Modular, Stereocontrolled Cβ–H/Cα–C Activation of Alkyl Carboxylic Acids Ming Shang,⊥,† Karla S. Feu,⊥,† Julien C. Vantourout,† Lisa M. Barton,† Heather L. Osswald,† Nobutaka Kato,§ Kerstin Gagaring,‡ Case W. McNamara,‡ Gang Chen,† Liang Hu,† Shengyang Ni,† Paula Fernández-Canelas,† Miao Chen,† Rohan R. Merchant,† Tian Qin,† Stuart L. Schreiber,ǁ,§ Bruno Melillo,*,†,§ Jin-Quan Yu,*,† Phil S. Baran*,† †Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 ‡Calibr at The Scripps Research Institute, La Jolla, California 92037 §Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142 ǁDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138 ABSTRACT: The union of two powerful transformations, directed C–H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vicinal difunctionalization of carbon centers in a way that is modular and thus amenable to rapid diversity incorporation. A simplification of routes to known preclinical drug candidates is presented along with the rapid diversification of an antimalarial compound series.

Introduction block like 3-(3-bromophenyl) propanoic acid (4) could be It is becoming increasingly clear that practitioners are no longer employed as its precursor (Figure 1b). Within the privileged bound by notion that the pervasive C–H bond is unresponsive realm of saturated cyclic heterocycles, such logic could be to manipulation. In fact, the past two decades have seen a employed to rapidly access libraries of enantiopure scaffolds 9 dramatic increase in the use of C–H functionalization logic1 to that would be rather difficult to otherwise prepare (Figure 1c). assemble molecules.2 At this juncture it can be considered part For example, chiral pyrrolidines such as 5 have previously been of the mainstream in terms of the way students learn prepared through labor-intensive routes that require chiral retrosynthetic analysis.3 One of today’s workhorse C–H resolution and are not amenable to late-stage diversity 10 activation strategies involves the use of native functional groups incorporation. In stark contrast, a combination of C–H and 8 to direct and guide the site of functionalization.4 As the most radical cross coupling strategies could access the same ubiquitous functional group in organic chemistry, carboxylic architectures in fewer steps with exquisite control of acids and their derivatives have naturally risen to the top in stereochemistry and allow for diverse arenes to be installed at terms of directed C–H functionalization reactions available to the end of the route starting from simple commercial carboxylic the practitioner (Figure 1a).5 With over one thousand reports acids. The difficulty in preparing such seemingly simple now present for the use of such guided C–H activations1 in molecules is directly related to the challenge of “escaping the 11 synthesis, it is fair to say that this is staple reaction manifold for flatland” as articulated by many in the field. Herein we present modern organic synthesis. In this context, an exploration of a strategy for the net vicinal difunctionalization of cyclic and serial reactivity in which the lingering carboxylate group is acyclic systems via sequential functionalization initiated by employed in successive reaction has been limited in scope. Of stereoselective C–H activation followed by decarboxylative the few notable examples, nearly all are restricted to restoration cross-coupling (dCC) to form a variety C–C and C–X bonds, 12 13 14 15,16 17 of the parent carboxylic acid followed by classic reactions such including aryl, alkenyl, alkynyl, alkyl, and boryl. The as amidation and esterification (Figure 1a).6,7 The recent inherent modularity of this strategic advance allows access to a development of robust methods to decarboxylate such systems wealth of acyclic and cyclic systems, some of which have been and programmably replace them with new C–C and C–B bonds prepared before in more laborious ways. Application to a in a stereochemically predictable way, a formal type of C–C promising series of heretofore inaccessible azetidine-based activation, opens new opportunities to leverage the power of antimalarial agents is also disclosed. carboxylate-directed C–H activation chemistry. This Results and discussion 8 combination of one- and two-electron disconnections would Proof of concept. In order to obtain a first proof of concept for enable pathways to potentially valuable chiral acyclic building the underlying strategy, a set of enantiopure carboxylic acids, blocks such as 3 that could be considered “retrosynthetically prepared using Pd-catalyzed ligand enabled asymmetric sp3 C– opaque” as it is not immediately apparent how a simple building H activation, were employed (Figure 2).18 Recalling the suite of 1

19 DG dCC reactions developed over the last several years, the 1 R -I, L* Removal R2–M 1 succeeding reaction was found to be tolerant of a variety H NHArF R R2 pendant functional groups, including esters (19 and 20) and R O Ligand Controlled dCC R boronic esters (14 and 16), as well as both free (18) and silyl- ArF = Asymmetric B = Borylation N = Negishi [Chiral] capped alkynes (15), all of which can be used in yet another 4-(CF3)C6H4 C–H Activation G = Giese S = Suzuki reaction sequence on liberation. Importantly, pyridine and boron can be incorporated in the challenging context of strained Me O iPr carbocycles to access trans-disubstituted cyclobutane (23) and Et N N N cyclopropane (24) rings with high enantiomeric purity, the NHAc L3 latter of which could be conducted without a directing group. Et L* = AcHN AcHN The ligand-controlled nature of the C–H activation step allows Ph for easily tunable access to either desired enantiomer (i.e. 14 vs. tBu tBu 18 NMe2 21). AcHN Scope of saturated heterocycles. In acknowledgement of the tBu L1 tBu L2 L4 increasing demand for saturated heterocycles in drug TMS development,20 the efficacy of this reaction sequence was Br Br Me Me demonstrated using an array of commercial heterocyclic acids

a Combination of C-H Activation with Decarboxylative Cross-Coupling O Bpin Me Bpin Me H DG Me Me Previous R1 10 10 Work OA* 14 [L1, B]: 15 [L1, N]: 16 [L1, B]: 17 [L1, N]: R O R2 R3 A* = NHPI, TCNHPI 46%, 90% ee 48%, 90% ee 85%, 88% ee 72%, 88% ee DG = OH, NHR etc. Me Me Me [ -C-H [Decarboxylative β >1000 papers Ref. 12-17 Activation] ca 60 reviews Cross-Coupling]

CO2Bn R4 DG R4 = Aryl, R1 R4 Alkyl, Alkyne, R2 Me Me Me R O R3 BPin 10 10 10 18 [L1, N]: 19 [L1, G]: 20 [L1, N]: CO Et This Work 2 53%, 88% ee 52%, 88% ee 58%, 88% ee Me Me Ph [β-C-H 1 (1 e–) R H DG Activation] 23 [L3, S]: R2 45%, 94% ee R R O (2 e–) [Decarboxylative 2 F 1 Cross-Coupling] N b Asymmetric Synthesis of Hypothetical Med. Chem. Building Block Br Br Bpin med. chem. Me [enantioselective] F building block Me 1. Asymmetric H H O C-H Activation 21 [L2, N]: 22 [L2, N]: 24 [L4, B]: Br 39%, 84% ee 51%, 84% ee 33%, 92% ee 2e– OH 2. Decarboxylative Figure 2. Proof of concept for the Cβ–H/Cα–C activation strategy. Br alkylation 4 ee were measured after the C–H activation step. 3-(3-bromophenyl) [modular] propanoic acid 3 1e– [programmable] ($3/g) (both enantiomers of each are available) as shown in Figure 3. Beyond their importance as a framework for the celebrated β- c Synthesis of Biologically Active Saturated Heterocycles 21 [not modular] [modular] lactam therapeutic class, azetidines have garnered recent OMe [racemic] CO2Et [diastereoselective] interest as scaffolds in diversity-oriented synthesis, through C-H which a wide variety of constrained (i.e., bridged or fused) or 22 7 1,4-addition; Activation; densely-substituted nitrogenous ring systems can be accessed. 5 DCC resolution CO H + N 2 To this point, arylated intermediates derived from N-protected Cbz 6 azetidine-2-carboxylic acid (Figure 3a) can be rapidly MeO [Previous] [Current] 8 Steps 6 Steps commercial diversified under the Suzuki (29-32), Negishi (28), and Giese N N H2N N H (26 and 27) protocols. In a similar vein, elaboration of Cbz- 8 protected proline via directed C–H arylation at C3 followed by C-H Activation/DCC of Commercially Available Chiral Acids dCC furnished a range of enantiopure trans-1,2- CO2H O CO2H difunctionalized pyrrolidines bearing diverse substituents such N O CO2H as aryl (35 and 39), heteroaryl (36-38 and 40), cycloalkyl (33), H 10 N CO2H N R N CO2H and alkenyl (34) functionalities (Figure 3b). Substrate 45 is of 9 N CO2H Boc Cbz R = Boc (11) 12 Cbz ent-6 13 particular note as prior routes to access such scaffolds involved [>50 examples] [modular] [regioselective] [diastereoselective] early-stage incorporation of methyl and phenyl substituents and a tedious separation of diastereomers.23 Figure 3c features the Figure 1. Introduction to the modular, stereocontrolled Cβ–H/Cα– C activation of alkyl carboxylic acids. same titular sequence as applied to a tetrahydrofuran core to furnish a variety of enantiopure THF-based building blocks (46- 52). Among the privileged N-heterocyclic fragments, piperidine

2

R1 R1 R1 H [>40 examples] N H 1 DG 2 R -I R –M BocN 2 2 [modular] N Removal 2 R R R N O [regioselective] X Cbz R1 O R1 [enantioselective] O C–H R1 Activation dCC [diastereoselective] 1 step from commercial N = Negishi N R2 BocN N R2 [drug-like scaffolds] chiral acids (ent-6, 9–13) S = Suzuki Boc R2 Cbz G = Giese K = Kumada

a Azetidine b Pyrrolidine 26 [G]: 35%, 33 [N]: 62%, N CN >99% ee 30 [S]: 91%, >99% ee SMe CO2H N >99% ee N CO2H N 25 O Me TFA 27 [G]: 50%, Cbz ent-6 34 [N]: 41%, 38 [S]: 85%, CO Me 2 97.5% ee 97.5% ee 98.5% ee Br R = R = 31 [S]: 57%, CF3 Me 28 [N]: 65%, >99% ee 35 [N]: 73%, >99% ee N Cl Ph 96% ee 39 [S]: 84%, 29 [S]: 90%, F 36 [S]: 84%, 97% ee >99% ee 32 [S]: 73%, 95.5% ee BocN R >99% ee O N R 26-32 CO2Me N Cbz 33-40 37 [S]: 71%, N c Tetrahydrofuran 98% ee 40 [S]: 50%, 46 [S]: 73%, N CF3 98.5% ee

R = Ph 96% ee 50 [S]: 22%, BocN 92% ee R = O CO2H F 42 [N]: 73%, 10 >99% ee Ph 47 [S]: 81%, N 93% ee S F 51 [S]: 46%, N 43 [N]: 85%, Br 93% ee Ph >99% ee N Me F Cbz 48 [S]: 94%, N CF3 R 94% ee N 41 [S]: 44 [S]: 81%, 45 [N]: 49% Cbz 82%, 41-44 >99% ee SMe 99% ee R N 52 [S]: 67%, Br O 49 [S]: 92%, 93% ee 46-52 93% ee N SMe e C-3 Piperidine 4 60 [N]: 85%, CO H Me 98% ee 61 [N]: 77%, d C-2 Piperidine 2 98% ee 53 [S]: 69%, 3 3 >99% ee 57 [S]: 95%, 2 N 99% ee N 63 [K]: 46%, OMe Boc 12 R = R = 96% ee N 2 CO2H Cl 62 [S]: 91%, Boc Cl 94% ee 11 54 [S]: 70%, Br R 98.5% ee OMe 58 [S]: 50%, 65 [S]: 75%, OMe >99% ee O 96% ee 60-65 NBoc Ph 64 [N]: 88%, 55 [S]: 71%, Br 96% ee 98.5% ee CO2Me f Morpholine O OMe O OMe O OMe R 59 [S]: 30%, O >99% ee 56 [S]: 77%, N Ph N N CO2Me NBoc >99% ee Cbz Cbz Cbz N OMe N CO2H 53-59 Cbz 66 [N]: 61%, 67 [S]: 60%, SMe 13 68 [G]: 39%, 96% ee 97% ee 97% ee

Figure 3. Scope of saturated heterocycles. remains prevalent, with disubstitution identified as the most to such scaffolds with either enantiomeric form available common decorative pattern.20 Here, commercially-available N- simply by choosing L or D forms of pipecolic acid. When 3,4- Boc-L-pipecolic acid (Figure 3d) first furnishes the 3-(4- piperidine substitution is desired, N-Boc-piperidine-3- methoxyphenyl) analog, after which the hydrolysis/dCC carboxylic acid (Figure 3e) may be employed (60–65) as the sequence provides a variety of 2,3-trans-substitutions, initial C–H activation takes place selectively at C–4 vs. C–2. including fused aryl (54), heteroaryl (57 and 59), and alkenyl Given the structural similarity to the blockbuster drug (53) moieties at C2. All of these structures are new chemical PaxilTM(paroxetine), rapid access to such systems is entities despite their simplicity – even distant relatives are rare. noteworthy. Finally, the logic outlined above can be applied to It is difficult to conceive of a more direct and modular approach substituted morpholines20—one of the rare saturated, bis- 3 heteroatom-containing systems to top frequency lists in FDA strategy deleted many of those concession steps and could be approvals—are detailed in Figure 3f. Although the C–H used to access 69 (11.2% overall yield, >20:1 dr, 97% ee) and, activation step is limited to methoxylation at this juncture (see in principle, a whole library of enantiopure analogs in only 6 SI for attempted C–H arylation and methylation), it does steps. The leukotriene B4 (LTB4) inhibitor, BIRZ-227 (Figure represent the first reported example of C–H activation of such 4b, 71), a trans-diarylpyrrolidine, is another prime example of heterocycle. how customary logic falter if a diverse, modularly assembled Synthesis of hit-to-lead candidates and late-stage library is targeted. Indeed, the sole reported preparative-scale intermediates. In addition to the diverse scope outlined above, protocol to its precursor 5 opts for a pyrrolidinone construction the described reaction series was next evaluated for its capacity in the initial step, placing severe limitations for rapid 10 to simplify the synthesis of active hit-to-lead series and late- diversification. In order to access enantiopure intermediates, stage intermediates (Figure 4). Of particular note in these case an enzyme-assisted resolution is required which itself requires studies is how the logic presented herein can be used as both a multiple extraneous steps. Instead, the sequential C–H means to effectively access a specific target or a library of arylation/dCC approach begins from an inexpensive similar structures simply by changing coupling partners. enantiopure amino acid building block (Pro) which is subjected Monoamine transporter ligand 69 is a vivid demonstration of to standard DG installation, followed by C–H this.24 The first synthesis of this molecule utilized conjugate arylation/hydrolysis, and the desired dCC to arrive at diarylated addition to arecoline 70 followed by a series of functional group compound 5. Should further diversification be of interest, any manipulations to arrive at 69 in 8.6% overall yield after chiral number of analogs may be forged in short order, with no resolution.25 Use of the current vicinal difunctionalization resolution necessary.

a Synthesis of Monoamine Transporter Ligand (69) [Previous] 8 steps Cl [Current] 6 steps + [H ]; DG DG CO H CO2Me chiral epimer- 2 resolution ization [O] H2, Pt HCHO, [H] removal installation

N n N ArMgBr base LAH Wittig MeN Pr2Zn Ar-I Me nPr 69 Boc dCC C–H Activation 12 70 9% (8 steps) monoamine transporter arecoline 1,4-addition: racemic (12:1 cis:trans) ligand (cocaine addiction) 11% (6 steps), >20:1 dr, 97% ee

b Modular Synthesis of LTB4 Inhbitor, BIRZ-227 (71) CO Et 11% (8 steps); 1,4-addition: racemic 2 [Previous] 8 steps OMe NH OH Ac O + BH 7 4 2 [H ] 3 MeO + OMe 1,4- HCHO lipase NH OH H2N 4 Ph2CO N addition resolution 8 5 2 steps N Ref. 10 N DG DG installation [H+] N O removal N N H BIRZ-227 N CO2H (71) Cbz 6 Ar-I (2 steps) Ar2Zn formal synthesis C-H Activation dCC This Work [Current] 6 steps 40% (6 steps), >20:1 dr, >99% ee

Figure 4. Synthesis of hit-to-lead candidates and late-stage intermediates. Structural diversification of azetidines with in vitro compounds acting through known MoA such as inhibitors of antimalarial activity. We finally applied the sequential PfATP4, PfPI4K and various targets in the mitochondrial functionalization tactic to the design and synthesis of azetidine- electron transport chain, such as PfDHODH (see SI; Pf refers to containing small molecules that potently inhibit the asexual P. falciparum, the deadliest species of Plasmodium that causes blood-stages of Plasmodium parasites. Plasmodium infections malaria in humans). Also of note, Cγ-epimer BRD5530 showed continue to cause over 200 million clinical cases of malaria each significantly lower potency than BRD8468 (up to 25-fold, see year, leading to an estimated 435,000 deaths in 2017.26 SI), indicating in turn that the trans relationship between the Emerging resistance to frontline drugs, an issue currently biaryl substituent and the vicinal alkyl group is critical for curbed by means of combination therapies,26,27 underscores the activity. In this context, we envisioned a structural need for antimalarials that act via novel mechanisms of action simplification of BRD8468 consisting in the removal of the (nMoA). Recently, Kato, Comer et al. reported the discovery of hydroxymethyl group at Cα. If successful, i.e., conducive to potent nMoA antimalarials enabled by phenotypic high- potent analogs, this strategy would enable both: 1) significant throughput screening.28 An unpursued, promising hit from the abbreviation of synthetic routes, rendering the chemical series same screening campaign is the trisubstituted azetidine more attractive in terms of developability,29 2) late-stage BRD8468 (72, Figure 5a and the Malaria Therapeutics exploration of novel chemical space via the sequential C–H Response Portal).28b Importantly, BRD8468 may inhibit activation/dCC tactic described above. The Diversity-Oriented parasite growth via nMoA because it remains equipotent against Synthesis compound collection that originally included a panel of drug-resistant lines that have been used to identify BRD8468 72 was constructed via functionalization of a Cγ-

4

a Analogs of phenotypic screening hit BRD8468 (72): approach F F [Previous] [Current] F

HO α β N H N H γ N N N F3C F3C R2 R1

BRD8468 (72) BRD6596 (73) Analogs 75-83 Pf Dd2 EC50 = 0.50 µM Pf Dd2 EC50 = 3.3 µM [Sequential C-H activation/dCC] [Diversity-Oriented Synthesis] [C-H activation] [New chemical space] [Screening hit] [Simplified scaffold PoC] [Late-stage functionalization]

Analog synthesis and biological evaluation b Route A F F3C I dCC

DG removal N = Negishi DG Ar S = Suzuki CO2H installation AQ G = Giese N TFA 75-79 Ar-I N O dCC ent-25 H 74 N >20:1 dr C-H Activation >99% ee 52% R1 + (2 steps) [Boc2O] [H ]; (3 steps from 74) DG removal F3C F3C Route B I

Me N N R1 = CN CF3 N SMe [N]: 17%A 75 [G]: 28%B 76 [N]: 16%A 77 [S]: 37%B 78 [S]: 50%B 79 80 81 (R2: Boc) (R2: H)

Legend: LOQ

NH BRD6596 82 83 BRD8468 Pf Dd2 EC50 [from 25] (73) (R2: Boc) (R2: H) (72) Pf D10 EC50 HEK293T CC50

c Analog 80 inhibits growth of wild-type and drug-resistant Pf strains in vitro with similar potencies

EC50 shift: 1.75x EC50 shift: 1.81x EC50 shift: 0.86x

EC50 shift: EC50 shift: EC50 shift: 8.69x 625x 543x

Figure 5. Structural diversification of azetidines with in vitro antimalarial activity. 5 nitrile (see ref. 22 and SI)—the ability to instead perform dCC Limitations. The strategy presented herein is not without at Cγ would therefore allow the preparation of a host of limitations. Foremost amongst these is the unfortunate previously inaccessible analogs. In order to establish proof-of- requirement for directing group installation and removal as the concept, we first synthesized disubstituted azetidine 73 (Figure free carboxylates can only be utilized for cyclopropane 5a). As expected, this could be achieved in 4 steps from C–H substrates (e.g. 24). For example, despite extensive efforts, arylation product 74 (Figure 5b). Encouragingly, in vitro piperazine heterocycles are completely inert to C–H activation evaluation of 73 showed that the structural simplification only attempts (see SI for details). In addition, when the C–H led to a modest loss in potency (6-fold) relative to parent alkynylation, alkoxylation, and fluorination of nitrogen based compound 72, and no significant shift in potency was observed saturated heterocycles were successfully achieved, the upon treatment of drug-resistant strains compared to their wild- subsequent removal of the directing group has proven type counterparts. Given this positive preliminary result, two challenging. A trans-relationship between vicinal substituents synthetic routes were designed to rapidly access simplified, is also an implicit limitation of the sequence. Finally, it is worth structurally novel Cγ analogs of 72 (Routes A and B, Figure 5b). noting that although an asymmetric conjugate addition strategy The former would enable late-stage diversification at Cγ; the could be envisaged to access acyclic (Figure 2) and C-3 latter would be optimal for diversification at nitrogen, although piperidine systems (Figure 3e), the remaining scaffolds would outside the scope of this study. In practice, Route A led to vinyl be difficult to obtain as asymmetric conjugate addition to and aryl analogs (75 and 77 respectively, Figure 5b) via heterocyclic enamides and enol ethers is poorly developed. Negishi-type dCC, albeit in low yield. Route B, in which the Conclusion dCC step is performed on a Boc-protected azetidine intermediate, allowed higher-yielding dCC. Suzuki-dCC The tactical combination of two powerful, recently invented readily led to pyridine 78 and pyrimidine 79; Giese-dCC in turn transformations (carboxylate-guided C–H activation and gave rise to nitrile 76. Evaluation in vitro of these N- decarboxylative cross-coupling) can thus be brought to bear to simplify the preparation of useful enantiopure building trifluoroalkyl analogs revealed inhibition of P. falciparum 33 growth with only micromolar potencies (Figure 5b, for details blocks. This formal vicinal difunctionalization permits the see SI Table 9), with pyrimidine 79 being one of the more active modular installation of an almost limitless variety of trans-1,2- disubstituted frameworks bearing aryl, alkyl, ether, and boron congeners (Pf D10 EC50 8.2 µM, Pf Dd2 EC50 12.3 µM). Generally, no effect was observed on human cell line HEK293T functional groups. Two distinct applications of these combined at concentrations below 20 µM, suggesting that these polar/radical retrosynthetic disconnections illustrate the power compounds lack overt toxicity in human cells. Given that the of this approach. Finally, the logic outlined herein shows parent scaffold (BRD8468, 72) had previously been shown to promise in accessing a new generation of antimalarial leads tolerate modifications at the azetidine nitrogen,28b we also based on a diverse library of azetidine scaffolds. evaluated 80 and 81, respectively tert-butyl-carbamate and N- ASSOCIATED CONTENT unsubstituted analogs (and synthetic intermediates) of 79. For reference, we introduced similar modifications on BRD6596 Supporting Information 73, leading in turn to carbamate 82 and N-unsubstituted The Supporting Information is available free of charge on the ACS azetidine 83. Potencies varied following the same trend in both Publications website. series of N-substitutions, with EC50 values decreasing in the order H > alkyl > carbamate (Figure 5b). We were however Detailed experimental procedures and data (PDF) delighted to find that C2-pyrimidine analog 80 (Pf D10 EC50 0.33 µM, Pf Dd2 EC50 0.17 µM, HEK293T CC50 > 20 µM), AUTHOR INFORMATION accessible in short order via sequential C–H arylation and dCC, exhibited superior potency and selectivity relative to both Corresponding Author BRD6596 (73, Pf D10 EC50 1.15 µM, Pf Dd2 EC50 3.3 µM, *[email protected] HEK293T CC50 13.4 µM) and the original screening hit *[email protected] BRD8468 (72, Pf D10 EC50 0.36 µM, Pf Dd2 EC50 0.50 µM, *[email protected] HEK293T CC50 > 20 µM). Author Contributions Finally, we demonstrated that 80 retains activity against drug- ⊥These authors contributed equally. resistant Pf strains (Figure 5c, see SI Table 10). Specifically, 80 remained equipotent against a Pf PI4K over-expression line, a Outside Professional Activities PfCARL/PfATP4 mutant, and transgenic Pf expressing S.L.S. is a member of the Board of Directors of the Genomics ScDHODH (< 2x EC50 shifts relative to wild-type parasites). In Institute of the Novartis Research Foundation (“GNF”); a good agreement with previously reported data, these parasites shareholder and member of the Board of Directors of Jnana 30 were resistant respectively to KDU-691 (8.7x EC50 shift), Therapeutics; a shareholder of Forma Therapeutics; a 31 GNF-156 (625x EC50 shift) and atovaquone (543x EC50 shareholder of and adviser to Decibel Therapeutics; an adviser 32 shift). As mentioned previously, these observations suggest to Eisai, Inc., the Ono Pharma Foundation, and F-Prime Capital that 80 may inhibit parasite growth via nMoA and therefore Partners; and a Novartis Faculty Scholar. warrant further study. To this end, additional structural modifications at Cγ and nitrogen and their impact on ACKNOWLEDGMENT antimalarial activity are now being investigated. Although Financial support for this work was provided by NIH (GM- certainly preliminary, the encouraging results reported here 118176), the Bill & Melinda Gates Foundation (OPP11823830), demonstrate how the C–H activation/dCC tactic may easily and Vividion, NSF GRFP (L.M.B.), the São Paulo Research productively augment the scope of medicinal chemistry Foundation (FAPESP, 2017/08128-7, K.S.F.), Zhejiang Yuanhong campaigns. Medicine Technology Co. Ltd. (M.S.), the China Scholarship 6

Council (CSC, L.H. and S.N.), and the Spanish Ministerio de C(sp3)–H α-Alkylation of Pyrrolidines. Org. Lett. 2014, 16, Economía, Industria y Competitividad (FPI predoctoral fellowship 1876−1879. c) Prokopcova,́ H.; Bergman, S. D.; Aelvoet, K.; BES-2014-069879 and EEBB-I-2018-12962, P.F.C.). We are Smout, V.; Herrebout, W.; Van der Veken, B.; Meerpoel, L.; grateful to Dr. Dee-Hua Huang and Dr. Laura Pasternack (Scripps Maes, B. U. W. C‐2 Arylation of Piperidines through Directed Research) for assistance with nuclear magnetic resonance (NMR) Transition‐Metal‐Catalyzed sp3 C–H Activation. Chem. Eur. J. spectroscopy, to Dr. Jason Chen and Brittany Sanchez (Scripps 2010, 16, 13063−13067. d) Pastine, S. J.; Gribkov, D. V.; Sames, 3 Automated Synthesis Facility) for assistance with HPLC, HRMS D. sp C−H Bond Arylation Directed by Amidine Protecting and LCMS, and to Dr. Arnold Rheingold, Dr. Curtis Moore and Dr. Group: α-Arylation of Pyrrolidines and Piperidines. J. Am. Chem. 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