Iridium-Catalyzed Enantioselective Intermolecular Indole C2-Allylation.

The enantioselective intermolecular C2-allylation of 3-substituted indoles is reported for the first time. This directing group-free approach relies on a chiral Ir-(P, olefin) complex and Mg(ClO4 )2 Lewis acid catalyst system to promote allylic substitution, providing the C2-allylated products in typically high yields (40-99 %) and enantioselectivities (83-99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2-allylation, rather than C3-allylation followed by in situ migration. Steric congestion at the indole-C3 position and improved π-π stacking interactions have been identified as major contributors to the C2-selectivity.

Low-Temperature, Transition-Metal-Free Cross-Dehydrogenative Coupling Protocol for the Synthesis of 3,3-Disubstituted Oxindoles.

A new low-temperature procedure for the synthesis of 3,3-disubstituted 2-oxindoles via cross-dehydrogenative coupling (CDC) is reported. The use of a strong, nonreversible base in these reactions has been found to effect a dramatic drop in reaction temperature (to room temperature) relative to the current state-of-the-art (>100 °C) procedure. When employing iodine as an "oxidant", new evidence suggests that this transformation may occur via a transiently stable iodinated intermediate rather than by direct single-electron oxidation.

Photoredox-catalyzed procedure for carbamoyl radical generation: 3,4-dihydroquinolin-2-one and quinolin-2-one synthesis.

A reductive approach for carbamoyl radical generation from N-hydroxyphthalimido oxamides under photoredox catalysis is outlined. This strategy was applied to the synthesis of 3,4-dihydroquinolin-2-ones via the intermolecular addition/cyclization of carbamoyl radicals with electron deficient olefins in a mild, redox-neutral manner. Under a general set of reaction conditions, diversely substituted 3,4-dihydroquinolin-2-ones, including spirocyclic systems can be prepared. By using chlorine-substituted olefins, aromatic quinolin-2-ones can also be accessed.

Selective synthesis of three product classes from imine and carboxylic acid precursors via direct imine acylation.

Three divergent Direct Imine Acylation (DIA) procedures are reported that allow the selective generation of δ-lactams, ß-lactams and tetrahydropyrimidinones (via a novel three-component coupling) from imine and carboxylic acid precursors. All operate via initial N-acyliminium ion formation and diverge depending on the reaction conditions and nature of the substrates.

A Cu-Catalysed Radical Cross-Dehydrogenative Coupling Approach to Acridanes and Related Heterocycles.

The synthesis of acridanes and related compounds through a Cu-catalysed radical cross-dehydrogenative coupling of simple 2-[2-(arylamino)aryl]malonates is reported. This method can be further streamlined to a one-pot protocol involving the in situ fomation of the 2-[2-(arylamino)aryl]malonate by α-arylation of diethyl malonate with 2-bromodiarylamines under Pd catalysis, followed by Cu-catalysed cyclisation.

Synthesis of Spirocyclic Indolenines.

This Review provides an in-depth account of the synthesis of spirocyclic indolenines. Over the last 77 years, a wide array of diverse synthetic methods has been developed in order to generate these synthetically useful and biologically important spirocyclic scaffolds. The main synthetic strategies discussed are grouped into three main categories, namely interrupted Fischer indolisations, dearomatisation reactions of indoles and condensation reactions. The historical background, common synthetic challenges, current state-of-the-art and future perspectives of this field are examined.

From Heteroaromatic Acids and Imines to Azaspirocycles: Stereoselective Synthesis and 3D Shape Analysis.

Heteroaromatic carboxylic acids have been directly coupled with imines using propylphosphonic anhydride (T3P) and NEt(iPr)2 to form azaspirocycles via intermediate N-acyliminium ions. Spirocyclic indolenines (3H-indoles), azaindolenines, 2H-pyrroles and 3H-pyrroles were all accessed using this metal-free approach. The reactions typically proceed with high diastereoselectivity and 3D shape analysis confirms that the products formed occupy areas of chemical space that are under-represented in existing drugs and high throughput screening libraries.

Catalyst-Driven Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles and Quinolines from Indolyl Ynones.

Medicinally relevant spirocyclic indolenines, carbazoles and quinolines can each be directly synthesised selectively from common indolyl ynone starting materials by catalyst variation. The high yielding, divergent reactions all proceed by an initial dearomatising spirocyclisation reaction to generate an intermediate vinyl-metal species, which then rearranges selectively by careful choice of catalyst and reaction conditions.

Phosphorylated cyclopropanes in the synthesis of α-alkylidene-γ-butyrolactones: total synthesis of (±)-savinin, (±)-gadain and (±)-peperomin E.

Phosphorylated cyclopropanes, generated via the Rh(ii)-catalysed intramolecular cyclopropanation of α-(diethoxyphosphoryl)acetates, have been found to be useful precursors in the synthesis of α-alkylidene-γ-butyrolactones. These cyclopropyl intermediates undergo regioselective reductive ring-opening and subsequent Horner-Wadsworth-Emmons olefination to complete the synthesis. Total syntheses of (±)-savinin and (±)-gadain, as well as the first total synthesis of (±)-peperomin E, are all described using this method.

A selective C-H insertion/olefination protocol for the synthesis of α-methylene-γ-butyrolactone natural products.

A regio- and stereoselective one-pot C-H insertion/olefination protocol has been developed for the late stage installation of α-methylene-γ-butyrolactones into conformationally restricted cyclohexanol-derivatives. The method has been successfully applied in the total synthesis of eudesmanolide natural product frameworks, including α-cyclocostunolide.

Dearomatisation approaches to spirocyclic dienones via the electrophilic activation of alkynes.

Two complementary dearomatising spirocyclisation protocols to generate spirocyclic dienones from anisole and phenol-tethered ynones are described, each proceeding via electrophilic alkyne activation. The first approach focuses on the spirocyclisation of para-substituted anisoles using either SnCl2·2H2O or Cu(OTf)2. The second approach, which enables the spirocyclisation of both ortho- and para-substituted phenols, uses silica-supported AgNO3 to generate similar scaffolds with much greater efficiency. Initial asymmetric studies are also outlined.

Selective Synthesis of Six Products from a Single Indolyl α-Diazocarbonyl Precursor.

Indolyl α-diazocarbonyls can be selectively cyclized to give six distinct products through the careful choice of catalyst and reaction conditions. A range of catalysts were used, including complexes of Rh(II) , Pd(II) , and Cu(II) , as well as SiO2 , to promote diazo decomposition and subsequent cyclization/rearrangement through a range of mechanistic pathways.

Silica-Supported Silver Nitrate as a Highly Active Dearomatizing Spirocyclization Catalyst: Synergistic Alkyne Activation by Silver Nanoparticles and Silica.

Silica-supported AgNO3 (AgNO3 -SiO2 ) catalyzes the dearomatizing spirocyclization of alkyne-tethered aromatics far more effectively than the analogous unsupported reagent; in many cases, reactions which fail using unsupported AgNO3 proceed effectively with AgNO3 -SiO2 . Mechanistic studies indicate that this is a consequence of silver nanoparticle formation on the silica surface combined with a synergistic effect caused by the silica support itself. The remarkable ease with which the reagent can be prepared and used is likely to be of much synthetic importance, in particular, by making nanoparticle catalysis more accessible to non-specialists.

Total Synthesis and Stereochemical Revision of Phacelocarpus 2-Pyrone A.

The first total synthesis of phacelocarpus 2-pyrone A is reported. The original natural compound was tentatively assigned (by NMR spectroscopy) as containing two cis-alkenes and a trans-vinyl ether connected to a 2-pyrone ring motif. Our computational predictions indicated that a cis-vinyl ether motif was equally feasible. Attempts to prepare the trans-vinyl ether were met with no success. The all cis-target compound was synthesised in nine steps, employing key regio- and stereoselective reactions including Au(I)-catalysed vinyl etherification, Wittig alkenylation and end-game Stille macrocyclisation. Analysis of the NMR data enabled identification and confirmation of the correct structure of phacelocarpus 2-pyrone A, containing a cis-vinyl ether. Our studies pave the way for future development of methodologies to these structurally distinct pyrone skipped-polyenyne natural products.

Silver(I)- or copper(II)-mediated dearomatization of aromatic ynones: direct access to spirocyclic scaffolds.

A high-yielding silver(I)- or copper(II)-catalyzed dearomatizing spirocyclization strategy allows the conversion of simple aromatic compounds that contain ynone substituents, including indole, anisole, pyrrole, and benzofuran derivatives, into functionalized spirocyclic scaffolds. A high-yielding asymmetric variant furnishes spirocyclic indolenines in up to 89:11 e.r.

A direct C-H/Ar-H coupling approach to oxindoles, thio-oxindoles, 3,4-dihydro-1 H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines.

A copper(II)-catalysed approach to oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines via formal C-H, Ar-H coupling is described. In a new variant, copper(II) 2-ethylhexanoate has been identified as an inexpensive and efficient catalyst for this transformation, which utilises atmospheric oxygen as the re-oxidant.

Direct imine acylation for molecular diversity in heterocyclic synthesis.

Imines and carboxylic acids have been directly coupled using propylphosphonic acid anhydride and NEt(i-Pr)2 to give N-acyliminium ions, which were intramolecularly trapped with oxygen, nitrogen, sulfur, and carbon nucleophiles to provide a wide range of structurally diverse heterocycles.

4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions.

Two mild and efficient strategies have been developed for the O-functionalisation of 4-hydroxy-6-alkyl-2-pyrones, by using them as nucleophilic partners in oxa-Michael additions and the Mitsunobu reaction. The reactions proceed in moderate to excellent yields on a range of substrates containing useful functionality. The reactions serve as practical and valuable synthetic methods to construct complex 2-pyronyl ethers, which are found embedded in a number of natural products.

'Upenamide: trials and tribulations.

The complex macrocycle 'upenamide was isolated in 2000, stimulating significant effort from synthetic chemists to complete its total synthesis and verify its structure. Progress made by several groups is detailed, culminating in the synthesis of both of the proposed structures of this unique natural product, neither of which matched the natural material according to spectroscopic analysis. The evolution of the synthetic route and the development of associated methodologies are described.

The Cope rearrangement of gem-dimethyl substituted divinylcyclopropanes.

The reactivity of a range of substituted divinylcyclopropanes towards the thermal Cope rearrangement has been examined. The effects of gem-dimethyl substitution on the cyclopropane, the alkene geometry, the relative stereochemistry of the cyclopropane and the steric and electronic effects of a range of functional groups were all examined, and the methods developed were used to synthesise a range of functionalised 1,4-cycloheptadienes in high yields.