Minimal fluorous tagging strategy that enables the synthesis of the complete stereoisomer library of SCH725674 macrolactones.
ABSTRACT: Four mixtures of four fluorous-tagged quasiisomers have been synthesized, demixed, and detagged to make all 16 stereoisomers of the macrocyclic lactone natural product Sch725674. A new bare-minimum tagging pattern needs only two tags--one fluorous and one nonfluorous--to encode four isomers. The structure of Sch725674 is assigned as (5R,6S,8R,14R,E)-5,6,8-trihydroxy-14-pentyloxacyclotetradec-3-en-2-one. Various comparisons of spectra of 32 lactones (16 with tags, 16 without) and 16 ester precursors (8 with tags, 8 without) provide insights into when and why related compounds have the same or different spectra.
Project description:Fluorous mixture synthesis minimizes the effort to synthesize small-molecule libraries by labelling the molecules rather than the reaction vessels. Reactants are labelled with fluorinated tags and products can later be demixed based on the fluorine content. A limit in the number of available tags can be overcome by using binary encoding so that a total of four tags can label uniquely a library of 16 compounds. This strategy, however, means that separation based on fluorine content alone is not possible. Here, we solve this problem by selectively removing one tag after an initial demixing step; a second demixing provides each individual compound. The usefulness of this strategy is demonstrated by the synthesis of a library that contains all 16 diastereomers of the natural products macrosphelides A and E. Macrosphelide D was not in this library, and so its assigned structure was incorrect. We determined its constitution by using NMR spectroscopy and its configuration by synthesizing four candidate stereoisomers.
Project description:?-Hydroxytropolones (?HTs) are troponoids that demonstrate inhibition against an array of therapeutically significant targets, making them potential drug leads for several human diseases. We have utilized a recently discovered one-pot three-component oxidopyrylium cycloaddition in a solid-supported synthesis of ?HTs. Though the procedure is time efficient and generates assay-ready molecules, the system suffers from low yields and an inability to perform reaction modifications on resin-bound intermediates. In order to combat these issues with the solid-phase platform, we incorporated fluorous tags into our synthetic route. Through the implementation of fluorous phase chemistry, we demonstrate a substantial increase in the overall yield of ?HTs, as well as an ability to execute metal-catalyzed cross coupling and amide coupling on fluorous tagged intermediates. We also show that tagged molecules can be separated from nonfluorous impurities, and vice versa, by utilizing fluorous liquid-liquid and solid-phase extractions. Hence, these proof-of-principle investigations describe the viability of a fluorous phase approach to ?HT synthesis and its potential to serve as a combinatorial technique to produce structurally diverse substrates.
Project description:Diversity-oriented synthesis (DOS) and fluorous mixture synthesis (FMS) are two aspects of combinatorial chemistry. DOS generates library scaffolds with skeletal, substitution, and stereochemistry variations, whereas FMS is a highly efficient tool for library production. The combination of these two aspects in solution-phase synthesis of two novel heterocyclic compound libraries is presented in this paper. Mixtures of different fluorous amino acids undergo [3 + 2] cycloadditions followed by postcondensation reactions. The mixtures are then demixed by fluorous HPLC. Fluorous tags are removed by cyclization to afford hydantoin- and benzodiazepinedione-fused heterocyclic compounds as individual, pure, and structurally defined molecules. The application of MS-directed HPLC purification and parallel four-channel LC/MS analysis further increases the efficiency of FMS.
Project description:All four diastereomers of a typical saturated oligoisoprenoid, 4,8,12-trimethylnonadecanol, are made by an iterative three-step cycle with the aid of traceless thionocarbonate fluorous tags to encode configurations. The tags have a minimum number of total fluorine atoms, starting at zero and increasing in increments of one. With suitable acquisition and data processing, each diastereomer exhibits characteristic chemical shifts of methyl resonances in its (1)H and (13)C NMR spectra. Together, these shifts provide a basis to predict the appearance of the methyl region of the spectrum of every stereoisomer of higher saturated oligoisoprenoids.
Project description:[reaction: see text] A series of asymmetric free-radical-mediated intermolecular conjugate additions using a fluorous oxazolidinone chiral auxiliary has been completed. The fluorous auxiliary facilitated product isolation using fluorous solid phase extractions (FSPE), effectively removing excess organic and organometallic reagents. Parallel reactions carried out with a similar but nonfluorous norephedrine-derived oxazolidinone demonstrated the superior stereoselectivity and purification obtainable with the fluorous chiral auxiliary.
Project description:A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of ?-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from the reaction mixture by simple fluorous solid-phase extraction (F-SPE) and used for the next round of reaction without further purification.
Project description:A modular, cost-effective route to a library of branched fluorous tags with two short, biocompatible, fluorinated chains (C6F13) is reported. These branched fluorous tags provide high fluorous content without the use of long-chain linear perfluorocarbons, which have rising health concerns due to their bioaccumulation. By attaching these tags to a porphyrin, it is demonstrated that high solubility can be achieved in fluorous solvents that are readily cleared from mammals. This work enhances the biocompatibility of perfluorocarbon nanoemulsions for photodynamic therapy.
Project description:A series of colored hydrocarbon and fluorocarbon tagged 1-fluoro-4-alkylamino-anthraquinones and 1,4-bis-alkylamino-anthraquinone probe molecules were synthesized from a (fluorinated) alkyl amine and 1,4-difluoroanthraquinone to aid in the development of fluorous separation applications. The anthraquinones displayed stacking of the anthraquinone tricycle and interdigitation of the (fluorinated) alkyl chains in the solid state. Furthermore, intramolecular N-H···O hydrogen bonds forced the hydrocarbon and fluorocarbon tags into a conformation pointing away from the anthraquinone tricycle, with the angle of the tricycle plane normal and the main (fluorinated) alkyl vector ranging from 1 to 39°. Separation of the probe molecules on fluorous silica gel showed that the degree of fluorination of the probe molecules plays only a minor role with most eluents (e.g., hexane-ethyl acetate and methyl nonafluorobutyl ethers-ethyl acetate). However, toluene as eluent caused a pronounced separation by degree of fluorination for fluorocarbon, but not hydrocarbon tagged probe molecules on both silica gel and fluorous silica gel. These studies suggest that hydrocarbon and fluorocarbon tagged anthraquinones are useful probe molecules for the development of laboratory scale fluorous separation applications.
Project description:Miscibility tests between sixty pairs of fluorous and organic solvents have been performed, and a number of biphasic systems based on hydrofluoroether solvents have been identified. Mutual solubilities of a series of fluorous and organic solvents have been measured to ascertain the compositions of the biphasic systems. A qualitative solvent tuning strategy based on solvent polarity and fluorophilicity/phobicity is introduced. Solvent tuning is then used to modulate the partition coefficients (P) of triarylphosphines with 0-3 fluorous tags. The results lay a foundation for future applications of these and related biphasic systems in catalysis and extraction.
Project description:Fluorous mixture synthesis provided all eight diastereomers of the phytophthora hormone ?1 with the R configuration at C11 as individual samples after demixing and detagging. The library of all possible bis-Mosher esters (16) was then made by esterification. Complete sets of (1)H, (13)C, and (for the Mosher esters) (19)F NMR spectra were recorded, assigned, and compared with each other and with published spectra. Not all of the spectra are unique, and the (1)H NMR spectra of the Mosher esters provided the most information. The previous assignment of the natural sample as an "all-R" stereoisomer mixed with its 3S-epimer was confirmed.