Asymmetric approach towards the total synthesis of (+)-actinopyllic acid

This paper describes our efforts towards the asymmetric total synthesis of (+)-actinophyllic acid. Starting from the chiral oxazolidinone 9, an azocino [4,3-b]indolyl intermediate (5) possessing the A/B/C ring system and the C16 quaternary stereogenic center of actinophyllic acid has been synthesized. Key steps include a LHMDS-promoted condensation to establish the critical C2–C16 bond and a successive four-step transformation to assemble the eight-membered C-ring of the target molecule.     

Synthesis of the C8-C20 and C21-C30 segments of pectenotoxin 2

In this study, we synthesized the C8-C20 and C21-C30 segments of the diarrhetic shellfish toxin pectenotoxin 2. The C8-C20 segment was assembled from a phosphonate corresponding to the C8-C15 segment (prepared from l-malic acid in 19 steps) and an aldehyde corresponding to the C16-C20 segment (synthesized from 3-methyl-3-butenol in nine steps) by a twelve-step process including the Horner-Wadsworth-Emmons reaction, regio- and stereoselective reduction of the resulting enone, diastereoselective epoxidation, and 5-exo epoxide cleavage forming the C-ring. The C21-C30 segment was constructed in 13 steps from (S)-glycidol via a route involving E-ring formation by 5-exo epoxide cleavage and stereoselective methylation at C27 by the Evans method.     

Enantioselective preparation of C-ring fragment of cotylenin A via catalytic asymmetric intramolecular cyclopropanation of α-diazo β-keto ester

A synthetic pathway to the C-ring fragment of cotylenin A which emerged from our retrosynthetic analysis of cotylenin A is described. The catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of the α-diazo-β-keto ester bearing 2,4,6-trimethylphenyl group as the ester part has been found to afford the crystalline product with high ee, which allowed to establish the approach to the C-ring fragment which required ten-pot operations. The developed approach would be beneficial to a large scale synthesis of the C-ring fragment for the total synthesis of cotylenin A.     

An efficient synthesis of ([F]fluoropropyl)quinoline-5,8-diones by rapid radiofluorination-oxidative demethylation

Since many molecules bearing quinoline-5,8-dione or fused 1,4-quinone moieties possess a wide spectrum of biological activities, efficient methods for incorporation of fluorine-18 (F-18) into quinoline-5,8-diones have received considerable attention in positron emission tomography (PET) molecular imaging studies. In this paper, we describe an efficient synthetic route for the regioselective preparation of fluoropropyl-substituted quinoline-5,8-diones on the C3, C4, and C6 positions by tert-alcohol media fluorination, followed by oxidative demethylation of the corresponding dimethoxy compound using N-bromosuccinimide (NBS) in the presence of catalytic amounts of sulfuric acid. Moreover, F-18 labeled [¹⁸F]fluoropropylquinoline-5,8-diones [¹⁸F]21-23 were prepared from the corresponding mesylate precursors by a method of rapid and efficient one-pot, two-step reactions: radiofluorination using TBA [¹⁸F]F generated under no-carrier-added (NCA) conditions; oxidative demethylation, resulting in a 45% radiochemical yield of [¹⁸F]21-23 (decay-corrected) with a total synthesis time (including HPLC purification) of 75 min and high radiochemical purity (>99%), as well as high specific activity (∼230 GBq/μmol).     

Automated synthesis of [18F]FMISO on IBA Synthera®

In cancer cells hypoxia can cause resistance to both radio- and chemo-therapy. Being able to quantify, the degree of hypoxia in the cells is a useful tool in therapy planning. The positron emitting 1-[¹⁸F]fluoro-3-(2-nitro-1H-imidazol-1-yl)propan-2-ol ([¹⁸F]FMISO) is the most extensively used tracer for imaging hypoxia. Automated synthesis of [¹⁸F]FMISO was set up on IBA Synthera^®. The precursor 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-p-toluenesulfonyl propanediol (NITTP) was heated at 100 °C for 10 min with [K/K 2.2.2.]⁺[¹⁸F]^? and thereafter hydrolyzed with 0.1 M hydrochloric acid at 90 °C for 2 min. Purification was performed on solid-phase extraction (SPE) cartridges. [¹⁸F]FMISO was obtained in 50 ± 3 % (n = 6) radiochemical yield (decay-corrected) in 35 min synthesis time with radiochemical purity of ≥98 %. The use of disposable Integrated Fluid Processors (IFP?:s) and cartridge purification simplifies the handling and shortens the synthesis time. This is a no frills setup based on all commercially available materials and the synthesis is performed with minor changes from the FDG time-list.     

Construction of the taxane skeleton via the stereoselective conjugate addition of cyanide and the intramolecular B-alkyl Suzuki-Miyaura coupling reaction

Construction of the taxane skeleton via the stereoselective conjugate addition of cyanide and the intramolecular B-alkyl Suzuki-Miyaura coupling reaction is described. A conjugate addition of cyanide to enone 17 proceeded diastereoselectively to provide the desired 18 incorporating the correct C3 stereogenic center in the taxol C-ring. The intramolecular B-alkyl Suzuki-Miyaura coupling reaction of 22, which was derived from 18, successfully furnished the taxol B-ring in 81% yield.     

Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy

An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.     

An efficient synthesis of the carbocyclic core of zoanthenol

A concise strategy for the synthesis of the carbocyclic portion of zoanthenol is disclosed. The key step involves a 6-endo radical-mediated conjugate addition that constructs the quaternary stereocenter at C(12) and closes the B ring in a stereoselective manner. The synthesis of the C-ring fragment uses an enantioselective desymmetrization to simultaneously establish the absolute stereochemistry of two vicinal quaternary stereocenters. In only 17 steps from known compounds, the route affords an ABC ring system containing all three quaternary stereocenters and appropriate functionality to complete the synthesis of zoanthenol.     

Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1-C13 vinyl iodide and C14-C22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1-C13 and C14-C22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13-C28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting β-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.     

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [¹¹C]MPbP (4′-[¹¹C]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T_1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [¹⁸F]F-IV in a rodent model of neuroinflammation. [¹⁸F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by ¹⁸F-fluoroethylation of the precursor with Boc-protecting group (15) with [¹⁸F]2-fluoro-1-bromoethane ([¹⁸F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [¹⁸F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [¹¹C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [¹⁸F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.     

Total synthesis of natural (+)-sesbanimide a and (-)-sesbanimide b

The first total synthesis of natural (+)-sesbanimide A (1) and (-)-sesbanimide B (2), potent antitumor alkaloids isolated from the seeds of the leguminous plant, Sesbania drummondii, has been accomplished starting from D-(+)-xylose. This total synthesis involves efficient construction of the optically active AB-ring system from D-(+)-xylose, introduction of the C₅-unit into the AB-ring system in a form of exo-methylene-γ-lactone, and elaboration of the labile C-ring system at the last stage of the synthesis. The absolute configurations of natural 1 and 2 could be obviously established by our total synthesis.     

New fluorine-18 labeled benzaldehydes as precursors in the synthesis of radiopharmaceuticals for positron emission tomography

4,5-Bis(butoxy)-2-nitrobenzaldehyde and 4,5-bis(tert-butoxycarbonyloxy)-2-nitrobenzaldehyde, as well as their fluorine-18 labeled derivatives (the half-life of F¹⁸ is T_1/2 = 110 min) were synthesized for use as precursors in the synthesis of fluorine-18 labeled catecholamines and 6-[¹⁸F]fluoro-l-DOPA ((S)-3-[4,5-dihydroxy-2-[¹⁸F]fluorophenyl]-2-aminopropionic acid), important radiopharmaceutical agents (RPAs) for positron emission tomography. An advantageous feature of the newly obtained substituted nitrobenzaldehydes is the presence of labile protective groups which can be removed without using aggressive chemicals and severe conditions, which is of fundamental importance for automation of the RPA synthesis in modern synthesis apparatus. A high and stable radiofluorination yield achieved under the optimum fluorination conditions (Kryptofix 222 [K/K2.2.2.]⁺[¹⁸F^–], DMF, 140 °C, 10 min) using 4,5-bis(butoxy)-2-nitrobenzaldehyde as a substrate (83±6%, the number of experiments was n = 15) makes this compound a precursor of choice for the radioactive synthesis.     

Fluorinated vs hydrogenated surfactants in mixtures with valinomycin—The Langmuir monolayer study

Selected fluorinated and hydrogenated surfactants, namely a semifluorinated alkane (SFA): 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10-henicosafluorononacosane (F10H19), two long chain alcohols: 18,18,18,17,17,16,16,15,15,14,14,13,13,12,12,11,11-heptadecafluorooctadecane-1-ol (F8H10OH) and octadecane-1-ol (C18OH) and with two long chain thiols of the analogous apolar part structure to the above-mentioned alcohols, i.e.: 18,18,18,17,17,16,16,15,15,14,14,13,13,12,12,11,11-heptadecafluorooctadecane-1-thiol (F8H10SH) and octadecane-1-thiol (C18SH) have been tested in mixtures with valinomycin as potential artificial matrixes for its immobilization. The thermodynamic analysis (ΔG^exc vs X_val plots) based on surface pressure–area isotherm registration for particular valinomycin/surfactant mixtures, complemented with BAM images of the films structure indicate that only fluorinated surfactants are suitable materials for valinomycin incorporation as they form homogeneous miscible monolayers at X_val below 0.5.     

Difluorocarbene-derived rapid late-stage trifluoromethylation of 5-iodotriazoles for the synthesis of 18F-labeled radiotracers

Difluorocarbene has emerged as a valuable intermediate to synthesize fluorides. However, difluorocarbene-derived synthesis of ¹⁹F/¹⁸F-trifluoromethyl triazoles has not been explored. Herein, we reported the Cu(I)-promoted difluorocarbene-derived ¹⁹F/¹⁸F-trifluoromethylation of iodotriazoles using KF/K¹⁸F as the fluorine source. This approach rapidly generated a wide range of 5-trifluoromethyl-1,2,3-triazoles in good yields showing high functional group compatibility. The reaction was effective for late-stage functionalization of bioactive molecules and ¹⁸F-trifluoromethylation of iodotriazoles. This work provides a practical synthetic methodology for the development of triazole drugs and ¹⁸F-radiotracers for positron emission tomography.     

Protecting group directed cyclization: asymmetric synthesis of both cis- and trans-dihydrexidine from a common precursor

Protection group of amino- and tethered o-arene functionality of 1,4-aryl-2-amino-1-butanol derived from l-serine dictates the cyclization mode under acidic conditions leading to reverse diastereoselectivity. N-Boc and acetal protected amino alcohol undergo cascade cyclization providing exclusively cis-dihydrexidine via reduction, where formation of C-ring (isoquinoline unit) prior to Friedel–Crafts cyclization control the cis-stereochemistry of the B-ring. N-Cbz and O-benzyl protection direct first F–C cyclization yielding the trans-1-aryl-2-aminotetralin and subsequent deprotection-cyclization forming the C-ring afforded dihydrexidine.     

Electrophilic radiofluorination of aryltrimethylsilanes as a general route to 18F-labeled aryl fluorides

The reactions of a variety of aryltrimethylsilanes with elemental fluorine and acetyl hypofluorite have been studied with the aim of developing a general method for labeling aromatic compounds with fluorine-18. Extensive ¹⁸F incorporation into the aromatic ring of the selected aryltrimethylsilanes was invariably observed, leading to the ipso (¹⁸F-for-Si) electrophilic substitution products together with variable yields of other (¹⁸F-for-H) electrophilic substitution products. The relative extent of the ¹⁸F substitution processes [(C-Si/C-H)subst.] is found to depend largely upon the substituent group on the aromatic ring of the substrate, the leaving moiety, and the radiofluorination procedure used. The utility of aryltrimethylsilyl derivatives as precursors for the rapid synthesis of high specific activity of ¹⁸F-labeled radiopharmaceuticals is discussed.     

Regioselective ring opening of 2-methylaziridine derivatives with F- and F-fluoride

Regioselectivity of the nucleophilic ring opening of N-benzoyl (Bz) and N-benzyloxycarbonyl (Cbz) activated 2-methylaziridines with anhydrous tetramethylammonium fluoride, anhydrous hydrogen fluoride, and ¹⁹F or [¹⁸F]-labelled potassium cryptand fluoride ([K₂₂₂][^18/19F]) were investigated. Whereas all reactions with rigorously anhydrous N(CH₃)₄F did not ring-open the aziridines, reactions with anhydrous HF exclusively yielded the 2-fluoropropanamine derivatives. Reactions of Bz-protected and Cbz-protected 2-methylaziridine with [K₂₂₂][^18/19F] yielded the 2-fluoropropanamine and 1-fluoro-2-propanamine derivatives as the major products, respectively, and represents the first example of regiocontrol during ring opening of aziridines with [¹⁸F]-fluoride.     

A facile direct nucleophilic synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) without HPLC purification

Due to favourable in vivo characteristics, its high specificity and the longer half-life of ¹⁸F (109.8 min) allowing for remote-site delivery, O-(2-[¹⁸F]fluoroethyl)-l-tyrosine ([¹⁸F]FET) has gained increased importance for molecular imaging of cerebral tumors. Consequently, the development of simple and efficient production strategies for [¹⁸F]FET could be an important step to further improve the cost-effective availability of [¹⁸F]FET in the clinical environment. In the present study [¹⁸F]FET was synthesized via direct nucleophilic synthesis using an earlier developed chiral precursor, the Ni^II complex of an alkylated (S)-tyrosine Schiff base, Ni-(S)-BPB-(S)-Tyr-OCH₂CH₂OTs. The purification method has been developed via solid phase extraction thereby omitting cumbersome HPLC purification. The suggested SPE purification using combination of reverse phase and strong cation exchange cartridges provided [¹⁸F]FET in high chemical, radiochemical and enantiomeric purity and 35 % radiochemical yield (decay-corrected, 45 min synthesis time). The method was successfully automated using a commercially available synthesis module, Scintomics Hotbox^one. Based on the current results, the proposed production route appears to be well suited for transfer into an automated cassette-type radiosynthesizers without using HPLC.     

Radiosynthesis of 10-(2-[18F]fluoroethoxy)-20(S)-camptothecin as a potential positron emission tomography tracer for the imaging of topoisomerase I in cancers

The preparation of 10-(2-[¹⁸F]fluoroethoxy)-20(S)-camptothecin, a potential positron emission tomography tracer for the imaging of topoisomerase I in cancers, is described. 10-(2-[¹⁸F]Fluoroethoxy)-20(S)-camptothecin was synthesized by the [¹⁸F]fluoroalkylation of the corresponding hydroxy precursor molecule with 2-[¹⁸F]fluoroethyl bromide ([¹⁸F]FEtBr) in dimethylsulfoxide (DMSO) at 55 °C for 20 min; this was followed by purification using high performance liquid chromatography (HPLC) with a total preparation time of 60 min. The overall radiochemical yield was approximately 5.4–12 % (uncorrected), and the radiochemical purity was above 96 %.     

Coenzyme F430 from Methanogenic Bacteria: Complete Assignment of Configuration Based on an X-Ray Analysis of 12,13-Diepi-F430 Pentamethyl Ester and on NMR Spectroscopy

The structure of a derivative of coenzyme F430 from methanogenic bacteria, the bromide salt of 12,13-diepi-F430 pentamethyl ester ( 5 , X = Br), was determined by X-ray structure analysis. It reveals a more pronounced saddle-shaped out-of-plane deformation of the macrocycle than any hydroporphinoid Ni complex investigated so far. The crystal structure confirms the constitution proposed for coenzyme F430 ( 2 ) and shows that in the epimer 5 , the three stereogenic centers in ring D, C(17), C(18), and C(19), have the (17S)-, (18S)-, and (19R)-configuration, respectively. Deuteration and 2D-NMR studies independently demonstrate that native coenzyme F430 (2) has the same configuration in ring D as the epimer 5 . Therefore, our original tentative assignment of configuration at C(19) and C(18) [1] has to be reversed. This completes the assignment of configuration for all stereogenic centers in coenzyme F430, which has the structure shown in Formula 2 .