ORGANIC CHEMISTRY

Enantiodivergent Pd-catalyzed C–Cbond formation enabled throughligand parameterizationShibin Zhao1,2*, Tobias Gensch3*, Benjamin Murray1,2, Zachary L. Niemeyer3,Matthew S. Sigman3†, Mark R. Biscoe1,2†

Despite the enormous potential for the use of stereospecific cross-couplingreactions to rationally manipulate the three-dimensional structure of organicmolecules, the factors that control the transfer of stereochemistry in thesereactions remain poorly understood. Here we report a mechanistic and syntheticinvestigation into the use of enantioenriched alkylboron nucleophiles instereospecific Pd-catalyzed Suzuki cross-coupling reactions. By developing a suiteof molecular descriptors of phosphine ligands, we could apply predictive statisticalmodels to select or design distinct ligands that respectively promoted stereoinvertiveand stereoretentive cross-coupling reactions. Stereodefined branched structureswere thereby accessed through the predictable manipulation of absolutestereochemistry, and a general model for the mechanism of alkylborontransmetallation was proposed.

Palladium-catalyzed cross-coupling reactionshave revolutionized the construction ofC(sp2)–C(sp2) bonds. Among these cross-coupling processes, the Suzuki-Miyaurareaction has found particularly broad ap-

plication owing to its extensive reaction scope, aswell as the stability, availability, and low toxicityof organoboron reagents (1). The 2010Nobel Prizein chemistry was awarded, in part, to recognizethe transformative impact of the Suzuki cross-coupling reaction on chemical synthesis. How-ever, although C(sp2)–C(sp2) bond constructionis now considered routine using the Suzuki re-action, extension of this process to the forma-tion of C(sp3)–C(sp2) bonds using alkylboronnucleophiles remains a considerable challenge.Of particular interest, a variant using secondaryalkylboron nucleophiles with predictable and

controllable stereospecificity would establish apowerful synthetic strategy to access moleculargeometries with precise three-dimensional con-trol, expanding the exceptional capabilities of theSuzuki reaction (Fig. 1A).Many efforts have focused on the use of en-

antioenriched secondary alkylboron nucleophilesin Suzuki cross-coupling reactions (2–4). Con-siderable limitations remain because of slowtransmetallation of the highly covalent andsterically congested C(sp3)–B bond in these re-agents, as well as the propensity of the resultingPd-alkyl species to undergo b-hydride elimination-reinsertion sequences, which can result in isom-erization of the alkyl group and racemizationof the stereocenter. To circumvent prohibitivelyslow transmetallation, as well as competingb-hydride elimination-reinsertion pathways, most

stereospecific Suzuki reactions have required theuse of secondary alkylboron nucleophiles thatare electronically activated via inclusion of aC(sp2) a-carbon, an a-heteroatom, and/or astrongly coordinating b-carbonyl group (5–17).In addition, alkylboron nucleophiles can undergotransmetallation via either stereoretentive orstereoinvertive pathways depending on thenatureof the substrate, catalyst, and/or reaction con-ditions. Inmany cases, the factors controlling thedominant mechanism of transmetallation are notunderstood (Fig. 1B). Thus, a predictive stereo-chemical model for transmetallation of alkylboronreagents remains elusive.Recently, we reported a stereospecific Pd-

catalyzed cross-coupling reaction using unacti-vated secondary alkylboron nucleophiles (18).With PtBu3 (

tBu, tert-butyl) as a supporting lig-and, enantioenriched arylation products wereobtained with transmetallation proceeding pri-marily via a stereoinvertivemechanism.Whereasseveral enlightening mechanistic studies haverecently been conducted on the transmetallationof arylboron nucleophiles (19–23), these studieshave not addressed the transmetallation ofalkylboron nucleophiles in C(sp3)–C(sp2) bond-forming processes (24, 25). Thus, unactivatedalkylboron nucleophiles constitute an attractivestarting point from which to investigate thereaction parameters most influential to the mech-anism of alkylboron transmetallation. Thismech-anistic work should simultaneously facilitate thedevelopment of new synthetic methods to ratio-nally incorporate or manipulate stereocenters viacross-coupling strategies. To this end, we report astudy using predictive statistical models (26, 27)

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1Department of Chemistry, The City College of New York,160 Convent Avenue, New York, NY 10031, USA. 2Ph.D.Program in Chemistry, The Graduate Center of the CityUniversity of New York, 365 Fifth Avenue, New York, NY10016, USA. 3Department of Chemistry, University of Utah,315 South 1400 East, Salt Lake City, UT 84112, USA.*These authors contributed equally to this work.†Corresponding author. Email: sigman@chem.utah.edu (M.S.S.);mbiscoe@ccny.cuny.edu (M.R.B.)

Fig. 1. Reaction development. (A) Enantiodivergent Suzukireactions of secondary alkylboron nucleophiles. (B) Generalmechanism. (C) Initial investigation of substrate and ligandinfluences on stereoselectivity. A positive % ee value indicates

net retention; a negative % ee value indicates net inversion.* indicates an enantioenriched stereocenter. L, ligand;Tf, trifluoromethanesulfonyl; Ar, aryl; Et, ethyl; Me, methyl;Ms, methylsulfonyl; o-tol, ortho-tolyl.

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to relate phosphine ligand properties to stereo-chemical outcomes obtained from Pd-catalyzedSuzuki reactions of unactivated enantioenrichedsecondary alkylboron nucleophiles and aryl elec-trophiles. With statistical models that rely on anext-generation set of molecular descriptors,we achieved a stereoretentive Pd-catalyzed cross-coupling reaction of such nucleophiles. Further-more, we have identified an improved ligand forthe stereoinvertive variant, thus enabling anentirely ligand-controlled enantiodivergent pro-cess from a single-enantiomer organoboron nu-cleophile (28). Our statisticalmodels also providecompelling evidence that each transmetallationpathway is intimately tied to specific electronicproperties of the supporting ligand, which servesas a predictive guide to the mechanism of alkyl-boron transmetallation to palladium.

Initial investigations using electronically dif-ferentiated aryl chlorides with enantioenrichedsBuBF3K (sBu, sec-butyl) revealed a trend corre-lating diminished stereofidelity with the use ofmore electron-deficient coupling partners (sec-tion I of Fig. 1C). This observation suggestedthat subtle electronic effects could influence themechanism of transmetallation and the result-ing stereochemical outcome. Additionally, whenthe phosphine ligand was varied in an initialscreenwith a common aryl chloride electrophile,a considerable change in the reaction outcomefrom stereoinvertion to stereoretention wasfound (section II of Fig. 1C). No obvious corre-lation was observed between these results andthe steric properties (solid angle) of the ligand.Taken together, these outcomes were difficultto interpret and inspired the use of ligand param-

eterization tools to provide a platform for bothpredictive ligand performance and mechanisticinterrogation.An expanded inventory of commonphosphines

with varied properties was evaluated in theSuzuki reaction of enantioenriched sBuBF3K andethyl 4-chlorobenzoate. This dataset was thensubjected to correlation analysis of phosphinestructural features with the stereochemical out-comes as well as the ratios of branched:linearproducts in these reactions. We devised a work-flow and universal parameter set to describethe catalyst properties from the phosphine it-self (29–32). The workflow was initiated byperforming a molecular mechanics (MM) con-formational search to reveal representative low-energy conformers (Fig. 2A). Next, geometryoptimization of the conformers using density

Zhao et al., Science 362, 670–674 (2018) 9 November 2018 2 of 5

Fig. 2. Phosphine parameterization. (A) Workflow of parametergeneration and statistical modeling. DDG‡, relative free energy ofactivation; f(xi), function of parameter xi. (B) Application ofphosphine parameterization to ligand optimization of the reaction

shown in Fig. 1C with Z = CO2Et. b:l = branched-to-linear ratio.A positive % ee value indicates net retention; a negative % eevalue indicates net inversion. es, enantiospecificity; R2, coefficientof determination.

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functional theory (DFT) was followed by pa-rameter collection. Subsequently, four descriptorsubsets were defined to capture the conforma-tional dynamics of the ligands by includingthe mathematical extreme descriptor values

(minimum and maximum), the lowest-energy-conformer values, and the Boltzmann weightedaverages. We viewed the specific treatment ofrepresentative conformers as a crucial means ofdescribing ensemble properties such as chemical

shift while also probing structural flexibility duringcatalysis.The final step in the workflow involved the

analysis of both the stereofidelity and thebranched:linear product ratio. These two readouts

Zhao et al., Science 362, 670–674 (2018) 9 November 2018 3 of 5

Fig. 3. Stereodivergent Pd-catalyzed cross-coupling reactions usingenantioenriched alkylboron nucleophiles.The general reactionscheme is shown at the top. (A to C) Isolated yields are shown forstereoretentive and stereoinvertive cross-coupling reactions (A), diastereo-

selective cross-coupling reactions (B), and additional individual reac-tions (C). iPr, isopropyl; dr, diastereomeric ratio. % es = % ee (finalproduct) divided by % ee (starting material). †44% yield and 84% ee(86% es) when run at 60°C.

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presumably describe two stages of the reactionmechanism (Fig. 1B): (i) the competing stereo-retentive and stereoinvertive transmetallationmechanisms that determine the final stereo-chemistry of the cross-coupling product and (ii) thecompetitive b-hydride elimination-isomerizationsequences that follow transmetallation.A correlationof the branched:linear ratio with the final en-antiopurity of the product reveals that b-hydrideelimination is responsible for both racemizationand isomerization to the linear side product.Furthermore, amodest trend is observed relatingthe minimum width B1 of the phosphine ligandto the branched:linear ratio (Fig. 2B). This is con-sistent with reports of large ligands facilitatingreductive elimination over b-hydride elimination(33) and suggests the use of a parameterizationapproach to take into account the conformationalflexibility of ligands.Because the inherent selectivity of the trans-

metallationmechanism is masked by deleteriousracemization as a consequence of b-hydrideelimination, only ligands providing high selec-tivity were further investigated [>30% enanti-omeric excess (ee), Fig. 2B]. The molecularelectrostatic potential minimum in the phos-phorus lone pair region (Vmin) has been shownto correlate with the classical Tolman electronicparameter (34). Thus, Vmin serves as an easilycomputable measure for the overall ligand elec-tronics. A correlation between enantioselectiv-ity and Vmin was observed within the abridgeddataset, indicating that electronic properties ofthe ligand determine the mechanism of trans-

metallation. Specifically, electron-rich trialkyl-phosphines promoted stereoinvertive reactions,whereas the electron-poorer triarylphosphinesprovided modest selectivity for stereoretention.Use of the bulky, electron-rich ligand PAd3 (Ad,adamantyl) (9), which was recently reported byCarrow and co-workers (35), resulted in a par-ticularly large preference for the stereoinvertiveoutcome. Based on these data, we hypothesizedand virtually evaluated ligands for improvedstereoretentive outcomes with the followingfeatures: (i) large ligand bulk to prevent b-hydrideelimination and racemization and (ii) electron-deficient aryl substituents at phosphorus topromote the stereoretentive mechanism andto accelerate reductive elimination (Fig. 2B).Among the proposed ligands was a set of biarylphosphines (11 to 15), as pioneered by Buchwaldand colleagues (36), featuring various electron-deficient aryl groups at phosphorus. Gratifyingly,ligands 11 and 14 promote the alkyl Suzukicross-coupling reaction with considerably en-hanced selectivity (up to 90% ee) and minimalalkyl isomerization. Thus, parameterization-drivenoptimization facilitated development of a stereo-retentive Suzuki reaction involving unactivatedalkylboron nucleophiles. When considered along-side the introduction of 9 to achieve stereo-invertive couplings, predictable control of theabsolute sense of enantioselectivity (retentionor inversion) can be engendered by simply se-lecting the appropriate ligand.Our stereochemical investigations of secondary

alkylboron transmetallation in the Suzuki reac-

tion suggested that both enantiomers of a cross-coupling product could be selectively accessedthrough use of a single enantioenriched alkyl-boron reagent with the proper selection of thephosphine ligand. The scope of this process isdepicted in Fig. 3. Using enantioenriched, un-activated alkyltrifluoroborate nucleophiles,ligand-controlled stereoselectivity was broadlyachieved in cross-coupling reactions with arylelectrophiles. Strongly p-accepting ligands bis-CF3PhSPhos (Ph, phenyl) (11) and bis-CF3PhXPhos(14), which emerged from our parameterization-guided optimization, preferentially promotethe stereoretentive pathway, whereas stronglys-donating ligand PAd3 (9) preferentially pro-motes the stereoinvertive pathway. Becauseelectron-poor palladium catalysts commonly un-dergo slow oxidative addition with aryl chlo-rides, we also evaluated aryl bromide and triflateelectrophiles in reactions involving 11 and 14.A particular highlight of this protocol is theuniformity of the conditions used for both thestereoinvertive and stereoretentive reactions:each operates in a toluene and water mixtureas solvent, with a carbonate base, and no addi-tional additives. Both reaction variants toleratedthe use of electron-rich and electron-deficientaryl electrophiles, as well as an aryl electrophilebearing an ortho substituent. High stereofidelitywas achieved for all of these reactions, includingthose involving alkylboron nucleophiles bearingthiophenyl and phenoxide substituents. Use ofan alkylboron nucleophile containing a largersubstituent (replacingmethyl with ethyl) at the

Zhao et al., Science 362, 670–674 (2018) 9 November 2018 4 of 5

Fig. 4. Mechanistic investigation by multidimensional regressionmodeling. (A) Data from the arylation of 20 was used. [PdL] is theprecatalyst as shown in Fig. 3 with varying ligands. * indicates anenantioenriched stereocenter. (B) Regression model containing all24 ligands of this dataset. Es*(P−C)avg

Boltz is the Boltzmann-weightedaverage across the conformers of the average energies of the threeP−C s* antibonding orbitals in each phosphine. ELP(P)

Boltz is theBoltzmann-weighted average of the energy of the phosphorus lone-pair

orbital. Sterimol B1Boltz is the least width, and sterimol Lminconf is the length

of the lowest-energy conformer as seen from opposite the P substituents.Red points in the diagram indicate validation data (EV) not used in themodel training. LOO, leave-one-out cross-validation score; K-fold, averagethreefold cross-validation score. (C) Illustration and interpretation of themodel terms. (D) Regression model after removing the four smallestligands in this dataset to exclude the influence of competitive b-hydrideelimination on the data.

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stereogenic center was also well tolerated (16i).In the absence of a methyl substituent, thestereoinvertive variant shows modestly reducedselectivity that may be improved by reducing thereaction temperature. This was partially antici-pated because of the greater sensitivity of themetal fragment to steric congestion at carbonin the stereoinvertive SE2 transmetallationmechanism. Diastereomeric products 17a and17b could be generated from a single alkylborondiastereomer (37) using 14 and PAd3, respec-tively (Fig. 3B). In these reactions, replacement ofligand 14 with PAd3 resulted in a change in dia-stereoselectivity from 30:1 to 1:5, a 3.6 kcal/molfree energy of activation difference dependentonly on the ligand identity. No erosion of spec-ificity was observed for electron-deficient arylsubstrates in stereoinvertive Suzuki reactionsusing PAd3, in contrast to analogous reactionsusing PtBu3. Furyl and thiophenyl electrophilesare also compatible with our system (Fig. 3C).As an additional mechanistic probe, trans-2-methylcyclopentyltrifluoroborate was subjectedto the stereodivergent reaction conditions. Be-cause trans-2-methylcyclopentyltrifluoroborateis sterically impeded from undergoing stereo-invertive transmetallation, only the stereoreten-tive process using 14 should be mechanisticallyviable. Indeed, we observed that use of ligand 14smoothly generates 18 with stereoretention,whereas use of PAd3 results in low alkylboronconversion.To further probe the origin of the ligand-

dependent enantiodivergent process, we inter-rogated the mechanism of transmetallationusing the parameterization strategy describedabove (Fig. 4). To accomplish this, phenyl-substituted substrate 20 was selected becauseof enhanced performance and thus a greateroutput range. A singular aryl chloride electro-phile was chosen for this analysis to avoid po-tential attenuation of the ligand effects by theinfluence of different counterions (e.g., bromideor triflate). Additionally, 24 ligands were tested,excluding smaller ligands to reduce the com-plexity associated with b-hydride elimination.Multivariate linear regression revealed that mostof the outputs can be expressed in two readilyinterpretable terms that discriminate the trans-metallation pathways: the average energy of theP−C antibonding orbitals Es*(P−C), representativeof p-back bonding, and the energy of the lonepair orbital of phosphorus ELP(P), a measure ofthe ligand’s s-donation capability (Fig. 4B). Thisoutcome suggests that the stereoinvertive pathwayis dependent on strong s-donation from the

ligand, which may stabilize a two-coordinate,cationic palladium complex. Conversely, thestereoretentive pathway is enhanced by p-backbonding, which may stabilize the coordinationof a p-donor ligand X (presumably OH−) to Pd.Including two steric descriptors such as B1 andL (length of ligand L) improves the model fit bytreating the competitive b-hydride eliminationthat occurs using smaller ligands and decreasesthe observed specificity. This becomes evidentwhen the four smallest ligands in this datasetare removed from the analysis, which resultsin an excellent correlation using just the twoelectronic descriptors with the experimentallyobserved stereochemical outcomes (Fig. 4D).Multivariate regression analysis thereby providescompelling evidence for the electronic factorsfavoring each transmetallation mechanism andthus a guideline for future developments instereospecific cross-coupling reactions.

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ACKNOWLEDGMENTS

We acknowledge R. Kinthada for contributions to thediastereoselectivity studies. We thank G. Ralph for assistancewith chiral high-performance liquid chromatography analysis.We thank L. Cavallo for providing us with the command linetool for computing percent buried volume. Funding: Weare grateful to the National Institutes of Health (grantSC1GM110010 to M.R.B.), the National Science Foundation(grant CHE-1665189 to M.R.B. and grants CHE-1361296 andCHE-1763436 to M.S.S.), and the Leopoldina FellowshipProgramme of the German National Academy of SciencesLeopoldina (LPDS 2017-18 to T.G.). The support and resourcesfrom the Center for High Performance Computing (CHPC) at theUniversity of Utah are gratefully acknowledged. Furthercomputational resources were provided by the Extreme Scienceand Engineering Discovery Environment (XSEDE), which issupported by the NSF (ACI-1548562) and provided throughallocation TG-CHE180003. Author contributions: S.Z. andB.M. performed all synthetic experiments and isolated allproducts. T.G. computed all ligand parameters and performedmultivariate analyses. Z.L.N. performed initial multivariateanalyses. M.R.B., M.S.S., and T.G. wrote the manuscript.M.R.B. and M.S.S. directed the project. Competing interests:The authors declare no competing interests. Data andmaterials availability: All additional data are in thesupplementary materials.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/362/6415/670/suppl/DC1Materials and MethodsSupplementary TextFig. S1Tables S1 to S6NMR SpectraReferences (38–80)

18 May 2018; accepted 6 September 2018Published online 20 September 201810.1126/science.aat2299

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C bond formation enabled through ligand parameterization−Enantiodivergent Pd-catalyzed CShibin Zhao, Tobias Gensch, Benjamin Murray, Zachary L. Niemeyer, Matthew S. Sigman and Mark R. Biscoe

originally published online September 20, 2018DOI: 10.1126/science.aat2299 (6415), 670-674.362Science 

, this issue p. 670Scienceconfigurations in the products.initial configuration in chiral alkyltrifluoroborate reactants. Conversely, bulky electron-rich phosphines lead to invertedthe catalyst influence the stereochemical outcome. Certain electron-withdrawing phosphines favored retention of the

systematically studied how the properties of the phosphine ligands that are coordinated toet al.pressing challenge. Zhao protocol has been widely extended to chiral saturated alkyl carbons, but control over product stereochemistry is a

The venerable Suzuki coupling reaction originally used palladium to pair up unsaturated carbon centers. TheThe staying power of electron-poor ligands

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