Applications of domino transformations in organic synthesis, volume 1

Science of SynthesisScience of Synthesis is the authoritative andcomprehensive reference work for the entirefield of organic and organometallic synthesis.Science of Synthesis presents th

Science of Synthesis

Science of Synthesis is the authoritative andcomprehensive reference work for the entirefield of organic and organometallic synthesis.Science of Synthesis presents the importantsynthetic methods for all classes of compoundsand includes:

– Methods critically evaluated

by leading scientists

– Background information and detailedexperimental procedures

– Schemes and tables which illustrate

the reaction scope

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K K WanS.-H Wang

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ISBN 978-3-13-173141-8

eISBN 978-3-13-202851-7

As the pace and breadth of research intensifies, organic synthesis is playing an

increasing-ly central role in the discovery process within all imaginable areas of science: from maceuticals, agrochemicals, and materials science to areas of biology and physics, themost impactful investigations are becoming more and more molecular As an enablingscience, synthetic organic chemistry is uniquely poised to provide access to compoundswith exciting and valuable new properties Organic molecules of extreme complexity can,given expert knowledge, be prepared with exquisite efficiency and selectivity, allowingvirtually any phenomenon to be probed at levels never before imagined With ready ac-cess to materials of remarkable structural diversity, critical studies can be conducted thatreveal the intimate workings of chemical, biological, or physical processes with stunningdetail

phar-The sheer variety of chemical structural space required for these investigations andthe design elements necessary to assemble molecular targets of increasing intricacy placeextraordinary demands on the individual synthetic methods used They must be robustand provide reliably high yields on both small and large scales, have broad applicability,and exhibit high selectivity Increasingly, synthetic approaches to organic moleculesmust take into account environmental sustainability Thus, atom economy and the over-all environmental impact of the transformations are taking on increased importance.The need to provide a dependable source of information on evaluated syntheticmethods in organic chemistry embracing these characteristics was first acknowledged

der Organischen Chemiewas first introduced Recognizing the necessity to provide amodernized, comprehensive, and critical assessment of synthetic organic chemistry, in

Transformations This effort, assembled by almost 1000 leading experts from both dustry and academia, provides a balanced and critical analysis of the entire literaturefrom the early 1800s until the year of publication The accompanying online version of

in-Science of Synthesisprovides text, structure, substructure, and reaction searching bilities by a powerful, yet easy-to-use, intuitive interface

Synthesis Knowledge Updatesis to provide a continuous review of the field of syntheticorganic chemistry, with an eye toward evaluating and analyzing significant new develop-ments in synthetic methods A list of stringent criteria for inclusion of each synthetictransformation ensures that only the best and most reliable synthetic methods are incor-

up-to-date electronic database available for the documentation of validated syntheticmethods

Library, comprising volumes covering special topics of organic chemistry in a modularfashion, with six main classifications: (1) Classical, (2) Advances, (3) Transformations, (4)

Water in Organic Synthesis, and Asymmetric Organocatalysis, among others With

Syn-The overarching goal of theScience of SynthesisEditorial Board is to make the suite

ofScience of Synthesisresources the first and foremost focal point for critically

evaluat-ed information on chemical transformations for those individuals involvevaluat-ed in the designand construction of organic molecules

Throughout the years, the chemical community has benefited tremendously fromthe outstanding contribution of hundreds of highly dedicated expert authors who havedevoted their energies and intellectual capital to these projects We thank all of these in-dividuals for the heroic efforts they have made throughout the entire publication process

P J Reider (Princeton, USA)

Science of Synthesis Reference Library

Applications of Domino Transformations in Organic Synthesis(2 Vols.)

Catalytic Transformations via C—H Activation(2 Vols.)

Biocatalysis in Organic Synthesis(3 Vols.)

C-1 Building Blocks in Organic Synthesis(2 Vols.)

Multicomponent Reactions(2 Vols.)

Cross Coupling and Heck-Type Reactions(3 Vols.)

Water in Organic Synthesis

Asymmetric Organocatalysis(2 Vols.)

Stereoselective Synthesis(3 Vols.)

Volume Editors Preface

Domino reactions have been a mainstay of synthetic chemistry for much of its history.Domino chemistrys roots trace to achievements such as the one-pot synthesis of tropi-none in 1917 by Robinson and the generation of steroidal frameworks through polyenecyclizations, as originally predicted by the Stork–Eschenmoser hypothesis In the ensuingdecades, chemists have used these, and other inspiring precedents, to develop even morecomplicated domino sequences that rapidly and efficiently build molecular complexity,whether in the form of natural products, novel pharmaceuticals, or materials such asbuckminsterfullerene

Despite this body of achievements, however, the development of such processes mains a deeply challenging endeavor Indeed, effective domino chemistry at the highestlevels requires not only creativity and mechanistic acumen, but also careful planning atall stages of a typical experiment, from substrate design, to reagent and solvent choice, totiming of additions, and even the quench Thus, if the frontiers are to be pushed even fur-ther, there is certainly much to master

myriad ways that these sequences can be achieved with the full array of reactivity able, whether in the form of pericyclic reactions, radical transformations, anionic andcationic chemistry, metal-based cross couplings, and combinations thereof In an effort

avail-to provide a unique approach in organizing and presenting such transformations relative

to other texts and reviews on the subject, the sections within this book have been ized principally by the type of reaction that initiates the sequence Importantly, only keyand representative examples have been provided to highlight the best practices and pro-cedures that have broad applicability The hope is that this structure will afford a clearsense of current capabilities as well as highlight areas for future development and re-search

organ-A work on such a vibrant area of science would not have been possible, first and most, without a talented and distinguished author team Each is mentioned in the intro-ductory chapter, and I wish to thank all of them for their professionalism, dedication, andexpertise I am also grateful to all of the coaching, advice, and assistance provided by

also go, of course, to the entire editorial team at Thieme, particularly to Robin Padilla andKaren Muirhead-Hofmann who served as the scientific editors in charge of coordinatingthis reference work; Robin started the project, and Karen saw it through to the end Theirattention to detail and passion to produce an excellent final product made this project atrue pleasure Last, but not least, I also wish to thank my wife Cathy and my son Sebastianfor their support of this project over the past two years

Finally, I wish to dedicate this work, on behalf of the chapter authors and myself, toour scientific mentors It was through their training that we learned how to better under-stand reactivity, propose novel chemistry, and identify the means to actually bring thoseideas to fruition Hopefully this text will serve the same role to those who study its con-tents, with even greater wisdom achieved as a result

p 131.1 Polyene Cyclizations

R A Shenvi and K K Wan

A domino transformation consists of a first chemical reaction enabling a second reaction,which can then effect a third reaction, and so on, all under the same reaction conditions

A polyene cyclization is defined as a reaction between two or more double bonds tained within the same molecule to form one or more rings via one or more C-C bond-forming events Herein, domino polyene cyclizations are discussed, with an emphasis onoperationally simple methods of broad utility From the perspective of synthesis theory,polyene cyclizations are a powerful approach for the efficient generation of both com-plexity and diversity, with the potential for a single synthetic route to generate a series

con-of both constitutional and stereochemical isomers However, with some noteworthy ceptions, the ability to controllably cyclize a linear chain to multiple products with highselectivity still generally eludes synthetic chemists and represents a significant chemicalfrontier for further development

ex-domino polyene cyclizations

Keywords: polyenes•cyclization•carbocations•radicals•polycycles

p 431.2 Cation–ðCyclizations of Epoxides and Polyepoxides

K W Armbrust, T Halkina, E H Kelley, S Sittihan, and T F Jamison

This chapter describes the formation of complex polycyclic fragments from linear ide and polyepoxide precursors via domino reactions Depending on the reaction condi-

Applica-tions of these domino reacApplica-tions toward the synthesis of complex natural products are cussed

dis-HO O

O O

HO

HO

p 67

D Lee and M OConnor

Enyne-metathesis-based domino processes are highlighted in the context of natural uct synthesis; these include domino double ring-closing metathesis, enyne metathesis/metallotropic [1,3]-shifts, enyne metathesis/Diels–Alder reaction, and other variations oftheir domino combinations Issues regarding selectivity and mechanism are also dis-cussed

Keywords: enyne metathesis•-bond exchange•domino transformations•natural

p 135

H Renata and K M Engle

This review describes different methods to perform net carbonyl–alkene metathesis actions of this type generally involve domino transformations employing organometallicreagents Different conditions and procedures are surveyed and strategic applications ofcarbonyl–alkene metathesis in the synthesis of natural products are highlighted

Re-O

O

Cl Al Ti Cp Cp Me Me

Keywords: metathesis•alkenylation•carbonyl compounds•alkenes•ring closure•

rt, 1 week

O O OOH

Keywords: peroxide synthesis•endoperoxides•cyclic peroxides•radical addition•

p 187

J J Devery, III, J J Douglas, and C R J Stephenson

This chapter details recent examples of domino radical reactions that are initiated via anintramolecular radical cyclization

X Y Z

Keywords: radicals•domino reactions•cyclization•tin•samarium•organo-SOMO•

reac-O

O TBDMSO

TBDPSO

O

H OAc

Keywords: tandem radical cyclization•radical domino cyclization•radical cascade

cy-p 243

D Adu-Ampratwum and C J Forsyth

This chapter covers synthetic domino processes that are induced by protic acid or base.They are broadly classified into those that capitalize upon the release of oxirane ringstrain under acidic or basic conditions, and carbocyclic ring expansions and contractionsunder protic acid or basic conditions The focus here is upon single substrate, monocom-ponent domino processes, rather than multicomponent variants

H H H

OH

OH HO

HO

44%

Keywords: carbocyclic compounds•cyclization•epoxy compounds•ethers•Favorskii

p 269

S.-H Wang, Y.-Q Tu, and M Tang

The efficient construction of complex molecular skeletons is always a hot topic in organicsynthesis, especially in the field of natural product synthesis, where many cyclic structur-

al motifs can be found Under the assiduous efforts of synthetic chemists, more and moremethodologies are being developed to achieve the construction of cyclic skeletons In par-ticular, the beauty and high efficiency of organic synthesis are expressed vividly amongthose transformations realized through a domino strategy Based on these importantmethodologies, selected Lewis acid/base induced domino reactions leading to ring expan-sions, contractions, and closures are presented in this chapter

O O

N OH

SnCl 4

O O

A Kirschning, F Gille, and M Wolling

The Brook rearrangement has lost its Cinderella status over the past twenty years sincebeing embedded into cascade reaction sequences The powerful formation of carbanionsthrough silyl migration has been exploited for the development of many new methodol-ogies and has been used as a key transformation in complex natural product syntheses.Now, the Brook rearrangement belongs to the common repertoire of synthetic organicchemists

n

Keywords: Brook rearrangement•domino reactions•migration•organosilicon

N O

O I

N BnO

N BnO

X Xu, P Truong, and M P Doyle

With dirhodium carbenes generated from diazocarbonyl compounds, azoles, or cyclopropenes, a subsequent intramolecular cyclization forms a reactive inter-mediate that undergoes a further transformation that usually terminates the reactionprocess Commonly, the electrophilic dirhodium carbene adds intramolecularly to aC”C bond to provide a second rhodium carbene Catalytically generated dirhodium-bound nitrenes initiate domino reactions analogously, and recent examples (nitrene tocarbene to product) have also been documented

Keywords: Æ-carbonyl carbenes•(azavinyl)carbenes•cyclopropenes•[3 + 2] annulation•

substi-tution

p 535

E Merino, A Salvador, and C Nevado

In this review, a selection of the most relevant examples featuring gold-catalyzed dominotransformations are presented Processes catalyzed by both gold(I) and gold(III) complexesare described, including multicomponent reactions, annulations, cycloisomerizations,and cycloadditions The scope, limitations, and mechanistic rationalization of thesetransformations are also provided

Keywords: domino transformations•multicomponent reactions•cycloisomerizations•

Lewis acids and are stable and active in the presence of many Lewis bases Another

Lewis acidity and Brønsted basicity These collated characteristic features of rare earthbased complexes, such as high coordination numbers, a hard Lewis acidic nature, high

MX 3 (cat.) BINOL (cat.)

Keywords: lanthanide contraction•rare earth metal trifluoromethanesulfonates•rare

multifunctionality

p 601

and Its Use in Natural Product Total Synthesis

L Shi and Z Yang

The Pauson–Khand reaction constitutes one of the most formidable additions to the ertoire of synthetically useful reactions It rapidly affords a cyclopentenone skeleton from

rep-an alkene, rep-an alkyne, rep-and carbon monoxide, based on a domino sequence of bond structions In this chapter, the prowess of the Pauson–Khand reaction is illustrated by ju-dicious selection of complex target molecules, the total syntheses of which are cleverlyorchestrated by the key Pauson–Khand reaction sequence Emphasis is placed on cobalt-mediated processes to exemplify the applicability of this classical reaction

con-O

heat

Keywords: Pauson–Khand reaction•alkenes•carbon monoxide•alkynes•

asymmetric synthesis

Applications of Domino Transformations in

R A Shenvi and K K Wan 13

1.2 Cation–ðCyclizations of Epoxides and Polyepoxides

K W Armbrust, T Halkina, E H Kelley, S Sittihan, and T F Jamison 43

1.3 Metathesis Reactions 67

D Lee and M OConnor 67

H Renata and K M Engle 135

1.4 Radical Reactions 157

X Hu and T J Maimone 157

J J Devery, III, J J Douglas, and C R J Stephenson 187

K A Parker 217

1.5 Non-Radical Skeletal Rearrangements 243

D Adu-Ampratwum and C J Forsyth 243

1.5.3 Brook Rearrangement as the Key Step in Domino Reactions

A Kirschning, F Gille, and M Wolling 355

1.6 Metal-Mediated Reactions 449

E A Anderson 449

X Xu, P Truong, and M P Doyle 511

E Merino, A Salvador, and C Nevado 535

T Ohshima 577

The Pauson–Khand Reaction and Its Use in Natural Product Total Synthesis

L Shi and Z Yang 601

Keyword Index 633

Author Index 669

Abbreviations 693

Epoxides by Alkylaluminum Lewis Acids 15

Chloride Complex 19

Mediated by Aluminum Lewis Acids 21

Scalemic Iridium Complexes 24

by Manganese(III) Acetate 26

1.1.2.2.2 Manganese-Catalyzed Hydrogenative Polycyclization 29

Retrocycloisomerization with a Cobalt–salen Catalyst 30

a Metal Center or Metathesis 32

Diels–Alder Cycloaddition Followed by Aldol Condensation 37

1.2 Cation–ðCyclizations of Epoxides and Polyepoxides

K W Armbrust, T Halkina, E H Kelley, S Sittihan, and T F Jamison

1.2 Cation–ðCyclizations of Epoxides and Polyepoxides 43

1.2.2.3.3 Carbocation-Initiated Cascades via Halide Abstraction 55

1.3 Metathesis Reactions

D Lee and M OConnor

Ring-Closing Metathesis, and Cross Metathesis/Cross Metathesis Sequences 112

1.3.2 Domino Metathesis Reactions Involving Carbonyls

H Renata and K M Engle

1.4 Radical Reactions

X Hu and T J Maimone

1.4.2 Radical Cyclizations

J J Devery, III, J J Douglas, and C R J Stephenson

K A Parker

Tin, 2,2¢-Azobisisobutyronitrile, and Peroxides 221

1.4.3.3.4.2 Triethylborane-Mediated Atom Transfer and Cobaloxime-Initiated

Reductive Tandem Cyclization 227

Reductive Cyclization 228

1.5 Non-Radical Skeletal Rearrangements

D Adu-Ampratwum and C J Forsyth

1.5.2 Lewis Acid/Base Induced Reactions

S.-H Wang, Y.-Q Tu, and M Tang

A Kirschning, F Gille, and M Wolling

1.5.3.1.2 1,2-Brook Rearrangement with Acylsilanes 358

Carbonyl Groups 393

Conclusions 444

1.6 Metal-Mediated Reactions

E A Anderson

X Xu, P Truong, and M P Doyle

Cyclopropenes and Their Subsequent Reactions 516

Nucleophiles to-Electrophiles 542

1.6.3.3 Gold-Catalyzed Domino Reactions via Addition of Heteroatom

Nucleophiles to-Electrophiles 551

Propargyl Esters 557

1.6.4.4.2 Ring-Closing Reactions 594

The Pauson–Khand Reaction and Its Use in Natural Product Total Synthesis

L Shi and Z Yang

The Pauson–Khand Reaction and Its Use in Natural Product Total Synthesis 601

(+)-Magellaninone, and (+)-Paniculatine 607

Keyword Index 633

Author Index 669

Abbreviations 693

S A Snyder

There is something inherently satisfying about setting up a number of dominoes in series,pushing one down at the end of the chain, and watching the rest tumble as if in slow mo-tion until all have been knocked over; I remember spending hours doing this as a child,once my father showed me the principle and I had enough dexterity to not knock any-thing down before the right moment I felt the same way about playing with a Newtonscradle, where, although the movement does not cease in the same way as a domino chain,the idea of setting something into motion and causing a series of subsequent reactionswas certainly pleasing and mesmerizing to watch

My first experience with a “domino”, or “cascade”, sequence in the chemistry worldcame right at the start of my graduate career in K C Nicolaous laboratory at The ScrippsResearch Institute, in the summer of 1999 For weeks I watched my talented neighbors inthe lab strive to achieve a biomimetic synthesis of trichodimerol (2) (Scheme 1) from pro-tected forms of the natural product sorbicillin, e.g 1 Although they registered a number

of successes in merging 1 with itself to create other members of the bisorbicillinoid

Each day, several different products were generated from individual experiments, and Iremember my colleagues picking out which ones they would try and characterize, andthen thinking about what conditions to change in the hope of achieving success based

on the structures they deduced that they had produced Ultimately, in near-concomitant

deter-mined that low water content in the presence of a soluble base was the key to the dominoseries of Michael reactions and ketalizations needed to form the unique caged structure of2; this sequence of events was impressive, even though only relatively modest yieldscould be achieved

Scheme 1 Domino Construction of Trichodimerol through Sequential Michael Reactions

OH HO

HO OH

OH

O HO

O HO

O HO

O

O OH HO

HO

O

HO

OH O

O AcO

O

OH O HO

HO HO

O O

1 NaOMe, MeOH

HCl in MeOH or

ic effect on the outcome, it is deep thinking based on first principles coupled with propertechnique that can change those outcomes, ultimately putting everything into place sothat the domino process can properly orchestrate itself Second, it opened up that samejoy I felt as a child with my toy dominoes, indicating that I would want to devote a signi-ficant portion of my research career into pursuing strategies, reactions, and tactics thatcould similarly bring molecules together and forge bonds with ballet-like efficiency and

precision Finally, it made me realize how much I still needed to learn and master if I wasever to reach that goal.

communicate that same sense of inherent pleasure in the power, artistry, and challenge

of domino chemistry, highlighting the current state of the art by teaching the skills andproviding the tools needed for success, while also demarcating frontiers for future devel-opments With the efforts of a spectacular group of world-class authors who have contrib-uted their time and talent to this work, I am confident that this goal has been achieved.Unlike other excellent reviews and monographs that exist on the subject (and there aremany, for which no attempt at referencing will be made here; the leading and influentialworks are cited in the subsequent individual chapters), a different organization frame-work for domino chemistry has been sought for these volumes based on the reactiontype that initiates the sequence In some cases, this is a specific process such as theDiels–Alder reaction, while in other chapters it is a slightly broader presentation, for ex-ample reaction sequences initiated by gold What has resulted is an effective way to com-pare and contrast approaches In addition, because the contributors have provided onlythe most representative examples along with experimental procedures for processesthat have high generality, rather than attempt to be comprehensive, key lessons can beimparted effectively for developing even more powerful approaches

The first volume opens with polyene cyclizations, a classic domino sequence datingback over half a century to the pioneering ideas inherent in the Stork–Eschenmoser hy-pothesis, which have been explored non-stop in the ensuing decades In a welcome con-tribution by Shenvi and Wan (Section 1.1), not only is a clear sense of the history of thereaction provided with several classic transformations, but the vitality of research in thisarena is also evident by the inclusion of newer advances, such as the Corey groups use ofindium(III) bromide to activate terminal alkynes for highly efficient domino bond con-

TBDMSO

H H TBDMSO

condi-tions, careful substrate design, and knowledge of key physical organic principles proveessential to the successful examples that have been achieved to date, as this chapter effec-tively illustrates

Scheme 3 An Epoxide-Opening Domino Sequence To Form an Oxepane [5]

ring-open-ing metathesis of a strained alkene within bicycle 5 sets the stage for cyclization onto aneighboring carbonyl that affords a highly strained, four-membered ring en route to cap-nellene

sense of the state of the art in this important area