused cyclohexane adduct that, after isolation, is subsequently engaged in a transannular alkylation/hydrolysis through enamine activation by the use of a primary amine. On the other hand, the corresponding C-2 epimers are directly obtained from the same starting materials in a single operation through a cascade Michael/Michael/transannular alkylation/hydrolysis sequence through sequential iminium/enamine/enamine combination of aminocatalytic activation manifolds.

An efficient and easy protocol for promoting a C → N acyl transfer reaction in diverse enantiopure densely substituted pyrrolidine 2,2-dicarboxylates was performed, yielding the corresponding proline ester derivatives with yields in the range of 68–99% and total diastereoselection (dr > 95 : 5 in all cases). The substitution patterns both at C-3 and C-5 present in starting pyrrolidines as well as the viability of presenting different alkoxycarbonyl moieties have been evaluated observing good reaction performance in all cases.

The experimental and computational study of the mechanism of the iminium‐organocatalyzed formation of N‐hydroxypyrrolidines from nitrones, revealed up to three activation levels of the Schreiner's thiourea used as co‐catalyst, i.e: (i) formation of the iminium ion through hydroxyl anion recognition forming a stable ion pair; (ii) enolization of the nitrone through a H‐bond network and (iii) activation of the nitrone moiety towards the final ring closure. The computational model supports the mechanism and the catalytic cycle. This mechanistic rationale is supported by the lack of reactivity of preformed iminium ion with the nitrone in the absence of thiourea‐hydroxyl complex and the observed reactivity when a complex thiourea‐tetrabutylammonium hydroxide is added., This research was supported by the Spanish MINECO (FEDER-CTQ2016-76155-R, to PM and FEDER-CTQ2014-52107-P, to J.L.V.), the Government of Aragon (Grupos Consolidados, E.10) and the Basque Government (Grupos IT328-10), UPV/EHU (UFI QOSYC 11/22). V.J. thanks MEC for a pre-doctoral FPI fellowship.

Formylcyclopropanes undergo activation in the presence of an N-heterocyclic carbene catalyst generating a donor-acceptor cyclopropane intermediate with the ability to undergo ring-opening followed by formal [4+2] cycloaddition with alkylideneoxindoles. This enables the direct enantio- and diastereoselective synthesis of tetrahydropyrano[2,3-b]indoles through the use of a chiral NHC catalyst.

The enantioselective synthesis of tropanols has been accomplished through chiral phosphoric acid catalyzed pseudotransannular ring opening of 1‐aminocyclohept‐4‐ene‐derived epoxides. The reaction proceeds together with the desymmetrization of the starting material and leads to the direct formation of the 8‐azabicyclo[3.2.1]octane scaffold with excellent stereoselectivity. The synthetic applicability of the reaction was demonstrated by the enantioselective synthesis of the two natural products (−)‐α‐tropanol and (+)‐ferruginine., This research was supported by the Spanish MCIU (FEDER‐CTQ2017‐83633‐P, FEDER‐CTQ2016‐76155‐R and FPU fellowship to S. R.), Basque Government (IT908‐16) and Government of Aragón (Grupos Consolidados, E.34‐17R).

Medium-sized carbocycles containing an α,β-unsaturated ketone moiety as Michael acceptor site and a ketone moiety as internal electrophilic site are ideal substrates to conduct Cu(I)-catalyzed conjugated borylation followed by electrophilic intramolecular trapping that results into a pioneer transannular borylative ring closing reaction. The relative configuration of three adjacent stereocenters is controlled, giving access to a single diastereoisomer for a wide range of substrates tested. Moreover, when a chiral ligand is incorporated, the reaction provides enantioenriched polycyclic products with up to 99 % ee.

Catalytic and enantioselective approaches to transannular reactions are very limited and mostly are based on chiral Lewis acid catalyzed pericyclic reactions. In this report, we present an efficient and straightforward methodology to access bicyclic carbo- and heterocyclic scaffolds combining different ring sizes through transannular Morita-Baylis-Hillman reaction catalyzed by a chiral enantiopure bifunctional phosphine. The reaction is remarkably wide in scope and enables the use of a variety of medium and large size ketoenone substrates leading to the final products in high yields and providing excellent stereocontrol in the formation of a quaternary stereogenic center at the ring fusion. Moreover, its potential as a general tool in organic synthesis has been highlighted through the accomplishment of the first enantioselective total synthesis of (-)-γ-gurjunene, a sesquiterpene natural product.

The nucleophilic attack of a series of nucleobase derivatives on the [(η6-p-cymene)RuCl(μ-Cl)]2 dinuclear entity has yielded four mononuclear complexes with the general formula [Ru(η6-p-cymene)(L)Cl2], in which L stands for cytosine (1), 2-thiouracil (2), hypoxanthine (3) and 5-aminouracil (4). Furthermore, the sieving of chlorido from compound 1, assisted by a mild base, has prompted the formation of a tetranuclear ruthenium cationic complex which crystallizes as [(η6-p-cymene)4Ru4(μ-cytosinato-κN1:κN3,O2)4](CF3SO3)4 (compound 5). The crystal structure analysis of compounds 1–4 reveals that the supramolecular packing is dominated by the self-assembly capabilities provided by the stabilized nucleobase-tautomer, which is at the same time dependent on the Ru/nucleobase coordination mode. In this regard, the assembly of the complex units is conducted through base-pairing interactions, and is also assisted by means of nucleobase/chloride hydrogen bonding. The stability of these monomeric entities in water and phosphate buffered solution is analysed by means of 1H- and 31P-NMR. The tetranuclear entity of compound 5 presents an available hydrogen-donor set (exocyclic amino group) but it lacks any available acceptor atom, which prevents the nucleobase mediated self-assembly of the complex units. Consequently, a doubly interpenetrated supramolecular network is woven by the hydrogen bonding between the triflate (CF3SO3−) anions and complex cationic entities.

The use of chiral N-heterocyclic carbenes (NHCs) as catalysts in asymmetric synthesis has opened a wide range of applications due to their unique ability to generate reaction intermediates with unusual reactivity patterns that very often involve the reversal of the typical polarity associated with the functional groups present in the starting materials. In this sense, the direct activation of aldehydes or surrogates by these reactive species provides different chemical structures (conjugated Breslow intermediates, azolium enolates and dienolates, or unsaturated acyl azolium cations) which constitute excellent platforms for initiating cascade or domino reactions in the presence of a polyfunctional reagent. 1 Introduction 2 Cascade Reactions Initiated by the Participation of Homoenolate Equivalents 3 Cascade Reactions Initiated by the Participation of Azolium Enolates 4 Cascade Reactions Initiated by the Participation of Dienolate Equivalents 5 Cascade Reactions Initiated by the Participation of α,β-Unsaturated Acyl Azolium Intermediates 6 Summary and Outlook

We have demonstrated that dihydropyrrole-based enamide derivatives can act as efficient precursors of chiral quaternary N-acyliminium salts under Bronsted acid catalysis that undergo reactions with hydrazones, the latter participating as masked nucleophilic carbonyl group equivalents. The optimized methodology provides a variety of enantiopure α-substituted proline derivatives in excellent yields, being even compatible with disubstituted β-enamides that generate two contiguous stereocentres.

Complete stereocontrol on the transition-metal-free hydroboration of the distal double bond of allenamides could be achieved when allenamides contained acetyl substituents, which provided exclusively the Z-isomer. The consecutive Pd-catalyzed cross-coupling reaction allowed the straightforward formation of trisubstituted enamides, with total control of the stereoselectivity.

In this work, carboxylic acids, which are typically regarded as poor nucleophiles, are demonstrated to be competent reagents to promote the ring‐opening of formylcyclopropanes after activation of the latter through iminium ion formation. Under optimized reaction conditions, a variety of γ‐acyloxy‐substituted aldehydes can be obtained in high yields and enantioselectivities through the desymmetrization of substituted meso‐formylcyclopropanes in the presence of a chiral secondary amine as catalyst., This research was supported by Spanish MINECO (FEDER‐CTQ2017‐83633‐P and FEDER‐CTQ2016‐76155‐R), Basque Government (IT908‐16), UPV/EHU (fellowship to E. D.) and Government of Aragon.

The catalytic modes of action of three squaramide-derived bifunctional organocatalysts have been investigated using DFT methods. The [5+2] cycloaddition between oxidopyrylium ylides and enals was used as the model reaction. Two primary modes were possible for the different catalysts studied. The preference for one mode over the other was due to the possibility of additional favorable π-π interactions between the hydrogen-bond activated pyrylium ylide and an electron-deficient aromatic ring bonded to the squaramide NH group. The model can be extended to other reactions catalyzed by the same catalysts, such as formal [2+2] cycloadditions between nitroalkenes and α,β-unsaturated aldehydes. The computational results were in excellent concurrence with the available experimental reports on the observed total enantioselectivity and differences in diastereoselectivity depending on the substrate and the reaction., This work was supported by Spanish MINECO Contracts CTQ2013-44367-C2-1-P (to P. M.) and CTQ2014-52107 (to J. L.V.). We also acknowledge the Government of Aragon (Spain) (Group E-10), the Basque Government (Spain) (IT328-10) and Aarhus University (Denmark) for financial support. D.R.-L. thanks the Spanish Ministry of Education (MEC) for a predoctoral grant (FPU program).

The asymmetric and catalytic Michael reaction between α-nitroesters and nitroalkenes has been studied in the presence of two bifunctional catalysts both containing the same absolute chirality at the carbon backbone. The reaction performed in similar conditions allows us to control the syn or anti selectivity of the Michael adduct obtaining good yields and high enantiocontrol in all cases.

Benzopyrylium ylides generated in situ from 1-acetoxyisochroman-4-ones reacted with α,β-unsaturated aldehydes in the presence of a bifunctional secondary-amine/squaramide catalyst to furnish [5+2] cycloaddition products in good yield with high diastereo- and enantioselectivity. The reaction proceeds by dienamine activation and involves β,γ-functionalization of the enal. The dienamine intermediates showed exclusive β,γ-reactivity and provided direct access to compounds with the 8-oxabicyclo[3.2.1]octane framework. The ability of the bifunctional secondary-amine/squaramide catalyst to engage in hydrogen-bonding interactions with the ylide made it particularly effective in terms of both the yield and the stereoselectivity of the transformation.

BINOL-based N-trifluoromethanesulfonyl phosphoramides catalyze the enantioselective (4+3) cycloaddition between furans and oxyallyl cations, the latter being generated in situ by oxidation of allenamides. The chiral organic phosphoramide counteranion is proposed to engage in the activation of the oxyallyl cation intermediate through cooperative hydrogen-bonding and ion-pairing interactions, enabling an efficient chirality transfer that provide the final adducts with high diastereo- and enantioselectivities. Remarkably, the reaction shows a wide substrate scope that includes a variety of substituted allenamides and furans.

We have developed a procedure for the stereoselective and diastereodivergent synthesis of densely functionalised cyclohexanes containing four stereocentres through an asymmetric Michael-initiated ring closure (MIRC) cascade reaction employing hydrogen-bond catalysis, which is able to prepare adducts with different absolute configurations starting from the same starting materials. The overall process involves a highly diastereo- and enantioselective Michael/Henry cascade reaction between a wide range of nitroalkenes and α-nitro-δ-oxo esters, allowing access to different diastereoisomers of the final adduct by introducing subtle changes in the general (R,R)-configured bifunctional tertiary amine/squaramide catalyst structure. Moreover, this methodology is also amenable to a three-component one-pot procedure, leading to the formation of the same adducts with very good results directly from commercially available reagents, on a multigram scale, and employing a very low catalyst loading. Furthermore, a detailed experimental and computational study is described which shows the origin of the diastereodivergent behaviour of these structurally similar catalysts and the nature of the substrate–catalyst interaction.

We have discovered that N-alkyl aminomalonates undergo a fast and selective intramolecular C→N acyl rearrangement reaction in the presence of a strong base, leading to N-protected glycinates in excellent yield. Moreover, the fact that the reaction proceeds through a nucleophilic enolate intermediate has been used for implementing a tandem rearrangement/alkylation sequence that has been applied to the preparation of synthetically relevant nonproteinogenic tertiary and quaternary N-alkyl α-amino acids in a very simple and reliable way.

The Michael reaction of bis(phenylsulfonyl)methane with α,β-unsaturated aldehydes in the presence of catalytic amounts of a chiral secondary amine is presented. This transformation proceeds in good to excellent yields furnishing the corresponding Michael adducts in excellent enantioselectivities. Furthermore, other chiral building blocks are accessible from the obtained adducts by carrying out selective manipulation of the functional groups present at their structure, being possible to obtain a wide variety of sulfones with good results.

Ethyl glyoxylate N-tosylhydrazone has been identified as an excellent sulfonyl anion surrogate in the DBU-catalyzed conjugate addition reaction with enones and enals for the synthesis of functionalized sulfones. The reaction proceeds under base-catalyzed conditions and provides a direct access to γ-keto- and γ-hydroxy sulfones in a simple and reliable way through a sulfa-Michael reaction that proceeds with high yield and chemoselectivity.

The synthesis of densely functionalized pyrrolo[2,1- a ]isoquinolines was accomplished using the organocatalytic [3+2] cycloaddition between enals and azomethine ylides under iminium catalysis developed in our group some years ago as the key step. The cycloaddition proceeds smoothly yielding the corresponding pyrrolidine as a single endo diastereoisomer with enantiopurity in the range of 94–96% and further manipulations of the obtained cycloadducts using high yielding reaction protocols and a final mesylation/intramolecular N-alkylation sequence allowed the synthesis of target compounds in which the integrity of all stereocenters installed during the first step is maintained.

A simple one-pot procedure was developed for [3+2]-cycloaddition reactions of α,β-unsaturated aldehydes, diethyl aminomalonate, and aromatic aldehydes in the presence of diphenyl[(2 S )-pyrrolidin-2-yl]methanol as catalyst. This reaction converts simple, commercially available, starting materials into densely functionalized polysubstituted pyrrolidines under mild conditions and in a fully stereoselective fashion. Moreover, the use of brine as the reaction medium has remarkable beneficial effects in preventing the formation of self-condensation byproducts, cutting the reaction time, and reducing the production of wastes.