ABSTRACT
Cu-catalyzed asymmetric allylic borylation of 3,3'-disubstituted 1-vinylcyclobutan-1-ols renders axially chiral allylborane systems, with high asymmetric induction for both enantiomers, by precise selection of the cis or trans substrate. The enantioenriched alkylidenecyclobutanes served as chiral platform to prove the conceptually challenging transference of the axial-to-point chirality through two new stereocenters and one pseudoasymmetric carbon generated via diastereoconvergent allylation of aldehydes, without enantioselective erosion.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Acids , Stereoisomerism , CatalysisABSTRACT
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.
Subject(s)
CatalysisABSTRACT
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.
Subject(s)
Biological Products , Catalysis , Biological Products/chemistry , Chemistry, PharmaceuticalABSTRACT
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.
ABSTRACT
Medium-sized carbocycles containing an α,ß-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 %â ee.
ABSTRACT
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.
Subject(s)
Tropanes/chemistry , Tropanes/chemical synthesis , Alkenes/chemistry , Catalysis , Chemistry Techniques, Synthetic , Hydrogen-Ion Concentration , StereoisomerismABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
BINOL-based N-trifluoromethanesulfonyl phosphoramides catalyze the enantioselective (4+3) cycloaddition between furans and oxyallyl cations, the latter being generated inâ 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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
We have discovered that N-alkyl aminomalonates undergo a fast and selective intramolecular CâN 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.