Versatile Synthetic Precursor Research Articles

Gem-Difluoroallene (DFA): an emerging versatile synthetic precursor to enable diverse fluorinated molecules.

Organofluorine compounds are increasingly found in diverse fields, such as pharmaceuticals, agrochemicals, and materials science. gem-Difluoroallenes, which have gem-difluoro alkenes and allenes-like properties, offer a distinct and adaptable platform for novel synthetic transformations. Their distinctiveness is highlighted by various strategies, where the gem-difluoro group's presence plays a pivotal role in successful reactions. This review article presents a comprehensive overview of the latest progress in utilizing gem-difluoroallenes for selective additions, defluorination, as well as cycloaddition and cyclization reactions. We also discuss the limitations and future directions in this area, inspiring further exploration and innovation.

Recent trends in the synthesis and applications of β-iodovinyl sulfones: a decade of progress.

Direct vicinal difunctionalization of π-systems has emerged as a powerful platform for constructing multiple bonds in a single synthetic operation using simple chemical feedstocks. Over the past decade, there has been exponential growth in the direct construction of successive C-S and C-I bonds using a wide variety of sulfonyl and iodide reactants through 1,2-iodosulfonylation of alkynes in a regio- and stereo-selective manner. In this review, we mainly focus on the recent developments in the preparation of β-iodovinyl sulfones and their practical applications in organic synthesis. The most promising photoredox and electrochemical transformations for synthesizing β-iodovinyl sulfones are also reviewed. The multifunctional β-iodovinyl sulfones have recently been burgeoning as versatile synthetic precursors due to the combination of vinyl iodide and vinyl sulfone moieties, essential building blocks for diverse synthetic manipulations. We hereby present the chemistry of β-iodovinyl sulfones, which can be classified into numerous sections based on the sulfonyl surrogates, and potential synthetic approaches are systematically outlined.

Metal‐Free Defluoroborylation of 3,3‐Difluoropropenes

AbstractThe defluorinative functionalization of allylic fluorides represents an attractive approach for the preparation of molecules containing a monofluoroalkene core. In that sense, introducing a “boryl nucleophile” is a powerful strategy to obtain polyvalent borylated intermediates as versatile synthetic precursors. To perform this reaction without the use of transition metals, the nucleophilic character of a diborane/fluoride system was exploited in a SN2′ type‐substitution reaction of gem‐difluoropropenes to install a pinacolborane group. The use of HMDS as a silylated additive is necessary to improve the reactivity. A direct oxidation of the intermediate boronates allowed the isolation of the corresponding β‐fluoroallyl alcohols in low to good yields (9–81 %). Other synthetic transformations of a (2‐fluoroallyl)boronate are also illustrated.

A Universal Organocatalyst for Selective Mono-, Di-, and Triboration of Terminal Alkynes

Multiboronate compounds are valuable synthetic building blocks for the construction of complex organic architectures via cross-coupling chemistry at the C–B bonds. Hence, there has been a tremendous amount of work in the past decades to develop practical multiboration reactions. Many of the developed methods start from alkynes, the most versatile synthetic precursors for multiboronates, and use transition-metal complexes as catalysts. However, several drawbacks such as low efficiency, poor selectivity, and narrow substrate and catalyst scopes remain major challenges to be addressed in this research area. Herein, we report the development of a universal organocatalytic system to promote the mono-, di-, and triboration of terminal alkynes in a highly efficient and selective manner. The reaction outcomes can be manipulated at will by varying the catalyst loading, reagent stoichiometry, and reaction time. A combined computational and experimental mechanistic study offers interesting insights into the selectivity of these sequential reactions.

Visible light-assisted chemistry of vinyl azides and its applications in organic synthesis.

Vinyl azides have emerged as highly versatile precursors in organic synthesis due to their rich reactivity driven by the excellent leaving-group ability of molecular nitrogen. Over the years, significant advancement has been achieved in the manipulation of vinyl azides for the construction of C-C and C-X bonds. Typical methods involve the application of transition metals and strong oxidants for the conversion of vinyl azides into useful compounds employing harsh reaction conditions coupled with intense product purification. In this regard, visible light chemistry has become one of the most exciting fields in organic synthesis for being mild, sustainable, and often orthogonal to conventional approaches. Visible light-induced reactions involving vinyl azides generate either 2H-azirines or iminyl radicals as key intermediates, which may undergo further useful transformations to form the desired cyclic or acyclic products. Herein, we provide the most significant transformations of vinyl azides as versatile synthetic precursors or transient intermediates for compounds of synthetic and biological significance under visible light photocatalysis. We have classified this review into two parts: (i) formation of an iminyl radical intermediate and (ii) formation of 2H-azirine intermediate-based reactions.

Chlorination of arenes via the degradation of toxic chlorophenols

Aryl chlorides are among the most versatile synthetic precursors, and yet inexpensive and benign chlorination techniques to produce them are underdeveloped. We propose a process to generate aryl chlorides by chloro-group transfer from chlorophenol pollutants to arenes during their mineralization, catalyzed by Cu(NO3)2/NaNO3 under aerobic conditions. A wide range of arene substrates have been chlorinated using this process. Mechanistic studies show that the Cu catalyst acts in cooperation with NOx species generated from the decomposition of NaNO3 to regulate the formation of chlorine radicals that mediate the chlorination of arenes together with the mineralization of chlorophenol. The selective formation of aryl chlorides with the concomitant degradation of toxic chlorophenol pollutants represents a new approach in environmental pollutant detoxication. A reduction in the use of traditional chlorination reagents provides another (indirect) benefit of this procedure.

Catalytic Asymmetric Alkynylation of 3,4-Dihydro-β-carbolinium Ions Enables Collective Total Syntheses of Indole Alkaloids.

Chiral tetrahydro-β-carboline (THβC) is not only a prevailing structural feature of many natural alkaloids but also a versatile synthetic precursor for a vast array of monoterpenoid indole alkaloids. Asymmetric synthesis of C1-alkynyl THβCs remains rarely explored and challenging. Herein, we describe the development of two complementary approaches for the catalytic asymmetric alkynylation of 3,4-dihydro-β-carbolinium ions with up to 96 % yield and 99 % ee. The utility of chiral C1-alkynyl THβCs was demonstrated by the collective total syntheses of seven indole alkaloids: harmicine, eburnamonine, desethyleburnamonine, larutensine, geissoschizol, geissochizine, and akuammicine.

Catalytic Asymmetric Alkynylation of 3,4‐Dihydro‐β‐carbolinium Ions Enables Collective Total Syntheses of Indole Alkaloids

AbstractChiral tetrahydro‐β‐carboline (THβC) is not only a prevailing structural feature of many natural alkaloids but also a versatile synthetic precursor for a vast array of monoterpenoid indole alkaloids. Asymmetric synthesis of C1‐alkynyl THβCs remains rarely explored and challenging. Herein, we describe the development of two complementary approaches for the catalytic asymmetric alkynylation of 3,4‐dihydro‐β‐carbolinium ions with up to 96 % yield and 99 % ee. The utility of chiral C1‐alkynyl THβCs was demonstrated by the collective total syntheses of seven indole alkaloids: harmicine, eburnamonine, desethyleburnamonine, larutensine, geissoschizol, geissochizine, and akuammicine.

Metal-Free Twofold Electrochemical C-H Amination of Activated Arenes: Application to Medicinally Relevant Precursor Synthesis.

The efficient production of many medicinally or synthetically important starting materials suffers from wasteful or toxic precursors for the synthesis. In particular, the aromatic non‐protected primary amine function represents a versatile synthetic precursor, but its synthesis typically requires toxic oxidizing agents and transition metal catalysts. The twofold electrochemical amination of activated benzene derivatives via Zincke intermediates provides an alternative sustainable strategy for the formation of new C−N bonds of high synthetic value. As a proof of concept, we use our approach to generate a benzoxazinone scaffold that gained attention as a starting structure against castrate‐resistant prostate cancer. Further improvement of the structure led to significantly increased cancer cell line toxicity. Thus, exploiting environmentally benign electrooxidation, we present a new versatile and powerful method based on direct C−H activation that is applicable for example the production of medicinally relevant compounds.

Synthesis of new ß-lactam- N-(thiazol-2-yl)benzene sulfonamide hybrids: Their in vitro antimicrobial and in silico molecular docking studies

New ß-lactam- N-(thiazol-2-yl) benzene sulfonamide hybrids were synthesized via [2+2] keteneimine cycloaddition (Staudinger reaction) reaction starting from sulfathiazole, a versatilesynthetic precursor. The structures of the newly synthesized compounds were supported by theirspectral data. Some of the newly synthesized compounds exhibited promising antimicrobialactivities against resistant strains. For all newly synthesized compounds, in silico ADME werecalculated and the molecular docking studies were carried out with the target penicillin-bindingprotein 2a (PDB ID: 1VQQ) from a methicillin-resistant S. aureus strain to study good bindinginteractions. In vitro cytotoxicity and haemolysis effects were also evaluated

Visible‐Light‐Induced Selective Defluoroborylation of Polyfluoroarenes, gem‐Difluoroalkenes, and Trifluoromethylalkenes

AbstractFluorinated organoboranes serve as versatile synthetic precursors for the preparation of value‐added fluorinated organic compounds. Recent progress has been mainly focused on the transition‐metal catalyzed defluoroborylation. Herein, we report a photocatalytic defluoroborylation platform through direct B−H activation of N‐heterocyclic carbene boranes, through the synergistic merger of a photoredox catalyst and a hydrogen atom transfer catalyst. This atom‐economic and operationally simple protocol has enabled defluoroborylation of an extremely broad scope of multifluorinated substrates including polyfluoroarenes, gem‐difluoroalkenes, and trifluoromethylalkenes in a highly selective fashion. Intriguingly, the defluoroborylation protocol can be transition‐metal free, and the regioselectivity obtained is complementary to the reported transition‐metal‐catalysis in many cases.

Visible-Light-Induced Selective Defluoroborylation of Polyfluoroarenes, gem-Difluoroalkenes, and Trifluoromethylalkenes.

Fluorinated organoboranes serve as versatile synthetic precursors for the preparation of value-added fluorinated organic compounds. Recent progress has been mainly focused on the transition-metal catalyzed defluoroborylation. Herein, we report a photocatalytic defluoroborylation platform through direct B-H activation of N-heterocyclic carbene boranes, through the synergistic merger of a photoredox catalyst and a hydrogen atom transfer catalyst. This atom-economic and operationally simple protocol has enabled defluoroborylation of an extremely broad scope of multifluorinated substrates including polyfluoroarenes, gem-difluoroalkenes, and trifluoromethylalkenes in a highly selective fashion. Intriguingly, the defluoroborylation protocol can be transition-metal free, and the regioselectivity obtained is complementary to the reported transition-metal-catalysis in many cases.

2-Activated 1,3-enynes in enantioselective synthesis

The rapid enantioselective synthesis of valuable building blocks and pharmaceutically important compounds from easily accessible precursors is one of the major areas of focus in organic chemistry. In this context, 2-activated 1,3-enyne has emerged as a powerful synthon in recent years for the efficient synthesis of enantioenriched furans, allenes, 4-H-pyrans, and 4-isoxazolines, which are privileged scaffolds in bioactive compounds and natural products. This review will cover the history of the development of 2-activated 1,3-enyne in enantioselective synthesis along with the corresponding mechanisms, which may motivate further development in this area to forge more complex and valuable molecules.

A Ru(II) polypyridyl complex bearing aldehyde functions as a versatile synthetic precursor for long-wavelength absorbing photodynamic therapy photosensitizers.

The use of Photodynamic Therapy (PDT) for the treatment of several kinds of cancer as well as bacterial, fungal or viral infections has received increasing attention during the last decade. However, the currently clinically approved photosensitizers (PSs) have several drawbacks, including photobleaching, slow clearance from the organism and poor water solubility. To overcome these shortcomings, many efforts have been made in the development of new types of PSs, such as Ru(II) polypyridyl complexes. Nevertheless, most studied Ru(II) polypyridyl complexes have a low absorbance in the spectral therapeutic window. In this work, we show that, by carefully selecting substituents on the polypyridyl complex, it is possible to prepare a complex absorbing at a much higher wavelength. Specifically, we report on the synthesis as well as in-depth experimental and theoretical characterisation of a Ru(II) polypyridyl complex (complex 3) combining a shift in absorbance towards the spectral therapeutic window with a high 1O2 production. To overcome the absence or poor selectivity of most approved PSs into targeted cells/bacteria, they can be linked to targeting moieties. In this line, compound 3 was designed with reactive aldehyde groups, which can be used as a highly versatile synthetic precursor for further conjugation. As a proof of concept, 3 was reacted with benzylamine and the stability of the resulting conjugate 4 was investigated in DMSO, PBS and cell media. 4 showed an impressive ability to act as a PDT PS with no measurable dark cytotoxicity and photocytotoxicity in the low micromolar range against cancerous HeLa cells from 450 nm up to 540 nm.

Brønsted Acid-Catalyzed Tandem Cyclizations of Tryptamine-Ynamides Yielding 1H-Pyrrolo[2,3-d]carbazole Derivatives.

Ynamides, as versatile synthetic precursors, have attracted much attention from synthetic chemists and sparked the development of a number of methodologies for the construction of various structures. 1H-Pyrrolo[2,3-d]carbazole is a core scaffold of a series of monoterpene indole alkaloids found in Kopsia, Strychnos, and Aspidosperma, for example. In this study, 1H-pyrrolo[2,3-d]carbazole derivatives were synthesized by a Brønsted acid-catalyzed tandem cyclization starting from tryptamine-based ynamides. This strategy prevented Wagner-Meerwein rearrangement by instantaneous intramolecular nucleophilic trapping of the indoleninium to afford a tetracyclic indoline via an in situ-formed enol species induced by the formation of a more stable conjugate diene moiety. The functional group tolerances were investigated by using a series of readily available substrates. A plausible mechanism has been proposed based on the evidence of the capture of the hemiaminal intermediate. Lastly, a Büchi ketone, which is the pivotal intermediate in the synthesis of the indole alkaloid vindorosine, was synthesized by utilizing our newly developed methodology.

Kinetic Resolution of Planar-Chiral (η5-Bromocyclopentadienyl)manganese(I) Complexes by Molybdenum-Catalyzed Asymmetric Ring-Closing Metathesis

Kinetic resolution of racemic planar-chiral (η5-1-alkenyl-2-bromocyclopentadienyl)manganese(I) complexes 1 was realized by the molybdenum-catalyzed asymmetric ring-closing metathesis. While vinyl-Cp derivative 1a was resolved in excellent enantioselectivity with the krel values of up to 127, the selectivity in the ARCM reaction of allyl-Cp derivative 1b was modest (krel = 3.0). ARCM product 2a, which was obtained in an enantiomerically pure form by the two successive ARCM reactions or recrystallization of the enantiomerically enriched products, was found to be a versatile synthetic precursor to various planar-chiral cymantrene derivatives.

D-Ribonolactone, A Versatile Synthetic Precursor of Biologically Relevant Scaffolds

D-Ribonolactone is a carbohydrate derivative of the aldonolactone family which serves as a versatile chiral pool for the total synthesis of natural products such as malayamycin, varitriol, mannostatin, shikimic acid, herbarumins, neplanocins, and many others. Also, the preparation of new C-nucleosides starting from D-ribonolactone has attracted the attention of several groups in the past decade, since this class of molecules is much less amenable to enzymatic and acid-catalyzed hydrolysis than natural and synthetic N-nucleosides. In addition, the extension of the genetic alphabet could produce new combinations of three-letter codons, potentially generating proteins containing nonbiogenic amino acids, resulting in non-natural properties. This review addresses recent methodologies (published in the past two decades) for the preparation of D-ribonolactone and its analogues, as well as their use as building blocks for the synthesis of naturally occurring compounds and biologically relevant entities in the fields of medicinal chemistry and chemical biology. Keywords: D-Ribonolactone, C-nucleosides, Heterocycle, Synthesis, Medicinal Chemistry.

Collective synthesis of humulanolides using a metathesis cascade reaction.

A new method has been developed for the concise and asymmetric synthesis of seven humulanolides in 5-7 steps without the need for protecting groups. Notably, the challenging 11-membered ring and bridged butenolide moieties in asteriscunolide D and 6,7,9,10-tetrahydroasteriscunolide were introduced in one step using a ring-opening/ring-closing metathesis cascade reaction. Asteriscunolide D was used as a versatile synthetic precursor to prepare asteriscunolides A-C via a photoinduced isomerization reaction, asteriscanolide via a unique transannular Michael reaction, and 6,7,9,10-tetradehydroasteriscanolide via a transannular Morita-Baylis-Hillman-type reaction. The unique bicyclo[6.3.0]undecane core was introduced diastereoselectively.

ChemInform Abstract: Cephalosporolide B Serving as a Versatile Synthetic Precursor: Asymmetric Biomimetic Total Syntheses of Cephalosporolides C, E, F, G, and (4‐OMe‐)G.

AbstractCephalosporolide B (I) is efficiently synthesized and exploited for the first time as a versatile biomimetic synthetic precursor for the chemical syntheses of not only cephalosporolides C (II) and G (V) via a challenging diastereoselective oxa‐Michael addition but also the structurally unprecedented cephalosporolides E (III) and F (IV) via a novel biomimetic ring‐contraction rearrangement.

Cephalosporolide B Serving as a Versatile Synthetic Precursor: Asymmetric Biomimetic Total Syntheses of Cephalosporolides C, E, F, G, and (4-OMe-)G

Cephalosporolide B (Ces-B) was efficiently synthesized and exploited for the first time as a versatile biomimetic synthetic precursor for the chemical syntheses of not only cephalosporolides C, G, and (4-OMe-) G via a challenging diastereoselective oxa-Michael addition but also the structurally unprecedented cephalosporolides E and F via a novel biomimetic ring-contraction rearrangement. These findings provide the first direct chemical evidence that Ces-B may be the true biosynthetic precursor of cephalosporolides.