Asymmetric Synthesis

Two new pyridine-based asymmetric bifunctional organocatalysts containing one or two camphorsulfonamide units were synthesized. Asymmetric Michael addition of pentane-2,4-dione to β-nitrostyrene was catalyzed by these organocatalysts. During our experiments, influence of the solvent and temperature on the yield and enantioselectivity was studied. Using monocamphorsulfonamide derivative the S enantiomer of the corresponding Michael adduct was gained with moderate yield (up to 51 %) and low enantiomeric excess (up to 18 %). Organic solvent nanofiltration was successfully applied for the recovery of these organocatalysts. Furthermore, pyridine camphorsulfonamide was reduced to its piperidine derivative. Using piperidine monosulfonamide derivative racemic Michael adduct was obtained with excellent yield (up to 89 %). Beside its organocatalytic relevance, piperidine monosulfonamide derivative may also possess biological activity.

The enzymatic synthesis of esters and peptides is unfavoured in aqueous solvent systems due to competing hydrolysis. This can be overcome by using energy rich substrate analogues: elimination of a good leaving group temporarily establishes more favourable equilibrium conditions, allowing for (nearly) complete conversion. While kinetically controlled syntheses of esters and peptides in water are common knowledge in biocatalysis textbooks, the prevalence of kinetic control is less well known for other enzyme classes. Here, the general concepts of thermodynamic and kinetic control are illustrated at the example of the well‐studied synthesis of β‐lactam antibiotics and are shown to similarly also apply to other enzyme classes. Notably, the enzymatic synthesis of diastereomers shows the same characteristic energy profile as that of Diels‐Alder reactions. This allows for the selective synthesis of different diastereomers under either thermodynamically or kinetically controlled conditions....

We report the first Ir(I)-catalyzed enantioselective intramolecular C-H silylation of ferrocenes for the efficient construction of planar-chiral 5and 6-membered ferrocenyl silacycles. This method overcomes key limitations of existing Rh(I)-based systems, offering superior reactivity, enhanced cost-effectiveness, and broader substrate scope, including challenging C3-and C6-substituted derivatives, as well as excellent enantiocontrol under mild conditions without requiring exogenous H 2 acceptors. The utility of the obtained planar-chiral scaffolds is preliminarily demonstrated through the synthesis of novel monophosphine ligands, which exhibit promising activity in asymmetric catalysis.

Improved syntheses are described for nagilactone F and the antibiotic LL-Z1271ct, two of the most potent bioactive members of the podolactone family. The allelopathic potential of some members of this podolactone series has been evaluated, with the result that the metabolite LL-Z1271(z is one of the most active compounds.

We describe the first synthesis of 3β-hydroxydihydroconfertifolin (3) and 3β-hydroxycinnamolide ( ), together with improved procedures for the preparation of other 3-hydroxydrimanes (2 and 5) scarce in nature. The key step was the titanocene(III)-promoted cyclization of epoxypolyprenes, readily prepared from commercial polyenes. In this way, we confirm

As part of our program aimed at the synthesis of bioactive products, the enantiospecific synthesis of 8-epi-vernolepin derivatives, starting from accessible germacrolides, was attempted. Synthesis of (ϩ)-8-O-acetyl-1,2,11β,13-tetrahydro-8-epi-vernolepin ( ) from (ϩ)-salonitenolide (6) was performed in nine steps with an acceptable overall yield. On the other hand, the synthesis from (ϩ)-stenophyllolide ( ) presented several intrinsic difficulties and was discarded. (ϩ)-Salonitenolide provides one of the most useful raw materials for the synthesis of (ϩ)-vernolepin related compounds preserving its functionalization at C-8.

A two-step synthesis of (R)-and (S)-[ 2 H 1 ]-fluoroacetate (sodium salts) in high enantioselectivity is reported. The synthesis is the development of a previous one in which the enantioselectivity has been increased from $38% ee to >95% ee. The improvement in enantioselectivity applied Bio's methodology, which involved a deoxyfluorination reaction with DAST on either enantiomer of [ 2 H 1 ]-benzyl alcohol, adding TMS-morpholine to the reaction. The additive promotes an S N 2 inversion process, and suppresses a competing non-stereospecific S N 1 reaction course, and as a result significantly improves the stereointegrity of the C-F bond formation. The intermediate [ 2 H 1 ]-benzyl alcohols, [ 2 H 1 ]-benzyl fluorides and the product [ 2 H 1 ]-fluoroacetates as their hexyl esters were separately assayed for their stereochemical integrity, using the Courtieu method. This method involved measuring their 2 H NMR spectra in a chiral matrix of poly-c-benzyl L-glutamate. The chiral assay demonstrated that there was no significant loss in stereointegrity during the deoxyfluorination reaction and showed that the enantiomers of [ 2 H 1 ]-fluoroacetate were generated with high enantiomeric purity (95% ee).

The new asymmetric click CuAAC reaction is used for the first time to induce asymmetry in planar chiral compounds. There are only three classes of stereogenicity (atom‐centred, axial and planar), and these results are therefore of fundamental importance as well as practical significance, providing access to chiral ferrocenes at near enantiopurity. Here, we report asymmetric induction (AI) and kinetic resolution (KR) studies on a novel library of prochiral 1,2,3‐trisubstituted bis‐alkynylferrocenes, obtained by diiodination, derivatisation (including reduction and etherification), double Sonogashira coupling and finally transesterification, azidation or silylation. Desymmetrisation using chiral ligands to modify the CuAAC reaction proceeds in up to 60 % yield and >99.5 % ee, yielding planar chiral ferrocenes. The absolute configuration of two of the preferred products was proved by chemical correlation and related to the entire series by circular dichroism spectroscopy (CD)

Diastereoselective lithiation of (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline followed by addition of HgCl2 resulted in the formation by transmetallation of an (S,Sp)-configured mercury substituted complex. Addition to this of [Cp*IrCl2]2 and tetrabutylammonium chloride resulted in a second transmetallation reaction and formation of an (S,Sp,RIr)-configured chloride-substituted half-sandwich iridacycle as exclusively a single diastereoisomer. By reversing the lithiation diastereoselectivity by use of a deuterium blocking group an alternative (S,Rp,SIr)-configured iridacycle was synthesised similarly. Use of (R)-Ugi’s amine as substrate in the lithiation/double transmetallation sequence gave a (R,Sp,SIr)-configured half-sandwich iridacycle, complexes of this type being previously unavailable by direct cycloiridation. Lithium to gold transmetallation was also demonstrated with the synthesis of an (S,Sp)-configured Au(I) ferrocenyloxazoline derivative. Use of the (S,Rp,SIr)-iridacycle a...

A practical, chemoenzymatic, four-step synthesis of the LTD4 antagonist MK-0679 is described. The key steps are enzymatic hydrolysis of the prochiral diester to the ester-acid in 99% enantiomeric excess followed by aluminum mediated amidation of the methyl ester to afford MK-0679 in high overall yield. This synthesis is superior to the synthesis of the racemate MK-0571.

Introduction 2-Historical Background 3-General Mechanistic Principles 4-Reaction Mechanism 5-Limitations and challenges 6-Conclusion 7-Textbook References -Conjugate addition reactions represent a cornerstone of modern organic chemistry , especially when carbon-carbon bond formation is required under thermodynamically controlled conditions . Among these reactions ,The Michael Addition stands as one of the most powerful and widely use tools in synthetic organic chemistry . It enables nucleophiles to add to α,β-unsaturated carbonyl systems , resulting in the formation of 1,5-difunctionalized products , which serve as strategic intermediates in numerous multistep syntheses. -The reaction is considered a "1,4-conjugate addition " because the nucleophile attacks the β-carbon , rather than the carbonyl carbon (1,2-addition ). This pathway is favored when the nucleophile is soft and the electrophile is resonance-stabilized .

Project XXVI extends the structural line of the Coral Corpus by examining the conditions under which one operative articulation becomes translucent to another without merging, collapsing, or transforming. It does not treat translucency as metaphor or introspection; it formalizes the structural dynamics through which cross-visibility emerges, stabilizes, and becomes perceptible within consciousness.

The asymmetric isomerization of alkyne to allene is the most efficient and the completely atomeconomic approach to this class of versatile axial chiral structure. However, the state-of-the-art is limited to tertbutyl alk-3-ynoate substrates that possess requisite acidic propargylic C-H bonds. Reported here is a strategy based on gold catalysis that is enabled by a designed chiral bifunctional biphenyl-2-ylphosphine ligand. It permits isomerization of alkynes with nonacidic α-C-H bonds and hence offers a much-needed general solution. With chiral propargylic alcohols as substrates, 2,5-disubstituted 2,5-dihydrofurans are formed in one step in typically good yields and with good to excellent diastereoselectivities. With achiral substrates, 2,5-dihydrofurans are formed with good to excellent enantiomeric excesses. A novel center-chirality approach is developed to achieve a stereocontrol effect similar to an axial chirality in the designed chiral ligand. The mechanistic studies established that the precatalyst axial epimers are all converted into the catalytically active cationic gold catalyst owing to the fluxional axis of the latter. Axially chiral allenes are versatile and highly valuable intermediates in asymmetric synthesis. 1 Various preparative methods have been documented. 2 Notwithstanding, the direct isomerization of alkyne to chiral allene, the arguably simplest and the most atom-economic approach, has only been reported with alkynes featuring rather acidic propargylic hydrogens, 3 such as 1,3-diphenylpropyne 3c , f and t-butyl alk-3-ynoates 3d , e , and moreover, high e.e. values are only realized with the latter substrates. To date, there is no asymmetric isomerization of a vast range of other alkynes and especially those devoid of acidic propargylic hydrogens. We previously reported the isomerization of arylalkynes into 1-aryl-1,3-dienes via the intermediacy of an allene (Scheme 1A). This reaction is enabled by a bifunctional biphenyl-2-ylphosphine (i.e., L1) that features a remote aniline moiety and was specifically *

Lithium-ion batteries are produced on a large scale mainly for powering electronic devices, but simultaneously intensive research is carried out on the development of large, hi systems for other applications, as accumulating energy obtained from renewable sources, load leveling and also powering hybrid and plug-in electric vehicles (HEVs). From among the requirements put before batteries, their reliability, especially regarding safety issues is a very important problem which must be solved to develop large, high power and high voltage lithium batteries [1].

THF was purified by passing it through a neutral alumina column. Zinc metal (Strem) was activated with hydrochloric acid. Benzaldehyde (Aldrich), ptrifluoromethylbenzaldehyde (Aldrich), p-tolualdehyde (Aldrich), and 2-bromo-2methylpropanoylbromide (Aldrich) were distilled prior to use. Quinidine (Avocado), LiClO 4 (Alfa Aesar), 2-napthaldehyde (Aldrich), 4-acetylbenzaldehyde (Aldrich), DIBAL-H (1.0 M in THF; Aldrich), sodium azide (Alfa Aesar), DMSO (Aldrich), and npropylamine (Aldrich) were used as received. Non-commercially available αbromoacid bromides were synthesized according to a literature procedure. 1 Catalysts 1, 2 2, 3 and O-TMS-quinidine 4 were prepared as previously reported. All reactions were carried out under an atmosphere of nitrogen or argon in ovendried glassware with magnetic stirring, unless otherwise indicated.

The complex, dichloro(triphenylphosphine){1-[N,N-α-dimethylaminoethyl]-2-diphenylphosphinoferrocene}ruthenium(II), prepared from RuCl2(PPh3)3 by ligand displacement, catalyzes the hydrogenation of terminal olefins under mild conditions. The experimental rate-law for hydrogenation of hexene-1 in n-butanol at 40 °C shows a first-order dependence on both olefin and hydrogen, and an inverse dependence to added triphenylphosphine. The dependence on ruthenium goes from first- to half-order with increasing metal concentration. The kinetic data, together with spectroscopic data, and studies on reactivity of the complex toward hydrogen, are interpreted in terms of catalysis via a ruthenium(I) complex that dissociates a phosphine ligand to generate the active species.

Flame-dried (under vacuum) glassware was used for all non-aqueous reactions. All reagents and solvents were commercial grade and purified prior to use when necessary. Diethyl ether (Et 2 O), tetrahydrofuran (THF), dichloromethane (CH 2 Cl 2 ), and benzene (C 6 H 6 ) were dried by passage through a column of activated alumina as described by Grubbs. 1 Benzene was additionally passed through a column containing activated Q-5 reactant. Solvents other than benzene were degassed using the freeze-pump-thaw method when necessary. All additional solvents were dried by distillation from calcium hydride when necessary. Molecular sieves (spheres, 4Å) were calcined at 400 °C and stored at room temperature in an air-tight container. AIBN was recrystallized prior to use, and tri-n-butyl tin hydride ( n Bu 3 SnH) was used as received from Aldrich. 2 Preparations for previously unreported phenethyl amine derivatives used in this study will be reported later in an Article after optimization. Thin layer chromatography (TLC) was performed using glass-backed silica gel (250 µ) plates and flash chromatography utilized 230-400 mesh silica gel from Scientific Adsorbents. Neutral Alumina was used as received from Scientific Adsorbents for chromatography of acidsensitive intermediates or products. Products were visualized by UV light, iodine, and/or the use of ceric ammonium molybdate, potassium permanganate, ninhydrin, p-anisaldehyde, and potassium iodoplatinate solutions. IR spectra were recorded on a Nicolet Avatar 360 spectrophotometer. Liquids and oils were analyzed as neat films on a salt plate (transmission), whereas solids were applied to a diamond plate (ATR). Nuclear magnetic resonance spectra (NMR) were acquired on either a Varian Inova-400 or VXR-400 instrument. Chemical shifts are measured relative to tetramethylsilane, as judged by the residual partially deuterated solvent peak. Mass spectra were obtained using a Kratos MS-80 spectrometer using the ionization technique indicated. Combustion analyses were performed on a Perkin-Elmer 2400 Series II CHNS/O Analyzer. Ratios of diastereomers and isomeric products were measured directly from integration of 1 H NMR absorptions of protons common to the components. Precision was checked by varying the relaxation delay for measurements on the same compound. Where possible, ratios were corroborated using GC-mass spectrometry. Peak assignments were made from authentic samples in every case. Ratios reported generally represent a lower limit defined by multiple runs.

Two nonnatural proline derivatives, (S)- and (R)-7-azaindoline a-amino acid have been prepared and isolated as their trifluoro- acetate salt on gram scale. The convergent sequence (6 steps from 2-bromopyridine) employs a combination of enantioselective phase trans- fer catalyzed glycine alkylation and free radical-mediated aryl amination. Implementation of the solid-liquid phase transfer conditions requires manual pulverization of cesium hydroxide, efficient mechanical stirring, and effective low temperature control. This large scale free radical cyclization protocol replaces benzene solvent with toluene without complication, and the crystalline nature of the intermediates and final product enables straightforward purification at each stage, including enantiomeric enrichment (89% to >99% ee for 4b, Scheme 1).

A new approach for the immobilization onto organic insoluble polymers of Cinchona alkaloid derivatives was developed and the resulting insoluble polymer-bound (IPB) systems were used as enantioselective organocatalysts in different metal-free asymmetric transformations. Landmarks of this work were the scalable preparation of the IPB derivatives, the attainment of excellent catalytic performance (up to 97% ee) in selected enantioselective processes (dimerization of ketenes and a-amination of 2-oxindoles) and extended serviceability (up to 100 reaction cycles and 5300 h reaction time) of the supported catalysts

We present a study on sequential conjugate addition of ­Grignard reagents to alkenyl-heteroarenes followed by trapping of the resulting enolates, yielding moderate to good diastereoselectivities. Contrary to conventional wisdom, one-pot conjugate addition/trapping using two reactive Michael acceptors in combination with Grignard reagents can proceed via conjugate addition to the least reactive Michael acceptor. This unusual chemoselectivity is triggered by the presence of a Lewis acid, reverting the usual reactivity order of Michael acceptors.

The 5'-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2',3'-di-O-protecting groups (R 1 ): O-alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5'R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5'S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.

The first total synthesis of the natural enantiomer of the insect-antifeedant dihydroclerodin (1) and lupulin C (40) has been achieved starting from (R)-(−)-carvone (2). In the applied strategy, the hexahydrofuro[2,3-b]furan moiety was introduced in an early stage of the synthesis. The correct configuration at C-9, C-11, C-13, and C-16 was established by application of a remarkably diastereoselective Mukaiyama reaction. The desired configuration at C-10 was obtained by catalytic reduction of the intermediate enone 21. After annulation of the second ring, the structural features at C-4, C-5, and C-6 were introduced. The successful finishing of the synthesis included a Chugaev elimination to give the exocyclic double bond at C-4 that is present in lupulin C. Oxidation of this double bond with m-CPBA afforded dihydroclerodin.

Herboxidiene is a potent inhibitor of spliceosomes. It exhibits excellent anticancer activity against multiple human cancer cell lines. Herein, we describe an enantioselective synthesis of a desmethyl derivative and the corresponding carba-derivatives of herboxidiene. The synthesis involved Suzuki coupling of a vinyl iodide with boronate as the key reaction. For the synthesis of carba-derivatives, the corresponding optically active cyclohexane-1,3-dicarbonyl derivatives were synthesized using an enantioselective desymmetrization of meso-anhydride. The biological properties of these derivatives were evaluated in an in vitro splicing assay.

The C11–C17 segment of the antifungal agent soraphen A1α was prepared from glyceraldehyde acetonide in nine steps. The C12 stereocenter is derived from glyceraldehyde, while the C17 stereocenter as introduced by 1,6-asymmetric control via the coordinated Fe(CO)3.

In this study, a series of γ,γ-disubstituted and β,γ-disubstituted allylic alcohols were prepared and successfully hydrogenated using suitable N,P-based Ir complexes. High yields and excellent enantioselectivities were obtained for most of the substrates studied. This investigation also revealed the effect of the acidity of the N,P–Ir-complexes on the acid-sensitive allylic alcohols. DFT ΔpKa calculations were used to explain the effect of the N,P-ligand on the acidity of the corresponding Ir-complex. The selectivity model of the reaction was used to accurately predict the absolute configuration of the hydrogenated alcohols.

Human cognition is fundamentally asymmetric. It does not evaluate all alternatives symmetrically, nor does it operate from neutrality. Instead, it moves through gradients of orientation, threshold-based transitions, and multi-scale dynamics that shape its capacity for sudden resolution. This project develops a structural and proto-dynamic framework for understanding intuition as an emergent effect of asymmetric organization. The analysis integrates conceptual, mathemati
cal and topological perspectives to clarify how directionality, nonlinearity and irreversibility produce cognitive movement. The result is a non-mystical, non-reductive account of intuition and a rigorous foundation for understanding the asymmetric

This research has been divided into two subjects. The first w as com prised o f the study o f vinyl triflates and term inal acetylenes used as precursors for Ao-polydiacetylenic precursors. The second study was to assess the asymm etric addition o f dimethyl thiophosphite to im ines with chiral auxiliaries. In the first study, palladium catalyzed cross-coupling o f a term inal acetylene and vinyl triflate, which produced a dim er that could be converted into either a terminal acetylene or vinyl triflate was accomplished. The dim er was then converted into a terminal acetylene and coupled with the vinyl triflate m onom er to produce a trim er that allowed linear chain growth. The sequence was repeated until the tetram er was produced establishing the possibility for Ao-polydiacetylenic precursors to be made by the established method. In the second study dimethyl thiophosphite was added across im ines made from chiral amines and aldehydes. The diastereom er ratio ranged from poor (10:9) to good (11:2) and was independent o f hydrogen bonding auxiliaries. Separation o f diastereomers was accomplished w ith some o f the compounds using silica chrom atography. The asymmetric dealkylation using potassium ethyl xanthate was studied and found to be successful on the com pounds that did not possess a hydroxy functional group on the chiral amine. iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chuck has m y up most respect as a synthetic medicinal chem ist, m entor, and friend. Many times his advice and inspiration have helped me through the battle o f graduate school. I w ould also like to thank m y thesis com mittee Professors Edw ard Rosenberg, Ed Waali, N igel Priestley, and Howard Beal. All have been very resourceful for expanding my know ledge by teaching me to think through a problem rather than around the problem. I m ust also express m y adm iration o f the Thom pson group w hom all have become more than ju st people w ith whom I work. Professor Sean Esslinger has been a constant friend and associate that I could approach with any problem w hether it was about science or life. Dr. Joseph D egraw for all o f his insight, patience, and the countless reminder o f what a true chem ist lives for; g olf and beer. Travis Denton and Jam es Cox for their cam araderie in the lab and conversations at the watering holes. Todd Talley, whom always had the answer on how to feel better and Katie George for her constant support and insight on what really matters. Jason M ullins for rem inding me to not go back to graduate school along w ith Nate Tamblyn, Lisa Sandoval, H olly and, o f course, Karma. v Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. There is no w ay to list all who helped me get here today but I know that I would not be a chem ist if Dr. Eric D. Edstrom had not spent so m any days m entoring me through undergraduate school. But m ost o f all I m ust acknowledge m y wife, Sarah V oelker, who is m y purpose for making m y self a better person. vi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

The role of the helicity of small molecules in enantioselective catalysis, molecular recognition, self-assembly, material science, biology and nanoscience is much less understood than that of point-, axial- or planar-chiral molecules. To uncover the envisaged potential of helically chiral polyaromatics represented by iconic helicenes, their availability in an optically pure form through asymmetric synthesis is urgently needed. We provide a solution to this problem present since the birth of helicene chemistry in 1956 by developing a general synthetic methodology for the preparation of uniformly enantiopure fully aromatic [5]-, [6]- and [7]helicenes and their functionalised derivatives. [2+2+2] Cycloisomerisation of chiral triynes combined with asymmetric transformation of the first kind (ultimately controlled by the 1,3-allylic-type strain) is central to this endeavour. The point-to-helical chirality transfer utilising a traceless chiral auxiliary features a remarkable resistance to...

Both enantiomers of the key intermediate, 2-benzyl-5-oxo-tetrahydro-furan-2-carboxylic acid were obtained by asymmetric oxidation of 3-benzyl-2-hydroxy-2-cyclopenten-1-one with an ee P96%, using the tartaric ester/Ti(OiPr) 4 /t-BuOOH complex, and transformed to the corresponding 4 0 -substituted nucleoside analogues with up to 61% overall yield.

Alkyl-1,2-cyclopentanediones 1 are transformed into 2-alkyl-2-hydroxyglutaric acid c-lactones 3 in up to 83% isolated yields and up to 96% ee, affording a simple access to many bioactive compounds, including diacylglycerol lactones (DAG-lactones).

3-Aryl-2-hydroxycyclopent-2-en-1-ones, when subjected to asymmetric oxidation, result in enantiomerically enriched 2aryl-5-oxotetrahydrofuran-2-carboxylic acids. Electron-donating substituents in the para position of the phenyl ring increase the yield and decrease the enantioselectivity of the process.

Bifunctional primary amine thiourea (PAT) organocatalysts show remarkable improvement in enantioselectivity and catalytic activity (turnover frequency■■OK?■■) in the asymmetric Michael addition of acetone to β-nitrostyrenes upon dilution. Mechanistic investigations indicate that this behavior corresponds to the inhibition of off-cycle catalyst deactivation at low concentration, rather than to the operation of aggregation phenomena at high concentration. Reaction at low concentration (≤0.2 M in β-nitrostyrene) leads to the minimization of catalyst deactivation and, thus, to the optimization of yield and ee of the Michael addition products.

Reacti on of azaphospholes (L ) [2-phosphaindoli zines (1) and I ,3-azaphospholo[S , I-a]isoquinolines (2)] with [1'( Cp*RhC1 2 h (Cp* = pentamethylcyclopentadienyl) and [Ru(116-cy mene)CI 2h in 2: I molar ratio in dichl oromethane y ields monon ucl ear complexes of the type [Cp*RhCl i L)] .H 2 0 and [Ru(cy mene)Cl i L)] .H 2 0. These complexes have been characterized by elemental analysis, FAB mass, IR and NMR (IH and 31p) spectral data. Stereochemistry of these compl exes has been discussed based on NMR data. NMR studies revea l a dynamic equilibrium between covalent and ionic forms of the compl exes derived from 1 in solution.

The object of the present thesis was the development and synthesis of combretastatin A4 derivatives and their cytotoxical evaluation on 518A2 melanoma cells. Combretastatin A4 is known for its highly effective but unstable Z-configuration. A five-membered heterocycle should be inserted to guarantee stability of its Z-configuration followed by cytotoxical potency. By the variation of substitution patterns of the heterocycle, a set of highly potent cytotoxical combretastatin A4 derivatives was synthesized. Their IC50-values were scaled from the middle to low nanomolar range. Compared to the standard care for patients with melanoma metastasis, Dacarbazin shows an activity of 548 µM, the most active compound 55 (0,070 µM) gives an 8000-fold increase of potency. Cell cycle analysis showed that the high effectiveness of the new compounds could be based on inhibition of cell division and the induction of apoptosis. The results of these highly effective compounds could present them as poten...

A diastereo- and enantioselective approach to access chiral CF 2 -functionalized aziridines from difluorodiazoethyl phenyl sulfone (PhSO 2 CF 2 CHN 2 ) and in situ-formed aldimines is described. This multicomponent reaction is enabled by a combined strong Brønsted acid catalytic platform consisting of a chiral disulfonimide and 2-carboxyphenylboronic acid. The optical purity of the obtained CF 2 -substituted aziridines could be further improved by a practical dissolution–filtration procedure.