Timothy J. Donohoe

Identification of epigenetic DNA modifications with a protein nanopore.

Two DNA bases, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (hmC), marks of epigenetic modification, are recognized in immobilized DNA strands and distinguished from G, A, T and C by nanopore current recording. Therefore, if further aspects of nanopore sequencing can be addressed, the approach will provide a means to locate epigenetic modifications in unamplified genomic DNA.

Recent developments in methodology for the direct oxyamination of olefins.

1,2-Amino alcohols are high-value, versatile functional groups that are found in scores of biologically active molecules and other interesting synthetic targets such as ligands and auxiliaries. Given their prominent position within organic compounds of import, it is no surprise to note that many routes have been developed to access this motif and there are many different starting points from which a synthetic chemist might embark on a synthesis. However, one particular approach stands out from the others, and this is the direct conversion of an alkene to a vicinal amino alcohol derivative (oxyamination). Research in this field has been particularly active in recent years and many interesting new methodologies have been reported. The purpose of this review is to give the reader a tour of the methods that have emerged in the last few years so one can appreciate the myriad of different metals and reagents that can accomplish the oxyamination of alkenes. There are still many challenges to be overcome and, herein, we also outline the areas that are ripe for further development and which bode well for the future.

Ruthenium-catalyzed isomerization of terminal olefins: applications to synthesis.

developed by Grubbs and co-workers and have expanded our options regarding C C bond formation with reactions such as ring-closing metathesis (RCM), olefin cross-metathesis, and ring-opening olefin metathesis polymerization. Catalysts derived from ruthenium carbenes have also been found to be adept at promoting the isomerization of terminal alkenes to internal alkenes. This Highlight summarizes the application of this observation in the total synthesis of complex natural products. Olefin isomerization with transition-metal catalysts is well established in organic chemistry. For example, catalysts such as [(PPh3)3RhCl] (the Wilkinson catalyst) are frequently employed in the isomerization of allylic ethers. However, the use of a ruthenium hydride generated from a catalyst such as A provides especially mild and effective conditions that ensure that the olefin is not hydrogenated and that the terminal olefin is only isomerized to the adjacent position. The discovery that ruthenium metathesis catalysts can be used in the isomerization of terminal olefins is potentially very useful in synthesis, especially in cases in which the introduction of a vinyl or propenyl substituent is problematic. Allyl groups have the advantage that they can be installed readily in procedures that are more convenient than the addition of a vinyl group, for example, through a radical Keck-type allylation of haloalkanes, the allylation of an enolate, or the addition of an allylic organometallic reagent to a carbonyl group. Subsequent isomerization of the terminal olefin to the internal position affords a propenyl group, which can be further functionalized. Therefore, this sequence builds a bridge between the chemistry of an allyl group and that of a vinyl group; this tactic is particularly useful in synthesis. The use of the Grubbs second-generation catalyst A for general olefin isomerization was reported by Nishida and coworkers in 2002. During the attempted cross-metathesis of alkene 1 with silyl enol ether 2, an unexpected reaction occurred, which resulted in the selective isomerization of the terminal olefin to give the corresponding propenyl species 3 (Scheme 2). The product was obtained as a 3.5:1 mixture of E and Z isomers. Several other terminal olefins were subjected to the reaction conditions, and the corresponding products of isomerization were obtained in moderate to excellent yield.

Rhodium-Catalyzed Ketone Methylation Using Methanol Under Mild Conditions: Formation of α-Branched Products†

The rhodium-catalyzed methylation of ketones has been accomplished using methanol as the methylating agent and the hydrogen-borrowing method. The sequence is notable for the relatively low temperatures that are required and for the ability of the reaction system to form α-branched products with ease. Doubly alkylated ketones can be prepared from methyl ketones and two different alcohols by using a sequential one-pot iridium- and rhodium-catalyzed process.

Ring-Closing Metathesis : Novel Routes to Aromatic Heterocycles

Olefin metathesis has been established as an important and general reaction in synthetic organic chemistry. Recently, it has attracted interest as a powerful tool for the construction of aromatic heterocycles. The importance of heteroaromatic motifs in medicinal chemistry and biology, as well as the efficiency and wealth of metathesis transformations, have resulted in significant success in this rapidly developing area.

The directed dihydroxylation of allylic alcohols

Abstract The preparation and dihydroxylation of a series of polyenes and cyclic allylic alcohols using the TMEDA/osmium tetroxide mixture is reported. Remarkably, these reagents lead to high levels of regiochemical and stereochemical control as the oxidant hydrogen-bonds to the allylic alcohol group. A mechanistic hypothesis is presented which invokes the formation of a reactive, bidentate complex between osmium tetroxide and TMEDA at low temperatures.

Olefin cross-metathesis for the synthesis of heteroaromatic compounds

The olefin metathesis reaction has underpinned spectacular achievements in organic synthesis in recent years. Arguably, metathesis has now become the foremost choice for a carbon-carbon double bond disconnection. Despite this general utility, de novo routes to heteroaromatic compounds using the cross-metathesis (CM) reaction have only recently emerged as an efficient strategy. This approach allows a convergent union of simple, functionalised, three- to four-carbon olefinic core building blocks, to generate furans, pyrroles and pyridines with a high degree of control of substitution pattern in the product.

An expedient route to substituted furans via olefin cross-metathesis

The olefin cross-metathesis (CM) reaction is used extensively in organic chemistry and represents a powerful method for the selective synthesis of differentially substituted alkene products. Surprisingly, efforts to integrate this remarkable process into strategies for aromatic and heteroaromatic construction have not been reported. Such structures represent key elements of the majority of small molecule drug compounds; methods for the controlled preparation of highly substituted derivatives are essential to medicinal chemistry. Here we show that the olefin CM reaction, in combination with an acid cocatalyst or subsequent Heck arylation, provides a concise and flexible entry to 2,5-di- or 2,3,5-tri-substituted furans. These cascade processes portend further opportunities for the regiocontrolled preparation of other highly substituted aromatic and heteroaromatic classes.

Heteroaromatic Synthesis via Olefin Cross-Metathesis: Entry to Polysubstituted Pyridines

The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of α,β-unsaturated 1,5-dicarbonyl derivatives which then serve as effective precursors to mono-tetrasubstituted pyridines. Manipulation of the key 1,5-dicarbonyl intermediate allows access to pyridines with a wide range of substitution patterns. An extension of this methodology facilitates the preparation of pyridines embedded within macrocycles, as exemplified by an efficient synthesis of (R)-(+)-muscopyridine. High levels of regiocontrol, short reaction sequences, and facile substituent variation are all notable aspects of this methodology.

Substituted pyrroles via olefin cross-metathesis

Olefin cross-metathesis (CM) provides a short and convenient entry to diverse trans-γ-aminoenones. When exposed to either acid or Heck arylation conditions, these intermediates are converted to mono-, di-, or trisubstituted pyrroles. The value of this chemistry is demonstrated by its application to the tetrasubstituted pyrrole subunit of Atorvastatin.