REVIEW SUMMARY◥

ORGANIC CHEMISTRY

Transition metal–catalyzed alkyl-alkylbond formation: Another dimensionin cross-coupling chemistryJunwon Choi and Gregory C. Fu*

BACKGROUND: The development of usefulnew methods for the construction of carbon-carbon bonds has had an impact on the manyscientific disciplines (including materials sci-ence, biology, and chemistry) that use organiccompounds. Tremendous progress has beenmade in the past several decades in the creationof bonds between sp2-hybridizedcarbons (e.g., aryl-aryl bonds), partic-ularly through the use of transitionmetal catalysis. In contrast, untilrecently, advances in the develop-ment of general methods that formbonds between sp3-hybridized car-bons (alkyl-alkyl bonds) had beenrather limited. A variety of approach-es, such as classical SN2 reactionsand transition metal catalysis, typ-ically led to side reactions ratherthan thedesiredcarbon-carbonbondformation.With transitionmetal ca-talysis, theunwantedbutoften facileb-hydride elimination of alkylmetalcomplexes presented a key imped-iment to efficient cross-coupling ofalkyl electrophiles.In the case of many alkyl-alkyl

bonds, there is an additional chal-lenge beyond construction of thecarbon-carbon bond itself: control-ling the stereochemistry at one orboth carbons of the new bond. Itis important to control the stereo-chemistry of organic molecules be-cause of its influence on propertiessuch as biological activity.Each of these two challenges is

difficult to solve individually; ad-dressing them simultaneously iseven more demanding. Until re-cently, the methods for achievingalkyl-alkyl bond formation werecomparatively limited in scope, typ-ically involving the use of unhin-dered (e.g., primary) electrophilesand unhindered, highly reactive

nucleophiles (e.g., Grignard reagents, whichhave relatively poor functional group compat-ibility). With respect to enantioconvergentreactions, there were virtually no examples.

ADVANCES: In recent years, it has been estab-lished that, through the action of an appropri-

ate transition metal catalyst, it is possible toachieve a broad range of alkyl-alkyl bond-forming processes; nickel-based catalysts haveproved to be especially effective. With respect

to the electrophilic cou-pling partner, a wide rangeof secondary alkyl halidesare now suitable. This hasenabled the developmentof enantioconvergent reac-tions of readily available

racemic secondary electrophiles. In view ofthe abundance of tertiary stereocenters in or-ganic molecules, this is a noteworthy advancein synthesis.With respect to the nucleophilic partner,

alkylboron and alkylzinc reagents (Suzuki- andNegishi-type reactions, respectively) can nowbe used in a wide variety of alkyl-alkyl coupl-ings, which greatly increases the utility of suchprocesses, as these nucleophiles are more read-ily available and havemuch improved functionalgroup compatibility relative to Grignard reagents.

These new methods for alkyl-alkylbond formation have been appliedto the synthesis of natural productsand other bioactive compounds.

OUTLOOK: A number of majorchallenges remain. For example, withregard to the electrophilic couplingpartner, there is a need to developgeneral methods that are effectivefor tertiary alkyl halides, includingenantioconvergent processes. Withregard to the nucleophilic partner,there is a need to discover more ver-satile catalysts that can use a widerange of hindered (e.g., secondaryand tertiary) alkylmetal reagents, aswell as to achieve a broad spectrumof enantioconvergent couplings of ra-cemic nucleophiles. These advancescan enable the doubly stereoconver-gent coupling of a racemic electro-phile with a racemic nucleophile.The synthesis of alkyl-alkyl bonds

is arguably the most important bondconstruction in organic synthesis. Theability to achieve this bond formationat will, as well as to control the prod-uct stereochemistry, would transformorganic synthesis and empower themany scientists who use organic mol-ecules. Recent work has provided evi-dence that transition metal catalysiscan address this exciting challenge.▪

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The list of author affiliations is available in the fullarticle online.*Corresponding author. Email: gcfu@caltech.eduCite this article as J. Choi, G. C. Fu, Science 356,eaaf7230 (2017). DOI: 10.1126/science.aaf7230

Alkyl-alkyl bond formation, including control of stereochemistry:an ongoing challenge in organic synthesis. From top to bottom: sp2-versus sp3-hybridized carbon-carbon bonds; a challenge for stereo-chemical control; and enantioconvergent reactions of racemic secondaryelectrophiles and racemic nucleophiles. X, leaving group; M, metal.

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REVIEW◥

ORGANIC CHEMISTRY

Transition metal–catalyzed alkyl-alkylbond formation: Another dimension incross-coupling chemistryJunwon Choi1 and Gregory C. Fu2*

Because the backbone of most organic molecules is composed primarily of carbon-carbonbonds, the development of efficient methods for their construction is one of the centralchallenges of organic synthesis.Transition metal–catalyzed cross-coupling reactionsbetween organic electrophiles and nucleophiles serve as particularly powerful tools forachieving carbon-carbon bond formation. Until recently, the vast majority of cross-couplingprocesses had used either aryl or alkenyl electrophiles as one of the coupling partners. In thepast 15 years, versatile new methods have been developed that effect cross-couplings of anarray of alkyl electrophiles, thereby greatly expanding the diversity of target molecules that arereadily accessible.The ability to couple alkyl electrophiles opens the door to a stereochemicaldimension—specifically, enantioconvergent couplings of racemic electrophiles—thatsubstantially enhances the already remarkable utility of cross-coupling processes.

The construction of carbon-carbon bonds iscentral to organic chemistry. During thepast several decades, a wide array of pow-erful newmethods for carbon-carbon bondformation have been developed, including

two transition metal–catalyzed processes thathave recently been recognized with Nobel Prizesin Chemistry [olefin metathesis in 2005 (1) andcross-coupling in 2010 (2)]. Such methods havean impact not only on synthetic organic chemistry,but also on the many other disciplines that in-volve organic compounds, including biology andmaterials science.Metal-catalyzed cross-coupling can provide a

particularly straightforward, modular approachto carbon-carbon bond formation through theunion of two coupling partners, an organic elec-trophile and an organometallic nucleophile, which

may be either commercially available or readilysynthesized (Fig. 1A) (2). Early studies of such pro-cesses were dominated by the use of palladiumcatalysts to accomplish couplings that generate abond between two sp2-hybridized carbons, andthesemethods have found application in industry(Fig. 1; R and R1 = aryl or alkenyl).Althoughmethods to construct carbon-carbon

bonds between sp2-hybridized carbons (e.g., “aryl-aryl” bonds) are exceptionally powerful tools inorganic synthesis, bonds between sp3-hybridizedcarbons (“alkyl-alkyl” bonds) are much morecommon. Figure 2A provides illustrative examplesof bioactive compounds that include a variety ofalkyl-alkyl bonds. The development of effectivecross-coupling catalysts that could generate suchbonds at will would have a substantial impact onthe retrosynthetic analysis (3) and, in turn, the

synthesis of a broad array of organic molecules.Until recent years, progress in addressing thischallenge had been limited; thus, Denmark andSweis observed in 2004 that, despite the perva-siveness of alkyl-alkyl bonds, “alkyl-alkyl cross-coupling reactions have historically been themostdifficult to realize” (4).Examination of the bioactive molecules de-

picted in Fig. 2A serves as a reminder that, inaddition to constructing the carbon-carbon bonditself, another challenge—controlling the stereo-chemistry at the carbon derived from the electro-phile (Fig. 2B)—can arise when an alkyl, ratherthan an aryl, electrophile is used as the cross-coupling partner; in the case of cross-couplingsthat generate biaryl compounds, the opportuni-ties for enantioselective catalysis are limited (5).Stereochemistry can, of course, play a key role indetermining properties such as biological activity(6), and selective control of product stereochemistryindependent of the stereochemistry of the startingmaterial (Fig. 2C) is advantageous.Here, we describe recent progress in addressing

these objectives, with a focus on initial break-throughs (new families of coupling partners andnew transitionmetal catalysts) in alkyl-alkyl cross-couplings of unactivated alkyl electrophiles (Box 1)(7–9); except as noted, we do not include reactionsof activated electrophiles that bear a p systemadjacent to the leaving group. In view of the im-portance of this objective, it is not surprising thata number of related strategies for metal-catalyzedalkyl-alkyl bond construction are now being pur-sued that build on the discoveries describedbelow, including reductive couplings (10, 11)and decarboxylative couplings (12, 13).

An impediment to alkyl-alkylcross-coupling: b-hydride elimination

As mentioned above, most early studies of cross-couplings used palladium catalysts and focused

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1Department of Chemistry, Stanford University, Stanford, CA94305, USA. 2Division of Chemistry and Chemical Engineering,California Institute of Technology, Pasadena, CA 91125, USA.*Corresponding author. Email: gcfu@caltech.edu

Fig. 1. Transition metal–catalyzed cross-coupling to form carbon-carbon bonds. (A) General scheme. (B) Application of a Suzuki cross-coupling toform a Csp2−Csp2 bond in an industrial synthesis of BASF’s agricultural fungicide Boscalid (>1000 tons/year).

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on reactions of aryl electrophiles (2). The typicalmechanism for such processes (Fig. 3A) involvesa sequence of oxidative addition of the organicelectrophile (R–X) to a Pd(0) complex (1) to gen-erate an organopalladium(II) complex (2), trans-metalation by the nucleophilic coupling partner(M–R1) to furnish a diorganopalladium(II) com-plex (3), and reductive elimination to form thecarbon-carbonbond (R–R1) and regenerate a Pd(0)complex (1) (2).Organopalladium(II) complex 2 is a key inter-

mediate in this catalytic cycle (Fig. 3A). Organo-metallic compounds that bear a hydrogen in theb position have the potential to undergo b-hydrideelimination, an intramolecular process that gen-erates a metal hydride (Fig. 3B). In the case ofarylpalladium(II) complexes, there is no precedentfor b-hydride elimination to form a palladium-aryne complex; correspondingly, cross-couplings

of aryl electrophiles are not diverted by this un-desired side reaction. In contrast, b-hydride elim-ination of an alkylpalladium(II) complex to

generate a palladium-alkene complex is a com-mon pathway, the efficiency of which is criticalfor important palladium-catalyzed processes such

Choi and Fu, Science 356, eaaf7230 (2017) 14 April 2017 2 of 8

Fig. 2. Stereochemistry as an added dimension in cross-coupling reactions of alkyl electrophiles. (A) Bioactive compounds that include an array of alkyl-alkyl bonds. (B) Aryl electrophiles (top) versus alkyl electrophiles (bottom). (C) Use of a chiral catalyst to control stereochemistry: enantioconvergent cross-couplings of racemic alkyl electrophiles. Me, methyl; ee, enantiomeric excess.

Fig. 3. Mechanisticdetails ofmetal-catalyzedcross-couplings, illustrated forpalladium. (A) An outline of a catalytic cycle. (B) b-Hydride elimination as a side reaction.

Box 1. Recent progress in transition metal–catalyzed alkyl-alkyl coupling.

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Fig. 4. Cross-couplings of primary alkyl electro-philes: Early (pre-2000) methods. (A) Examples.(B) An application in the total synthesis of a nat-ural product. (C) Use of nucleophiles with im-proved functional group compatibility. n-Hex, n-hexyl;THF, tetrahydrofuran; n-Pr, n-propyl; n-Bu, n-butyl;Tf, trifluoromethylsulfonyl; Et, ethyl; 9-BBN, 9-borabicyclo[3.3.1]nonane; Ph, phenyl; Ac, acetyl;acac, acetylacetonate; NMP, 1-methyl-2-pyrrolidone.

Fig. 5. Cross-couplings of primaryalkyl electrophiles:Recent (post-2000)methods that usealkylboron andalkylzinc reagentsas nucleophiles.(A) Examples withalkylboron reagents.(B) Applications ofalkylboron reagents inthe total synthesis ofnatural products.(C) Examples withalkylzinc reagents.(D) An application ofan alkylzinc reagent inthe total synthesisof a natural product.Cy, cyclohexyl; r.t.,room temperature;Ts, p-toluenesulfonyl;t-Bu, tert-butyl;DMF, N,N-dimethylformamide;i-Pr, isopropyl;xantphos, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;TBDPS, tert-butyldiphenylsilyl;TBS, tert-butyldimethylsilyl; dba,dibenzylideneacetone.

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as the Wacker (14) and Heck reactions (15). Theunwanted, but often facile, b-hydride eliminationof alkylmetal complexes presents a key impedimentto efficient cross-coupling of alkyl electrophiles.

Primary alkyl electrophiles

In early studies, primary alkyl electrophiles werecoupled with alkylmagnesium reagents (Grignardreagents) in the presence of transition metal cat-alysts such as copper (Fig. 4A) (16–19). Althoughsuchmethods have found application in the totalsynthesis of natural products (Fig. 4B) (20), Grignardreagents can be incompatible with many func-tional groups, such as carbonyl compounds, thatare commonly encountered in organic chemistry(21). More recently, palladium and nickel catalystshave achieved cross-couplings of primary alkylhalides with alkylboron and alkylzinc reagents(Fig. 4C) (22, 23), which have improved func-tional group compatibility (2).Since 2000, the scope ofmethods for the cross-

coupling of primary alkyl electrophiles with mildorganometallic nucleophiles has increased con-siderably. For example, palladium complexes that

bear a bulky, electron-rich phosphine have provedto be versatile catalysts (Fig. 5A) (24), enablingthe coupling of an array of alkyl electrophileswith alkylboron reagents; in contrast to theearlier palladium/PPh3-based method, which wasonly applied to primary alkyl iodides (Fig. 4C),palladium/trialkylphosphine catalysts are effec-tive for cross-couplings of alkyl bromides, chlorides,and tosylates. More recently, copper and ironcatalysts have proved useful for cross-couplingsof primary alkyl electrophiles with alkylboronreagents (Fig. 5A) (25, 26). The palladium-based method has been applied to late-stage frag-ment couplings in the total synthesis of naturalproducts such as (+)-spirolaxine methyl ether and(+)-pyranicin (Fig. 5B) (27–29).The use of a bulky, electron-rich ligand has

enabled palladium-catalyzed cross-couplings notonly of alkylboron reagents, but also of alkylzincreagents; this has opened the door to carbon-carbon bond formation with a wide range of pri-mary alkyl electrophiles, including iodides, bro-mides, chlorides, and tosylates (Fig. 5C) (30, 31).A subsequent report showed that copper can

catalyze alkyl-alkyl cross-couplings of primaryalkyl bromides with alkylzinc reagents (Fig. 5C)(32). These methods have found application inthe synthesis of bioactive compounds such asMaR1n–3 DPA (Fig. 5D) (33).Stereochemical studies of a palladium/

trialkylphosphine-catalyzedalkyl-alkylcouplingwereconsistent with an SN2 pathway for oxidative addi-tion under these conditions (34). This mechanismcanaccount for the inability of this catalyst to accom-plish alkyl-alkyl cross-couplings of secondary alkylelectrophiles.

Secondary alkyl electrophiles

As in the case of metal-catalyzed alkyl-alkyl cross-coupling reactions of primary alkyl electrophiles,early proof-of-principle studies showed that cou-plings of secondary alkyl electrophiles are indeedpossible (Fig. 6A) (35, 36). As with primary electro-philes (Fig. 4A), these early methods used reactiveGrignard reagents as the nucleophilic couplingpartner. Despite this limitation, such cross-couplings have found application in the total syn-thesis of natural products (Fig. 6B) (37).

Choi and Fu, Science 356, eaaf7230 (2017) 14 April 2017 4 of 8

Fig. 7. Cross-couplings of secondary alkyl electrophiles: Recent (post-2000) methods that use nucleophiles with improved functional group compat-ibility. (A) Alkylboron reagents. (B) Alkylzinc reagents. (C) An application in synthesis. TMEDA, N,N,N′,N′-tetramethylethylenediamine; glyme, 1,2-dimethoxyethane;i-Bu, isobutyl; pin, pinacolato;Cbz,carboxybenzyl; cod, 1,5-cyclooctadiene; s-Bu, sec-butyl; DMA,N,N-dimethylacetamide;Bn, benzyl;DMI, 1,3-dimethyl-2-imidazolidinone.

Fig. 6. Cross-couplings of secondary alkyl electrophiles: Early (pre-2000) methods. (A) Examples. (B) An application in the total synthesis of a naturalproduct. HMPA, hexamethylphosphoramide.

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More recently, the first methods for couplingsecondary alkyl electrophiles with mild organo-metallic nucleophiles (alkylboron and alkylzincreagents) have been described [Fig. 7A (26, 38, 39)and Fig. 7B (40)]. To date, nickel-based complexeshave proved to be the most versatile, enablingalkyl-alkyl couplings of a range of secondary alkylelectrophiles (iodides, bromides, and chlorides),although copper-catalyzed methods (limited toallylboron reagents) and iron-catalyzed methodshave also been reported. Nickel-catalyzed cross-couplings have been applied, for example, to the di-astereoselective synthesis of C-alkyl glycosides, animportant family of bioactivemolecules (Fig. 7C) (41).

Catalytic asymmetric carbon-carbonbond formationThe ability to use secondary electrophiles as part-ners opened the door to an additional dimensionin cross-coupling chemistry: catalytic enantio-selective carbon-carbon bond formation startingwith racemic alkyl electrophiles (Fig. 2C) (42). Pre-liminarymechanistic data indicated that the nickel-catalyzed cross-coupling methods described aboveproceed via the formation of a radical intermediatefrom the electrophile, which is ideal for an en-antioconvergent process (Fig. 8A). Thus, bothenantiomers of the electrophile could generatethe same secondary radical upon homolytic cleav-

age of the C–X bond, thereby ablating the originalstereochemistry and enabling a chiral catalyst toreact with the alkyl radical and transform bothenantiomers of the electrophile into a single en-antiomer of the product. Because catalytic asym-metric alkyl-alkyl cross-couplings are still in arelatively early stage of development [with theexception of allylic electrophiles (43)], we describecouplings not only of unactivated alkyl electrophiles,but also of several activated alkyl electrophiles.Activated racemic alkyl halides, specifically

a-bromoamides and benzylic halides, served asthe electrophilic partner in early examples ofcatalytic asymmetric alkyl-alkyl cross-coupling(Fig. 8B) (44–46). In the presence of a chiral nickelcatalyst, an array of alkylzinc reagents can be usedas the nucleophilic partner. These methods havefound application in the total synthesis of naturalproducts such as (–)-daphenylline (Fig. 8C) (47).Unactivated electrophiles can also serve as

useful partners in enantioconvergent alkyl-alkylcross-couplings. In this case, alkylboron reagentshave proved to be the nucleophiles of choice,coupling with an array of racemic alkyl halidesin good enantiomeric excess and yieldwith the aidof chiral nickel/diamine catalysts (Fig. 9) (48–52).For these methods, the presence of a directinggroup, which likely interacts with the chiral catalystin the stereochemistry-determining step of thecross-coupling, is essential forhighenantioselectivity.Enantioconvergent reactions of racemic elec-

trophiles are not the only opportunity in the fieldof catalytic asymmetric alkyl-alkyl cross-coupling.The umpolung (53) process (i.e., enantiocon-vergent couplings of racemic nucleophiles) isalso conceivable (Fig. 10A); such a reaction withan alkenyl halide has been reported (54). An ex-ample of such a process has recently been de-scribed, wherein a racemic alkylzinc reagent iscoupled with an array of alkyl halides (Fig. 10B)(55). This study sets the stage for addressing aninteresting new challenge: the doubly stereo-convergent cross-coupling of two racemic partners(electrophile and nucleophile) to generate eachof the four possible stereoisomeric productssimply through the appropriate choice of cat-alyst (Fig. 10C).

Tertiary alkyl electrophiles

Although quaternary carbons are less commonthan tertiary carbons, the development of alkyl-alkyl cross-couplings to generate such fully sub-stituted centers is nonetheless an importantobjective in organic synthesis. As in the case ofprimary and secondary alkyl electrophiles, theinitial advances in the use of tertiary electro-philes as coupling partners involved the use ofGrignard reagents as nucleophiles. For example,cobalt, silver, and copper complexes serve as ef-fective catalysts for such cross-couplings, but onlyin the case of allylmagnesium and benzylmag-nesium reagents (Fig. 11A) (56–58). More recently,silver-catalyzed couplings of tertiary alkyl bromideswith organozinc reagents have been described(Fig. 11B) (59), although these methods are alsolimited to allyl and benzyl nucleophiles, andthe mechanism of these processes has not been

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Fig. 8. Catalytic asymmetric carbon-carbon bond formation. (A) Enantioconvergent cross-couplingvia a radical intermediate. (B) Methods for activated electrophiles. (C) An application in the total synthesisof a natural product. diglyme, diethylene glycol dimethyl ether.

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elucidated. In contrast to alkyl-alkyl cross-couplingsof secondary electrophiles, general methods thatuse organozinc or organoboron nucleophileshave not yet been developed for couplings oftertiary electrophiles, nor have highly enantio-selective variants.

Outlook and conclusions

Because alkyl-alkyl bonds are commonplace in or-ganic molecules, the development of increasinglypowerful methods for their construction (and for

the control of any associated stereochemistry) fromreadily available coupling partnerswill have a sub-stantial impact on the many disciplines that makeuse of organic compounds. In the case of a syn-thesis of a particular target compound, the avail-ability of tools to reliably achieve alkyl-alkyl bondformation will provide versatile options for retro-synthetic analysis and, in turn, the synthesis of thedesired molecule.In recent years, diversity-oriented library syn-

thesis, which is focused on the efficient genera-

tion of families ofmolecules rather than a particularmolecule, has become an increasingly importanttool in science, especially in drug discovery (60, 61).This strategy depends on reliable reactions thatprovide ready access to diverse collections ofmolecules for compound libraries and for leadoptimization. Recently, medicinal chemists haveobserved that many current efforts in drug de-velopment may be biased toward compoundsthat have aromatic subunits, as a consequenceof the dependability of (and therefore the reliance

Choi and Fu, Science 356, eaaf7230 (2017) 14 April 2017 6 of 8

Fig. 9. Enantioconvergent cross-couplings of unactivated alkyl electrophiles, directed by the indicated functional groups.

Fig. 10. Enantioconvergent alkyl-alkyl cross-couplings. (A) Use of a racemic electrophile or a racemic nucleophile. (B) Enantioconvergent nickel-catalyzed coupling of a racemic alkylzinc reagent. (C) Doubly stereoconvergent coupling of a racemic electrophile and a racemic nucleophile. Boc, tert-butoxycarbonyl; de, diastereomeric excess.

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on) cross-coupling reactions of readily availablearyl electrophiles and nucleophiles (62). On theother hand, an analysis has suggested that ahigher percentage of sp3-hybridized (rather thansp2-hybridized) carbons, as well as a larger num-ber of stereogenic centers, can increase theprobability of clinical success for a compound(62, 63). Thus, the development of increasinglyversatile tools for alkyl-alkyl bond formation,including stereoselective processes, may facilitatean “escape from flatland” (62, 63). A number ofchallenges remain, including further expandingthe scope of coupling partners and of enantiose-lective processes.

REFERENCES AND NOTES

1. K. Grela, Ed., Olefin Metathesis: Theory and Practice(Wiley, 2014).

2. A. de Meijere, S. Bräse, M. Oestreich, Eds., Metal-CatalyzedCross-Coupling Reactions and More (Wiley-VCH, 2014).

3. E. J. Corey, X.-M. Cheng, The Logic of Chemical Synthesis(Wiley, 1995).

4. S. E. Denmark, R. F. Sweis, in Metal-CatalyzedCross-Coupling Reactions, A. de Meijere, F. Diederich, Eds.(Wiley-VCH, 2004), pp. 163–216.

5. P. Loxq, E. Manoury, R. Poli, E. Deydier, A. Labande,Synthesis of axially chiral biaryl compounds by asymmetriccatalytic reactions with transition metals. Coord. Chem. Rev.308, 131–190 (2016). doi: 10.1016/j.ccr.2015.07.006

6. G.-Q. Lin, Q.-D. You, J.-F. Cheng, Eds., Chiral Drugs: Chemistryand Biological Action (Wiley, 2011).

7. T. Iwasaki, N. Kambe, in Comprehensive Organic Synthesis,Vol. 3, P. Knochel, G. A. Molander, Eds. (Elsevier, 2014),pp. 337–391.

8. E. Geist, A. Kirschning, T. Schmidt, sp3-sp3 couplingreactions in the synthesis of natural products andbiologically active molecules. Nat. Prod. Rep. 31, 441–448(2014). doi: 10.1039/c3np70108e; pmid: 24573302

9. B. W. Glasspoole, C. M. Crudden, Cross-coupling: The finalfrontier. Nat. Chem. 3, 912–913 (2011). doi: 10.1038/nchem.1210; pmid: 22109267

10. X. Yu, T. Yang, S. Wang, H. Xu, H. Gong, Nickel-catalyzedreductive cross-coupling of unactivated alkyl halides.Org. Lett. 13, 2138–2141 (2011). doi: 10.1021/ol200617f;pmid: 21434609

11. J.-H. Liu et al., Copper-catalyzed reductive cross-coupling ofnonactivated alkyl tosylates and mesylates with alkyl andaryl bromides. Chem. Eur. J. 20, 15334–15338 (2014).doi: 10.1002/chem.201405223; pmid: 25308802

12. T. Qin et al., A general alkyl-alkyl cross-coupling enabledby redox-active esters and alkylzinc reagents. Science352, 801–805 (2016). doi: 10.1126/science.aaf6123;pmid: 27103669

13. C. P. Johnston, R. T. Smith, S. Allmendinger, D. W. C. MacMillan,Metallaphotoredox-catalysed sp3-sp3 cross-coupling ofcarboxylic acids with alkyl halides. Nature 536, 322–325(2016). doi: 10.1038/nature19056; pmid: 27535536

14. B. W. Michel, L. D. Steffens, M. S. Sigman, in OrganicReactions, Vol. 84, S. E. Denmark, Ed. (Wiley, 2014),pp. 75–413.

15. M. Oestreich, Ed., The Mizoroki-Heck Reaction (Wiley, 2009).16. M. Tamura, J. Kochi, Coupling of Grignard reagents

with organic halides. Synthesis 1971, 303–305 (1971).doi: 10.1055/s-1971-35043

17. J. G. Donkervoort, J. L. Vicario, J. T. B. H. Jastrzebski,G. Cahiez, G. van Koten, Novel organomanganese(II)complexes active as homogeneous catalysts in manganese(II)/copper(I) catalyzed carbon-carbon bond formationreactions. Recl. Trav. Chim. Pays Bas 115, 547–548 (1996).doi: 10.1002/recl.19961151117

18. P. L. Castle, D. A. Widdowson, New developments inpalladium catalysed cross coupling: The coupling of alkyliodides with alkyl Grignard reagents. Tetrahedron Lett. 27,6013–6016 (1986). doi: 10.1016/S0040-4039(00)85386-1

19. K. Yuan, W. J. Scott, A re-examination of the palladium-catalyzed cross coupling of alkyl iodides with alkyl Grignardreagents. Tetrahedron Lett. 30, 4779–4782 (1989).doi: 10.1016/S0040-4039(01)80506-2

20. C. Herber, B. Breit, Enantioselective total synthesis anddetermination of the absolute configuration of the4,6,8,10,16,18-hexamethyldocosane from Antitrogusparvulus. Angew. Chem. Int. Ed. 44, 5267–5269 (2005).doi: 10.1002/anie.200501612; pmid: 16035027

21. Z. Rappoport, I. Marek, Eds., The Chemistry ofOrganomagnesium Compounds (Wiley, 2008).

22. T. Ishiyama, S. Abe, N. Miyaura, A. Suzuki, Palladium-catalyzed alkyl-alkyl cross-coupling reaction of9-alkyl-9-BBN derivatives with iodoalkanes possessingb-hydrogens. Chem. Lett. 21, 691–694 (1992).doi: 10.1246/cl.1992.691

23. A. Devasagayaraj, T. Stüdemann, P. Knochel, A new nickel-catalyzed cross-coupling reaction between sp3 carboncenters. Angew. Chem. Int. Ed. Engl. 34, 2723–2725 (1995).doi: 10.1002/anie.199527231

24. M. R. Netherton, C. Dai, K. Neuschütz, G. C. Fu,Room-temperature alkyl-alkyl Suzuki cross-couplingof alkyl bromides that possess b hydrogens. J. Am. Chem.Soc. 123, 10099–10100 (2001). doi: 10.1021/ja011306o;pmid: 11592890

25. C.-T. Yang, Z.-Q. Zhang, Y.-C. Liu, L. Liu, Copper-catalyzedcross-coupling reaction of organoboron compoundswith primary alkyl halides and pseudohalides.

Angew. Chem. Int. Ed. 50, 3904–3907 (2011). doi: 10.1002/anie.201008007; pmid: 21455914

26. T. Hatakeyama et al., Iron-catalyzed alkyl-alkylSuzuki-Miyaura coupling. Angew. Chem. Int. Ed. 51,8834–8837 (2012). doi: 10.1002/anie.201202797;pmid: 22848024

27. K. A. Keaton, A. J. Phillips, A cyclopropanol-based strategyfor subunit coupling: Total synthesis of (+)-spirolaxinemethyl ether. Org. Lett. 9, 2717–2719 (2007). doi: 10.1021/ol0710111; pmid: 17559220

28. N. D. Griggs, A. J. Phillips, A concise and modular synthesisof pyranicin. Org. Lett. 10, 4955–4957 (2008). doi: 10.1021/ol802041c; pmid: 18844364

29. S. Das, S. Abraham, S. C. Sinha, Studies toward the totalsynthesis of sorangiolides and their analogues. Aconvergent stereoselective synthesis of the macrocycliclactone precursors. Org. Lett. 9, 2273–2276 (2007).doi: 10.1021/ol070517g; pmid: 17503834

30. J. Zhou, G. C. Fu, Palladium-catalyzed Negishicross-coupling reactions of unactivated alkyl iodides,bromides, chlorides, and tosylates. J. Am. Chem. Soc.125, 12527–12530 (2003). doi: 10.1021/ja0363258;pmid: 14531697

31. M. G. Organ et al., A user-friendly, all-purpose Pd-NHC(NHC=N-heterocyclic carbene) precatalyst for the Negishireaction: A step towards a universal cross-coupling catalyst.Chem. Eur. J. 12, 4749–4755 (2006). doi: 10.1002/chem.200600206; pmid: 16568493

32. E. Erdik, E. Z. Serdar, Reactivity of mixed organozincand mixed organocopper reagents: 5-A kinetic insight tocompare the transfer ability of the same group in coppercatalyzed alkylation of mixed and homozincates.J. Organomet. Chem. 703, 1–8 (2012). doi: 10.1016/j.jorganchem.2011.11.027

33. J. E. Tungen et al., Total synthesis of the anti-inflammatoryand pro-resolving lipid mediator MaR1n–3 DPA utilizing ansp3-sp3 Negishi cross-coupling reaction. Chem. Eur. J. 20,14575–14578 (2014). doi: 10.1002/chem.201404721;pmid: 25225129

34. M. R. Netherton, G. C. Fu, Suzuki cross-couplingsof alkyl tosylates that possess b hydrogenatoms: Synthetic and mechanistic studies. Angew. Chem.Int. Ed. 41, 3910–3912 (2002). doi: 10.1002/1521-3773(20021018)41:20<3910::AID-ANIE3910>3.0.CO;2-W;pmid: 12386889

35. D. H. Burns, J. D. Miller, H.-K. Chan, M. O. Delaney, Scopeand utility of a new soluble copper catalyst [CuBr–LiSPh–LiBr–THF]: A comparison with other copper catalysts intheir ability to couple one equivalent of a Grignard reagentwith an alkyl sulfonate. J. Am. Chem. Soc. 119, 2125–2133(1997). doi: 10.1021/ja963944q

36. J. G. Donkervoort et al., Novel tridentate diaminoorganomanganese(II) complexes as homogeneous catalystsin manganese(II)/copper(I) catalyzed carbon–carbonbond forming reactions. J. Organomet. Chem. 558, 61–69(1998). doi: 10.1016/S0022-328X(97)00675-X

37. S. Xu et al., Highly efficient, convergent, andenantioselective synthesis of phthioceranic acid. Angew.Chem. Int. Ed. 54, 9319–9322 (2015). doi: 10.1002/anie.201503818; pmid: 26088188

38. B. Saito, G. C. Fu, Alkyl-alkyl Suzuki cross-couplings ofunactivated secondary alkyl halides at room temperature.J. Am. Chem. Soc. 129, 9602–9603 (2007). doi: 10.1021/ja074008l; pmid: 17628067

39. G.-Z. Wang et al., Copper-catalyzed cross-coupling reactionof allyl boron ester with 1°/2°/3°-halogenated alkanes.Org. Lett. 17, 3682–3685 (2015). doi: 10.1021/acs.orglett.5b01612; pmid: 26181828

40. J. Zhou, G. C. Fu, Cross-couplings of unactivatedsecondary alkyl halides: Room-temperature nickel-catalyzedNegishi reactions of alkyl bromides and iodides. J. Am.Chem. Soc. 125, 14726–14727 (2003). doi: 10.1021/ja0389366; pmid: 14640646

41. H. Gong, R. Sinisi, M. R. Gagné, A room temperatureNegishi cross-coupling approach to C-alkyl glycosides.J. Am. Chem. Soc. 129, 1908–1909 (2007). doi: 10.1021/ja068950t; pmid: 17261000

42. F. Glorius, Asymmetric cross-coupling of non-activatedsecondary alkyl halides. Angew. Chem. Int. Ed. 47,8347–8349 (2008). doi: 10.1002/anie.200803509;pmid: 18814168

43. G. Helmchen, U. Kazmaier, S. Förster, in Catalytic AsymmetricSynthesis, I. Ojima, Ed. (Wiley, 2010), chapter 8B.

Choi and Fu, Science 356, eaaf7230 (2017) 14 April 2017 7 of 8

Fig. 11. Cross-couplings of tertiary alkyl electrophiles. (A) Early methods. (B) Recent method that usesa nucleophile with improved functional group compatibility. dppp, 1,3-bis(diphenylphosphino)propane.

RESEARCH | REVIEWon M

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http://science.sciencemag.org/

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44. C. Fischer, G. C. Fu, Asymmetric nickel-catalyzed Negishicross-couplings of secondary a-bromo amides withorganozinc reagents. J. Am. Chem. Soc. 127, 4594–4595(2005). doi: 10.1021/ja0506509; pmid: 15796523

45. F. O. Arp, G. C. Fu, Catalytic enantioselective Negishireactions of racemic secondary benzylic halides. J. Am.Chem. Soc. 127, 10482–10483 (2005). doi: 10.1021/ja053751f; pmid: 16045323

46. J. T. Binder, C. J. Cordier, G. C. Fu, Catalytic enantioselectivecross-couplings of secondary alkyl electrophiles withsecondary alkylmetal nucleophiles: Negishi reactions ofracemic benzylic bromides with achiral alkylzinc reagents.J. Am. Chem. Soc. 134, 17003–17006 (2012). doi: 10.1021/ja308460z; pmid: 23039358

47. R. Yamada, Y. Adachi, S. Yokoshima, T. Fukuyama,Total synthesis of (–)-daphenylline. Angew. Chem. Int. Ed.55, 6067–6070 (2016). doi: 10.1002/anie.201601958;pmid: 27062676

48. B. Saito, G. C. Fu, Enantioselective alkyl-alkyl Suzukicross-couplings of unactivated homobenzylic halides.J. Am. Chem. Soc. 130, 6694–6695 (2008). doi: 10.1021/ja8013677; pmid: 18447357

49. X. Jiang, M. Gandelman, Enantioselective Suzuki cross-couplings of unactivated 1-fluoro-1-haloalkanes: Synthesisof chiral b-, g-, d-, and e-fluoroalkanes. J. Am. Chem. Soc.137, 2542–2547 (2015). doi: 10.1021/jacs.5b00473;pmid: 25630234

50. N. A. Owston, G. C. Fu, Asymmetric alkyl-alkyl cross-couplings of unactivated secondary alkyl electrophiles:Stereoconvergent Suzuki reactions of racemic acylatedhalohydrins. J. Am. Chem. Soc. 132, 11908–11909 (2010).doi: 10.1021/ja105924f; pmid: 20701271

51. Z. Lu, A. Wilsily, G. C. Fu, Stereoconvergent amine-directedalkyl-alkyl Suzuki reactions of unactivated secondaryalkyl chlorides. J. Am. Chem. Soc. 133, 8154–8157 (2011).doi: 10.1021/ja203560q; pmid: 21553917

52. A. Wilsily, F. Tramutola, N. A. Owston, G. C. Fu, Newdirecting groups for metal-catalyzed asymmetric carbon-carbon bond-forming processes: Stereoconvergentalkyl-alkyl Suzuki cross-couplings of unactivatedelectrophiles. J. Am. Chem. Soc. 134, 5794–5797 (2012).doi: 10.1021/ja301612y; pmid: 22443409

53. D. Seebach, Methods of reactivity umpolung. Angew. Chem.Int. Ed. Engl. 18, 239–258 (1979). doi: 10.1002/anie.197902393

54. T. Hayashi, M. Tajika, K. Tamao, M. Kumada, Highstereoselectivity in asymmetric Grignard cross-couplingcatalyzed by nickel complexes of chiral(aminoalkylferrocenyl)phosphines. J. Am. Chem. Soc. 98,3718–3719 (1976). doi: 10.1021/ja00428a061

55. C. J. Cordier, R. J. Lundgren, G. C. Fu, Enantioconvergentcross-couplings of racemic alkylmetal reagents withunactivated secondary alkyl electrophiles: Catalyticasymmetric Negishi a-alkylations of N-Boc-pyrrolidine.J. Am. Chem. Soc. 135, 10946–10949 (2013). doi: 10.1021/ja4054114; pmid: 23869442

56. T. Tsuji, H. Yorimitsu, K. Oshima, Cobalt-catalyzed couplingreaction of alkyl halides with allylic Grignard reagents.Angew. Chem. Int. Ed. 41, 4137–4139 (2002). doi: 10.1002/1521-3773(20021104)41:21<4137::AID-ANIE4137>3.0.CO;2-0;pmid: 12412107

57. H. Someya, H. Ohmiya, H. Yorimitsu, K. Oshima, Silver-catalyzed benzylation and allylation reactions of tertiaryand secondary alkyl halides with Grignard reagents.

Org. Lett. 10, 969–971 (2008). doi: 10.1021/ol800038a;pmid: 18247499

58. M. Sai, H. Yorimitsu, K. Oshima, Copper-catalyzedallylation of alkyl halides with allylic Grignard reagents.Bull. Chem. Soc. Jpn. 82, 1194–1196 (2009). doi: 10.1246/bcsj.82.1194

59. Y. Mitamura et al., Silver-catalyzed benzylationand allylation of tertiary alkyl bromides withorganozinc reagents. Chem. Asian J. 5, 1487–1493 (2010).pmid: 20446338

60. S. L. Schreiber, Target-oriented and diversity-orientedorganic synthesis in drug discovery. Science 287,1964–1969 (2000). doi: 10.1126/science.287.5460.1964;pmid: 10720315

61. R. J. Bienstock, Ed., Library Design, Search Methods, andApplications of Fragment-Based Drug Design (AmericanChemical Society, 2011).

62. F. Lovering, J. Bikker, C. Humblet, Escape from Flatland:Increasing saturation as an approach to improving clinicalsuccess. J. Med. Chem. 52, 6752–6756 (2009).doi: 10.1021/jm901241e; pmid: 19827778

63. F. Lovering, Escape from Flatland 2: Complexity andpromiscuity. MedChemComm 4, 515–519 (2013).doi: 10.1039/c2md20347b

ACKNOWLEDGMENTS

Supported by National Institute of General Medical Sciences grantR01-GM62871.

10.1126/science.aaf7230

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chemistrycatalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling−Transition metal

Junwon Choi and Gregory C. Fu

DOI: 10.1126/science.aaf7230 (6334), eaaf7230.356Science 

, this issue p. eaaf7230Sciencetargeted products.a powerful method to access individual mirror-image isomers selectively and thereby tune the biological properties of thethat underlie diverse molecules with complex three-dimensional structures. Nickel catalysis in particular has emerged as carbons. Choi and Fu review recent developments in forming bonds between the more abundant alkyl carbon centersmolecules. This geometrical constraint is associated with the comparative ease of linking together aryl and alkenyl

Chemical reactions such as Heck and Suzuki coupling facilitate access to an enormous range of relatively flatStitching one alkyl group to another

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