- Self-Assembly and Molecular Recognition in Water: Tubular Stacking and Guest-Templated Discrete Assembly of Water-Soluble, Shape-Persistent Macrocycles
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Supramolecular chemistry in aqueous media is an area with great fundamental and practical significance. To examine the role of multiple noncovalent interactions in controlled assembling and binding behavior in water, the self-association of five water-soluble hexakis(m-phenylene ethynylene) (m-PE) macrocycles, along with the molecular recognition behavior of the resultant assemblies, is investigated with UV-vis, fluorescence, CD, and NMR spectroscopy, mass spectrometry, and computational studies. In contrast to their different extents of self-aggregation in organic solvents, all five macrocycles remain aggregated in water at concentrations down to the micromolar (μM) range. CD spectroscopy reveals that 1-F6 and 1-H6, two macrocycles carrying chiral side chains and capable of H-bonded self-association, assemble into tubular stacks. The tubular stacks serve as supramolecular hosts in water, as exemplified by the interaction of macrocycles 1-H6 and 2-H6 and guests G1 through G4, each having a rod-like oligo(p-phenylene ethynylene) (p-PE) segment flanked by two hydrophilic chains. Fluorescence and 1H NMR spectroscopy revealed the formation of kinetically stable, discrete assemblies upon mixing 2-H6 and a guest. The binding stoichiometry, determined with fluorescence, 1H NMR, and ESI-MS, reveals that the discrete assemblies are novel pseudorotaxanes, each containing a pair of identical guest molecules encased by a tubular stack. The two guest molecules define the number of macrocyclic molecules that comprise the host, which curbs the "infinite" stack growth, resulting in a tubular stack with a cylindrical pore tailoring the length of the p-PE segment of the bound guests. Each complex is stabilized by the action of multiple noncovalent forces including aromatic stacking, side-chain H-bonding, and van der Waals interactions. Thus, the interplay of multiple noncovalent forces aligns the molecules of macrocycles 1 and 2 into tubular stacks with cylindrical inner pores that, upon binding rod-like guests, lead to tight, discrete, and well-ordered tubular assemblies that are unprecedented in water.
- Wang, Qiuhua,Zhong, Yulong,Miller, Daniel P.,Lu, Xiaoxing,Tang, Quan,Lu, Zhong-Lin,Zurek, Eva,Liu, Rui,Gong, Bing
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p. 2915 - 2924
(2020/02/04)
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- Sequence-Controlled Polymers Through Entropy-Driven Ring-Opening Metathesis Polymerization: Theory, Molecular Weight Control, and Monomer Design
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The bulk properties of a copolymer are directly affected by monomer sequence, yet efficient, scalable, and controllable syntheses of sequenced copolymers remain a defining challenge in polymer science. We have previously demonstrated, using polymers prepared by a step-growth synthesis, that hydrolytic degradation of poly(lactic-co-glycolic acid)s is dramatically affected by sequence. While much was learned, the step-growth mechanism gave no molecular weight control, unpredictable yields, and meager scalability. Herein, we describe the synthesis of closely related sequenced polyesters prepared by entropy-driven ring-opening metathesis polymerization (ED-ROMP) of strainless macromonomers with imbedded monomer sequences of lactic, glycolic, 6-hydroxy hexanoic, and syringic acids. The incorporation of ethylene glycol and metathesis linkers facilitated synthesis and provided the olefin functionality needed for ED-ROMP. Ring-closing to prepare the cyclic macromonomers was demonstrated using both ring-closing metathesis and macrolactonization reactions. Polymerization produced macromolecules with controlled molecular weights on a multigram scale. To further enhance molecular weight control, the macromonomers were prepared with cis-olefins in the metathesis-active segment. Under these selectivity-enhanced (SEED-ROMP) conditions, first-order kinetics and narrow dispersities were observed and the effect of catalyst initiation rate on the polymerization was investigated. Enhanced living character was further demonstrated through the preparation of block copolymers. Computational analysis suggested that the enhanced polymerization kinetics were due to the cis-macrocyclic olefin being less flexible and having a larger population of metathesis-reactive conformers. Although used for polyesters in this investigation, SEED-ROMP represents a general method for incorporation of sequenced segments into molecular weight-controlled polymers.
- Nowalk, Jamie A.,Fang, Cheng,Short, Amy L.,Weiss, Ryan M.,Swisher, Jordan H.,Liu, Peng,Meyer, Tara Y.
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supporting information
p. 5741 - 5752
(2019/04/26)
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- DRUGS AND COMPOSITIONS FOR THE TREATMENT OF OCULAR DISORDERS
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The present invention provides new prodrugs of therapeutically active compounds, including oligomeric prodrugs, and compositions to treat medical disorders, for example glaucoma, a disorder or abnormality related to an increase in intraocular pressure (IOP), a disorder requiring neuroprotection, age-related macular degeneration, or diabetic retinopathy.
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Page/Page column 374
(2018/10/19)
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- Compounds And Compositions for the Treatment of Ocular Disorders
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The disclosure describes prodrugs and derivatives of prostaglandins, carbonic anhydrase inhibitors, kinase inhibitors, beta-adrenergic receptor antagonists and other drugs, as well as controlled delivery formulations containing such prodrugs and derivatives, for the treatment of ocular disorders.
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Paragraph 0515
(2017/04/11)
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- Total Synthesis of the GRP78-Downregulatory Macrolide (+)-Prunustatin A, the Immunosuppressant (+)-SW-163A, and a JBIR-04 Diastereoisomer That Confirms JBIR-04 Has Nonidentical Stereochemistry to (+)-Prunustatin A
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A unified total synthesis of the GRP78-downregulator (+)-prunustatin A and the immunosuppressant (+)-SW-163A based upon [1 + 1 + 1 + 1]-fragment condensation and macrolactonization between O(4) and C(5) is herein described. Sharpless asymmetric dihydroxylation was used to set the C(2) stereocenter present in both targets. In like fashion, coupling of the (+)-prunustatin A macrolide amine with benzoic acid furnished a JBIR-04 diastereoisomer whose NMR spectra did not match those of JBIR-04, thus confirming that it has different stereochemistry than (+)-prunustatin A.
- Manaviazar, Soraya,Nockemann, Peter,Hale, Karl J.
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p. 2902 - 2905
(2016/07/06)
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- Stereochemical diversity of AI-2 analogs modulates quorum sensing in Vibrio harveyi and Escherichia coli
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Bacteria coordinate population-dependent behaviors such as virulence by intra- and inter-species communication (quorum sensing). Autoinducer-2 (AI-2) regulates inter-species quorum sensing. AI-2 derives from the spontaneous cyclisation of linear (S)-4,5-d
- Rui, Fabio,Marques, Jo?o C.,Miller, Stephen T.,Maycock, Christopher D.,Xavier, Karina B.,Ventura, M. Rita
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p. 249 - 256
(2012/03/10)
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- Total synthesis and cytotoxicity evaluation of an oxazole analogue of tubulysin U
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Tubulysins are strongly cytotoxic natural tetrapeptides with potent antiproliferative, antimitotic, and antiangiogenic activities which might find use in oncology. We herein report the first total synthesis of a stereoisomerically pure oxazole analogue of
- Shankar, P. Sreejith,Sani, Monica,Saunders, Fiona R.,Wallace, Heather M.,Zanda, Matteo
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scheme or table
p. 1673 - 1676
(2011/09/15)
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- New insights into poly(lactic- co -glycolic acid) microstructure: Using repeating sequence copolymers to decipher complex NMR and thermal behavior
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Sequence, which Nature uses to spectacular advantage, has not been fully exploited in synthetic copolymers. To investigate the effect of sequence and stereosequence on the physical properties of copolymers, a family of complex isotactic, syndiotactic, and atactic repeating sequence poly(lactic-co-glycolic acid) copolymers (RSC PLGAs) were prepared and their NMR and thermal behavior was studied. The unique suitability of polymers prepared from the bioassimilable lactic and glycolic acid monomers for biomedical applications makes them ideal candidates for this type of sequence engineering. Polymers with repeating units of LG, GLG and LLG (L = lactic, G = glycolic) with controlled and varied tacticities were synthesized by assembly of sequence-specific, stereopure dimeric, trimeric, and hexameric segmer units. Specifically labeled deuterated lactic and glycolic acid segmers were likewise prepared and polymerized. Molecular weights for the copolymers were in the range Mn = 12-40 kDa by size exclusion chromatography in THF. Although the effects of sequence-influenced solution conformation were visible in all resonances of the 1H and 13C NMR spectra, the diastereotopic methylene resonances in the 1H NMR (CDCl3) for the glycolic units of the copolymers proved most sensitive. An octad level of resolution, which corresponds to an astounding 31-atom distance between the most separated stereocenters, was observed in some mixed sequence polymers. Importantly, the level of sensitivity of a particular NMR resonance to small differences in sequence was found to depend on the sequence itself. Thermal properties were also correlated with sequence.
- Stayshich, Ryan M.,Meyer, Tara Y.
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supporting information; experimental part
p. 10920 - 10934
(2010/09/17)
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- Synthesis of 7-oxa-phomopsolide e and its C-4 epimer
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A flexible, enantioselective route to highly functionalized α,β-unsaturated δ-lactones has been applied to the synthesis of 7-oxa-phomopsolide E and its C-4 epimer. This approach relies on the application of the Noyori asymmetric hydrogenation of furyl ke
- Li, Miaosheng,Scott, Jana,O'Doherty, George A.
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p. 1005 - 1009
(2007/10/03)
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- An enantioselective total synthesis of phomopsolide C
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A flexible enantioselective route to highly functionalized α,β-unsaturated δ-lactones, has allowed for the synthesis of phomopsolide C. This approach derives its asymmetry from (S)-lactic acid and by applying the Sharpless catalytic asymmetric dihydroxylation to vinylfuran. The resulting diols are produced in high enantioexcess and can be stereoselectively transformed into α,β-unsaturated-δ-lactones via a short highly diastereoselective oxidation and reduction sequence. A Wittig olefination reaction was used to introduce the side chain in either cis or trans form that was further elaborated into phomopsolide C.
- Harris, Joel M.,O'Doherty, George A.
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p. 8195 - 8199
(2007/10/03)
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- Asymmetric intramolecular [2 + 2] photocycloadditions: α- and β-hydroxy acids as chiral tether groups
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Chiral α- and β-hydroxy acids such as (S)-lactic acid, (S)-phenyllactic acid, (S)-mandelic acid, or (3R)-3-hydroxybutyric acid have been used as tether groups for intramolecular and diastereoselective [2 + 2] photocycloaddition of 3-oxocyclohexene carboxylic acid derivatives. Total regiocontrol toward the straight adduct and high diastereoselectivities (up to 94%) were observed in the case of butenyl lactate 11. After separation of the two diastereoisomers, cleavage of the chiral tether under basic conditions afforded cyclobutane lactones in good yield and enantiomeric pure form. An X-ray structure has been recorded that confirmed the relative and absolute configuration of the three contiguous stereogenic centers assigned according to CD spectra.
- Faure, Sophie,Piva-Le-Blanc, Sylvie,Bertrand, Cyrille,Pete, Jean-Pierre,Faure, Rene,Piva, Olivier
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p. 1061 - 1070
(2007/10/03)
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- Stereoselective synthesis of allylic amines by rearrangement of allylic trifluoroacetimidates: Stereoselective synthesis of polyoxamic acid and derivatives of other α-amino acids
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On heating in xylene under reflux, allylic trifluoroacetimidates undergo [3,3] sigmatropic rearrangement to regioisomeric allylic trifluoroacetamides. Examples include the rearrangements of the trifluoroacetimidates 16 and 73 to the trifluoroacetamides 17 and 74, which were incorporated into stereoselective syntheses of polyoxamic acid 1, and the rearrangement of the trifluoroacetimidate 26. The rearrangement was the key step in asymmetric syntheses of the (S)- and (R)-valine derivatives 37 and 48. Other examples include rearrangements of the trifluoroacetimidates 52, 54 and 56 prepared from geraniol, cinnamyl alcohol and sorbyl alcohol, respectively, and the more complex trifluoroacetimidates 62 and 69. The stereoselectivity of these rearrangements, which are somewhat faster than rearrangements of analogous allylic trichloroacetimidates, is consistent with the participation of chair-like, six-membered, transition structures. The Royal Society of Chemistry 1999.
- Savage, Ian,Thomas, Eric J.,Wilson, Peter D.
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p. 3291 - 3303
(2007/10/03)
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- Zirconocene-catalyzed epoxy ester - ortho ester rearrangement: A new method for the protection of polyfunctionalized carboxylic acids and the asymmetric synthesis of ortho esters
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In situ prepared Cp2(CI)Zr+ catalyzes the formation of ortho esters from epoxy esters. Acid-sensitive α-amino and α-hydroxy acid derivatives are converted in high yield to 2,7,8- trioxabicyclo[3.2.1]octanes (ABO-esters) using this protocol. This strategy is complementary to the OBO-ester technology, and orthogonal methods for the deprotection of ABO- and OBO-esters have been developed. The syntheses of the mushroom components (S)-γ- hydroxyleucine lactone and (S)-α-vinylglycine underline the value of ABO-ester protective group strategy. Using chiral epoxy alcohol derivatives, the first convenient and general asymmetric synthesis of bicyclic ortho esters has been achieved.
- Wipf, Peter,Wenjing, Xu,Hongyong, Kim,Takahashi, Hidenori
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p. 16575 - 16596
(2007/10/03)
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- Synthesis of Two Key Intermediates for Hennoxazole a
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Two key intermediates used for the synthesis of hennoxazole A have been synthesized. The anti-β-protected hydroxyl epoxide 5 was prepared from (R)-(+)-malic acid by the stereoselective alkylation utilizing a chiral borane reagent as a key step. Construction of the dithiane substituted oxazole 6 was achieved by the coupling of L-(+)-lactic acid and L-serine methyl ester hydrochloride with diethyl phosphorocyanidate, followed by the construction of the oxazole ring.
- Cheng, Zhenzhuang,Hamada, Yasumasa,Shioiri, Takayuki
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p. 109 - 110
(2007/10/03)
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- Asymmetric α-Amino Acid Synthesis: Synthesis of (+)-Polyoxamic Acid using a Allylic Trifluoroacetimidate Rearrangement
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The stereoselective rearrangement of allylic trifluoroacetimidate (15) has been used in a synthesis of (+)-polyoxamic acid (1).
- Savage, Ian,Thomas, Eric J.
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p. 717 - 719
(2007/10/02)
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- DIASTEREOSELECTIVE AND ENANTIOSPECIFIC SYNTHESIS OF KEY INTERMEDIATES TO L-SUGARS FROM ETHYL L-LACTATE
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"Building blocks" 3 , which are potential intermediates for the synthesis of L-pentoses or L-hexoses, have been prepared stereoselectively in both diastereomeric forms starting from the ethyl L-lactate.
- Guanti, Giuseppe,Banfi, Luca,Narisano, Enrica
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p. 681 - 688
(2007/10/02)
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