SYNFORM is available as part of the online editions of SYNTHESIS, SYNLETT and SYNFACTS through Thieme eJournals. This supplementary feature is available free of charge. SYNFORM presents people, trends, and views in synthetic organic chemistry with direct links to all quoted original papers. To view or download issues of SYNFORM, please click here.
Do you like good food? I would guess the answer is a unanimous yes. But what is “good food”? Here I am afraid we would not have a unanimous answer, although some degree of agreement is expected in some cases. For example, most of you would recognize Italian “lasagne”, French “crepes” and Japanese “sushi” as delicious. However, it all comes down to the personal taste because some others like Scottish “haggis” or French “escargots” or Italian “trippa” which personally I don’t find particularly attractive... Let’s take a globalized, apparently very simple food like pizza. What makes a good pizza? Have you ever tried a wood fired oven baked “pizza margherita” in a typical restaurant in the Naples area? It’s an extremely simple, yet delicious food, and what makes it really fantastic is the combination of a handful of basic ingredients: mozzarella and tomato on a fragrant layer of pizza bread, with a few basil leaves (personally I love to add a few drops of good “extravergine” olive oil). You don’t need many sophisticated or unusual toppings to make a fantastic pizza, just the combi - nation of two or three simple, well-chosen and tasty ingredients. Are you hungry now? If yes, you might want to have a good pizza tonight for dinner, but let me just conclude my thought before heading to a pizzeria. Personally, I am convinced that, like a good pizza comes from simple ingredients cooked in just five minutes, a brilliant idea comes from the combination of few simple and linear thoughts which simultaneously enter your mind at the right moment and come out as a flash of genius. Simplicity is the key, for good food as well as for good ideas! And if you can resist a few more minutes before biting your well deserved pizza, you might want to have a look at this new issue of SYNFORM which is full of tasty and creative chemistry. The first SYNSTORY is about a novel enantioselective organocatalytic cyclization process developed by B.-C. Hong (Taiwan). The second SYNSTORY deals with a synthetically very useful radical cyclization reported by J. Lebreton and F. Dénès (France). Last but certainly not least, the fascinating organometallic synthesis of long helicenes reported by I. Starý (Czech Republic). Enjoy your pizza! Pardon, your reading...
Cascade reactions are extremely attractive in terms of synthetic efficiency, particularly when they allow for the preparation of complex structures with good stereochemical control. Recently, Professor Bor-Cherng Hong and his coworkers from the National Chung Cheng University (Taiwan) have discovered a novel organocatalytic enantioselective cascade nitro-Michael–Michael–Wittig reaction involving a dynamic kinetic asymmetric transformation. This annulation reaction provides a simple and direct protocol for the stereoselective construction of trisubstituted cyclohexenecarboxylates in a multicomponent one-pot operation.
To read more please download SYNFORM 2010/03 online, free of charge.
Over the last two decades, free-radical chemistry has increasingly attracted the attention of organic chemists, result - ing in the development of new efficient tools to achieve functional group transformation as well as carbon–carbon and carbon–heteroatom bond formation. The methods that have come from this work have found numerous applications in organic synthesis. Recently, the group of Professor Jacques Lebreton from the University of Nantes (France) published a novel methodology based on the use of free radicals generated from α-bromo aluminum acetals, which holds remarkable potential for organic synthesis.
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In the realm of organic chemistry there are numerous fascinating structures, and unquestionably helicenes are among them. For over five decades, these chiral screw-like molecules consisting of all-ortho-fused benzene rings have attracted significant attention but they were predominantly considered fascinating stereochemical curiosities rather than useful organic materials. Nowadays, the situation is different. A race for finding new intriguing helicene applications has recently started hand in hand with remarkable advances in their synthesis. “That is not surprising as more complex molecules become generally more fashionable and, therefore, attractive utilizations of helicenes in enantioselective catalysis and technology- oriented science can be envisaged,” said Dr. Ivo Starý from the Academy of Sciences of the Czech Republic in Prague.
To read more please download SYNFORM 2010/03 online, free of charge.
This winter is bringing lots of ice and snow in many parts of Europe, including the UK, where we are experiencing an unusually tough and freezing season. Does this mean that global heating is just a legend? Clearly not, as other places in the Northern Hemisphere are currently seeing weather that is unseasonably warm. What is definitely sure is that these days most of us need something hot to compensate the wintry conditions. What about some hot chemistry? If you think this would help, then you are in the right place because this issue of SYNFORM is full of very hot science! In the first SYNSTORY, for example, Professor Rainer Mahrwald (Germany) illustrates a new organocatalytic process allowing for the synthesis of stereodefined quaternarystereocenters from enolizable aldehydes. In the second SYNSTORYProfessor Jon A. Tunge (USA) tells us more about his recent intermolecular redox amination leading to N-alkylpyrroles. Not enough to heat up? You can try with some sunlight from Italy, which, as explained by Professor Maurizio Fagnoni, can also be used to photocatalyze different alkylation reactions. And if, after reading all this, you still feel cold, you can always try with a hot drink but at least. I hope you enjoyed the reading...
Environmental concerns in organic synthesis are increasing and require a reconsideration of all the aspects of chemical processes. An ideal eco-friendly process must take place efficiently starting from non-toxic and cheap substrates, minimizing the amounts of additives, solvent (unless water is chosen) and external energy involved. A very interesting contribution to the development of “green chemistry” has been recently achieved by the group of Professor Maurizio Fagnoni from the University of Pavia (Italy), which authored a communication describing novel selective activations of C–H bonds driven by sunlight.
To read more please download SYNFORM 2010/02 online, free of charge.
According to Dr. Rainer Mahrwald from the Humboldt University of Berlin (Germany), the direct asymmetric crossaldol addition of two different enolizable aldehydes has been a challenge in organic chemistry since time immemorial. “With the exception of enzymatic catalysis (W.-D. Fessner, In Modern Aldol Reactions, Vol. 1; R. Mahrwald, Ed.; Wiley-VCH, 2004, 201.), no reaction conditions have been found that both suppress side reactions and, at the same time, sufficiently discriminate between the different reactivities of the aldehydes,” explained Dr. Mahrwald.
To read more please download SYNFORM 2010/02 online, free of charge.
The development of environmentally friendly and economically sustainable methods is one of the current priorities in the area of organic synthesis. Catalysis offers an increasing number of potential solutions to a wide range of synthetic problems, but there is still a strong need for more efficient technologies characterized by high atom-economy and the use of non-hazardous chemicals and procedures. An important achievement was reported recently by the group of Professor Jon A. Tunge from the University of Kansas (Lawrence, USA), who developed an intermolecular redox amination process that produces a wide range of N-alkylpyrroles. The new method features excellent atom-economy, high yields and user-friendly experimental protocols.
To read more please download SYNFORM 2010/02 online, free of charge.
Cycloaddition reactions are very useful tools in an organic chemist’s arsenal and have found countless applications in synthesis. Classically, these reactions involve a dipole and a dipolarophile, although several classes of compounds are known to behave as masked dipoles. Among them, appropriately functionalized cyclopropanes are known to be effective substrates in dipolar cycloadditions, whereas the homologous com pounds (cyclobutanes) are much less recognized as masked dipoles in spite of their high ring-strain energy. Recently, Professor Jeffrey S. Johnson from the University of North Carolina (USA) described a powerful methodology which makes use of functionalized donor–acceptor cyclobutanes in a formal [4+2] cycloaddition with aldehydes to give substituted tetrahydropyrans.
To read more please download SYNFORM 2010/01 online, free of charge.
Silole-based π-electron systems are currently receiving much attention as new organic optical materials because of their low-lying LUMOs. π-Extended silole derivatives show desirable properties, such as high fluorescence quantum yields and high glass-transition temperatures. Various synthetic methodologies for the construction of the silole framework have been developed so far. However, these methodologies have been limited to the synthesis of ladder-type or spiro-type compounds. Recently, the group of Professor Takayuki Kawashima and Dr. Junji Kobayashi from the Department of Chemistry, The University of Tokyo (Japan), reported a further step towards the exploration of silole systems; namely, the synthesis of benzosilole derivatives.
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This issue of SYNSTORY features catalysis by metal complexes as the common element of the three SYNSTORY articles. Professor D. Seidel (USA) describes his recent methodology for achieving the synthesis of ring-fused tetrahydroisoquinolines using an intramolecular hydride-shift triggered by a Mg(II)-DBFox ligand. In the second SYNSTORYProf. X. Hu (Switzerland) shows how new Ni(II) pincer complexes can catalyze a functional-group-tolerant Kumada–Corriu–Tamao coupling producing a wide range of aryl- and heteroaryl-alkyl compounds. Last but not least, Professor M. Lautens (Canada) elaborates on his recent synthesis of benzothiophenes using a quite rare Pd-catalyzed vinylation of thiols. Metals rule!
According to Professor Daniel Seidel from the Department of Chemistry and Chemical Biology of Rutgers University (New Jersey, USA), there is a major current focus on the development of methods that lead to the direct functionalization of relatively unreactive C–H bonds. “Exciting progress in this highly competitive and intensely active research area has been achieved and many more advances can be anticipated,” said Professor Seidel.
To read more please download SYNFORM 2009/08 online, free of charge.
Csp2–Csp3 coupling reaction of aryl or heteroaryl organomagnesium reagents with non-activated primary and secondary alkyl halides is an attractive method for the synthesis of the corresponding aryl- or heteroaryl-alkyl derivatives, but the presence of sensitive functional groups can make the reaction difficult. Recently, the group of Professor Xile Hu from the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland reported a valuable methodology to perform a functional-group-tolerant Kumada–Corriu–Tamao (KCT) coupling which proceeds under mild reaction conditions and leads to short reaction times.
To read more please download SYNFORM 2009/08 online, free of charge.
The efficient synthesis of sulfur-containing heterocycles remains a rather challenging endeavor, particularly when using catalytic methods based on metal catalysts, despite the importance of thiophenes and related structures in drug discovery and materials science. Recently, the group of Mark Lautens, a Professor of Organic Synthesis from the University of Toronto (Ontario, Canada) and an Editorial Board Member of Synthesis and Synfacts, reported a novel palladium-cata lyzed process which conveniently produces functionalized benzothiophenes.
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There is little doubt that Chinese chemistry is becoming a major player in the global arena of international science. In a period when most of the Western countries are cutting research expenses and funding is becoming increasingly tight, P. R. of China is boosting its investments in science and technology, and the effects are evident both in terms of quantity and quality of the Chinese research production, including patents and publications. It is therefore not surprising that two SYNSTORIES in this issue of SYNFORM come indeed from the P. R. of China: Professor Weike Su (Zhejiang University) and his new approach to benzo naphthyridines, and Professor Ning Jiao (Peking University) and his direct transformation of methyl arenes to aryl nitriles. The issue is completed by a brief report on the 19th International Symposium on Fluorine Chemistry that was held from August 23–28, 2009, in Jackson Hole, Wyoming, USA.
Efficient and selective functionalization of benzyl C–H bonds has been an interesting topic in recent years due to the potential application of this synthetic strategy in concise and economical organic synthetic processes. However, the related developments are limited. Recently, an important advance in this area of research was published by the group of Professor Ning Jiao from Peking University, Beijing (P. R. of China), who showed that a toluene derivative can be transformed into the corresponding benzonitrile using a simple yet powerful procedure.
To read more please download SYNFORM 2009/08 online, free of charge.
New synthetic methods to effectively prepare heteroaromatic structures are of great interest in medicinal chemistry and drug discovery, and represent a priority research area for the pharmaceutical industry. Recently, an interesting piece of research in this area was published by the group of Professor Weike Su from Zhejiang University (P. R. of China) which disclosed a very efficient entry to benzonaphthyridines using a Morita–Baylis–Hillman reaction followed by an amination reaction involving the intermediate acetates.
To read more please download SYNFORM 2009/08 online, free of charge.
I am writing this short Editorial while I am flying over the Atlantic Ocean, back to Aberdeen (Scotland, UK) from Jackson Hole (Wyoming, USA), where I have attended the 19th International Symposium on Fluorine Chemistry (a special section about this very well organized conference will be featured in the next issue of SYNFORM). Here, in this short night, 11 km higher than the huge (and a bit frightening to me...) ocean, I am trying to finalize this issue of SYNFORM, as sleep doesn’t come even though I am dead tired. Curiously, I am realizing just now that all of the three SYNSTORIES cover the work of Japanese scientists; as far as I remember this is the first time that such a total predominance occurs. Well deserved predominance, I would say. In the first SYNSTORY, Professor S. Kobayashi (Tokyo) explains how to use simple aqueous ammonia to synthesize primary amines with high yields and selectivity. Then, Professor K. Itami (Nagoya) explains how his group was able to achieve the synthesis of [12]cycloparaphenylene. Last but not least, Professor F. Kakiuchi (Yokohama) tells us more about his recent catalytic synthesis of hexaarylanthracenes.
“Can you imagine how embarrassing it is for chemists to accept that there exist many aesthetically appealing molecules that can be easily assembled with molecular models by kids, but not in the flask by us?,” asked Professor Kenichiro Itami from the Nagoya University, Japan.
To read more please download SYNFORM 2009/07 online, free of charge.
Ammonia is one of the most attractive nitrogen sources from a cost and atom-economical point of view, and increasing attention has recently been paid to the direct use of ammonia as a nitrogen source for organic synthesis. Now, according to Professor Shu Kobayashi from The Department of Chemistry, University of Tokyo (Japan), it is possible to use aqueous ammonia for palladium-catalyzed allylic amination to prepare primary allylic amines.
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In late 1993, a new synthetic procedure using carbon–hydrogen bonds as a functional group was reported by Murai and co-workers. This reaction enabled efficient and selective introduction of alkyl groups onto aromatic rings via regioselective carbon-hydrogen bond cleavage and opened a new research area in organic synthesis.
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I am writing this brief editorial while spending my holidays in Sardinia. Right now, I am on a terrace with a wonderful view of the sea, blue sky, a delightful breeze and an ice-cold cocktail. But SYNFORM can’t wait; therefore, my laptop had to come out from the bag where it spent one entire week of unusual rest. But I am sure it’s a worth deal, because also in this issue SYNFORM features very interesting science. In the first SYNSTORY Professor Chiba from Singapore discloses new information about his novel approach to isoindoles and isoquinolines, whereas in another SYNSTORY Professor Soai from Japan explains how he and his co-workers were able to publish the first example of stereoselectivity controlled by stereogenic centers bearing 12C or 13C carbon isotopes. The issue is closed by a brief report on the Thieme-Chemistry Journals Editorial Board Meetings recently held in Granada (Spain).
Nitrogen-containing heterocycles (azaheterocycles) are im - portant and widespread structures, present in numerous natural products, potent pharmaceutical drugs, and various kinds of functional materials. Although a number of diverse synthetic approaches toward azaheterocycles have been developed it is still highly desirable to exploit versatile methodologies to construct such molecules with selective control of substitution patterns using readily accessible building blocks. The group of Professor Shunsuke Chiba from the Nanyang Technological University in Singapore has recently been interested in the chemical reactivity of organic azides to synthesize azaheterocycles via various types of C–N bond formations.
To read more please download SYNFORM 2009/06 online, free of charge.
The origin of homochirality of biomolecules such as Lamino acids and D-sugars has attracted significant interest of many researchers. Many apparently achiral molecules may be chiral because of random substitution of the 1.1% naturally abundant 13C for 12C.1 Hydrogen isotope chirality (H/D) in a polymer has been shown to cooperatively control macromolecular helical handedness.
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The 2009 Editorial Boards Meeting of the Thieme Chemistry journals SYNLETT, SYNTHESIS and SYNFACTS, including the supplement SYNFORM, was held on June 5th and 6th in the city of Granada (Spain). The Editorial Boards of the three journals and the staff of the Thieme Chemistry editorial office met at the Alhambra Palace Hotel. A manuscript submission system and initiatives to further increase the quality of the journals were among the most relevant issues which were discussed in a friendly and relaxed atmosphere.
To read more please download SYNFORM 2009/06 online, free of charge.
the Thieme Chemistry Editorial Board Meeting 2009 is looming (further information about it will be provided in the next issue of SYNFORM); this time we are about to meet in Granada (Spain). While waiting for this important event which will set the future goals and the statement of direction for the three Thieme Chemistry journals SYNLETT, SYNTHESIS and SYNFACTS, this issue of SYNFORM visits three important research labs, well known for their contributions in the field of organic synthesis. The first SYNSTORY brings you to Switzerland, where Professor D. Seebach and his group give us an insight intotheir recent discoveries in the field of organocatalysis intermediates. The second SYNSTORY reports on a totally new synthetic strategy developed by the group of Professor I. Marek (Israel) to prepare aldol frameworks. Last but not least, the group of Professor P. G. Cozzi (Italy) describes a new or ganocatalytic strategy for the asymmetric α-alkylation of aldehydes.
Those who think that nothing conceptually new remains to be invented in the realm of synthetic methodology should perhaps give a glance to the recent article published by the group of Professor Ilan Marek from the Technion – Israel Institute of Technology (Haifa, Israel). In this paper, in fact, an aldol frame - work is disconnected and synthesized according to an original and innovative perspective, without any real sacrifice in terms of synthetic efficiency.
To read more please download SYNFORM 2009/05 online, free of charge.
The exact nature of reactive intermediates in organocatalytic reactions, particularly those involving proline (and derivatives) and chiral imidazolidinones, is still a matter of considerable debate. Considerable progress in the field has been achieved recently by the group of Professor Dieter Seebach from the Department of Chemistry and Applied Biosciences of the ETH Zürich (Switzerland).
To read more please download SYNFORM 2009/05 online, free of charge.
Catalysis using chiral secondary amines (asymmetric aminocatalysis) has recently increased opportunities in the domain of stereoselective catalysis through catalytically generated covalent intermediates. These intermediates, formed by unique and peculiar aminocatalytic activation modes, provide new solutions for challenging synthetic problems. “Even reactions considered impossible have become a reality through aminocatalysis!,” confirmed Professor Pier Giorgio Cozzi from the Chemistry Department of the University of Bologna (Italy).
To read more please download SYNFORM 2009/05 online, free of charge.
for the first time this editorial is, to a large extent, autobiographical. In fact, I would like to share with you my excitement for a big change that is going to happen in my life and career: I accepted the NRP (Northern Research Partnership) Chair in Medical Technologies at the University of Aberdeen, Scotland (UK), and I will soon move to the Highlands with my family. My research group will be based mainly at the Institute of Medical Sciences (IMS), which opened in 1996 and currently is home to ca. 130 principal investigators leading important biomedical research in a variety of fields. The University of Aberdeen, and particularly the College of Life Sciences and Medicine, recently decided to integrate organic chemistry into the research activities of the IMS, with an emphasis on medicinal chemistry. Furthermore, it was decided to potentiate the chemical research in support of the Bio medical Imaging Center, within the frame of the NRP. I feel lucky for having been chosen to address these exciting scientific challenges, even though I heard that the weather in the Highlands is not as good as in Italy... Despite the presumably bad Scottish weather, I am by no means planning to give up my editorial activity for SYNFORM that will continue exactly as it used to be. This is further demonstrated by the three new SYNSTORIES featured in this issue of SYNFORM, which highlights the exciting discoveries recently reported by the groups of C. D. Bray (UK), G. Cahiez (France) and P. Knochel (Germany).
Spiroketals are found in a huge range of natural products. The simplest examples are found as insect pheromones, with each enantiomer being gender-specific. They are also building blocks in a number of incredibly complex compounds such as spongistatin and okadaic acid. Significant work has been carried out by a number of research groups looking into the synthesis of molecules, where the spiroketal moiety is invariably formed via an acid-catalyzed spirocyclization of a suitable keto-diol precursor or its equivalent.
To read more please download SYNFORM 2009/04 online, free of charge.
In these last years, sustainable development has led organic chemists to search for less expensive and more eco-friendly reactions. As an example, in the field of transition-metal-catalyzed cross-coupling reactions, a very important effort was made to replace palladium or nickel by iron. Manganese is also an interesting candidate (Chem. Rev. 2009, 109, 1434). A very efficient manganese-catalyzed aryl–aryl coupling was described some years ago (Synthesis 1999, 2138). It is applied for on industrial scale for the production of an intermediate used in the synthesis of Irbesartan®, an antihypertensive drug from Sanofi Aventis.
To read more please download SYNFORM 2009/04 online, free of charge.
The synthesis of complex molecular frameworks using economically and environmentally sustainable methodologies is becoming an absolute research priority in organic chemistry. The Kumada cross-coupling allows a direct Pd-catalyzed carbon–carbon bond formation between unsaturated halides and organomagnesium reagents (without further transmetalations) and is therefore a highly atom-economical cross-coupling reaction. Recently, the group of Professor Paul Knochel from the Ludwig Maximilians University Munich (Germany) described a novel strategy that makes it possible to perform a Kumada cross-coupling via radical catalysis at room temperature, using short reaction times and inexpensive reagents like aryl bromides, including functionalized ones, in the presence of an alkyl iodide.
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this issue features three SYNSTORIES which highlight important advances in the art of synthesis. The first article reports on an industrially important transformation, the synthesis of aromatic azo compounds, that is now possible through a direct oxidation from anilines which in turn can be obtained by reduction of the corresponding nitroaromatics using the same gold catalyst. This striking achievement is due to the work of Professor Avelino Corma and his group from the University of Valencia (Spain). The second SYNSTORY covers a novel methodology for the synthesis of important compounds like halogenated heterocycles, based on the use of a rather peculiar and inexpensive reagent like a pool sanitizer (trichloroisocyanuric acid) developed by Professor Roman Dembinski and co-workers (USA). The third SYNSTORY reports on a conceptually innovative, exciting methodology for converting, in a stereocontrolled manner, chiral secondary alcohols into teriary alcohols using boron reagents, as described in the original Nature report by Professor Varinder K. Aggarwal (UK).
Organic chemistry is doing an outstanding job in creating new highly complex molecules. Meanwhile, it has been responsible, in conjunction with catalysis and chemical engineering, for many manufactured products that improve both the quality and length of our lives. However, when one reviews industrial processes involving the production of chemicals, one sees that there are still cases where dangerous and/or sacrificial stoichio - metric reactants are being used. Now, the group of Professor Avelino Corma from the University of Valencia (Spain) has developed a novel technology allowing for the direct oxida tion of anilines and nitroaromatics to azo compounds, in high yields and selectivities, by exploiting a novel gold catalyst.
To read more please download SYNFORM 2008/03 online, free of charge.
The development of simple and inexpensive procedures for the preparation of complex building blocks, like halogenated heterocycles and their derivatives, continues to be an important area of research. Recently, Professor Roman Dembinski and his co-workers Dr. Adam Sniady and Marco S. Morreale from the Oakland University (Rochester, USA), together with Professor Kraig A. Wheeler from the Eastern Illinois University (Charleston, USA), described a novel electrophilic halocyclization reaction that represents an efficient and potent methodology leading to functionalized heterocycles by a tandem cycloisomerization–halogenation processes.
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A straightforward and enantiodivergent reaction allowing for the preparation of tertiary alcohols in both optical forms starting from a single enantiopure secondary alcohol was a sort of dream reaction for organic chemists. Now such a process has become reality thanks to the work of Professor Varinder K. Aggarwal and his group from the University of Bristol (UK). This striking methodology, which has a broad scope as it can be used for the synthesis of both cyclic and acyclic tertiary carbinols, is based on the formation of an intermediate carbon–boron bond from a metalated N,N-diisopropyl carbamate (Cb) alcohol derivative.
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Recently, Professor Victor Snieckus from the University of Kingston (Ontario, Canada), who is a Regional Editor of SYNLETT, wrote in a letter to Chemical & Engineering News (2009, no. 2, 4) that “green chemistry is defined as attempting to do chemistry the way Nature does chemistry” thus emphasizing “how incompetent we (especially organic chemists) ... are in the lab compared to Nature’s ways.” I think this definition captures very well the current level of chemistry, and particularly of organic chemistry, which remains way too far from the efficiency the World would need. However, organic chemists are working hard to meet that challenging goal. This is also well demonstrated by the high level of innovation and originality featured by the pieces of research highlighted in this issue of SYNFORM. Direct ?-functionalization of amino acids and small peptides was achieved by the group of Professor C.-J. Li (Canada), while Professor S. D. Lepore (USA) found an amazingly simple and direct method to displace hydroxy groups by many nucleophiles in a stereoretentive manner. Finally, Professor S. G. Nelson (USA) developed a versatile new entry to nitrogen-containing heterocycles using N-alkenyl iminium ions as heterodienes in Diels–Alder-type reactions. We are still far from Mother Nature’s efficiency, but work is definitely in progress...
Direct ?-functionalization of ?-amino acid derivatives with nucleophiles has recently attracted much interest in the field of organic chemistry due to the fact that ?-amino acid derivatives can be used as nucleophiles by first letting them react with a stoichiometric amount of base. The carbanion thus formed will be able to undergo several reactions, such as substitutions with electrophiles, Claisen rearrangements, and tran sition-metal-catalyzed cross-coupling reactions.
To read more please download SYNFORM 2009/02 online, free of charge.
Having played a key role in such powerful reactions as the Mukaiyama aldol and the Nobel prize winning Sharpless epoxidation, titanium(IV) reveals its utility once again in a recent contribution from the group of Professor Salvatore D. Lepore from the Florida Atlantic University, Boca Raton (USA) on stereoretentive and chemoselective halogenations and azidations of hindered secondary sulfonates. “For the first time,” said Professor Lepore, “alcohols as their sulfonates can now be converted into azides with retention of configuration without having to resort to a double inversion technique. In addition, this method actually favors more hindered substrates and is thus complementary to SN2-based methods.”
To read more please download SYNFORM 2009/02 online, free of charge.
Nitrogen-containing heterocycles, including piperidine structural motifs, are ubiquitous substructures in a myriad of biologically active natural products and small-molecule pharmaceuticals. Accordingly, a wide range of target-directed and diversity-oriented synthesis activities are devoted to heterocycle synthesis. Recently, the group of Professor Scott G. Nelson from the University of Pittsburgh, Pennsylvania (USA) reported a novel approach to piperidine scaffolds based on a hetero-Diels–Alder reaction employing N-alkenyl iminium cations as heterodienes. “As part of our research in the University of Pittsburgh Center for Chemical Methodologies and Library Development (UPCMLD),” said Professor Nelson, “we were interested in developing reactions capable of generating structurally complex and diverse heterocycles in a single operation from readily available reaction components.”
To read more please download SYNFORM 2009/02 online, free of charge.
The “2nd EuCheMS Chemistry Congress” was held in Turin (Italy) from September 16–20, 2008. About 2100 attendees (in line with the 1st EuCheMS held in Budapest, Hungary, in 2006), including four Nobel Prize awardees, seven plenary lectures, a number of “key note” and “invited lectures”, 270 oral communications and 1250 poster communications, distributed over 25 scien - tific sessions are the main numbers of this conference. The congress was flanked by the initiative “Chemistry Meets the Public”, with many authoritative speakers, who helped informing young people and the general public about the importance of chemistry in the modern world. An exposition featuring about 40 exhibitors was also available. My personal feeling is that the EuCheMS is still far from reaching the quality and quantity of the ACS Conferences, but work is in progress and the perspectives are rather promising. This issue of SYNFORM features two SYNSTORIES reporting on communications presented at the 2nd EuCheMS. The 3rd SYNSTORY is dedicated to an important work published by the group of Professor J. Barluenga (Spain), dealing with the biocompatible modification of unprotected peptides in water. The issue is completed by a brief report on a recent symposium on fluorinated peptides that was held in Tokyo (Japan).
Positron emission tomography (PET) is a medical imaging technique for investigating physiological parameters, such as blood-flow studies, glucose metabolism, receptors properties, or drug distribution, in living human and animal bodies (Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 9226). PET imaging in volves different steps, among which is the chemical synthesis of an appropriate radiotracer. This radiotracer is a significant molecule, for example, a ligand bearing a short-lived radio isotope, like 18F or 11C, produced by a biomedical cyclotron. After its intravenous injection, the radiotracer fixes onto tissues, and imag ing with a PET camera allows for localization of the radiotracer, and this in turn can be used for a medical diagnosis. 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) is commonly used as a radiotracer to follow glucose metabolism and hence to de -tect tumor cells, which have a strongly enhanced metabolism. The chemistry of this radiotracer is well developed and its use has been implemented in hospitals.
To read more please download SYNFORM 2009/01 online, free of charge.
The conjugate addition reaction of aldehydes to nitroolefins has been a focus of research in recent years since it provides γ-nitroaldehydes as versatile building blocks to a plethora of other compound classes. The use of organocatalysts represents an efficient and straightforward route to perform this im portant process. Among the different types of organocatalysts, peptides are an attractive yet scarcely explored tool. “‘It is impossible that short-chain peptides can function as catalysts’ was typically heard in the last century from scientists reflecting on the possibility of applying peptides as catalysts,” said Professor Helma Wennemers from the Department of Chemistry, University of Basel (Switzerland). This is not surprising since the flexibility of short-chain peptides is typically high. Thus, predicting the conformation of a peptide, and even more so its catalytic activity, is a significant challenge.
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Site-selective chemical modification of peptides and proteins is an important tool for understanding the function of these ubiquitous compounds. Among the possible structural variations, modification of aromatic amino acids would be particularly desirable, but few efficient methods are available to functionalize aromatic groups in peptides or proteins. Recently, the group of Professor José Barluenga from the University of Oviedo (Spain) in collaboration with Dr. Gregorio Valencia and Dr. Gemma Arsequell from the CSIC of Barcelona (Spain), reported a novel methodology for the functionalization of phenylalanine and tyrosine aryl groups of unprotected peptides through a Suzuki–Miyaura reaction taking place in water as solvent.
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The Ochanomizu University of Tokyo, one of the two national women’s universities in Japan, recently hosted “The International Meeting on Fluorinated-Peptide Chemistry”, held in conjunction with the “Ishikawa-Kobayashi Fluorine Symposium”, named after the two Japanese fluorine chemists Professor Nobuo Ishikawa (1926–1991) and Professor Yoshiro Kobayashi (b. 1924). The event was organized by Dr. Tomoko Yajima of Ochanomizu University, supported by Professor Koichi Mikami from the Tokyo Institute of Technology (Japan) and by the “Career Opportunity Support Model from Ocha nomizu Scientists”. The one-day symposium featured a good scientific program with an international group of speakers, who gave an overview of the current status of the emerg ing field of fluorine-containing peptides and proteins, and contiguous areas of research.
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This last 2008 issue of SYNFORM comes in a period of deep global financial depression. It is not clear yet how and how much the crisis will affect scientific research, but in the long run one could expect hard times in terms of further tightening of resources and funding, particularly in those countries (such as my own) where science is considered all but a priority. Fortunately the crisis does not involve the creativity of scientists, particularly of those who are protagonists of the SYNSTORIES featured in this issue of SYNFORM. Indeed, great creativity is one of the many merits of Professor C. Bertozzi (USA) who recently discovered how to harness the potential of click chemistry in in vivo systems. And creativity is one of the main components in the total synthesis of the antibiotic platencin, developed by the group of Dr. D. Chen and Professor K. C. Nicolaou (Singapore/USA). When it comes to design a novel stereocontrolled synthetic approach to allenes, creativity becomes a key element of success, as demonstrated by the work of Professor J. M. Ready (USA). Last but not least, how much creativity is needed to miniaturize a windmill to a nanomill, as exemplified in a communication presented at the ACS Philadelphia meeting by Professor B. L. Feringa and coworkers (The Netherlands)? A lot, I guess...
Recently the group of Professor Carolyn R. Bertozzi from the University of California, Berkeley (USA), introduced a difluorinated cyclooctyne reagent having enhanced reactivity toward azides. This first generation reagent, dubbed DIFO, was demonstrated to undergo reaction with azides on intact proteins even in the absence of Cu(I), at a comparable rate to that of Cu(I)-catalyzed click chemistry. The main drawback of DIFO was represented by its difficult preparation, comprising 12 overall steps and an overall yield of about 1%. Recently, Professor Bertozzi and coworkers reported the second-generation DIFO reagents, featuring a greatly simplified synthesis and holding a strong potential to become very important tools for the site-selective labeling of biomolecules.
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In recent years, the rampant emergence of drug-resistant pathogens has escalated the search of novel antibiotics to new heights, and the discovery of platensimycin and platencin by the Merck team in 2006 generated much excitement within the scientific community. In a combination between classical highthroughput screening and the application of RNA-silencing technology, these compounds were identified as potent and selective inhibitors of the condensing enzymes involved in the bacterial fatty-acid biosynthesis (Fab) pathway. As these targeted enzymes are highly conserved among the clinically important pathogens, the broad-spectrum activities of platensimycin and platencin are particularly noteworthy.
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Allenes are cumulated dienes endowed with a rigid and linear double bond array, and a very interesting and rather peculiar reactivity. However, the synthesis of allenes, particularly in stereodefined manner, poses some challenges despite the presence of some versatile methodology in the arsenal of the synthetic chemist. Recently, Professor Joseph M. Ready and postdoctoral fellow Xiaotao Pu, both from the University of Texas Southwestern Medical Center in Dallas (USA), reported a significant advancement in the field.
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this is a significant innovation in stereoselective synthesis. as we all know that optically active allenes are difficulty to make, which call for a advanced method.
Posted By: jeff de branbender on Jul 02, 2009 08:50AM
Biomolecular motors are omnipresent in natural systems where they are used for different tasks. Much of the mechanical work in biological systems is performed by coherent supramolecular structures utilizing the cooperative motion of these motors. The attachment of biological or synthetic rotary motors to solid substrates is considered to be a key step toward the fabrication of nanomechanical devices that exploit the rotational motion generated by the action of these molecules. Additional progress in the field was presented at the Philadelphia ACS meeting by Tatiana Fernández Landaluce, graduate student in the group of Professor Petra Rudolf from the University of Groningen (The Netherlands), in collaboration with Professor Ben L. Feringa from the same university.
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With more than 14,000 attendees and more than 8,000 papers presented, the 236th American Chemical Society (ACS) National Meeting and Exposition that was held on August 17–21, 2008 in Philadelphia established itself as one of the most important events for the international chemistry community. This time, in addition to the usual highly heterogeneous nature, the attendees had also to struggle a little bit with the dispersion of the Divisions’ Symposia throughout a number of different locations, not necessarily close to each other. In fact, the Convention Center could host ‘just’ a few Divisions, such as the Organic, the Medicinal, the Fluorine, and the Inorganic Chemistry. In spite of some logistic trouble, the ACS Philadelphia conference hosted a lot of excellent science. This issue of SYNFORM will try to give the flavor of the high quality organic chemistry presented in Philadelphia, publishing three SYNSTORIES for just as many communications presented in The City of Brotherly Love: a synthesis of the cyclic depsipeptide largazole presented by the group of Professor Jiyong Hong and co-workers (USA), a new synthesis of the antiviral (–)-oseltamivir (Tamiflu) by the group of Professor Barry Trost (USA), and a novel entry into functionalized biaryls by the group of Professor Rich Carter (USA). Last, but certainly not least, the issue is completed by a SYNSTORY article covering a recent breakthrough reported by the group of Professor Brian Stoltz (USA) concerning a conceptually innovative total synthesis of the marine diterpenoid (–)-cyanthiwigin F.
Organic synthesis can be considered a science as well as an art, and sometimes the artistic aspect becomes particularly evident. One such example was recently published by the group of Professor Brian M. Stoltz, Ethel Wilson Bowles and Robert Bowles Professor of Chemistry at the California Institute of Technology, Pasadena (USA). The synthesis of the marine diterpenoid (–)-cyanthiwigin F was completed in nine synthetic steps. Of these nine reactions, seven form new carbon–carbon bonds, and four of those reactions establish more than one carbon–carbon bond in a single synthetic operation. Additionally, no protecting groups were employed. All of these facts were made possible by means of an extremely powerful double catalytic enantioselective alkylation, that represented the pivotal reaction in the synthesis.
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Macrocyclic natural products often exhibit unique biological properties and thus are attractive candidates for drug development in many diseases. Professor Hendrik Luesch and coworkers from the University of Florida (USA) have recently reported the isolation and structural determination of largazole, a cyclic depsipeptide from a cyanobacterium of the genus Symploca (J. Am. Chem. Soc. 2008, 130, 1806). Largazole potently inhibited the growth of transformed mammary epithelial cells (MDA-MB-231) in the low nanomolar range and induced cytotoxicity at higher concentrations. In contrast, non-transformed mammary epithelial cells (NMuMG) were less susceptible to largazole. Similarly, transformed fibroblastic osteosarcoma cells (U2OS) were more susceptible to largazole than non-transformed fibroblasts NIH3T3.
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The constant threat of avian influenza outbreaks generates a large demand for the current anti-flu drug Tamiflu [(–)-Oseltamivir Phosphate]. The current industrial preparation route starts from naturally occurring (–)-Shikimic acid, whose source is limited. Therefore, developing alternative routes starting from easily accessible simple starting materials is desirable. Multiple research groups have contributed to the total synthesis of the drug. However, all reported syntheses involve more than 12 steps and many of them require the use of hazardous azides as reagents (for a recent review, see: M. Shibasaki, M. Kanai Eur. J. Org. Chem. 2008, 1839).
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Biaryls represent a privileged structure in a number of fields, such as catalysis, materials science, nanotechnology, natural substances and biomedicinal chemistry. It is therefore not surprising that the synthesis of this stereogenic structural element continues to be the object of intensive research efforts. A conceptually new approach to the synthesis of biaryls and their subsequent functionalization was reported at the 236th ACS National Meeting in Philadelphia by graduate student Johanna Perkins and Professor Rich Carter from the Department of Chemistry, Oregon State University (USA).
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The season of conferences is moving into top gear, and the agenda of SYNFORM is becoming quite crowded. Indeed, in the forthcoming issues we will report on several top events of the year 2008, such as the 236th ACS Conference that was recently held in Philadelphia (in the next issue of SYNFORM), and the looming 2nd EuCheMS Chemistry Congress in Turin. Although there are no conference reports in this issue, we cover some of the most exciting achievements in the area of organic synthesis, published in the current literature. Two out of four come from Japan, and specifically from the lab of Dr. Yukishige Ito, who revealed a stereoselective entry to ?-L-rhamnopyranosides, and from the group of Professor Naoto Chatani and Dr. Mamoru Tobisu, who discovered how to use anisole derivatives as substrates for the Suzuki–Miyaura cross-coupling. Europe is represented by the group of Dr. Jieping Zhu (France), who developed an elegant and effective total synthesis of the alkaloid (–)-quinocarcin. Since the issue would not be complete without America, the fourth SYNSTORY article is focused on another innovative cross-coupling reaction, recently reported by the group of Professor Jin-Quan Yu (USA).
The glycosylation reaction is an important synthetic process particularly because of the remarkable biological significance of complex oligosaccharides and glycoconjugates. However, stereoselective glycosylation is still a challenging endeavor. Indeed, one of the most serious problems in synthetic carbohydrate chemistry is the stereoselective synthesis of 1,2-cis glycosides. A number of strategies toward 1,2-cis glycoside formation have been explored. Among them, approaches based on intramolecular aglycon delivery (IAD)1 are especially promising, because they are expected to occur with the exclusive formation of 1,2-cis glycosides. “The concept of IAD was first proposed by Baressi and Hindsgaul in 1991 who employed isopropylidene mixed acetal as a tether for ?-mannopyranosylation,” explained Dr. Yukishige Ito from The Institute of Physical and Chemical Research of RIKEN, Wako (Japan).
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Quinocarcin belongs to the family of complex tetrahydroisoquinoline natural products that include naphthyridinomycins, saframycins, renieramycins, and ecteinascidins. These compact polyheterocycles display potent antitumor and antimicrobial activities. Indeed, ecteinascidin 743 (Et 743, Yondelis®) has recently received authorizations from the European Medicines Agency (EMEA) for the treatment of advanced soft-tissue sarcoma.
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Mild and selective activation of tetrahedral C–H bonds still represents a challenging endeavor in modern organic synthesis, and research in this particular area is very active and competitive. One important step forward was reported recently, by the research group of Associate Professor Jin-Quan Yu from The Scripps Research Institute in La Jolla (California, USA). Professor Yu and co-workers discovered that the sp3 C–H bond in the ?-position with respect to a methoxy hydroxamate function can be activated in the presence of a Pd(II) catalyst and the resulting Pd(II)-alkyl intermediate undergoes crosscoupling reaction with both sp2- and sp3-boronic acids. This new C–H activation/C–C coupling reaction exploits air as the oxidant, instead of Ag(I) or Cu(II) salts previously used by the same group, thus representing a truly “green” and environmentally benign process.
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The Suzuki–Miyaura reaction is recognized as an indispensable tool for organic chemists, allowing for the building of complex molecules via the palladium- or nickel-catalyzed cross-coupling of organoboron compounds with electrophiles. Although this reaction has seen explosive advancement since it was first discovered in 1979, the choice in terms of electrophilic coupling partner remains essentially limited to organic halides and sulfonates. If anisole derivatives could be used in place of aryl halides for the Suzuki–Miyaura coupling, this would significantly expand the utility of the methodology. The C–OMe bond in anisoles, however, is inactive for most organic transformations. Recently a group of researchers from the Osaka University (Japan) has established the first catalytic system that cross-couples aryl methyl ethers with organoboronic esters.
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August is holiday time for many colleagues, particularly in the south of Europe, but SYNFORM is still fully operative and eager to inform you about the latest trends and the most exciting achievements in organic chemistry. Certainly exciting is the total synthesis of the complex natural structure pinnatoxin A that was elegantly synthesized by the group of Professor A. Zakarian (USA). Another important work covered in this issue of SYNFORM is the use of an abundantly available building block like ethylene for catalytic enantioselective synthesis, as described by Professor T. V. RajanBabu (USA). For the first time, SYNFORM presents a report on a symposium, specifically the Second European Workshop in Drug Synthesis, recently held in Siena (Italy). The organizers of conferences who are interested in having their event covered by SYNFORM are invited to get in touch synform@chem.polimi.it well in advance. The issue closes with a brief report on the 2008 Thieme Chemistry journals editorial board meetings recently held in Thessaloniki (Greece).
From May 25th to 30th 2008, Siena (Italy) hosted the Second European Workshop in Drug Synthesis (II EWDSy). The venue was the prestigious “Certosa di Pontignano”, with its beautiful and charming cloisters, the Congress Center of the University of Siena. The site has a rich and ancient history, dating back to 1314 when the order of Carthusian monks was expanding throughout Italy.
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According to Professor T. V. RajanBabu from the Chemistry Department of the Ohio State University in Columbus (USA) the “discovery of efficient catalytic processes for activation and selective incorporation of abundantly available feedstocks such as ethylene, butadiene, styrene, HCN, CO, and H2 could have an enormous impact on how chemical intermediates are synthesized in the lab, and eventually manufactured on an industrial scale. Among these,” he continued, “processes that yield practical levels of asymmetric induction will be especially attractive to synthetic chemists. Seldom has chemistry seen an area where the scientific goals are so challenging, the economic and environmental benefits so obvious, and the intellectual and ethical reasons for doing the research so compelling.
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The 2008 Editorial Board Meetings of the Thieme-Chemistry journals SYNTHESIS, SYNLETT, and SYNFACTS, including the supplement SYNFORM, were held on June 20th and 21st 2008, in the vibrant city of Thessaloniki (Greece). The Editorial Boards of the three journals and the staff of the Thieme-Chemistry editorial office met at the Mediterranean Palace Hotel as shown in the group picture. Many topics were addressed in the general meeting session, as well as in the single journals meetings, including a brand new joint Editorial Advisory Board that will be fully operative from 2009 onwards, and a stimulating discussion on the strategies that will be pursued to further increase the quality of the journals. The program was completed by a highly appreciated cultural event – a guided tour of the archaeological site of Vergina, about 80 km from Thessaloniki, that hosts the magnificent palaces and tombs of ancient Macedonian kings, including Philip II, and queens, with perfectly preserved works of miniature art and original paintings. The appointment for the next Editorial Board Meetings is in 2009 in Granada (Spain).
According to Professor Armen Zakarian from the University of California at Santa Barbara (USA), from a certain perspective the total synthesis of complex natural products can be occasionally regarded as a ‘guilty pleasure’ of Organic Chemistry. “For example,” he said, “for many people outside the field, it is sometimes not easy to imagine that the chemical synthesis of 0.9 mg of the powerful marine toxin palytoxin A would be anything more than a high-level chemical chess game, which requires a very expensive chess board with no apparent practical benefits.” Possibly, one of the reasons is that the benefits, although substantial, are not direct. “Unlike aspirin,” continued Professor Zakarian, “which can be used to relieve a headache, the anesthetic potential of palytoxin A is unlikely to attract consumers, not to mention its prohibitive cost.” Another possible reason might be that the endeavor of complex molecule synthesis is largely unpredictable.
To read more please download SYNFORM 2008/08 online, free of charge.
This issue of SYNFORM is somewhat special for at least two reasons: (1) for the first time there is an article authored by somebody else than me, specifically by the SYNLETT Regional Editor Professor Laurence M. Harwood; (2) we have the privilege to publish an INSIDE STORY based on an exclusive interview with Professor Jack E. Baldwin, one of the scientists who most deeply influenced modern organic chemistry and who discloses herein unknown aspects of his life, of his career, and much more. The issue is completed by two SYNSTORY articles, both related to the total synthesis of natural compounds: the first accomplished by Professor Eun Lee (South Korea), and the second by Professor Mercedes Amat (Spain).
Question 1: Could you give a personalised summary of your life and career? Answer 1: I was born on the 8th of August 1938 – 8/8/38; three eights are a symbol of good luck for the Chinese –within the sound of Bow bells which means I can lay claim to being a genuine Cockney. My father moved to Sussex during 1941 in order to escape the bombing of London and I grew up in Haywards Heath. One of my earliest memories was of arriving there in a taxi in deep snow. My childhood was spent in a very rural environment. After primary school I first went to Brighton Grammar School and, after the family moved to Maresfield, I attended Lewes Grammar School for Boys.
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When Sang Kook and Min Sang, who started as MS students in Professor Eun Lee’s group from the Department of Chemistry, Seoul National University (South Korea) some time ago, were ready for the kick-off of their PhD research projects, Professor Lee suggested they could collaborate. Indeed, in Professor Eun Lee’s group, students frequently collaborate on projects. “I have this vague realization from the experience that ‘two projects for two students’ is somehow more productive than ‘one student, one project’ provided they do not quarrel with each other,” said Professor Lee. Their first project was the total synthesis of exiguolide, which was successfully concluded in a relatively short time (Angew. Chem. Int. Ed. 2008, 47, 1733).
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According to Professor Mercedes Amat from the Faculty of Pharmacy, University of Barcelona (Spain), “ants, frogs of the Dendrobatidae family, the polyketide route, and decahydroquinoline alkaloids are four elements of an incompletely solved ecological and biosynthetic puzzle.” In fact, the source of decahydroquinoline amphibian alkaloids remains an intriguing question, in particular after the discovery that some of these alkaloids also occur in ants, thus strengthening a dietary hypothesis for their origin in frogs. Although there are no conclusive studies concerning the biosynthesis of these biologically active alkaloids, it is thought that they might derive from the polyketide route by aminocyclization of 1,5-polycarbonyl intermediates, leading to decahydroquinolines with a side chain substituent at both the C2 and C5 positions.
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Organocatalysis continues to represent a major topic and a very competitive area of research in the arena of organic chemistry. It is therefore not surprising that three out of the four SYNSTORIES that constitute this new issue of SYNFORM are dedicated to new organocatalytic processes. Professor Kuiling Ding (P. R. of China) shows how to perform an old Baeyer–Villiger reaction in a brand new enantioselective manner using a chiral Brønsted acid as organocatalyst. Professor Benjamin List (Germany) describes how to use a simple yet challenging substrate like acetaldehyde as nucleophile in organocatalytic Mannich reactions. Finally, Dr. Matthew J. Gaunt (UK) reports how phenols can be oxidatively dearomatized in an enantioselective manner by means of organocatalysis. There is little doubt that organocatalysis is progressively broadening its scope, although much research remains to be done in order to see more reallife synthetic problems solved by means of this powerful technology. The fourth SYNSTORY covers an extremely exciting piece of bioorganic synthesis reported jointly by Dr. Arata Yajima (Japan) and Professor Yong Qin (P. R. of China) who were able to synthesize and characterize stereochemically a structurally challenging hormone of a funguslike plant pathogen.
The Baeyer–Villiger (BV) reaction, discovered in 1899, represents one of the most well-known and widely applied reactions in organic synthesis. Although more than a century has gone by since its discovery, the BV reaction is far from being at the end of its development. The use of stoichiometric amounts of peracid as the oxidant suffers from disadvantages– such as expensive and hazardous (because of shock-sensitivity) reagents, with the simultaneous formation of one equivalent of corresponding carboxylic acid waste – which limit their practical application. Therefore, the use of aqueous hydrogen peroxide as the stoichiometric oxidant in the presence of a promoter has been the focus of attention from the viewpoint of green chemistry. On the other hand, the area of catalytic asymmetric BV reactions is also far from fully developed even though its first enantioselective version was realized in 1994 by Strukul and Bolm independently.
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According to Professor Benjamin List from the Max-Planck-Institute für Kohlenforschung of Mülheim (Germany), “even though acetaldehyde is structurally the simplest enolizable carbonyl compound, it can be difficult to use in chemical reactions. The undesired products stem mainly from self-aldolization pathways.” The few attempts at employing the molecule include a report on the self-aldolization of acetaldehyde by Barbas and co-workers1 in which very poor yields of an acetaldehyde trimer were isolated with respectable enantioselectivity, and Jørgensen’s finding of a high-yielding but racemic cross-aldol reaction.2 These results seemed to confirm the notion of acetaldehyde being uncontrollable. “However,” said Professor List, “we decided to see these results as encouragement instead: They showed that it is possible to (a) achieve decent enantioselectivities and (b) high yields in organocatalytic reactions of acetaldehyde. Now all we had to do was to combine these features in one reaction.”
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Dearomatization of substituted phenols followed by a desymmetrization reaction to form chiral intermediates represents a popular strategy for synthesizing natural product molecules. A further contribution in this area was recently reported by Dr. Matthew J. Gaunt and his group at the University of Cambridge (UK), who disclosed a catalytic enantioselective single-reaction method for direct conversion of phenols into highly functionalized chiral molecules. Gaunt and coworkers carried out fast oxidation of para-substituted phenols to form cyclohexadienones coupled with an amine-catalyzed intramolecular Michael addition. Oxidation of the phenol ring occurs rapidly without affecting the aldehyde side chain by using methanol as the solvent and nucleophile and a hypervalent iodine oxidizing reagent, PhI(OCOMe)2.
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Phytophthora, whose name translates as “plant-destroyer”, is one of the most destructive pathogens in the world. In the mid-1840s, late blight, the plant disease caused by a member of this fungus-like genus, destroyed potato crops in Europe and the United States and caused the Irish potato famine. The life cycle of Phytophthora species features characteristic biological events, including sexual reproduction. Each individual is bisexual, capable of producing both female (oogonia) and male (antheridia). There are two mating types, A1 and A2, with sexual reproduction requiring the interaction of both. After sexual reproduction, the oogonia develop into sexual spores called oospores, which can survive harsh conditions such as drying or freezing for months or years in the absence of a living host plant. “In 1929, Ashby proposed that sexual reproduction in Phytophthora was regulated by a hormonelike compound,” explained Dr. Arata Yajima from the Faculty of Applied Bio-Science, Tokyo University of Agriculture (Japan).
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this new issue of SYNFORM presents an INSIDE STORY article dedicated to one of the most impressive examples of a fast-growing economy that is fully committed to the pursuit of an aggressive national research & development program: Singapore. This small country is becoming a major hub for research and education, and SYNFORM could not miss the chance to report on this sort of “paradise for scientists”. This INSIDE STORY has been possible thanks to the generous collaboration of several people in Singapore, including Dr. Christina Chai, Dr. David Chen, Dr. Steven Collier, Professor Teck-Peng Loh, and others who accepted the invitation to provide valuable information and dedicate some of their precious time to SYNFORM during my recent trip to Singapore. The Singapore model is probably difficult to export to the Western world, and there are many reasons for that. However, more long-term investments in infrastructure, research and education are needed in Europe, and even in America; Singapore may represent an important stimulus in this direction and not just a competitor in the global world market. The issue is completed by a SYNSTORY article on a new remarkable synthetic strategy – a modular approach to polyene natural products via iterative cross-coupling – developed by the group of Professor Martin D. Burke (USA).
Background. I had a dream. A place where scientists can do excellent research without wasting their time and energy desperately looking for funding, because money is already there, available and ready to use. A place where new, modern, state-of-the-art research buildings and labs pop up everywhere like mushrooms. A place where science and research are considered a true national priority, where talented scientists are considered a national treasure. Well, this is not a dream – such a place actually exists and has a name: Singapore!
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Question 1: What are the main fields of interest of ICES, particularly those related to organic chemistry?
Answer 1: The main interests are in the area of synthetic methodologies, total synthesis, medicinal chemistry, catalysis, polymer chemistry. The research that we do is not as academic as in some universities as our research should have some potential applications in industry.
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Question 1: Nurturing a home-grown talent pool is a priority for science and research in Singapore. What are the strategy and the contribution of NTU in this respect, particularly in the area of chemistry?
Answer 1: An aggressive outreach to cultivate interest in chemistry, to create an alumni spirit and a good environment for research and scholarships for locals, encourage research at a young age, and so on.
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Question 1: Why are K. C. Nicolaou and David Chen lending their name recognition to the chemistry in Singapore? Answer 1: Having been involved in chemical synthesis over the years, apart from our roles as scientists, it is also our passion as educators to promote the arts and sciences of chemical synthesis to regions of the world where this discipline is still underdeveloped, or perhaps its full potential has not yet been tapped into. As scientists and educators, clearly, fame and name recognition is never on the top of the agenda, and simply having the opportunity to bring our passions to a wider audience is a priceless reward by itself. At the same time, it is important to focus on the quality of our research and to maintain at the world standard, such that Singapore, as a country, will be recognized for its strength in chemical synthesis in the days to come.
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Complex small molecules (natural products and drug-like compounds) have seemingly limitless potential to promote advances in science and medicine, but the degree to which this potential can be realized is ultimately a function of the simplicity, efficiency, and flexibility with which these types of compounds can be synthesized in the laboratory. In this regard, an inspiring benchmark can be found in the process of modern peptide synthesis in which the target molecules are made via the simple, iterative coupling of commercially available bifunctional amino acid building blocks. This process is now routinely automated and readily utilized not only by chemists, but also by biologists and physicists to promote discoveries across a wide range of disciplines.
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this time I am writing while on sabbatical at the University of Toronto in Canada, hosted by one of the editors of SYNTHESIS, Professor Mark Lautens. The University of Toronto offers a vibrant scientific atmosphere, and together with my family, I am enjoying the warm hospitality provided by both the faculty members and the students. I hope this will have a positive effect on the forthcoming issues of SYNFORM that are currently in preparation, and, of course, on this issue that features three SYNSTORY articles. The first of these reports on a new technology developed in Germany for the fabrication of peptide arrays on a microchip. The second covers another breakthrough achievement coming from Germany that demonstrates that even those aspects of chemistry that seem to be very well established and taught in every basic organic chemistry course, such as the nucleophilic substitution reaction (SN2), may be the source of unexpected and fundamental new discoveries. The third SYNSTORY deals with a new and efficient strategy developed at the University of Texas Southwestern (USA), for performing a rather difficult reaction, the oxy-Michael reaction, in enantioselective fashion.
Background and Purpose. Peptide arrays are composed of a large number of diverse peptidic molecules and enable high-throughput screening of compounds that may interact with one or more peptides in the array. Thus, an array of peptidic molecules potentially suitable as ligands for a particular biological receptor or an enzyme may be prepared and “screened” with respect to interaction partners. Another option is that arrays of peptide antigens may be used to screen a patient’s sera for antibodies that are related to any kind of disease. This would allow the use of peptide arrays by clinicians to determine whether or not a patient has developed antibodies to particular peptidic antigens. It is possible as well to use combinations of proteins to screen for molecules which interact or are part of a similar metabolic pathway. Although peptidic arrays are very promising, their potential so far has not been fully realized, and this is in large part due to manufacturing challenges.
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Question: What about the applications for high-density peptide arrays? Answer: For example, to target a highly expressed protein in cancer cells with D-peptides that specifically bind to that target protein. We need D-peptides (= mirror-image peptides of L-peptides) for that because naturally occurring L-peptides are simply digested, i.e. don’t reach the tumor. Depending on the targeted protein, sometimes it is sufficient to block/compete for the binding of that target protein to another protein to get a therapeutic effect. This can be exemplified by HPV’s oncogenic E6 protein, which blocks apoptosis of deregulated cells by degrading p53 in cervical cancer. There is an L-peptide, which in turn blocks E6 restoring apoptosis, but it is digested much too fast to be used as a therapeutic.
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The chemical reaction, that means the omnipresent rearrangement of atoms to new molecules, continues to pose many open questions to scientists and engineers. Nowadays a detailed understanding of the mechanisms of chemical reactions is required to optimize the production of synthetics and drugs or to alleviate the destruction of our earth’s ozone layer. For his groundbreaking studies of chemical reactions on surfaces, which are important in catalysts, the German physicist Gerhard Ertl was awarded the Nobel Prize in Chemistry in December 2007. One of the most important classes of chemical reactions have now been uncovered in detail in an experiment carried out by scientists at the Physics Institute of the University of Freiburg (Germany) in a collaboration with a chemical dynamics theory group at Texas Tech University (USA).
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Structural motif 1 is present in a wide range of natural products and synthetic intermediates. While Michael additions of hydroxide or synthetic equivalents to α,β-unsaturated carbonyls represent an attractive approach to this moiety, the strong basicity of the former and generally poor nucleophilicity or lability of the latter often render this option problematic. In its place, the intramolecular oxy-Michael addition of hemiacetal/hemiketal-derived alkoxides has emerged as a popular alternative strategy, although the resultant cyclic acetals/ketals can be difficult to remove. Recently Professor J. R. Falck and Dr. D. Li from the University of Texas Southwestern Medical Center, Dallas (USA) reported a new strategy based on the use of boronate-amine complexes as chiral hydroxide equivalents.
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Singapore is booming both in basic and applied research. Universities, research organizations and companies in Singapore are attracting talent from around the world. Perhaps other countries, including some on the Old Continent, should be more inspired by the strategy that Singapore is pursuing, and try to follow its example. It was therefore mandatory for this new issue of SYNFORM to have a closer look at this nation where so many important things are occurring. One of the next issues will be largely dedicated to “Chemistry in Singapore”, whereas this issue features a special section focusing on the International Symposium on Catalysis and Fine Chemicals – Singapore, which was held from December 16–21, 2007 at the Nanyang Technological University in a vibrant scientific atmosphere. The Organizing Committee, chaired by Professor Pak Hing Leung, did an excellent job, as the conference was superbly organized and offered a very interesting scientific program under the supervision of the Scientific Committee chaired by Professor Roderick W. Bates. Three communications from the C&FC conference are featured in this issue, which is completed by two SYNSTORIES: one about a new and selective aliphatic C–H oxidation reaction that can be exploited for the synthesis of complex molecules, described by Professor Christina White (USA), while the second reports on a new access to functionalized indoles, established by Professors Louis Fensterbank and Max Malacria (France).
If organic chemists were asked “What is your dream reaction?”, many of them would probably answer “a mild and selective functionalization of unactivated sp3 C–H bonds, having a predictable outcome and with no protection required.” One important step forward in this direction has been recently reported by Professor M. Christina White and graduate student Mark S. Chen from the University of Illinois, Urbana (USA) who described an iron-based catalyst that, in the presence of H2O2, oxidizes selectively and under mild conditions the aliphatic C–H bond of a broad range of substrates, without the need for activating or protecting groups.
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The indole nucleus is present in numerous compounds of biological and/or pharmaceutical interest and new chemical methods for its synthesis have been developed for more than a hundred years. In the last two decades, metal-catalyzed transformations and especially those applying palladium complexes (the topic has been recently reviewed, for example, by S. Cacchi, G. Fabrizi: Chem. Rev. 2005, 105, 2873) have proven to be among the most versatile methods to synthesize indole substrates. However, most of these strategies rely on the 5-endo addition of the nitrogen to an unsaturation in the ortho position. On the other hand, the 5-exo methodology has been the subject of far less interest. In the meantime, propargylic alcohols have exhibited a vast array of reactivities when submitted to noble metal catalysts.
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The Mitsunobu reaction is a dehydration reaction to introduce an acidic pronucleophile replacing an alcoholic function under complete stereo-inversion. The procedure simply consists of mixing an alcohol and a pronucleophile with diethyl or diisopropyl azodicarboxylate (DEAD or DIAD) and triphenylphosphine at room temperature to give a condensed product. However, both DEAD and DIAD are potentially explosive and shock-sensitive liquids (particularly the former); therefore, their shipment and commercialization have become a major problem, particularly when dry and neat. Another major drawback of the Mitsunobu process is the formation of two co-products, hydrazinedicarboxylate and triphenylphosphine oxide. Formation of Ph3P=O is certainly not a problem in the separation process, due to its facile crystallization in non-polar solvents, but separation of diethyl or diisopropyl hydrazinedicarboxylate requires highly capable column chromatography to isolate the target Mitsunobu-reaction product.
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Bistramides are macrolide metabolites, produced by the marine organism Lissoclinum bistratum, which exhibit cytotoxic properties against a variety of human cancer cells. Bistramide D is particularly interesting, as it seems to be less toxic than bistramides A, B, and C. Interestingly, no total synthesis of bistramide D has appeared except for a hemisynthesis, 1 although elegant syntheses of bistramides A and C have been reported.
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Qinghaosu (artemisinin; 1) was isolated from the traditional herb qing hao (Artemisia annua) by Chinese groups working together in the remarkable collaborative effort known as ‘Project 523’.1 This compound and derivatives such as artesunate are now used for the treatment of malaria.2 However, chemical and metabolic instabilities and neurotoxicity in laboratory studies bestow difficulties both in formulation and compliance with drug regulatory guidelines.3 Therefore, under a contract agreement with Bayer AG, the group of Professor Richard K. Haynes from the Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong University of Science and Technology, Hong Kong (P. R. of China) embarked on a medicinal-chemistry-guided program to develop new artemisinin derivatives.
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this new issue of SYNFORM presents four SYNSTORY articles covering new exciting developments in organic chemistry: the construction of quaternary carbon stereocenters in a highly enantiocontrolled manner by means of a keto ester-ene reaction catalyzed by chiral palladium(II) complexes reported by the group of Professor Koichi Mikami (Japan), a new strategy for the diastereoselective alkylation of prochiral enediolates reported by the group of Dr. Steve Marsden (UK), a very challenging enantioselective hydrogenation of tetrasubstituted olefins developed by the group of Professor Andreas Pfaltz (Switzerland), and last, but not least, the double-Michael reactions catalyzed by chiral bisphosphines reported by Professor Ohyun Kwon USA).
The asymmetric ene reaction catalyzed by chiral Lewis acids is one of the most efficient methodologies for atom-economical carbon–carbon bond formation. The ene reaction of silyl enol ethers and carbonyl compounds is synthetically important as a short access to optically active alcohols with not only homoallylic but also remaining silyl enol ether functionality. Although various efficient ene reactions have been reported, only few reports on the asymmetric version with silyl enol ethers exist. The group of Professor Koichi Mikami from the Tokyo Institute of Technology (Japan) is very active in this field and has previously reported the asymmetric glyoxylate-ene reaction with trimethylsilyl enol ether catalyzed by chiral BINOL-Ti complexes to afford chiral b-hydroxy silyl enol ethers (J. Am. Chem. Soc. 1993, 115, 7039; Tetrahedron Lett. 1997, 38, 579).
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The control of absolute stereochemistry in the alkylation of prochiral enolates is an enduring challenge in asymmetric synthesis in both academic and industrial settings. According to Dr. Steve Marsden from the University of Leeds (UK) “Typically this has been achieved by the temporary covalent attachment of a chiral substituent to the acyl group (the chiral auxiliary approach), such that the two faces of the resulting enolate are diastereotopic rather than enantiotopic, and control of the new stereocenter can be engineered.”
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The enantioselective hydrogenation of unfunctionalized olefins is a useful tool for organic chemists, and opens new routes for producing enantioenriched chiral compounds.
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Tertiary phosphines catalyze a diverse array of reactions, including the Morita–Baylis-Hillman (MBH) reaction, Michael addition, aldol condensation, acylation of alcohols, silylcyanation of aldehydes, isomerization of olefins and acetylenes, conjugate addition of alcohols to propiolates, and allylic substitution.1 “Inspired by Lu’s pioneering use of allenes to extend the single-C–C bond-forming MBH reaction into a [3+2] cycloaddition, our group has been engaged in the development of phosphine-catalyzed annulations of allenoates with electrophiles such as alkenes, imines, and aldehydes,” said Professor Ohyun Kwon from the Department of Chemistry and Biochemistry of the University of California, Los Angeles (USA). “These reactions produce carbo- and heterocycles regio- and diastereoselectively; gratifyingly, the use of chiral phosphines induces highly enantioselective annulations.”
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The final score in this new issue of SYNFORM is Japan–UK 2-2. In terms of SYNSTORY articles, of course!Indeed, Japan and UK rule this issue, thanks to the excellent work and creative solutions in organic chemistry that were recently published by the Japanese groups of Professor Masahiro Terada, University of Tohoku, with his new organocatalytic tandem aza-ene/cyclization process, and of Professor Takashi Ooi, University of Nagoya, with his organocatalytic Henry-type reaction. The two SYNSTORIES from the UK were “scored” by Professor Thomas Wirth, University of Cardiff, with his new hypervalent iodine reagents for organic synthesis, and by Professor Anthony Davis, University of Bristol, with his biomimetic supramolecular recognition of disaccharides. Obviously we are eagerly waiting for new articles “scored” by scientists in other parts of the world in the forthcoming issues of SYNFORM, which constantly monitors the best organic chemistry that is going on in the labs of all five continents.
With my best wishes for a healthy, successful and prosperous New Year 2008!
Catalytic cascade reactions are powerful tools in synthesis as they can produce a rapid increase in molecular complexity from simple and readily available starting materials. Enantioselective organic transformations using chiral Brønsted acids as green catalysts are of special interest because such catalytic processes would allow environmentally friendly and economically advantageous production of chiral non-racemic compounds. A new tandem aza-ene type reaction/cyclization cascade catalyzed by binaphthol-derived chiral monophosphoric acids 1 has been recently disclosed by Professor Masahiro Terada and co-workers from the Tohoku University (Sendai, Japan). The method enables the rapid and highly enantioand diastereoselective construction of piperidine derivatives with multiple stereogenic centers.
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Reagents containing hypervalent iodine have a reputation of great usefulness in organic chemistry. Among them, one could mention the Dess–Martin periodinane and other compounds like IBA and IBX, which are extensively used in synthesis. The arsenal of hypervalent iodine reagents available to the synthetic chemist has been recently enriched by two novel compounds, namely FIBX and FIBA (both characterized by the presence of a fully fluorinated aromatic ring), which have been reported by Professor Thomas Wirth and his coworkers from the School of Chemistry of Cardiff University (UK).
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Control of the stereochemical outcome of organic reactions is becoming increasingly sophisticated in order to meet the stringent economic, environmental and safety requirements of modern chemistry. Organocatalysis holds great promise in relationship with the aforementioned issues; therefore, research in the area of asymmetric organocatalysis is very competitive and regularly produces important breakthroughs. One of them was recently achieved by Professor Takashi Ooi and his coworkers at the Department of Applied Chemistry of Nagoya University (Japan), who developed a new strategy for inducing a highly enantioselective outcome in direct Henrytype reactions between nitroalkanes and aromatic as well as aliphatic aldehydes.
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The chemistry of carbohydrates is still a very challenging area of research. The strongly hydrophilic character of carbohydrates as well as their stereochemical complexity are among the most difficult issues to deal with for the organic chemist. This is particularly true in the field of supramolecular chemistry because the energies involved in host–guest interactions and molecular recognition phenomena are relatively weak, and discrimination between substrate and water as well as between subtly different carbohydrates can be extremely difficult. An important step forward has been accomplished recently by Professor Anthony Davis and coworkers from the School of Chemistry of the University of Bristol (UK), who described a synthetic lectin analogue for the biomimetic recognition of disaccharides.
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The 234th American Chemical Society (ACS) National Meeting & Exposition held in Boston on August 19–23, 2007 was, as usual, a huge event, featuring several thousands of communications, including oral presentations and posters, with a very high average level of quality. A number of outstanding speakers, including Nobel prize winners, and events, such as the Arthur C. Cope Awards as well as the Tetrahedron Prize Symposia, a very rich program of parallel sessions (perhaps even too many...), and an extremely rich exposition gave to the many attendees from all over the world a great opportunity to gather together and be exposed to the newest trends in the field of chemical sciences, and beyond. Every time I attend an ACS Meeting have the feeling that if something is not presented there, then it probably doesn’t exist... Particularly impressive to me was the high level of the many presentations offered by young people, namely graduate students and postdocs, that certainly warrant a brilliant future to chemistry. The work of two of them, namely Jessica Raushel (and Professor V. Fokin) from the The Scripps Research Institute (USA) and Julio Piera (together with Professor J.-E. Bäckvall) from the University of Stockholm (Sweden), is presented in two SYNSTORY articles. Two more SYNSTORIES complete this issue. One is focused on a work published by Professor Tomislav Rovis (Colorado State University, USA), that was recently selected as a Synfact of the Month, on a new methodology in enantioselective synthesis. The other one deals with a new strategy for the selective preparation of organofluorine compounds, which was recently developed by Dr. Veronique Gouverneur and her group from Oxford University (UK).
Organic azides and alkynes offer a unique window of reactivity, which can be useful in addressing the current challenges faced by chemists working in the fields of diversity-oriented synthesis of functional small molecules, chemical biology, and materials science. Owing to their chemical inertness, both are virtually ‘silent’ under most common synthetic and physiological conditions, and can be introduced in the synthetic scaffolds through standard transformations or in biomolecules of interest at genetic and post-translational levels. Products of their traceless union, 1,2,3-triazoles are among the most hydrolytically and oxidatively stable heterocycles. Furthermore, due to the high activation barrier of the reaction, azides and alkynes remain invisible to each other until the reaction between them is triggered by an appropriate catalyst.
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Oxidation reactions are of fundamental importance in nature and selective aerobic oxidations of organic molecules are of key interest in modern organic chemistry. In the past decades there has been an increasing demand to develop catalytic processes where the terminal oxidant is molecular oxygen. The advantages of using molecular oxygen as oxidant are obvious not only from an environmental point of view but also for economical reasons. However, there is usually a high energy barrier for the direct reoxidation of the reduced form of the metal. This problem can be circumvented by mimicking biological oxidations, where large jumps in oxidation potentials are avoided by the use of several coupled redox catalysts as electron-transfer mediators (ETMs).
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In spite of the recent progress in methodology of stereoselective fluorination, certain commonplace organic structural motifs do exist for which the efficient preparation of fluoro analogues remains challenging. One example of such a motif is the six-membered, non-aromatic carbocycle. A popular method for the expedient preparation of nonfluorinated, substituted carbocycles is the Diels–Alder reaction. The high regio- and diastereoselectivities of this reaction are well known and numerous enantioselective variants have been documented. In pursuit of a general strategy for the enantioselective synthesis of fluorinated six-membered carbocycles, it is therefore tempting to resort to this cycloaddition starting from fluorinated reactants (eq. 1, 2).
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Cyclic meso anhydrides offer the potential for desymmetrization reactions which would thus define multiple stereocenters in a single transformation. This strategy has been used to great effect by asymmetric alcoholysis to make succinic and glutaric acid half-esters in enantioenriched form. “Since we began our independent work in 2000,” explained Professor Tomislav Rovis from the Colorado State University (USA), “we have been interested in using carbon nucleophiles to effect the desymmetrization of meso anhydrides, which would provide a keto-acid product and thus increase the synthetic utility of this approach.”
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The “41st World Chemistry Congress” of the International Union of Pure and Applied Chemistry (IUPAC) was held on August 5–11, 2007, in Turin (Italy). The congress venue was the former FIAT cars factory “Lingotto Conference Center” which is a modern and functional structure that hosts concert halls, a theatre, a convention center, shopping arcades and hotels. The “Gianni Agnelli” Auditorium, that can accommodate more than 2000 people, hosted the lectures of three Nobel Awardees and the play “Should’ve” authored by Professor Roald Hoffmann. A rich and multidisciplinary program of lectures and posters was distributed among the many lecture halls of the “Lingotto”. The conference was very well organized and scientifically very stimulating: it’s a pity that the attendance to the lectures has been often rather modest, at least according to my experience. Two remarkable lectures presented at the IUPAC conference are covered and analyzed in this issue of SYNFORM: one by Professor Lukas J. Gooßen (University of Kaiserslautern, Germany) and one by Professor Maurizio Benaglia (University of Milan, Italy). Two SYNSTORIES focusing on recent groundbreaking articles from the literature complete this issue: Professor David Milstein from the Weizmann Institute of Science (Rehovot, Israel) with his new synthetic strategies for the synthesis of amide bonds, and Professor Julius Rebek, Jr., from the Scripps Research Institute (USA) with his new strategy for taking snapshots of chemical reactions by using synthetic receptors.
Many biologically active and functional molecules contain the biaryl substructure, which is therefore a very important synthetic target. Among the most valuable biaryl-containing molecules, Biphenomycin should be mentioned, as well as several pharmaceuticals having an immense economic value including Valsartan and Telmisartan, agrochemicals such as Boscalid, and liquid crystals for LCD screens.
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Organocatalysis holds great promise with the view of developing environmentally benign chemical processes and water is by definition “the green solvent”. Therefore, the combination of organocatalysis and water is apparently a win-win situation in terms of eco-sustainability. However, the challenges connected with the development of truly effective organocatalytic processes in water appear to be daunting and solutions are unlikely to be just around the corner. Many research groups are actively working to address these challenges; one of them is the group of Professor Maurizio Benaglia from the University of Milano, Italy. “Our group became interested in studying enantiocatalysis in water a few years ago already (see M. Benaglia et al. Org. Biomol. Chem. 2004, 3401–3407),” confirmed Professor Benaglia.
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Amides have wide utility, both as synthetic intermediates and as end products in a variety of industrial applications. Current use includes plasticizers, detergents, lubricants, and foamers. The synthetic fibers Nylon and Aramide (Kevlar, Twaron) are polyamides. In biology, peptides and proteins are based on the amide linkage.
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The biological solution to the problem of highly selective and efficient catalysis involves macromolecules that use weak binding forces to stabilize reactive intermediates and transition states. Enzymes both isolate intermediates from the reactive outer medium and provide them with hydrogen-bonding and other non-covalent forces to lower their barriers to undergo reactions. This concept is well precedented, but most of the evidence comes from indirect analysis methods, because the high activity of natural enzymes means that intermediates are very rapidly converted into products. Direct detection of labile intermediates is rare, and generally occurs at cryogenic temperatures (e.g., A. Heine et al. Science 2001, 294, 369–374).
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The 15th European Symposium on Organic Chemistry 2007 was held from July 8–13, 2007 in Dublin (Ireland) with Professor Pat Guiry chairing the local organizing committee. The symposium was very well organized in the superb venue of the University College Dublin and featured a strong scientific program including 44 oral lectures and high-level poster sessions. The weather, on the other hand, gave a very important contribution in keeping the attendees very much concentrated on the scientific program, effectively advising against any kind of trip in the beautiful and green Irish countryside. This new issue of SYNFORM presents three SYNSTORIES based on very exciting communications presented at the ESOC 2007, namely a challenging total synthesis presented by the Shibasaki group in Japan, new epothilone derivatives disclosed by Altmann’s group in Switzerland, and new functions of a molecular motor developed by the Feringa group in The Netherlands. This issue is completed by a SYNSTORY based on a recent publication by the group of Keith Fagnou in Canada on a tremendously exciting synthetic methodology that allows for the catalytic cross-coupling of two unactivated arenes.
Biaryl molecules are prevalent in a wide range of molecules of societal importance including medicines, organic lightemitting diodes and electron-transfer devices. For this reason, methods enabling their rapid and cost-efficient synthesis are in high demand. Of the methods available to the synthetic chemist today, Suzuki couplings are arguably the most commonly employed and have had the greatest impact on our ability to prepare these molecules. These couplings are broad in scope, high-yielding and can frequently be performed with very low catalyst loadings. These traits set the bar very high for a new methodology, which aims to improve on the state of-the-art.
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Garsubellin A, although a compact molecule, is one of the most daunting synthetic targets. Both bridgehead centers are quaternary, one of which is adjacent to another quaternary center. Furthermore, a tetrahydrofuran ring is fused with the central bicyclo backbone. This compound potently induces choline acetyltransferase, therefore it is anticipated to be a drug lead for treating Alzheimer’s disease. At the recent ESOC 15 conference, Akiyoshi Kuramochi, a PhD student from the group of Professor Masakatsu Shibasaki (University of Tokyo, Japan), brilliantly presented a new total synthesis of this target, that was experimentally carried out by A. Kuramochi himself, Dr. H. Usuda, Y. Shimizu, and K. Yamatsugu. “By the time we started this project,” explained Mr. Kuramochi, “there was no completed total synthesis, although Nicolaou’s group reported the synthesis of the fully functionalized bicyclic core of garsubellin A. So we aimed at the first total synthesis of this compound.”
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Natural products have proven to be valuable lead structures for anticancer drug discovery time and again and there can be no doubt that compounds originating from natural sources will continue to play an important role in the development of new medicines against cancer in the future. “On one hand, advances in isolation and analytical techniques and, in particular, the exploration of secondary metabolites from non-terrestrial organisms, will provide a continuous flow of new and diverse structures with various biological activities,” explained Prof. Karl-Heinz Altmann from the Department of Chemistry and Applied Biosciences of the Swiss Federal Institute of Technology (ETH) Zürich (Switzerland). “On the other hand, the design and synthesis of natural-product-inspired compound libraries by diversity- (DOS)1 or biology-oriented synthesis (BIOS)2 will lead to the creation of new (synthetic) leads for medicinal chemistry.”
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In 1999, the group of Professor Ben Feringa from the University of Groningen (The Netherlands) reported the first light-driven unidirectional molecular motor. The two halves rotate unidirectionally with respect to each other, by irradiation with UV light. “Before we can implement a molecular rotor as motor in a nanodevice, we first need to understand their behavior in complex matrices,” explained Giuseppe Caroli, a PhD student in Prof. Feringa’s group. “We found, indeed, that the environment and conditions strongly affect their performance.”
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The REACh (Registration, Evaluation and Authorisation of Chemicals) is the new regulatory framework on Chemicals that came into force on June 1, 2007. According to the European Commission “The aim of REACh is to improve the protection of human health and the environment through the better and earlier identification of the properties of chemical substances” (http://ec.europa.eu/environment/chemicals/reach/reach_intro.htm), so it is generally welcome by the European citizens. However, the REACh is also raising legitimate industry concerns in Europe as well as in America and Asia. The new INSIDE STORY presents a “face-to-face” between Dr. Geert Dancet, the interim Executive Director of the European Chemicals Agency, ECHA, and two experts from the world of industry, Mr. Steven Russell, Senior Director for Health, Products and Science Policy of the American Chemistry Council (ACC) and Dr. Martin Kayser, Head Product Safety of BASF AG. The three SYNSTORY articles deal with new exciting developments of organic chemistry. Professor Werner Hug and Dr. Christian Bochet (Switzerland) bring us to the known limits of the universe of chirality. Professor Alison Frontier (USA) discloses some very interesting “behind-thescenes” in her recent elegant synthesis of racemic merrilactone A. Last but not least, Professor Yoshiji Takemoto (Japan) elaborates on a new enantioselective Petasis-type reaction promoted by thiourea catalysts, within the frame of a Special Topic on “Thiourea as Catalyst” to be published in SYNTHESIS issue 16/2007. We hope you will appreciate this fourth issue of SYNFORM.
Topic description. What are the objectives and scope of REACh? The EU’s new chemicals legislation REACh stands for the Registration, Evaluation, Authorisation and Restriction of Chemicals, and it came into force on June 1, 2007. The objectives of REACh are to:
• Protect human health and the environment • Maintain and enhance the competitiveness of the EU chemicals industry • Prevent the fragmentation of the internal market • Increase transparency • Integrate with international efforts • Promote non-animal testing • Comply with EU international obligations under the WTO.
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Question 1 (S.R.): One of the stated objectives of REACh is to protect the competitiveness of the European industry. Many people outside the EU interpret this as a fairly straightforward admission and that REACh is in fact a protectionist regime. This view is reinforced by the requirement of importers to register monomers in imported polymers, and by the initial reports from some companies that the scope of work and potential liability is making it difficult (as a practical matter) to find sufficient “only representative” service providers. How do you react to that view? Answer 1: According to the first recital of the Regulation, the aims of REACh are to ensure a high level of protection of human health and the environment as well as the free movement of substances (on their own, in preparations and in articles) while enhancing the competitiveness and innovation. The second recital stresses that the efficient functioning of the internal market for substances can be achieved only if requirements for substances are harmonized across the EU.
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The “Molecule of the Month” (MOM) competition in the Trost Research Group at Stanford University (California, USA) is held four times a year. Each of the four teams of 10– 12 people are expected to develop a synthetic strategy for the chosen target molecule that is creative, novel and experimentally feasible. For each team, a postdoctoral researcher and a graduate student are appointed “leaders,” and are expected to present the team’s route at a group meeting held to discuss, criticize, compare and contrast the four approaches proposed by the four teams. Thus, the leaders most directly suffer the humiliation of a poorly conceived strategy, and this serves as a powerful motivating force. In the spring of 2001, merrilactone A was the target molecule chosen for the MOM competition.
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A chirally deuterated neopentane has never been prepared before, neither in enantiopure nor racemic form. The chirality of this molecule arises from the unsymmetrical isotope distribution around the carbon atoms. Concerning the detection of the chirality of the molecule, since the deuterium and the hydrogen are almost identical, any method based on group differentiation by size would almost certainly fail. Now, these extremely challenging tasks have been successfully achieved by the groups of Professors Werner Hug and Christian Bochet from the Department of Chemistry of the University of Fribourg(Switzerland).
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The standard Petasis reaction is a three-component condensation of amine, aldehyde, and vinyl or aryl boronic acid (J. Am. Chem. Soc. 1997, 119, 445–446). This process has been extensively developed over the last few years. However, the full potential of this reaction remains unrealized, and its stereocontrol is the subject of current interest. Studies on asymmetric induction led to some remarkable success, particularly in diastereoselective processes using chiral a-hydroxy aldehydes. However, there are no reports on catalytic enantioselective processes using chiral catalysts. Now, Professor Yoshiji Takemoto and coworkers from the University of Kyoto (Japan) have developed a catalytic enantioselective variant of this transformation using a newly designed organocatalyst.
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This issue of SYNFORM presents four SYNSTORIES focused on new exciting scientific advances in the realm of organic synthesis. Professor G. K. Surya Prakash and Nobel Laureate Professor George Olah (USA) tell us more about their new gallium(III)-catalyzed Strecker reaction of ketones. A new gold(I)-catalyzed process developed by the group of Dr. Fabien Gagosz (France) is covered in the second SYNSTORY, within the frame of a Cluster on “Gold Chemistry in Organic Synthesis” published by SYNLETT in issue 11/2007. Professor Marc Snapper (USA) elaborates on his newest exciting synthetic methodology that can be applied to the total synthesis of complex natural cyclic molecules. Finally, Professor Shang-Cheng Hung (Taiwan) and his powerful new methodology for the regioselective protection of carbohydrates are the protagonists of the fourth SYNSTORY. With these features, scientific excitement is guaranteed! Let me end this brief editorial with a thought for Professor Charles Mioskowski, who left us on June 2nd 2007. I had the privilege of spending one year (1999) as a postdoctoral fellow in his group in Strasbourg. I will always remember his enthusiasm and creativity in research, his friendly character, and his unmistakable voice from the “salle café” ironically asking “Do you want green tea, Matteo?”, as he already knew my overwhelming preference for coffee. He is a great loss to the chemical community, as a chemist, as a respected colleague and as a friend. Ciao, Miko
Gold complexes have emerged as efficient and mild catalysts for the activation of alkynes towards addition by a variety of nucleophiles. The potential of these catalysts has been demonstrated recently by Dr. Fabien Gagosz and coworkers from the Ecole Polytechnique of Palaiseau (France) who described the hydroxy- and alkoxycyclization of enynes, leading to the formation of carbocycles through the creation of two new C–C and C–O bonds.
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As evidenced by the landmark syntheses of vitamin B12, palytoxin, and brevetoxin B, chemists, given the appropriate resources, can match nature’s ability to construct molecules of incredible structural complexity. In terms of cost and practicality, however, we still fall far short of achieving nature’s efficiency. For example, while all are notable achievements, none of the laboratory syntheses of paclitaxel are considered practical and economical routes to this important anticancer drug. Unfortunately, chemists still lack the tools (i.e. reactions) to build complex products in a fashion that is economically competitive with nature. For this reason, the development of new reactions (and strategies on how to use these transformations) remains an important research objective.
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One of the most important multicomponent reactions connected with the origin of life on earth is the Strecker reaction to synthesize a-amino acids via the formation of a-aminonitriles. However, successful three-component Strecker reactions using ketones and fluorinated ketones are rare. Fluorinated amino acids are becoming increasingly important in pharmaceutical and other biological applications, such as the development of anticancer drugs for attenuating tumor growth, and drugs for controlling blood pressure and allergies. They have been widely used in biological tracers, as mechanistic probes, enzyme inhibitors, and in many medical applications, and also as a valuable tool for the screening of protein dynamics by 19F NMR spectroscopic studies.
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Carbohydrates are involved in numerous important life processes. Structurally, they are present in micro-heterogeneous forms in nature and are much more diverse and complex than proteins and nucleic acids. The chemical synthesis of carbohydrates is thus immensely important to the realization of structurally well-defined and functionally endowed oligosaccharides and glycoconjugates. However, the high complexity which enables them to participate in diverse biological domains also renders their synthesis difficult. In the assembly of sugar-biopolymers, it is necessary to control regioselectivity of glycosylation so that only a specific hydroxyl group is coupled with the donor sugar in a stereoselective manner, producing either the a- or the b-anomer. Consequently, the regioselective differentiation of each hydroxyl group present on a sugar unit is the first and foremost problem.
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The quest for funding is certainly one of the principal activities for researchers worldwide. European researchers, regardless of their area of research, know very well that it is time for undertaking a new campaign of “money-hunting”. Why? Well, the answer is easy: the European Commission has very recently launched the Seventh Framework Research Programme (FP7), which is the tool of the executive body of the European Union (EU) to fund research until 2013. In this huge “melting pot” of opportunities, schemes, research areas, topics, and projects, European researchers will try to find a way to obtain the often desperately needed money to both experimentally test and put into practice projects and ideas. This represents a daunting competition with success rates often lower than 5%. The situation is even more complicated if you are an organic chemist. In fact, at first sight, organic chemistry as such seems to have almost disappeared from the funding priorities of the EU. Is this true? SYNFORM decided to learn more about the role of chemistry in FP7 by interviewing an EU officer who accepted the invitation to answer some basic questions on the importance of (organic) chemistry in FP7 – what a chemist should do in order to get funded in FP7, what the opportunities are for extra-European chemical scientists, and much more – for our INSIDE STORY in this issue of SYNFORM. One of the SYNSTORIES this month introduces an upandcoming young researcher, Professor Qian Wang, the first in the series Young Career Focus. One of the latest articles that was chosen as Synfact of the Month in SYNFACTS, namely Professor Kazuaki Ishihara’s fantastic work on the enantioselective halocyclization of polyprenoids, is the focus of another SYNSTORY. The third SYNSTORY is dedicated to an article dealing with an aspect of copper catalysis in natural product synthesis. Recently, SYNTHESIS devoted a Special Topic to “Copper in Organic Synthesis”, where you can find more in the way of interesting, current research results in this specific area of chemistry.
Let me conclude by inviting all of you, kind readers, to get in touch with us for ideas, comments, and (why not!) criticism, through our e-mail Synform@chem.polimi.it.
Question 1: What are the funding opportunities for a chemist, particularly for an organic chemist, in FP7?
Answer 1: It is not only a matter of getting grants for a lab. Chemistry is everywhere in FP7. I will return your question by saying: How can chemists best contribute to achieve the FP7 objectives? Certainly in providing new knowledge and transforming it into innovations. Organic chemistry is an asset for designing innovative medicines or better drug delivery based on nanosystems, for manufacturing performance and ‘intelligent’ special materials. Combined with research on catalysis, it also contributes to pave the way for reducing greenhouse gases from industrial processes and transports. From frontier research to applied research, the spectrum of opportunities for chemists is broad. FP7 is a flexible programme; there are many opportunities to grab, as long as excellence and innovation are addressed, of course…
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The cladiellin (eunicellin) family of natural products comprises over 60 members which have been isolated from marine invertebrates. The cladiellins possess substantial and varied biological activities and several of them display potent cytotoxicity against tumor cell lines (e.g., scleropytin A, which displays activity against L1210 cells at concentrations of 1 ng/mL). The cladiellins are highly alluring synthetic targets as a consequence of the synthetic challenges they present and the significant biological activities that some of them display. In recent years, intensive efforts to synthesize the cladiellins have resulted in impressive total syntheses of several members of the family (see the original article for a bibliography).
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Polycyclic bioactive natural products that contain halogen atoms have been isolated from a number of different marine organisms. The biosynthesis of these natural products appears to be initiated by an electrophilic halogenation reaction at a carbon–carbon double bond via a mechanism that is similar to a proton-induced olefin polycyclization. Enzymes such as haloperoxidases generate an electrophilic halonium ion (or its equivalent), which reacts with the terminal carbon–carbon double bond of the polyprenoid enantioselectively, inducing a cyclization reaction that produces a halogenated polycyclic terpenoid. Use of an enantioselective halocyclization reaction is one possible way to chemically synthesize these halogenated cyclic terpenoids. Now Kazuaki Ishihara, chemistry professor at the Nagoya University, Japan, and co-workers have developed the first enantioselective halocyclization of simple polyprenoids using a nucleophilic promoter.
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Background and Purpose. From this issue on, SYNFORM will regularly meet young up-and-coming researchers who are performing exceptionally well in the arena of organic chemistry and related fields of research, in order to introduce them to the readership. In this first SYNSTORY with a Young Career Focus, we learn about Dr. Qian Wang, Assistant Professor at the University of South Carolina, Department of Chemistry and Biochemistry and NanoCenter, Columbia (USA) (wang@mail.chem.sc.edu).
To read more please download SYNFORM 2007/02 online, free of charge.
this new editorial initiative, SYNFORM, aims at complementing the information provided by the Thieme Chemistry journals. SYNFORM will serve the international chemistry community by publishing timely information about new scientific advances in organic chemistry and related fields of research. In addition, SYNFORM will inform you about facts and people from the world of chemical sciences – all this in a stimulating and thought-provoking manner. SYNFORM consists of two sections: THE INSIDE STORY and SYNSTORIES. THE INSIDE STORY is a peer interview in which the main author of a recent groundbreaking article, an opinion leader in the chemical sciences, or an expert in an important area dealing with chemistry (politics, ethical issues, society, etc.) will be interviewed by an eminent competent personality. SYNSTORIES is a format for important information about new scientific advances, as reported in the most exciting recent papers in the field of organic chemistry, accompanied by both the author’s personal views and comments by other experts. In addition, SYNSTORIES will present accurate and up-to-date news about people, institutions, new trends, conferences and perspectives of the world of chemical sciences, and much more. You, dear readers, will be the true protagonists of SYNFORM. For this reason we hope that you will contribute with your feedback, opinions, ideas, suggestions, and (why not!) criticism, in order to make SYNFORM a dynamic and stimulating public space for scientific scholarly discussion on topics of interest for the world of chemical sciences.
Background and Purpose. The same authors previously reported the development of CB-25 and CB-52, two fatty acid and olivetol- or resorcinol-derived ligands of CB1 and CB2 cannabinoid receptors, showing improved metabolic stability and receptor affinity over the parent compounds. In this paper their functional activity is assessed.
Experimental Approach. The effect of the two compounds on forskolin-induced cAMP formation in intact cells or on GTP-g-S binding to cell membranes, as well as their action on nociception in vivo, was determined.
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Question 1: You have recently reported the discovery of the first “hybrid’’ cannabinoid and vanilloid receptor ligands. Are there any other molecular/therapeutic areas in which you foresee a role for a ligand hybrid with cannabinoid compounds?
Answer 1: Absolutely! After the first series of “hybrid” agonists of CB1 and TRPV1 receptors (arvanil), with potential application in the treatment of pain, emesis, spasticity in multiple sclerosis, cancer and neuronal excitotoxicity, we have already developed: 1) “hybrid” TRPV1 agonists and CB2 antagonists, with potential application in inflammation, and 2) “hybrid” inhibitors of the enzyme fatty acid amide hydrolase (FAAH), which catalyze the hydrolysis of endocannabinoids and antagonists of vanilloid receptors. The prototype of the latter compounds is N-arachidonoylserotonin, which proved to be efficacious in an experimental model of neuropathic pain. Others have found that some< COX inhibitors can also bind to cannabinoid CB2 receptors and /or inhibit FAAH.
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The aldol reaction is one of the most powerful tools for stereoselective carbon–carbon bond formation, and hence, it is widely used in organic synthesis. However, the cross-aldol reaction between two different aldehydes is all but a trivial process, due to undesired side reactions such as dehydration of the product, self-aldol reaction and multiple addition of the enolate to the aldol product. Thus, not surprisingly, only a few examples of catalytic asymmetric cross-aldol reactions have been developed to date. Very recently, L-proline was found to enantioselectively catalyze the cross-aldol reaction between aldehydes to give the aldol product without prior formation of activated enolate species. This methodology was applied to the facile synthesis of carbohydrates (see for example: D. W. C. MacMillan and coworkers Angew. Chem. Int. Ed. 2004, 43, 2152).
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Asymmetric catalytic reactions aim at an efficient transfer of the chiral environment of a reaction to the transition state. In principle, any asymmetric structure or influence may contribute to this, including the product itself. Such asymmetric autocatalysis, i.e. the process of automultiplication of a chiral compound in which the chiral product acts as a chiral catalyst for its own formation, was introduced by K. Soai et al. [Nature (London) 1995, 378, 767] and was demonstrated to occur for the alkylation reactions of aldehydes with i-Pr2Zn, involving a zinc alkoxide of the product as the catalytically active species.
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The development of syntheses leading to a-amino acids has intrigued generations of chemists who have delivered a diversity of methodologies based on carbon–carbon bond-forming reactions. In addition to the classic Strecker reaction (path a), there are two more recent versatile approaches consisting of the addition of nucleophilic species, either organometallic reagents (path b) or alkyl radicals (path d), to electrophilic glycine equivalents. Recently, the group of Ombretta Porta at the Chemistry Department of Politecnico di Milano reported on a conceptually new radical approach to a-amino acids.
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