Biomimetic synthesis can be an attractive approach to access complex natural products by addressing challenging structural features through cascade reactions, which are inferred through tangible biosynthetic hypotheses. In some instances, the originally proposed structure or biosynthetic path might be revised through synthesis. In this communication we report a short and efficient bioinspired synthesis of Alstoscholarinoids A and B, rearranged triterpenes from the Alstonia scholaris tree. Salient features of the synthesis include a transannular aldol addition as well as a cascade consisting of a Schenck-Ene reaction, Hock rearrangement, and aldol addition. This culminated in a revision of the likely biosynthetic origin of Alstoscholarinoid A and a thorough exploration of the previously proposed intermediates.

Our studies toward the total synthesis of the natural product euphosalicin (1) are presented. Different approaches targeting key intermediates are described, the synthesis of which includes findings on asymmetric dihydroxylations and ring-closing enyne metatheses (RCEYM). Their connection allowed the isolation of highly advanced precursors for studies on macrocyclizations. Our efforts culminated in the preparation of the unique C11/C12 (Z) isomer of the C13 nor methyl skeleton of euphosalicin (1).

A general protocol for the europium-catalyzed rearrangement of aryl-pentadienyl-ethers is described. The mode of rearrangement and product formation in this reaction was solely determined by the aryl substituent para to the phenol. If the para-position is occupied by a substituent, the substrate undergoes a [3,3] rearrangement to the ortho-position to form a prochiral branched diene. In turn, a free para-position in the starting material allows the reaction to proceed via a [5,5] rearrangement and leads to a linear conjugated diene product. The severely underdeveloped and synthetically valuable [5,5] rearrangement was investigated in terms of scope and mechanism.

A concise, racemic total synthesis of three sesquiterpenoid alkaloids (greenwaylactams A-C) exhibiting an unprecedented 8-membered benzolactam is disclosed. Key transformations of this work include the ring expansion through cleavage of an indole via Witkop oxidation, as well as an HFIP mediated cationic cyclisation to build up the pentacyclic carbon skeleton.

The two substituted 1,2,3,4-tetrahydronaphthalenes, methyl ( R )-3-{(1 R ,4 S )-6-methoxy-4,7-dimethyl-5,8-bis[(triisopropylsilyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}butanoate, C 36 H 66 O 5 Si 2 , ( 2 ), and methyl ( E )-3-{(1 R ,4 S )-8-hydroxy-6-methoxy-4,7-dimethyl-5-[(triisopropylsilyl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}acrylate, C 26 H 42 O 5 Si, ( 8 ), crystallize in the Sohncke space groups P 2 1 2 1 2 1 and P 2 1 , respectively, with the absolute structure determined on the basis of anomalous dispersion effects. The configurations of the stereo centres in the 1,2,3,4-tetrahydronaphthalene moiety of ( 2 ) and ( 8 ) are the same, and the conformation of the non-aromatic part of the ring system is nearly identical. In the crystal of ( 2 ), weak non-classical C—H...O interactions consolidate the packing, whereas in ( 8 ), intermolecular O—H...O hydrogen-bonding interactions of medium-to-weak strength direct the molecules into Z -shaped strands extending parallel to [010].

We describe our efforts toward the total synthesis of the natural product elisabethin A. The first route was guided by the proposed biosynthesis, assembling the 6,6-ring system before forming the five-membered ring including the quaternary carbon. The second approach includes a high yielding cyclization under Mitsunobu conditions as a key step. It allowed the preparation of an unusual and highly functionalized bicyclic 6,5-spiro compound. Both routes share a common advanced precursor obtained from an "underdeveloped" Claisen rearrangement of an aryl dienyl ether.

ABS TRACT Dehydrochloromethyltestosterone (DHCMT) is one of the most detected illicit used anabolic-androgenic steroids in professional sports. Therefore, a fast and accurate analysis of this substance is of great importance for a constructive fight against doping abuse. The conventional method for the analysis of this drug, GC-MSMS, is very sensitive and selective but also very time-and resource-consuming. With the presented work, a new approach for simple detection with LC-HRMSMS without any sample preparation is introduced. The method is based on the direct analysis of two newly described phase-II metabolites of the DHCMT long-term metabolite 4-chloro-18-nor-17(i-hydroxymethyl-17 alpha-methyl-5(i-androst-13-en-3 alpha-ol (M3). LC-HRMSMS, GC-MSMS, fractionation and deriv-atization experiments are combined to identify and characterize for the first time two different glucuronide-acid conjugates of this metabolite in positive human urine samples. In addition, a third glucuronide metabolite was identified, however without isomeric structure determination. The detection of these metabolites is particularly interesting for confirmation analyses, as the method is rapid and requires little sample material.

The urinary steroid profile established for the monitoring of eventual testosterone or testosterone precursor application by athletes includes concentrations and ratios of various endogenously produced steroidal hormones and metabolites. Due to enzymatic activities in urine specimens, the concentrations of these endogenous steroids and consequently their ratios may alter, leading to potential misinterpretation of analytical results. Microbiological contamination in athletes' urine samples can occur due to urinary tract infections or due to contamination by the non-sterile sample collection conditions. Depending on the duration of transportation of urine samples, the transport and storage conditions may favour microorganisms' growth, and therefore, the enzymatic activity can be accelerated. Degradation effects on endogenous steroids caused by microorganisms have been observed, such as hydrolysis of steroid conjugates, increase of testosterone in the free fraction or modification of the steroid structure by oxidoreductive reactions. The World Anti-Doping Agency (WADA) implemented criteria to check for signs of microbial degradation in a technical document dealing with the detection, analysis and reporting of endogenous androgenic anabolic steroids (TD EAAS) in urine samples. During the endogenous steroid profile confirmation procedures (CPs) of the WADA accredited Seibersdorf Laboratory, significant differences in the concentrations of markers of the steroid profile were observed compared to the initial testing procedures (ITPs). The changes in concentrations of the urinary steroid profile were attributed to the reduction of the 17-keto group to a 17β-hydroxy group caused by increased enzymatic activity during the hydrolysis step. In order to monitor the 17-keto reduction activity in athletes' urine specimens, possible marker substances containing a 17-keto group were synthesised and added in the internal standards mixture (ISTD) of the ITP. The presence of the reduced 17β-hydroxy form of the marker substance indicated enzymatic activity leading to 17-keto reduction reactions. The substance 3β-ethoxy-5α-androstane-17-one was defined to be suitable to indicate 17-keto reduction reactions occurring during hydrolysis carried out at moderate temperatures.

The concise synthesis of a potentially “super-armed” glucuronidation donor is reported. The α-anomer was crystallized and analyzed by single crystal X-ray diffraction. The pyranose ring was found to be in a twist-boat conformation in the solid state. To confirm the relevance of this finding for the solution state, and explain the failure of analysis by NMR, DFT calculations were performed. They revealed the twist-boat to be the dominant among a group of several possible conformers at ambient temperature. Graphical abstract

The exogenous anabolic-androgenic steroid (AAS) stanozolol stays one of the most detected substances in professional sports. Its detection is a fundamental part of doping analysis, and the analysis of this steroid has been intensively investigated for a long time. This contribution to the detection of stanozolol doping describes for the first time the unambiguous proof for the existence of 17-epistanozolol-1 ' N-glucuronide and 17-epistanozolol-2 ' N-glucuronide in stanozolol-positive human urine samples due to the access to high-quality reference standards. Examination of excretion study samples shows large detection windows for the phase-II metabolites stanozolol-1 ' N-glucuronide and 17-epistanozolol-1 ' N-glucuronide up to 12 days and respectively up to almost 28 days. In addition, we present appropriate validation parameters for the analysis of these metabolites using a fully automatic method online solid-phase extraction (SPE) method already published before. Limits of identification (LOIs) as low as 100 pg/ml and other validation parameters like accuracy, precision, sensitivity, robustness, and linearity are given.

Nachrichten aus der ChemieVolume 69, Issue 9 p. 108-108 GÖCH Nachruf: Prof. Maximilian Knollmüller Christian Noe, Christian NoeSearch for more papers by this authorPeter Gärtner, Peter GärtnerSearch for more papers by this authorHannes Fröhlich, Hannes FröhlichSearch for more papers by this authorMarko Mihovilovic, Marko MihovilovicSearch for more papers by this author Christian Noe, Christian NoeSearch for more papers by this authorPeter Gärtner, Peter GärtnerSearch for more papers by this authorHannes Fröhlich, Hannes FröhlichSearch for more papers by this authorMarko Mihovilovic, Marko MihovilovicSearch for more papers by this author First published: 01 September 2021 https://doi.org/10.1002/nadc.20214115788Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume69, Issue9September 2021Pages 108-108 RelatedInformation

We herein report the synthesis of the long-term metabolites "M4" (IUPAC: 4-chloro-17-hydroxymethyl-17-methyl-18-norandrosta-4,13-dien-3-ol) of dehydrochloromethyl-testosterone (DHCMT, Oral Turinabol) and "Oxy M9" (4-hydroxy-17β-hydroxymethyl-17α-methyl-18-norandrosta-4,13-dien-3-one) of oxymesterone (Oranabol). Both compounds were derived from a common synthetic route starting from dehydroepiandrosterone acetate. Four different stereoisomers were evaluated for metabolite M4. The previously assigned structure could be corrected regarding the C-3 and C-17 stereocenters.

Stanozolol is still the most commonly used illicit anabolic-androgenic steroid (AAS) in professional sports. Therefore, accurate and fast analysis and long detection windows are of great interest in the field of antidoping analysis. In this work, a very simple, fast, and highly sensitive online solid-phase extraction method coupled with liquid chromatography-high-resolution tandem mass spectrometry (HPLC-HRMSMS) for the analysis of stanozolol-N-glucuronides was developed. This fully validated procedure is characterized by only a few manual steps (dilution and addition of internal standard) in the sample preparation. A limit of identification (LOI) of 75 pg/mL, high accuracy (87.1%-102.1%), precision (3.1%-7.8%), and sensitivity was achieved. Furthermore, good linearity (> 0.99) and robustness, as well as no carry-over effects, could be observed. In addition to excellent confirmation analysis performance, this method shows sufficient potential for the identification and characterization of unknown metabolites. Using this method, it was possible to unambiguously confirm the presence of 1'N- and 2'N-stanozolol-glucuronide in human urine for the first time due to the access to reference material.

Nachrichten aus der ChemieVolume 68, Issue 9 p. 97-97 GÖCH Nachruf auf Prof. Fritz Sauter (1930 – 2020) Hannes Fröhlich, Hannes FröhlichSearch for more papers by this authorPeter Gärtner, Peter GärtnerSearch for more papers by this authorUlrich Jordis, Ulrich JordisSearch for more papers by this authorMarko Mihovilovic, Marko MihovilovicSearch for more papers by this authorPeter Stanetty, Peter StanettySearch for more papers by this author Hannes Fröhlich, Hannes FröhlichSearch for more papers by this authorPeter Gärtner, Peter GärtnerSearch for more papers by this authorUlrich Jordis, Ulrich JordisSearch for more papers by this authorMarko Mihovilovic, Marko MihovilovicSearch for more papers by this authorPeter Stanetty, Peter StanettySearch for more papers by this author First published: 01 September 2020 https://doi.org/10.1002/nadc.20204101795Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume68, Issue9September 2020Pages 97-97 RelatedInformation

The preparation, separation, and analysis of two regioisomeric N-glucuronides of the common doping agent stanozolol are described in this manuscript. Glucuronidation was carried out using modified Königs–Knorr conditions developed specifically for pyrazoles. After preparative HPLC separation both isomers could be isolated in a pure form. Global cleavage of protecting groups furnished the putative human phase II metabolites STN1 and STN2 which were compared with human excretion studies.

A long-term metabolite of the doping agent oxymetholone (OXM-M2, 17β-hydroxymethyl-2,17α-methyl-18-norandrost-13-en-3-one) which has been identified by GC-MS/MS was synthesized from commercially available materials. Two efficient synthetic routes to access both C-17 epimers of tentative metabolites were developed. The identity and molecular configuration of the in vivo metabolite: 17β-hydroxymethyl-2α,17α-methyl-18-norandrost-13-en-3-one was confirmed by single crystal X-ray diffraction.

The human urinary long-term metabolite "M3" (4-chloro-17β-hydroxymethyl-17α-methyl-18-norandrost-13-en-3-ol) of the common doping agent DHCMT has thus far been detected via GC/MS-MS, creating ambiguities concerning its absolute configuration. Its structure was elucidated via the synthesis of all eight possible stereoisomers with 17β-hydroxymethyl configuration. The highlights of the synthesis consist of a novel first generation approach to 4β-chloro-5β compounds as well as a divergent route which allows easy access to the remaining A-ring chlorohydrins.