Rearrangement Cascade Reaction Research Articles

Synthesis of Cyclic β-Amino Acid Derivatives by Desymmetrization and Lossen Rearrangement of N-Sulfoxy Meso-Succinimides.

Bifunctional thiourea-based organocatalysts facilitate an enantioselective desymmetrization and Lossen rearrangement cascade reaction of N-sulfoxy meso-succinimides, resulting in the synthesis of cyclic β-amino acid derivatives. This catalytic system was optimized for bicyclic and tricyclic succinimide substrates affording yields from 61-91% and up to 96:4 er. This reaction proceeds via the group selective addition of the primary alcohol nucleophile to an enantiotopic carbonyl group with sequential rearrangement of the intermediate O-sulfonyl hydroxamate ester.

Novel Stereo-Induction Pattern in Pudovik Addition/Phospha-Brook Rearrangement Towards Chiral Trisubstituted Allenes.

Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide-mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha-Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central-to-axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo-induction pattern in the Pudovik addition/phospha-Brook rearrangement cascade reaction.

Novel Stereo‐Induction Pattern in Pudovik Addition/Phospha‐Brook Rearrangement Towards Chiral Trisubstituted Allenes

AbstractDespite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al., there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide‐mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha‐Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central‐to‐axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo‐induction pattern in the Pudovik addition/phospha‐Brook rearrangement cascade reaction.

Direct synthesis of sila-benzoazoles through hydrosilylation and rearrangement cascade reaction of benzoazoles and silanes

Sila-isosteres have attracted increasing attention due to their potential application in a variety of fields and their different properties compared to their carbon-containing analogs. However, the preparation of these silicon-containing compound remains challenging and thus the development of alternative synthetic methodologies is desirable. Here, we employ B(C6F5)3 as catalyst to enable the synthesis of highly functionalized sila-benzoazoles via hydrosilylation and rearrangement cascade reaction of benzoazoles and commercially available silanes. This strategy also exhibits remarkable features such as 100% atom-economy, good functional group tolerance, broad substrate scope, easy scale-up and good catalytic performance, demonstrating its potential application in sila-isostere synthesis.

Divergent Total Syntheses of (-)-Crinipellins Facilitated by a HAT-Initiated Dowd-Beckwith Rearrangement.

A hydrogen atom transfer (HAT)-initiated Dowd-Beckwith rearrangement reaction was developed, which enables the efficient assembly of diversely functionalized polyquinane frameworks. By incorporation of an iridium-catalyzed regio- and enantioselective hydrogenation and a diastereocontrolled ODI-[5+2] cycloaddition/pinacol rearrangement cascade reaction, the asymmetric total syntheses of eight tetraquinane natural products, including (-)-crinipellins A-F and (-)-dihydrocrinipellins A and B, have been achieved in a concise and divergent manner.

Electrochemical ODI-[5+2] Cascade for the Syntheses of Diversely Functionalized Bicyclo[3.2.1]octane Frameworks.

A metal- and hypervalent iodine reagent-free electrochemical oxidative dearomatization-induced [5+2] cycloaddition/pinacol rearrangement cascade reaction was described. The electrosynthetic method showed strong tolerance for vinylphenols, ethynylphenols, and allenylphenols, which thus enabled the rapid assembly of diversely functionalized bicyclo[3.2.1]octanes in 41-95% yields and up to >20:1 dr. This protocol could be scaled up to gram amounts and should find wide application in complex natural product synthesis.

Tetracyclic Diterpenoid Synthesis Facilitated by ODI-Cascade Approaches to Bicyclo[3.2.1]octane Skeletons.

Tetracyclic diterpenoids (C20) mainly refer to the plant terpenoids bearing biogenetically related carbon skeletons derived from copalyl diphosphates (ent-CPP and syn-CPP). This large family contains over 1600 known members that can be categorized into 11 major structural types. Among them, more than three-quarters share a bridged bicyclo[3.2.1]octane subunit, which is also an important branching point in biosynthesis en route to the other types of bicyclic scaffolds, such as bicyclo[2.2.2]-, bicyclo[3.3.0]-, and tricyclo[3.2.1.0]octanes. Combined with the significance of its stereochemical importance in biological activity, the assembly of the bicyclo[3.2.1]octane skeletons is critical to the success of the whole synthesis blueprint toward tetracyclic diterpenoids. Although a number of inspiring methodologies have been disclosed, general approaches by the incorporation of innovative cascade reactions permitting access to diverse structural types of tetracyclic diterpenoids remain limited and in urgent demand.Because of the long-standing interest in the synthesis of bridged diterpenoids, we have recently developed two complementary types of oxidative dearomatization induced (ODI) cascade approaches to the rapid and efficient construction of bicyclo[3.2.1]octane skeletons. In this Account, we summarize our original synthesis design, methodology development, and the application of these two strategies in tetracyclic diterpenoid synthesis during the past few years in our laboratory.First, we detail our preliminary investigation of the ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade reaction, which showed a wide scope of vinylphenol substrates and led to cyclopentane and cyclohexane-fused bicyclo[3.2.1]octanes in good yields with excellent dr values. Next, we describe the utilization of this ODI-[5 + 2] cascade reaction which resulted in the asymmetric total syntheses of four highly oxygenated ent-kauranoids. The strategy concerning accurate stereochemical control in the ODI-[5 + 2] cycloaddition was then successfully transplanted to the total syntheses of three stemaranoids, thus providing a straightforward and diastereoselective route to C9-ethano-bridged tetracyclic diterpenoids. To access more complex diterpenoid rhodomollanol A, we exploited two additional biomimetic rearrangements, namely, the retro-Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade and the photo-Nazarov cyclization/intramolecular cycloetherification cascade. Taken together with the ODI-[5 + 2] cascade, the asymmetric total synthesis of the target molecule was realized, which shed light on the biogenetic pathway of the unprecedented rhodomollane-type carbon framework. Finally, we describe an ODI-Diels-Alder/Beckwith-Dowd cascade approach as a valuable supplement to the ODI-[5 + 2] cascade for the fabrication of cycloheptane-fused bicyclo[3.2.1]octane skeletons. Its versatility was also demonstrated by the total syntheses of two challenging grayanane diterpenoids. In view of the high functional-group compatibility and scalability, we anticipate that the two novel cascade approaches will find further use in the field of complex natural product synthesis.

Chemoselective Rearrangement Reactions of Sulfur Ylide Derived from Diazoquinones and Allyl/Propargyl Sulfides.

Here, we describe three types of rearrangement reactions of sulfur ylide derived from diazoquinones and allyl/propargyl sulfides. With Rh2(esp)2 as the catalyst, diazoquinones react with allyl/propargyl sulfides to form a sulfur ylide, which undergoes a chemoselective tautomerization/[2,3]-sigmatropic rearrangement reaction, a Doyle-Kirmse rearrangement/Cope rearrangement cascade reaction, or a Doyle-Kirmse rearrangement/elimination reaction, depending on the substituent of the sulfides. The protocol provides alkenyl and allenyl sulfides and multisubstituted phenols with moderate and high yields.

Highly selective discrimination of cysteine from glutathione and homo-cysteine with a novel AIE-ESIPT fluorescent probe

Biothiols, including cysteine (Cys), homocysteine (Hcy) and glutathione (GSH), play pivotal roles in numerous physiological events, however, due to the similar structures and reactivities, differentiation of these biothiols remains a challenging task. Herein, we reported a maleimide-appended fluorescent probe ABTT-MA capable of specific sensing of Cys over other structure-alike biothiols with an ultralow detection limit (9.4 nM). Via a series of investigations into the mechanism, the high selectivity toward Cys is ascribed to a Michael addition/S,N-intramolecular rearrangement cascade reaction, in which the involvement of the mercapto and the adjacent amino groups is necessary to proceed the sensing process. Given this presupposition, Cys could be kinetically discriminated from Hcy and GSH. Upon the addition of Cys, a strong fluorescence appeared and the intensity at 503 nm was correlated with Cys concentration linearly over a wide range (0–10 μM). Thanks to the aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT) activity, the selective detection of Cys was realized not only in aqueous media but in the paper-based point-of-care test (POCT). Significantly, the practicability of ABTT-MA in exogenous and endogenous Cys imaging in living cells was elucidated as well.

Highly Selective Fluorescent 4-(4-(Diethylamino)-2-Hydroxystyryl)-1-Methylpyridine Iodide and Nitrobenzofurazan Based Probe for Cysteine with Application in Living Cells

Biological thiols, such as homocysteine, cysteine, and glutathione play key roles in physiological processes. However, due to the similarity of their structures and chemical properties, it has been a challenge to distinguish these compounds. In this work, a new fluorescent probe (E)-4-(4-(diethylamino)-2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)oxy) styryl)-1-methylpyridine iodide (Y-OH-NBD) is reported for the determination of cysteine. Based on the nucleophilic aromatic substitution and rearrangement cascade reaction, Y-OH-NBD was demonstrated to be a selective turn-on fluorescence probe for cysteine without interferences and probe consumption caused by high concentration of glutathione in phosphate buffer pH 7.4 containing 5% dimethyl sulfoxide. The Y-OH-NBD system determined cysteine with a response time of less than 5 min and a low limit of detection equal to 1.88 µM. Moreover, the probe showed low cytotoxicity and was conveniently applied to image intracellular cysteine in HeLa cells, indicating its significant potential biological applications.

Synthesis of γ‐Spirolactams from Blaise Reaction Intermediates and 1,2‐Dicarbonyl Compounds

AbstractA intermolecular nucleophilic addition/pinacol rearrangement cascade reaction of 1,2‐dicarbonyl compounds and Blaise reaction intermediates has been developed. This highly efficient transformation enables the quick construction of γ‐spiro lactams in a single operation with moderate to good yields as well as mild reaction condition.

Synthesis of ortho-Phenolic Sulfilimines via an Intermolecular Sulfur Atom Transfer Cascade Reaction.

To expand the toolbox for the synthesis of ortho-phenolic sulfilimines, sigmatropic rearrangements were introduced to the field of sulfilimine chemistry. Herein we report a N-H sulfenylation/[2,3]-sigmatropic rearrangement cascade reaction. This mild reaction enables commercially available thiols to serve as the sulfenylation reagent and generates water as the sole byproduct. Moreover, the reaction has a wide substrate scope and can be conducted on a gram scale with excellent reaction efficiency.

Synthesis of indoline-piperidinonesviaa novel Ugi, ring expansion,pseudo-Dieckmann condensation and rearrangement cascade reaction

Synthesis of functionalized indoline-piperidinones through an Ugi, ring expansion,pseudo-Dieckmann and rearrangement cascade reaction in one-pot.

Rearrangement of Hydroxylated Pinene Derivatives to Fenchone-Type Frameworks: Computational Evidence for Dynamically-Controlled Selectivity.

An acid-catalyzed Prins/semipinacol rearrangement cascade reaction of hydroxylated pinene derivatives that leads to tricyclic fenchone-type scaffolds in very high yields and diastereoselectivity has been developed. Quantum chemical analysis of the selectivity-determining step provides support for the existence of an extremely flat potential energy surface around the transition state structure. This transition state structure appears to be ambimodal, i.e., the fenchone-type tricyclic scaffolds are formed in preference to the competing formation of a bornyl (camphor-type) skeleton under dynamic control via a post-transition state bifurcation (PTSB).

Pyridinium substituted BODIPY as NIR fluorescent probe for simultaneous sensing of hydrogen sulphide/glutathione and cysteine/homocysteine

A BODIPY based NIR turn-on fluorescent probe (1) carrying a 7-nitro-2,1,3-benzoxadiazole (NBD) moiety linked at meso position of the BODIPY through benzyl pyridinium moiety as self-immolative linker was designed and successfully constructed. Such a probe selectively respond to H2S and biothiol species. It was able to differentiate H2S/GSH and Cys/Hcy under dual channels imaging with good spectroscopic separation and fluorescence enhancement. The studies on sensing mechanism supported thiols-induced SNAr substitution–rearrangement cascade reaction which allowed differentiation of H2S/GSH and Cys/Hcy via amino- and thiol-NBD derivatives with exhibited distinct photo-physical properties. Such a probe was successfully used to image GSH in living Hela cells and to detect endogenous biothiols in living mouse.

A bioinspired and biocompatible ortho-sulfiliminyl phenol synthesis

Synthetic methods inspired by Nature often offer unique advantages including mild conditions and biocompatibility with aqueous media. Inspired by an ergothioneine biosynthesis protein EgtB, a mononuclear non-haem iron enzyme capable of catalysing the C–S bond formation and sulfoxidation, herein, we discovered a mild and metal-free C–H sulfenylation/intramolecular rearrangement cascade reaction employing an internally oxidizing O–N bond as a directing group. Our strategy accommodates a variety of oxyamines with good site selectivity and intrinsic oxidative properties. Combining an O–N bond with an X–S bond generates a C–S bond and an S=N bond rapidly. The newly discovered cascade reaction showed excellent chemoselectivity and a wide substrate scope for both oxyamines and sulfenylation reagents. We demonstrated the biocompatibility of the C–S bond coupling reaction by applying a coumarin-based fluorogenic probe in bacterial lysates. Finally, the C–S bond coupling reaction enabled the first fluorogenic formation of phospholipids, which self-assembled to fluorescent vesicles in situ.

Seco -Polycyclic polyprenylated acylphloroglucinols with unusual carbon skeletons from Hypericum ascyron

Three new seco-polycyclic polyprenylated acylphloroglucinols (PPAPs), ascyronones A–C (1–3), and a new biosynthetic precursor, ascyronone D (4), were isolated from Hypericum ascyron together with three known analogues (5–7). Compounds 1 and 2, sharing an unusual seven-membered carbon core fused with a γ-lactone ring, could be derived from 1,9-seco-PPAPs via further rearrangement. A biomimetic transformation from 5 to 1 was performed by using base-driven retro-Claisen and rearrangement cascade reaction, which further confirmed the structure of 1 and shed light to its possible biosynthetic pathway. Interestingly, all these compounds are decorated with a methyl group at C-5 instead of a prenyl or geranyl group in many other PPAPs. The isolates were evaluated for their inhibitory activities against five human tumor cell lines.

Host‐Catalyzed Cyclodehydration–Rearrangement Cascade Reaction of Unsaturated Tertiary Alcohols

AbstractThe Brønsted acidic resorcin[4]arene hexamer can be applied as an effective catalyst in the dehydrative cyclization and subsequent rearrangement of unsaturated tertiary alcohols. This is the first report on catalyzing such a reaction with a Brønsted acid. Scope and limitations of this cyclopentene‐forming reaction sequence are presented. Furthermore, substrate‐selective conversion as well as competitive inhibition are described and provide evidence that the reactions proceed within the cavity of the self‐assembled structure. Additionally, a cyclobutanone‐forming intramolecular hydride transfer of an encapsulated cyclopropyl acetate is reported.magnified image

A selective and sensitive fluorescent probe for homocysteine and its application in living cells

Biological thiols, such as cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) are important for maintaining the cellular redox equilibrium and play critical roles in physiological and pathological processes. It is necessary to detect Cys, Hcy and GSH for obtaining important physiological and pathological information, which would promote the development of the medical profession. In this paper, we have successfully developed a new fluorescent probe OH1-NBD for Hcy detection. Based on the nucleophilic aromatic substitution (SNAr) and rearrangement cascade reaction and the distance-dependent PET process, OH1-NBD shows to be a selective turn-on fluorescent probe for Hcy with a fast (a few minutes) and sensitive (16 nM) response. It can function as a fluorescence probe for imaging of Hcy in the living cell. At the same time, it can also be used for living cells as a potential probe for biothiol-relevant oxidant-governed redox status assay. We expect that the probe will provide a valuable approach to gain a better understanding of the roles of biothiols especially Hcy.

Trifluoroacetic Acid-Mediated Nucleophilic Substitution/Smiles Rearrangement Cascade Reaction: An Alternative Approach to Constructing Pyrrole-Fused Dihydropteridines

A trifluoroacetic acid-mediated cascade reaction involving nucleophilic substitution and Smiles rearrangement is described. The reaction of hydroxydihydrodiazepines with primary amines led to amino-substituted dihydrodiazepines, which readily underwent Smiles rearrangement to give pyrrolo[1,2-f]pteridine derivatives.