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1.  Optogenetic Engineering: Light-Directed Cell Motility 
Genetically encoded, light activatable proteins furnish the means to probe biochemical pathways at specific sub-cellular locations with exquisite temporal control. However, engineering these systems to provide a dramatic jump in localized activity while retaining a low dark-state background remains a significant challenge. We describe herein an actin-remodelling protein cofilin that, when placed within the framework of a genetically encodable, light activatable heterodimerizer system, induces dramatic changes in the F-actin network and consequent cell motility upon illumination. We demonstrate that the use of a partially impaired mutant of cofilin is critical for maintaining low background activity in the dark. We also show that light-directed recruitment of the reduced activity cofilin mutants to the cytoskeleton is sufficient to induce F-actin remodeling, formation of filopodia, and directed cell motility.
PMCID: PMC4196877  PMID: 25156888
optogenetics; cofilin; cell motility; F-actin; protein design
2.  Photocatalytic Synthesis of Dihydrobenzofurans by Oxidative [3+2] Cycloaddition of Phenols** 
We report a protocol for oxidative [3+2] cycloadditions of phenols and alkenes applicable to the modular synthesis of a large family of dihydrobenzofuran natural products. Visible light-activated transition metal photocatalysis enables the use of ammonium persulfate as an easily handled, benign terminal oxidant. The broad range of organic substrates that are readily oxidized by photoredox catalysis suggests that this strategy may be applicable to a variety of useful oxidative transformations.
PMCID: PMC4220618  PMID: 25155300
cycloaddition; heterocycles; phenols; photocatalysis; photooxidation
3.  A Multitasking Vanadium-Dependent Chloroperoxidase as an Inspiration for the Chemical Synthesis of the Merochlorins** 
The vanadium-dependent chloroperoxidase Mcl24 was discovered to mediate a complex series of unprecedented transformations in the biosynthesis of the merochlorin meroterpenoid antibiotics. In particular, a site-selective naphthol chlorination is followed by a sequence of oxidative dearomatization/terpene cyclization reactions to build up the stereochemically complex carbon framework of the merochlorins in one step. Inspired by the enzyme reactivity, we developed a chemical chlorination protocol paralleling the biocatalytic process. These chemical studies led to the identification of previously overlooked merochlorin natural products.
PMCID: PMC4226426  PMID: 25147132
biosynthesis; vanadium-dependent haloperoxidase; oxidative dearomatization; biomimetic synthesis; chlorination
4.  One-pot Enzymatic Synthesis of Merochlorin A and B** 
The polycyclic merochlorin A and B are complex halogenated meroterpenoid natural products with significant antibacterial activities that are produced by the marine bacterium Streptomyces sp. strain CNH-189. Here we employ heterologously produced enzymes and chemical synthesis to fully reconstitute the merochlorin biosynthesis in vitro. The interplay of a dedicated type III polyketide synthase, a prenyl diphosphate synthase, and an aromatic prenyltransferase allow formation of a highly unusual aromatic polyketide-terpene hybrid intermediate that features an unprecedented branched sesquiterpene moiety. As supported by in vivo experiments, this precursor is furthermore chlorinated and cyclized to merochlorin A and isomeric merochlorin B by a single vanadium-dependent haloperoxidase, thus completing the remarkably efficient pathway.
PMCID: PMC4229033  PMID: 25115835
biosynthesis; enzyme catalysis; natural products; polyketides; terpenoids
5.  Spiroacetal Formation through Telescoped Cycloaddition and Carbon–Hydrogen Bond Functionalization: Total Synthesis of Bistramide A 
Spiroacetals can be formed through a one-pot sequence of a hetero Diels-Alder reaction, an oxidative carbon–hydrogen bond cleavage, and an acid treatment. This convergent approach expedites access to a complex molecular subunit that is present in numerous biologically active structures. The utility of the protocol is demonstrated through its application to a brief synthesis of the actin-binding cytotoxin bistramide A.
PMCID: PMC4234310  PMID: 25196585
cycloaddition; C–H activation; spiro compound; natural products; stereoselectivity
6.  Total Synthesis of Myceliothermophins C, D and E** 
The total synthesis of cytotoxic polyketides myceliothermophins E (1), C (2) and D (3) through a cascade-based cyclization to form the trans-fused decalin system is described. The convergent synthesis delivered all three natural products through late-stage divergence and facilitated unambiguous C21 structural assignments for 2 and 3 through X-ray crystallographic analysis which revealed an interesting dimeric structure between its enantiomeric forms.
PMCID: PMC4257465  PMID: 25163463
cascade reaction; decalin; natural products; polyketides; total synthesis
7.  Asymmetric gold-catalyzed lactonizations in water at room temperature** 
Asymmetric gold-catalyzed hydrocarboxylations are reported that show broad substrate scope. The hydrophobic effect associated with in situ-formed aqueous nanomicelles leads to good-to-excellent ee’s of product lactones. In-flask product isolation, along with recycling of the catalyst and reaction medium, combine to arrive at an especially environmentally friendly process.
PMCID: PMC4193796  PMID: 25124085
Micellar catalysis; gold catalysis; asymmetric catalysis; designer surfactant TPGS-750-M
8.  Coupling of Sterically Hindered Trisubstituted Olefins and Benzocyclobutenones via C–C Activation: Total Synthesis and Structural Revision of Cycloinumakiol ** 
The first total synthesis of the proposed structure of cycloinumakiol (1) and its C5-epimer (18) are achieved in a concise and efficient fashion: 9 and 5 steps from known 3-hydroxybenzocyclobutenone with overall yields of 15% and 33%, respectively. A key for the success of this approach is use of a catalytic C–C activation strategy for constructing the tetracyclic core of 1 through carboacylation of a sterically hindered trisubstituted olefin with benzocyclobutenone. In addition, the structure of the natural cycloinumakiol was reassigned to 19-hydroxyltotarol (7) through X-ray diffraction analysis. This work demonstrates the potential of C–C activation for streamlining complex natural-product synthesis.
PMCID: PMC4214140  PMID: 25138969
total synthesis; C–C activation; cycloinumakiol; structural revision; Rh catalysis
9.  Polymerization of tellurophene derivatives via microwave-assisted palladium-catalyzed ipso-arylative polymerization** 
We report the synthesis of a tellurophene-containing low bandgap polymer, PDPPTe2T, via microwave-assisted palladium-catalyzed ipso-arylative polymerization of 2,5-bis[(α-hydroxy-α,α-diphenyl)methyl]tellurophene with a diketopyrrolopyrrole (DPP) monomer. Compared with the corresponding thiophene analog, PDPPTe2T absorbs light of longer wavelengths and has a smaller bandgap. Bulk heterojunction solar cells prepared from PDPPTe2T and PC71BM show PCE values of up to 4.4%. External quantum efficiency measurements show that PDPPTe2T produces photocurrent at wavelengths up to 1 μm. DFT calculations suggest that the atomic substitution from sulfur to tellurium increases electronic coupling to decrease the length of the carbon-carbon bonds between the tellurophene and thiophene rings, which results in the red-shift in absorption upon substitution of tellurium for sulfur.
PMCID: PMC4487642  PMID: 25145499
tellurophene; low bandgap polymer; ipso-arylative polymerization; microwave-assisted reaction; organic solar cells
10.  Pushing the Limits of Neutral Organic Electron Donors: A Tetra(iminophosphorano)-Substituted Bispyridinylidene 
A new ground-state organic electron donor has been prepared that features four strongly π-donating iminophosphorano substituents on a bispyridinylidene skeleton. Cyclic voltammetry reveals a record redox potential of −1.70 V vs. saturated calomel electrode (SCE) for the couple involving the neutral organic donor and its dication. This highly reducing organic compound can be isolated (44 %) or more conveniently generated in situ by a deprotonation reaction involving its readily prepared pyridinium ion precursor. This donor is able to reduce a variety of aryl halides, and, owing to its redox potential, was found to be the first organic donor to be effective in the thermally induced reductive S–N bond cleavage of N,N-dialkylsulfonamides, and reductive hydrodecyanation of malonitriles.
PMCID: PMC4581462  PMID: 26213345
electron transfer; iminophosphoranes; organic reductants; reduction; substituent effects
11.  One-Pot Cannizzaro Cascade Synthesis of ortho-Fused Cycloocta-2,5-dien-1-ones from 2-Bromo(hetero)aryl Aldehydes 
An intramolecular Cannizzaro-type hydride transfer to an in situ prepared allene enables the synthesis of ortho-fused 4-substituted cycloocta-2,5-dien-1-ones with unprecedented technical ease for an eight-ring carboannulation. Various derivatives could be obtained from commercially available (hetero)aryl aldehydes, trimethylsilylacetylene, and simple propargyl chlorides in good yields.
PMCID: PMC4581465  PMID: 26230528
aldehydes; annulation; carbocycles; medium-ring compounds; synthetic methods
12.  Total Synthesis of Δ12-Prostaglandin J3, a Highly Potent and Selective Antileukemic Agent** 
A catalytic asymmetric total synthesis of the potent and selective antileukemic Δ12-prostaglandin J3 (Δ12-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, constructed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule.
PMCID: PMC4169176  PMID: 25098181
asymmetric catalysis; C–H activation; leukemia; natural products; total synthesis
13.  Spectroscopic Capture and Reactivity of a Low-Spin Cobalt(IV)-Oxo Complex Stabilized by Binding Redox-Inactive Metal Ions 
High-valent cobalt-oxo intermediates are proposed as reactive intermediates in a number of cobalt complex-mediated oxidation reactions. Herein we report the spectroscopic capture of low-spin (S = 1/2) Co(IV)-oxo species in the presence of redox-inactive metal ions, such as Sc3+, Ce3+, Y3+, and Zn2+ and investigation of their reactivity in C-H bond activation and sulfoxidation reactions. Theoretical calculations predict that the binding of Lewis-acidic metal ions to the cobalt-oxo core increases the electrophilicity of the oxygen atom, resulting in the redox tautomerism of a highly unstable [(TAML)CoIII-(O•)]2− species to a more stable [(TAML)CoIV-(O)(Mn+)] core. The present report supports the proposed role of the redox-inactive metal ions in facilitating formation of high-valent metal-oxo cores as a necessary step for oxygen evolution in chemistry and biology.
PMCID: PMC4506312  PMID: 25081948
Cobalt; Oxo ligand; Lewis acid stabilization; Redox tautomerization; Oxygenation
14.  Mapping Polyamide–DNA Interactions in Human Cells Reveals a New Design Strategy for Effective Targeting of Genomic Sites** 
Targeting the genome with sequence-specific synthetic molecules is a major goal at the interface of chemistry, biology, and personalized medicine. Pyrrole/imidazole based polyamides can be rationally designed to target specific DNA sequences with exquisite precision in vitro; yet, the biological outcomes are often difficult to interpret using current models of binding energetics. To directly identify the binding sites of polyamides across the genome, we designed, synthesized, and tested polyamide derivatives that enabled covalent crosslinking and localization of polyamide–DNA interaction sites in live human cells. Bioinformatic analysis of the data reveals that clustered binding sites, spanning a broad range of affinities, best predict occupancy in cells. In contrast to the prevailing paradigm of targeting single high-affinity sites, our results point to a new design principle to deploy polyamides and perhaps other synthetic molecules to effectively target desired genomic sites in vivo.
PMCID: PMC4160732  PMID: 25066383
genome targeting; molecular recognition; DNA; polyamides; COSMIC
15.  Cobalt-Catalyzed, Aminoquinoline-Directed sp2 C-H Bond Alkenylation by Alkynes** 
We have developed a method for cobalt-catalyzed, aminoquinoline- and picolinamide-directed sp2 C-H bond alkenylation by alkynes. Method shows excellent functional group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs Co(OAc)2*4H2O catalyst, Mn(OAc)2 cocatalyst, and oxygen from air as a terminal oxidant.
PMCID: PMC4167400  PMID: 25060365
Alkenes; C-H Activation; Alkynes; Cobalt
16.  Sequential Gene Silencing Using Wavelength-Selective Caged Morpholinos** 
Sequential gene silencing in zebrafish embryos has been achieved using caged morpholino oligonucleotides with spectrally distinct triggers. Using these optochemical tools, the genetic interactions that dynamically regulate mesoderm patterning have been examined.
PMCID: PMC4206551  PMID: 25130695
antisense oligonucleotides; caged compounds; gene expression; developmental biology; zebrafish
17.  Expedient Synthesis of Fused Azepine Derivatives using a Sequential Rh(II)-Catalyzed Cyclopropanation/1-Aza-Cope Rearrangement of Dienyltriazoles** 
A general method for the formation of fused dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α-imino Rh(II)-carbenoid, leading to a transient 1-imino-2-vinylcyclopropane intermediate which rapidly undergoes a 1-aza-Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram-scale. The use of catalyst-free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle.
PMCID: PMC4266427  PMID: 25044869
α-Iminocarbene; Rh catalysis; Dihydroazepine; Triazole; N-Heterocycle
18.  Ligand Modification Transforms a Catalase Mimic into a Water Oxidation Catalyst** 
The catalytic reactivity of the high-spin Mn(II) pyridinophane complexes [(Py2NR2)Mn(H2O)2]2+ (R = H, Me, tBu) towards O2 formation is reported. With small macrocycle N-substituents (R = H, Me), the complexes catalytically disproportionate H2O2 in aqueous solution. While this catalysis is shut down with a bulky substituent (R = tBu), the complex becomes active for electrocatalytic H2O oxidation in aqueous solution. Control experiments are in support of a homogeneous molecular catalyst and preliminary mechanistic studies suggest the catalyst is mononuclear. This ligand-controlled switch in catalytic reactivity has implications for the design of new manganese-based water oxidation catalysts.
PMCID: PMC4167389  PMID: 25044487
water splitting; catalysis; manganese; macrocycles; molecular electrochemistry
19.  Simple Sulfinate Synthesis Enables C–H Trifluoromethylcyclopropanation 
A simple method to convert readily available carboxylic acids into sulfinate salts employing an interrupted Barton decarboxylation reaction is reported. A medicinally oriented panel of ten new sulfinate reagents was created using this method, including a key trifluoromethylcyclopropanation reagent TFCS-Na. The reactivity of six of these salts towards C–H functionalization was field-tested using several different classes of heterocycles.
PMCID: PMC4186797  PMID: 25088979
bioisosteres; sulfinate salts; heterocycles; C–H functionalization; analogue synthesis
20.  Targeting Human C-Type Lectin-Like Molecule-1 (CLL1) with a Bispecific Antibody for Acute Myeloid Leukemia Immunotherapy** 
Acute myeloid leukemia (AML), the most common acute adult leukemia and the second most common pediatric leukemia, still has a poor prognosis. Human C-type lectin-like molecule-1 (CLL1) is a recently identified myeloid lineage restricted cell surface marker, which is overexpressed in over 90% of AML patient myeloid blasts and in leukemic stem cells. Here, we describe the synthesis of a novel bispecific antibody, αCLL1-αCD3, using the genetically encoded unnatural amino acid, p-acetylphenylalanine. The resulting αCLL1-αCD3 recruits cytotoxic T cells to CLL1 positive cells, and demonstrates potent and selective cytotoxicity against several human AML cell lines and primary AML patient-derived cells in vitro. Moreover, αCLL1-αCD3 treatment completely eliminates established tumors in an U937 AML cell line xenograft model. These results validate the clinical potential of CLL1 as an AML specific antigen for the generation of a novel immunotherapeutic for AML.
PMCID: PMC4280064  PMID: 25056598
CLL1; unnatural amino acid; cancer immunotherapy; bispecific antibody; Acute Myeloid Leukemia
21.  Total Synthesis of Celogentin C** 
PMCID: PMC4559083  PMID: 19554590
natural products; oxidative coupling; peptides; radical reactions; total synthesis
22.  Cooperative Gold Nanoparticle Stabilization by Acetylenic Phosphaalkenes 
Acetylenic phosphaalkenes (APAs) are used as a novel type of ligands for the stabilization of gold nanoparticles (AuNP). As demonstrated by a variety of experimental and analytical methods, both structural features of the APA, that is, the P=C as well as the C≡C units are essential for NP stabilization. The presence of intact APAs on the AuNP is demonstrated by surface-enhanced Raman spectroscopy (SERS), and first principle calculations indicate that bonding occurs most likely at defect sites on the Au surface. AuNP-bound APAs are in chemical equilibrium with free APAs in solution, leading to a dynamic behavior that can be explored for facile place-exchange reactions with other types of anchor groups such as thiols or more weakly binding phosphine ligands.
PMCID: PMC4557036  PMID: 26211907
ab initio studies; acetylenic phosphaalkenes; dynamic behavior; gold nanoparticles
23.  Rise of the Molecular Machines 
PMCID: PMC4557038  PMID: 26219251
molecular devices; molecular machines; molecular motors; molecular nanotechnology
24.  P–C-Activated Bimetallic Rhodium Xantphos Complexes: Formation and Catalytic Dehydrocoupling of Amine–Boranes** 
{Rh(xantphos)}-based phosphido dimers form by P–C activation of xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) in the presence of amine–boranes. These dimers are active dehydrocoupling catalysts, forming polymeric [H2BNMeH]n from H3B⋅NMeH2 and dimeric [H2BNMe2]2 from H3B⋅NMe2H at low catalyst loadings (0.1 mol %). Mechanistic investigations support a dimeric active species, suggesting that bimetallic catalysis may be possible in amine–borane dehydropolymerization.
PMCID: PMC4557049  PMID: 26140498
amine–boranes; homogeneous catalysis; P ligands; rhodium; X-ray diffraction
25.  Following the Reaction of Heteroanions inside a {W18O56} Polyoxometalate Nanocage by NMR Spectroscopy and Mass Spectrometry** 
By incorporating phosphorus(III)-based anions into a polyoxometalate cage, a new type of tungsten-based unconventional Dawson-like cluster, [W18O56(HPIIIO3)2(H2O)2]8−, was isolated, in which the reaction of the two phosphite anions [HPO3]2− within the {W18O56} cage could be followed spectroscopically. As well as full X-ray crystallographic analysis, we studied the reactivity of the cluster using both solution-state NMR spectroscopy and mass spectrometry. These techniques show that the cluster undergoes a structural rearrangement in solution whereby the {HPO3} moieties dimerize to form a weakly interacting (O3PH⋅⋅⋅HPO3) moiety. In the crystalline state the cluster exhibits a thermally triggered oxidation of the two PIII template moieties to form PV centers (phosphite to phosphate), commensurate with the transformation of the cage into a Wells–Dawson {W18O54} cluster.
PMCID: PMC4557056  PMID: 26013548
cluster compounds; electronic structure; NMR spectroscopy; phosphorus; polyoxometalates

Results 1-25 (1655)