Total Synthesis of (±)-Baphicacanthcusine A Enabled by Sequential Ring Contractions.

Reported herein is the first total synthesis of the poly-pseudoindoxyl natural product baphicacanthcusine A. The synthesis leverages the oxidative rearrangement of indoles to pseudoindoxyls to install vicinal pseudoindoxyl heterocycles in a diastereoselective manner. Key steps include an acid-mediated cyclization/indole transposition, two diastereoselective oxidative ring contractions, and a site-selective C--H oxygenation. The synthesis of the oxidation precursors was guided by recognition of an element of hidden symmetry. This work provides a foundation for the chemical synthesis of other poly-pseudoindoxyl alkaloids.

Ring Contraction of Saturated Cyclic Amines and Rearrangement of Acyclic Amines Through Their Corresponding Hydroxylamines.

Compared to modifications at the molecular periphery, skeletal adjustments present greater challenges. Within this context, skeletal rearrangement technology stands out for its significant advantages in rapidly achieving structural diversity. Yet, the development of this technology for ring contraction of saturated cyclic amines remains exceedingly rare. While most existing methods rely on specific substitution patterns to achieve ring contraction, there is a persistent demand for a more general strategy for substitution-free cyclic amines. To address this issue, we report a B(C6F5)3-catalyzed skeletal rearrangement of hydroxylamines with hydrosilanes. This methodology, when combined with the N-hydroxylation of amines, enables the regioselective ring contraction of cyclic amines and proves equally effective for rapid reorganization of acyclic amine skeletons. By this, the direct scaffold hopping of drug molecules and the strategic deletion of carbon atoms are achieved in a mild manner. Based on mechanistic experiments and density functional theory calculations, a possible mechanism for this process is proposed.

Synthesis of 1,2-Disubstituted Adamantane Derivatives by Construction of the Adamantane Framework.

This review summarizes achievements in the synthesis of 1,2-disubstituted adamantane derivatives by the construction of the tricyclic framework either by total synthesis or by ring expansion/contraction reactions of corresponding adamantane homologues. It is intended to complement reviews focusing on the preparation of 1,2-disubstituted derivatives by C-H functionalization methods.

Simultaneous Ring Contraction and Expansion Reaction: Electrosynthesis of Heterocycle-Fused Fulleroids and Photovoltaic Application.

Simultaneous electrochemical ring contraction and expansion reactions remain unexplored to date. Herein, the reductive electrosynthesis of heterocycle-fused fulleroids from fullerotetrahydropyridazines and electrophiles in the presence of a trace amount of oxygen has been achieved with concurrent ring contraction and ring expansion. When trifluoroacetic acid and alkyl bromides are employed as electrophiles, heterocycle-fused fulleroids with a 1,1,2,6-configuration are regioselectively formed. In contrast, heterocycle-fused fulleroids with a 1,1,4,6-configuration are regioselectively produced as two separable stereoisomers if phthaloyl chloride is used as the electrophile. The reaction proceeds through multiple steps of electroreduction, heterocycle ring-opening, oxygen oxidation, heterocycle contraction, fullerene cage expansion, and nucleophilic addition. The structures of these fulleroids have been determined by spectroscopic data and single-crystal X-ray diffraction analyses. The observed high regioselectivities have been rationalized by theoretical calculations. Representative fulleroids have been applied in organic solar cells as the third component and exhibit good performance.

Single Atom Ring Contraction of Peptide Macrocycles Using Cornforth Rearrangement.

Site-selective transformations of densely functionalized scaffolds have been a topic of intense interest in chemical synthesis. Herein we have repurposed the rarely used Cornforth rearrangement as a tool to effect a single-atom ring contraction in cyclic peptide backbones. Investigations into the kinetics of the rearrangement were carried out to understand the impact of electronic factors, ring size, and linker type on the reaction efficiency. Conformational analysis was undertaken and showed how subtle differences in the peptide backbone result in substrate-dependent reaction profiles. This methodology can now be used to perform conformation-activity studies. The chemistry also offers an opportunity to install building blocks that are not compatible with traditional C-to-N iterative synthesis of macrocycle precursors.

A Photochemical Strategy for ortho-Aminophenol Synthesis via Dearomative-Rearomative Coupling Between Aryl Azides and Alcohols.

ortho-Aminophenols are aromatic derivatives featuring vicinal N- and O-based functionalities commonly found in the structures of many high-value materials. These molecules are generally prepared using multistep strategies that follow the rules of electrophilic aromatic substitution (SE Ar) chemistry. Despite their high fidelity, such approaches cannot target substrates featuring a "contra-SE Ar" arrangement of N- and O-groups. Here we report an alternative strategy for the preparation of such ortho-aminophenols using aryl azides as the precursors. The process utilizes low-energy photoexcitation to trigger the decomposition of aryl azides into singlet nitrenes that undergo a dearomative-rearomative sequence. This allows the incorporation of alcoholic nucleophiles into a seven-membered ring azepine intermediate via temporary disruption of aromaticity, followed by electrophile-induced re-aromatization. The net retrosynthetic logic is that the alcohol displaces the azide, which, in turn, moves to its ortho position and furthermore is converted into an amide. The synthetic value and complementarity of this strategy has been demonstrated by the coupling of aryl azides with complex, drug-like alcohols and phenols as well as amines, thiols and thiophenols, which provides a general platform for the fast and selective heterofunctionalization of aromatics.

Unprecedented synthesis of a 14-membered hexaazamacrocycle.

The transformation of 3-[(ethoxymethylene)amino]-1-methyl-1H-pyrazole-4-carbonitrile into the 14-membered macrocycle, 2,10-dimethyl-2,8,10,16-tetrahydrodipyrazolo[3,4-e:3',4'-l][1,2,4,8,9,11]hexaazacyclotetradecine-4,12-diamine, by the reaction with excess hydrazine under various conditions was studied in detail. The reaction proceeded through the initial formation of 4-imino-2-methyl-2,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-amine followed by dimerization to give the final macrocycle. A convenient synthesis of the latter starting from 4-imino-2-methyl-2,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-amine was developed. A plausible pathway for the macrocycle self-assembly is discussed. Some features of the structure and reactivity of the obtained macrocycle are outlined.

Synthesis of enantioenriched 2,2-disubstituted pyrrolidines via sequential asymmetric allylic alkylation and ring contraction.

The synthesis of a variety of enantioenriched 2,2-disubstituted pyrrolidines is described. A stereogenic quaternary center is first formed utilizing an asymmetric allylic alkylation reaction of a benzyloxy imide, which can then be reduced to a chiral hydroxamic acid. This compound can then undergo a thermal "Spino" ring contraction to afford a carbamate protected 2,2-disubstituted pyrrolidine stereospecifically. These pyrrolidines can be further advanced to enantioenriched indolizidine compounds. This reaction sequence allows access to new molecules that could be useful in the development of pharmaceutical agents.

Two Radical SAM Enzymes Are Necessary and Sufficient for the In Vitro Production of the Oxetane Nucleoside Antiviral Agent Albucidin.

Oxetanocin A and albucidin are two oxetane natural products. While the biosynthesis of oxetanocin A has been described, less is known about albucidin. In this work, the albucidin biosynthetic gene cluster is identified in Streptomyces. Heterologous expression in a nonproducing strain demonstrates that the genes alsA and alsB are necessary and sufficient for albucidin biosynthesis confirming a previous study (Myronovskyi et al. Microorganisms 2020, 8, 237). A two-step construction of albucidin 4'-phosphate from 2'-deoxyadenosine monophosphate (2'-dAMP) is shown to be catalyzed in vitro by the cobalamin dependent radical S-adenosyl-l-methionine (SAM) enzyme AlsB, which catalyzes a ring contraction, and the radical SAM enzyme AlsA, which catalyzes elimination of a one-carbon fragment. Isotope labelling studies show that AlsB catalysis begins with stereospecific H-atom transfer of the C2'-pro-R hydrogen from 2'-dAMP to 5'-deoxyadenosine, and that the eliminated one-carbon fragment originates from C3' of 2'-dAMP.

Diastereodivergent Synthesis of Cyclopentyl Boronic Esters Bearing Contiguous Fully Substituted Stereocenters.

The synthesis of molecules bearing two or more contiguous, quaternary stereocenters is challenging, owing to the difficulty in controlling stereochemistry whilst simultaneously constructing a sterically congested motif. Herein, we report the electrophile-induced ring contractive 1,2-metallate rearrangement of 6-membered cyclic alkenyl boronate complexes for the synthesis of cyclopentyl boronic esters bearing two contiguous, fully substituted stereocenters with high levels of stereocontrol. Remarkably, simple variation of the reaction solvent enabled their diastereodivergent construction with facile access to complementary diastereomeric pairs. The utility of our methodology is demonstrated in the asymmetric total synthesis of (+)-herbertene-1,14-diol.

From BN-Naphthalenes to Benzoborole Dianions.

The synthesis of benzoborole dianions by alkali metal reduction of BN-naphthalene derivatives via a ring-contraction strategy has been developed. Reduction of 1-alkynyl 2,1-benzazaborine 1 a in Et2 O led to the elimination of alkynyllithium with the formation of 1-amino-1-benzoborole trilithium salt 2 a, whereas reduction of 1-phenyl 2,1-benzazaborine 1 c in THF yielded 1-phenyl-1-benzoborole dilithium salt 2 c with the elimination of ArNHLi. The trilithium and dilithium salts 2 a and 2 c have been fully characterized. Treatment of trilithium salt 2 a with Et3 NHCl led to the selective protonation of the amino lithium to afford the dilithium salt 2 aH, which could be cleanly oxidized to 1-amino-1-benzoborole 3 in an excellent yield. Reaction of 1-phenyl-1-benzoborole dilithium salt 2 c with MeI yielded the lithium borate 4 c, which is luminescent both in solution and in the solid state.

Naphthalenediimides with Cyclic Oligochalcogenides in Their Core.

Naphthalenediimides (NDIs) are privileged scaffolds par excellence, of use in functional systems from catalysts to ion channels, photosystems, sensors, ordered matter in all forms, tubes, knots, stacks, sheets, vesicles, and colored over the full visible range. Despite this extensively explored chemical space, there is still room to discover core-substituted NDIs with fundamentally new properties: NDIs with cyclic trisulfides (i.e., trisulfanes) in their core absorb at 668 nm, emit at 801 nm, and contract into disulfides (i.e., dithietes) upon irradiation at <475 nm. Intramolecular 1,5-chalcogen bonds account for record redshifts with trisulfides, ring-tension mediated chalcogen-bond-mediated cleavage for blueshifts to 492 nm upon ring contraction. Cyclic oligochalcogenides (COCs) in the NDI core open faster than strained dithiolanes as in asparagusic acid and are much better retained on thiol exchange affinity columns. This makes COC-NDIs attractive not only within the existing multifunctionality, particularly artificial photosystems, but also for thiol-mediated cellular uptake.

Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids.

Tropolone sesquiterpenoids (TS) are an intriguing family of biologically active fungal meroterpenoids that arise through a unique intermolecular hetero Diels-Alder (hDA) reaction between humulene and tropolones. Here, we report on the combinatorial biosynthesis of a series of unprecedented analogs of the TS pycnidione 1 and xenovulene A 2. In a systematic synthetic biology driven approach, we recombined genes from three TS biosynthetic gene clusters (pycnidione 1, xenovulene A 2 and eupenifeldin 3) in the fungal host Aspergillus oryzae NSAR1. Rational design of the reconstituted pathways granted control over the number of hDA reactions taking place, the chemical nature of the fused polyketide moiety (tropolono- vs. monobenzo-pyranyl) and the degree of hydroxylation. Formation of unexpected monobenzopyranyl sesquiterpenoids was investigated using isotope-feeding studies to reveal a new and highly unusual oxidative ring contraction rearrangement.

Visible-Light-Driven Strain-Increase Ring Contraction Allows the Synthesis of Cyclobutyl Boronic Esters.

There are a limited number of ring-contraction methodologies which convert readily available five-membered rings into strained four-membered rings. Here we report a photo-induced radical-mediated ring contraction of five-membered-ring alkenyl boronate complexes into cyclobutanes. The process involves the addition of an electrophilic radical to the electron-rich alkenyl boronate complex, leading to an α-boryl radical. Upon one-electron oxidation, ring-contractive 1,2-metalate rearrangement occurs to give a cyclobutyl boronic ester. A range of radical precursors and vinyl boronates can be employed, and chiral cyclobutanes can be accessed with high levels of stereocontrol. The process was extended to the preparation of benzofused cyclobutenes and the versatility of the boronic ester was demonstrated by conversion to other functional groups.

Recent synthesis of thietanes.

Thietanes are important aliphatic four-membered thiaheterocycles that are found in the pharmaceutical core and structural motifs of some biological compounds. They are also useful intermediates in organic synthesis. Various synthetic methods of thietanes have been developed, including inter- and intramolecular nucleophilic thioetherifications, photochemical [2 + 2] cycloadditions, ring expansions and contractions, nucleophilic cyclizations, and some miscellaneous methods. The recently developed methods provide some new strategies for the efficient preparation of thietanes and their derivatives. This review focuses on the synthetic methods to construct thietane backbones developed during 1966 to 2019.

Expanded Porphyrin Contraction: From [22]Triphyrin(6.6.0) to [22]Triphyrin(6.5.0).

An expanded triphyrin containing a bipyrrole moiety and annulene links, namely tetraphenyl-[22]triphyrin(6.5.0), 2, has been synthesized. The synthesis proceeded by a postsynthetic transformation of tetraphenyl-[22]triphyrin(6.6.0), 1, in a metal-free unexpected and unprecedented ring contraction during column chromatography on alumina. The observed transformation, located at the hydrocarbon chain linking the pyrrole units, formally corresponds to a subtraction of one carbon atom from an annulene circuit. In contrast to the flexible substrate 1, the product 2 is conformationally rigid, and capable of chloride anion binding in its protonated form.

Organoboron chemistry comes to light: recent advances in photoinduced synthetic approaches to organoboron compounds.

Photoinduced synthetic approaches to organoboron compounds have attracted significant attention in the recent years. Photochemical activation of organic molecules enables generation of reactive intermediates from a variety of precursors, resulting in borylation methods with improved and broader substrate scopes. The review summarizes recent developments in the area of photoinduced reactions of organoboron compounds with an emphasis on borylation of haloarenes, amine derivatives, and redox-active esters of carboxylic acids, as well as photoinduced rearrangements of organoboron compounds and photoinduced synthesis of organoboron compounds from alkenes and alkynes.

Synthesis, Structure, and Reactivity of Binaphthyl Supported Dihydro[1,6]diazecines.

A short approach to chiral diaza-olefines from protected 2,2'-diamino-1,1'-binaphthyl is presented. Cis- and trans-olefines can be selectively obtained by twofold N-allylation followed by RCM or by bridging a 2,2'-diamino-1,1'-binaphthyl precursor with trans-1,4-dibromo-2-butene. Deprotection afforded cis- and trans-dihydro[1,6]diazecines 1 in 58 and 64% overall yield. The reactivity of the but-2-ene-1,4-diyl fragment was investigated yielding corresponding epoxides, diols, and mono- and dibromo products. In several cases rearrangements and participation of the proximate N-Boc group was observed. In no case could allylic substitution be accomplished. From 13 compounds X-ray structure analyses could be obtained.

Ring Contraction by NHC-Induced Pnictogen Abstraction.

The reaction of [Cp'''Co(η4 -P4 )] (1) (Cp'''=1,2,4-tBu3 C5 H2 ) with Me NHC (Me NHC=1,3,4,5-tetramethylimidazol-2-ylidene) leads through NHC-induced phosphorus cation abstraction to the ring contraction product [(Me NHC)2 P][Cp'''Co(η3 -P3 )] (2), which represents the first example of an anionic CoP3 complex. Such NHC-induced ring contraction reactions are also applicable for triple-decker sandwich complexes. The complexes [(Cp*Mo)2 (µ,η6:6 -E6 )] (3 a, 3 b) (Cp*=C5 Me5 ; E=P, As) can be transformed to the complexes [(Me NHC)2 E][(Cp*M)2 (µ,η3:3 -E3 )(µ,η2:2 -E2 )] (4 a, 4 b), with 4 b representing the first structurally characterized example of an NHC-substituted AsI cation. Further, the reaction of the vanadium complex [(Cp*V)2 (µ,η6:6 -P6 )] (5) with Me NHC results in the formation of the unprecedented complexes [(Me NHC)2 P][(Cp*V)2 (µ,η6:6 -P6 )] (6), [(Me NHC)2 P][(Cp*V)2 (µ,η5:5 -P5 )] (7) and [(Cp*V)2 (µ,η3:3 -P3 )(µ,η1:1 -P{Me NHC})] (8).

Enantioselective Organocatalytic Four-Atom Ring Expansion of Cyclobutanones: Synthesis of Benzazocinones.

An enantioselective Michael addition- four-atom ring expansion cascade reaction involving cyclobutanones activated by a N-aryl secondary amide group and ortho-amino nitrostyrenes has been developed for the preparation of functionalized eight-membered benzolactams using bifunctional aminocatalysts. Taking advantage of the secondary amide activating group, the eight-membered cyclic products could be further rearranged into their six-membered isomers having a glutarimide core under base catalysis conditions without erosion of optical purity, featuring an overall ring expansion- ring contraction strategy.