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Archive for the ‘Organic’ Category

A new, functionally tolerant route to organo-aluminium reagents

13 Sep 2013

Paul Knochel and colleagues at the Ludwig Maximilians University in Munich have reported a new general synthesis of aryl and heteroaryl aluminium reagents. The route described allows a larger range of functional groups to be incorporated, compared with the more usual approach of inserting Al into aryl halide bonds directly. The synthetic methodology uses di-isobutyl aluminium chloride and n-BuLi at -78C in an exchange reaction with a functionalised aryl or heteroaryl halide.

General scheme for preparation and derivitisation of aryl aluminium reagents

The synthesis of a group of derivatives is described, via the reaction of the aluminium reagents with a variety of electrophiles. Typical cross coupling reactions using palladium catalysis, as well as copper-catalysed Michael additions, allylation and acylations are reported, involving a rich variety of incorporated functional groups. Importantly, further derivitisation of the organo-aluminium reagents includes no further transmetalation steps.

Of note are the reactivities of electron-rich furan and thiophene bromides functionalised with ester groups, which also could remain intact during the reaction with di-isobutylaluminium chloride and butyl-lithium at -78C, yielding the desired reagents that were further derivatised, as in other examples.

N-heterocycles such as 3-bromo-quinoline also received attention, yielding the aluminium reagent in 73% yield, and smoothly converting in a palladium catalysed cross coupling reaction with 4-iodobenzonitrile. Full NMR data for the products of the reactions described is given in the supplementary information.

In general, this Communication describes a considerable step forward in the field of organo-aluminium reagents for organic synthesis, and no doubt will be of interest to synthetic chemists in many fields.

Read this HOT ChemComm article today!

Generation of Functionalised Aryl and Heteroaryl Aluminium Reagents by Halogen/Lithium Exchange
Thomas Klatt, Klaus Groll and Paul Knochel
Chem. Commun., 2013,49, 6953-6955
DOI: 10.1039/C3CC43356K, Communication

Kevin Murnaghan is a guest web-writer for Chemical Communications. He is currently a Research Chemist in the Adhesive Technologies Business Sector of Henkel AG & Co. KGaA, based in Düsseldorf, Germany. His research interests focus primarily on enabling chemistries and technologies for next generation adhesives and surface treatments. Any views expressed here are his personal ones and not those of Henkel AG & Co. KGaA.

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Synthesis of non-toxic HSP90 inhibitors via Suzuki–Miyaura reaction

02 Jul 2013

HSP90 (Heat Shock Protein 90) is a chaperone protein which is involved in the disease pathways of many cancers, and such neurodegenerative illnesses as Alzheimer’s and Parkinson’s disease. The inhibition of HSP90 has gained a great deal of attention since its discovery, and offers the potential to treat many serious illnesses. Much interest has focused on geldanamycin—a benzoquinone ansamycin which is highly effective in the inhibition of HSP90. Unfortunately, geldanamycin suffers from high liver toxicity in addition to poor stability and solubility which greatly limits its therapeutic utility.

Christopher Moody at the University of Nottingham has devoted much research toward the targeting and inhibition of HSP90. His group recently discovered that the 19-position plays a key role in geldanamycin’s toxicity, and that substitution at that position can render the compound non-toxic, through the suppression of conjugate addition reactions which are thought to be responsible for its hepatotoxicity.

While Moody previously utilized the Stille reaction for substitution at this position, the transformation was limited in cases, not scalable, and its industrial application was hampered by undesirable, toxic reagents and waste products. In this Communication, Moody and Kitson overcome these problems by employing the Suzuki–Miyaura reaction to install functionality at the 19-position. Using a modification of the Suzuki–Miyaura reaction previously described by Eli Lilly researchers, Moody was able to obtain functionalised geldanamycins in yields which compare well with or exceed those obtained by the Stille protocol.

Beginning with readily accessible 19-iodogeldanamycin (1), the cross-coupling reaction allows a range of substituents to be installed easily, using an array of widely available boronic acids and esters. Aryl-, vinyl- and allyl-groups could be installed with excellent yields, while the use of alkyl boronic acids and esters afforded moderate results. The electronic supplementary information contains full details of the reaction optimisation.

This method allows non-toxic 19-substituted-geldanamycins to be prepared efficiently and without the disadvantages associated with the previous Stille route. Not only will this benefit the synthesis of geldanamycins within the pharmaceutical industry, but it should also encourage further clinical research of these important compounds.

For more, check out the ChemComm article in full:

An improved route to 19-substituted geldanamycins as novel Hsp90 inhibitors – potential therapeutics in cancer and neurodegeneration
Russell R. A. Kitson and Christopher J. Moody
Chem. Commun., 2013, Advance Article
DOI: 10.1039/C3CC43457E

Ruth E. Gilligan is a guest web-writer for ChemComm. She has recently completed her PhD in the group of Prof. Matthew J. Gaunt at the University of Cambridge, focusing on the development and application of C–H functionalisation methodology.

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Simple synthesis of heavy oxygen-labelled alcohols

23 May 2013

Rozen and co-workers report a novel and extremely simple method for synthesising ¹⁸O-labelled alcohols using commercial boronic acids and a reagent prepared from elemental fluorine.

Alcohols labelled with ¹⁸O are very valuable as biological probes for a variety of studies which are often limited by the availability of labelled precursors for use in the synthesis of the compounds of interest.

Scientists in Israel prepared an ¹⁸O-labelled acetonitrile complex of hypofluorous acid by simply bubbling dilute F2 through acetonitrile and ¹⁸O-labelled water. They performed a series of reactions of this complex with a variety of aliphatic and aromatic boronic acids at room temperature to produce a series of ¹⁸O-labelled alcohols within just a few minutes and in excellent yields – generally upwards of 90 per cent.

Read this ‘HOT’ ChemComm Communication for free:

The first general route for efficient synthesis of 18O labelled alcohols using the HOF⋅CH3CN complex
Shlomo Rozen, Julia Luria and Inna Vints
Chem. Commun., 2013, Accepted Manuscript
DOI: 10.1039/C3CC42337A

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ChemComm-RSC Prizes and Awards Symposium: Supramolecular Chemistry

19 Apr 2013

We invite you to join us for the ChemComm-RSC Prizes and Awards Symposium which will be taking place on 24 May 2013 in Dublin, Ireland.

This free one-day event will comprise of stimulating lectures reflecting the academic and industrial breadth of supramolecular chemistry, delivered by RSC Prize and Award winners and leaders in the field.

Confirmed Speakers:

Jerry Atwood, University of Missouri-Columbia – Winner of the 2012 RSC Supramolecular Award
John Callan, University of Ulster
Chris Chang, University of California, Berkeley – Winner of the 2012 RSC Chemistry of Transition Metals Award
Sylvia Draper, Trinity College Dublin
Phil Gale, University of Southampton – ChemComm sponsored lecture
David Leigh, University of Manchester – ChemComm sponsored lecture
Donal O’Shea, University College Dublin
Susan Quinn, University College Dublin
Eoin Scanlon, Trinity College Dublin
Jonathan Steed, Durham University – ChemComm sponsored lecture

We hope you and your colleagues will be able to attend the ChemComm-RSC Prizes and Awards Symposium. For further information about this event and to register, please visit the dedicated webpage.

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23rd International Symposium: Synthesis in Organic Chemistry

26 Feb 2013

The deadline for submitting poster abstracts for the 23rd International Symposium: Synthesis in Organic Chemistry is fast approaching – 11 March 2013.

The Synthesis in Organic Chemistry conference is the flagship event of the RSC’s Organic Division. This conference will provide an international showcase for the core area of organic chemistry – synthesis – covering all aspects of contemporary organic synthesis and providing a forum for the ever more exciting methodologies and strategies that continue to emerge.

Don’t miss out – reserve your poster presentation space for a chance to showcase your own work, and register early to take advantage of the £50 saving on the standard fee.

Remember too that there are a limited number of bursaries on offer for students and younger members of the RSC in the early stages of their career – worth £150.

Make sure you take the opportunity to join us to hear outstanding speakers across the many themes of the symposium in an extremely stimulating programme of plenary and keynote lectures.

Check out the event website to find out more – http://rsc.li/os23

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Novel silicon-mediated transannular cyclopropanation

23 Jan 2013

An intriguing new method of transannular cyclopropanation has been reported by Prof. James Dowden‘s group at the University of Nottingham. This cyclopropanation, mediated by the presence of a trimethylsilyl group, allows the rapid formation of 4-azabicyclo(5.1.0)octenones (3) from simple starting materials. Divinyl beta-lactam (1) was elegantly formed via a Staudinger cycloaddition reaction beginning from 3-trimethylsilylpropenal, 4-methoxyaniline and crotonyl chloride. Next, researchers were able to transform 1 into dihydroazocinone (2) using a thermal Cope rearrangement.

The Dowden group discovered that if 2 was treated with TBAF or aqueous sodium hydroxide, 4-azabicyclo(5.1.0)octenone (3) could be formed. Interestingly, the reaction was dependent on the presence of the silicon group; when the trimethylsilyl group was replaced with an ester, no cyclopropanation occurred. The researchers proposed that the transannular cyclopropanation could be viewed as a Lewis-base–promoted Hosomi–Sakurai reaction proceeding via intramolecular 1,4-conjugate addition. 4-azabicyclo(5.1.0)octenones (3) are an unusual structural motif and it is hoped that this facile method for their construction may facilitate further examination of chemical space interactions.

Read this ‘HOT’ Chem Comm article today:

An unusual silicon mediated transannular cyclopropanation

Bing You, Kate Hamer, William Lewis and James Dowden

Chem. Commun., 2013, 49, 795-797

DOI: 10.1039/C2CC37739J

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True racemic crystals: Surprising new insights on preparation and structure

16 Jan 2013

Isopropyl 3,3,3-trifluoro-2-hydroxypropanoate (1) is an important compound for the study of self-disproportionation of enantiomers (SDE), in which an enantiomerically enriched mixture can be separated into enantiopure and racemic portions under achiral conditions. This remarkable separation is made possible by the differences in physicochemical properties of enantiopure and racemic substances. Research led by Professor Vadim A. Soloshonok at the University of the Basque Country has now shed light on the unusual properties of racemic crystals of 1.

True racemic crystals were obtained by sublimation of a mixture of (S)- and (R)- crystal conglomerates at ambient temperature and atmospheric pressure. Surprisingly, when these racemic crystals were analysed, the unit cell was not dimeric in nature as previously thought, but rather contained two distinct (S)- and (R)- enantiomers with no heterochiral H-bonding. The preference of 1 for homochiral intermolecular interactions may explain its extraordinary ability for SDE. Indeed, Soloshonok and co-workers showed that achiral chromatography could be used to obtain enantiopure 1 from an original sample with just 75% ee (see above).

For more, read this ‘HOT’ Chem Comm article today:

Unconventional preparation of racemic crystals of isopropyl 3,3,3-trifluoro-2-hydroxypropanoate and their unusual crystallographic structure: the ultimate preference for homochiral intermolecular interactions

José Luis Aceña, Alexander E. Sorochinsky, Toshimasa Katagiri and Vadim A. Soloshonok

Chem. Commun., 2013, 49, 373–375

DOI: 10.1039/c2cc37491a

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Metal Free Thiolation Reactions of a Series of Heteroaromatics

12 Nov 2012

Aromatic compounds substituted with a C-S bond are of importance for pharmaceutical and medicinal chemistry, and materials science. A widely employed route to such compounds is a cross coupling reaction, between an aryl halide and a thiol, to yield a thioether. The reaction is usually mediated and catalysed by a metal centre such as palladium, indium or nickel, present as a salt or complex. In this communication, the authors report a high yielding, transition metal free route to aryl thioethers, using just a disulfide and a weak base, in a suitable solvent, under an inert gas.

The authors proved early in their study that a metal salt was not required for reactivity, with better yields being recorded for such reactions, versus a metal salt containing control. A further control reaction was carried out, to disprove the presence or effect of any trace transition metal by using ultrapure caesium carbonate (99.994% purity) and freshly distilled solvent.

The model reaction investigated and optimised was the thiolation of 2-phenyl-1,3,4-oxadiazole with di-p-tolyl disulfide. Reaction conditions which gave the best yields involved the use of 2 equivalents of base and 1,4-dioxane as solvent, under an argon atmosphere, for typically 18-24 h. 5 equivalents of disulfide were found to be the most effective. Using 7 equivalents gave no benefit to the final yield. Coincidently, the excess disulfide proved easily recoverable from the reaction mixture.

Electronic effects proved to be important in the reactivity of the phenyl-oxadiazoles with electron donating groups present on the arene promoting the reaction and electron withdrawing groups having a negative effect. The reaction also shows a good degree of robustness in being effective in thiolating indole and 5-methyl-indole at the 3 positions in excellent yield, as well as other substrates such as caffeine and benzimidazole.

This synthetic methodology represents an important simplification in the preparation of heteroaromatic thioethers, and should prove of interest to synthetic chemists, particularly in the areas of medicinal chemistry, materials science and total synthesis.

Read this HOT Chem Comm article today (free to access until the 7th of December 2012):

Transition metal-free direct C–H bond thiolation of 1,3,4-oxadiazoles and related heteroarenes

Liang-Hua Zou, Jens Reball, Jakob Mottweiler and Carsten Bolm, Chem. Commun., 2012, 48, 11307–11309

Published on behalf of Kevin Murnaghan, Chemical Communications web science writer.

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Biocatalysis: an article collection

05 Oct 2012

Beers, wines and cheeses are enjoyed around the world today and have been for millennia. In fact the practices of brewing and cheese-making pre-date recorded history so it is difficult to accurately determine when we first started using naturally occurring enzymes and microorganisms to create valuable (and in this case, tastier!) products.

Biocatalysts are of course used in far more diverse applications than the creation of food-stuffs, including in many organic syntheses and in the generation of fine chemicals. Due to their natural design, they can offer superior selectivity for particular products and have a far lower environmental impact than many traditional catalysts. Our knowledge and understanding of biocatalysts has increased dramatically in the last few decades, which has allowed us to develop biologically modified and biomimetic catalysts for a range of applications.

To keep you up to date with the latest advances in this rapidly expanding field we have collected together these high impact articles and made them free to access until the 31^st October!

Click here for the full list of free articles

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A look at Gregynog 2012

03 Oct 2012

The annual Gregynog Synthesis Meeting was recently held at Gregynog Hall (Thursday 13^th to Saturday 15^th September), amidst the stunning beauty of mid-Wales and accompanied by fair weather. A group of 55 chemists came together to discuss recent progress in organic synthesis. As befits such a broad remit, the range of stakeholders present was pronounced with academic, industrial and scientific publishing attendees all present. As synthesis is an enabling and under-pinning scientific discipline, it was perhaps not surprising to see the range of contexts in which speakers discussed their synthesis. Catalysis, methodology and natural product chemistry were not-surprisingly representative; however, the audience was also treated to medicinal, process and supramolecular chemistries.

The relaxed and residential character of this event helps to encourage a collegiate ethos, helping to welcome younger chemists into the wider synthesis community. Such an ethos facilitates the discussion of initial results on new and adventurous projects in a supportive environment. In this regard, the fresh-faced Dr David France (University of Glasgow) struck a chord with the audience through his imaginative Pd-catalysis work.

The meeting is structured around the complementary formats of a number of short “chalk+talk” presentations (15 minutes with lively discussion and questions) supporting the two main keynote speakers in the evening, one of which has travelled beyond these shores. These keynote speakers have the opportunity to convey what exactly has made them the international names they are. What does the genesis of an idea require? How do the independent research strands in a research group interact with each other? And, importantly for the younger colleagues, how are difficult scientific challenges conquered? The Thursday evening saw Prof Jonathan Clayden (University of Manchester) present the Chemical Communications keynote talk and embraced the meeting’s ethos with a career spanning discussion of the intertwining chemistry problems his group have tackled. The Friday evening session had Prof Dirk Trauner (LMU, Münich) present the Nature keynote talk. Earlier in the meeting, a member of the organising committee had suggested that his talk would be all the better, fitting the meeting’s remit, if he presented lots of “failed reactions” as a vehicle to conveying how he tackled organic synthesis problems. In this respect, it was a delight to later find, in my opinion, the most visually striking slide in a chemistry presentation I have yet seen. Prof Trauner went the extra mile in passing on his undoubted experience in synthesis problem-solving with some exquisite answers and suggestions. These keynote talks, as indeed were the short presentations, were interspersed with comments, suggestions and questions from the floor, indicative of the discerning yet approachable audience.

Finally, the Dave Kelly cup is awarded annually to a chemist who has engaged the audience with difficult concepts in a concise manner, with clarity at the chalk board. This prize is awarded in memory of our colleague Dr Dave Kelly, who was, for many years, synonymous with this important pillar in the synthesis calendar. Without doubt, Dr Steve Goldup (QMUL) was the chemist who hit the spot in this regard. The cup is on the way to the East End as I type.

Posted on behalf of Dr David Carbery, University of Bath

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