Helmut Spreitzer

Baeyer-Villiger oxidations of representative heterocyclic ketones by whole cells of engineered Escherichia coli expressing cyclohexanone monooxygenase

Whole cells of an Escherichia coli strain overexpressing Acinetobacter sp. NCIB 9871 cyclohexanone monooxygenase (CHMO; E.C. 1.14.13.22) have been used for the Baeyer-Villiger oxidation of representative heterocyclic six-membered ketones to probe the potential impact of nitrogen, sulfur and oxygen on the chemoselectivity of these reactions. The fact that all of these heterocyclic systems were accepted as substrates by the enzyme and gave normal Baeyer-Villiger products broadens the synthetic utility of the engineered E. coli strain and emphasizes the chemoselectivity achievable with enzymatic oxidation catalysts.

Green Solvents in Organic Synthesis: An Overview

Research concerning green solvents is focused on reducing environmental damages due to the use of toxic solvents in organic chemistry. Hence, there have been developed a lot of solvent-free processes as well as more efficient recycling protocols in the last dec- ades. Unfortunately, these approaches have their limitations. Therefore, the authors review different environmentally benign solvent al- ternatives. This report highlights reactions using water, fluorous solvents, ionic liquids, organic carbonates, supercritical carbon dioxide, as well as biosolvents instead of conventional organic solvents.

Microfluidic preparation of [18F]FE@SUPPY and [18F]FE@SUPPY:2 — comparison with conventional radiosyntheses

INTRODUCTION Recently, first applications of microfluidic principles for radiosyntheses of positron emission tomography compounds were presented, but direct comparisons with conventional methods were still missing. Therefore, our aims were (1) the set-up of a microfluidic procedure for the preparation of the recently developed adenosine A(3)-receptor tracers [(18)F]FE@SUPPY [5-(2-[(18)F]fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and [(18)F]FE@SUPPY:2 [5-ethyl-2,4-diethyl-3-((2-[(18)F]fluoroethyl)sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and (2) the direct comparison of reaction conditions and radiochemical yields of the no-carrier-added nucleophilic substitution with [(18)F]fluoride between microfluidic and conventional methods. METHODS For the determination of optimal reaction conditions within an Advion NanoTek synthesizer, 5-50 μl of precursor and dried [(18)F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (26 °C-180 °C) with defined reactant bolus flow rates (10-50 μl/min). Radiochemical incorporation yields (RCIYs) and overall radiochemical yields for large-scale preparations were compared with data from conventional batch-mode syntheses. RESULTS Optimal reaction parameters for the microfluidic set-up were determined as follows: 170 °C, 30-μl/min pump rate per reactant (reaction overall flow rate of 60 μl/min) and 5-mg/ml precursor concentration in the reaction mixture. Applying these optimized conditions, we observed a significant increase in RCIY from 88.2% to 94.1% (P < .0001, n ≥ 11) for [(18)F]FE@SUPPY and that from 42.5% to 95.5% (P<.0001, n ≥ 5) for [(18)F]FE@SUPPY:2 using microfluidic instead of conventional heating. Precursor consumption was decreased from 7.5 and 10 mg to 1 mg per large-scale synthesis for both title compounds, respectively. CONCLUSION The direct comparison of radiosyntheses data applying a conventional method and a microfluidic approach revealed a significant increase of RCIY using the microfluidic approach.

Struktur/Geruchs-Beziehungen von mit β-Santalol verwandten Verbindungen:E-Homo-β-santalol undE-Dehydrohomo-β-santalol

SummaryTo study the structure/odour relationships of β-santalol analogues two homologous β-santalol derivatives5 and6 were synthesized. The key steps thereby were the α-alkylation of the bicyclic starting ketones8 and14 accomplished by using more drastic conditions as usual. The odours of5 and6 are described in detail.

A study of selective oxime reduction methods

Abstract The title compound 2 is easily available in good yields by selective reduction of oxime 1 with TiCl4/NaBH4 or Na0/n-C3H7OH. The selectivities of numerous reduction methods are compared.

[18F]FE@SNAP—A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): Microfluidic and vessel-based approaches

Graphical abstract SNAP-7941 derivatives 1–4 (1: SNAP-7941; 2: [18F]FE@SNAP; 3: SNAP-acid; 4: Tos@SNAP).

Absolute configuration and odour analysis of the enantiomeric tert.-Butylbicyclo[4.4.0]decan-3-ols

Abstract Both enantiomers of tert.-butylbicyclo[4.4.0]decan-3-ol, a Sandalwood odorant, used as standard for molecular calculations on the group of Sandalwood fragrant molecules, were separated and analyzed in terms of their odour impression as well as their absolute configuration.

Synthesis and olfactoric activity of keto-β-santalol and methoxy-β-santalol

Abstract In extension of structure-activity relationship investigations on β-santalol, where the shape of the molecular surface was found to be of high importance, the influence of the electrostatic properties of the molecules was investigated. Two derivatives of β-santalol with similar molecular shape but with an oxygen atom instead of carbon atoms were synthesized: keto-β-santalol and methoxy-β-santalol. These two oxygen-containing santalol analogues were synthesized by total syntheses starting from apocamphenilone. A common intermediate for both target molecules, an appropriate tricyclic ketoaldehyde, proved to be inapplicable. Therefore methoxy-β-santalol was prepared by insertion of an ethyldioxolane sidechain into apocamphenilone and completing the synthesis by five additional steps. Keto-β-santalol was prepared on a convergent route by insertion of the already prefabricated sidechain into the starting ketone, followed by one additional step. The presence of the second oxygen atom leads to the complete loss of the odour, which is the evidence that apart from the molecular shape, the electrostatic potential has to be taken into account in molecular similarity studies of this class of compounds.

Preclinical in vitro & in vivo evaluation of [11C]SNAP-7941 – the first PET tracer for the melanin concentrating hormone receptor 1

INTRODUCTION Due to its involvement in a variety of pathologies (obesity, diabetes, gut inflammation and depression), the melanin concentrating hormone receptor 1 (MCHR1) is a new target for the treatment of these lifestyle diseases. We previously presented the radiosynthesis of [(11)C]SNAP-7941, the first potential PET tracer for the MCHR1. METHODS We herein present its in vitro and in vivo evaluation, including binding affinity, plasma stability, stability against liver mircrosomes and carboxylesterase, lipohilicity, biodistribution, in vivo metabolism and small-animal PET. RESULTS [(11)C]SNAP-7941 evinced high stability against liver microsomes, carboxylesterase and in human plasma. The first small-animal PET experiments revealed a 5 fold increased brain uptake after Pgp/BCRP inhibition. Therefore, it can be assumed that [(11)C]SNAP-7941 is a Pgp/BCRP substrate. No metabolites were found in brain. CONCLUSION On the basis of these experiments with healthy rats, the suitability of [(11)C]SNAP-7941 for the visualisation of central and peripheral MCHR1 remains speculative.

[18F]FE@SUPPY and [18F]FE@SUPPY:2 — metabolic considerations

INTRODUCTION Recently, [(18)F]FE@SUPPY and [(18)F]FE@SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A(3) receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A(3) receptor PET tracers. METHODS In vitro carboxylesterase (CES) experiments were conducted using incubation mixtures containing different concentrations of the two substrates, porcine CES and phosphate-buffered saline. Enzymatic reactions were stopped by adding acetonitrile/methanol (10:1) after various time points and analyzed by a high-performance liquid chromatography (HPLC) standard protocol. In vivo experiments were conducted in male wild-type rats; tracers were injected through a tail vein. Rats were sacrificed after various time points (n=3), and blood and brain samples were collected. Sample cleanup was performed by an HPLC standard protocol. RESULTS The rate of enzymatic hydrolysis by CES demonstrated Michaelis-Menten constants in a micromolar range (FE@SUPPY, 20.15 microM, and FE@SUPPY:2, 13.11 microM) and limiting velocities of 0.035 and 0.015 microM/min for FE@SUPPY and FE@SUPPY:2, respectively. Degree of metabolism in blood showed the following: 15 min pi 47.7% of [(18)F]FE@SUPPY was intact compared to 33.1% of [(18)F]FE@SUPPY:2; 30 min pi 30.3% intact [(18)F]FE@SUPPY was found compared to 15.6% [(18)F]FE@SUPPY:2. In brain, [(18)F]FE@SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [(18)F]FE@SUPPY was not observed before 30 min pi CONCLUSION Knowing that metabolism in rats is several times faster than in human, we conclude that [(18)F]FE@SUPPY should be stable for the typical time span of a clinical investigation. As a consequence, from a metabolic point of view, one would tend to decide in favor of [(18)F]FE@SUPPY.