Pawel Jankowski

Synthesis and anti-inflammatory properties of 1alpha,25-dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3, a hypocalcemic, stable metabolite of 1alpha,25-dihydroxy-16-ene-20-cyclopropyl-vitamin D3.

1alpha,25(OH)(2)-16-ene-20-cyclopropyl-vitamin D(3) (13) is several fold more potent than the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1) as an anti-inflammatory agent. Here, we have further analyzed the anti-inflammatory properties of 13, confirming it as the most potent analogue tested within this family. We then determined the structures of all the natural metabolites of 13, including the 24-oxo metabolite 14, and carried out its synthesis. A comparison of 13 with 14 showed a similar induction of the primary VDR target genes CYP24A1 and CAMP and comparable anti-inflammatory properties as revealed by a similar inhibition of TNF-alpha, IL-12/23p40, IL-6, and IFN-gamma production. Interestingly, 14 displays a 3-fold lower calcemic activity in vivo compared to 13. Collectively, these findings indicate that the strong potency of 13 can be explained by the accumulation of its stable 24-oxo metabolite, which shows immunoregulatory and anti-inflammatory properties superimposable to those exerted by 13 itself.

Hydrophilic polycarbonate for generation of oil in water emulsions in microfluidic devices

This report details the method for rendering hydrophilic surfaces of microchannels fabricated in polycarbonate (PC). We characterize the wetting properties and stability of the hydrophilic character of two coatings--one formed by a layer of poly(allylamine) (PAH*) and the second including an additional layer of poly(styrene-sulfonate) (PSS). This second (PC-PAH/PSS) coating yields highly hydrophilic surface that is stable against weeks of exposure to various fluids including organic oils. This coating allows for stable generation of oil-in-water emulsions of hydrocarbon, silicone and fluorinated oils without the use of surfactants and over days of continuous use.

FACILE SYNTHESIS OF ENANTIOMERICALLY PURE TERT-BUTYL(METHYL)PHENYLSILANES

Abstract A method for the preparation of both enantiomers of tert-butyl(methyl)phenylsilane 2 is presented. Racemic tert-butyl(methyl)phenylsilyl chloride 3 was allowed to react with (R)-(−)-2-amino-1-butanol 4 to give hydrochloride 5. Diastereomer separation via treatment of the respective free amine 6 with 0.5 mol equivalent of HCl in hexane-2-propanol yielded crystalline diastereomerically pure hydrochloride (R)Si-5. The corresponding free amine (R)Si-6 was reduced with LiAlH4 to give (S)-2. The mother liquors obtained after separation of (R)Si-5 on treatment with oxalic acid provided a crystalline salt that eventually afforded (R)-2. The optical purity of (S)-2 (98% ee) was documented by its reaction (hydrosilylation) with propargylic alcohol derivative 10 and HPLC analysis of product 11 using a chiral column.

Enantioselective syntheses of a 1α-hydroxyvitamin D ring A precursor from 3-(triphenylsilyl)glycidol and from malic acid

Abstract Syntheses of the 1α-hydroxyvitamin D 3 A ring fragment 2 from (2 R ,3 R ) 3-(triphenylsilyl)glycidol 5a and from L-(−)-malic acid are described.

The reaction of trimethylsilyl ethylene oxide with α-sulfonyl anions and α,α-sulfonyl dianions. A method for stereocontrolled synthesis of (E)- and (Z)-allylic alcohols

Abstract Trimethylsilyl ethylene oxide has been shown to react with α-sulfonyl carbanions generated from representative primary alkyl phenyl sulfones to give the corresponding O-trimethylsilyl allylic alcohols, with higher selectivity of ( Z )-isomers. The reaction proceeds by attachment of the nucleophile to the α-position of the α,β-epoxyalkylsilane followed by a carbon-to-oxygen shift to the trimethylsilyl group and expulsion of the benzenosulfonyl anion. The reaction of trimethylsilyl ethylene oxide with α,α-sulfonyl dianions followed by partial protonation of the immediate adducts affords O-trimethylsilyl allylic alcohols, mainly ( E )-isomers. The reaction of trimethylsilyl ethylene oxide with α-sulfonyl carbanions generated from secondary alkyl phenyl sulfones affords α-trimethylsilyl carbinols as the only or predominant product. In this case the attachment of the nuclephile takes place at the β-position of the α,β-epoxyalkysiane. The origin of the regio- and stereo-selectivity in reactions of sulfonyl carbanions with α,β-epoxyalkylsilanes is discussed.

Scaling up the Throughput of Synthesis and Extraction in Droplet Microfluidic Reactors

AbstractConducting reactions in droplets in microfluidic chips offers several highly attractive characteristics, among others, increased yield and selectivity of chemical syntheses. The use of droplet microfluidic systems in synthetic chemistry is, however, hampered by the intrinsically small throughput of micrometric channels. Here, we verify experimentally the potential to increase throughput via an increase of the scale of the channels.We use the results of these experiments characterizing the processes of (1) generation of droplets, (2) mixing in droplets, (3) inter-phase extraction, and (4) the yield of synthesis of pyrrole, to postulate a number of guidelines for scaling up the throughput of microfluidic droplet systems. In particular, we suggest the rules for maximizing the throughput via an increase of the size of the channels and via parallelization to optimize the throughput of synthesis against the cost of fabrication of the chips and against the kinetic requirements of specific reactions.

Migration of aryl groups from silicon to carbon in α,β-epoxysilanes. A new model for hypervalent silicon study

Abstract The reaction of (2 R ,3 R )-3-(triphenylsilyl)glycidol ( 1 ) with n -Bu 4 NF·3H 2 O in THF, followed by treatment of the product with p -nitrobenzoyl chloride yields (2 S )-glycidol p -nitrobenzoate ( 4 ) and trans -cinnamyl p -nitrobenzoate ( 6 ) in a ratio of 1:1.5. The reaction of ( R )Si-( 2R,3R )- or ( R )Si-( 2S, 3 S )-3-[(methyl)(phenyl)(1-naphthyl)silyl]-glycidols, 7 or 8 respectively, with n -Bu 4 NF·3H 2 O affords mixtures of the respective glycidol, trans -cinnamyl alcohol and 3-(1-naphthyl)allyl alcohol. No significant difference in the product distribution in reaction of these two diasteromers was observed.

An Efficient Method for Preparation of Trimethylsilyl Ethylene Oxide and Some Other Trimethysilyl Oxiranes

Abstract Trimethylsilyl ethylene oxide and other α,β-epoxysilanes were obtained from corresponding (trimethylsilyl)alkenes by an one-pot procedure involving successive treatment with N-bromosuccinimide and aqueous sodium hydroxide.

Blood diagnostics using sedimentation to extract plasma on a fully integrated point‐of‐care microfluidic system

Blood is the richest source of diagnostic information. The growing interest in point‐of‐care analytics prompted several attempts to extract plasma from whole blood in simple diagnostic devices. The simplest method of separation is sedimentation. Here we show the first microfluidic system that uses sedimentation to extract plasma from undiluted blood and integrates execution of liquid assays on the extracted material. We present a microfluidic chip that accepts a small sample (27 μL) of whole blood, separates up to 6 μL of plasma, and uses metered volumes of plasma and of reagent (2‐chloro‐4‐nitrophenyl‐α‐maltotrioside, CNP‐G3) for a liquid enzymatic assay. With a custom designed channel, the system separates blood by sedimentation within few minutes of accepting the sample, mixes it with the reagent, and quantifies spectrophotometrically the product of the enzymatic reaction. As a model demonstration, we show a quantitative enzymatic α‐amylase assay that is routinely used in diagnosis of pancreas diseases. The paper reports the design and characterization of the microfluidic device and the results of tests on clinically collected blood samples. The results obtained with the microfluidic system compare well to a reference bench‐top analyzer.

Preparation of optically activen-butyl(methyl)phenyl-, tert-butyl(methyl)phenyl- andisopropyl(methyl)phenylsilanes from the corresponding silyl chlorides using2,2′-dihydroxy-1,1′-binaphthyls as resolving agents

Enantiomeric silanes 4a, 4b and 4c were obtained from the corresponding racemic silyl chlorides via diastereomeric derivatives with (R)-[1,1′]binaphthalenyl-2,2′-diol; the optical purity of silanes 4a and 4c was determined (>98% ee) by HPLC using a chiral cyclodextrin-based column.