Domino Block Synthesizer
2.2.1. Description of the Synthesizer A Domino Block is a liquid distribution manifold that is made of Teflon and has a footprint of a 96-well plate Fig. 4 . The Domino Block has two functions i to clamp hold reaction vessels and ii to connect all reaction vessels to one common port. This common port is used to introduce and remove solvent. Plastic polypropylene syringes, equipped with a porous disk porosity 60 m 3 at the bottom of the syringe barrel, are used as reaction vessels. The syringes,...
References Xxr
1. Stinson, S. C. 1995 Chiral Drugs. Chem. Eng. News 73 41 , Oct. 9, 44-74. 2. Pirkle, W. H. and Welch, C. J. 1994 Chromatographic and 1H NMR support for a proposed chiral recognition model. J. Chromatogr. A 683, 347-353. 3. Armstrong, D. W., Ward, T. J., Armstrong, R. D., and Beesley, T. E. 1986 Separation of drug stereoisomers by the formation of cyclodextrin inclusion complexes. Science 232, 1132-1135. 4. Berthod, A., Liu, Y., Bagwill, C., and Armstrong, D. W. 1996 Facile LC...
Conclusion
Parallel solid phase organic synthesis has become an integral part of many laboratories involved in organic synthesis. Consequently, reliable, simple, and affordable tools are needed. There is no simple solution as to what instrumentation is best suited to perform organic solid phase synthesis. The instrumentation is a tool and the selection of the most appropriate tool should be dictated by the project needs. Three manual synthesizers are described in this chapter that are convenient for...
HPLC Analysis
The retention times of library compounds can be exploited for an automated structure control 42 . The principle relies on the fact that the individual con- Fig. 7. Graphical results from an AutoDROP calculation shown in a data panel from which spectra, structures, and graphical patterns can be selected. The calculation of NMR and MS methods is visualized in the data panel NMR results left hemisphere, MS results right hemisphere . Fig. 7. Graphical results from an AutoDROP calculation shown in a...
Sulfonamide Linker 2 1
1. In a flame dried 200-mL round bottom flask, preswell 2.5 g of amino methylated resin 0.8 meq g with 20.0 mL of dry THF. 2. Add 13 mL of THF, 0.336 g 2.67 mmol of DICI, 0.35 g 2.67 mmol of HOBT, and 0.52 g 2.67 mmol of crude 3-carboxypropane sulfonamide 6 under anhydrous conditions see Note 9 . 3. Cap the round bottom flask with a polypropylene cap and shake on a shaker at RT for 12 h see Note 10 . 4. Filter the beads through a fritted glass funnel and wash them three times with 25 mL of...
Linkers Cleaved by Gaseous Reagents
Liquid TFA and HF are typical cleavage reagents for acid-cleavable linkers. Alternatively, cleavage may be effected by the use of gaseous HCl or HF. The efficiency of gaseous HCl cleavage can be compared to diluted TFA the effectiveness of gaseous HF is comparable to liquid HF. Among the commonly used acid-cleavable linkers, the esters of Merrifield resin 8 and carboxamides of the MBHA linker 9 Fig. 3 are the most acid stabile. Gaseous HF was required to cleave acids from the Merrifield resin...
Apparatus for LLE
1. 96-well 2-mL capacity hydrophobic GF C glass fiber filter plate Whatman, Clifton, NJ . Diatomaceous earth particle gt HCI aqueous layer Diatomaceous earth particle gt HCI aqueous layer Fig. 1. Schematic representation of automated 96-well liquid-liquid extraction for the removal of basic and water soluble components such as amines from crude library samples. 2. 96-well 1- and 2-mL capacity collection plate Varian . 3. Polypropylene reagent reservoir with 2 baffles Tomtec, Hamden, CT . 4....
Isothermal Calorimetry
1. Prepare a solution roughly 1 mM of each member of the receptor library in DMSO see Note 11 . 2. Rinse the cell of the isothermal titration calorimeter once with this receptor solution, then fill the cell with a second aliquot of the same solution. 3. Prepare a second solution in DMSO containing the guest at roughly 6-7 times the concentration of the receptor. Fill the injection syringe with the guest solution and place it into the calorimeter cell. Equilibrate to a constant baseline over...
TFA Deprotection and Coupling Reaction
1. Prior to beginning the first deprotection, the activation of the upcoming monomers must be planned according to the times listed in Tables 1 and 2. The time required per cycle can be estimated as 30 min. 2. Py, P-Ala, y-Abu activation Dissolve the monomers in 0.75 mL 1 1 DMF NMP per 100 mg of resin. This is typically done at the end of the previous 20 min coupling cycle, or before synthesis is begun for the first step. Then, add 12 equivalents of DIEA to the solution approx 3 min or greater,...
Dithizone Assay
1. To a standard 1.0 cm quartz cuvet, add 3 mL of CHCl3 and measure a blank on the UV-Vis spectrophotometer. Add the dithizone solution in CHCl3 and adjust the concentration such that the absorbance of dithizone ranges between 0.7 and 0.9 absorbance units. Always prepare the dithizone solution fresh see Note 4 . 2. To monitor metal ion extractions see Note 5 , add a known volume from the extracted CHCl3 phase of the sample complex to the dithizone solution and record the change in absorbance of...
Wittig Coupling of Various Aldehydes 10
1. To each of the sealed 40 vessels containing the above resin 9, deliver via a dry syringe and needle, 3.0 mL 0.27 mmol, 10.8 eq of a solution of 0.09 M potassium i-butoxide in dry THF see Note 19 . 2. Deliver a unique aryl aldehyde to each sealed reaction vessel with a dry syringe and needle liquid aldehydes 0.1 mL, approx 0.7 mmol, 28 eq , solid aldehydes 0.7 mL of a 1 M solution in THF, 0.7 mmol, 28 eq . 3. Program the reaction vessel to shake at 450 rpm for 25 h at RT see Note 20 . 4....
SplitSplit Concept
Synthesis of combinatorial arrays of compounds can, in principle, be performed three different ways. The Split and Mix split and pool recombine concept introduced by Furka 4-6 is the most efficient method for preparation of sizable libraries tens of thousands of compounds . However, the technique requires tracking of the chemical history of the resin beads and limits the quantity of synthesized material to the loading per solid phase unit one unit can be represented by one particle, bead,...
Resin Aminolysis Product Purification and Characterization
1. Dimethylaminopropylamine DMPA , 99 . Store at RT. 2. 5i's-aminopropylmethylamine BAPMA , 96 Lancaster, Windham, NH . Store at RT under nitrogen when not in use. 3. HPLC Buffer A 0.1 v v TFA in water. Filter through a 0.4 im filter and degas prior to use. 4. HPLC Buffer B acetonitrile. Prepare as for Buffer A. 5. HPLC columns Reversed-phase C18 columns are used for both analytical and preparative HPLC. In these studies, Varian Microsorb MV, 5 m, 100 , 250 x 4.6 mm, and Waters NovaPak, 6 im,...
Flushing Lines with Nitrogen
The reagent gas remaining in the line has to be flushed out using nitrogen. The flow of nitrogen is turned on flow rate 2-3 L min from the main valve while reagent gas continues to flow. The gas selection valve V1 is turned from reagent gas to nitrogen and the flow of reagent gas is turned off at the source of the reagent gas. Reagent gases typically dissolve very quickly in water. If the flow of reagent gas were to be turned off without an inert gas to replace it, a vacuum would be formed in...
Synthesis of Benzopiperazinone 26
1. Dissolved the PEG-supported diamine 500 mg in 5 mL dichloromethane at room temperature in 25 mL round bottom flask. 2. To this homogeneous solution, add by syringe 3 eq triethylamine and 3 eq chloroacetyl chloride use freshly distilled . 3. Stir the reaction mixture at room temperature for 24 h under nitrogen atmosphere. 4. After completion of the reaction, slowly add diethyl ether 30 mL to the reaction mixture. 5. Collect the precipitated polymer bound acylated product on a glass funnel and...
Nmr
Bruker DRX400-spectrometer 1H, 400.1 MHz 13C, 100.6 MHz Bruker 5-mm inverse broadband NMR probe Bruker B-ACS 120 sample changer for acquisition of spectra using standard NMR probes 5-mm . Bruker Efficient Sample Transfer BEST-NMR for flow-injection acquisition, 4-mm flow cell, 120 L cell volume, Gilson 215 Liquid Handler is used for sample transfer. Data processing using Xwinnmr 2.6. AutoDROP is implemented in AMIX software Bruker . With the exception of Gilson 215 Liquid Handler Gilson , all...
Combinatorial Chemistry Notes
1. PNA monomers should be stored under dry, cold conditions. If the physical appearance of the monomers changes from a free-flowing powder form to aggregates, then the monomers should be dried in vacuo overnight before use. 2. Dry DMF is required in the synthesis of PNAs to dissolve the monomers and the activating reagent HATU under anhydrous conditions. The presence of moisture interferes with the purity and yield of the final products especially in the case of long PNAs 18-mers and longer ....