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Lambert W.D.,University of Delaware | Scinto S.L.,University of Delaware | Dmitrenko O.,University of Delaware | Boyd S.J.,University of Delaware | And 6 more authors.
Organic and Biomolecular Chemistry | Year: 2017

The use of organic chemistry principles and prediction techniques has enabled the development of new bioorthogonal reactions. As this "toolbox" expands to include new reaction manifolds and orthogonal reaction pairings, the continued development of existing reactions remains an important objective. This is particularly important in cellular imaging, where non-specific background fluorescence has been linked to the hydrophobicity of the bioorthogonal moiety. Here we report that trans-5-oxocene (oxoTCO) displays enhanced reactivity and hydrophilicity compared to trans-cyclooctene (TCO) in the tetrazine ligation reaction. Aided by ab initio calculations we show that the insertion of a single oxygen atom into the trans-cyclooctene (TCO) ring system is sufficient to impart aqueous solubility and also results in significant rate acceleration by increasing angle strain. We demonstrate the rapid and quantitative cycloaddition of oxoTCO using a water-soluble tetrazine derivative and a protein substrate containing a site-specific genetically encoded tetrazine moiety both in vitro and in vivo. We anticipate that oxoTCO will find use in studies where hydrophilicity and fast bioconjugation kinetics are paramount. © The Royal Society of Chemistry.

Pascal R.A.,Tulane University | Dudnikov A.,Tulane University | Love L.A.,Tulane University | Geng X.,Tulane University | And 5 more authors.
European Journal of Organic Chemistry | Year: 2017

A series of propeller-shaped, C3-symmetric cyclophanes have been synthesized by the macrocyclization of 1,3,5-trimercaptobenzene (12) with either a tris[o-(halomethyl)aryl]phosphine (e.g. 11) or a tris[o-(halomethyl)aryl]benzene (e.g. 24). Two phosphine-capped cyclophanes (5 and 6) were prepared in this way; they proved to be configurationally stable, and both were resolved into pure enantiomers by supercritical fluid chromatography on chiral supports. Compound 6, in particular, displayed a large specific rotation ([α]D ≈ 800) and strong circular dichroism. The one triarylbenzene-capped cyclophane (9) that was made possessed a modest barrier to racemization (ΔGrac ‡ = 15.7 kcal/mol). Computational studies of the trends in optical rotation for this class of compounds as well as the pathway for the racemization of 9 are also reported. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Dougherty K.J.,Tulane University | Mague J.T.,Tulane University | Wilson L.J.,Lotus Separations LLC | Kraml C.M.,Lotus Separations LLC | Pascal R.A.,Tulane University
Tetrahedron Asymmetry | Year: 2016

A wide variety of common TD-DFT methods predict that chiral cyclophane 1 should exhibit a specific rotation ranging from large ([α]D ∼ 1000) to unreasonably large ([α]D > 1,000,000) with numerous estimates between these values. Compound 1 was prepared in two steps from 1,8-dichloroanthraquinone, and its X-ray structure showed it to be, as expected, a C2-symmetric, roughly triangular macrocycle. Compound 1 was resolved into nearly pure enantiomers by chromatography on a chiral support, and the specific rotations of the two components were determined to be [α]D 23 = +1520 and [α]D 23 = −1470. These values are large, but not exceptionally so, and the wildly inaccurate TD-DFT estimates of the specific rotation of compound 1 are shown to be closely related to the failure of the same TD-DFT methods to predict accurately the absorption spectrum of 1. © 2016 Elsevier Ltd

Dougherty K.J.,Tulane University | Kraml C.M.,Lotus Separations LLC | Byrne N.,Lotus Separations LLC | Porras J.A.,Carnegie Mellon University | And 3 more authors.
Tetrahedron | Year: 2015

Diazotization of 3-aminophthalic acid in the presence of 7,9-di(1-naphthyl)-8. H-cyclopent[. a]acenaphthylen-8-one (9, a dinaphthyl analog of the common cyclopentadienone acecyclone), followed by treatment with thionyl chloride in toluene, gave 11-(1-naphthyl)-7. H-fluorantheno[9,8,7-. no]tetraphen-7-one (3), an orange luminescent helicene. Similar treatment of 1,3-di(1-naphthyl)-2. H-cyclopenta[. l]phenanthren-2-one (11, a dinaphthyl analog of phencyclone) gave 11-(1-naphthyl)-7. H-triphenyleno[3,2,1-. no]tetraphen-7-one (4), a highly luminescent derivative of hexahelicene. Both 3 and 4 are composed of four stable conformational isomers: two diastereomers, each of which contains a pair of enantiomers. One pure isomer of 3 and two isomers of 4 were ultimately obtained by supercritical fluid chromatography (SFC) of the mixtures on chiral supports. These isolated components exhibited high specific rotations and strong circular dichroism. Attempts to prepare a third helicene by diazotization of 3-aminophthalic acid in the presence of aceanthrenecyclone (5) gave no helicene products, but instead resulted in the oxidation of 5 to two unusual chiral diketones (7 and 8) whose structures were determined by X-ray diffraction. © 2015 Elsevier Ltd.

Zong J.,Tulane University | Mague J.T.,Tulane University | Kraml C.M.,Lotus Separations LLC | Pascal R.A.,Tulane University
Organic Letters | Year: 2013

The synthesis and characterization of the bis(triarylphosphine) 3 are described. Slow protonation of an inwardly directed phosphine is possible, but the phosphines do not react with larger reagents. X-ray structures of the parent compound, its HCl salt, and the corresponding trisulfone are reported. Compound 3 was resolved by chiral chromatography, but the barrier to racemization is only 20.7 kcal/mol. © 2013 American Chemical Society.

Zong J.,Tulane University | Mague J.T.,Tulane University | Welch E.C.,Lotus Separations LLC | Eckert I.M.K.,Lotus Separations LLC | Pascal Jr. R.A.,Tulane University
Tetrahedron | Year: 2013

A series of cyclophanes composed of two triarylelement caps linked by two-atom bridges has been synthesized. The bridgehead functional groups include phosphines in combination with amines, hydrosilanes, methylsilanes, and ethoxysilanes. Computational studies accurately predicted that when the bridgehead substituents are small (lone pairs or protons), an in,in bridgehead stereochemistry is strongly favored, but larger bridgehead substituents favor the formations of in,out stereoisomers. The X-ray structures, spectra, and reactivity of these compounds are discussed, as well as the resolution of one of the cyclophanes into pure enantiomers. © 2013 Elsevier Ltd. All rights reserved.

Ng W.-L.,Princeton | Perez L.J.,Princeton University | Wei Y.,Princeton | Kraml C.,Lotus Separations LLC | And 3 more authors.
Molecular Microbiology | Year: 2011

Quorum sensing is a process of bacterial cell-cell communication that enables populations of cells to carry out behaviours in unison. Quorum sensing involves detection of the density-dependent accumulation of extracellular signal molecules called autoinducers that elicit population-wide changes in gene expression. In Vibrio species, CqsS is a membrane-bound histidine kinase that acts as the receptor for the CAI-1 autoinducer which is produced by the CqsA synthase. In Vibrio cholerae, CAI-1 is (S)-3-hydroxytridecan-4-one. The C170 residue of V. cholerae CqsS specifies a preference for a ligand with a 10-carbon tail length. However, a phenylalanine is present at this position in Vibrio harveyi CqsS and other homologues, suggesting that a shorter CAI-1-like molecule functions as the signal. To investigate this, we purified the V. harveyi CqsS ligand, and determined that it is (Z)-3-aminoundec-2-en-4-one (Ea-C8-CAI-1) carrying an 8-carbon tail. The V. harveyi CqsA/CqsS system is exquisitely selective for production and detection of this ligand, while the V. cholerae CqsA/CqsS counterparts show relaxed specificity in both production and detection. We isolated CqsS mutants in each species that display reversed specificity for ligands. Our analysis provides insight into how fidelity is maintained in signal transduction systems. © 2011 Blackwell Publishing Ltd.

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