Free radical-mediated aryl amination: convergent two- and three-component couplings to chiral 2,3-disubstituted indolines

5-exo-trig Cyclization of an aryl radical to the nitrogen of an azomethine is used as the key annulating step in a modular preparation of 2,3-cis- and trans-disubstituted indolines. The precursors are readily prepared by phase-transfer-catalyzed Michael addition of a glycine Schiff base to a variety of acceptors. When the more reactive alkylidene malonate Michael acceptors are implemented, a one-pot three-component coupling is possible. The net result is a convergent [3 + 2] coupling strategy for the construction of highly functionalized indolines, a substructure occurring in numerous biologically active natural products.     

2-Phospha[3]ferrocenophanes with planar chirality: synthesis and use in enantioselective organocatalytic [3 + 2] cyclizations

Planar chiral phosphines displaying a new ferrocenophane scaffold have been prepared via a stereoselective approach. The P-cyclohexyl substituted phosphine affords high levels of asymmetric induction in the organocatalytic [3 + 2] annulation reaction between allenes and electron-poor olefins.     

Highly enantioselective synthesis of silahelicenes using Ir-catalyzed [2+2+2] cycloaddition

Silahelicenes, which contain two silole moieties in a helically chiral structure, were synthesized by a chiral Ir-catalyzed intermolecular [2+2+2] cycloaddition of tetraynes with diynes along with a Ni-mediated intramolecular [2+2+2] cycloaddition. The photophysical properties of the obtained highly enantiomerically enriched silahelicenes (up to 93% ee) were also measured.     

Electrooxidative palladium- and enantioselective rhodium-catalyzed [3 + 2] spiroannulations

Despite indisputable progress in the development of electrochemical transformations, electrocatalytic annulations for the synthesis of biologically relevant three-dimensional spirocyclic compounds has as of yet not been accomplished. In sharp contrast, herein, we describe the palladaelectro-catalyzed C–H activation/[3 + 2] spiroannulation of alkynes by 1-aryl-2-naphthols. Likewise, a cationic rhodium(iii) catalyst was shown to enable electrooxidative [3 + 2] spiroannulations via formal C(sp³)–H activations. The versatile spiroannulations featured a broad substrate scope, employing electricity as a green oxidant in lieu of stoichiometric chemical oxidants under mild conditions. An array of spirocyclic enones and diverse spiropyrazolones, bearing all-carbon quaternary stereogenic centers were thereby accessed in a user-friendly undivided cell setup, with molecular hydrogen as the sole byproduct.

Despite indisputable progress in the development of electrochemical transformations, electrocatalytic annulations for the synthesis of biologically relevant three-dimensional spirocyclic compounds has as of yet not been accomplished.     

Synthesis of the cyclic nonapeptide of chlorofusin using a convergent [3+3+3]-fragment coupling strategy

A [3+3+3]-fragment coupling strategy was successfully applied in the synthesis of the nonacyclopeptide of chlorofusin, a potent natural antagonist against p53-MDM2 interactions. The accomplished convergent synthesis includes parallel syntheses of three tripeptides and their sequential assembly, and macrocyclization of the linear precursor to the required 27-membered nonacyclopeptide.     

A simple and general chiral silicon Lewis acid for asymmetric synthesis: highly enantioselective [3+2] acylhydrazone-enol ether cycloadditions

A highly diastereo- and enantioselective [3 + 2] acylhydrazone-enol ether cycloaddition mediated by a simple chiral silane Lewis acid is described. The reactions are highly practical, as demonstrated by a larger scale (5 g of the hydrazone) reaction in which the product was obtained after recrystallization in 93% yield and 99% ee. Evidence for a stepwise mechanism and a model for the asymmetric induction are presented, as well.     

2,6-Diazaspiro[3.3]heptanes: synthesis and application in Pd-catalyzed aryl amination reactions

A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of piperazine is shown in arene amination reactions yielding a variety of N-Boc- N'-aryl-2,6-diazaspiro[3.3]heptanes.     

Silyl-enolization-asymmetric Claisen rearrangement of 2-allyloxyindolin-3-one: enantioselective total synthesis of 3a-hydroxypyrrolo[2,3-b]indoline alkaloid alline

Asymmetric Claisen rearrangement triggered by silyl-enolization of 2-(1′-nonel-3′-yloxy)indolin-3-ones was performed in order to prepare 3-(2′-nonenyl)-3-hydroxyindolin-2-ones. Total synthesis of 3-hydroxypyrrolo[2,3-b]indoline alkaloid, (+)-alline was achieved by transformation of the allylic moiety of 3-(2′-nonenyl)-3-hydroxyindolin-2-one to amine followed by reductive cyclization.     

Recent advances in enantioselective [2 + 2 + 2] cycloaddition

Enantioselective cycloaddition using chiral transition metal catalysts is an atom-economical and efficient synthetic tool for the construction of chiral carbo- and heterocyclic skeletons. This short account discloses our recent results of inter- and intramolecular enantioselective [2 + 2 + 2] cycloadditions of alkyne and/or alkene moiety(ies). Chiral iridium complexes catalyzed the alkyne trimerization for the generation of axial chirality(ies), and chiral rhodium ones catalyzed alkyne-alkyne-alkene cyclization for the generation of a quaternary carbon including spirocyclic system.     

Catalytic enantioselective [2 + 4] and [2 + 2] cycloaddition reactions with propiolamides

We report here the catalytic and highly enantioselective [2 + 4] and [2 + 2] cycloaddition reactions of electron-rich dienes or silyl enol ethers with electron-deficient propiolamide derivatives induced by copper(II).3-(2-naphthyl)-L-alanine amide complex.     

NHC-catalyzed enantioselective [2 + 2] and [2 + 2 + 2] cycloadditions of ketenes with isothiocyanates

The enantioselective N-heterocyclic carbene-catalyzed formal [2 + 2] and [2 + 2 + 2] cycloaddition of ketenes and isothiocyanates were developed. Reaction with N-aryl isothiocyanates at room temperature favors the [2 + 2] cycloaddition, while reaction with N-benzoyl isothiocyanates at -40 °C favors the [2 + 2 + 2] cycloaddition.     

Facile and quick synthesis of 1-monosubstituted aryl 1,2,3-triazoles: a copper-free [3+2] cycloaddition

An efficient copper-free synthesis of 1-monosubstituted aryl 1,2,3-triazoles from sodium acetylide and aryl azides was developed, which was found suitable for various aryl azides and completed within 15 min at room temperature with moderate to excellent yields.     

[3+2] Cycloaddition-mediated synthesis of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester

1,3-Dipolar cycloaddition reactions are fundamental processes in organic chemistry. Herein we report [3+2] annulation of thiomethylacrylate 2 and azomethine ylide precursor 3 towards the synthesis of novel 3-methylsulfanyl-pyrrolidine 5. Alternatively, we have also explored the alkylation of 7 with dimethyldisulfide/LDA for the introduction of thiomethyl group towards the synthesis of 5 in moderate to good yields. Efficacy of these two routes under various conditions/catalysts for the synthesis of 5 is presented.     

Efficient synthesis of butenolide-medium ring ether hybrids by a [3 + 2] cyclization-ring-closing metathesis strategy

A new strategy for the synthesis of bicyclic gamma-alkylidenebutenolides, butenolide-medium ring ether hybrids, is reported which involves Me(3)SiOTf-catalyzed cyclization of 1, 3-bis(trimethylsilyloxy)-1,3-butadienes with oxalyl chloride, Mitsunobu reaction, and subsequent ring-closing metathesis.     

Recent advances in radical-mediated [2+2+m] annulation of 1,n-enynes

1,n-Enynes are a versatile class of unsaturated hydrocarbons that found broad applications in the synthetic community of natural products, biologically active structures and functional materials. Typical methods for the transformations of 1,n-enynes include the radical-mediated [2+2+m] annulation reaction as they are particularly efficient accesses to functionalized polycyclic compounds. We herein highlighted recent process in the radical-mediated [2+2+m] annulation of 1,n-enynes, including [2+2+1] and[2+2+2] modes, for the construction of five-to six-membered-ring-fused polycyclic scaffolds. Meanwhile, the mechanisms for these transformations were described.     

Short, enantioselective total synthesis of aflatoxin B2 using an asymmetric [3+2]-cycloaddition step

A highly enantioselective [3+2]-cycloaddition reaction of 2,3-dihydrofuran with 1,4-benzoquinones using a chiral oxazaborolidinium triflimidate as catalyst has been developed which allows rapid access to a variety of chiral phenolic tricycles (enantiomeric excesses ranging from 91 to 98%). The utility of this new methodology is demonstrated by a short synthesis of the important pentacyclic natural product, aflatoxin B2. This exploratory study indicates that an even broader application of these catalysts to enantioselective cycloadditions may be possible.     

Modular strategy for the synthesis of functionalized aryl-fused azabicyclo[2.2.2]octanes via radical-mediated cascade cyclization

A two-step synthesis of rare 2-azabicyclo[2.2.2]octanes is described. N-propargyl amides obtained via Cu(I)-catalyzed three-component coupling, underwent radical-mediated cascade cyclization to afford 5,6-aryl-fused 2-azabicyclo[2.2.2]octanes with arylidene functionality on the two-carbon bridge in 43–62% yields. Phenylidene and 1-naphtylidene derivatives were obtained exclusively as Z diastereomers, whereas electron rich groups in the arylidene substituent afforded product mixtures favoring the Z diastereomer by 2.3:1 M ratio.     

Diastereo- and enantioselective palladium-catalyzed dearomative [4+2] cycloaddition of 3-nitroindoles

A Pd-catalyzed asymmetric decarboxylative [4+2] cycloaddition of 3-nitroindoles and vinyl benzoxazinanones is developed through a dearomatization approach. The reaction provides an efficient protocol for constructing a series of chiral tetrahydro-5H-indolo[2,3-b]quinolines in high yields and with excellent diastereo- and enantioselectivities.     

Catalytic enantioselective [3 + 2]-cycloadditions of diazoketone-derived aryl-substituted carbonyl ylides

An evaluation of alpha-aryl-alpha-diazodiones in tandem carbonyl ylide formation-enantioselective [3 + 2]-cycloaddition reactions is described. Such substrates were designed to allow investigation of the electronic characteristics of the dipole upon asymmetric induction. Intramolecular cycloadditions (with a tethered alkene dipolarophile) were found to occur in good to quantitative yields, with a difference in ee exhibited by the two electronically different diazodiones 8 and 9. Intermolecular cycloadditions using diazodiones 12 and 13 with DMAD and arylacetylenes 16-18 again demonstrated that electronics play a key role in determining the outcome of the cycloaddition reactions. Enantioselectivities of up to 76% were observed.