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Cover page of Stereochemical Control Yields Mucin Mimetic Polymers.

Stereochemical Control Yields Mucin Mimetic Polymers.

(2021)

All animals except sponges produce mucus. Across the animal kingdom, this hydrogel mediates surface wetting, viscosity, and protection against microbes. The primary components of mucus hydrogels are mucins-high molecular weight O-glycoproteins that adopt extended linear structures. Glycosylation is integral to mucin function, but other characteristics that give rise to their advantageous biological activities are unknown. We postulated that the extended conformation of mucins is critical for their ability to block microbial virulence phenotypes. To test this hypothesis, we developed synthetic mucin mimics that recapitulate the dense display of glycans and morphology of mucin. We varied the catalyst in a ring-opening metathesis polymerization (ROMP) to generate substituted norbornene-derived glycopolymers containing either cis- or trans-alkenes. Conformational analysis of the polymers based on allylic strain suggested that cis- rather than trans-poly(norbornene) glycopolymers would adopt linear structures that mimic mucins. High-resolution atomic force micrographs of our polymers and natively purified Muc2, Muc5AC, and Muc5B mucins revealed that cis-polymers adopt extended, mucin-like structures. The cis-polymers retained this structure in solution and were more water-soluble than their trans-analogs. Consistent with mucin's linear morphology, cis-glycopolymers were more potent binders of a bacterial virulence factor, cholera toxin. Our findings highlight the importance of the polymer backbone in mucin surrogate design and underscore the significance of the extended mucin backbone for inhibiting virulence.

Cover page of Syntheses of Molybdenum and Tungsten Imido Alkylidene Complexes that Contain a Bidentate Oxo/Thiolato Ligand

Syntheses of Molybdenum and Tungsten Imido Alkylidene Complexes that Contain a Bidentate Oxo/Thiolato Ligand

(2020)

3,3′,5,5′-Tetra-tert-butyl-2′-sulfanyl[1,1′-biphenyl]-2-ol (H2[tBu4OS]) was prepared in 24 % yield overall from the analogous biphenol using standard techniques. Addition of H2[tBu4OS] to Mo(NAr)(CHCMe2Ph)(2,5-dimethylpyrrolide)2 led to formation of Mo(NAr)(CHCMe2Ph)[tBu4OS], which was trapped with PMe3 to give Mo(NAr)(CHCMe2Ph)[tBu4OS](PMe3) (1(PMe3)). An X-ray crystallographic study of 1(PMe3) revealed that two structurally distinct square pyramidal molecules are present in which the alkylidene ligand occupies the apical position in each. Both 1(PMe3)A and 1(PMe3)B are disordered. Mo(NAd)(CHCMe2Ph)(tBu4OS)(PMe3) (2(PMe3); Ad=1-adamantyl) and W(NAr)(CHCMe2Ph)(tBu4OS)(PMe3) (3(PMe3)) were prepared using analogous approaches. 1(PMe3) reacts with ethylene (1 atm) in benzene within 45 minutes to give an ethylene complex Mo(NAr)(tBu4OS)(C2H4) (4) that is isolable and relatively stable toward loss of ethylene below 60 °C. An X-ray study shows that the bond distances and angles for the ethylene ligand in 4 are like those found for bisalkoxide ethylene complexes of the same general type. Complex 1(PMe3) in the presence of one equivalent of B(C6F5)3 catalyzes the homocoupling of 1-decene, allyltrimethylsilane, and allylboronic acid pinacol ester at ambient temperature. 1(PMe3), 2(PMe3), and 3(PMe3) all catalyze the ROMP of rac-endo,exo-5,6-dicarbomethoxynorbornene (rac-DCMNBE) in the presence of B(C6F5)3, but the polyDCMNBE that is formed has a random structure.

Cover page of Molybdenum Disubstituted Alkylidene Complexes

Molybdenum Disubstituted Alkylidene Complexes

(2020)

Through relatively straightforward techniques that begin with Mo(NAr)(CH-t-Bu)[OCMe(CF3)2]2 (Ar = 2,6-i-Pr2C6H3), we have prepared Mo(NAr)(CMePh)(OMesityl)2, [Mo(NAr)(CMePh)(OC6F5)2]2, Mo(NAr)(CMePh)(OC6F5)2(MeCN), Mo(NAr)(CMePh)(OC6F5)2(bipyridyl), Mo(NAr)(CMePh)(Cl)2(bipyridyl), Mo(NAr)(CMePh)(Cl)(OHMT)(MeCN) (OHMT = O-2,6-(2,4,6-Me3C6H2)2C6H3), and Mo(NAr)(CMePh)(Pyrrolide)(OHMT). X-ray studies reveal that in five compounds the alkylidene isomer (A) is that in which the phenyl group in the alkylidene points toward the imido nitrogen. In Mo(NAr)(CMePh)(OC6F5)2(MeCN) the isomer in which the methyl group points toward the imido nitrogen (isomer B) has cocrystallized with isomer A (12%). In two 14e compounds that contain isomer A, the Mo═C-C angles differ by 30-36°, consistent with a Mo...C-Hβ agostic interaction. Several of the complexes reported here react readily with ethylene, 1-decene, or cyclooctene to give the expected products, thus confirming their viability as initiators or intermediates in metathesis reactions.

Cover page of Synthesis of Molybdenum(VI) Neopentylidene Neopentylidyne Complexes

Synthesis of Molybdenum(VI) Neopentylidene Neopentylidyne Complexes

(2019)

Mo(C-t-Bu)(CH-t-Bu)(Cl)(PMe2Ph)2 (1) was prepared as off-white crystals in 26% yield through addition of 2.5 equiv of Mg(CH2-t-Bu)2 to Mo(O)[OC(CF3)3]4 in diethyl ether followed by 3 equiv of PMe2Ph and a workup that includes dichloromethane (the source of Cl). Compound 1 is largely a syn isomer initially that equilibrates to give approximately a 1:1 mixture of syn and anti isomers within 1-2 h. Compound 1 reacts with Li(3,5-dimethylpyrrolide) to give Mo(C-t-Bu)(CH-t-Bu)(η1-Me2Pyr)(PMe2Ph)2 (2a) as a pale yellow solid in 76% yield, and 2a reacts with Ph3SiOH to give a mixture of syn and anti Mo(C-t-Bu)(CH-t-Bu)(OSiPh3)(PMe2Ph)2 (3a) in 84% yield. All three compounds tend to lose PMe2Ph to give 14e monophosphine complexes with the formulas Mo(C-t-Bu)(CH-t-Bu)(X)(PMe2Ph) (X = Cl, Me2Pyr, or OSiPh3), none of which could be isolated. X-ray studies show the structures of 1, 2a, and 3a to be analogous with τ values of 0.45, 0.53, and 0.69, respectively.

Cover page of E- and Z-, di- and tri-substituted alkenyl nitriles through catalytic cross-metathesis.

E- and Z-, di- and tri-substituted alkenyl nitriles through catalytic cross-metathesis.

(2019)

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for the preparation of di- or tri-substituted alkenyl nitriles. Related approaches that are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-di-substituted cyano-substituted alkenes or their corresponding tri-substituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy to apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to the synthesis of biologically active compounds.

Cover page of Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis.

Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis.

(2017)

Catalytic cross-metathesis is a central transformation in chemistry, yet corresponding methods for the stereoselective generation of acyclic trisubstituted alkenes in either the E or the Z isomeric forms are not known. The key problems are a lack of chemoselectivity-namely, the preponderance of side reactions involving only the less hindered starting alkene, resulting in homo-metathesis by-products-and the formation of short-lived methylidene complexes. By contrast, in catalytic cross-coupling, substrates are more distinct and homocoupling is less of a problem. Here we show that through cross-metathesis reactions involving E- or Z-trisubstituted alkenes, which are easily prepared from commercially available starting materials by cross-coupling reactions, many desirable and otherwise difficult-to-access linear E- or Z-trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to 98 per cent E or 95 per cent Z). The utility of the strategy is demonstrated by the concise stereoselective syntheses of biologically active compounds, such as the antifungal indiacen B and the anti-inflammatory coibacin D.

Cover page of Kinetically E-selective macrocyclic ring-closing metathesis.

Kinetically E-selective macrocyclic ring-closing metathesis.

(2017)

Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization-a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl-B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib-a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis-was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.

Cover page of Synthesis of <i>Cis</i>,<i>syndiotactic</i> A<i>-alt</i>-B Copolymers from Two Enantiomerically Pure <i>Trans</i>-2,3-Disubstituted-5,6-Norbornenes.

Synthesis of Cis,syndiotactic A-alt-B Copolymers from Two Enantiomerically Pure Trans-2,3-Disubstituted-5,6-Norbornenes.

(2016)

Cis,syndiotacticA-alt-B copolymers, where A and B are two enantiomerically pure trans-2,3-disubstituted-5,6-norbornenes with "opposite" chiralities, can be prepared with stereogenic-at-metal initiators of the type M(NR)(CHR')(OR")(pyrrolide). Formation of a high percentage of alternating AB copolymer linkages relies on an inversion of chirality at the metal with each propagating step and a relatively fast formation of an AB sequence as a consequence of a preferred diastereomeric relationship between the chirality at the metal and the chirality of the monomer. This approach to formation of an alternating AB copolymer contrasts dramatically with the principle of forming AB copolymers from achiral monomers and catalysts.

Cover page of Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis.

Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis.

(2016)

Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by small amounts of a catalyst that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, and proceed to high conversion at ambient temperature within four hours. We obtain many alkenyl chlorides, bromides and fluorides in up to 91 per cent yield and complete Z selectivity. This method can be used to synthesize biologically active compounds readily and to perform site- and stereoselective fluorination of complex organic molecules.

Cover page of The discovery of Mo(III) in FeMoco: reuniting enzyme and model chemistry.

The discovery of Mo(III) in FeMoco: reuniting enzyme and model chemistry.

(2015)

Biological nitrogen fixation is enabled by molybdenum-dependent nitrogenase enzymes, which effect the reduction of dinitrogen to ammonia using an Fe7MoS9C active site, referred to as the iron molybdenum cofactor or FeMoco. In this mini-review, we summarize the current understanding of the molecular and electronic structure of FeMoco. The advances in our understanding of the active site structure are placed in context with the parallel evolution of synthetic model studies. The recent discovery of Mo(III) in the FeMoco active site is highlighted with an emphasis placed on the important role that model studies have played in this finding. In addition, the reactivities of synthetic models are discussed in terms of their relevance to the enzymatic system.