synf orm - thieme...highly enantioselective synthesis of 3,4-dihydropyrans through a...

SYNFORMPeople, Trends and Views in Chemical Synthesis

2015/04

Thieme

SynSTorIES

Synthesis of Chiral Heterocycles

by Ligand-Controlled Regiodiver gent

and Enantiospecific Suzuki–Miyaura

Cross-Coupling

Young Career Focus:

Dr. Ivana Fleischer

(University of Regensburg, Germany)

Chemoselective Activation of sp3

vs sp2

C–H Bonds with Pd(II)

Highly Enantioselective

Synthesis of 3,4-Dihydropyrans

through a Phosphine-Catalyzed

[4+2] Annulation of Allenones and

β,γ-Unsaturated α-Keto Esters

ConTACT

Your opinion about Synform is

welcome, please correspond if you like:

[email protected]

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mailto:[email protected]

Dear readers,

During particularly busy times my editorial activity for SYNFORM has tocoexist with my other academic duties,so occasionally I have to squeeze itbetween meetings or during lunchtimes. This is exactly one such busy

situation, so I am typing this editorial with just one fingerwhile holding a sandwich (or what remains of it) in the otherhand. I know it is not a healthy habit, in fact it is not even ahabit for me, but it happens and I just have to live with that,and so does my digestion, which – I bet – will haunt me during the next meeting and throughout the afternoonahead…

OK, so what do we have in this new issue of SYNFORM?Well, the usual load of high quality organic chemistry, ofcourse! Starting from the synthesis of chiral heterocycles viaSuzuki–Miyaura cross-coupling developed by D. Hall(Canada) and continuing with the Young Career Focus ofwhich I. Fleischer (Germany) is the protagonist. The thirdSynSTory covers a novel chemoselective activation of C–H bonds described by M. C. Kozlowski (USA). The issueis completed by the enantioselective approach to 3,4-dihydro -pyrans stemming from the work of Y. Lu (Singapore).

Meanwhile I have already experienced the first signs of hic-cup… Enjoy your reading!!

Editor of SYNFORM

Synform A48

In THIS ISSUE

SynSTorIES

Young Career Focus: Dr. Ivana Fleischer

(University of Regensburg, Germany) . . . . . . . . . . . . . . . A49

Synthesis of Chiral Heterocycles by Ligand-

Controlled Regiodivergent and Enantiospecific

Suzuki–Miyaura Cross-Coupling. . . . . . . . . . . . . . . . . . . . . A51


vs sp2

C–H

Bonds with Pd(II) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A54

Highly Enantioselective Synthesis of 3,4-Dihydro -

pyrans through a Phosphine-Catalyzed [4+2]

Annulation of Allenones and β,γ-Unsaturated

α-Keto Esters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A57

ComInG Soon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A59

Synform, 2015/03Published online: 16.02.2015, DOI: 10.1055/s-0034-1380327

2 0 1 5 © T H I E M E S T U T T G A RT · N E W Y O R K

ConTACT

If you have any questions or wish to send

feedback, please write to Matteo Zanda at:

[email protected]

matteo Zanda

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SYNFORM, 2015/04Published online: 18.03.2015, DOI: 10.1055/s-0034-1380327


SYNSTORIES A49

Background and Purpose. From time to time SYN-

FORM meets 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 Focus pre -sents Dr. Ivana Fleischer (University of Regensburg, Ger -many).

INTERVIEW

SYNFORM What is the focus of your current researchactivity?

Dr. I. Fleischer Our research focuses on the developmentof new catalytic transformations for organic synthesis. The main subjects of our investigations are non-classical C1building blocks for various metal- and organocatalyzed reac-tions. We are interested in the whole picture: from the mech-anistic understanding of the reactions to useful syntheticapplications.

SYNFORM When did you get interested in synthesis?

Dr. I. Fleischer In secondary school, I participated in the chemistry olympiad and I enjoyed, most of all, topics inorganic chemistry – primarily at the theoretical level. I wasfascinated by its logic and ease of comprehension. Theattraction of science of organic synthesis persisted through-out my studies, and was even strengthened by the excitingand multifaceted laboratory work. I was lucky to be taughtby amazingly gifted teachers and lecturers, whom I wouldlike to thank at this point.

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

Dr. I. Fleischer Recent years have shown that catalysishas played a central role in the progress of modern organicsynthesis. The current focus lies in the development of effi-cient, selective and sustainable chemical transformations forthe synthesis of value-added chemicals, materials and naturalcompounds. The interest in utilization and transformation of renewable raw materials is growing and requires newmethods. Theoretical chemistry and spectroscopic methodswill become more important tools in the elucidation of reac-tion mechanisms and design of catalyst structures. But still, I think that serendipity will continue to surprise us and pro-vide the most astonishing discoveries.

Young Career Focus: Dr. Ivana Fleischer

(University of Regensburg, Germany)

BIOGRAPHICAL SKETCH

Ivana Fleischer was born and

raised in Poprad, (Czecho)Slovakia.

She studied chemistry at the

Commenius University in Bratislava

(Slovakia), where she conducted

her Diploma thesis under the

supervision of Professor Štefan

Toma in the field of ferrocene syn-

thesis. Following a family break,

she moved to Basel (Switzerland)

to work with Professor Andreas

Pfaltz on mass spectrometric

screening methods for chiral organocatalysts. After receiving

her PhD in 2010, she joined the group of Professor Matthias

Beller at the Leibniz Institute for Catalysis in Rostock

(Germany) as a postdoctoral fellow of the Swiss National

Science Foundation, where she spent three years. She

developed new ruthenium-based catalysts for hydroformyl -

ation reactions. Since September 2013, she is a group

leader at the University of Regensburg (Germany) and Liebig

Fellow of the Fonds der chemischen Industrie. Her research

interests center on the field of homogeneous catalysis and

organic synthesis with emphasis on method development.

Dr. I. Fleischer

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SYNFORM Your research group is active in the areas of catalysis and new methodology in organic synthesis.Could you tell us more about your research and its aims?

Dr. I. Fleischer Our research aims at the construction ofcarbonyl compounds, which are among the most versatilesynthetic intermediates. Our synthetic approach is based onthe use of metal- and organocatalysts for the functionaliza-tion of the available feedstock with C1 building blocks. The most attractive and especially challenging C1 source iscarbon dioxide, which constitutes an easily accessible andnon-toxic gas. Its use would expand the resource base, andvaluable products could be produced from this renewablecarbon source. However, its reactivity is low and new me -thods are required for its functionalization. Our strategy isbased on a two-step protocol, which consists of two catalytictransformations taking place under mild conditions. We alsowant to apply the developed methods to the synthesis of natural compounds. Figure 1 depicts the overall conversionof CO2 to complex molecules. In addition, we are investi -gating new tandem reactions of carbonyl compounds basedon one metal-catalyzed and one organocatalyzed step. Suchreaction sequences enable the effective formation of severalbonds and are characterized by atom-, step- and redox-economy.

SYNFORM What is your most important scientificachieve ment to date and why?

Dr. I. Fleischer I stand at the beginning of my indepen -dent research career, so it is difficult to answer this question.Nevertheless, the ongoing research of my group is veryexciting and I hope we will be able to communicate ourresults soon. So far, we have developed a convenient proto-col for acid-catalyzed hydroarylation of activated alkenes

(RSC Adv. 2015, 5, 493) and a new defined ruthenium-based catalyst for the alkoxycarbonylation of alkenes usingformates (Org. Biomol. Chem. 2014, 12, 6972).



SYNSTORIES A50

Matteo Zanda

Figure 1 Envisioned conversion of carbon dioxide into complex

compounds

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http://dx.doi.org/10.1039/C4RA13647K

http://dx.doi.org/10.1039/C4OB01246A

Controlling the regioselectivity of an organic reaction atone’s discretion while also maintaining full control of thestereochemistry of the process is a luxury in organic synthesisand not many methods are known for achieving such an out-standing level of control in the generation of stereogenicallylic systems. Recently, Professor Dennis Hall and co-work-ers at the University of Alberta (Canada) described the firstexample of a Suzuki–Miyaura cross-coupling with allylicboronates where both the configuration of an sp3 carbon (ste -reo selectivity) and the regioselectivity of the coupling processare fully controlled by the catalyst and especially the nature ofthe ligand (Figure 1).

What distinguishes this work from prior contributions isnot only the merging of stereo- and regiocontrol, but also theability to achieve this feat with functionalized allylic boro n -ates. Professor Hall explained: “The heterocyclic allylic bo -ron ates employed as substrates contain a conjugated hetero -atom and as such are more complex than a majority of chiralsecondary allylboronates reported in the literature.”

“These chiral heterocyclic allylic boronates are precursorsof important varieties of substituted pyran and piperidine

units present in a vast number of natural products and drugs,”said Professor Hall, continuing: “These key precursors high-light the usefulness (or utility) of the catalytic enantioselec-



SYNSTORIES A51

Synthesis of Chiral Heterocycles by Ligand-Controlled

Regiodivergent and Enantiospecific Suzuki–Miyaura

Cross-Coupling

Nat. Commun. 2014, 5, 5474

Figure 1 The regiochemical direction of a stereospecific allylic

Suzuki–Miyaura cross-coupling is controlled by a judicious choice

of ligand on the palladium catalyst.

Scheme 1 Hall’s methodology

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http://dx.doi.org/10.1038/ncomms6474

tive borylative isomerization that we previously reported andthat we also employed in carbonyl allylboration.”

According to Professor Hall, this work also highlights thepower and complementarity of state-of-the-art ligand systemsfor cross-coupling reactions, such as the biaryldialkylphos-phines (Stephen Buchwald) and the NHC carbene catalysts(Michael Organ).

“All of the experimental work was performed in the skilledhands of 5th year graduate student Jinyue Ding and 4th yeargraduate student Taras Rybak,” acknowledged Professor Hall.“Shortly after completing this work, Ding defended his PhDthesis and has now taken up a position as a Research Scientistin medicinal chemistry at Inception Sciences in Vancouver.”

“Ironically, the most difficult part of the project often wasnot the actual reaction, but the development of chiral HPLCconditions to measure the enantioselectivity of the reaction,”continued Professor Hall. “In some cases, the preparation ofderivatives of the products was necessary. On the other hand,these derivatization reactions and the synthetic application toanabasine and paroxetine further exhibit the versatility of thecross-coupling products.”

The group is now investigating the application of theirmethodology on other heterocyclic allylboronates and fine-tuning the regioselectivity with other unexplored ligands. “Wewould like to further demonstrate the value of this methodol-ogy towards the synthesis of other natural products and valu-able drug targets that are currently difficult to access,” saidProfessor Hall, concluding: “Future work will also include themechanistic study of stereoselective and regioselectiveSuzuki–Miyaura reactions. Based on the mechanistic under-standing, more novel and practical reactions could be devel-oped.”



SYNSTORIES A52

Matteo Zanda

Figure 2 Some of the compounds synthesized using Hall’s methodology

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SYNSTORIES A53

About the authors

Dennis Hall was born in Baie-Comeau, Province of Québec

(Canada) in 1968. In 1991, he enrolled in graduate studies

under the guidance of Professor Pierre Deslongchamps at

Université de Sherbrooke (Canada). His graduate research pro-

ject involved new synthetic methods and strategies applicable

to natural product synthesis. His work culminated on the devel -

opment of a new tandem transannular [4+2]/aldol approach to

diterpenes such as Aphidicolin, and on new findings on the

mechanism of the Diels –Alder reaction. After obtaining his PhD

degree in 1995, Hall moved on to explore new areas of investi-

gation such as bioorganic chemistry and combinatorial chemi-

stry, working as an NSERC Postdoctoral Fellow in the laborato-

ry of Professor Peter G. Schultz, then at the Department of

Chemistry at UC Berkeley (USA). In his postdoctoral stay from

1995–1997, he was involved in various projects and learned to

apply his knowledge of organic synthesis to problems in bio -

organic chemistry. In August 1997, he returned to Canada to

take an academic position at the Department of Chemistry,

University of Alberta. He was promoted to Professor of Chem -

istry level in July 2005.

Jinyue Ding was born in Henan (P. R. of China). He obtained

his BSc at Zhengzhou University in 2008 in the same province.

He moved to Canada in 2009 and obtained his PhD at the

University of Alberta in 2014 under the supervision of Professor

Dennis Hall. He is currently living in Vancouver and employed

as a Senior Scientist I at Inception Sciences Canada.

Taras Rybak was born in Hamilton (Canada) in 1985. He

received his BSc degree in Honours Chemistry at the University

of Waterloo (Canada). He is currently a PhD student at the

University of Alberta under the supervision of Professor Dennis

Hall. His research focuses on the development of new methods

for preparing and functionalizing pyran compounds towards

the synthesis of medicinally relevant natural products.

From left: T. Rybak, Dr. J. Ding, Prof. D. Hall

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Oxidative C–H activation is the most atom-economicalprocess for the construction of carbon–carbon bonds. Yu,White, Sanford, Fagnou and Davies (for references see theoriginal article) have pioneered the activation of C(sp3)–Hbonds with directing groups (heteroatom, allyl, carbene, etc.).The ability of some metals, such as Pd catalysts, to insertselectively into C–H bonds has provided a host of new, usefulmethods for the synthesis of organic molecules. Consideringas an example the Pd-mediated carboxylation of toluene,selective insertion into C(sp2)–H bonds (110–115 kcal/mol)by palladium is remarkable when considering bond strengthsof the competing C(sp3)–H bonds (benzylic 85–90 kcal/mol).Typically, the arene π-system positions the metal carboxylatefor a favorable deprotonative insertion that relies on formingthe stronger C(sp2)–Pd bonds.

The group of Professor Marisa C. Kozlowski at theUniversity of Pennsylvania (USA) has had an ongoing inte -rest in oxidative C–H activation. Initial studies on the chemo -selective activation of toluene arose from a serendipitous dis-covery; in the course of attempting an arylation of azlactones,an unusual benzyl product was observed (Scheme 1). “This isa perfect example of how chance favors the prepared mind,”said Professor Kozlowski. “Since the targeted compound wasnot observed, many scientists would have moved on. Only thecuriosity and diligence of the graduate student undertakingthe experiments, Dr. John Curto, brought this result to light.Upon further study, we discovered that a selective insertioninto the benzylic position of toluene was occurring under con-ditions that would typically cause insertion into one of thearene C–H bonds.” In fact, methyl and other alkyl sub-

stituents on arenes have been shown to be compatible to manyPd-catalyzed C(sp2)–H insertions. “Thus, this discovery re -presents a novel mode of reactivity for Pd,” added ProfessorKozlowski, who explained that toluene derivatives are theideal benzylation reagent because they are stable, commer-cially available, and easy to handle, while being far moreatom-economical than the corresponding benzyl halides.

Professor Kozlowski said: “Our initial success with theselective C(sp3)–H bond activation of tolyl and methylnaph-thyl analogues prompted our exploration of secondary ben-zylic C–H bonds. Extension of the alkyl chain on benzene toethyl, propyl and butyl most surprisingly gave rise to the ter-minal alkylated product (Scheme 2, top). This chemoselecti -vity provides access to chemical space that would not be feasible via a radical-mediated process.” A mechanism consi -stent with the C–H activation step involving a benzylic metal -ation is supported by kinetic isotope effect studies performedby Professor Kozlowski and Dr. Curto. For ethylbenzene,deuterium scrambling supports a zipper mechanism, involv-ing β-hydride elimination and rearrangement of a benzylicpalladium species (Scheme 2, bottom). “If the conditions thatpermit this novel pathway of alkyl benzene activation can beunderstood, then similar migrations could be achieved in abroad range of known Pd-catalyzed coupling processes,” saidProfessor Kozlowski.

Upon discovering this novel C(sp3)–H activation of alkylarene bonds, a primary goal for the Kozlowski group was toidentify catalytic conditions, which would greatly expand theutility of this transformation. “We utilized the UPenn High-Throughput Experimentation Center, one of the few academic



SYNSTORIES A54


vs sp2

C–H Bonds

with Pd(II)

J. Am. Chem. Soc. 2015, 137, 18–21

Scheme 1

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http://dx.doi.org/10.1021/ja5093166

centers with this technology, to screen multiple variables andrapidly identify trends,” said Professor Kozlowski. “Parallelmicroscale experimentation (Scheme 3, left) revealed thatmost transition-metal oxidants used extensively in the Pd-ca -talyzed C(sp2)–H processes were ineffective in this transfor-mation. The highlighted oxidants were identified as potentialleads and eventually led to the discovery of catalytic condi-tions using fewer equivalents of the alkyl benzene reactionpartner (Scheme 3, right).”

“In summary, a novel reactivity mode for alkyl arenes wasdiscovered from the investigation of a serendipitous result,”said Professor Kozlowski. With a simple system consisting ofPd(OAc)2 and pivalic acid, catalytic dehydrogenative cross-coupling with a carbon nucleophile occurs readily for the ter-minal methyl positions of methyl, ethyl, propyl and butylarenes. Notably, selective C(sp3)–H insertion is observed inbenzylic systems even though Pd(OAc)2 typically causes

arene C(sp2)–H insertion. Double C–H activation to form aC–C bond is a difficult transformation because two differentC–H bonds need to be activated in a selective manner. “Wehope to extend the scope of this technology and are exploringother acidic C–H partners. Although the full mechanisticdetails of this transformation remain to be elucidated, ourongoing efforts lend support for a mechanism that representsa shift in our understanding of Pd,” concluded ProfessorKozlowski.



SYNSTORIES A55

Matteo Zanda

Scheme 2

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SYNSTORIES A56

About the authors

John Curto was born and raised

in western Massachusetts (USA).

He obtained his undergraduate

degree at the College of the Holy

Cross in Worcester, MA (USA), where

he was first introduced to research

while working for Kevin Quinn on the

synthesis of small natural products. In

2014, John graduated from the Uni -

versity of Pennsylvania (USA) with a

PhD under the guidance of Professor

Marisa Kozlowski on the asymmetric

synthesis of α,α-disubstituted α-amino acids and studies on

the Pd-catalyzed C(sp3) –H activation of alkyl arenes. John and

his wife Barb currently live in Connecticut where John has

begun his career as a medicinal chemist.

Marisa Kozlowski received an A.B.

in Chemistry from Cornell University

(USA) in 1989 and a PhD under the

direction of Paul Bartlett from the

University of California at Berkeley

(USA) in 1994. After an NSF postdoc-

toral fellowship with David A. Evans

at Harvard University (USA), she joined

the faculty at the University of Penn -

sylvania (USA) in 1997 and is currently

Professor of Chemistry. The Kozlowski

group’s research focuses on the

design of new catalysts and transformations. She has also co-

authored ‘Fundamentals of Asymmetric Catalysis’ with Patrick

Walsh.

Scheme 3

Dr. J. Curto Prof. M. Kozlowski

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Phosphine-catalyzed cyclization reactions are of enormoussynthetic value, evidenced by the ubiquitous presence of ringstructures in natural products and bioactive molecules. Overthe last few years, the group of Professor Yixin Lu at theNational University of Singapore has been interested in devel-oping novel and versatile organic catalysts that can be readilyderived from amino acids. Thus, explained Professor Lu, oneof the main research efforts of his group is to devise powerfulapproaches to access chiral ring motifs, especially those struc-tures that are not yet accessible via existing methods, and thedihydropyrans synthesized in this paper are important skele-tons of biological significance. Professor Lu said: “In the areaof phosphine catalysis, we designed a series of amino acidbased bifunctional phosphines and demonstrated their effec-tiveness for a wide range of reactions, including (aza)-MBH

reactions, various [3+2] cycloadditions, [4+2] cyclization,[4+1] annulation, asymmetric allylic alkylation, phosphine-mediated Michael addition, and ?-addition. Our catalysts canbe easily assembled and the structures are highly tunable, andsuch features are crucial in asymmetric catalysis as a ‘univer-sal’ catalyst does not exist.”

Professor Lu explained: “In phosphine catalysis, it is im -perative to expand the scope of substrates suitable for phos-phine activation. While allene esters have been widelyemployed, utilization of allene ketones is rare. This paper doc-uments an unprecedented utilization of allenones as a reactionpartner. The reaction system is complex,” continued ProfessorLu, “and achieving the desired [4+2] cyclization was quitetricky.” Professor Lu explained that the activation ofallenones by phosphines creates a phosphonium enolate,



SYNSTORIES A57

Highly Enantioselective Synthesis of 3,4-Dihydropyrans

through a Phosphine-Catalyzed [4+2] Annulation of

Allenones and β,γ-Unsaturated α-Keto Esters

J. Am. Chem. Soc. 2015, 137, 54–57

Figure 2

Figure 1

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http://dx.doi.org/10.1021/ja5109358

which possesses different resonance forms. “The subsequentadvanced intermediate generated upon addition of the enolateanion to an electrophile also has different reaction pathways.In this paper, we suppressed undesired modes of reaction bycareful selection of reaction systems,” he added.

This work not only demonstrates an unprecedented utiliza-tion of allenones as a reaction partner, but also represents thefirst asymmetric synthesis of dihydropyrans via phosphinecatalysis. “We hope this work will lead to the discovery ofmore novel approaches to access oxygen-containing ringstruc tures via phosphine catalysis,” said Professor Lu.

“The complexity in phosphine-catalyzed reaction sy -stems is challenging, but also truly exciting. Discoveries onnew reactions and novel modes of activations are well antici-pated, if one can discern subtle mechanistic differences anddesign catalytic systems accordingly,” he concluded.



SYNSTORIES A58

Matteo Zanda

About the authors

Weijun Yao was born in Zhejiang

(P. R. of China) in 1983. He re -

ceived his B.Sc. and Ph.D. (under

the supervision of Professor Cheng

Ma) from Zhejiang University in

2006 and 2011, respectively. Cur -

rently, he is a postdoctoral follow

working with Professor Yixin Lu at

National University of Singapore

(NUS).

Xiaowei Dou was born in Shan -

dong (P. R. of China) in 1987. He

received his B.Sc. from Nanjing

University (P. R. of China) in 2009,

and he then joined the research

group of Professor Lu at NUS. He

received his Ph.D. in 2013, and he

is now working with Professor

Tamio Hayashi as a postdoctoral

fellow at NUS.

Yixin Lu received his Ph.D. from

McGill University (Montreal, Ca -

nada) under the supervision of the

late Professor George Just in

2000. He then carried out post-

doctoral research with Professor

Peter W. Schiller at the Clinical

Research Institute of Montreal

(Canada), and subsequently work -

ed as an RCMS fellow with Prof -

essor Ryoji Noyori at Nagoya

University (Japan). He joined the

Department of Chemistry, NUS, in September 2003 where

he is now a professor.

Dr. W. Yao

Dr. X. Dou

Prof. Y. Lu

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ComInG Soon ComInG Soon

Synform 2015/05

is available from April 17, 2015

In the next issues:

SynSTorIES

Organocatalytic Enantioselective Formal C(sp2)–H Alkylation

(Focus on an article from the current literature)

The Phosphinoboration Reaction


Catalytic Enantioselective Synthesis of Indanes by a

Cation-Directed 5-endo-trig Cyclization


Synform

ConTACT

Matteo Zanda,

NRP Chair in Medical Technologies

Institute of Medical Sciences

University of Aberdeen

Foresterhill, Aberdeen, AB25 2ZD, UK

and

C.N.R. – Istituto di Chimica del Riconoscimento Molecolare,

Via Mancinelli, 7, 20131 Milano, Italy,

e-mail: [email protected], fax: +39 02 23993080

fUrTHEr HIGHLIGHTS

SYNTHESIS

Review on: Synthesis of Pillar[6]arenes and Their Host-Guest

Complexes

(by D. Cao, H. Meier)

SYNLETT

Synpacts on: Lithium Chloride Carbenoids in Bond Activation

Reactions

(by S. Molitor, V. H. Gessner)

SYNFACTS

Synfact of the Month in category “Metal-Mediated Synthesis”:

Addition of Carboxylic Acids Using Chiral Lithium Amides as

Auxiliaries

Editor

Matteo 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. [email protected]; fax: +39 02 23993080

Editorial Office

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http://dx.doi.org/10.1055/s-0034-1380000

http://dx.doi.org/10.1055/s-0034-1380000

http://dx.doi.org/10.1055/s-0034-1380309

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