The Diels-Alder Reaction in Total Synthesis, chemia, Chemia Teoretyczna
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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]
1433-7851/02/4110-1669 $ 20.00+.50/0
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¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
REVIEWS
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
REVIEWS
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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