SYNFORMPeople, Trends and Views in Synthetic Organic Chemistry

2013/11

Thieme

SYNSTORIES

A General Strategy for theChemoenzymatic Synthesis ofAsymmetrically Branched N-Glycans

Total Synthesis of Vinigrol

Palladium-Catalyzed ReductiveCarbonylation of Aryl Halides withN-Formylsaccharin as a CO Source

Young Career Focus: Professor Mary P. Watson(University of Delaware, Newark,USA)

CONTACT

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Dear readers,

I have been in Brussels this week,dealing with one of the last activitiesof the Framework Programme 7 (FP7),which is about to be replaced by thenew giant and glittering Horizon 2020,

the new European Framework Programme for Research andInnovation that will run from 2014 to 2020 with a budget ofabout 70 billion Euros. At first sight one may think that therewon’t be much on the plate for chemists, but actually thereis more than that which meets the eye. In fact, chemistry isprogressively becoming a pervasive and essential componentof many projects and research initiatives in biomedicalresearch, environmental and materials sciences, and energy,just to mention a few. No surprise therefore in realizing that,although a bit beneath the surface, chemistry is actually scattered throughout the whole Horizon 2020, with hugeopportunities for all of us, chemists. The keyword is: col -laborations! Inter- and multidisciplinary collaborations, to be precise. Chemistry is the enabling tool that will allowmany projects in Horizon 2020 to take-off and fly. Let’s lookfor collaborations then, and let’s take on this new excitingopportunity for chemistry and for us chemists, becausechemistry is and will continue to be “the central science”, in Horizon 2020 and beyond.

Let’s have a look at this new SYNFORM issue now. Well,it’s also very exciting, I have to say. The first SYNSTORYtakes us through the daunting synthetic efforts that allowedProfessor J. T. Nyardarson (USA) to assemble the structureof vinigrol. Next, we’ll learn about the Pd-catalyzed carbon -ylation reaction discovered by Professor K. Manabe (Japan),and then about the groundbreaking synthesis of branched N-glycans developed by Professor G.-J. Boons (USA). Last but not least, we’ll know more about a young up-and-coming researcher, Professor M. Watson (USA) and herresearch.

Enjoy your reading!

Editor of SYNFORM

SYNFORM A133

IN THIS ISSUE

SYNSTORIES

Total Synthesis of Vinigrol . . . . . . . . . . . . . . . . . . . . . . . . . . . . A134

Palladium-Catalyzed Reductive Carbonylation of Aryl Halides with N-Formylsaccharin as a CO Source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A137

A General Strategy for the ChemoenzymaticSynthesis of Asymmetrically Branched N-Glycans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A139

Young Career Focus: Professor Mary P. Watson(University of Delaware, Newark, USA) . . . . . . . . . . A141

COMING SOON . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A144

SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

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CONTACT

If you have any questions or wi

sh to send

feedback, please write to Matteo

Zanda at:

Synform@chem.polimi.it

Matteo Zanda

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Vinigrol is a diterpenoid first reported in 1987 (J. Org.Chem. 1987, 52, 5292). The molecule was isolated from thefungal strain Virgaria nigra and its structure was elucidatedby spectroscopic and X-ray diffraction studies. From the bio-logical activity viewpoint, vinigrol has anti-hypertensive andplatelet aggregation inhibiting properties, and was alsodemonstrated to be capable of arresting the progression ofHIV to AIDS. Vinigrol has remarkable structural complexity,as it contains a cis-decalin bridged by an eight-membered ringcontaining eight contiguous stereocenters. The first total syn-thesis of vinigrol was reported by Baran in 2009 (J. Am.Chem. Soc. 2009, 131, 17066). Recently, Professor Jon T.Njardarson from the University of Arizona (Tucson, USA)published a conceptually new total synthesis of vinigrol.

Professor Njardarson said: “I am particularly proud of ourtotal synthesis of vinigrol, not only because of the excellentand creative efforts of the individuals involved but becausewe never compromised on the key design aspects of theroute.” He continued: “Although the details of our route haveevolved over time (Tetrahedron Lett. 2009, 50, 1684;Synlett 2009, 23; Org. Lett. 2009, 11, 4492), the route’sdesign has always involved an oxidative dearomatizationreaction followed by an intramolecular Diels–Alder cyclo -

addition, a cyclization cascade to form a tetracyclic cage, late-stage unraveling of the vinigrol core via a C–C bond-frag-mentation reaction and strategic substrate-controlled transfor-mations to set key stereocenters.” As shown in the scheme be -low, the Arizona-based researchers have realized the original-ly envisioned in situ oxidative dearomatization/Diels–Aldercascade as well as a palladium-mediated cyclization cascadeto form the complex tetracyclic pre-fragmentation core inonly two steps from an achiral resorcinol-based aromatic pre-cursor. “The trifluoroethyl protecting group is particularlynoteworthy in this sequence,” remarked Professor Njardarson.“It plays two important deactivation roles: to ensure that 1) the oxidative dearomatization is directed to the more hin-dered phenolic ether, and 2) the intermediate quinol mono -ketal does not fragment prior to undergoing the intramolecularDiels–Alder cycloaddition.” This protecting group was alsoessential for ensuring a high-yielding Dakin oxidation reac-tion in the previous step. Professor Njardarson continued:“From what we can gather, this is the first use of a trifluo-roethyl ether protecting group in targeted organic synthesis.The last step of the total synthesis involves a highly unusualtrifluoroethyl ether deprotection strategy employing LDA andosmium(IV) oxide.”

SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

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SYNSTORIES A134

NEWS AND VIEWS NEWS AND VIEWS NEWS AND VIEWS

Total Synthesis of VinigrolAngew. Chem. Int. Ed. 2013, 52, 8648–8651

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As is often the case with complex molecule synthesis, itinvariably reveals the limits and strengths of existing methodswhile also demanding new solutions and strategies (new pro-tecting group). “Because of the rigidity and compactness ofthe tetracyclic cage,” said Professor Njardarson, “our synthet-ic route showcases many interesting reactions in ‘tight’ spacesas exemplified by the transformations shown below, whereinin one case a remarkable directed hydrogenation ensured for-mation of the C8 stereocenter, while in the other a favorable

interruption of the classic allylic oxidation promoted by sele-nium dioxide resulted in a one-step incorporation of the C16hydroxyl group.”

Professor Njardarson concluded: “Our long-term goal is todevelop an asymmetric oxidative dearomatization protocolthat we can apply to vinigrol and other complex diterpenoidnatural products.”

SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

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Matteo Zanda

SYNSTORIES A135

About the authors

Jon T. Njardarson was born and raised in the small town of Akranes,Iceland. After graduation, he left hishometown and moved to Reykjavik tostart his studies at the University ofIceland. Jon then followed in the foot-steps of his Icelandic ancestors andmoved west, to America. This journeybrought him to New Haven, Connecti -cut (USA), where he chose to pursuea graduate career in Organic Chem -istry at Yale University. While at Yale,

he joined the research group of a newly hired assistant profes-sor, John L. Wood, after becoming affected by his enthusiasm,energy and exciting new research program. During his doctoralstudies Jon worked on the total synthesis of the nonadridenatural products CP-225,917 and CP-263,114. At the end ofhis graduate studies Jon was presented with the irresistibleoffer of moving to New York City to work in the laboratory ofProfessor Samuel J. Danishefsky at the Memorial Sloan-Kettering Cancer Center (MSKCC). While in the Danishefskygroup, as a General Motors Cancer Research Scholar, he work -ed on the total syntheses of the natural products epothilone490 and migrastatin. Jon moved to Ithaca in 2004 to start his

independent career at Cornell University, where he launched aresearch program focused on natural products and the deve-lopment of new methods. In 2010 Jon and his group loadedthe wagons, journeyed across the continent, and settled inTucson where he is currently an associate professor of chem -istry at the University of Arizona.

Cristian Draghici received his BSdegree in chemistry and biochemistryin 2003 from Western ConnecticutState University (USA). During thistime he worked in the laboratory ofProfessor Paula M. Secondo. Cristianthen moved to the University ofVermont (USA) where he received hisPh.D. in 2009 under the guidance ofProfessor Matthias Brewer. While inProfessor Brewer’s laboratory, Cristiandeveloped a new carbon–carbon

bond-fragmentation protocol and pursued natural products tar-gets using this new strategy. Cristian joined Professor Jon T.Njardarson’s laboratory at Cornell University as a postdoctoralfellow, during which time he worked on the total synthesis ofvinigrol and assisted with the creation and launch of a new

Prof. J. T. Njardarson

Dr. C. Graghici

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SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

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SYNSTORIES A136

educational app (Chemistry By Design). Cristian is currently apostdoctoral fellow with Professor David A. Spiegel at YaleUniversity.

Qingliang Yang was born and raisedin a small village in Hubei province (P. R. of China). He completed hisundergraduate education at SichuanUniversity in Chengdu (P. R. of China)and studied medicinal chemistry withProfessor William Groutas at WichitaState University (USA), and receivedhis M.S. degree in 2006. After work -ing briefly as research scientist atAMRI in New York, he attendedCornell University and studied natural

product total synthesis with Professor Jon T. Njardarson. Shortlyafter completing the total synthesis of vinigrol he obtained hisPh.D. (summer 2013).

Dr. Q. Yang

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Carbon monoxide (CO) is widely used for transition-metal-catalyzed carbonylation reactions, such as hydroformylations,Reppe-type chemistry or CO insertions on aromatic halidesand related substrates. However, CO gas is highly toxic andnot easy to handle safely. Therefore, “CO gas free” carbonyl -ation chemistry has become the focus of extensive research.Recently, Professor Kei Manabe and members of his group inthe School of Pharmaceutical Sciences at the University ofShizuoka (Japan) reported on the palladium-catalyzed car-bonylation of aryl halides with CO sources such as phenyl for-mate (Org. Lett. 2012, 14, 3100) and 2,4,6-trichlorophenylformate (Org. Lett. 2012, 14, 5370) for the synthesis of car-boxylic acid derivatives. Professor Manabe said: “Now, wehave developed a method of reductive carbonylation for the

synthesis of aldehydes. The key of the reaction is the use ofN-formylsaccharin as a crystalline CO source that can be handled easily. N-Formylsaccharin was originally developedby Professor Cossy as a new and inexpensive formylatingagent for amines (Synlett 2011, 1920), and we found that itgradually generates CO in situ in the presence of Na2CO3.”Aromatic and heteroaromatic aldehydes can be synthesizedfrom the corresponding halides and triflates in good yields.This reductive carbonylation is advantageous over traditionalreactions under an atmosphere of CO gas, not only because N-formylsaccharin is easy to handle but also because gradualgeneration of near-stoichiometric CO can avoid the catalystdeactivation that is sometimes observed in reactions under anatmosphere of CO gas (i.e., in the presence of large excess ofCO).

Professor Manabe concluded: “Thus, this ‘easy-peasy’ re -ductive carbonylation will provide an efficient method for thesynthesis of various aldehydes.” Indeed, the reaction scope isremarkably broad, and structurally diverse bromoaryl orbromo heteroaryl derivatives having either electron-deficientor electron-rich cores can be successfully subjected to thiscarbonylation reaction, which holds promise to find wideapplication in organic synthesis.

SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

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Palladium-Catalyzed Reductive Carbonylation of ArylHalides with N-Formylsaccharin as a CO Source Angew. Chem. Int. Ed. 2013, 52, 8611–8615

SYNSTORIES A137

Scheme 1 Pd-catalyzed reductive carbonylation using N-formylsac-charin as a CO source

Matteo Zanda

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SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

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SYNSTORIES A138

About the authors

Tsuyoshi Ueda was born in Ishikawaprefecture (Japan) in 1978. He re -ceived his M.S. degree in 2003 inIndustrial Chemistry from Meiji Uni ver -sity (Japan) and subsequently joinedthe Department of Process Develop -ment at Sankyo Co., Ltd. He com -pleted his Ph.D. under the guidanceof Professor Kei Manabe at the Uni versity of Shizuoka (Japan) in2013. He is currently an AssociateSenior Researcher in Daiichi Sankyo

Co., Ltd., working on the development of practical syntheticmethods and large-scale synthesis of active pharmaceuticalingredients.

Hideyuki Konishi was born in Taka -matsu (Japan) in 1979. He obtainedhis Ph.D. in Pharmaceutical Sciencesat The University of Tokyo (Japan) in2008 under the direction of ProfessorShū Kobayashi. He carried out hispostdoctoral research in ProfessorViresh H. Rawal’s laboratory at theUniversity of Chicago (USA). In 2009,he became a Research AssistantProfessor in the group of ProfessorKei Manabe at the University of

Shizuoka. His research interests include the development ofpractical and efficient catalytic reactions for the construction ofpharmaceutically and synthetically important compounds.

Kei Manabe was born in Kanagawa(Japan). He completed his doctoralwork in 1993 at The University ofTokyo. After working as a postdoc -toral fellow at Columbia University(USA), he went back to the Universityof Tokyo and worked as an AssistantProfessor, Lecturer, and AssociateProfessor. In 2005, he moved toRIKEN (Japan) as an Initiative Re -search Scientist. He joined the facultyat the University of Shizuoka as a

Professor in 2009. His research interests include the develop-ment of new catalytic reactions for organic synthesis.

Dr. T. Ueda

Prof. H. Konishi

Prof. K. Manabe

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Glycans are oligo- or polysaccharides in which mono -saccharide units are linked through O-glycosidic bonds. N-Linked glycans constitute a particular class of glycans,which are attached in the cellular endoplasmic reticulum tothe side-chain nitrogen of asparagine in the so-called‘sequon’, which is an Asn-X-Ser or Asn-X-Thr tripeptidesequence, where X is any amino acid except proline and theglycan can be N-acetyl galactosamine, galactose, neuraminicacid, fructose or other monosaccharides. Of all the post-trans-lational modifications of proteins, complex N-linked glycansare the most prominent in terms of complexity and diversity.Although these compounds, which are essential mediators ofa number of biological processes such as protein folding, cellsignalling and proliferation, are usually asymmetricallybranched, synthetic efforts have focused almost exclusivelyon the preparation of simpler symmetrical structures. Thisstems from the difficulties in controlling diversification at thevarious sites of branching, especially when several differentcomplex terminal structures need to be appended. Recently,the group of Professor Geert-Jan Boons from the Universityof Georgia (Athens, USA), in collaboration with researchersfrom the Scripps Research Institute (La Jolla, USA), pub-lished a novel revolutionary chemo-enzymatic strategy thatmakes it possible to prepare libraries of highly complex sym-metrical and asymmetrical N-glycans.

Professor Boons said: “Unique aspects of the approachinclude the use of a core pentasaccharide 1 that is common toall eukaryotic N-linked glycans and is modified at key branch-ing positions by a set of orthogonal protecting groups thatmakes it possible to diversify by chemical glycosylation.” Thespeed of oligosaccharide synthesis and the complexity of thetargets were further increased by the identification of saccha-ride appendages that allowed each antenna of deprotectedcompounds to be uniquely extended by glycosyltransferases.Professor Boons continued: “Further control of regioselec -tivity in antenna modification was achieved by exploiting theinherent selectivities of glycosyltransferases. It is the uniquecombination of these strategic features that made it possibleto prepare the most complex N-glycan ever reported, beingtri-antennary and having different complex oligosaccharideextensions at each antenna.”

The new synthetic strategy will make it possible to fab -ricate the next generation of glycan microarrays, to developalgorithms for the assignment of MS spectra, and preparewell-defined glycoforms of glycoproteins.

“We are focusing on the preparation of full N-glycomes ofbronchial epithelial cells, oocytes and immune cells,” saidProfessor Boons. He concluded: “The resulting compoundswill be employed to define the biological glycan receptors ofinfluenza virus, and glycans that are important for fertilizationand modulating immunological reactions. The novel com-pounds will also be employed as standards in developing bet-ter protocols for structural identification of glycans isolatedfrom natural sources.”

SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

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A General Strategy for the Chemoenzymatic Synthesis ofAsymmetrically Branched N-GlycansScience 2013, 341, 379–383

SYNSTORIES A139

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About the authors

Geert-Jan Boons received an M.Sc.in Chemistry in 1987 and a Ph.D. inSynthetic Carbohydrate Chemistry in1991 from the State University ofLeiden (The Netherlands). Prior tojoin ing the faculty at the ComplexCarbo hydrate Research Center(CCRC) at the University of Georgia(Athens, USA) in 1998, he spentseven years in the UK, first as a Post -doctoral Fellow at Imperial College,London, and the University of Cam -

bridge, and then as a Lecturer and Professor at the Universityof Birmingham. In 2003, Dr. Boons was awarded the Carbo -hydrate Research Award for Creativity in Carbohydrate Scienceby the European Carbohydrate Association. Also in 2003, hewas elected Chairman for the 2005 Gordon Research Confe -rence on Carbohydrates. In 2004, Dr. Boons received theHorace Isbell Award by the Division of Carbohydrate Chemistryof the American Chemical Society and was appointed FranklinProfessor of Chemistry in the College of Arts and Sciences atthe University of Georgia. In 2012, he received the CreativeResearch Inventor’s Award by the University of Georgia Re -search Foundation and was appointed Distinguished Professorin Biochemical Science in the Franklin College of Arts andSciences at the University of Georgia. He was awarded the RoyL. Whistler International Award in Carbohydrate Chemistry for2013 by the International Carbohydrate Organization. Theresearch of the Boons group deals with the synthesis and bio-logical functions of complex carbohydrates and glycoconju -gates.

Zoeisha S. Chinoy received herBachelor of Science in Chemistry fromthe University of West Georgia(Carrollton, USA) in 2008, where shepursued undergraduate researchunder the supervision of ProfessorPartha S. Ray. She then enrolled inthe PhD Program in Chemistry at theUniversity of Georgia. Since 2009, she has been a student in ProfessorGeert-Jan Boons’ laboratory. Herdoctoral studies focus on the synthe-

sis of glycopeptides and the chemo-enzymatic synthesis ofcomplex N-glycans.

Zhen Wang received his Ph.D. fromthe University of Toledo (USA) in 2008under the supervision of ProfessorXuefei Huang. After one year postdoc-toral training at Michigan State Uni -versity (East Lansing, USA) in thesame research group, he joined theCCRC as a Postdoctoral ResearchAssociate under the guidance ofProfessor Geert-Jan Boons. He is cur-rently a research scientist at MomentaPharmaceuticals, Inc.

Shailesh Ambre was born in Baroda(India). He was awarded his Bachelorsin Applied Chemistry from SardarPatel University (India) in 2001 and hisMasters in Organic Chemistry from M. S. University of Baroda (India) in2004. After a short productive stay inindustry as a process chemist,Shailesh moved to the University ofGeorgia to pursue doctoral studies.He joined the group of ProfessorGeert Jan Boons at the CCRC and

graduated with a PhD in the summer of 2012. Currently,Shailesh is a Postdoctoral Fellow at the Centennial Centre forInterdisciplinary Science, University of Alberta (Canada) in thegroup of Professor Ratmir Derda.

Dr. G.-J. Boons

Z. S. Chinoy

Dr. Z. Wang

Dr. S. Ambre

SYNSTORIES A140

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SYNSTORIES A141

Background and Purpose. SYNFORM will from timeto time meet young up-and-coming researchers who are per-forming exceptionally well in the arena of organic chemistryand related fields of research, in order to introduce them to thereadership. This SYNSTORY with a Young Career Focuspresents Professor Mary P. Watson, University of Delaware,Newark, USA.

INTERVIEWSYNFORM What is the focus of your current researchactivity?

Prof. M. P. Watson We are developing new catalyticmethods for organic synthesis. In particular, we are focusedon transition-metal catalysis of non-traditional electrophilesto enable the efficient preparation of highly enantioenrichedproducts. In one area, we are developing enantioselectiveadditions to cationic intermediates, such as oxocarbeniumions, to deliver highly enantioenriched α-substituted hetero-cycles. In a second area, we have begun to develop enan-tiospecific, nickel-catalyzed cross-couplings of benzylicelectrophiles to provide di- and tri-arylalkanes in high ee.

SYNFORM When did you get interested in synthesis?

Prof. M. P. Watson As a high-school and college student,one of the first things that intrigued me about chemistry wasits hands-on aspect. I loved being able to observe colorchanges, crystals forming, exotherms, etc. I felt a special satisfaction from collecting a high yield of pure, white solidat the end of a reaction and purification sequence. That waswhen I knew I wanted to synthesize organic compounds asmy career.

As I matured in my understanding of chemistry, I becameincreasingly motivated by the many unsolved problems inorganic synthesis. There are still so many reactions we can-not yet accomplish with high efficiency and selectivity andso many synthetic disconnections that we haven’t discoveredyet. Further, although we have begun to understand how catalysts impart reactivity and selectivity, we still lack thedepth of understanding to rationally design catalysts in manycases and must rely on an empirical approach at least in part.These challenges highlight how much we have yet to dis -cover in synthetic chemistry, and I am excited to be part ofthe community pushing our knowledge and capabilities for-ward.

Young Career Focus: Professor Mary P. Watson (University of Delaware, Newark, USA)

BIOGRAPHICAL SKETCHMary P. Watson was born inBoston, MA (USA) in 1977 andgrew up in Tampa, FL (USA). Shecompleted an A.B. in Chemistry atHarvard University (USA) in 2000.During college, she performedundergraduate research withProfessor David A. Evans atHarvard University, as well as withProfessor Kenneth B. Wagener atthe University of Florida (USA). Under the direction of Professor

Larry E. Overman, Mary earned a Ph.D. in organic chemistryin 2006 from the University of California, Irvine (USA). Herdoctoral thesis focused on the development and mechanisticinvestigation of the palladium(II)-catalyzed asymmetric allylicimidate rearrangement. During the course of this work, shehad the opportunity to collaborate with Professor Robert G.Bergman at the University of California, Berkeley (USA),where she performed kinetic and computational studies.

From 2006–2009, Mary was a National Institutes of HealthNRSA Postdoctoral Fellow at Harvard University in Profes -sor Eric N. Jacobsen’s research group. During her postdoc,she developed a nickel-catalyzed method for enantioselectiveolefin arylcyanation via activation of C–CN bonds.

In July 2009 Mary joined the faculty at the University ofDelaware, where she has been working with her researchgroup to develop new catalytic methods for the synthesis oforganic molecules. The group’s work has been recognizedby a Rising Star Award from the American Chemical SocietyWomen Chemists’ Committee and a Thieme ChemistryJournal Award. Their research has been generously support - ed by the University of Delaware Research Foundation, theAmerican Chemical Society Petroleum Research Fund, theNIH COBRE program, and an NSF CAREER grant.

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SYNFORM What do you think about the modern role andprospects of organic synthesis?

Prof. M. P. Watson The importance of organic synthesisto human health, materials science, and energy research isundeniable. These applications emphasize the tremendousimpact that advances in synthetic chemistry have on ourdaily lives.

It is exciting that new discoveries – new reactions, as wellas synthetic strategies – are reported every day, pushing thefrontier of organic synthesis forward. Current challenges toorganic synthesis (increased efficiency, decreased cost andwaste, greener reaction and purification conditions, etc.) re -quire further innovation and discovery and are very motivat-ing for my generation of chemists.

SYNFORM Your research group is active at the frontierof organic synthesis and catalysis. Could you tell us moreabout your research and its aims?

Prof. M. P. Watson In the celebrations for Nobel LaureateRichard Heck at the University of Delaware, I had the oppor -tunity to interview him about his research and his motivationfor developing the Heck reaction. He humbly stated that hewas just trying to make life a little simpler. This pursuit –to make life simpler, to facilitate access to important mole-cules – sums up the ultimate goal of my research program.By discovering new catalytic methods, we hope to enablepreparation of molecules crucial for advancing science.

More specifically, in our research on enantioselectiveadditions to oxocarbenium ion intermediates, we have de -monstrated that chiral copper catalysts enable highly enantio -selective additions of terminal alkynes to prochiral oxocar-benium ions, formed in situ from racemic acetals (Scheme1). We are excited about the potential of a metal-catalyzed

strategy for enantioselective additions to such intermediatesand are aggressively developing analogous reactions withother classes of cationic intermediates, as well as othernucleophiles.

In our efforts on enantiospecific cross-couplings of benz -ylic electrophiles, we have demonstrated that di- and tri-arylalkanes can be prepared in exceptional levels of enantio -purity via nickel-catalyzed couplings of organoboranes witheither benzylic ammonium triflates or benzylic pivalates(Scheme 2). Both these classes of electrophiles are particu-larly attractive, because they can be readily prepared withhigh enantioenrichment. Our mild reaction conditions enableexcellent functional group tolerance, setting the stage forfurther elaboration of the enantioenriched products. We arenow pursuing a deeper mechanistic understanding, as well asincreased scope, of these reaction manifolds.

SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

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SYNSTORIES A142

Scheme 2

Scheme 1

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SYNFORM What is your most important scientific achieve -ment to date and why?

Prof. M. P. Watson Within our research program onmetal-catalyzed transformations of non-traditional electro -philes, we have demonstrated that metal catalysts can beeffectively used to control reactivity and selectivity with arange of non-traditional electrophiles, including oxocarbeni-um and iminium ion intermediates, as well as benzylic am -monium salts and pivalates. Our results greatly expand therange of electrophiles amenable to transition-metal catalysisand offer exciting possibilities for organic synthesis.

SYNFORM, 2013/11Published online: 18.10.2013, DOI: 10.1055/s-0033-1339906

2 0 1 3 © T H I E M E   S T U T T G A RT · N E W   Y O R K

SYNSTORIES A143

Matteo Zanda

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COMING SOON COMING SOON

SYNFORM 2013/12is available from November 18, 2013In the next issues:

SYNSTORIES

Synchronous Ar–F and Ar–Sn Bond Formation throughFluorostannylation of Arynes(Focus on an article from the current literature)

Direct Catalytic Cross-Coupling of Organolithium Compounds(Focus on an article from the current literature)

Total Synthesis of the Daphniphyllum Alkaloid Daphenylline(Focus on an article from the current literature)

SYNFORM

CONTACTMatteo Zanda,NRP Chair in Medical TechnologiesInstitute of Medical SciencesUniversity of AberdeenForesterhill, Aberdeen, AB25 2ZD, UKand C.N.R. – Istituto di Chimica del Riconoscimento Molecolare,Via Mancinelli, 7, 20131 Milano, Italy,e-mail: Synform@chem.polimi.it, fax: +39 02 23993080

FURTHER HIGHLIGHTSSYNTHESISReview on: Current Developments in the Synthesis of 1,2-Dihydropyridines(by A. M. S. Silva et al.)

SYNLETTSpecial Issue dedicated to the 5th Young InvestigatorsWorkshop, July 4–6, 2013, Marseille, France(contributions by all participants)

SYNFACTSSynfact of the Month in category “Synthesis of Heterocycles”:Organocatalytic Route to 2,3,4,6-Tetra- and 2,3,4,5,6-Pentasubstituted Pyridines

EditorMatteo Zanda, NRP Chair in Medical Technologies, Institute of MedicalSciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UKand C.N.R. – Istituto di Chimica del Riconoscimento MolecolareVia Mancinelli, 7, 20131 Milano, ItalyEditorial Assistant: Alison M. SageSynform@chem.polimi.it; fax: +39 02 23993080

Editorial OfficeManaging Editor: Susanne Haak,susanne.haak@thieme.de, phone: +49 711 8931 786Scientific Editor: Selena Boothroyd,selena.boothroyd@thieme.deAssistant Scientific Editor: Michael Binanzer,michael.binanzer@thieme.de, phone: +49 711 8931 768Senior Production Editor: Thomas Loop,thomas.loop@thieme.de, phone: +49 711 8931 778Production Editor: Helene Deufel,helene.deufel@thieme.de, phone: +49 711 8931 929Production Editor: Thorsten Schön,thorsten.schoen@thieme.de, phone: +49 711 8931 781Editorial Assistant: Sabine Heller,sabine.heller@thieme.de, phone: +49 711 8931 744Marketing Manager: Julia Stötzner,julia.stoetzner@thieme.de, phone: +49 711 8931 771Postal Address: SYNTHESIS/SYNLETT/SYNFACTS, Editorial Office,Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany, Homepage: www.thieme-chemistry.com

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