Search

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

oBromophenyl isocyanide 1Br reacts with various primary amines under CuIcatalysis to afford 1substituted benzimidazoles 4in moderate to good yields 38–70 , 13 examples. Analogously, 2bromo3isocyanothiophene 6 furnishes 3substituted 3Hthieno[2,3d]imidazoles 744–49 , 3 examples. © WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

N2,3Dibromopropyl and N3,4dibromobutylmethoxycarbonylmethanesulfanilides upon treatment with potassium carbonate in DMF furnish methyl 3aryl2,2dioxo2thia3azabicyclo[n.1.0]alkane1carboxylates in yields ranging from 54 to 84  10 examples. The starting materials were obtained by sulfonylation of Nalkenylanilines with methyl chlorosulfonylacetate and subsequent bromination. For the Nalkenylanilines 10 examples, 60–77  yield an efficient new synthesis employing a 2nitrophenylsulfonyl substituent as a protective as well as an activating group has been developed. The 4methoxyphenyl PMP group could easily be removed from the sultam nitrogen atom by treatment with ceriumIV ammonium nitrate.© WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

Cyclopropane‐ and alkylcyclopropane‐annelated methyl imidazolidinecarboxylates 5are formed from unsubstituted 1‐H and from 2′‐substituted methyl 2‐chloro‐2‐cyclopropylideneacetates (1‐R) and N,N′,N″‐triarylguanidines (2) in a domino process consisting of a Michael addition and an immediately ensuing ring closure by intramolecular nucleophilic substitution in moderate to very good yields (30–95 %, 8 examples). The products 5with alkyl substituents on the spirocyclopropane moiety are formed diastereoselectively.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) Mixtures of two diastereometric 2′‐alkyl‐substituted methyl 2‐chloro‐2‐cyclopropylideneacetates react with N,N′,N″‐triarylguanidines to furnish a single diastereomer each of an alkylcyclopropane‐annelated2‐arylimino‐1,3‐diaryl‐4‐carboxylate.

Methyl 2benzyloxycarbonylamino2cyclopropylideneacetate 2 was prepared in nine steps starting from Lserine in an overall yield of 24 . It has been demonstrated to be reasonably reactive in Michael additions of various nucleophiles 6 examples, 75–98  yields as well as Diels–Alder reactions, both leading to new cyclopropylcontaining amino acids in protected form. An application of 2in the synthesis of methyl 4tertbutoxycarbonylmethyl5oxo4,7diazaspiro[2.5]octane8carboxylate 15, a precursor for geometrically constrained bicyclic peptidomimetics of type 16, has also been proved.© WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

1,1′‐Bi(endo,exo,syn‐pentacyclo[3.3.3.02,4.06,8.09,11]undecyl)[1,1′‐bi(trishomobarrelenyl)] (4) has been prepared as a 1:1 mixture of its meso‐ and d,l‐diastereomers in six steps from trishomobarrelene 1via the amine 5, the N,N′‐bis(trishomobarrelenyl)sulfamide 6and the 1,2‐(trishomobarrelenyl)diazene 7in 16 % overall yield. Crystals of meso‐4were grown from a pentane solution of the mixture and subjected to an X‐ray structure analysis. The (+)‐ and the (–)‐enantiomer were isolated by HPLC on a chiral‐phase column. They exhibited significantly enhanced molar optical rotations which are consistent with the presence of three helically arranged 1,2‐dicyclopropylethane units in their skeletons. The absolute configuration of the (+)‐enantiomer was assigned on the basis of DFT computed optical rotations of both enantiomers to be all‐(S).(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The formal cycloaddition of α‐metallated methyl isocyanides 1onto the triple bond of electron‐deficient acetylenes 2represents a direct and convenient approach to oligosubstituted pyrroles 3. The scope and limitations of this reaction (24 examples, 25–97 % yield) are reported along with an optimization of the reaction conditions and a rationalization of the mechanism. In addition, a related newly developed CuI‐mediated synthesis of 2,3‐disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides is described (11 examples, 5–88 %yield).

The outcomes and the mechanistic pathways of the palladiumcatalyzed Hecktype cascade oligocyclizations of various 2bromoalkenediynes were explored with respect to the lengths of the tethers between the multiple bonds and the nature of the substituent at the acetylenic terminus. Just like substrates containing two threeatom tethers, 2bromotridec1ene6,13diynes 10a,bwith one three and one fouratom tether undergo two consecutive intramolecular 5 and 6exodigcarbopalladations with subsequent 6πelectrocyclization and βhydride elimination to form tricycles 35a,bwith a central benzene ring in 67 and 61  yield, respectively, independent of the fact that 10acontains an electron donor and 10ban electron acceptor at the acetylene terminus. However, when 2bromotetradec1ene7,13diynes 22, 29on one side and 16, 27, 31on the other are subjected to Heck reaction conditions, tricycles with a central benzene ring are formed only, when the substituent at the acetylene terminus is not a methoxycarbonyl group as in 22, 29. Thus, the bisannelated benzene derivatives 36and 37are formed from 22and 29in 79 and 18  yield, respectively, whereas 16, 27and 31with their methoxycarbonyl substituents at the acetylenic end yield tetracyclic systems 38, 39and 40, consisting of a central fivemembered and two annelated sixmembered as well as an additional annelated threemembered ring, predominantly 54, 19 and 18  yield, respectively. The cascade reaction leading to the latter products must involve a 5exotrigcarbopalladation rather than 6πelectrocyclization as the third step. Apparently, the nature and the substitution pattern of the tether in the substrates 16, 22, 31linking the vinyl bromide moiety with the internal acetylene affect the yield of the tetracyclic product.© WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008

A number of tertiary secalkylamines 22 examples, 29–80  yield have been prepared according to a simple onepot procedure by the addition of Grignard reagents to N,Ndialkylformamides in the presence of TiOiPr4and Me3SiCl. © WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008

Syntheses of the labelled oxidative metabolites of acrylamide and acrylonitrile – reference compounds for the evaluation of human exposure to important toxicants – are reported. For that, Lcystine tertbutyl ester was acetylated and the product reductively cleaved to Lcysteine tertbutyl ester, which reacted with carbamoyl[D3]oxirane obtained from [D3]acrylonitrile and 30  aq. H2O2at pH = 7.0–7.5 and afforded a separable mixture of tertbutyl NacetylS2hydroxy2carbamoyl[D3]ethylcysteinate and tertbutyl NacetylS1carbamoyl2hydroxy[D3]ethylcysteinate ca. 9:1. Removal of the tertbutyl group in these intermediates with aq. HCl gave the final deuterated internal standards with carbamoyl residues. Protection of the secondary hydroxy group in the major intermediate with tBuMe2SiClimidazole in DMF followed by dehydration of the carbamoyl group trifluoroacetic anhydridepyridine in CH2Cl2 and stepwise removal of the tertbutyl and tBuMe2Si protecting groups TFA, Et3SiH,CH2Cl2; aq. HF in MeCN yielded NacetylS2cyano2hydroxy[D3]ethylcysteine. Monoprotection of [D4]ethylene glycol with tBuMe2SiCl and NaH in THF, oxidation to tBuMe2SiOCD2CDO, conversion to tBuMe2SiOCD2CDOHCN and tBuMe2SiOCD2CDOTsCN followed by nucleophilic substitution of the tosyloxy group with NacetylLcysteine MeOD, Et3N and deprotection with 4 MHCl in dioxane resulted in NacetylS1cyano2hydroxy[D3]ethylcysteine. All transformations except the last but one gave the respective products in good yields.© WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008

Various steroid analogues were synthesized by Stille coupling of bicyclo[4.3.0]nonenylstannanes cis‐/trans‐8and 14with cyclohexenol triflates 17and 18and subsequent Diels–Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0]nonenylstannanes cis‐ and trans‐8were prepared in good yields via the enol triflates cis‐ and trans‐7, obtained from the bicyclo[4.3.0]non‐2‐en‐3‐one 5. The alkenylstannane 14was obtained from the [2+2] cycloadduct 10 aproduced from addition of dichloroketene to the enantiomerically pure and protected bishydroxycyclohexadiene 9 a(65 %). Treatment of 10 awith diazomethane, reduction of the dichloromethylene group, and trapping with tributyltin chloride after lithium‐for‐bromine exchange, yielded the bicyclo[4.3.0]nonenylstannane 14(23 % over four steps). Stille couplings provided the tricyclic dienes cis‐/trans‐19in good yields (73–77 %), whereas the tricyclic diene 20was obtained in only 34 % yield at best. Diels–Alder reactions of trans‐19with various reactive dienophiles yielded the novel steroidal compounds trans‐21to trans‐26with complete diastereoselectivity. Heating the dienes cis‐19or 20with maleic acid derivatives provided the corresponding tetracycles cis‐23α,β and 27α,β with a cis‐C,D ring junction, each as mixtures of two diastereomers. Less reactive dienophiles required higher temperatures to promote the relevant cycloaddition with trans‐19to furnish several stereoisomeric forms of trans‐28and trans‐29in significantly lower yields (31–45 %). The selected steroid analogues trans‐22and trans‐23were deprotected in two steps by using acid catalysis to provide trans‐31and trans‐33(91 and 80 % over two steps). Cyclopropanation of trans‐30yielded the cyclopropasteroid analogue 34(74 %), treatment of which with trifluoroacetic acid furnished the cyclopropasteroid 35and the 2‐methyl‐substituted steroid analogue 36in 40 and 12 % yield, respectively. Aromatic B‐ring steroids 38(69 %) and 39(5 %) were accessed by dehydrogenation of trans‐24with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone.

Michael additions of carboxamides 2a–dunder basic conditions onto methyl 2‐chloro‐2‐cyclopropylideneacetate (1) with subsequent ring closure furnished the 4‐spirocyclopropanated methyl oxazolinecarboxylates 3a–d(51–81 % yields), from which the corresponding free carboxylic acids 4a–dwere obtained by hydrolysis in excellent yield (89–93 %). Coupling reactions of 4a–dwith different o‐hydroxyaniline derivatives in the presence of HOAt/EDC and 2,4,6‐collidine gave the anilides 5in good to very good yields (55–92 %). The latter under Mitsunobu reaction conditions (Ph3P/DEAD) furnished the benzoxazole derivatives 6(81–88 %). The bromine substituent in the N‐methylated 4‐spirocyclopropanated 2‐(bromophenyl)oxazoline‐5‐carboxanilides 8c,dwere aminated with various secondary amines under Buchwald–Hartwig reaction conditions to give the 2‐(aminophenyl)oxazolinecarboxanilides 9(12–90 %). Suzuki cross‐couplings of 8cwith arene‐ and hetareneboronic acids provided theoxazolines with 2‐biaryl substituents 10–13(65–90 %). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) 4‐Spirocyclopropanated methyl oxazolinecarboxylates, which are easily obtained from methyl 2‐chloro‐2‐cyclopropylideneacetate and arenecarboxamides under basic conditions, can further be modified at the carboxylate group and at the appropriately substituted aryl moiety to provide a library of such heterocyclic compounds for biological testing.

A three-component domino Heck–Diels–Alder reaction involving pinacol bicyclopropylideneboronate (8b), iodobenzene (9) and methyl acrylate (12) under Jeffery conditions [Pd(OAc)2, PPh3, K2CO3, Et4NCl, MeCN] produced a mixture of phenylspiro[2.5]octeneboronates syn/anti-(E)-14b and methyl phenylspirooctenecarboxylate 25 in 25 and 38 % yield, respectively. The major product 25 was most probably formed via the homoallylpalladium complex 23b undergoing deboropalladation rather than dehydropalladation. Similarly, reactions of tributylstannyl- and hydroxydimethylsilyl-substituted bicyclopropylidenes 8c–d with 9 and tert-butyl acrylate gave the tert-butyl phenylspirooctenecarboxylate 26 via the diene 24 formed by demetallopalladation processes. The reaction of methyl 1,1′-bicyclopropylidene-2-carboxylate (8e) with iodobenzene (9) in the presence of tert-butyl acrylate (13) furnished a mixture of regioisomeric and diastereomeric spirooctenes syn/anti-(E)-15e and syn/anti-(Z)-15e in 69 and 6 % yield, respectively. The structures of the major pair of diastereomers syn-(E)-15e and anti-(E)-15e were rigorously proved by X-ray crystal structure analyses. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A series of 3-spirocyclopropanedihydro- and -tetrahydropyrid-4-ones have been synthesized by nitrone cycloaddition to 1,1′-bicyclopropylidene (BCP), chemoselective reduction of the N–O bond of the isoxazolidine ring, and PdII-catalyzed cascade rearrangement of the β-aminocyclopropanol derivatives into the final products. The new tetrahydropyridone derivatives were also prepared by thermal rearrangement of the isoxazolidines. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Aliphatic dialdehydes of rigid structures having a cyclohexane, a bicyclo[2.2.2]octane or a [7]triangulane skeleton, have been condensed with enantiomerically pure trans‐1,2‐diaminocyclohexane to give [3+3] or [2+2] macrocyclization products. Unlike acyclic aliphatic imines, these macrocyclic oligoimines show enhanced stabilities and their structures in the crystals could be determined by X‐ray diffraction analyses. The enantiomerically pure [7]triangulane dialdehyde showed remarkable diastereoselectivity in the condensation with the two enantiomers of trans‐1,2‐diaminocyclohexane: only one of the enantiomers gave a [2+2] macrocyclization product. Circular dichroism measurements combined with computational analysis show that the lowest energy electronic transition in these cyclic oligoimines is of n–π* type.

The reaction of (benzyloxymethylene)cyclopropane (1a) with alkylidenemalononitriles 2 at ambient pressure afforded the corresponding cyclobutane derivatives 3 in good-to-high yields. For example, the reaction of 1a with benzylidenemalononitrile (2a), (2-naphthylmethylene)malononitrile (2e), and tert-butylmethylenemalononitrile (2f) in acetonitrile at 80 °C gave the corresponding cyclobutanes 3a, 3e, and 3f in 96, 96, and 91 % yield, respectively. Control experiments proved that the reaction proceeds via well-stabilized zwitterionic intermediate 6. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A palladium-catalyzed reaction of methylenespiropentane (11) with iodobenzene (12) under typical Heck conditions [Pd(OAc)2, PPh3, Et3N, DMF] produced a mixture of the unstable [3]dendralene 13 and allylidenecyclopropane 14 in 38 % yield. When an analogous reaction with iodobenzene was carried out in the presence of morpholine (25) and of tris(2-furyl)phosphane (TFP) instead of triphenylphosphane, the dienes 26, 28 and 31 were generated by nucleophilic trapping of π-allylpalladium intermediates 30 and 32. The cross coupling of methylenespiropentane (11) with the functionalized aryl iodides 33a–g in the presence of a palladium precatalyst [Pd(OAc)2, TFP, Et3N, DMF] at 80 °C, 3 h, provided the seven-membered 3,4-dimethylene-substituted heterocycles 34a–g and 35b which, upon addition of dimethyl fumarate (19), underwent Diels–Alder reactions to furnish bicyclic and higher oligocyclic dihydrobenzoxepine and-benzazepine derivatives 36a–g and 37b, yet in rather moderate yields of 18–29 % only. The overall process constitutes a one-pot, two-step, three-component queuing cascade.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

An acyclic, two heterocyclic, and two bicyclic alkenylstannanes, 3, 4a, 4b, 8 and 11, respectively, were synthesized in yields ranging from 43 to 97 %, and each was subjected to a sequence of Stille and Heck couplings with 2-bromocyclohexenyl triflate (13) and alkyl (tert-butyl and methyl) acrylate to furnish seven new 1,3,5-hexatrienes 19, 20, 21, 22-tBu, 22-Me, 23 and 43, respectively, in 58–84 % yields. For the alkenylstannanes 4a,b, 8 and 11, customized combinations of catalysts had to be used. The Stille–Heck sequence involving 13, 3 and tert-butyl acrylate could be performed in a one-pot mode and proceeded in 75 % yield. The hexatrienes were heated in decalin solutions so as to effect 6π-electrocyclization. Temperatures and reaction times were optimized individually. The hexatrienes 29, 31 and 36 gave the bi- and tricyclic cyclohexadienes 28, 30 and 34, incorporating allylic alcohol and allyl ether termini, by 6π-electrocyclization and subsequent [1,5]-hydrogen shift, as single products in good yields (85–93 %). In contrast, the hexatrienes 19, 20, 21 and 39 furnished mixtures of the initial electrocyclization products 26, 32, 37 and 40 as well as the products of a subsequent [1,5]-hydrogen shift 27, 33, 38 and 41, respectively. The tricyclic hexatrienes 22-tBu, 22-Me and 23 bearing alkyl (tert-butyl, methyl) acrylate termini also selectively gave the tetracyclic dienes 48-tBu, 48-Me and 50 in 71–77 % yields by electrocyclizations and subsequent hydrogen shifts.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

1 Tin(II) chloride-mediated Barbier-type coupling of ethyl glyoxylate with 2,3-dibromopropene followed by Simmons–Smith cyclopropanation and subsequent Dess–Martin oxidation, afforded ethyl 3-(1-bromocycloprop-1-yl)-2-oxopropionate (5), a stable precursor of ethyl cyclopropylidenepyruvate (1j), in good overall yield (65 %), even on a multi-gram scale. The potentially rich chemistry of this novel cyclopropyl building block was illustrated by some basic transformations such as Michael additions of N-, S-, O- and C-nucleophiles (10–91 % yields), Diels–Alder reactions with cyclopentadiene (65 %) and 2,3-dimethylbuta-1,3-diene (66 %) as well as [4+2] cycloadditions across the enone moiety of 1j (hetero-Diels–Alder reactions) with furan and enol ethers (65–79 %), thus opening up a ready access to a wide range of new variously functionalized cyclopropane derivatives.

A variety of enantiomerically pure steroidal compounds was synthesized utilizing a sequence of Stille and Heck cross‐coupling reactions and subsequent thermal 6π‐electrocyclizations. Highly chemoselective Stille couplings on the triflate moiety of several 2‐bromocyclohex‐1‐enyl triflates with cis‐ and trans‐fused bicyclo[4.3.0]nonenylstannanes furnished the corresponding tricyclic bromobutadienes in good to excellent yields (70–97 %). These were subjected to Heck reactions with tert‐butyl acrylate to provide pentasubstituted tricyclic 1,3,5‐hexatrienes. A significant increase in efficiency could be achieved by applying a novel protocol with a precatalyst on the basis of the palladacycle prepared from Pd(OAc)2and P(o‐Tol)3with added triarylphosphines as co‐ligands (73–90 % yield). Upon heating to 205–215 °C in decalin or to 140 °C in toluene (for certain cases), these hexatrienes yielded (78–90 %) various unsaturated steroid analogues as single diastereomers. A particular oxohexatriene, obtained after deprotection of an adjacent carbonyl group, underwent 6π‐electrocyclization at the unusually low temperature of 140 °C to yield (75 %) an interesting 7‐carboxyl‐substituted steroidal dienone. Attempts to remove the remaining protecting groups from some of the other new steroidal compounds under acidic conditions furnished a novel 3‐oxo‐7‐carboxyl steroid analogue and a 3‐hydroxy‐substituted steroidal diene. A novel estradiol derivative could be obtained in 69 % yield from the synthesized steroidal dienone. Deprotection furnished the corresponding unprotected 7‐carboxylestradiol in 81 % yield.

An excess of bis‐1,3‐(4‐iodophenyl)bicyclo[1.1.1]pentane, prepared in 63 % yield by iodination of 1,3‐diphenylbicyclo[1.1.1]pentane, was selectively mono‐coupled with 9‐ethynyl‐1,5‐dimethoxy‐10‐phenylethynylanthracene (26), and subsequently with the zinc derivatives of 1‐(2‐methyl/methoxy‐4‐methyl‐5‐phenylthiophen‐3‐yl)‐2‐(2‐methyl/methoxy‐4‐methylthiophen‐3‐yl)perfluorocyclopentenes (38‐H–41‐H). Regioselective synthesis of the 2‐unsubstituted thiophenes 38‐H–41‐H required intermediate preparation of 2‐trimethylsilyl‐3,5‐dimethyl‐4‐bromothiophene (37) or 2‐trimethylsilyl‐5‐methoxy‐3‐methyl‐4‐bromothiophene (40). Protection of the α‐position of the thiophene ring with a 2‐trimethylsilyl group blocks the rearrangement of the 4‐lithio derivatives into the corresponding 2‐lithiated thiophenes. With the bicyclo[1.1.1]pentane fragment linking the photochromic units 1–3and 1,5‐dimethoxy‐9,10‐di(phenylethynyl)anthracene as a fluorescent part, quantitative resonance energy transfer between the excited state of the fluorophore (donor) and the closed form of the photochromic units 1–3(acceptors) was observed. The closed forms of the methoxy‐substituted photochromic units 2and 3are less resistant to UV light (313 nm) than the closed form of 1.

The overall and the individual rate constants of the unimolecular thermal isomerization of methylenespiropentane (4) to 1,2- and 1,3-dimethylenecyclobutanes (7 and 8) have been determined to be lg (k–4/s–1) = (13.78 ± 0.06) – (49.7 ± 0.2) kcal mol–1/RT·ln 10, lg (k7/s–1) = (13.03 ± 0.19) – (48.0 ± 0.6) kcal mol–1/RT·ln 10 and lg (k8/s–1) = (14.15 ± 0.19) – (52.4 ± 0.5) kcal mol–1/RT·ln 10, respectively. The activation energies are significantly lower than that for the rearrangement of the parent spiropentane.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)