The Diels-Alder Reaction in Total Synthesis.pdf

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The Diels±Alder Reaction in Total Synthesis

K.C. Nicolaou,* ScottA. Snyder, Tamsyn Montagnon, and Georgios Vassilikogiannakis

The Diels±Alder reaction has both

enabledandshapedtheartandscience

of total synthesis over the last few

decades to an extent which, arguably,

has yet to be eclipsed by any other

transformationinthecurrentsynthetic

repertoire.Withmyriadapplicationsof

this magnificent pericyclic reaction,

often as a crucial element in elegant

and programmed cascade sequences

facilitating complex molecule con-

struction, the Diels±Alder cycloaddi-

tion has afforded numerous and un-

paralleled solutions to a diverse range

ofsyntheticpuzzlesprovidedbynature

in the form of natural products. In

celebrationofthe100thanniversaryof

Alder×sbirth, selected examples of the

awesome power of the reaction he

helpedtodiscoverarediscussedinthis

review in the context of total synthesis

to illustrate its overall versatility and

underscoreitsvast potentialwhich has

yet to be fully realized.

Keywords: biomimetic synthesis ¥

cycloaddition ¥ Diels±Alder

reaction ¥ molecular diversity ¥ total

synthesis

1. Introduction

Afternumerousnear-discoveriesofthe[4 2]cycloaddition

reactionbyseveralluminariesinthefieldoforganicchemistry

during the early part of the 20th century, [1, 2] the keen insight

of Professor Otto Diels [3] and his student, Kurt Alder, [4] in

properly identifying the products (4 and 6, Scheme1) arising

from the reaction of cyclopentadiene (1) with quinone (2)

denotes a historic event in the field of chemistry for which

these two individuals were rewarded with a reaction that

would henceforth bear their names. [5] With prophetic fore-

sight, Diels and Alder clearly anticipated the importance of

this discovery in their landmark 1928 paper, particularly as

applied to natural product synthesis, through the following

remark:™Thusitappearstousthatthepossibilityofsynthesis

of complex compounds related to or identical with natural

products such as terpenes, sesquiterpenes, perhaps even

alkaloids, has been moved to the near prospect.∫ However,

in an intriguing moment of scientific territoriality, which

might appear slightly off-color or even amusing to a contem-

[*] Prof.Dr. K.C. Nicolaou, S.A. Snyder, Dr. T. Montagnon,

Dr. G. Vassilikogiannakis

Department of Chemistry

and The Skaggs Institute for Chemical Biology

The Scripps Research Institute

10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)

Fax: (

Scheme 1. The discovery of the Diels±Alder reaction in 1928, a reaction

for which the namesakes would receive the Nobel Prize in Chemistry in

1950: Diels the professor, Alder the student. [5]

1)858-784-2469

E-mail:kcn@scripps.edu

and

Department of Chemistry and Biochemistry

University of California San Diego

9500 Gilman Drive, La Jolla, CA 92093 (USA)

porary audience, the authors issued the following ominous

warning to those researchers interested in applying their

discovery to total synthesis: ™We explicitly reserve for

ourselves the application of the reaction developed by us to

the solution of such problems.∫ [2]

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¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002

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K.C. Nicolaou et al.

UptothetimeoftheirreceiptoftheNobelPrizein1950it

seemsthat,forthemostpart,thesyntheticcommunityheeded

thedemandofDielsandAlder,astheircycloadditionreaction

didnotfeatureprominentlyinanytotalsynthesispriortothe

stereocontrolledgenerationofcantharidin [6] byStorketal.in

1951, or the first synthesis of morphine [7] reported a few

months later in which Gates and Tschudi employed the

pericyclic process. The apparent delay in applying the Diels±

Alder reaction, or ™diene synthesis∫ as it was known at the

time,tototalsynthesiswaslikelytheconsequenceofavariety

of factors. First, with few exceptions, total synthesis during

that period played a role inclined more towards structure

verificationthanasitsownuniquevehicletoadvancethefield

of organic synthesis, as it is practiced today. As such, in a

discipline defined by converting known materials by existing

methodsintoothercompounds,practitionerswouldnotlikely

have regarded being the ™first∫ to employ a particular

transformation in a synthesis as an important contribution,

and the number of compounds in which the Diels±Alder

reaction had been demonstrated was limiting in terms of

potential synthetic targets. Moreover, the founders of the

reaction, while they certainly made significant forays in the

G.E. Vassilikogiannakis

K.C. Nicolaou

S.A. Snyder

T. Montagnon

ProfessorK.C.Nicolaou,borninCyprusandeducatedinEnglandandtheUS,iscurrentlyChairmanoftheDepartmentof

Chemistry at The Scripps Research Institute, where he holds the Darlene Shiley Chair in Chemistry and the AlineW. and

L.S. Skaggs Professorship in Chemical Biology, as well as Professor of Chemistry at the University of California, San

Diego. His impact on chemistry, biology, and medicine flows from his works in chemical synthesis and chemical biology

describedinover500publicationsand70patentsandhisdedicationtochemicaleducation,asevidencedbyhistrainingof

more than 400graduate students and postdoctoral fellows. His recent book titled Classics inTotal Synthesis, which he co-

authored with ErikJ. Sorensen, is used around the world as a teaching tool and source of inspiration for students and

practitioners of organic synthesis.

ScottA. Snyder, born in Palo Alto, California in 1976, spent his formative years in the suburbs of Buffalo, New York. He

receivedhisB.A.inChemistry(summacumlaude)fromWilliamsCollege,Williamstown,Massachusetts,in1999,wherehe

explored the hetero-Diels±Alder reaction with Prof. J.Hodge Markgraf. He then began graduate studies with Prof. K.C.

Nicolaou, where he has devoted his attention to the chemistry and biology of the marine-derived antitumor agent

diazonamideA. He is the recipient of a BarryM. Goldwater Fellowship in Science and Engineering, a National Science

Foundation Predoctoral Fellowship, and a Graduate Fellowship from Pfizer, Inc. His research interests include complex

natural product synthesis, reaction mechanism and design, and application of these fields to chemical biology.

TamsynMontagnonwasborn inHongKongin1975.ShereceivedherB.Sc.inChemistrywithMedicinalChemistryfrom

theUniversityofLeeds,UK,whichwasfollowedbyamovetotheUniversityofSussexwheresheobtainedaD.Philin2000

forresearchconductedunderthesupervisionofProfessorP.J.Parsons,towardsthesynthesisofcomplexnaturalproducts,

including the squalestatins and triptoquinoneC. She was awarded a GlaxoWellcome post-doctoral fellowship and joined

Professor K.C. Nicolaou×s group in January 2001. Her research interests include natural product synthesis, medicinal

chemistry, and reaction methods and mechanisms.

GeorgiosE.VassilikogiannakiswasborninIraklion,Crete,Greecein1970.HereceivedhisB.Sc.inChemistryin1993and

his Ph.D. in 1998 from the University of Crete under the guidance of Professor Michael Orfanopoulos exploring the

mechanisms oftheelectrophilicadditions ofsinglet oxygen,tetracyanoethylene,triazolinediones,andfullerenes toalkenes

and dienes. He joined Professor K.C. Nicolaou×s group in 1999, and was involved in the total syntheses of bisorbicillinol,

bisorbibutenolide, trichodimerol, and colombiasinA. He was recently appointed Assistant Professor of chemistry at the

University of Crete, Greece. His primary research interests involve the synthesis of natural products as an enabling

endeavor for the discovery of new chemical knowledge and its application to chemical biology.

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The Diels±Alder Reaction in Total Synthesis

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areaofterpenesynthesis, [8] becamedivertedbyotherresearch

concerns of greater interest to them, particularly in regard to

understanding the mechanistic underpinnings of the reaction

they had discovered. [9] Significantly, these efforts ultimately

resulted in such important advances as the Alder endo rule

that governs the stereochemical outcome of the typical

Diels±Alder reaction. [10] The most dominant reason for the

delay in the incorporation of the Diels±Alder cycloaddition

into total synthesis, however, might be attributed to World

War II and its aftermath, a period for which no analysis can

properly estimate the challenges to conducting research in

organic synthesis, particularly in Germany.

Assuch,thetrulyvisionaryapplicationoftheDiels±Alder

reaction to total synthesis would have to await the imagina-

tion of chemical artists such as R.B. Woodward, who would

apply new levels of creativity to the reaction athandthrough

some highly elegant and instructive syntheses. In 1952,

Woodwardetal.disclosedtheirhistoricroutestothesteroids

cortisone and cholesterol (12 and 13, respectively, Scheme2)

morestable trans -fusedsystempresentinthetargetednatural

products would be relatively simple to achieve. Thus, in the

next synthetic operation, base-induced epimerization readily

providedthecoveted trans -fusedringsystem(10),thussetting

the stage for an eventual ring-contraction process that would

allow completion of this region of the steroid nucleus. [12]

Similar levels of synthetic ingenuity are reflected in the

totalsynthesisofreserpine(17,Scheme3)byWoodwardetal.

in 1956, [13] where again an opening Diels±Alder reaction

forgedthecriticalbicyclicsystem(16)thatwouldserveasthe

Scheme 3. Application of the Diels±Alder reaction in the total synthesis

of reserpine (17) by Woodward etal. in 1956. [13]

scaffold for the ensuing synthetic sequence. [14] This use of a

Diels±Alder strategy to form an initial array of rings and

stereocenters, elements which pave the way for subsequent

stereocontrolled elaboration to the final target molecule,

represents a distinctive hallmark of Woodward×s synthetic

acumen. Moreover, these two examples from Woodward×s

researchgroupareillustrativeofanewschoolofthoughtthat

emerged in the 1950s which involved approaching the syn-

thesis of complex molecules by rational synthetic strategies,

andtheyadmirablydemonstratedtheinherentstrengthofthe

Diels±Alder reaction to solve challenging synthetic puzzles

which might otherwise have remained hopelessly complex.

In this review, we hope to highlight didactic exemplars of

the Diels±Alder reaction in the context of natural product

total synthesis representing work which has decisively ad-

vanced both the power and scope of this pericyclic process

beyondthepioneeringapplicationsofWoodward.Inselecting

ourcasestudies,weacceptedthefactthatanyreviewofsucha

widelyusedreactionwithnearlythree-quartersofacenturyof

historycouldnotpossiblybecomprehensive.Ouraspirationis

that the delineated examples will sufficiently cover the

various areas in which Diels±Alder methodology represents

an indispensable tool for the art of total synthesis, and will

reflect key paradigm shifts in the field through novel and

inventive approaches to this classic reaction. We hope that

these discussions will inspire you not only to further explore

theliteratureintermsofsynthesesnotexpoundeduponhere,

but also to create even more fantastic applications of the

Diels±Alder reaction in your own research.

Scheme 2. The pioneering adoption of a quinone-based Diels±Alder

reactionbyWoodwardetal.in1952asthekeystepinthetotalsynthesisof

the steroid hormones cortisone (12) and cholesterol (13). [11]

where,intheinitialstep,reactionofquinone7withbutadiene

in benzene at 100 C for 96hours effected a smooth Diels±

Alder cycloaddition to form bicyclic adduct 9 via the

intermediacy of endo transition state 8. [11] Several features

of this particular [4

2]cycloaddition reaction are of note.

First, Woodward recognized that by using a differentiated

quinone nucleus it would be possible to effect regioselective

controloftheintermolecularDiels±Alderunion,asthemore

electron-richmethoxy-substitutedolefinwouldbelessdieno-

philic than its methyl-substituted counterpart. An equally

insightful design element was the anticipation that even

though a cis -fused adduct would arise from the Diels±Alder

reaction, conversion into the requisite thermodynamically

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K.C. Nicolaou et al.

2. Regiocontrol and Beyond: Achieving

Stereoselection

The early total syntheses by Woodward described above

amply illustrate the ability of the Diels±Alder reaction to

create molecular complexity. Not only is a cyclohexene ring

generated through the formation of two new

bonds, but up

to four contiguous stereocenters are also concomitantly

fashioned in the process. Fortunately, as a result of the regio-

andstereospecificnatureoftheDiels±Alderreaction(always

a cis addition)andthediastereoselectivityoftheunionbased

on the Alder endo rule [10] (where a more sterically crowded

and seemingly less thermodynamically stable transition state

results when the dienophile possesses a suitable conjugating

substituent), the formation of these chiral elements is often

predictable in a relative sense. However, new principles and

approaches to the Diels±Alder reaction would be needed

beyond those delineated in the syntheses of reserpine and

cholesterol if absolute control of stereochemistry is required.

In addition, although Woodward×s Diels±Alder reactions

elegantly achieved regioselectivity, results which can be

rationalized successfully on the basis of frontier molecular

orbitaltheory, [15] theseexamplesdonotreflectthechallenges

facedinattemptingtoachievesuchcontrolincertaincontexts

whereparticularunsymmetricaldieneand/ordienophileunits

havingspecificsteric andelectronicproperties areemployed.

As such, general solutions would be required to address the

problem of selectively incorporating useful sets of diverse

functionality in Diels±Alder cycloaddition products. In this

section,wehighlight someanswerstotheissuesofregio-and

stereoselectivity which have been developed by leading

synthetic chemists to provide a qualitative measure of the

current state of the art in Diels±Alder technology.

A classical method to enhance regioselectivity is based on

the use of Lewis acid catalysts. Upon complexation of such

species to the dienophile, the normal demand Diels±Alder

reactionispromotedsincetheenergygapbetweenthelowest

unoccupiedmolecularorbital(LUMO)ofthedienophileand

thehighestoccupiedmolecularorbital(HOMO)ofthediene

is reduced, thus decreasing the activation energy required to

achieve the cycloaddition. Moreover, as this stabilization is

greater for the endo transition state, as a result of beneficial

enhancement of secondary orbital overlap that is unobtain-

ableinan exo modeofreaction,theuseofLewisacidsfavors

an increased ratio of endo : exo products. More valuable

synthetically, however, is the fact that Lewis acids can often

reverse the regiochemical course of a Diels±Alder addition

and generate products that would not otherwise be observed

in a simple, thermally induced reaction. [16] An early and

elegant example of this concept is provided by the total

synthesis of tetrodotoxin (22, Scheme4) by Kishi etal. [17] As

in the Woodward paradigm, an initial Diels±Alder union

between quinone 18 and butadiene (19) was employed to

generate a preliminary set of rings and stereocenters for

subsequent elaboration. However, the intriguing feature of

this example is that the use of SnCl 4 in the Diels±Alder

reactionprovedcriticalforthechemoselectiveengagementof

butadienewiththeoxime-bounddienophiletoform20;inthe

absenceoftheLewisacid,theotherolefinicbondofquinone

Scheme 4. Use of Lewis acid catalysis by Kishi etal. (1972) to achieve

chemoselective control in the formation of key intermediate 21 leading to

tetrodotoxin (22). [17]

18 reacted exclusively. Although oximes normally behave

mesomerically as electron-donating substituents, thus deacti-

vating the neighboring olefin for Diels±Alder reaction,

coordination of the Lewis acid reverses this behavior by

drawingelectrondensityawayfromthisgroup,whichleadsto

anadjacenthighlycompetentelectron-deficientdienophile. [18]

Thus, Lewis acid activation nicely effected regiochemical

control in the employed [4 2]cycloaddition that could not

have been achieved otherwise.

Among other methods introduced to achieve excellent

regioselectivity, as well as to incorporate useful functional

groups, Danishefsky×s widely applicable diene system (23,

Scheme5a)representsoneofthemostimportantadvancesin

this regard within the past quarter century. [19] Initially

developed as part of a method to selectively generate pyran

ringsuponreactionwithaldehydedienophiles, [20] thepowerof

the prototype diene 23 rests in the synergistic effects of the

two incorporated oxygen groups, which provide mutually

reinforcing electronic contributions to the diene system such

that regiospecific formation of a lone endo adduct results

upon reaction with most dienophiles. In addition, upon

treatment with mild acid after the Diels±Alder reaction,

cleavage of the silyl protecting group residing within the

product and the strategic location of the methoxy leaving

groupenablesanensuingcascadesequencethatresultsinthe

formation of an , -unsaturated system. An early demon-

stration of this strategy in total synthesis can be found in the

routeusedbyDanishefskyetal.toformdisodiumprephenate

(27, Scheme5b), [21] where, although the target may not seem

to possess great molecular complexity, application of this

designed diene technology provided a highly elegant and

concise solution to the synthetic problem at hand. As

illustrated, after regioselective formation of Diels±Alder

product25,insitutreatmentofthiscompoundwithaceticacid

formedthedesired

-unsaturatedsystemwhichconcurrent-

lyeliminatedphenylsulfoxidetoprovide26,aproductwhich

was easily elaborated to the target structure.

The versatility of this particular technology is underscored

by the wide variety of such dienes that can be employed. [22]

Forexample,useofaDanishefsky-typediene(28,Scheme5c)

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