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Belactosin A, a β-lactone proteasome inhibitor, contains a unique 3-(trans-2′-aminocyclopropyl)alanine moiety. We recently identified the biosynthetic gene cluster of the belactosin series from Streptomycessp. UCK14. To shed light on the formation of the aminocyclopropylalanine, we established a heterologous pathway expression, constructed a set of gene deletion mutants, and performed feeding studies for a chemical complementation that include the incorporation of stable isotope-labeled precursors. We thereby show that, in the biosynthesis of this building block, a cryptic nitrocyclopropylalanine intermediate is generated from l-lysine. The subsequent reduction of the N-oxygenated precursor to the corresponding amine is mediated by the molybdopterin-dependent enzyme BelN.

An original synthesis of the acetogenin muricadienin, the bioprecursor of solamin, has been developed. The key step in the five-step 41% overall yield synthesis is the catalytic cross-cyclomagnesiation reaction of functionally substituted 1,2-dienes with EtMgBr in the presence of Cp2TiCl2and magnesium metal. It has been demonstrated for the first time that muricadienin exhibits a moderate in vitro inhibitory activity against topoisomerases I and IIα, key cell cycle enzymes. Using flow cytometry, muricadienin was shown to have high cytotoxicity toward the HEK293 kidney cancer cells (IC500.39 μM).

The structure of hormaomycin has been determined in two crystals grown under different conditions, i. e. in the absence and in the presence of magnesium chloride. In both crystals, the macrocyclic hexadepsipeptide assumes a rather flat conformation, and the dipeptide side chain resides in the same equatorial plane. This is a significant difference in comparison with the compact bent conformation of hormaomycin in solution, as previously determined by an extensive NMR study

The straightforward synthesis of new bicyclopropyl‐substituted alkynes and 1,3‐dienes and their application in cobalt‐catalyzed Diels–Alder reactions are described. The cycloaddition processes generated the desired bicyclopropyl‐substituted arene derivatives in moderate to good yields, depending on the steric congestion of the reaction partners. The regioselectivity of the cycloaddition was controlled by the ligand coordinated to the cobalt center. The cyclopropyl moiety remained unchanged over the course of the Diels–Alder reaction, indicating that no radical type intermediates were formed. Only in a single case did the DDQ oxidation of the primarily formed dihydroaromatic product lead to ring opening of a cyclopropyl subunit. In all of the other cases, cyclopropyl‐modified arenes with various functionalities were obtained.

A new original strategy for the synthesis of axially and helically chiral bidentate diphosphane ligands featuring a rigid triangulanyl backbone has been elaborated and executed for several representative enantiomerically pure ligands. Thus,(1R,3S,4S)‐1,4‐bis[(diphenylphosphanyl)methyl]spiro[2.2]pentane [(1R,3S,4S)‐24·(BH3)2], [(1R,3R,4S)‐4‐(diphenylphosphanyl)methylspiro[2.2]pentan‐1‐yl]diphenylphosphane [(1R,3R,4S)‐27·(BH3)2], [(1R,3R,4S,5R)‐5‐(diphenylphosphanyl)methyldispiro[2.0.2.1]heptan‐1‐yl]diphenylphosphane [(1R,3R,4S,5R)‐30·(BH3)2], (1S,3S,4S)‐1,4‐bis(diphenylphosphanyl)spiropentane [(1R,3S,4S)‐35·(BH3)2], (1S,3S,4S)‐1,4‐bis(diphenylphosphanyl)spiropentane [(1S,3S,4S)‐35·(BH3)2], (1S,3S,4S)‐1,4‐bis(diphenylphosphanyl)spiropentane [(1R,3R,4S)‐35·(BH3)2], and (1R,3R,4R,5R)‐1,5‐bis(diphenylphosphanyl)dispiro[2.0.2.1]heptane [(1R,3R,4R,5R)‐36·(BH3)2] with a spiropentyl and a dispiro[2.0.2.1]heptyl moiety, respectively, have been prepared as bishydroborane complexes applying repetitively the same set of standard synthetic operations, starting from [(1S,3R)‐4‐methylenespiropent‐1‐yl]methyl acetate [(1S,3R)‐7], (4,4‐dibromospiropent‐1‐yl)methanols [(1S,3R)‐8and (1R,3S)‐8] and (dibromodispiro[2.0.2.1]heptyl)methanols (1R,3S,4R)‐9, (1S,3R,4S)‐9and (1S,3R,4R)‐9in 4–7 steps. The relative configurations of all important intermediates as well as the absolute configurations of the key intermediates and most final products were established by X‐ray crystal structure analyses.

A new rearrangement of the cyclic L‐glutamine derivative(S)‐6‐carbamoylamino‐3‐(methylamino)‐2,3,4,5‐tetrahydropyridin‐2‐one (2) and its descarbamoyl analogue 10‐H was found to yield enantiomerically pure 5‐carbamoylimino‐1‐methyl‐L‐proline amide (12‐CONH2) and its descarbamoyl analogue 12‐H, respectively. Cyclic amidines 2and 10‐H were generated from the amide N2‐ZGlnOEt 3in seven and six steps, respectively. Deprotection of (S)‐6‐amino‐3‐[(N‐benzyloxycarbonyl‐N‐methyl)amino]‐2,3,4,5‐tetrahydropyridin‐2‐one (8) led directly to 5‐iminoproline amide 12‐H (via 10‐H and the bicyclic orthoamidine 11‐H) in 66 % overall yield from 3. Carbamoylation of 8with ZNCO (Z = PhCH2OCO) followed by hydrolytic removal of both Z groups gave 5‐(carbamoylimino)proline amide 12‐CONH2(via 2and orthoamidine 11‐CONH2) in 70 % overall yield from 3.

Thirty‐three different N,N‐dialkyl‐ and N‐alkyl‐N‐phosphorylalkyl‐substituted carboxamides 9–17were treated with unsubstituted as well as with 2‐alkyl‐, 2,2‐dialkyl‐, and 3‐alkenyl‐substituted ethylmagnesium bromides 6in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20–25in 20–98 % yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98 %) of the cyclopropylamines 20–28without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane‐protected ketones and halogen‐substituted and chiral as well as achiral alkyloxyalkyl‐substituted carboxamides could be converted to the correspondingly substituted cyclopropylamines with unsubstituted as well as phenyl‐ and a variety of alkyl‐substituted ethylmagnesium bromides in addition to numerous heteroatom‐containing (e.g., halogen‐, trityloxy‐, tetrahydropyranyloxy‐substituted) Grignard reagents (62 examples altogether). The transformation of N,N‐diformylalkylamines 54with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N‐dicyclopropyl‐N‐alkylamines 55can be brought about in up to 82 % yield (6 examples). An asymmetric variant of the titanium‐mediated cyclopropanation of N,N‐dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding cyclopropylamines with enantiomeric excesses (ee) of up to 84 %. Evaluation of several silyl‐based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 mol %) of the titanium reagent, as long as 2‐aryl‐ or 2‐ethenyl‐substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)‐Cotinine as well as the insecticides Dinotefuran and Imidacloprid.

Isocyanides have long proved themselves to be irreplaceable building blocks in modern organic chemistry. The unique features of the isocyano group make isocyanides particularly useful for the synthesis of a number of important classes of nitrogen heterocycles, such as pyrroles, indoles, and quinolines. Several cocyclizations of isocyanides via zwitterions and radical intermediates as well as transition‐metal‐catalyzed syntheses of different types of heterocycles have recently been developed. Methods starting from isocyanides often have distinct advantages over alternative approaches to the same heterocycles because of their enhanced convergence, the great simplicity of most of the operations with them, and the great variety of isocyanides readily available for use. Isocyanides have also been used in some enantioselective syntheses of chiral heterocyclic compounds, including natural products as well as precursors thereof.

Isocyanide bewähren sich seit langem als unersetzliche Bausteine in der modernen organischen Chemie. Die einzigartigen Eigenschaften der Isocyanogruppe machen Isocyanide für die Synthese etlicher wichtiger Klassen von Stickstoff‐Heterocyclen wie Pyrrolen, Indolen oder Chinolinen besonders wertvoll. In letzter Zeit wurde eine ganze Reihe von Cocyclisierungen von Isocyaniden über Zwitterionen und radikalische Intermediate ebenso wie übergangsmetallkatalysierte Synthesen verschiedener Arten von Heterocyclen entwickelt. Methoden, die von Isocyaniden ausgehen, weisen oftmals deutliche Vorteile gegenüber alternativen Wegen auf, was oft der verbesserten Konvergenz und der Einfachheit solcher Verfahren sowie der großen Vielfalt einfach zugänglicher Isocyanide geschuldet ist. So finden Isocyanide auch in enantioselektiven Synthesen chiraler heterocyclischer Verbindungen einschließlich Naturstoffen Verwendung.

The cascade reaction modes and hence the outcomes of the palladiumcatalyzed oligocyclizations of various 2bromoalka1,n+m+1dienen+1yne substrates were found to be highly dependent on the tether lengths between the multiple bond fragments, and on the nature of the substituent at the nonbrominated vinylic terminus. Just like 2bromododeca1,11dien6ynes with their two threeatom tethers, 2bromotrideca1,12dien7ynes 8and 2bromotetradeca1,13dien8ynes 17, with combinations of four and three as well as five and threeatom tethers, under Hecktype reaction conditions undergo, after the initial oxidative addition step, two consecutive nexodigand mexotrigcarbopalladations followed by βhydride elimination and ensuing 6πelectrocyclization to furnish tricyclic bisannelated cyclohexadiene derivatives, such as 37and 40, in moderate yields 30 and 29 . On the other hand, when 2bromoalka1,n+m+1dienynes with a four, five or even a sixatom tether between the bromoene and the yne moiety, and a fouratom tether between the yne and the terminal ene unit, such as 34, 35and 36, are subjected to Hecktype reaction conditions, they undergo a cascade oligocyclization involving a 5exotrig and ensuing 3exotrigcarbopalladation as the fourth and fifth steps before the terminating βhydride elimination, eventually leading to tetracyclic skeletons such as 43, 44and 45with a bridging threemembered ring in yields of 74, 76 and 32 , respectively.

Under a newly developed set of mild conditions [EtNiPr2, LiI, DMF, 20 °C, 3 d], methyl 2chloro2cyclopropylideneacetate 1 smoothly undergoes Michael addition ofvarious benzylamines 4 examples with ensuing ring enlargement and elimination to give in very good yields 81–99  the correspondingly substituted methyl 2benzylaminocyclobutenecarboxylates 3a–d, which were subsequently converted into the NBocprotected derivatives 4a–d. After hydrolysis of the esters, the free βamino acids 5a,bwere cleanly condensed with the methyl esters of glycine, Sproline, Sphenylglycine and Stryptophan to give the dipeptides 6a–8a, 9bin 58–89  yield. The cyclic dipeptides 15e,f, consisting of a 2aminocyclobutenecarboxylic acid and a glycine fragment, were obtained in 38 and 45  yield, respectively, upon treatment of the spirocyclopropanated chlorohexahydrodiazepinediones 10e,fwith sodium cyanide in DMSO at elevated temperatures. Palladiumcatalyzed hydrogenation of 4aafforded methyl NBoc2aminocyclobutanecarboxylate 19as a mixture of cisand transisomers.

1Bromo1cyclopropylcyclopropane 1, which is easily accessible in two steps from methyl cyclopropanecarboxylate, does not form a stable Grignard reagent upon reaction with elemental magnesium, yet it readily undergoes brominelithium exchange without rearrangement upon treatment with tertbutyllithium in diethyl etherpentane at –78 °C, and the resulting 1lithio1cyclopropylcyclopropane can be trapped with various electrophiles to give the correspondingly 1substituted bicyclopropyl derivatives 10in yields ranging from 38 to over 90  13 examples. The 1cyclopropylcyclopropylboronate 10m, which is also obtained from the 1lithio derivative, has been subjected to Suzuki cross couplings with a number of aryl halides to furnish 1aryl1,1′bicyclopropyl compounds 114 examples, 14–50  yield, predominantly without rearrangement. Further transformations of 1cyclopropylcyclopropanecarbaldehyde 10e have provided 21cyclopropylcyclopropylglycine 16, ethyl 31cyclopropylcyclopropylacrylate 17, and its cycloadducts with the nitrone 18and cyclopentadiene 19, albeit the latter only in poor yield.

A practical synthesis of bicyclic sultams with a pyramidal bridgehead nitrogen atom and a sulfur atom in the apex position has been elaborated. Compounds with 1azathiabicyclo[2.2.1]heptane 12a, bicyclo[3.2.1]octane 12b, 12d, and bicyclo[3.3.1]nonane 13b skeletons were obtained by direct twofold interintramolecular alkylation of corresponding monocyclic sultams 9and 10with α,ωdihalides 11in K2CO3DMF in 56, 68, 52 and 52  yield, respectively. On the other hand, a 1aza9thiabicyclo[4.2.1]nonane derivative 12c could be prepared only by stepwise dialkylation in 24  overall yield. Structural and conformational properties of four of the newly prepared bicyclic sultams in solution as well as in the solid state are discussed.

Various 1substituted cyclopentylamines 25 examples, 10–89  yield have been prepared according to a onepot procedure by the addition of tetramethylenebismagnesium dibromide in the presence of TiOiPr4to aliphatic, aromatic and heteroaromatic nitriles, respectively.

Selective single and double labelling of the natural ganglioside GM1 enables one to introduce various markers into different parts of the glycosphingolipid molecule without changing the natural skeleton. To that end, NFmoc2amino, NFmoc18amino and Sethoxythiocarbonyl18mercaptostearic acids have been prepared and coupled with the primary amino group in the sphingosine part of lysoGM1 and deAcdeAcylGM1 gangliosides. The products of these coupling reactions – building blocks 16a, 16b, 16c, 26and 27– may be used for the synthesis of GM1 derivatives with one or two fluorescent dye moieties or other labels of various polarities. Examples of various labelling strategies, using hydrophilic and lipophilic photostable fluorescent dyes, have been made available. The GM1 derivatives 17a, 22aand 23clabelled with the fluorescent dye ATTO 647N or the doubly labelled derivative 25bcan be used as probes in fluorescence correlation spectroscopy in conventional microscopy or stimulated emission depletion nanoscopy to study the diffusion of lipid analogues in model or live cell membranes.© WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009