RESEARCH ARTICLE SUMMARY◥

ORGANIC CHEMISTRY

Decarboxylative borylationChao Li,* Jie Wang,* Lisa M. Barton, Shan Yu, Maoqun Tian, David S. Peters,Manoj Kumar, Antony W. Yu, Kristen A. Johnson, Arnab K. Chatterjee,Ming Yan, Phil S. Baran†

INTRODUCTION: The boronic acid is a func-tional group of enormous utility in materialsscience, chemosensor development, and drugdiscovery. In medicinal chemistry, boronic acidshave been harnessed as a replacement for var-ious structural motifs (a bioisostere) to improvethe potency or pharmacokinetic profiles of leadcompounds. However, the widespread incorpor-ation of alkyl boronic acids has been largelyhampered by the challenges associated withtheir preparation. Consequently, only two alkylboronic acids are currently in clinical use, name-

ly Velcade and Ninlaro. Few methods are capa-ble of delivering alkyl boronates from readilyavailable starting materials; most exhibit mod-est functional group compatibility. Indeed, boro-nate motifs are often installed at the early stageof a synthesis and thus consume disproportion-ate effort from the standpoint of planningand manipulation in multistep processes.

RATIONALE: Alkyl carboxylic acids, as themost variegated chemical building blocks onEarth, are present in a myriad of natural prod-

ucts and medicines. They represent an idealprecursor to boronic acids. Previous efforts fromour laboratory revealed that, through the inter-mediacy of simple redox-active esters (RAEs,e.g., N-hydroxyphthalimide esters), alkyl car-

boxylic acids could be har-nessed as convenient alkylhalide surrogates in metal-catalyzed decarboxylativecross-coupling reactionswith carbon nucleophiles,using the same activating

principles as amide bond formation. It wastherefore surmised that such reactivity couldbe exploited in a decarboxylative borylationprocess wherein structurally diverse and ever-present carboxylic acids could be converteddirectly into high-value boronic acids.

RESULTS: Through the exclusive use of N-hydroxyphthalimide RAEs, a simple means toconvert carboxylic acids into boronate esterswas enabled with an inexpensive nickel cata-lyst. This reaction was broad in scope (>40examples) and demonstrated excellent func-tional group compatibility (tolerating alkyl/aryl halides, amides/carbamates, alcohols, ke-tones, and olefins), and high levels of diaster-eoselectivity, allowing transformations of denselyfunctionalized drug molecules (e.g., vancomycinand Lipitor) and natural products (e.g., enox-olone) into the analogous boronic acids. Thismethod’s unique capacity to access a-aminoboronic acids from native peptides not onlyallowed the concise syntheses of both Velcadeand Ninlaro, it also enabled the expedient dis-covery of three highly potent human neutro-phil elastase (HNE) inhibitors, the most potentof which has shown improved in vitro in-hibitory activities (IC50 = 15 pM, Ki = 3.7 pM)relative to leading candidates previously testedin clinical trials. Enzymatic and pharmacoki-netic studies indicated high functional stabil-ity in physiologically relevant media.

CONCLUSION:The nickel-catalyzed decarbox-ylative cross-coupling of RAEs enables substi-tution of ubiquitous alkyl carboxylic acidswith boronate esters using an inexpensive bo-ron source: B2pin2 (Bpin = pinacol boronate).This process provides simple and practical accessto complex boronic acids that were heretoforedifficult to prepare. The wide diversity of use-ful reactivity that is exclusive to boronic acids,such as cross-coupling, oxidation, amination,and homologation, will open distinct possibilitiesin retrosynthetic analysis. This work may alsoaccelerate the discovery and development ofnew boron-containing therapeutics.▪

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Li et al., Science 356, 1045 (2017) 9 June 2017 1 of 1

The list of author affiliations is available in the full article online.*These authors contributed equally to this work.†Corresponding author. Email: pbaran@scripps.eduCite this article as C. Li et al., Science 356, eaam7355(2017). DOI: 10.1126/science.aam7355

Decarboxylative borylation.Decarboxylative borylation replaces alkyl carboxylic acids with boronateesters (top) across a broad range of substrates (middle left), enabling convenient disconnectionsfor synthesis (middle right) and leading to the discovery of potent elastase inhibitors (bottom).

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RESEARCH ARTICLE◥

ORGANIC CHEMISTRY

Decarboxylative borylationChao Li,1* Jie Wang,1* Lisa M. Barton,1 Shan Yu,2 Maoqun Tian,1 David S. Peters,1

Manoj Kumar,2 Antony W. Yu,1 Kristen A. Johnson,2 Arnab K. Chatterjee,2

Ming Yan,1 Phil S. Baran1†

The widespread use of alkyl boronic acids and esters is frequently hampered by thechallenges associated with their preparation.We describe a simple and practical method torapidly access densely functionalized alkyl boronate esters from abundant carboxylicsubstituents.This broad-scope nickel-catalyzed reaction uses the same activating principleas amide bond formation to replace a carboxylic acid moiety with a boronate ester. Applicationto peptides allowed expedient preparations of a-amino boronic acids, often with highstereoselectivity, thereby facilitating synthesis of the alkyl boronic acid drugs Velcade andNinlaro as well as a boronic acid version of the iconic antibiotic vancomycin. The reaction alsoenabled the discovery and extensive biological characterization of potent human neutrophilelastase inhibitors, which offer reversible covalent binding properties.

Boronic acids and their esters are of para-mount importance to all facets of chem-ical science. Although their popularizationhas largely been spurred by the incredibleutility of the Suzuki coupling (1), boronic

acids have, to date, found countless applicationsin fields far outside of cross-coupling, such as ma-terials science (2), chemosensor development (3),and drug discovery (4, 5). Boronic acids displayunique chemical and biological properties as aresult of their Lewis acidity, their propensity toreversibly engage various nucleophiles (e.g., alco-hols and amines), and their ability to form hy-drogen bonds. For example, in materials science,the reversible covalent bonding of boronic acidshas enabled the development of self-assemblednanomaterials, hydrogels, and macromolecularsaccharide sensors (2, 3). In medicinal chemis-try, boronic acids have been harnessed as bio-isosteres, where they replace structural motifs ofsimilar physical and chemical properties, such ascarboxylic acids (6), to alter the physiochemicalproperties of lead candidates (4, 5). The revers-ible covalent binding properties allow tuningof the amount of time the drug remains on thetarget at an active dose as evidenced by its phar-macodynamic activity rather than by affinity, whileavoiding permanent covalent adducts with off-targetproteins that could lead to associated toxicity.Alkyl boronic acids, and a-amino boronic acids

in particular, have attracted considerable attentionas potent protease inhibitors (7). Currently, twoalkyl boronic acids are approved by the FDA forvarious oncology indications: Ninlaro (1) (Fig. 1A)and Velcade (49). However, efforts to fully exploitthe vast potential of these promising medicinal

scaffolds are often hampered by the challengesassociated with their preparation; relatively fewcomplex alkyl boronic acids have been synthe-sized for biological evaluations (4). Unlike car-boxylic acids, which are ubiquitous in nature andinexpensive, boronic acids are almost entirely de-rived through synthesis. The retrosynthetic anal-ysis of alkyl boronic acids can itself be a deterrentto their incorporation into drug candidates. Gen-eral methods to forge alkyl C–B bonds include hy-droboration of alkenes (8, 9), Miyaura borylationof alkyl halides (10–14), transmetallation (e.g.,with alkyl organolithium species) (15), and con-jugate addition (16, 17). a-Amino boronic acidsare typically accessed through metal-catalyzedaddition of diboron species onto imines (18),where elegant asymmetric variants have been re-ported (19). Although these approaches have beenhighly enabling, few of them use naturally oc-curring or readily available starting materials;many of these methods also possess modest func-tional group compatibility. Path-pointing advancesin metal-catalyzed C–H activation highlight thepossibilities of transforming Csp3–H bonds di-rectly into alkyl boronates at a late stage of asynthesis (20). Currently, however, alkyl boronicacids are usually installed at an early stage whenfew reactive functionalities are present. Thus, asillustrated with 1 (Fig. 1A), the conventional ap-proach focuses all strategic attention on the meansby which the boron atom will be incorporated,even though this represents <5% of the total mo-lecular weight of 1 (21). The synthesis of an en-gineered amino acid is therefore required. Anysystematic examination of the structure-activityrelationship of lead compounds would requireeach analog to be made individually.In contrast, the direct transformation of a

carboxylic acid–containing native peptide intothe corresponding boronic acid at a late stageconstitutes a far easier and more logical approach.Given the sheer number of alkyl carboxylic acids

in feedstock chemicals, natural products, anddrug molecules, this transformation could pro-vide the unique opportunity to expediently pro-cure a myriad of previously difficult-to-accessboronic acids as versatile building blocks, func-tional materials, and potent medicines.Here, we present a simple method for nickel-

catalyzed decarboxylative borylation that is mild,scalable, and general across a range of primary,secondary, tertiary, peptidic, and even naturalproduct–derived substrates. A diverse array ofboronates that would otherwise require lengthyde novo synthesis was furnished directly fromthe corresponding carboxylic acids. This method’scapacity to transform native peptides into a-aminoboronic acids has led to the discovery of threepotent small-molecule elastase inhibitors.

Development of the decarboxylativeborylation reaction

Recent efforts in our laboratory revealed redox-active esters (RAEs; e.g., N-hydroxyphthalimideester 2) derived from alkyl carboxylic acids asconvenient surrogates for alkyl halides in nickel-or iron-catalyzed cross-coupling reactions. Theseversatile intermediates, most commonly used inamide bond–forming reactions, have enabled prac-tical means of C–C bond formation in various mod-alities, including decarboxylative Negishi (22, 23),Suzuki (24), and Kumada (25) couplings, as wellas Giese reactions (26). Although RAEs have yetto be used in carbon-heteroatom cross-couplingreactions, our earlier discoveries, coupled withDudnik and Fu’s (10) pioneering work on nickel-catalyzed Miyaura borylation of alkyl halides(11–14), prompted us to investigate the possibil-ity of harnessing them for C–B bond formation,thereby achieving the direct conversion of alkylcarboxylic acids into boronic acid derivatives.Realization of this transformation required

considerable experimentation. Figure 1B providesthe optimal reaction parameters alongside an ab-breviated picture of the optimization process on2-methyl-4-phenylbutanoic acid. N-hydroxyph-thalimide (NHPI) ester (2) proved to be the opti-mal substrate for borylation with B2pin2 (Bpin =pinacol boronate); other RAEs such as tetrachloro-NHPI (TCNHPI) ester were less effective (entry 1).The inexpensive combination of NiCl2•6H2O andbipyridine ligand L1 emerged as the best catalystsystem after an exhaustive screening; the use ofalternative catalysts (table S4) or ligands (entries 3to 5; see table S5) had deleterious effects. Thechoice of solvent was critical: A binary mixtureof tetrahydrofuran (THF) and dimethylformamide(DMF) gave the optimal result; lower yieldswere observed in the absence of DMF (entry 6).Premixing methyl lithium with B2pin2 was neces-sary to activate the diboron species toward trans-metallation; numerous other activating agentssurveyed (e.g., entries 7 to 10) were less effective,affording borylation products in lower yields, ifat all. Magnesium salts were also indispensableto the reaction: In the absence of the MgBr2•OEt2,virtually no product was obtained (entry 11),whereas other Lewis acidic additives surveyed(entries 12 and 13) gave lower yields. Although

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Li et al., Science 356, eaam7355 (2017) 9 June 2017 1 of 8

1Department of Chemistry, The Scripps Research Institute(TSRI), La Jolla, CA 92037, USA. 2Calibr, 11119 North TorreyPines Road, Suite 100, San Diego, CA 92037, USA.*These authors contributed equally to this work.†Corresponding author. Email: pbaran@scripps.edu

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its precise role is unclear, MgBr2•OEt2 is hy-pothesized to promote the transmetallation of bo-ronate species onto the metal catalyst (27, 28).Bpin ester product 3 could be accessed directlyfrom the carboxylic acid in comparable yieldsusing a one-pot procedure wherein a RAE wasformed in situ, in a similar vein to amide cou-pling (entry 14; see also Fig. 2). Overall, thereaction was found to proceed smoothly overthe course of 2 hours (1 hour at 0°C and 1 hourat room temperature).

Scope of the decarboxylativeborylation reaction

With the optimized conditions in hand, we nextexplored the scope of this methodology. RAEsderived from a broad selection of primary, sec-ondary, and tertiary carboxylic acids were allfound to be viable substrates (Fig. 2). These en-

compass acyclic, cyclic, caged, bridgehead, fluo-roalkyl, and benzylic acids, which were trans-formed to the corresponding Bpin esters smoothly.Scalability of the reaction was evident throughthe preparation of 29 in gram scale. Addition-ally, 12 of the products (3, 4, 7, 11, 12, 13, 16, 19,25, 29, 35, 38) were obtained in comparableyields when only 2.5 mol % of nickel catalyst(3.3 mol % of ligand) was used, further attest-ing to the adaptability of this method in a pro-cess setting.Because the methyl lithium was premixed

with B2pin2 to form the [B2pin2Me]Li complex,strongly nucleophilic/basic organometallic spe-cies were sequestered from the substrate: A gamutof functionalities such as ethers (30, 31, 35,37, 41), esters (5, 8, 21, 22, 39, 41), carbamates/amides (1, 8, 15, 28, 36, 37), ketones (34, 38,39, 40), olefins (39, 40, 41), and alcohol/phenol

(40, 41) were left unscathed under the mild re-action conditions. Indeed, even the highly base-sensitive fluorenylmethyloxycarbonyl group wastolerated (see 8). The compatibility with alkyl bro-mides (7) and chlorides (33) points to the orthog-onality of this reaction to halide-based Miyauraborylations. Enoxolone-derived boronates 39 and40 were obtained in similar yields, which suggeststhat the free hydroxyl group had minimal in-fluence on the reaction. The discrete isolation ofRAEs, as alluded to earlier, is not necessary. Ter-tiary and secondary boronate esters can be pre-pared directly from carboxylic acids when RAEsare generated in situ. This one-pot procedure al-so pertains to some primary substrates, albeit inlower yields.Although some of the products presented here-

in (e.g., 9, 16, 17, 19, 20, 23) can be synthesizedfrom the analogous halides via Miyaura boryla-tion reactions (10–14), organohalides are oftennot commercially available and require extra-neous steps to prepare (usually from the corres-ponding alcohols). Conversely, the use of readilyavailable carboxylic acids largely circumvents thisproblem. A great majority of products in Fig. 2are derived from commercially available acids.For instance, 21 was conveniently prepared froma cubane-based carboxylic acid, whereas the re-ported synthesis of the analogous bromide en-listed a harsh Hunsdiecker reaction (Br2 andHgO) on the same acid (29). Furthermore, thescope of this borylation protocol can be extend-ed to amino acid derivatives to furnish a-aminoboronate esters such as 15. The synthesis of 15through halide-based Miyaura borylation is sim-ply not feasible; the corresponding a-aminohalide starting material would be unstable. Inthis regard, the decarboxylative borylation strat-egy allows explorations of previously elusive chem-ical space.The prevalence of alkyl carboxylic acids is dem-

onstrated by their presence in more than 450marketed drug molecules (30). To this end, theimpressive chemoselectivity of this reaction offersthe unique opportunity to pursue late-stage modi-fications of bioactive molecules that are denselyadorned with reactive functionalities. More than10 carboxylate-containing drug molecules or nat-ural products have been successfully convertedinto Bpin esters (28 to 41), which would other-wise only be accessible through multistep func-tional group interconversions or de novo syntheses.

Synthetic applications of thedecarboxylative borylation reaction

The Bpin esters can be conveniently hydrolyzedinto the corresponding boronic acids (e.g., 1, 3a,4a, 33a) (Fig. 2). This allows the transformationof carboxylic acids into their borono-bioisosteresto identify compounds with superior potency orpharmacokinetic properties. Alternatively, boro-nate esters could be diversified into a varietyof structural motifs (31–33). As an illustrativeexample, the Lipitor-derived Bpin ester (36) canbe expediently elaborated into the correspondingcarbamate (36a) (34) or alcohol (36b) upon treat-ment with appropriate oxidants (Fig. 3A). Under

Li et al., Science 356, eaam7355 (2017) 9 June 2017 2 of 8

Fig. 1. Development of the decarboxylative borylation reaction. (A) Strategic value of thedecarboxylative borylation illustrated through the retrosynthetic analysis of Ninlaro (1).(B) Development and optimization of the decarboxylative borylation reaction. Footnotes: *Reactionconducted on 0.10 mmol scale. †Yield by gas chromatography. ‡Isolated yield.

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conditions reported in (35), 36c and 36d weredirectly accessed through reaction with aryllith-ium species. Decarboxylative borylation couldalso convert RAEs, which are electrophiles incross-couplings, into Bpin esters that serve asnucleophiles in Suzuki reactions (e.g., 36 to 36eand 36 to 36f) (36). This “umpolung” approachis particularly strategic in the case of 36e, as2-pyridylboronic acid or organozinc species areoften not viable Suzuki/Negishi coupling sub-strates, owing to a lack of stability.Moreover, selective decarboxylative borylation

at the C terminus of native peptides allowedrapid access to coveted a-amino boronic acids,

which are privileged medicinal chemistry motifs(18, 37). Ninlaro (1), for example, was obtainedin three steps from a simple peptide (Fig. 2). Thisopens up a distinct dimension to the study ofpeptide-based therapeutics: In perhaps the moststriking example, vancomycin was converted intoa boronic acid analog (44) through the decarbox-ylative borylation of 42 (Fig. 3B) (38). This processproceeded smoothly in the presence of four meth-ylated phenoxy groups, two tert-butyldimethylsilylethers, two aryl chlorides, six secondary amides,one primary amide, one secondary amine, andseven epimerizable stereocenters. Although 44showed less activity than the parent acid 43

(Fig. 3B and table S12), such remarkable chemo-selectivity still attests to the potential utility ofthis reaction.The unpredictable stereoselectivity of radical

processes often presents a hurdle to their broadadoption in late-stage modifications of drug leadsor natural products. Complex a-amino boronicacid 44 was obtained as a single diastereomerin this radical-based decarboxylative borylationreaction. This result prompted us to investigatethe stereoselectivity of the decarboxylative bor-ylation on several dipeptides (Fig. 3C). We foundthat increased steric bulk on the N-terminal resi-due resulted in better diastereoselectivity: Both

Li et al., Science 356, eaam7355 (2017) 9 June 2017 3 of 8

Fig. 2. Scope of the Ni-catalyzed decarboxylative borylation reaction of redox-active esters. Standard reaction conditions: Redox-active NHPI ester(1.0 equiv), NiCl2•6H2O (10 mol %), L1 (13 mol %), MgBr2•OEt2 (1.5 equiv), [B2pin2 (3.3 equiv), MeLi (3.0 equiv)] precomplexed,THF/DMF (2.5:1), 0°C to roomtemperature, 2 hours. Footnotes: *Using THF as the solvent. †Using L2 as the ligand. ‡Using tetrachloro-NHPI (TCNHPI) ester. §Using 1.0 equiv of MgBr2•OEt2.¶Using 2.5 mol % of NiCl2•6H2O and 3.3 mol % of ligand (L1 or L2). (See supplementary materials for experimental details.)

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diastereomers were furnished in almost equalquantities for 45, whereas higher selectivitieswere observed for 46 and 47. Meanwhile, 46was obtained in the same diastereomeric ratiofrom (tert-butoxycarbonyl)-L-valine-L-valine and(tert-butoxycarbonyl)-L-valine-D-valine. Lower reac-tion temperatures could also be used to enhancethe stereoselectivity. At –15°C, 48 was furnishedin greater than 5:1 diastereomeric ratio, enabl-ing a stereoselective synthesis of Velcade (49) ina short sequence.

Discovery of potent human neutrophilelastase inhibitors

By wedding the rich medicinal potential of boro-nates to the ubiquity of alkyl carboxylic acids,the decarboxylative borylation reaction has thepotential to open up new vistas in drug devel-opment. For example, application of the decar-boxylative borylation reaction to readily availabletripeptides allowed the expedient preparations of50, 51, and 52, which were formed as singlediastereomers and were found to be potent in-hibitors of human neutrophil elastase (HNE)(Fig. 4, A and B). Notably, the carboxylic acidprecursor to 50 (50b) was found to be devoid

of any inhibitory activities, whereas 50 and 51displayed substantially enhanced potency rel-ative to their trifluoromethyl ketone congeners(50a and 51a), which have been examined inphase II clinical trials for lung diseases such ascystic fibrosis (CF) (39–45). HNE, a highly activeserine protease, plays a pivotal role in the im-mune response, tissue remodeling, and onset andresolution of inflammation by breaking downmechanically important structures of the body’scellular matrix as well as proteins of foreign ori-gin (46). Although five generations of HNE inhib-itors have been evaluated clinically in multipleinflammatory lung diseases (e.g., CF, emphysema,and bronchiectasis), none have been sufficientlyefficacious in humans to make a significant im-pact in these conditions (46).Toward this end, 52 exhibited an IC50 value

of 15 pM, where IC50 is the concentration ofan inhibitor when the response (or inhibitionof cleavage of the HNE substrate) is reducedby half (Ki = 3.7 pM where Ki refers to theconcentration of inhibitor at which the reac-tion rate is half of the maximum reaction rateunder saturating substrate conditions) againstpurified HNE; 51 exhibited an IC50 of 30 pM

(Ki = 34 pM) against purified HNE (Fig. 4B).The IC50 values were determined head-to-headwith other preclinically and clinically validatedHNE inhibitors (53–57), including BAY 85-8501(54, a leading clinical candidate with reportedKi = 80 pM) (47), 55 (an analog in a series ofpeptide-based elastase inhibitors currently inclinical trials) (48), as well as 56 and 57 (reportedby Chiesi Pharmaceuticals) (49). Additionally, 51and 52 retained much of their inhibitory activitiesin sputum samples of CF and chronic obstructivepulmonary disease (COPD) patients, underscoringthe potency of these compounds in the context of amore pathophysiologically relevant environmentthan the traditional biochemical assay. Conversely,although dimeric compound 58 from AstraZeneca(IC50 = 11 pM, Ki = 2.7 pM) (50) and BAY 85-8501(54) displayed low IC50 values, their potencies di-minished in CF patient sputum. Comparison ofthe lipophilic efficiency (LipE) values in COPDsputum revealed that the superior potency of 52is not driven by increased lipophilicity (10.2 for52 versus 9.46 for 57) (51).Additionally, the IC50 value of 52 was found

to remain unchanged with increasing incuba-tion times (5 to 60 min), whereas that of 58, a

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Fig. 3. Applications of the decarboxylative borylation reaction. (A) Late-stage diversification of Lipitor. (B) Synthesis and biological evaluationof 44, a boronic acid analog of vancomycin. (C) Probing the stereoselectivity of peptide substrates and the ensuing stereoselective synthesis ofVelcade (49). Footnotes: *VRE(VanA). †VRE(VanB). ‡Yield and diastereoselectivity refer to the decarboxylative borylation of the corresponding RAE.See supplementary materials for experimental details.

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Li et al., Science 356, eaam7355 (2017) 9 June 2017 5 of 8

Fig. 4. Discovery of novel human neutrophil elastase (HNE) inhibitors. (A) Structures of selected elastase inhibitors. (B) IC50 values (nM) of selectedelastase inhibitors (average ± SD, n = 3 plotted, representative of three independent, triplicate experiments). A nonlinear three-parameter loginhibitor curve was used to calculate the IC50 values. Curve fit statistics: Purified HNE, R2 ≥ 0.95; CF patient sputum, R2 ≥ 0.93; COPD patient sputum,R2 ≥ 0.93. (C) ADME profile of 51, 51a, and 52.

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noncovalent inhibitor, exhibited a factor of 55increase in potency under the same conditions.These data retain the profile that is expected:Compound 52 is behaving like a partial mechanism-based inhibitor (or a covalent reversible inhib-itor), likely as a result of the potentially slowoff-rate of the a-amino boronic acid. This correlateswith tighter binding and potentially long resi-dence time, as seen in other amino boronic acidcompounds and unlike the many reversible elas-tase inhibitors (e.g., 58) (52). Clinically, this mech-anism has been proven successfully throughVelcade (49), which inhibits the catalytic site ofthe 26S proteasome. In this example, covalent re-versible bonding between the boronate and thenucleophilic oxygen results in a slow disassocia-tion rate (53, 54). Because many of the earlyclinical elastase inhibitors are mechanism-basedinhibitors that act through a covalent mannerwith the enzyme’s active site or nonreactive, re-versible inhibitors (such as 54, BAY 85-8501, one ofthe most potent HNE inhibitors reported to date),the high potency of 52 and the inherent mecha-nism of the amino boronic acids could help toimprove the limited clinical efficacy demonstratedto date. Through this “hybrid” enzymatic inhibitoryapproach (based on Fischer’s lock-and-key modeland Ehrlich’s pharmacophore model), boronicacids such as 52, which combine a rapid, potentbinding with a slow off-rate, may effectively restore

the protease-antiprotease balance in a clinicalsetting. They could therefore be tuned rapidlytoward lung-specific clinical applications.To further evaluate the therapeutic potential

of 51 and 52, we probed the in vitro adsorption,distribution metabolism, and excretion proper-ties (ADME properties) to determine whetherany deleterious effects of the boronate replace-ments of the trifluoromethyl ketone would berevealed (Fig. 4C). These amino boronic acidsdisplayed kinetic solubility comparable to thatof the trifluoromethyl ketone analog (51a). Sub-stantial proportions of 51 and 52 (90.3% and79.2%, respectively) were found to be intact inCD-1 mouse plasma after 2 hours. The metabolicstability exhibited by 51 and 52 was similar tothat of the trifluoromethyl ketone 51a. 51 and51a also demonstrated similar levels of perme-ability in human Caco-2 cells (see table S19).These data suggest that the novel boronates sim-ply improve potency without changing the drug-like properties of their ketone congeners.

Method summary

Procedurally, the conversion of redox-active estersinto boronate esters was achieved in three stages:the preparation of the catalyst mixture, the prep-aration of the [B2pin2Me]Li complex, and thenickel-catalyzed decarboxylative borylation reac-tion. The following is an abbreviated experimen-

tal protocol with a graphical guide (Fig. 5, from thegram-scale decarboxylative borylation of ibuprofen-derived RAE). See the supplementary materials forcomprehensive information on the commercialsource and purity of chemicals or variations in ex-perimental details for different substrate classes.

Preparation of NiCl2•6H2O/ligand stocksolution or suspension

A flask charged with NiCl2•6H2O (1.0 equiv) andligand (L1 or L2, 1.3 equiv) was evacuated andbackfilled with argon three times. After additionof THF (NiCl2•6H2O concentration, 0.025 M) orDMF (NiCl2•6H2O concentration, 0.050 M), theresulting mixture was stirred at room temper-ature overnight (or until no granular NiCl2•6H2Owas observed) to afford a green solution or sus-pension (for an example, see Fig. 5A, center left).

Preparation of [B2pin2Me]Li complex

MeLi (1.6 M in Et2O, 1.0 equiv) was added to asolution of B2pin2 (1.1 equiv) in THF (B2pin2concentration, 1.1 M) at 0°C under argon. Thereaction mixture was warmed to room temper-ature and stirred for 1 hour to afford a milkywhite suspension (Fig. 5A, center right).

Ni-catalyzed decarboxylative borylation

Aflask chargedwith the redox-active ester (1.0 equiv)and MgBr2•OEt2 (1.5 equiv) was evacuated and

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Fig. 5. A graphical guide to the decarboxylative borylation reaction. (A) General transformation and materials for the reaction. (B) Addition ofreagents. (C) Observations during the reaction. (D) Work-up and purification of the reaction mixture.

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backfilled with argon three times (Fig. 5A, left). Cat-alyst solution or suspension (containing 10mol%NiCl2•6H2Oand13mol% ligand) was added via asyringe (Fig. 5B, left).When a catalyst suspension/solution in DMF was used, an additional portionof THF (twice the volume of the DMF suspension/solution needed) was added to the reaction ves-sel before addition of the catalyst mixture. (Thisprocess can be exothermic on large scales, andcooling by ice/water bathmay be necessary.) Theresulting mixture was stirred vigorously untilno visible solid was observed at the bottom ofthe reaction vessel (Fig. 5B, center); this processwas found to be accelerated by sonication. Thismixture was cooled to 0°C before a suspension of[B2pin2Me]Li in THF (3 equiv) was added in oneportion (Fig. 5B, right). After stirring for 1 hour at0°C (Fig. 5C, left), the reaction was warmed toroom temperature and stirred for another 1 hour(Fig. 5C, center). When thin-layer chromatog-raphy (TLC) analysis indicated the completionof the reaction (Fig. 5C, right), the reaction wasquenchedwith aqueous HCl (0.1 M) or saturatedaqueous NH4Cl and extracted with diethyl ether(Et2O) or ethyl acetate (EtOAc). Alternatively, onlarger scales, as is the case shown in Fig. 5, thereaction mixture was directly poured onto Et2O(Fig. 5D, left) and the resulting suspension wasfiltered through a pad of silica gel and celite (Fig.5D, center). Purification by flash column chro-matography (Fig. 5D, right) afforded the desiredBpin ester.

REFERENCES AND NOTES

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ACKNOWLEDGMENTS

Supported by a China Scholarship Council postdoctoralfellowship (C.L.); a Shanghai Institute of Organic Chemistry,Zhejiang Medicine Co., and Pharmaron postdoctoral fellowship(J.W.); a Crohn’s and Colitis Foundation of America fellowship(S.Y.); a Deutsche Forschungsgemeinschaft postdoctoral

fellowship (M.T.); NIH grant GM-118176; and Bristol-MyersSquibb. We thank D. L. Boger and A. Okano for insightfuldiscussions and generous donation of vancomycin;F. E. Romesberg for help with antibacterial assays; D.-H. Huangand L. Pasternack for assistance with nuclear magneticresonance (NMR) spectroscopy; and A. L. Rheingold,C. E. Moore, and M. Gembicky for x-ray analysis. Crystallographicdata for compounds 28, 38, and 40a are available free ofcharge from the Cambridge Crystallographic Data Centre underreference numbers CCDC 1525341, 1525343, and 1533051,respectively. Experimental procedures, frequently askedquestions, extensive optimization data, biological testingprotocols, 1H NMR spectra, 13C NMR spectra, and MS data areavailable in the supplementary materials. A provisional U.S.patent application on this work has been filed (application

number 62474181), where P.S.B., C.L., J.W., A.K.C., M.K., S.Y.,and K.A.J. are listed as inventors.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/356/6342/eaam7355/suppl/DC1Materials and MethodsSupplementary TextFigs. S1 to S42Tables S1 to S25NMR spectraReferences (55–69)

12 January 2017; accepted 23 March 2017Published online 13 April 201710.1126/science.aam7355

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Decarboxylative borylation

Arnab K. Chatterjee, Ming Yan and Phil S. BaranChao Li, Jie Wang, Lisa M. Barton, Shan Yu, Maoqun Tian, David S. Peters, Manoj Kumar, Antony W. Yu, Kristen A. Johnson,

originally published online April 13, 2017DOI: 10.1126/science.aam7355 (6342), eaam7355.356Science 

, this issue p. eaam7355Scienceinhibitor of human neutrophil elastase, a target of interest in treating inflammatory lung diseases.well suited to late-stage modification of complex molecules. The authors used the approach to produce a potent in vitro

isnickel-catalyzed process to replace carboxylic acids with boronate esters by using a phthalimide activator. The reaction report a versatileet al.More recently, these chemicals have garnered pharmaceutical interest in their own right. Li

Carbon-bound boronic acids and their esters are widely used as coupling partners to make carbon-carbon bonds.Swapping boron acids for carbon acids

ARTICLE TOOLS http://science.sciencemag.org/content/356/6342/eaam7355

MATERIALSSUPPLEMENTARY http://science.sciencemag.org/content/suppl/2017/04/12/science.aam7355.DC1

REFERENCES

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is a registered trademark of AAAS.ScienceScience, 1200 New York Avenue NW, Washington, DC 20005. The title (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement ofScience

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