Robert Craig

All Publications

• Discovery of Potent and Selective Dual Leucine Zipper Kinase/ Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis JOURNAL OF MEDICINAL CHEMISTRY Craig II, R. A., Fox, B. M., Hu, C., Lexa, K. W., Osipov, M., Thottumkara, A. P., Larhammar, M., Miyamoto, T., Rana, A., Kane, L. A., Yulyaningsih, E., Solanoy, H., Nguyen, H., Chau, R., Earr, T., Kajiwara, Y., Fleck, D., Lucas, A., Haddick, P. G., Takahashi, R. H., Tong, V., Wang, J., Canet, M. J., Poda, S. B., Scearce-Levie, K., Srivastava, A., Sweeney, Z. K., Xu, M., Zhang, R., He, J., Lei, Y., Zhuo, Z., de Vicente, J. 2022

  Abstract

  Dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) are regulators of neuronal degeneration and axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- and structure-based drug design approaches for identifying novel amino-pyrazine inhibitors of DLK/LZK. DN-1289 (14), a potent and selective dual DLK/LZK inhibitor, demonstrated excellent in vivo plasma half-life across species and is anticipated to freely penetrate the central nervous system with no brain impairment based on in vivo rodent pharmacokinetic studies and human in vitro transporter data. Proximal target engagement and disease relevant pathway biomarkers were also favorably regulated in an in vivo model of amyotrophic lateral sclerosis.

  View details for DOI 10.1021/acs.jmedchem.2c01056

  View details for Web of Science ID 000893239300001

  View details for PubMedID 36469401

• Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on "toxin sponge" proteins. The Journal of general physiology Abderemane-Ali, F., Rossen, N. D., Kobiela, M. E., Craig, R. A., Garrison, C. E., Chen, Z., Colleran, C. M., O'Connell, L. A., Du Bois, J., Dumbacher, J. P., Minor, D. L. 2021; 153 (9)

  Abstract

  Many poisonous organisms carry small-molecule toxins that alter voltage-gated sodium channel (NaV) function. Among these, batrachotoxin (BTX) from Pitohui poison birds and Phyllobates poison frogs stands out because of its lethality and unusual effects on NaV function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NaV DIVS6 pore-forming helix N-to-T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog NaVs, incurs a strong cost compromising channel function, and fails to produce BTX-resistant channels in poison frog NaVs. We also show that captivity-raised poison frogs are resistant to two NaV-directed toxins, BTX and saxitoxin (STX), even though they bear NaVs sensitive to both. Moreover, we demonstrate that the amphibian STX "toxin sponge" protein saxiphilin is able to protect and rescue NaVs from block by STX. Taken together, our data contradict the hypothesis that BTX autoresistance is rooted in the DIVS6 NT mutation, challenge the idea that ion channel mutations are a primary driver of toxin resistance, and suggest the possibility that toxin sequestration mechanisms may be key for protecting poisonous species from the action of small-molecule toxins.

  View details for DOI 10.1085/jgp.202112872

  View details for PubMedID 34351379

• Veratridine: A Janus-Faced Modulator of Voltage-Gated Sodium Ion Channels. ACS chemical neuroscience Craig, R. A., Garrison, C. E., Nguyen, P. T., Yarov-Yarovoy, V., Du Bois, J. 2020

  Abstract

  Voltage-gated sodium ion channels (NaVs) are integral to both neuronal and muscular signaling and are a primary target for a number of proteinaceous and small molecule toxins. Included among these neurotoxins is veratridine (VTD), a C-nor-D homosteroidal alkaloid from the seeds of members of the Veratrum genus. VTD binds to NaV within the pore region, causing a hyperpolarizing shift in the activation threshold in addition to reducing peak current. We have characterized the activity of VTD against heterologously expressed rat NaV1.4 and have demonstrated that VTD acts on the channel as either an agonist or antagonist depending on the nature of the electrophysiological stimulation protocol. Structure-activity studies with VTD and VTD derivatives against NaV mutants show that the functional duality of VTD can be decoupled. These findings suggest that the dichotomous activity of VTD may derive from two distinct, use-dependent binding orientations of the toxin.

  View details for DOI 10.1021/acschemneuro.9b00621

  View details for PubMedID 31951114

• Enantioselective, Convergent Synthesis of the Ineleganolide Core by a Tandem Annulation Cascade. Chemical science Craig, R. A., Roizen, J. L., Smith, R. C., Jones, A. C., Virgil, S. C., Stoltz, B. M. 2017; 8 (1): 507-514

  Abstract

  An enantioselective and diastereoselective approach toward the synthesis of the polycyclic norditerpenoid ineleganolide is disclosed. A palladium-catalyzed enantioselective allylic alkylation is employed to stereoselectively construct the requisite chiral tertiary ether and facilitate the synthesis of a 1,3-cis-cyclopentenediol building block. Careful substrate design enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold by a diastereoselective cyclopropanation-Cope rearrangement cascade under unusually mild conditions. Computational evaluation of ground state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures. This work represents the first successful synthesis of the core structure of any member of the polycyclic norcembranoid diterpene family of natural products. Advanced synthetic manipulations generated a series of natural product-like compounds that were shown to possess selective secretory antagonism of either interleukin-5 or interleukin-17. This bioactivity stands in contrast to the known antileukemic activity of ineleganolide and suggests the norcembranoid natural product core may serve as a useful scaffold for the development of diverse therapeutics.

  View details for DOI 10.1039/C6SC03347D

  View details for PubMedID 28239443

  View details for PubMedCentralID PMC5321630

• Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on "toxin sponge'' proteins Abderemane-Ali, F., Rossen, N. D., Kobiela, M. E., Craig, R. Z., Garrison, C. E., Chen, Z., Colleran, C. M., O'Connell, L. A., Du Bois, J., Dumbacher, J. P., Minor, D. L. CELL PRESS. 2022: 25

  View details for Web of Science ID 000759523000117

• Unified Enantioselective, Convergent Synthetic Approach toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Synthesis of a Series of Ineleganoloids by Oxidation-State Manipulation of the Carbocyclic Core. The Journal of organic chemistry Craig, R. A., Smith, R. C., Roizen, J. L., Jones, A. C., Virgil, S. C., Stoltz, B. M. 2019; 84 (12): 7722-7746

  Abstract

  Late-stage synthetic efforts to advance the enatio- and diastereoselectively constructed [6,7,5,5]-fused tetracyclic scaffold toward the polycyclic norditerpenoid ineleganolide are disclosed. The described investigations focus on oxidation-state manipulation around the central cycloheptane ring. Computational evaluation of ground-state energies of dihydroineleganolide is used to rationalize empirical observations and provide insight for further synthetic development, enhancing the understanding of the conformational constraints of these compact polycyclic structures. Advanced synthetic manipulations generated a series of natural product-like compounds termed the ineleganoloids.

  View details for DOI 10.1021/acs.joc.9b00635

  View details for PubMedID 31066273

• Correction: Enantioselective, convergent synthesis of the ineleganolide core by a tandem annulation cascade. Chemical science Craig, R. A., Roizen, J. L., Smith, R. C., Jones, A. C., Virgil, S. C., Stoltz, B. M. 2019; 10 (4): 1254-1255

  Abstract

  [This corrects the article DOI: 10.1039/C6SC03347D.].

  View details for DOI 10.1039/c8sc90236d

  View details for PubMedID 30774926

  View details for PubMedCentralID PMC6349058

• Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade. The Journal of organic chemistry Craig, R. A., Smith, R. C., Roizen, J. L., Jones, A. C., Virgil, S. C., Stoltz, B. M. 2018; 83 (7): 3467-3485

  Abstract

  An enantioselective and diastereoselective approach toward the synthesis of the tetracyclic scaffold of the furanobutenolide-derived polycyclic norditerpenoids is described. Focusing on synthetic efforts toward ineleganolide, the synthetic approach utilizes a palladium-catalyzed enantioselective allylic alkylation for the construction of the requisite chiral tertiary ether. A diastereoselective cyclopropanation-Cope rearrangement cascade enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold. Investigation of substrates for this critical tandem annulation process is discussed along with synthetic manipulations of the [6,7,5,5]-tetracyclic scaffold and the attempted interconversion of the [6,7,5,5]-tetracyclic scaffold of ineleganolide to the isomeric [7,6,5,5]-core of scabrolide A and its naturally occurring isomers. Computational evaluation of ground-state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures.

  View details for DOI 10.1021/acs.joc.7b02825

  View details for PubMedID 29464957

  View details for PubMedCentralID PMC5889334

• Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts. Chemical reviews Craig, R. A., Stoltz, B. M. 2017; 117 (12): 7878-7909

  Abstract

  The polycyclic furanobutenolide-derived cembranoid and norcembranoid natural products are a family of congested, stereochemically complex, and extensively oxygenated polycyclic diterpenes and norditerpenes. Although the elegant architectures and biological activity profiles of these natural products have captured the attention of chemists since the isolation of the first members of the family in the 1990s, the de novo synthesis of only a single polycyclic furanobutenolide-derived cembranoid and norcembranoid has been accomplished. This article begins with a brief discussion of the proposed biosyntheses and biosynthetic connections among the polycyclic furanobutenolide-derived cembranoids and norcembranoids and then provides a comprehensive review of the synthetic efforts toward each member of the natural product family, including biomimetic, semisynthetic, and de novo synthetic strategies. This body of knowledge has been gathered to provide insight into the reactivity and constraints of these compact and highly oxygenated polycyclic structures, as well as to offer guidance for future synthetic endeavors.

  View details for DOI 10.1021/acs.chemrev.7b00083

  View details for PubMedID 28520418

  View details for PubMedCentralID PMC5497599

• Catalytic enantioselective total synthesis of (+)-eucomic acid. Tetrahedron Estipona, B. I., Pritchett, B. P., Craig, R. A., Stoltz, B. M. 2016; 72 (26): 3707-3712

  Abstract

  A catalytic enantioselective synthesis of (+)-eucomic acid is reported. A palladium-catalyzed asymmetric allylic alkylation is employed to access the chiral tetrasubstituted α-hydroxyacid moiety found in the natural product. The protecting group strategy was investigated, and a protecting group manipulation was made without any appreciable deleterious effects in the allylic alkylation reaction. Non-natural (+)-eucomic acid is synthesized in a longest linear sequence of 13 steps.

  View details for DOI 10.1016/j.tet.2016.02.059

  View details for PubMedID 27546916

  View details for PubMedCentralID PMC4986999

• Preparation of 1,5-Dioxaspiro[5.5]undecan-3-one. Organic syntheses; an annual publication of satisfactory methods for the preparation of organic chemicals Craig, R. A., Smith, R. C., Pritchett, B. P., Estipona, B. I., Stoltz, B. M. 2016; 93: 210-227

  View details for DOI 10.15227/orgsyn.093.0210

  View details for PubMedID 28729749

  View details for PubMedCentralID PMC5514842

• Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones. Organic letters Craig, R. A., Loskot, S. A., Mohr, J. T., Behenna, D. C., Harned, A. M., Stoltz, B. M. 2015; 17 (21): 5160-3

  Abstract

  The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee's up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.

  View details for DOI 10.1021/acs.orglett.5b02376

  View details for PubMedID 26501770

  View details for PubMedCentralID PMC4640231

• Synthesis and Exploration of Electronically Modified (R)-5,5-Dimethyl-(p-CF3)3-i-PrPHOX in Palladium-Catalyzed Enantio- and Diastereoselective Allylic Alkylation: A Practical Alternative to (R)-(p-CF3)3-t-BuPHOX. Tetrahedron letters Craig, R. A., Stoltz, B. M. 2015; 56 (32): 4670-4673

  Abstract

  The synthesis of the novel electronically modified phosphinooxazoline (PHOX) ligand, (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX, is described. The utility of this PHOX ligand is explored in both enantio- and diastereoselective palladium-catalyzed allylic alkylations. These investigations prove (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX to be an effective and cost-efficient alternative to electronically modified PHOX ligands derived from the prohibitively expensive (R)-t-leucine.

  View details for DOI 10.1016/j.tetlet.2015.06.039

  View details for PubMedID 26257445

  View details for PubMedCentralID PMC4524747

• An Efficient Protocol for the Palladium-catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst. Advanced synthesis & catalysis Marziale, A. N., Duquette, D. C., Craig, R. A., Kim, K. E., Liniger, M., Numajiri, Y., Stoltz, B. M. 2015; 357 (10): 2238-2245

  Abstract

  Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol % and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion.

  View details for DOI 10.1002/adsc.201500253

  View details for PubMedID 27042171

  View details for PubMedCentralID PMC4811629

• Highly functionalized donor-acceptor cyclopropanes applied toward the synthesis of the Melodinus alkaloids. Tetrahedron letters Goldberg, A. F., Craig, R. A., O'Connor, N. R., Stoltz, B. M. 2015; 56 (23): 2983-2990

  Abstract

  A series of highly substituted vinylcyclopropanes were prepared and examined as reaction partners in a palladium-catalyzed (3 + 2) cycloaddition with nitrostyrenes. Described herein are our efforts to synthesize an elusive 1,1-divinylcyclopropane by several distinct approaches, and to apply surrogates of this fragment toward the synthesis of the Melodinus alkaloids.

  View details for DOI 10.1016/j.tetlet.2014.09.016

  View details for PubMedID 26120207

  View details for PubMedCentralID PMC4479304

• Palladium-catalyzed decarboxylative allylic alkylation of diastereomeric β-ketoesters. Tetrahedron Ma, S., Reeves, C. M., Craig, R. A., Stoltz, B. M. 2014; 70 (27-28): 4208-4212

  Abstract

  The palladium-catalyzed decarboxylative allylic alkylation of diastereomeric β-ketoesters derived from 4-tert-butylcyclohexanone is described. These experiments were performed to elucidate our understanding of stereoablative enantioconvergent catalysis. A detailed analysis of the product distribution, including stereochemical outcome of the products, is included. These studies also reveal an interesting example of selectivity that is governed by competing modes of substrate and catalyst control.

  View details for DOI 10.1016/j.tet.2014.03.042

  View details for PubMedID 24999286

  View details for PubMedCentralID PMC4078409

• Stereoselective Lewis acid mediated (3+2) cycloadditions of N-H- and N-sulfonylaziridines with heterocumulenes. Chemistry (Weinheim an der Bergstrasse, Germany) Craig, R. A., O'Connor, N. R., Goldberg, A. F., Stoltz, B. M. 2014; 20 (16): 4806-13

  Abstract

  Alkyl and aryl isothiocyanates and carbodiimides are effective substrates in (3+2) cycloadditions with N-sulfonyl-2-substituted aziridines and 2-phenylaziridine for the synthesis of iminothiazolidines and iminoimidazolidines. Additionally, the stereoselective (3+2) cycloaddition of N-H- and N-sulfonylaziridines with isothiocyanates can be accomplished, allowing for the synthesis of highly enantioenriched iminothiazolidines. Evidence for an intimate ion-pair mechanism is presented herein in the context of these chemo-, regio-, and diastereoselective transformations. The demonstrated ability to remove the sulfonyl group from the heterocyclic products displays the utility of these compounds for further derivatization and application.

  View details for DOI 10.1002/chem.201303699

  View details for PubMedID 24604740

  View details for PubMedCentralID PMC4104980

• Enantioselective synthesis of a hydroxymethyl-cis-1,3-cyclopentenediol building block. Organic letters Craig, R. A., Roizen, J. L., Smith, R. C., Jones, A. C., Stoltz, B. M. 2012; 14 (22): 5716-9

  Abstract

  A brief, enantioselective synthesis of a hydroxymethyl-cis-1,3-cyclopentenediol building block is presented. This scaffold allows access to the cis-1,3-cyclopentanediol fragments found in a variety of biologically active natural and non-natural products. This rapid and efficient synthesis is highlighted by the utilization of the palladium-catalyzed enantioselective allylic alkylation of dioxanone substrates to prepare tertiary alcohols.

  View details for DOI 10.1021/ol3027297

  View details for PubMedID 23101616

  View details for PubMedCentralID PMC3506031

• Lewis acid mediated (3 + 2) cycloadditions of donor-acceptor cyclopropanes with heterocumulenes. Organic letters Goldberg, A. F., O'Connor, N. R., Craig, R. A., Stoltz, B. M. 2012; 14 (20): 5314-7

  Abstract

  Isocyanates, isothiocyanates, and carbodiimides are effective substrates in (3 + 2) cycloadditions with donor-acceptor cyclopropanes for the synthesis of five-membered heterocycles. These reactions exhibit a broad substrate scope, high yields, and well-defined chemoselectivity. Discussed herein are the implications of Lewis acid choice on the stereochemical outcome and the reaction mechanism.

  View details for DOI 10.1021/ol302494n

  View details for PubMedID 23046060

  View details for PubMedCentralID PMC3490221