Brønsted Acid versus Phase-Transfer Catalysis in the Enantioselective Transannular Aminohalogenation of Enesultams.

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.

Absence of Intermediates in the BINOL-Derived Mg(II)/Phosphate-Catalyzed Desymmetrizative Ring Expansion of 1-Vinylcyclobutanols.

The catalyzed desymmetrizative ring expansion of alkenylcyclobutanols promoted by halofunctionalization of the alkene moiety with N-bromosuccinimide has been experimentally and computationally studied. The reaction yields highly enantioenriched cyclopentanones bearing two all-carbon quaternary stereocenters, one of them being generated in the rearrangement of the cyclobutane ring and the other by enantioselective desymmetrization. The reaction is competitive with the formation of a spiroepoxide, but it turns completely selective toward the cyclopentanone when a chiral bisphosphonium magnesium salt is employed as a catalyst. Mechanistic studies support the formation of an ion pair leading to a complex with only a unit of phosphoric acid, which is the resting state of the catalytic cycle. Calculations reproduce in an excellent way the observed reactivity and predict the effect exerted by the substituents of the aromatic ring linked to the double bond. The computational studies also revealed the reaction as a highly asynchronous concerted process taking place as one kinetic step but in two stages: (i) halogenation of the double bond and (ii) rearrangement of the cyclobutane. No intermediates are present in the reaction as energy minima. The experimental scope of the reaction further confirms the predictions for the observed reactivity and selectivity.

Transannular Approach to 2,3-Dihydropyrrolo[1,2-b]isoquinolin-5(1H)-ones through Brønsted Acid-Catalyzed Amidohalogenation.

A transannular approach has been developed for the construction of pyrrolo[1,2-b]isoquinolinones starting from benzo-fused nine-membered enelactams. This process takes place in the presence of a halogenating agent and under Brønsted acid catalysis and proceeds via a transannular amidohalogenation, followed by elimination. The reaction has been found to be wide in scope, enabling the formation of a variety of tricyclic products in good overall yield, regardless of the substitution pattern in the initial lactam substrate. The reaction has also been applied to the total synthesis of a reported topoisomerase I inhibitor and to the formal synthesis of rosettacin. Further extension of this methodology allows the preparation of 10-iodopyrrolo[1,2-b]isoquinolinones by using an excess of halogenating agent and these compounds can be further manipulated through standard Suzuki coupling chemistry into a variety of 10-aryl-substituted pyrrolo[1,2-b]isoquinolinones.

Enantioselective construction of the 8-azabicyclo[3.2.1]octane scaffold: application in the synthesis of tropane alkaloids.

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.

Enantioselective Synthesis of Tropanes: Brønsted Acid Catalyzed Pseudotransannular Desymmetrization.

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.

Catalytic Enantioselective Transannular Morita-Baylis-Hillman Reaction.

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.

Carboxylates as Nucleophiles in the Enantioselective Ring-Opening of Formylcyclopropanes under Iminium Ion Catalysis.

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.

Kinetic Resolution of Secondary Allyl Boronates and Their Application in the Synthesis of Homoallylic Amines.

Highly enantioenriched, chromatographically-stable secondary allyl boronates featuring a 1,1,2,2-tetraethyl-1,2-ethanediol fragment (Epin) were obtained by kinetic resolution of their racemic mixtures. The Epin group at boron considerably improved stability of allyl boronates allowing them to be readily isolated by chromatography on silica. The resolved reagents were applied in stereoselective synthesis of homoallylic amines with an internal double bond employing unprotected imines formed in situ from aldehydes and ammonia. The reactions proceeded with an excellent transfer of chirality.

Organocatalytic Transannular Approach to Stereodefined Bicyclo[3.1.0]hexanes.

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.

Catalytic Enantioselective Cloke-Wilson Rearrangement.

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.

Regioselectivity Change in the Organocatalytic Enantioselective (3+2) Cycloaddition with Nitrones through Cooperative Hydrogen-Bonding Catalysis/Iminium Activation.

The reaction of nitrones with enals through iminium activation can be modulated by using cooperative hydrogen-bonding catalysis to induce the participation of a nitrone ylide (C-N-C) instead of the classical C-N-O dipole. As a consequence, N-hydroxypyrrolidines are obtained, rather than the expected isoxazolidines. The reaction proceeds smoothly and high enantioselectivities are observed in all cases. By using the appropriate substrate, polysubstituted pyrrolidines incorporating quaternary stereocenters can be efficiently prepared.

Enantioselective Oxidative (4+3) Cycloadditions between Allenamides and Furans through Bifunctional Hydrogen-Bonding/Ion-Pairing Interactions.

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.

Mechanistic Insights into the Mode of Action of Bifunctional Pyrrolidine-Squaramide-Derived Organocatalysts.

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,ß-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.

Enantioselective Synthesis of Tertiary Propargylic Alcohols under N-Heterocyclic Carbene Catalysis.

A straightforward procedure to carry out the enantioselective benzoin reaction between aldehydes and ynones by employing a chiral N-heterocyclic carbene (NHC) as catalyst was developed. Under the optimized reaction conditions, these ynones undergo a clean and selective 1,2-addition with the catalytically generated Breslow intermediate, not observing any byproduct arising from competitive Stetter-type reactivity. This procedure allows the preparation of tertiary alkynyl carbinols as highly enantioenriched materials, which have the remarkable potential to be used as chiral building blocks in organic synthesis.

Catalytic enantioselective [5+2] cycloaddition between oxidopyrylium ylides and enals under dienamine activation.

Benzopyrylium ylides generated in situ from 1-acetoxyisochroman-4-ones reacted with α,ß-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 ß,γ-functionalization of the enal. The dienamine intermediates showed exclusive ß,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.

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality.

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.

Gold-catalyzed asymmetric allylic substitution of free alcohols: an enantioselective approach to chiral chromans with quaternary stereocenters for the synthesis of vitamin E and analogues.

The enantioselective synthesis of α- and γ-tocopherol (the most biologically active members of vitamin E family) and analogues has been accomplished employing a new enantioselective gold catalyzed intramolecular allylic alkylation reaction followed by an olefin cross-metathesis as key steps. The methodology proved to be applicable to different olefins highlighting its potential for the synthesis of diverse libraries.

Base-promoted C→N acyl rearrangement: an unconventional approach to α-amino acid derivatives.

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.

Favoring trienamine activation through unconjugated dienals: organocatalytic enantioselective remote functionalization of alkenes.

Unconjugated 2,5-dienals are more reactive substrates than the corresponding fully conjugated α,ß,γ,δ-unsaturated aldehydes towards organocatalytic activation through trienamine intermediates. This difference in reactivity has been demonstrated in the Diels-Alder reaction with nitroalkenes, a reaction that proceeds with clean ß,ε-selectivity to afford the final products in high yields and stereoselectivities, the related polyconjugated 2,4-dienals being completely unreactive.

Ethyl glyoxylate N-tosylhydrazone as sulfonyl-transfer reagent in base-catalyzed sulfa-Michael reactions.

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.