Nickel-Catalyzed Reductive Cyclizations and Couplings

Multicomponent Coupling Reactions

Nickel-Catalyzed Reductive Cyclizations and CouplingsJohn Montgomery*

AngewandteChemie

Keywords:metallacycles · multicomponentreactions · nickel · reductivecoupling · reductivecyclization

In memory of Norman A. LeBel

J. MontgomeryReviews

3890 � 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200300634 Angew. Chem. Int. Ed. 2004, 43, 3890 – 3908

1. Introduction

Oligomerizations of acetylene and butadiene were amongthe earliest reports of synthetically useful nickel-catalyzedreactions, and contemporary applications of these processeshave resulted in methodological advances of substantialimportance.[1] For instance, nickel-catalyzed [4+4],[2]

[4+2],[3] and [2+2+2][4] cycloadditions have received consid-erable attention. Other important nickel-catalyzed processesinclude olefin polymerizations,[2b,5] dimerizations,[1a,6] hydro-cyanations,[7] and hydrometallations.[8] One particular group-ing of nickel-catalyzed reactions that has received substantialattention recently is the reductive coupling of two p compo-nents with one main-group organometallic reagent or metalhydride (Scheme 1).[9] Within this grouping of contemporary

studies, many fundamental advances in reaction discoveryand complex synthetic applications have been presented. Thepurpose of this Review is to highlight recent discoveries andapplications in nickel-catalyzed reductive couplings andcyclizations as well as mechanistic hypotheses that havegrown from studies in this area.

2. General Mechanistic Considerations

Despite the considerable attention that has been devotedto three-component couplings of two p components and amain-group organometallic reagent or metal hydride, manyinteresting mechanistic questions still remain. Of the various

mechanistic pathways that have beenadvanced, most fall into three generalgroupings. These three groupings can

be characterized according to the oxidative transformationthat initiates the overall coupling process (Scheme 2). Thefirst general mechanism is initiated by oxidative cyclization ofnickel(0) with two p components A=B and C=D to form ametallacycle 1. Transmetallation of a metal alkyl MR toafford 2 followed by reductive elimination affords product 3.The second general mechanism is initiated by oxidativeaddition of nickel(0) toMR (ametal hydride or metal alkyl) toform a reactive nickel hydride or nickel alkyl 4. Sequentialmigratory insertions of the two p components C=D and A=B,followed by reductive elimination of 5, affords product 3. Thethird general mechanism is initiated by oxidative addition ofnickel (0) to one of the p components A=B, often facilitatedby a Lewis acid (M’X), to form a reactive nickel alkyl 6 (mostoften a p-allyl complex). Migratory insertion of the secondp component C=D, followed by transmetallation of MR, andfinally reductive elimination affords product 3.

These are undoubtedly oversimplified descriptions, andmany variations on the three mechanism classes summarizedabove are possible. Issues such as metal coordination number,prior association of reactive components, and changes in thehapticity of unsaturated reactive ligands provide manyreasonable variations in the mechanisms highlighted above.Furthermore, electron-transfer processes are certainly possi-ble and have been well documented and thoroughly studied inother classes of nickel-catalyzed reactions.[10] The involve-ment of electron-transfer pathways could be important in theindividual steps of the three mechanism classes describedabove. Alternatively, entirely distinct mechanisms thatinvolve cyclizations of free radicals, radical anions, or para-magnetic nickel intermediates are also possible. This Review

For over 50 years, nickel catalysis has been applied in cycloadditionprocesses. Nickel-catalyzed reductive couplings and cyclizations,however, have only recently attracted a high level of interest. Thisgroup of new reactions allows a broad range of multicomponentcouplings involving two or more p components with a main-group ortransition-metal reagent. These processes allow the assembly ofimportant organic substructures from widely available reactioncomponents. Multiple contiguous stereocenters, polycyclic ringsystems, and novel arrays of complex functionality may often beprepared from simple, achiral, acyclic precursors. With three or morereactive functional groups participating in the catalytic processes,many mechanistic questions abound, including the precise timing ofbond constructions and the nature of reactive intermediates. ThisReview is thus aimed at providing a critical evaluation of recentprogress in this rapidly developing field.

From the Contents

1. Introduction 3891

2. General MechanisticConsiderations 3891

3. Choice of Catalysts 3892

4. Three-Component Couplings 3892

5. Applications in the Synthesis ofComplex Molecules 3903

6. Summary and Outlook 3906

Scheme 1. Intermolecular nickel-catalyzed coupling of p componentsin the presence of a main-group organometallic complex.

[*] Prof. J. MontgomeryDepartment of ChemistryWayne State UniversityDetroit, MI 48202-3489 (USA)Fax (+1)313-577-2554E-mail: [email protected]

Nickel-Catalyzed CouplingsAngewandte

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3891Angew. Chem. Int. Ed. 2004, 43, 3890 – 3908 DOI: 10.1002/anie.200300634 � 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

primarily presents the mechanistic descriptions provided bythe authors who initially reported the work, but readersshould be aware that most mechanistic proposals in this areaare largely speculative. Further study may involve revision ofmany of the mechanistic proposals summarized in this report.

3. Choice of Catalysts

The vast majority of reactions developed that fall withinthe scope of this Review utilize either [Ni(cod)2] (cod= 1,5-cyclooctadiene) or [Ni(acac)2] (acac= acetyl acetonate) asthe commercially available source of the active catalyst. It hasgenerally been proposed that the active oxidation state ofnickel in the catalytic processes is 0, and thus [Ni(cod)2]requires no prior activation for catalysis to occur. Whereasvarious complexes of nickel(0) with phosphanes and amines(and related derivatives) may be prepared, the typicalstrategy involves preparation of various catalysts in situsimply by premixing [Ni(cod)2] with the appropriate ligand.A description of the relative reactivities of various ligands willbe provided throughout this Review.

[Ni(acac)2] may often be used as the catalyst source,although this nickel(ii) species typically requires reduction forcatalysis to occur. Some of the more nucleophilic reducingagents such as dialkyl zinc reagents can reduce [Ni(acac)2] to alower oxidation state, but a reliable procedure that is oftenemployed involves prior reduction of [Ni(acac)2] withDIBAL-H (diisobutyl aluminum hydride). This procedurewas studied by Schwartz and co-workers in the context ofnickel-catalyzed conjugate additions, and those originalstudies included electrochemical evidence that DIBAL-Hpromotes the formation of a paramagnetic nickel(i) specieswhen [Ni(acac)2] and DIBAL-H in THFare employed in a 1:1ratio.[10a–b] Later studies by Mackenzie and Krysan demon-strated that a 1:2 ratio of [Ni(acac)2]:DIBAL-H in THF in thepresence of cod provides a convenient preparation of[Ni(cod)2],

[11] so it appears that there is little doubt that anickel(0) species may be produced under the appropriateconditions. The advantages of [Ni(acac)2] over of [Ni(cod)2]include the lower cost and air stability of [Ni(acac)2]([Ni(cod)2] requires storage and handling under inert atmos-phere). In addition to the stability and cost issues, it wasshown by Mori that DIBAL(acac), which is produced byreduction of [Ni(acac)2] with DIBAL-H, can have a substan-tial impact on some reactions. Hence [Ni(acac)2]/DIBAL-Hshould not be viewed as rigorously equivalent to [Ni(cod)2].

[12]

4. Three-Component Couplings

4.1. Couplings of Alkenes with Alkynes

The nickel-catalyzed coupling of an alkene, an alkyne, anda main-group organometallic reagent has been studiedintensively in a variety of contexts (Scheme 3). This processprovides an excellent way to control the stereochemistry of

John Montgomery was born in 1965 in Con-cord, NC. He studied chemistry at the Uni-versity of North Carolina with Prof. Joe Tem-pleton and Prof. Maurice Brookhart (1987).He received his PhD at Colorado State Uni-versity with Prof. Louis Hegedus (1991). Hewas an American Cancer Society Postdoc-toral Fellow at the University of California atIrvine (1991–1993) with Prof. Larry Over-man. In 1993, he moved to Wayne StateUniversity where he is now Professor ofChemistry. His work is focused on transitionmetals in reaction discovery, synthetic meth-odology development, mechanistic chemis-try, and complex molecule synthesis.

Scheme 2. Possible mechanisms for the three-component coupling oftwo p components with a main-group organometallic complex or amain-group-metal hydride: a) oxidative cyclization of two p compo-nents; b) oxidative addition to a reducing agent and subsequent inser-tion of the p components; c) oxidative addition to one p componentand subsequent insertion of the second component.

Scheme 3. Intramolecular coupling of enynes with main-group organo-metallic reagents.


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challenging tri- and tetrasubstituted alkenes. An apparentrequirement for the coupling or cyclization to proceedeffectively is that the alkene unit must be electron deficient.Intramolecular versions of this process, largely developed inour laboratories, have been demonstrated with organozincreagents (as in the production of 7 and 8),[13] organoaluminumreagents,[14] and alkenyl zirconium reagents (as in theproduction of 9, Scheme 4).[15] Both internal and terminal

alkynes are cleanly tolerated as the acetylenic component,and enones, alkylidene malonates, nitroalkenes, and unsatu-rated imides are tolerated as the electron-deficient alkenecomponent. The scope of the reaction is very broad(Scheme 4). Several total synthesis applications of thisreaction class have been demonstrated (Sections 5.1 and 5.2).

Organozinc reagents that bear b-hydrogen atoms aretolerated in the process, although ligand effects becomeimportant (Scheme 5). In the absence of phosphanes, alkyl-group transfer is observed, but when the nickel(0) catalyst ispretreated with triphenylphosphane, selective hydrogen-atom

incorporation occurs. This feature adds considerable flexibil-ity to the method. It was proposed that nickel species 10 is anintermediate for both alkylative and reductive manifolds, andthat the s-donating ability of the ligands controls the reactionoutcome.[13a,b]

The corresponding intermolecular couplings of enones,alkynes, and main-group organometallic reagents also pro-ceed efficiently to generate acyclic structures, which may befurther elaborated by a variety of procedures. The firstreported examples of couplings of this type from Ikeda et al.involved acetylenic tin reagents to generate conjugatedenynes such as 11 and 12 (Scheme 6).[16] Both internal and

terminal alkynes participate in the couplings, and regioselec-tivities are very high with terminal alkynes to generateproducts derived from coupling of the enone with theunsubstituted alkyne terminus. Acetylenic zinc reagentsparticipate in the couplings, although yields and regioselec-tivities of alkyne insertion are lower than in the correspondingalkynyl tin reagent couplings.[17] Alkyl zinc reagents, either inpure form or generated from the corresponding organo-lithium and zinc chloride, also participate cleanly in the three-component couplings, as demonstrated by the production of13.[18]

An asymmetric version of the intermolecular couplingswas developed by Ikeda et al., who used a nickel catalystmodified with a chiral monodentate oxazoline (Scheme 7).[19]

Yields and enantioselectivities ranged from good to modest inthis procedure. A variety of bidentate ligands includingbisphosphanes, bisoxazolines, phospanyloxazolines, and pyr-idinyloxazolines afforded poorer results both in efficiency andenantioselectivity.

A related process developed by Ikeda et al. involvescouplings of allylic halides and acetates with alkynes in thepresence of acetylenic stannanes (Scheme 8).[20] This proce-dure provides a very attractive entry to conjugated enynes.The reactions can be entirely intermolecular (!14) orpartially intramolecular (!15). Although the process was

Scheme 4. Examples for syntheses through coupling of enynes andmain-group organometallic reagents. TBS= tert-butyldimethylsilyl.

Scheme 5. Effect of phosphane additives on the reactivity of organo-zinc reagents that bear b-hydrogen atoms.

Scheme 6. Examples of the first intermolecular couplings of enones,alkynes, and main-group organometallic reagents.


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most extensively developed with acetylenic stannanes, orga-nozinc and organoaluminum reagents are also effectiveparticipants.[21]

The mechanistic proposals for the enone/alkyne couplingshave largely focused on the involvement of nickel metalla-cycles derived from the oxidative cyclization of an enone andan alkyne with nickel(0) (Scheme 9).[9] Once the initialoxidative cyclization occurs to produce metallacycle 16,transmetallation of the main-group organometallic reagentoccurs to generate intermediate 17. Direct reductive elimi-

nation of 17 provides the observed product 18, whereas b-Helimination occurs when phosphanes are used (Scheme 5). Byomitting the organozinc reagent, metallacycle 19 was isolatedand fully characterized as the h1, O-bound enolate(Scheme 10).[22] Treatment of metallacycle 19 with dimethyl-

zinc affords the same product 20, which may be obtained fromthe catalytic reaction of an alkynyl enal and dimethyl zinc.This observation in no way proves that catalytic reactionsproceed by this mechanism, but the sequence does providedirect precedent for each of the key individual steps of themetallacycle mechanism. Studies in our laboratory are aimedat directly investigating the kinetic competence of 19 incatalytic reactions, and a detailed full report of that studyinvolving both experimental and computational chemistry isforthcoming. Further synthetic applications of the proposednickel metallacycle and related metallacycles that are beyondthe scope of this Review have also been reported.[23]

An alternate mechanism for this class of transformationshas been discussed. If the reaction is initiated by Lewis acidpromoted oxidative addition of nickel(0) to the enone, then p-allyl intermediate 21 would result (Scheme 11). Alkyneinsertion, transmetallation of the organozinc reagent, andfinally reductive elimination would afford the observed

Scheme 7. Asymmetric variants of intermolecular coupling.

Scheme 8. Coupling of allyl halides or acetates with alkynes in thepresence of alkynyl stannanes.

Scheme 9. Proposed mechanism for intramolecular enone–alkyne cou-pling.

Scheme 10. Intramolecular enone–alkyne coupling without organozincreagents. tmeda=N,N,N’,N’-tetramethylethylenediamine.

Scheme 11. Alternative mechanism for enone–alkyne coupling in thepresence of Ni0.




product 22. The formation of p-allyl complexes from enones,nickel(0), and trimethylsilyl chloride is well precedented,[24]

but direct precedent for the conversion of p-allyl complex 21into products such as 22 has not been obtained. Furthermore,trimethylsilyl chloride is not a required additive in mostvariants. Therefore, the metallacycle-based mechanism isprobably more reasonable based on data currently available.The allyl chloride couplings by Ikeda et al. (Scheme 8) werereported to proceed through a similar p-allyl-based pathway,although a metallacycle-based mechanism may be operativewith that group of reactions as well.

Additional mechanistic pathways, including alkyne car-bometallation pathways with organozinc or organonickel aswell as radical cyclization pathways, have been considered.[25]

Various probe substrates were examined and provided datathat appeared to be most consistent with the metallacycle orp-allyl mechanisms described above.

4.2. Coupling of Two Alkenes

The nickel-catalyzed dimerization of olefins has a richhistory dating back to the elegant early studies of Wilke[1a]

into the dimerization of simple a-olefins such as propylene aswell as activated olefins such as methyl acrylate. A generaltheme of these early studies was that electrophilic nickel(ii)catalysts were employed. For instance, h3-allyl nickel(ii)halide catalysts were activated by Lewis acids to generate acationic nickel(ii) species (which can also be viewed as a Lewisacid activated neutral species), which catalyzes the dimeriza-tion of propylene. Similarly, treatment of [Ni(cod)2] withHBF4 or an h3-allyl nickel(ii) halide species with AgBF4

generates a cationic nickel(ii) tetrafluoroborate species thatcatalyzes the dimerization of methyl acrylate. These highlyactive species almost certainly operate by formation of acatalytically active nickel hydride that undergoes sequentialolefin insertions prior to b-hydride elimination to produce thedimeric product and regenerate the active nickel hydride(Scheme 12). This general mode of reactivity has been furtherillustrated in the nickel-catalyzed cyclization of a,w-dienes,[6b]

in the heterodimerization of ethylene and styrenes,[6a] and in

the polymerization of ethylene with highly active catalystsunder similar conditions.[5]

In contrast to the well-studied dimerization and cyclo-isomerization of olefins by highly active cationic nickelhydrides, much less is known about the correspondingnickel-catalyzed reductive cyclization of dienes catalyzed byelectron-rich nickel(0) catalysts. The cyclization of bis-enoneshas been developed in our laboratories by using [Ni(cod)2] ascatalyst and an organozinc complex as the reducing agent(Scheme 13).[13b,26] For instance, bis-enones undergo efficient

cyclization with BuLi/ZnCl2 to afford [3.3.0]bicyclooctanolproducts. Bis-enone 23 (R=Ph) undergoes efficient cycliza-tion to afford a single isomer of bicycloctanol 24 in 90% yield,whereas 23 (R=Me) provides 25 (3:1 ratio of diastereomers)in 71% combined yield. The organozinc structure plays acritical role, since more reactive sp2-hybridized organozincreagents undergo direct conjugate addition to provideproducts derived from tandem conjugate additions, as illus-trated by the formation of 26 with PhLi/ZnCl2 (Scheme 13).

Little is known about the mechanism of the potentiallyinteresting bis-enone cyclization, which involves a reductivecyclization/aldol addition sequence. The original report of thisreaction suggested that the cyclization is initiated by oxidativeaddition of nickel(0) to a single enone (in analogy toScheme 11),[26] although organozinc-promoted formation ofa metallacycle is also possible. In contrast to alkynyl enones,which cleanly afford metallacycles upon treatment with[Ni(cod)2] and tmeda, treatment of a bis-enone with astoichiometric quantity of nickel(0) leads to simple coordina-tion of the alkenes to nickel without cyclization. Thus, ifmetallacycles are involved in the catalytic cyclization of bis-enones, they are either generated in a small equilibriumconcentration, or their formation is promoted by the organo-zinc reagent. Bis-enones are good substrates for free radicalcyclizations, and the process could be initiated by electrontransfer from a low-valent Ni species, although this apparentlydoes not happen in the absence of an organozinc reagent oranother Lewis acidic reducing agent. Free radical cyclizations

Scheme 12. Catalytic cycle of olefin dimerization in the presence of aNiII complex.

Scheme 13. Reductive cyclization of bis-enones with [Ni(cod)2] catalyst.


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of bis-enones to afford [3.3.0]bicyclooctanols are well docu-mented.[27]

Whereas the intramolecular couplings of two enonesdescribed above require that both alkenes bear activatingsubstituents, an intermolecular process was developed byIkeda et al. that involves coupling of an electron-deficientolefin with a strained olefin (Scheme 14).[28] Upon treatment

of an enone with norbornene or norbornadiene and anacetylenic stannane in the presence of [Ni(acac)2]/DIBAL-H/TMSCl and a pyridinyloxazoline ligand, efficient couplingoccurs to generate products with up to five contiguousstereocenters in a highly diastereoselective sense. Both acyclicand cyclic enones participate in the process. This particularvariant was proposed to proceed by the mechanism describedin Section 4.1 for related alkyne couplings.

4.3. Coupling of Two Alkynes

The coupling of two alkynes with silyl hydrides is amongthe earliest examples of the general reactivity mode coveredin this Review. In the original reports of this process, Lappertet al. discussed the fully intermolecular variant, but the scopeand stereoselectivity of the process was not studied.[29] Thereal synthetic utility was not realized until the intramolecularvariant with diynes was examined by Tamao, Ito, and co-workers.[30] The coupling of 1,7-diynes with a variety of silanesproceeds cleanly to produce six-membered ring products witha Z-configured vinyl silane moiety, as illustrated by theproduction of 27 (Scheme 15). With mixed terminal/internaldiyne substrates, the silyl unit was chemoselectively intro-duced at the terminal alkyne to give product 28, and yieldswith tethered internal alkynes were poor. Cyclizations ofunsymmetrical diynes with basic nitrogen atoms in the tetherchain proceeded with modest regioselectivity to affordproducts 29a and 29b (71:29).

Both inter- and intramolecular couplings involving silyl-boranes provide a useful entry to interesting 1-silyl-4-boryl-1,3-dienes (Scheme 16).[31] Intermolecular couplings are mod-erately selective, with regioisomers 30a and 30b beingproduced in a 3:1 ratio in couplings of 1-hexyne. A smallamount of product 31, derived from silylboration of a singlealkyne, was also obtained. Yields were best when a largeexcess (6 equiv) of alkyne was used. The correspondingintramolecular coupling of 1,7-octadiyne proceeded in 55%yield to generate product 32. Attempts to effect intermolec-ular cross-dimerizations were modestly successful, and for-

mation of the homodimeric products was difficult to suppress.Related “germaboration” couplings of 1-hexyne proceededsmoothly to generate dimeric products 33a and 33b, whereas

Scheme 14. Intermolecular coupling of an electron-deficient olefin witha strained olefin.

Scheme 15. Intramolecular coupling of 1,7-diynes with silanes.

Scheme 16. Inter and intramolecular coupling of alkynes with silylbor-anes. pin=pinacolyl.




Pd and Pt catalysts produced substantial amounts of thesimple germaborated product 34.

The authors proposed mechanisms that involve initialoxidative addition of the Si�H, Si�B, or Ge�B bond tonickel(0) to afford intermediates such as 35 (Scheme 17).[31]

Several different options were considered for the timing ofthe following insertions, but the proposal for the intermolec-ular silylborative couplings is representative. An initialinsertion of one alkyne into the Ni�B bond and the secondalkyne into the Ni�Si bond of 35 would afford the divinylnickel species 36. Direct reductive elimination of this specieswould afford the observed product 37. The analogousmechanism that involves insertion of the second alkyne intothe initially formed vinyl nickel species is deemed unlikely inintermolecular couplings on the basis of regiochemicalconsiderations. The authors also argue against the potentialinvolvement of metallacycles since there is little precedent forthe cleavage of a nickel metallacyclopentadiene with silanesor silylboranes. (Most metallacycle-based mechanistic pro-posals described herein involve metallacycles that bear aligand activated for displacement, such as an alkoxide orenolate, whereas the metallacyclopentadiene derived fromnickel(0) and two alkynes would likely have a much higheractivation barrier towards cleavage by a reducing agent.)

4.4. Coupling of Carbonyl Compounds or Imines with Alkynes

The coupling of aldehydes with alkynes has been exten-sively developed in both reductive and alkylative processes inour laboratory. Couplings of this type provide access tostructurally diverse and synthetically useful allylic alcohols.Alkylative couplings with organozinc reagents were estab-lished as both intra- (e.g., 38 and 39) and intermolecular (e.g.,40) processes (Scheme 18).[32] In a similar fashion to thatdescribed with enone/alkyne cyclizations, a strong liganddependence was noted (Scheme 19): [Ni(cod)2] alone cata-lyzes alkylative cyclizations effectively with a variety oforganozinc reagents to give product 41a, and [Ni(cod)2]/PBu3

catalyzes reductive cyclizations with diethylzinc to giveproduct 41b.

Although alkylative cyclizations could be accessed with avariety of organozinc reagents, undesired 1,2-addition to thealdehyde is problematic with alkenyl zinc reagents. To avoidthis limitation and to expand the scope of readily availablealkenyl units, we examined the addition of alkenyl zirconiumreagents in both intra- (e.g., 42) and intermolecular (e.g., 43)additions (Scheme 20).[15] Both processes proceed efficientlyand avoid many of the limitations derived from the highreactivity of alkenyl zinc reagents. However, a surprisingobservation in the intermolecular couplings is that a regio-

Scheme 17. Proposed mechanism for the intermolecular coupling ofalkynes with silylboranes.

Scheme 18. Intra and intermolecular alkylative alkyne–aldehyde cou-plings. TMS= trimethylsilyl, Ts=p-toluenesulfonyl.

Scheme 19. Ligand dependence of the intramolecular alkylative alkyne–aldehyde coupling.

Scheme 20. Intra and intermolecular addition of alkenyl zirconiumcomplexes to aldehydes and alkynes.


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chemical reversal of the mode of terminal alkyne insertionoccurs with alkenyl zirconium reagents compared with ourearlier observations with alkyl zinc reagents.

Recent developments from Mori and co-workers illus-trated that couplings employing CO2 instead of an aldehydedirectly provide trisubstituted acrylic acid derivatives(Scheme 21).[33] Although couplings involving CO2 were

restricted to the stoichiometric use of [Ni(cod)2], functional-ized organozinc reagents derived from active zinc insertion toalkyl and aryl halides were efficient participants in theprocess.

Although simple reductive cyclizations of aldehydes andalkynes were effective with diethylzinc, we noted two prob-lems with more complex substrates. First, selectivity betweenhydrogen-atom and ethyl-group incorporation eroded withsubstrate complexity. Second, as the cyclizations becomemore demanding, direct 1,2-addition of diethylzinc to thealdehyde became a significant problem. To avoid thesecomplexities, a very efficient procedure employing triethylsi-lane as the reducing agent and tributylphosphane as ligandwas developed (Scheme 22).[34] These simple changes avoid

the need for selectivity for H vs. ethyl incorporation, as ahydrogen atom is directly transferred, and undesired alde-hyde reduction does not occur. The scope of reductivecyclizations that proceed under this set of conditions is verybroad, and the process has been used in several applications incomplex molecule synthesis (Section 5.4).

Despite the efficiency of a broad range of cyclizations thatproceed with [Ni(cod)2]/PBu3/Et3SiH, the correspondingintermolecular process is not effective under these conditions.Jamison, however, found that using the same catalyst/ligandcombination, but changing the reducing agent to Et3B, allowsthe intermolecular process to proceed efficiently(Scheme 23).[35] A range of intermolecular couplings wasthus developed, and couplings of enynes were recently foundto be particularly regioselective.[32d,35d] Additionally, a veryattractive asymmetric variant employing a menthyl-basedmonodentate phosphane proceeded with excellent enantio-selectivities.[36]

The corresponding alkylative intermolecular couplings ofimines and alkynes was also developed by Jamison and Patel(Scheme 24).[37] Interestingly, a similar set of conditions that

led to reductive couplings with aldehydes predominantly ledto the alkylative manifold with imines, although methanol is arequired cosolvent in imine couplings. Aryl and alkenylboronic acids were used to prepare a broad range of 1,3 dienesand styrene derivatives.

The fundamental mechanistic theme that we originallysuggested for this set of transformations involves oxidativecoupling of an alkyne and aldehyde with nickel(0) to affordoxametallacycle 44, followed by a transmetallation/reductiveelimination sequence (Scheme 25).[32a] The initial oxidativecyclization is clearly promoted by the reducing agent. Thestructures of the ligand, substrate, and reducing agent all playa role in controlling the b-hydride elimination/reductiveelimination selectivity. Subsequent reports by our group andothers on related processes suggested the same fundamentalmechanism or similar variations. A number of issues have notbeen explained, including the regiochemical reversal ofalkyne insertions with organozinc reagents versus alkenylzirconium reagents, and the crossover from reductive toalkylative manifolds based on subtle changes in substratestructure, reducing agent, or reaction conditions. In additionto the oxidative cyclization mechanism depicted (Scheme 25),hydrometallation or silylation mechanisms may be operativein some instances. Indeed, it is very likely that the differentvariants of aldehyde/alkyne couplings proceed by differentmechanisms. In recent developments from our group, acrossover deuterium-labeling study unambiguously demon-strated that two fundamentally different mechanisms are

Scheme 21. Reductive coupling of alkynes and organozinc reagentswith CO2. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.

Scheme 22. Reductive intramolecular coupling of alkynes and carbonylgroups with triethylsilane as the reducing agent and tributylphosphaneas ligand.

Scheme 23. Top: reductive coupling of alkynes to aldehydes with Et3Bas the reducing agent and tributylphosphane as ligand; bottom: asym-metric variant with a menthylphosphane derivative as ligand.

Scheme 24. Alkylative intermolecular coupling of imines with alkynesand alkenyl boronic acids.




operative in reductive couplings of aldehydes and alkynesinvolving triethylsilane, and that the change in mechanism isligand-dependent. This insight is likely applicable to otherrelated processes described in this Review.[32d]

4.5. Couplings of Carbonyls with Dienes

The reductive coupling of aldehydes with 1,3-dienes,largely developed by Mori and co-workers and by Tamaru,Kimura, and co-workers has been one of the most thoroughlydeveloped reaction classes covered within this Review.Reactions of this type may proceed in either the 1,4 or 1,2sense to afford either homoallylic or bis-homoallylic alcohols(Scheme 26). A variety of reducing agents have beenemployed, with triethylsilane, triethylborane, diethylzinc, orDIBAL(acac) being most common.

Catalytic intramolecular variants developed by Mori andco-workers employ either triethylsilane or DIBAL(acac) asthe reducing agent, although earlier examples employedstoichiometric quantities of [Ni(acac)2] and DIBAL-H.[12,38]

Alternatively, cyclizations developed by Tamaru and co-workers involved either diethylzinc or triethylborane as thereducing agent.[39] In the studies by Mori and co-workers, theselectivity for formation of homoallylic alcohols 45 or bis-homoallylic alcohols 46 completely switches between experi-ments that employ triethylsilane and DIBAL(acac) as thereducing agent (Scheme 27). A broad range of cyclizations

was demonstrated, and related couplings involvingMe3SiSnBu3 were reported.[40] Further applications of theseprocesses in complex synthetic applications are described inSections 5.4 and 5.5. An attractive asymmetric version wasdeveloped with a chiral monodentate phosphane ligand(Scheme 28).[41]

A proposal was advanced by Mori and co-workers thattwo mechanisms are operative in reductive cyclizations ofdiene aldehydes to produce internal and terminal alkeneisomers 48 and 50 (Scheme 29).[12] With triethylsilane asreducing agent, the reaction is initiated by oxidative additionof nickel(0) to the silane. Hydrometallation of the diene givesp-allyl intermediate 47, and subsequent carbonyl insertionand O�Si reductive elimination affords internal alkene 48.Alternatively, with DIBAL(acac) as the reducing agent,oxidative cyclization to metallacycle 49 is followed by a

Scheme 26. Reductive coupling of aldehydes with 1,3-dienes.

Scheme 27. Selective intramolecular coupling of aldehydes with 1,3-dienes: The selectivity of the reaction depends on the reducing agent.

Scheme 28. Asymmetric variant of the intramolecular coupling of alde-hydes with 1,3-dienes.

Scheme 29. Different mechanisms for the reductive cyclization ofdiene aldehydes lead to internal or terminal alkenes.

Scheme 25. Proposed mechanism for alkyne–aldehyde coupling with anickel(0) complex.


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transmetallation/reductive elimination sequence to affordterminal alkene product 50.

It was proposed that the metallacycle mechanism wasprobably not operative in the formation of internal alkeneproduct 48, largely on the basis that treatment of a diene/aldehyde substrate with stoichiometric amounts of [Ni(cod)2]did not generate substantial quantities of cyclized product.However, the catalytic generation of a reactive equilibriumquantity of a metallacycle or the promotion of metallacycleformation by the reducing agent (triethylsilane) are both fullyconsistent with this observation. Given that ligand substitu-tions and other modifications of reaction conditions areknown to alter regioselectivities substantially in reductiveeliminations of metal–allyl complexes,[42] a unified mechanisminvolving reductive elimination from either allyl terminus ofp-allyl 51 (derived from metallacycle 49) is an alternative thatshould be considered (Scheme 30). However, in the studies of

asymmetric catalysis described above (Scheme 28), the inter-nal and terminal alkene isomers of an asymmetric dienalcyclization were obtained with different ee values, thusproviding evidence that a common intermediate after theenantioselectivity-determining step is likely not involved.Additional mechanisms analogous to those recently proposedin ynal cyclizations are also possible.[32d]

Tamaru, Kimura and co-workers developed the intermo-lecular version of this process through the use of triethylbor-ane and diethylzinc as reducing agents (Scheme 31).[43] Thescope of both variants is broad, and of particular interest isthat triethylborane-mediated couplings work best for cou-plings of aromatic and unsaturated aldehydes, as demon-strated in the production of 52 and 53, whereas diethylzinc-promoted couplings work best for aliphatic aldehydes andketones, as shown by the synthesis of 54. These studiesprovided the first clear illustration of the complementarybehavior of these two reducing agents. The process worksvery nicely for solving problems in 1,2- and 1,3-acyclicstereocontrol, as the examples illustrate. Remarkably, theprocess was illustrated to be effective in water and alcohols,thus allowing aqueous solutions of glutaraldehyde and cyclichemiacetals to participate in the couplings, as illustrated bythe production of 55 (Scheme 31).[44] The mechanism pro-posed for this class of reactions involves metallacycleformation and transmetallation of Et3B, followed by ab-hydride elimination/reductive elimination sequence(Scheme 32). Related intermolecular procedures were devel-oped by Mori and co-workers[45] and Loh et al.[46]

The corresponding alkylative cyclizations and couplingsof carbonyls and dienes have been less well-developed

(Scheme 33).[47, 48] Several transmetallating agents that lackb-hydrogen atoms (e.g., dimethylzinc and diphenylzinc) areeffective participants in catalytic reactions, as demonstratedin the production of 56, and Grignard reagents are partici-pants in stoichiometric reactions in which metallacycle 57 ispreformed prior to the introduction of the reducing agent, asillustrated in the formation of 58a and 58b.

Scheme 30. Proposed mechanism for the reductive eliminationthrough a common intermediate.

Scheme 31. Intermolecular diene–aldehyde coupling with triethylboraneor diethylzinc.

Scheme 32. Proposed mechanism for the intermolecular diene–alde-hyde coupling with triethylborane.

Scheme 33. Examples of alkylative cyclizations and coupling reactionsof carbonyl compounds with dienes.




Surprisingly, attempts by Mori and co-workers to developthe analogous stoichiometric procedure with CO2 in place ofthe aldehyde component led to the discovery of a doublecarboxylation of dienes (Scheme 34).[49] Treatment of a diene

and CO2 in the presence of [Ni(cod)2] and DBU afforded asolution of metallacycles 59a and 59b, and the subsequentaddition of acid affords carboxylic acids 60a and 60b.However, treatment of 59a and 59b with dimethylzinc ledto the incorporation of a second equivalent of CO2 to affordproduct 61. Although the mechanism of this latter process isunclear, it was shown that the 2 equivalents of CO2 add in ananti sense across cyclic dienes.

4.6. Coupling of Alkenes or Carbonyl Compounds with Allenes

Alkylative coupling reactions of allenes with eitheraldehydes or electron-deficient alkenes have been developedas an approach to prepare homoallylic alcohols 62 and d,e-unsaturated carbonyl compounds 63 (Scheme 35). A metal-lacycle-based mechanism involving intermediates 64a and64b was proposed for these processes in direct analogy to theproposals made in the corresponding enone/alkyne andaldehyde/alkyne couplings (Sections 4.1 and 4.4). Theseprocesses were first reported by our group in the totalsyntheses of kainic acid (Section 5.1)[50] and testudinariol A(Section 5.6),[51] and more extensive methodology studies of

the allene/aldehyde cyclization process were concurrentlydeveloped by Kang and Yoon[52] and by us.[53]

It was demonstrated that both aldehydes and ketonesparticipate in the cyclization process as do monosubstitutedand 1,3-disubstituted allenes (Scheme 36). In most cases, thesubstituted cyclopentane rings were formed with high cisselectivities, and good selectivities in favor of the Z alkenewere typically observed.

4.7. Coupling of Aldehydes with Epoxides

Avery recent development by Jamison and Molinaro wasthe inter- and intramolecular reductive coupling of epoxidesand alkynes with triethylborane as the reducing agent(Scheme 37).[54] Intermolecular coupling, as illustrated by

the production of 65, is effective with internal alkynes, withmost examples involving aryl alkynes or enynes. A variety ofcyclizations to form five- and six-membered rings wereobserved. All examples involved monosubstituted epoxides,and addition always occurred at the unsubstituted epoxideposition (e.g., !67).

The regioselectivity of the addition to the unsubstitutedposition of the epoxide in intramolecular versions hasinteresting mechanistic implications, as a metallacycle-basedmechanism would likely require addition at the substitutedposition. The mechanism thus likely falls within the classi-fication involving oxidative addition to one of the reaction

Scheme 34. Diene–CO2 coupling with double carboxylation.

Scheme 35. Syntheses of homoallylic alcohols and d,e-unsaturated car-bonyl compounds through alkylative coupling of allenes with aldehydesor alkenes.

Scheme 36. Cyclization through coupling of aldehydes and ketoneswith monosubstituted and 1,3-disubstituted allene groups

Scheme 37. Examples of alkyne–epoxide coupling reactions


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components. As suggested by Jamison and Molinaro, directoxidative addition to the epoxide would afford a four-membered oxametallacycle 68 (Scheme 38). Alkyne inser-

tion, followed by reduction of the C�Ni bond by ethyl transferfrom boron to nickel, and then a b-hydride elimination/reductive elimination sequence would afford the observedproduct 67. The formulation of a mechanism that differs fromthat of most processes covered in this Review is reasonablebecause the epoxide opening involves the cleavage of a singlebond during the catalytic process, unlike the other reactionscovered herein.

4.8. Combinations and Domino Reactions

Whereas the previous sections largely focused on three-component couplings involving two p systems and a main-group organometallic reagent or metal hydride, severalprocesses have been developed that involve four or morecomponents through combinations of the previously reportedmethods.

In one example, our group recognized that strongsimilarities exist between the ynal cyclizations and alkynylenone cyclizations developed in our laboratories.[55] Thus, weexamined the reactivity of enals with the idea that both theC=C and C=Obonds could participate in sequential couplingsor cyclizations (Scheme 39). Coupling of an enal with analkyne and acetylenic stannane affords conjugated enynessuch as 69 and 71 with a tethered aldehyde, with the observedreaction taking place by addition to the C=C bond of the enal.Further treatment of the initial products 69 and 71 undersimilar conditions then results in cyclization of the aldehydeand alkyne units to afford products such as 70 and 72. In thesecond coupling event, organozinc reagents lead exclusivelyto the introduction of carbon substituents, whereas triethyl-borane leads exclusively to the introduction of a hydrogenatom. Fully intermolecular four-component couplings andpartially intramolecular variants are possible.

Tamaru and co-workers developed a one-pot combinationsequence involving a 1,3-diene, an alkyne, an organozincreagent, and an aldehyde (Scheme 40).[56] Impressive chemo-selectivity is illustrated in this process, which allows the rapidassembly of complex structures such as 74. It was proposedthat the diene, alkyne, and aldehyde form metallacycle 73prior to the transmetallation event.

Mori and Takimoto developed a different four-componentcoupling of two 1,3-dienes, CO2, and an organozinc reagent(Scheme 41).[57] The catalytic process allows densely function-alized ring systems such as 76 to be assembled in a

Scheme 38. Proposed mechanism for the alkyne–epoxide coupling.

Scheme 39. Sequential coupling and cyclization of an alkynyl enal withan acetylenic stannane.

Scheme 40. Chemoselective one-pot synthesis of 74.

Scheme 41. Example of a four-component reaction for the preparationof highly functionalized rings.




straightforward fashion from simple precursors. Avery recentreport describes asymmetric variants of this process.[57b] Arelated multicomponent coupling of two dienes, a silylchloride, and a Grignard reagent was developed by Kambeand co-workers to afford products such as 78 (Scheme 42).[58]

The mechanism of these processes likely involves theformation of metallacycle 75 or 77 by oxidative cyclizationof two dienes, followed by alkylation and transmetallation/reductive-elimination steps. Kambe and co-workers demon-strated that transmetallation likely precedes alkylation.

Ikeda et al. also developed a multicomponent couplingthat involves an enone, an alkyne, an alkene, ZnCl2, and Zndust as the reducing agent (Scheme 43).[59] This interesting

process was proposed to involve the formation of metalla-cycle 79, followed by ZnCl2-mediated metallacycle cleavage,5-exo and 3-exo cyclization, b-C�C cleavage, and b-hydrideelimination to afford product 80. The latter portion of thismechanism explains the stereochemistry reversal that wouldhave occurred if the process proceeded by a simpler 6-endo

pathway. A similar effect was elucidated by Negishi and co-workers in apparent 6-endo Heck cyclizations.[60]

5. Applications in the Synthesis of ComplexMolecules

As many of the methods described above constitute veryrecent developments, application of these methods in thesynthesis of complex molecules are just beginning to appear.In several examples below, the Ni-catalyzed process is criticalto the complete synthetic plan. The overall synthetic planswill only be described briefly, and the discussion that followswill focus on how a key nickel-catalyzed step is critical in theassembly of important structural features of the targetmolecules. Additionally, the reader is directed to the impor-tant advances that appeared since submission of thisReview.[35b,c]

5.1. Kainoid Amino Acids

The kainoid amino acids comprise a large class of naturalproducts ranging from the simplest members, kainic acid andallokainic acid, up to more complex members such asisodomoic acid G (Schemes 44–46). Through the use of

nickel-catalyzed unsaturated imide/alkyne and unsaturatedimide/allene cyclizations, our group recently completed thetotal syntheses of each of these three natural products. Kainicacid was prepared by the nickel-catalyzed cyclization of allene81 with dimethylzinc (Scheme 44).[50] This key cyclizationdirectly assembled the pyrrolidine nucleus and set the relativestereochemistry about the five-membered ring. The epimericstructure allokainic acid was prepared by the nickel-catalyzedcyclization of alkyne 82 with dimethylzinc, followed by a Tsujirearrangement to install the C4 stereocenter (Scheme 45).[14]

This complementary sequence allows allene cyclizations andalkyne cyclizations to provide a stereodivergent strategy forthe preparation of these two epimeric natural products.

Isodomoic acid G contains an exocyclic alkene at C4which is more structurally complex than the corresponding

Scheme 42. Example of a multicomponent coupling reaction with aGrignard reagent.

Scheme 43. Proposed mechanism for the multicomponent couplingreaction to form 80.

Scheme 44. Key step in the total synthesis of kainic acid.


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side chain of kainic and allokainic acids (Scheme 46). Thenickel-catalyzed cyclization of alkyne 85 with the vinylzirconium reagent 84 derived from alkyne 83 was used toprepare directly the isodomoic acid G core structure.[61]

Notably, the pyrrolidine unit, the C2/C3 relative stereochem-istry, and the complete densely functionalized 1,3-diene wereassembled in a single operation in a completely selectivefashion to allow an efficient total synthesis of this naturalproduct.

5.2. Indole Alkaloids

Geissoschizine, which has been isolated from a variety ofplant species, is an important biosynthetic precursor to a largenumber of polycyclic indole alkaloids. Through the use of anickel-catalyzed unsaturated imide/alkyne cyclization, ourgroup recently prepared the isogeissoschizoid skeleton(Scheme 47).[62] Cyclization of substrate 87, which was

prepared by ozonolysis and double reductive amination ofcyclopentene precursor 86, was cleanly effected in 84% yieldwith dimethylzinc and [Ni(cod)2] (10 mol%). A sequenceinvolving a Fischer indole synthesis proceeded with epimeri-zation to allow the preparation of the isogeissoschizineframework 88. This sequence allowed the construction ofthe alkaloid D-ring and the installation of the exocyclicethylidene in a single step.

5.3. Pentalenene Triquinanes

The angularly-fused triquinane unit is a common struc-tural motif in a variety of naturally occurring terpenes,including pentalenene, pentalenic acid, and deoxypentalenicacid. Through the use of a nickel-catalyzed bis-enonecyclization, our group prepared a triquinane structure bysequential reductive cyclization and Dieckmann condensa-tion (Scheme 48).[63] 1,2-Addition of an alkyllithium to

dimethylcyclopentenone, followed by oxidative transpositionwith pyridinium chlorochromate allowed efficient prepara-tion of cyclization substrate 89. Treatment of 89 with ZnEt2/ZnCl2 and [Ni(cod)2] (10 mol%) afforded triquinane 90 in56% yield as a mixture of epimers. Compound 90, which wasthus prepared in only five steps from dimethylcyclopente-none, had previously been converted into each of thetriquinane natural products noted above.[64]

Scheme 45. Key step in the total synthesis of allokainic acid.

Scheme 46. Key step in the total synthesis of isodomoic acid G.TIPS= triisopropylsilyl.

Scheme 47. Construction of the framework of isogeissoschizine.

Scheme 48. Triquinane synthesis through nickel-catalyzed bis-enonecyclization.




5.4. Indolizidine Alkaloids

The indolizidine skeleton is present in a diverse range ofalkaloids. Through the use of a nickel-catalyzed ynal cycliza-tion, our group completed the total syntheses of threemembers of the pumiliotoxin family.[34] In a representativeexample, (+)-allopumiliotoxin 339A was prepared fromstructurally complex ynal 91, which was assembled fromproline and threonine (Scheme 49). Cyclization of ynal 91

with triethylsilane and a catalytic quantity of [Ni(cod)2]/PBu3

proceeded in a remarkably efficient manner, furnishingbicycle 92 as a single diastereomer in 93%. This single stepassembles the six-membered ring of the indolizidine core,controls the relative stereochemistry adjacent to a quaternarycenter, and assembles the alkylidene unit, with each of these

features being controlled in a completely selective manner.Simple deprotection of the nickel-mediated cyclization prod-uct allowed completion of the synthesis.

The indolizidine alkaloid (�)-elaeokanine C was pre-pared by Mori and co-workers through a nickel-catalyzedaldehyde–diene cyclization (Scheme 50).[65] Cyclization pre-cursor 94, which was prepared from compound 93, wastreated with triethylsilane and catalytic quantities of[Ni(cod)2]/PPh3. Although a nearly 1:1 ratio of diastereomerswas obtained, the undesired isomer 95b was recycled by aMitsunobu reaction to 95a, which was then converted into anadvanced intermediate, thus completing the formal synthesisof elaeokanine C.

5.5. Prostaglandins

The prostaglandins comprise a very large class of naturalproducts with diverse biological activities. Through the use ofa nickel-catalyzed aldehyde/diene cyclization, Mori and co-workers synthesized a representative member of this class ofnatural products, prostaglandin F2a (Scheme 51).[66] Substrate

97 was efficiently prepared by a sequence involving theaddition of vinylmagnesium bromide to enantioenrichedepoxide 96. Treatment of 97 with DIBAL(acac), catalytic[Ni(cod)2]/PPh3, and 1,3-cyclohexadiene (as a critical additiveto control the position and stereochemistry of the desiredZ alkene) resulted in the selective formation of product 98,with complete control of the contiguous stereocenters andalkene stereochemistry. Compound 98 was then convertedinto prostaglandin F2a in a straightforward fashion to com-plete a very attractive synthesis of this natural product.

5.6. Testudinariol A

Testudinariol A is a member of a small family of C2-symmetric natural products with an internal butylene core.Through the use of a nickel-catalyzed aldehyde/allenecyclization, our group recently completed an asymmetrictotal synthesis of this natural product (Scheme 52).[51] The

Scheme 49. Total synthesis of (+)-allopumiliotoxin 339A. SEM= trime-thylsilylethoxymethyl.

Scheme 50. Total synthesis of (�)-elaeokanine C through nickel-cata-lyzed aldehyde–diene cyclization.

Scheme 51. Total synthesis of prostaglandin F2a (PGF2) through alde-hyde–diene cyclization.


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synthesis began with an Abiko–Masamune asymmetric antialdol reaction to assemble compound 99, which was convertedinto cyclization precursor 100. Treatment of 100 with dime-thylzinc and catalytic [Ni(cod)2]/PBu3, with Ti(OiPr)4 as acoadditive, resulted in the selective production of 101 as asingle diastereomer in 62% yield. Conversion of 101 into 102followed by a two-directional oxocarbenium ion cyclizationresulted in a very direct and efficient synthesis of (+)-testudinariol A. Notably, the nickel-catalyzed cyclizationallowed the stereoselective introduction of four contiguousstereocenters and directly assembled the requisite function-ality needed to complete the synthesis.

6. Summary and Outlook

Over the past decade, nickel-catalyzed reductive cycliza-tions and couplings have evolved into a broadly usefulstrategy for assembling synthetically versatile substructuresas well as complex molecules. The three-component nature ofthe processes lends itself very well to the rapid generation ofmolecular complexity from simple p components and main-group organometallic reagents. Although many differentclasses of reaction components have been demonstrated toparticipate in the processes, new variants are rapidly beingdiscovered, and that trend will likely continue for some time.Furthermore, useful asymmetric versions are just beginning toemerge. Many complex mechanistic questions surroundingthese processes exist, and future work will likely clarify manyof these questions. The complexity of problems that will beaddressed by these methods, as well as the frequency withwhich these methods are utilized, will also undoubtedlycontinue to increase. Nickel maintains a unique place among

the transition metals in terms of reactivity trends, functional-group tolerance, and catalytic activity. The reductive cycliza-tions and couplings described in this Review provide a clearillustration of this unique position.

I thank the National Institutes of Health, National ScienceFoundation, Petroleum Research Fund, Arthur C. CopeFoundation, Camille and Henry Dreyfus Foundation, Johnsonand Johnson, Pfizer, and 3M Pharmaceuticals for support ofour research in the area of developing nickel-catalyzedreactions.

Received: September 9, 2003 [A634]Published Online: June 17, 2004

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Scheme 52. Asymmetric total synthesis of testudinariol A throughnickel-catalyzed aldehyde–allene cyclization. Mes=2,4,6-trimethyl-phenyl, MEM=methoxyethoxymethyl.




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Nickel-Catalyzed Reductive Cyclizations and Couplings