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Symmetrical and unsymmetrical cyclobutanes are synthesized following an intermolecular homo or heterodimerization of various styrene derivatives.

The application of an iridium-catalyzed hydrogen borrowing process to enable the formation of α-branched ketones with higher alcohols is described. In order to facilitate this reaction, ortho-disubstituted phenyl and cyclopropyl ketones were recognized as crucial structural motifs for C–C bond formation. Having optimized the key catalysis step, the ortho-disubstituted phenyl products could be further manipulated by a retro-Friedel–Crafts acylation reaction to produce synthetically useful carboxylic acid derivatives. In contrast, the cyclopropyl ketones underwent homoconjugate addition with several nucleophiles to provide further functionalized branched ketone products.

The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an α-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after α-arylation with carbon or heteroatom-based electrophiles, or by performing an α,α-heterodiarylation to install aryl groups at this position. The α-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the α-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C-H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route.

A novel methodology for the synthesis of highly substituted pyridines based on the palladium-catalyzed enolate α-alkenylation of ketones is presented; the formation of aromatic compounds is a new direction for this catalytic C–C bond forming reaction. In the key step, a protected β-haloalkenylaldehyde participates in α-alkenylation with a ketone to afford a 1,5-dicarbonyl surrogate, which then undergoes cyclization/double elimination to the corresponding pyridine product, all in one pot. The β-haloalkenylaldehyde starting materials can be obtained from the corresponding methylene ketone via Vilsmeier haloformylation. Using this concise route, a variety of highly substituted pyridines were synthesized in three steps from commercially available compounds.

Over the last few years, a number of olefin metathesis catalysts have been disclosed that enable the synthesis of energetically disfavoured Z-alkenes. The application of this method to the synthesis of complex natural products has driven the development of new catalysts and furthered the understanding of their behaviour and reactivity. This digest discusses the progress made and highlights the benefits of this chemistry over more traditional protocols.

[IrCl(cod)]2 as the catalyst promotes hydrogen-borrowing reaction of ketone enolates with methanol to give enones (III) which can react with excess methanol as nucleophile to yield mixtures of methoxymethyl derivatives (IV) and the enones (III).

Aromatic heterocycles are a very well represented motif in natural products and have found various applications in chemistry and material science, as well as being commonly found in pharmaceutical agents. Thus, new and efficient routes towards this class of compound are always desirable, particularly if they expand the scope of chemical methodology or facilitate more effective pathways to complex substitution patterns. This perspective covers recent developments in the de novo synthesis of aromatic heterocycles via palladium-catalysed α-arylation reactions of carbonyls, which is itself a powerful transformation that has undergone significant development in recent years.

Natural products (IX)-(XII) are synthesized from the common precursor (VIII), which requires the change of the general procedure to the use of ZnCl2 as a catalyst because the more vigorous acetic acidic method leads to the products in significantly lower yield.

Olefin metathesis of allylic alcohols (I) with methyl vinyl ketones (II) in the presence of Zhan-1B catalyst and subsequent Dess-Martin-periodinane oxidation produces generally not-assigned mixtures of unsaturated diones.

Doubly alkylated ketones can be prepared from methyl ketones and two different alcohols by using a sequential one-pot iridium- and rhodium-catalyzed process [reaction of (VI)].

The total synthesis of (±)-streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki–Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic streptonigrin intermediates to be prepared for the first time.

The osmium-catalyzed oxidative cyclization of vicinal diols onto proximal olefins to generate 2,5-cis-substituted tetrahydrofurans (THFs) has been exploited as the key step for the construction of several complex THF-containing natural products, namely, the annona- ceous acetogenins cis-sylvaticin, sylvaticin, and the excitatory amino acid neo - dysiherbaine A. Recently modified conditions that employ a Lewis acid enable the cycliza- tion to proceed under milder conditions, providing greater tolerance to acid-sensitive functional groups, as demonstrated in two of the syntheses. Flexibility for the construction of 2,5-trans-THFs was demonstrated in the synthesis of sylvaticin by utilization of an intra - molecular hydride-shift sequence.

This paper describes the use of unsaturated Weinreb amides as excellent substrates for the Heck reaction. Subsequent derivatization of the products with organometallic reagents allowed access to a variety of substituted vinyl ketones that could not have been prepared directly via Heck reaction on unsaturated ketone precursors.

The development and application of novel methods for accomplishing the synthesis of heterocycles via osmium-catalyzed oxidative cyclization onto an alkene is described in this Perspective. Beginning with a fortuitous discovery, an extensive examination of the possible mechanism of cyclization has been carried out, and the method was continuously developed until it had been transformed into an extremely efficient and powerful new catalytic reaction for the formation of tetrahydrofurans and pyrrolidines with complete control over all aspects of relative and absolute stereochemistry. By working with Os(VI) rather than the more familiar Os(VIII), a highly potent yet mild set of reaction conditions were developed. In addition to the method development studies, this work also sets out some synthetic challenges against which the methodology was tested. Pleasingly, the catalytic oxidative cyclization has proved itself to be an efficient and functional group tolerant process that was pivotal to the completion of s...

This article describes the examination of several synthetic methodologies that have been developed in our laboratories, by application to the construction of a variety of natural product targets.

A range of heterocycles, namely thiazoles, imidazoles, imidazopyridines, thiazolidines and dimethoxyindoles, have been synthesised directly from alkenesvia a two-step ketoidoination/cyclisation protocol. The alkene starting materials are themselves readily accessible using many different and well-established approaches, and allow access to a variety of heterocycles with excellent yields and regioselectivity.

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.

This review highlights key aspects of the Tethered Aminohydroxylation from its discovery to its current incarnation, which employs N,O-acylated derivatives as reoxidants for osmium. The potential and generality of this reaction has been demonstrated by its application in the synthesis of several natural products.

Heck reactions are performed on α,β-unsaturated -δ-sulfonamido intermediates (III), derived from cross-metathesis, to allow the installment of substituents at the β-position.

The acyloin reaction of unsymmetrical diesters (V) leads regioselectively to derivatives (VI) in good yields.

Hydride transfer in the pyridinium salts (II) becomes possible in the presence of Bu4NF to give diastereomers (IV) as the main products.

The straightforward and efficient method to prepare mono-, di-, tri-, and tetrasubstituted pyridines can be applied to the synthesis of macrocyclic pyridines such as (+)-muscopyridine (XV).

Numerous synthetic protocols for producing syn-diols from the corresponding alkenes have been developed and published over recent years. It is the intent of the following tutorial review to present a concise summary of the main methods used to prepare syn-diol fragments directly from alkene precursors, and that do not make use of osmium oxo complexes as catalysts.

Aromatic heterocycles, such as thiazoles (III), imidazoles (V) and indole derivative (VII) are synthesized directly from alkenes (I) via a ketoiodination—cyclization protocol.

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.

A variety of tetrahydrofurans bearing a silyl group at the ring junction is prepared in good yields stereoselectively via a osmium-catalyzed oxidative cyclization of appropriate terminal vinyl silanes.

The reaction of trans-γ-aminoenones, generated from allylic amine derivatives and enones, under acidic or Heck arylation conditions lead to a variety of mono-, di- and trisubstituted pyrroles.

The stereoselective syntheses of mixed acetals derived from o-substituted benzaldehyde chromium tricarbonyl compounds are described. These acetals are shown to undergo highly selective displacement reactions in a process which involves neighbouring group participation from the chromium tricarbonyl unit. Asymmetric syntheses of a-methyl benzylamines and 2-aryl tetrahydropyrans, via this methodology, are described.

The BC-rings of taxol can be synthesized using an intramolecular [5+2]-pyrylium ylide-alkene cyclization, followed by gem -methylcyclopropanation and reductive cleavage of the internal cyclopropane bond.

Solvolysis of the neopentyl triflates 14, 25 and 32 resulted in ring expansion of a seven-membered ring into the eight-membered ring required for the synthesis of the taxanes diterpenoids.

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.

The title compounds are hydrothermally synthesized from LnCl3·6H2O in small amounts of H2O (autoclave, 220 °C, 21 d) and characterized by single crystal XRD, diffuse reflectance, FT-IR, and FT-Raman spectroscopy.

The osmium-catalyzed oxidative cyclization of amino alcohol initiators formally derived from 1,4-dienes is an effective method for the construction of pyrrolidines, utilizing a novel reoxidant (4-nitropyridine N-oxide = NPNO). The cyclization of enantiopure syn- and anti-amino alcohols gives rise to enantiopure cis- and trans-2,5-disubstituted pyrrolidines, respectively. Moreover, the cyclization of bis-homoallylic amines bearing an exocyclic chelating group is shown to be a complementary method for trans-pyrrolidine formation.

The preparation and Birch reduction of a series of electron-deficient pyrroles is described. This methodology allows the synthesis of a variety of C-2 substituted 3-pyrrolines‡ in good to excellent yields. The role of various activating groups (amide, ester, carbamate and urea) has been examined with regard to both stability under the Birch conditions and ease of deprotection after reduction. In addition, we discovered that the 3-pyrroline skeleton can be oxidised at C-5 with chromium trioxide–3,5-dimethylpyrazole to form the 3-pyrrolin-2-one nucleus. The identity of the Birch reduced products and also of the oxidised 3-pyrrolin-2-ones has been confirmed by X-ray crystallography on two derivatives.

The Birch reduction of electron-deficient 3-substituted pyrroles is described. Use of a reductive alkylation procedure involving sodium metal in liquid ammonia gave good yields of 4-alkyl-2-pyrrolines. The identity of these products was proven by an X-ray structure of a crystalline derivative. Moreover, the pyrroles used in this study could be readily prepared by reaction of TOSMIC with acrylic amides and esters and, once the reduction was complete, the ester activating group could be easily removed to yield the corresponding N-protected β-proline derivatives.

The preparation and Birch reduction of chiral 3-methyl-2-furoic acid derivatives is described. Using a C2 symmetrical amine as a chiral auxiliary, very high levels of sterochemical control could be obtained. Moreover, the auxiliary could be removed conveniently by heating in 6M HCl to liberate a carboxylic acid of high enantiomeric purity. The relative stereochemistry of the Birch reduced amides (and therefore the absolute stereochemistry of the corresponding acids) was determined unambiguously from an X-ray crystal structure.