Generation of alkoxysulfonyl radicals from chlorosulfates and their intramolecular capture with alkynes to obtain sultones.

An unprecedented radical-mediated reaction of alkyne-containing chlorosulfates to synthesize sultones has been established. The reaction leads to the formation and subsequent capture of alkoxysulfonyl radicals, which are species known for a long time but not studied for synthetic purposes.

Synthesis of Spirocyclic Compounds by a Ring-Expansion/Cationic Cyclization Cascade Reaction of Chlorosulfate Derivatives.

A novel cascade reaction to prepare spirocarbocyclic compounds from chlorosulfate derivatives has been developed. The process involves an unusual thermal elimination of the chlorosulfate moiety, a ring-expansion reaction, and a subsequent cationic cyclization reaction. Despite the relatively complex skeletal rearrangement, the reaction described here is featured by its operational simplicity, being just a thermal process that does not require additional reagents, catalysts, or additives.

Multicomponent and multicatalytic asymmetric synthesis of furo[2,3-b]pyrrole derivatives: further insights into the mode of action of chiral phosphoric acid catalysts.

Multicomponent and multicatalytic reactions are those processes that try to imitate the way the enzymatic machinery transforms simple building blocks into complex products. The development of asymmetric versions of these reactions is a step forward in our dream of mirroring the exquisite selectivity of biological processes. In this context, the present work describes a new reaction for the asymmetric synthesis of furo[2,3-b]pyrrole derivatives from simple 3-butynamines, glyoxylic acid and anilines in the presence of a dual catalytic system, formed from a gold complex and a chiral phosphoric acid. Computations, aimed to understand the exceptional performance of 9-anthracenyl-substituted BINOL-derived phosphoric acid catalyst, suggest a fundamental role of non-covalent interactions being established between the catalyst and the reagents for the outcome of the multicomponent process. The linear geometry of the anthracenyl substituent along with the presence of an electron-withdrawing group in the aniline and an aromatic substituent in the 3-butynamine derivative seem to be key structural factors to explain the experimental results and, particularly, the high stereoselectivity.

Synthesis of Sultones from Chlorosulfates by a Complex Cascade Reaction Occurring under Mild Thermal Conditions.

Chlorosulfate derivatives are interesting reagents that have been traditionally used to get other sulfur-containing compounds by formal nucleophilic substitution of the chlorine atom. This work describes a different mode of reactivity of alkyne-containing chlorosulfates to get sultones, the sulfur analogues of lactones. The complex skeletal rearrangement observed in this transformation is comparable to those intricate processes promoted or catalyzed by organometallic compounds. However, the reaction here described does not require any reagent or additive, being just a thermal process. Computational calculations support a mechanism based on a series of cascade reactions where almost every step is counterintuitive. Some of these steps include original processes related to classical reactions, thus adding complementary views to traditional organic chemistry.

Unusual Reactivity of Isoquinolinones Generated by Silver-Catalyzed Cycloisomerizations of Imines Derived from ortho-Alkynylsalicylaldehydes.

8-Isoquinolinones derived from a silver-catalyzed cycloisomerization of in situ formed ortho-alkynylsalicylaldimines react with 1 equiv of acetylenedicarboxylate derivatives to give pyrano[2,3,4- ij]isoquinolines through a [4 + 2]-cycloaddition reaction. When 2 equiv of the alkyne are used, structurally complex benzo[ de]chromenes are obtained through an intricate cascade process comprising unusual formal [4 + 2]- and [2 + 2]-cycloadditions followed by several ring-opening and ring-closing processes.

Construction of a diverse set of terpenoid decalin subunits from a common enantiomerically pure scaffold obtained by a biomimetic cationic cyclization.

An unprecedented biomimetic cationic cyclization reaction of an alkyne-containing geraniol-derived epoxide is used for the stereoselective synthesis of a novel enantiomerically pure scaffold that is easily transformed into a set of structurally diverse decalin derivatives with potential application in the synthesis of targeted natural products and/or natural-product-inspired new molecules.

Synthesis of Cyclohexanones through a Catalytic Cationic Cyclization of Alkynols or Enynes.

A novel procedure for the synthesis of cyclohexanones from alkynol or enyne derivatives through a cationic cyclization has been developed. The key points to obtain the six-membered ring derivatives are the use of starting materials containing a terminal alkyne, the use of tetrafluoroboric acid as a promoter of the cationic cyclization, and the appropriate selection of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as solvent. This strategy can be extended to the biomimetic cationic cyclization of several terpene-derived polyenynes.

Synthesis and Applications of Cyclohexenyl Halides Obtained by a Cationic Carbocyclisation Reaction.

The synthesis of cyclic alkenyl halides (mainly fluorides, chlorides and bromides) from alkynol or enyne derivatives by an acid-mediated cationic cyclisation reaction is disclosed. This high-yielding, scalable and technically simple method complements and challenges conventional methodologies. This study includes the development of biomimetic cationic cyclisation reactions of polyenyne derivatives to give interesting halogen-containing polycyclic compounds. The application of this reaction in the key step of the synthesis of two terpenes, namely austrodoral and pallescensin A, and the potent odorant 9-epi-Ambrox demonstrates the potential of the reaction for natural product synthesis.

Nitrogenated Azaphilone Derivatives through a Silver-Catalysed Reaction of Imines from ortho-Alkynylbenzaldehydes.

Nitrogenated azaphilones are interesting natural products with a wide range of applications. The structure of these compounds is characterized by the presence of an isoquinolinone framework. Here, we describe a new multicomponent silver-catalysed reaction that allows the transformation of simple imines derived from ortho-alkynylbenzaldehydes into complex nitrogenated azaphilone-type molecules in a straightforward way. This atom-economical process is high yielding, technically very simple and proceeds through a series of cascade processes that imply cycloisomerisation and formal cross-coupling reactions. This conceptually new process formally involves the synchronised catalytic generation and selective coupling of a nucleophile (isoquinolinone) and an electrophile (isoquinolinium). Some interesting colour properties of the synthesized azaphilone-type molecules are discussed.

Complex chromene derivatives through a silver-catalysed cascade reaction of simple o-alkynylsalicylaldehydes and alkenes.

The silver-catalysed reaction of simple ortho-alkynylsalicylaldehydes and alkenes gives complex benzo[de]chromenyl ketones through an unusual cascade process where the starting ortho-alkynylsalicylaldehyde behaves as a bis-diene derivative that participates in two different formal [4+2]-cycloaddition reactions.

Scalable Synthesis of the Amber Odorant 9-epi-Ambrox through a Biomimetic Cationic Cyclization/Nucleophilic Bromination Reaction.

A novel biomimetic nucleophilic bromocyclization reaction is used in the key step of a new and straightforward synthesis of 9-epi-Ambrox, an organic compound of high interest and value in the context of fragrances. This strategic reaction allows access to 9-epi-Ambrox on a gram scale from a dienyne derivative, easily available from geraniol, following a sequence of seven steps (35% global yield) with just one purification process. Both enantiomers of the molecule were obtained by a challenging enzymatic resolution.

Gold(I)-Catalyzed Generation of the Two Components of a Formal [4+2] Cycloaddition Reaction for the Synthesis of Tetracyclic Pyrano[2,3,4-de]chromenes.

Ortho-Alkynylbenzaldehydes have been widely used to generate isochromenylium derivatives through gold-catalyzed cycloisomerization. These isochromenylium derivatives have been exploited as formal diene derivatives for reactions with different dienophiles. Herein, we describe the behavior of ortho-alkynylsalicylaldehydes, a particular case of ortho-alkynylbenzaldehydes. The gold-catalyzed cycloisomerization of ortho-alkynylsalicylaldehydes delivers an unusual heterodiene derivative that reacts with electron-rich alkenes through a formal [4+2] cycloaddition. In this reaction, both the diene and dienophile are generated in situ through gold-catalyzed cycloisomerization of appropriate alkynamines or alkynols. This reaction was used to synthesize complex tetracyclic pyrano[2,3,4-de]chromenes from two very simple starting materials (an ortho-alkynylsalicylaldehyde and an alkynamine or alkynol) with complete atom economy and with selective formation of bonds, cycles, and stereocenters.

Manganese-Mediated C-H Alkylation of Unbiased Arenes Using Alkylboronic Acids.

The alkylation of arenes is an essential synthetic step of interest not only from the academic point of view but also in the bulk chemical industry. Despite its limitations, the Friedel-Crafts reaction is still the method of choice for most of the arene alkylation processes. Thus, the development of new strategies to synthesize alkyl arenes is a highly desirable goal, and herein, we present an alternative method to those conventional reactions. Particularly, a simple protocol for the direct C-H alkylation of unbiased arenes with alkylboronic acids in the presence of Mn(OAc)3 ⋅2H2 O is reported. Primary or secondary unactivated alkylboronic acids served as alkylating agents for the direct functionalization of representative polyaromatic hydrocarbons (PAHs) or benzene. The results are consistent with a free-radical mechanism.

Exploiting the Multidentate Nature of Chiral Disulfonimides in a Multicomponent Reaction for the Asymmetric Synthesis of Pyrrolo[1,2-a]indoles: A Remarkable Case of Enantioinversion.

A new multicomponent coupling reaction for the enantioselective synthesis of pyrrolo[1,2-a]indoles under the catalysis of a chiral disulfonimide is described. The high specificity of the reaction is a consequence of the multidentate character of the Brønsted acid catalyst. Insights from DFT calculations helped explain the unexpected high enantioselectivity observed with the simplest 3,3'-unsubstituted binaphthyl catalyst as a result of transition-state stabilization by a network of cooperative noncovalent interactions. The remarkable enantioinversion resulting from the simple introduction of substituents at 3- and 3'-positions, the first reported example of this phenomenon in the context of binaphthalene-derived Brønsted acid catalysis, was instead attributed to destabilizing steric interactions.

Synthesis of Cyclic Alkenyl Triflates by a Cationic Cyclization Reaction and its Application in Biomimetic Polycyclizations and Synthesis of Terpenes.

Cyclic alkenyl triflates are useful intermediates in organic synthesis usually synthesized from ketones through a reaction involving enolization and trapping with a triflating agent. This sequence suffers from some stereochemical drawbacks owing to the basic conditions required. Herein, we describe a new acid-mediated cationic cyclization reaction of enyne derivatives (or alkynols) to access cyclic alkenyl triflates. This new atom-economical process is high yielding, scalable, technically very simple, proceeds without the need of any metallic reagent or catalyst, and more importantly, it complements and challenges conventional methodologies. We have also developed new biomimetic cationic cyclization reactions to yield interesting polycyclic compounds. As a demonstration of the potential of this method in the context of total synthesis, we have synthesized two terpenes: austrodoral and pallescensin A. Using the cationic cyclization in the key step of the synthetic routes allowed the synthesis of these natural products in a very simple, concise, scalable, and efficient way.

Stereoselective [3+2] Carbocyclization of Indole-Derived Imines and Electron-Rich Alkenes: A Divergent Synthesis of Cyclopenta[b]indole or Tetrahydroquinoline Derivatives.

An unprecedented stereoselective [3+2] carbocyclization reaction of indole-2-carboxaldehydes, anilines, and electron-rich alkenes to obtain cyclopenta[b]indoles is disclosed. This pathway is different from the well-established Povarov reaction: the formal [4+2] cycloaddition involving the same components, which affords tetrahydroquinolines. Moreover, by simply changing the Brønsted acid catalyst, this multicomponent coupling process could be divergently directed towards the conventional Povarov pathway to produce tetrahydroquinolines or to the new pathway (anti-Povarov) to generate cyclopenta[b]indoles. Supported by computational studies, a stepwise Mannich/Friedel-Crafts cascade is proposed for the new anti-Povarov reaction, whereas a concerted [4+2] cycloaddition mechanism is proposed for the Povarov reaction.

Synthesis of pyrrolidine derivatives by a platinum/brønsted acid relay catalytic cascade reaction.

A new catalytic reaction for the synthesis of pyrrolidine derivatives is presented. The method implies the coupling of N-Boc-protected alkynamine derivatives and appropriate alkenes or alkynes in a process catalysed by a platinum/triflic acid catalytic binary system. This reaction is believed to proceed through a cascade process implying an initial platinum-catalysed cycloisomerization of the alkynamine derivative followed by a triflic acid promoted nucleophilic addition of the alkene or alkyne and trapping of the cationic species formed by the Boc group. Not only simple alkenes and alkynes were used in this reaction but also allyltrimethylsilane and propargyltrimethylsilane. Particularly, when allyltrimethylsilane is used as the alkene counterpart interesting bicyclic compounds containing a trimethylsilane group are obtained. However, when propargyltrimethylsilane is used in the presence of water we observed the formation of a related bicyclic compound lacking the trimethylsilane group and containing an exocyclic carbon-carbon bond.

A fast, efficient and simple method for the synthesis of cyclic alkenyl fluorides by a fluorinative carbocyclization reaction.

A simple transformation of alkynol or enyne derivatives into cyclic alkenyl fluorides by using tetrafluoroboric acid as the proton and fluoride source is reported. This study includes the first biomimetic cationic cyclization/nucleophilic fluorination reaction of polyenyne derivatives to give terpenoid derivatives.

Enantioselective synthesis of spiroacetals: the conquest of a long-sought goal in asymmetric catalysis.

This perspective article briefly outlines the very few and recent methods reported in the literature on catalytic asymmetric synthesis of spiroacetals from achiral substrates.

Catalytic generation and selective heterocoupling of two electron-rich alkenes.

Complex heterocyclic products were synthesized from simple alkynamine and alkynol derivatives in a double cycloisomerization/heterodimerization cascade reaction. The reaction includes the heterocoupling reaction of two different electron-rich alkenes and leads to the formation of four new bonds and three stereocenters (two of them quaternary).