palladium-catalyzed cross-coupling reactions in total synthesis.pdf

Reviews

K. C. Nicolaou et al.

Synthetic Methods

Palladium-Catalyzed Cross-Coupling Reactions in Total

Synthesis

K. C. Nicolaou,* Paul G. Bulger, and David Sarlah

Keywords:

C C coupling · cross-coupling ·

palladium catalysis · synthetic

methods · total synthesis

Dedicated to Richard F. Heck

on the occasion of his 74th birthday

Angewandte

Chemie

4442

DOI: 10.1002/anie.200500368

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2005, 44, 4442–4489

Angewandte

Chemie

C C Coupling

I n studying the evolution of organic chemistry and grasping its

essence, one comes quickly to the conclusion that no other type of

reaction plays as large a role in shaping this domain of science

than carbon–carbon bond-forming reactions. The Grignard,

Diels–Alder, and Wittig reactions are but three prominent exam-

ples of such processes, and are among those which have undeni-

ably exercised decisive roles in the last century in the emergence of

chemical synthesis as we know it today. In the last quarter of the

20th century, a new family of carbon–carbon bond-forming

reactions based on transition-metal catalysts evolved as powerful

tools in synthesis. Among them, the palladium-catalyzed cross-

coupling reactions are the most prominent. In this Review, high-

lights of a number of selected syntheses are discussed. The

examples chosen demonstrate the enormous power of these

processes in the art of total synthesis and underscore their future

potential in chemical synthesis.

From the Contents

1. Introduction

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2. The Heck Reaction

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3. The Stille Reaction

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4. The Suzuki Reaction

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5. The Sonogashira Reaction

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6. The Tsuji–Trost Reaction

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7. The Negishi Reaction

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8. Summary and Outlook

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1. Introduction

formally result from the substitution of a hydrogen atom in

the alkene coupling partner. The first examples of this

reaction as we would recognize it today were reported

independently by Mizoroki (1971) [2] and, in an improved

form, byHeck (1972). [3] However, it wouldprove to bemore

than a decade before the broader applicability of this

transformation began to be investigated by the wider

synthetic organic community. The development of catalytic

asymmetric Heck reactions in the late 1980s led to a further

resurgence of interest in this field. [4] The Heck reaction now

stands as a remarkably robust and efficient method for

carbon–carbonbondformation,particularlyinthegeneration

of tertiary and quaternary stereocenters and intramolecular

ring formation, and remains a flourishing area of research.

Significantly, it inspired important variations that, with time,

have assumed their own names, identities, and place in total

synthesis.

The palladium-catalyzed cross-coupling of organic elec-

trophiles with vinyl organotin compounds is today known as

the Stille reaction (Scheme1), [5] after the late Professor J.K.

Stille who pioneered (1978) [6] and subsequently developed [7]

this reaction, although the seeds of discovery were sown

earlier by Kosugi and his group, who published the first

reports of transition-metal-catalyzed carbon-carbon bond-

forming reactions with organotin compounds a year ear-

lier. [8,9] Nearly30yearslatertheStillereactionremainsoneof

Ever since the first laboratory construction of a carbon–

carbonbondbyKolbeinhishistoricsynthesisofaceticacidin

1845, carbon–carbon bond-forming reactions have played an

enormously decisive and important role in shaping chemical

synthesis. Aldol- and Grignard-type reactions, the Diels–

Alder and related pericyclic processes, and the Wittig and

related reactions are but a few examples of such processes

that have advanced our ability to construct increasingly

complexcarbonframeworksand,thus,enabledthesyntheses

of a myriad of organic compounds. In the last quarter of the

20th century, a new paradigm for carbon–carbon bond

formation has emerged that has enhanced considerably the

prowess of synthetic organic chemists to assemble complex

molecular frameworks and has changed the way we think

about synthesis. Based on transition-metal catalysis, this

newlyacquiredabilitytoforgecarbon–carbonbondsbetween

or within functionalized and sensitive substrates provided

new opportunities, particularly in total synthesis but also in

medicinal and process chemistry as well as in chemical

biology and nanotechnology.

Prominent among these processes are the palladium-

catalyzed carbon–carbon bond-forming reactions. Because

the historical, mechanistic, theoretical, and practical aspects

of these processes have been amply discussed, [1] in this

Review we focus only on selected applications of the most

commonlyappliedpalladium-catalyzedcarbon–carbonbond-

forming reactions in total synthesis, namely, the Heck, Stille,

Suzuki, Sonogashira, Tsuji–Trost, and the Negishi reactions,

withparticularemphasisonthepioneeringaswellassomeof

themostrecentandexcitingexamples.Indoingso,wehopeto

illustrate the tremendous enabling ability of these modern

synthetic tools.

The Heck reaction can be broadly defined as the

palladium-catalyzed coupling of alkenyl or aryl (sp 2 ) halides

or triflates with alkenes (Scheme1) to yield products which

[*] Prof. Dr. K. C. Nicolaou, Dr. P. G. Bulger, D. Sarlah

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: ( + 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)

4443

DOI: 10.1002/anie.200500368

Angew. Chem. Int. Ed. 2005, 44, 4442 –4489

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Reviews

K. C. Nicolaou et al.

the most widely applied palladium-catalyzed carbon–carbon

bond-forming reactions, in large part due to typically mild

reactionconditions,theeaseofpreparationofawiderangeof

coupling partners, and the tolerance of a wide variety of

sensitive functionalities in this transformation. In particular,

the number of ingenious and daring applications of Stille

couplingsinthechallengingprovinggroundoftotalsynthesis

bears testament to the faith placed in the robustness and

versatilityofthisreactionbypractitionersofthisart.Notably,

the Stille reaction can be viewed as a variation of the Heck

reactioninwhichahydrogenatomisreplacedbyatin-bearing

substituent. [10]

Another extraordinarily useful palladium-catalyzed

carbon–carbon bond-forming reaction involves the palla-

dium-mediatedcouplingoforganicelectrophiles,suchasaryl

oralkenylhalidesandtriflates,withorganoboroncompounds

in the presence of a base (Scheme1), [11] a process known

today as the Suzuki reaction. The first examples of this

protocol were reported by the Suzuki group in 1979 [12]

K. C. Nicolaou was born in Cyprus and edu-

cated in the UK and USA. He is Chairman

of the Department of Chemistry at The

Scripps Research Institute where he holds

the Darlene Shiley Chair in Chemistry and

the Aline W. and L. S. Skaggs Professorship

in Chemical Biology. He is also Professor of

Chemistry at the University of California,

San Diego. His impact on chemistry, biology

and medicine flows from contributions to

chemical synthesis, which are described in

numerous publications and patents.

Paul G. Bulger was born in London (UK) in

1978. He received his M.Chem in 2000

from the University of Oxford, where he

completed his Part II project under Dr.

Mark G. Moloney. He obtained his D.Phil in

chemistry in 2003 for research conducted

under Professor Sir Jack E. Baldwin. In the

fall of 2003, he joined Professor K. C. Nico-

laou’s group as a postdoctoral researcher.

His research interests encompass reaction

mechanism and design and their application

to complex natural product synthesis and

chemical biology.

Scheme 1. The most commonly utilized palladium-catalyzed

cross-coupling reactions.

David Sarlah was born in Celje, Slovenia in

1983. He is currently student in the Faculty

of Chemistry and Chemical Technology, Uni-

versity of Ljubljana (Slovenia). Since 2001,

he has been a research assistant at the Lab-

oratory of Organic and Medicinal Chemistry

at the National Institute of Chemistry (Slov-

enia) where he carried out research on

asymmetric catalysis under the direction of

Dr. B. Mohar. During the summer of 2004,

he was engaged in total synthesis endeavors

as a member of the azaspiracid team under

Professor K. C. Nicolaou.

although, again, the inspiration or the seeds of this develop-

ment can be found in earlier work by others, in this case the

groups of Heck (1973) [13] and Negishi (1977). [14] The ensuing

quarter of a century saw remarkable developments in the

field. Amongst its manifold applications, the Suzuki reaction

is particularly useful as a method for the construction of

conjugateddienesandhigherpolyenesystemsofhighstereo-

isomeric purity, as well as of biaryl and related systems.

Furthermore, tremendous progress has been made in the

development of Suzuki coupling reactions of unactivated

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Angew. Chem. Int. Ed. 2005, 44, 4442–4489

Angewandte

Chemie

C C Coupling

alkyl halides, enabling C(sp 2 )–C(sp 3 ) and even C(sp 3 )–C(sp 3 )

bond-forming processes. [15,16] The ease of preparation of

organoboron compounds (e.g. aryl, vinyl, alkyl) and their

relativestabilitytoairandwater,combinedwiththerelatively

mild conditions for the reaction as well as the formation of

nontoxic by-products, makes the Suzuki reaction a valuable

addition to the armory of the synthetic organic chemist.

Indeed, it has become one of the most reliable and widely

applied palladium-catalyzed cross-coupling reactions in total

synthesis, where it has found a prominent role. [17] It is, again,

worthmentioningthattheSuzukireactionmaybeconsidered

as a variation of the Heck reaction, in which a boron-

containing group replaces a hydrogen atom in the olefinic

partner of the cross-coupling.

The palladium-catalyzed coupling of terminal alkynes

withvinylorarylhalideswasfirstreportedindependentlyand

simultaneously by the groups of Cassar [18] and Heck [19] in

1975. A few months later, Sonogashira and co-workers

demonstratedthat,inmanycases,thiscross-couplingreaction

couldbeacceleratedbytheadditionofcocatalyticCu I saltsto

the reaction mixture. [20,21] This protocol, which has become

knownastheSonogashirareaction,canbeviewedasbothan

alkyne version of the Heck reaction and an application of

palladium catalysis to the venerable Stephens–Castro reac-

tion (the coupling of vinyl or aryl halides with stoichiometric

amountsofcopper( i )acetylides). [22] TheSonogashirareaction

provides a valuable method for the synthesis of conjugated

acetylenic systems, which are used in a diverse array of

important applications from natural products and pharma-

ceuticals to designed molecules of interest in biotechnology

and nanotechnology. Interestingly, the utility of the “copper-

free” Sonogashira protocol (i.e. the original Cassar–Heck

version of this reaction) has subsequently been “rediscov-

ered” independently by a number of other researchers in

recent years. [23]

The palladium-catalyzed nucleophilic substitution of

allylic compounds, known as the Tsuji–Trost reaction

(Scheme1), is arguably one of the most synthetically useful

carbon–carbon bond-forming reactions to emerge in the last

quarterofthepreviouscentury. [24] Allylacetatesarebyfarthe

mostcommonlyemployedelectrophiles,andsoftanionssuch

as those derived from b-dicarbonyl compounds are most

routinelyusedasthenucleophiliccouplingpartner.However,

a wide variety of substrate combinations is possible, which

givesthereactionanexceptionallybroadscope.Thedevelop-

mentofthepalladium-catalyzedasymmetricallylicalkylation

reaction over the last decade has considerably increased the

enablingnatureofthistransformation. [25] Anotablefeatureof

the allylic alkylation reaction is its net reaction at sp 3 -

hybridizedcarbonatomcenters,afeaturecommonamongthe

palladium-catalyzed coupling reactions only to the Fu mod-

ification of the Suzuki reaction. The asymmetric allylic

alkylation reaction now provides a powerful method for

ring formation, 1,3-chirality transfer, desymmetrization of

meso substrates, the resolution of racemic compounds, and a

plethora of other applications.

Historically, the use of organozinc reagents as the

nucleophilic component in palladium-catalyzed cross-coup-

ling reactions, known as the Negishi coupling (Scheme1),

actually predates the development of both the organostan-

nane- (Stille, 1978) [6] and organoborane-based (Suzuki,

1979) [12] procedures, with the first such examples being

reported in 1977. [26] Nevertheless, the rapid and widespread

embracementofthelattertwoprotocolsbysyntheticchemists

duringthe1980sledtothepotentialoforganozincreagentsin

cross-coupling processes being relatively underappreciated

and underutilized during this time, particularly in total

synthesis. However, recent years have witnessed a resurgent

interest in the development and application of organozinc-

mediated cross-couplings, largely fueled by the recognition

that these reagents offer complementary modes of reactivity

to those of the less electropositive metals species (e.g. B and

Sn). Organozinc reagents exhibit a very high intrinsic

reactivity in palladium-catalyzed cross-coupling reactions,

which combined with the availability of a number of

procedures for their preparation and their relatively low

toxicity, makes the Negishi coupling an exceedingly useful

alternative to other cross-coupling procedures, as well as

constituting an important method for carbon–carbon bond

formation in its own right. [27]

In the following sections, we discuss the contributions of

thesepalladium-catalyzedcarbon–carbonbond-formingreac-

tions to the art and science of total synthesis and the new

thinking that they have precipitated in the field.

2. The Heck Reaction

Total synthesis has benefited enormously from the Heck

reaction, which has been widely applied in both its intermo-

lecular and intramolecular variants. [28–30] The enabling attrib-

utes of this remarkable reaction manifest themselves in a

plethora of ways, including appendage attachments, polyene

construction, fragment couplings, and ring-closure reactions.

Inthissection,wehighlightafewexamplesthatdemonstrate

theeleganceandeffectivenessofstrategiesbasedontheHeck

reaction as the key step.

Among alkaloid total syntheses employing the Heck

reaction, that of dehydrotubifoline (3) by Rawal and co-

workers stands out (Scheme2). [31] In this instance the

palladium-catalyzed process was used to forge the final

carbon–carbon bond and cast the final ring of the polycyclic

structure of the target in 79% yield (1 ! 3, Scheme2). This

effectiveoperation,involvinga6- exo -palladationfollowedby

b-hydride elimination and tautomerization of the resulting

enamine species, would seem simple enough and certainly

predictable, until one considers the different outcome

observedwiththecorresponding N -carbomethoxycyclization

substrate 2.Inthatinitialattempt,theresearchersnoticedthe

exclusive formation of the unexpected compound 7, the

apparent product of a 7- endo -cyclopalladation reaction, in

84%yield.Moreover,closescrutinyofthespectroscopicdata

of pentacyclic compound 7 revealed that inversion of

geometry of the exocyclic double bond had occurred, an

outcome inconsistent with a direct 7- endo mode of ring

closure. The proposed mechanistic explanation for the

formation of 7 is both intriguing and illuminating. Thus,

under the Jeffery modification [32] of the Heck conditions

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Angew. Chem. Int. Ed. 2005, 44, 4442 –4489

2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Reviews

K. C. Nicolaou et al.

ence of a b-hydrogen atom. [33] Instead, this intermediate is

sufficientlylong-livedtoundergoasecondcyclopalladationto

form the cyclopropylmethyl palladium complex 5, which is

forced by steric congestion to undergo a 1208 rotation about

the s bond. This then allows the proper alignment required

for fragmentation of the other cyclopropane bond to give

palladium complex 6, which is no longer stabilized by

carbamate complexation and undergoes the anticipated b-

hydrideeliminationtoprovidetheobservedproduct 7.Based

on these mechanistic considerations, the Rawal group sub-

jected the “carbamate-free” substrate 1 to the same reaction

conditions realizing, much to their delight, the formation of

thenaturalproductdehydrotubifoline(3).Thiscaseservesto

illustrate the fact that the “normal” mechanistic pathways of

metal-catalyzed processes may be diverted, in certain cases,

by the judicious placementof coordinating groupswithin the

employed substrates. [34]

Palladium-catalyzed reactions abound in the spectacular

synthesis of quadrigemineC (13, Scheme3), a tetrameric

member of the polypyrrolidinoindoline alkaloid family, by

Overman and co-workers. [35] Noting that the quaternary C3

andC3’’’ stereocenterswithinthetargetmolecule 13 havethe

same absolute configuration, these researchers applied cata-

lytic asymmetric Heck reactions [4] to effect the desymmetri-

zationofanadvanced meso intermediate 10,formationofthe

two peripheral indoline residues, and installation of the final

twoquaternarystereocentersinasinglestep.Thisremarkable

double cyclization (10 ! 11 ! 12) was preceded by another

highly effective palladium-catalyzed carbon–carbon bond-

formingreaction,namelyaStillecoupling,whichwasusedto

assemble the required precursor 10 from its constituent

Scheme 2. Intramolecular Heck reactions in the total synthesis of

()-dehydrotubifoline (3) (Rawal et al., 1993). [31]

(Pd(OAc) 2 cat.,K 2 CO 3 , n Bu 4 NCl,DMF,608C),theexpected

6- endo cyclization occurs to yield initially s-alkyl–palladium

species 4 which, due to stabilization by intramolecular

carbamate complexation, is prevented from undergoing a

normally facile syn -b-hydride elimination, despite the pres-

Scheme 3. Sequential tandem Stille couplings and asymmetric intramolecular Heck reactions in the enantioselective synthesis of

()-quadrigemine C (13) (Overman et al., 2002). [35]

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2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2005, 44, 4442–4489

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