Stereoselective Approach Research Articles

Escape from Flatland: Stereoselective Synthesis of Hexa‐aryl Borazines and their sp²‐Based 3D Architectures

Borazine and its derivatives can be considered critical doping units for engineering hybrid C(sp2)‐based molecules with tailored optoelectronic properties. Herein, we report the first synthesis of hexaarylborazines that, bearing ortho‐substituted aryl moieties, extend three‐dimensionally. Using a one‐pot protocol, we first form an electrophilic chloroborazole and then react it with an aryl lithium (ArLi). By selecting the appropriate ortho‐substituent, we can guide the ArLi to add to the BN‐core in a specific way, ultimately controlling the stereochemical outcome of the three‐substitution reaction. Rationalization of the stereochemical model through computational analysis allowed us to show that when aryl lithium nucleophiles bearing rigid long‐range ortho‐substituents are used, i.e., stiff substituents. The ortho‐substituent shields its side of the electrophilic B3N3 core, biasing the incoming ArLi to add anti at each addition step, forming the final tri‐aryl borazine exclusively as cc‐isomer. Leveraging this stereoselective approach, prototypical multichromophoric borazine derivatives were prepared, and we showcased how the stereochemical arrangement of these chromophores distinctly influences their redox behavior. This methodology paves the way for previously inaccessible borazines to serve as privileged precursors to transcend the conventional bidimensionality associated with graphenoid systems and pioneer the construction of new forms of three‐dimensional C(sp2)‐based architectures.

Escape from Flatland: Stereoselective Synthesis of Hexa-aryl Borazines and their sp²-Based 3D Architectures.

Borazine and its derivatives can be considered critical doping units for engineering hybrid C(sp2)-based molecules with tailored optoelectronic properties. Herein, we report the first synthesis ofhexaarylborazines that, bearingortho-substituted aryl moieties, extend three-dimensionally.Using a one-pot protocol, we first form an electrophilic chloroborazole and then react it with an aryl lithium (ArLi). By selecting the appropriateortho-substituent, we can guide the ArLi to add to the BN-core in a specific way, ultimately controlling the stereochemical outcome of the three-substitution reaction. Rationalization of the stereochemical model through computational analysis allowed us to show thatwhen aryl lithium nucleophiles bearing rigid long-rangeortho-substituentsare used,i.e.,stiff substituents. Theortho-substituent shields its side of the electrophilic B3N3core, biasing the incoming ArLi to addantiat each addition step, forming the final tri-aryl borazine exclusively ascc-isomer.Leveraging this stereoselective approach, prototypical multichromophoric borazine derivatives were prepared, and we showcased how the stereochemical arrangement of these chromophores distinctly influences their redox behavior.This methodology paves the way for previously inaccessible borazines to serve asprivileged precursorsto transcend the conventional bidimensionality associated with graphenoid systems and pioneer the construction of new forms of three-dimensional C(sp2)-based architectures.

Manganese‐Catalyzed Three‐Component Vinylation of Phosphines with Sulfones and Alcohols

AbstractHerein, we report a manganese‐catalyzed three‐component vinylation strategy for the synthesis of vinylphosphines from readily available alcohols, sulfones, and phosphines via acceptorless dehydrogenative strategy. This multi‐component, four‐stage, one‐pot protocol offers a stereoselective approach, overcoming the challenges associated with achieving these products through the hydrophosphination of terminal alkynes. The reaction utilizes sulfones and common alcohols to access both (E)‐β‐substituted vinylphosphines (using methanol) and α‐substituted vinylphosphines (using primary alcohols) in yields ranging from 52% to 99%, with E:Z stereoselectivity of 95:5 to 99:1. Importantly, the synthesized branched‐substituted vinylphosphines exhibited superior ligand performance in the copper‐catalyzed cross‐coupling of aryl bromides with pyrazole compared to the commercially available PPh3 and diphenyl(vinyl)phosphane.

A Linear and Stereoselective Approach for the Synthesis of Dapoxetine from Benzaldehyde

Abstract: In addition to providing a succinct pathway for the stereoselective synthesis of dapoxetine, a potent SSRI employed in the treatment of premature ejaculation, this study highlights the strategic use of Ellman's sulfinamide as a chiral auxiliary. The key method involves the diastereoselective allylation of (S,E)-N-Benzylidenesulfinamide, resulting in the desired S-configuration critical for the pharmacological activity of dapoxetine. The utilization of readily available benzaldehyde as the starting material and 1-naphthol as a late-stage coupling partner contributes to the economic feasibility of the synthesis. Especially, the linear synthetic approach adopted in this study employs simplified and more efficient protocols for various transformations, culminating in an overall yield of 26%. This research not only presents a practical synthetic route for dapoxetine, but also underscores the importance of cost-effective and streamlined methodologies in drug development processes.

Versatile Two-Step Catalytic Stereoselective Approach to Chiral anti-2,4-Tetrahydrofuran Derivatives

Versatile Two-Step Catalytic Stereoselective Approach to Chiral anti-2,4-Tetrahydrofuran Derivatives

Stereoselective Approach to the Core Structure of (+)-Phainanoid A via Strategically Engineered Cascade Polyene Cyclization.

Stereoselective synthesis of 3b and its cascade polyene cyclization to 18b have been described. Acyclic polyene 3b was prepared from allyl bromide 4 and 1,3-dithiane 5, and intermediates 4 and 5 were synthesized from the commercially available geraniol (6) and cyclopenten-2-one (8), respectively, using enantioselective reduction of ketone, Johnson-Claisen rearrangement, and the Suzuki reaction as key steps. Au(I)-mediated diastereoselective polyene cyclization of 3b efficiently afforded tetracyclic compound 18b.

An alternative total synthesis of Aigialomycin D

Aigialomycin D, a 14-membered benzannulated macrolactone, was synthesized in a simple, efficient and stereoselective approach using inexpensive and commonly accessible starting materials. The main steps in this convergent synthesis are Corey-Fuchs reaction, Yamaguchi esterification and ring closing metathesis (RCM).

Humilisin E: Strategy for the Synthesis and Access to the Functionalized Bicyclic Core.

Humilisin E is a diterpenoid possessing a rare epoxidized cyclononene trans-fused with a bicyclo[3.2.0]heptane core. We have identified the P atropisomer of the corresponding cyclononadiene as a potential biosynthetic/synthetic precursor to humilisin E and reported two different strategies for the stereocontrolled synthesis of the appropriately functionalized bicyclic cores of humilisin E. The first route involves a Stork epoxynitrile cyclization via a Mg alkoxide, and the second, more stereoselective approach utilizes the Wolff rearrangement as the key step.

Reaction Pattern and Mechanistic Aspects of Iodine and Iodine-Based Reagents in Selenylation of Aliphatic, Aromatic, and (Hetero)Cyclic Systems.

Organoselenium compounds have been the subject of extensive research since the discovery of the biologically active compound ebselen. Ebselen has recently been found to show activity against the main protease of the virus responsible for COVID-19. Other organoselenium compounds are also well-known for their diverse biological activities, with such compounds exhibiting interesting physical properties relevant to the fields of electronics, materials, and polymer chemistry. In addition, the incorporation of selenium into various organic molecules has garnered significant attention due to the potential of selenium to enhance the biological activity of these molecules, particularly in conjunction with bioactive heterocycles. Iodine and iodine-based reagents play a prominent role in the synthesis of organoselenium compounds, being valued for their cost-effectiveness, non-toxicity, and ease of handling. These reagents efficiently selenylate a broad range of organic substrates, encompassing alkenes, alkynes, and cyclic, aromatic, and heterocyclic molecules. They serve as catalysts, additives, inducers, and oxidizing agents, facilitating the introduction of different functional groups at alternate positions in the molecules, thereby allowing for regioselective and stereoselective approaches. Specific iodine reagents and their combinations can be tailored to follow the desired reaction pathways. Here, we present a comprehensive review of the progress in the selenylation of organic molecules using iodine reagents over the past decade, with a focus on reaction patterns, solvent effects, heating, microwave, and ultrasonic conditions. Detailed discussions on mechanistic aspects, such as electrophilic, nucleophilic, radical, electrochemical, and ring expansion reactions via selenylation, multiselenylation, and difunctionalization, are included. The review also highlights the formation of various cyclic, heterocyclic, and heteroarenes resulting from the in situ generation of selenium intermediates, encompassing cyclic ketones, cyclic ethers, cyclic lactones, selenophenes, chromones, pyrazolines, pyrrolidines, piperidines, indolines, oxazolines, isooxazolines, lactones, dihydrofurans, and isoxazolidines. To enhance the reader's interest, the review is structured into different sections covering the selenylation of aliphatic sp2/sp carbon and cyclic sp2 carbon, and then is further subdivided into various heterocyclic molecules.

Unveiling the mechanism and regioselectivity of the [3 + 2] cycloaddition reaction between N-methylphenylnitrone and 1-sulphonyl-1-trifluoromethylallene. A MEDT study

The present study reports within the molecular electron density theory the mechanism and the selectivity of the [3 + 2] cycloaddition (32CA) reaction between an N-methyl-phenylnitrone (nitrone 5) toward the poorest electrophile1-sulphonyl-1-trifluoromethylallene (allene 6) using DFT method at the B3LYP/6-31G(d) theoretical level. Four reactive pathways associated with the ortho and meta regioselective channels and endo and exo stereoselective approaches modes have been explored and characterised. While the formation of the meta/exo cycloadduct as the major isomer proceeds via a stepwise mechanism with the participation of zwitterion intermediate. Whereas, the other three pathways follow a one-step mechanism, the conceptual DFT reactivity indices analysis explains correctly the polar character of this 32CA reaction, and the local Parr functions analysis enables us to explain the meta-regioselectivity observed experimentally. The presence of both trifluromethyl and sulphonyl as electron-withdrawing groups increase markedly the reactivity of the allene and produces the meta selectivity. The inclusion of the solvent effects does not modify the obtained gas-phase selectivities but slightly increases the activation energies as well as the meta-exo stereoselectivity. QTAIM analyse reveal that the presence of significant numbers of conventional and non-conventional interactions at both TSs of the most favourable meta channel is responsible for the complete regioselectivity observed experimentally at this 32CA reaction.

Why Is Thiol Unexpectedly Less Reactive but More Selective Than Alcohol in Phenanthroline-Catalyzed 1,2-cis O- and S- Furanosylations?

The lack of catalytic stereoselective approaches for producing 1,2-cis S-furanosides emphasizes the critical need for further research in this area. Herein, we present a stereoselective S-furanosylation method, utilizing a 4,7-dipiperidine-substituted...

A New Stereoselective Approach to the Substitution of Allyl Hydroxy Group in para-Mentha-1,2-diol in the Search for New Antiparkinsonian Agents.

Two approaches to the synthesis of para-menthene epoxide ((1S,5S,6R)-4) are developed. The first approach includes a reaction between chlorohydrin 7 and NaH in THF. The second involves the formation of epoxide in the reaction of corresponding diacetate 6 with sodium tert-butoxide. One possible mechanism of this reaction is proposed to explain unexpected outcomes in the regio- and stereospecificity of epoxide (1S,5S,6R)-4 formation. The epoxide ring in (1S,5S,6R)-4 is then opened by various S- and O-nucleophiles. This series of reactions allows for the stereoselective synthesis of diverse derivatives of the monoterpenoid Prottremine 1, a compound known for its antiparkinsonian activity, including promising antiparkinsonian properties.

A Biomimetic Stereoselective Approach to Euolutchuol C and Its Structural Assignment

AbstractThe first stereoselective total synthesis of euolutchuol C using a biomimetic cationic polyene cyclization is demonstrated, and its absolute structure has been established. Four potential stereoisomers of euolutchuol C were synthesized to confirm the structure as an aromatic abietane diterpenoid consisting of 15(S)‐stereogenic center. Asymmetric Sharpless dihydroxylation was employed to construct the chiral epoxide, while CBS‐reduction was utilized for enantiomerically pure benzylic alcohols. A convergent approach is used to synthesize euolutchuol C in seven longest linear steps to give an overall yield of 23 %.

Stereoselective Approach to Multisubstituted Enolates from Unactivated Alkynes: Oxyalkylidenation of Alkynyl Ketone Enolates with Aldehydes.

The preparation of multisubstituted enolates with precise regio- and stereocontrol is a nontrivial task when conventional deprotonation methods are used on the corresponding carbonyl compounds. We describe herein an approach to preparing stereodefined enolates by leveraging the stereoselective oxyfunctionalization of unactivated alkynes, particularly in the context of the alkynylogous aldol reaction. trans-Iodo(III)acetoxylation of alkynes and subsequent Sonogashira coupling allow for the facile preparation of multisubstituted enynyl acetates, which can be deacetylated by MeLi into the corresponding enolates. The alkynyl enolates react with aldehydes to afford γ,δ-unsaturated β-diketones through a cascade of alkynylogous aldol addition, intramolecular Michael addition, and ring opening of the oxetene intermediate.

2‐Ketophenyl Assisted Biomimetic Synthesis of 3‐Thio Substituted Glycals at Room Temperature

AbstractHerein we designed a strategy for the synthesis of regioselective and stereoselective displacement of C‐3 acetate group in the presence of other C‐4 and C‐6 acetate of 2‐ketophenyl‐glycal by different aromatic and cyclic aliphatic thiol nucleophiles taking inspiration from cytosolic esterase mediated thiolation of glucosamine sugars into cellular glycan. Under a mild base condition at room temperature, the protocol generated a library of 3‐arylthiosugars with excellent yields and high axial selectivity. This stereoselective approach tolerated well with different ester‐protected glycals and thiophenols, aliphatic cyclic thiols, and mercaptans. A variety of control experiments were conducted to establish the mechanism and reason behind the stereoselectivity.

Stereoselective Approach to Hydroxyalkyl-1,2,3-triazoles Containing Cyclooctane Core and Their Use for CuAAC Catalysis

1,2,3-Triazoles bearing additional functional groups have found applications as the ligands in catalysis of a broad scope of reactions, synthesis of transition metals complexes for various practicable purposes, and design of metal-based drugs. Triazolyl ligands accelerating CuAAC reactions, such as TBTA and TTTA, are nowadays commonly used in organic synthesis, and the search for novel ligands with a less complicated structure represents an important task. In the present work a series of hydroxyalkyltriazoles, containing a cyclooctane core, were synthesized via cycloaddition of readily available individual diastereomers of azidoalcohols or diazidodiols with phenylacetylene. The obtained hydroxyalkyltriazoles were probed as ligands for CuAAC reactions of benzyl azide with acetylenes, and 1-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cyclooctanol was demonstrated to act as an effective ligand for these processes. The complex salt of the abovementioned triazole and CuCl2 was readily obtained. According to X-ray diffraction analysis data, the complex contained two molecules of triazole, in which only N1-atoms of the triazole ring acted as coordination centers. Such a molecular structure correlates well with the efficiency of 1-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cyclooctanol as a ligand in CuAAC reactions: it is able to coordinate copper ions and, at the same time, it forms a sufficiently labile complex to not withdraw copper ions from the catalytic cycle.

Total Synthesis of GE81112A: An Orthoester-Based Approach.

The GE81112 series, consisting of three naturally occurring tetrapeptides and synthetic derivatives, is evaluated as a potential lead structure for the development of a new antibacterial drug. Although the first total synthesis of GE81112A reported by our group provided sufficient amounts of material for an initial in depth biological profiling of the compound, improvements of the routes toward the key building blocks were needed for further upscaling and structure-activity relationship studies. The major challenges identified were poor stereoselectivity in the synthesis of the C-terminal β-hydroxy histidine intermediate and a concise access to all four isomers of the 3-hydroxy pipecolic acid. Herein, we report a second-generation synthesis of GE81112A, which is also applicable to access further representatives of this series. Based on Lajoie's ortho-ester-protected serine aldehydes as key building blocks, the described route provides both a satisfactory improvement in stereoselectivity of the β-hydroxy histidine intermediate synthesis and a stereoselective approach toward both orthogonally protected cis and trans-3-hydroxy pipecolic acid.

Understanding the mechanism and regio- and stereo selectivity of [3 + 2] cycloaddition reactions between substituted azomethine ylide and 3,3,3-trifluoro-1-nitroprop-1-ene, within the molecular electron density theory.

The selectivity and the nature of the molecular mechanism of the [3 + 2] cycloaddition (32CA) reaction between 2-(dimethylamino)-1H-indene-1,3(2H)-dione (AY11) and trans(E)-3,3,3-trifluoro-1-nitroprop-1-ene(FNP10) has been studied, in which the molecular electron density theory using density functional theory methods at the MPWB1K/6-31G(d) computational level was used. Analysis of the global reactivity indices permits us to characterize FNP10 as a strong electrophile and AY11 as a strong nucleophile. Four reactive pathways associated with the ortho/meta regioselective channels and endo/exo stereoselective approaches modes have been explored and characterized in the gas phase and in the benzene solvent. The analysis of the relative energies associated with the different reaction pathways indicates that the 32CA reactions of the azomethine ylide (AY) with the nitroalkene (FNP) is meta regioselective with high endo stereoselectivity. This result is in good agreement with the experimental observations. electron localization function topological analysis of the most favored reactive pathways allows for characterizing the mechanism of this 32CA reactions as a non-concerted two-stage one-step mechanism. Finally, non-covalent interactions and quantum theory of atoms in molecule analyses at the meta/endo transition state structure indicate that the presence of different several weak interactions, namely, CF and NH contributed in favoring the formation of a meta-endo cycloadduct.

Catalytic Stereoselective Multicomponent Reactions for the Synthesis of Spiro Derivatives: Recent Progress

AbstractSpiro derivatives are important scaffolding substances found in many natural products and pharmaceuticals. In the last decade, numerous new approaches based on multicomponent reactions have been explored for the selective and efficient development of new spiro derivatives using various organocatalytic and transition metal‐based catalytic systems. This Review discusses pioneering advances in the field of catalytic stereoselective multicomponent reactions for the preparation of various spiro derivatives. These include stereoselective Michael cascade cyclization reactions, cycloadditions, diastereoselective reactions, and miscellaneous reactions for the synthesis of spiro‐hetero/carbocycles. Advances in the last decade have made it possible to synthesize various spiro compounds with good to excellent stereoselectivity under appropriate reaction conditions. However, achieving high regioselectivity in several described multicomponent reactions remains a challenge. Organocatalysts and transition‐metal‐based catalysts play a crucial role in achieving this milestone. Proposed catalytic mechanisms and supporting evidence are highlighted in this Review. The progress described in catalytic stereoselective approaches for spiro derivatives is immense. However, it is expected that new stereoselective synthetic methods will soon be developed that can be widely used for the preparation of spiro‐heterocycles/carbocycles.

Ligand-enabled stereodivergence in nickel-catalyzed regioselective hydroboration of internal allenes

•Regio- and stereoselective hydroboration of internal allenes •Stereodivergent synthesis of trisubstituted alkenylboronates •Isolation and characterization of nickel-allene and nickel-olefin intermediates •In-depth mechanistic and kinetic studies Developing protocols for stereodivergent synthesis of multi-substituted alkenylboronates will simplify and unify the synthesis of Z- and E-stereoisomers of multi-substituted alkenes. Although tremendous efforts have been made to devise stereoselective approaches to access Z- or E-alkenylboronates, catalyst-controlled stereodivergence in their synthesis remains extremely rare. Herein, we demonstrate that such stereodivergence can be achieved for nickel-catalyzed hydroboration of internal allenes, which enables convenient synthesis of both stereoisomers of trisubstituted alkenylboronates from the same starting reagents. Mechanistic studies reveal that these nickel-catalyzed allene hydroboration reactions do not follow conventional hydrometallation or borylmetallation pathways with metal-hydride or metal-boryl intermediates. On the basis of the synthesis of potential nickel intermediates and their stoichiometric reactions, we propose new pathways for this nickel-catalyzed allene hydroboration, involving initial complexation of allenes to low-valent nickel catalysts followed by the stereo-determining reaction of bisphosphine-ligated nickel-allene intermediates with pinacolborane (HBpin) to form nickel-olefin compounds, which contain coordinated Z- or E-alkenylboronates. Developing protocols for stereodivergent synthesis of multi-substituted alkenylboronates will simplify and unify the synthesis of Z- and E-stereoisomers of multi-substituted alkenes. Although tremendous efforts have been made to devise stereoselective approaches to access Z- or E-alkenylboronates, catalyst-controlled stereodivergence in their synthesis remains extremely rare. Herein, we demonstrate that such stereodivergence can be achieved for nickel-catalyzed hydroboration of internal allenes, which enables convenient synthesis of both stereoisomers of trisubstituted alkenylboronates from the same starting reagents. Mechanistic studies reveal that these nickel-catalyzed allene hydroboration reactions do not follow conventional hydrometallation or borylmetallation pathways with metal-hydride or metal-boryl intermediates. On the basis of the synthesis of potential nickel intermediates and their stoichiometric reactions, we propose new pathways for this nickel-catalyzed allene hydroboration, involving initial complexation of allenes to low-valent nickel catalysts followed by the stereo-determining reaction of bisphosphine-ligated nickel-allene intermediates with pinacolborane (HBpin) to form nickel-olefin compounds, which contain coordinated Z- or E-alkenylboronates.