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Substituted alkylidenecyclopropanes reacted with 5 equivalents each of Me3Al and CH2I2 at room temperature in hexane to give 1-mono- and 1,1-disubstituted spiro[2.2]pentanes in high yields. Surprisingly, the same reaction with substituted alkylidenecyclopropanes in CH2Cl2 afforded exclusively 1,1-disubstituted spiro[2.3]hexanes. The transformation of 1,1-diphenylspiro[2.2]pentane into 1,1-diphenylspiro[2.3]hexane was studied with the use of CD2I2 and a plausible mechanism was suggested. The reaction of substituted alkylidenecyclobutanes with the Me3Al/CH2I2 reagent in CH2Cl2 gave only 1,1-disubstituted spiro[2.3]hexanes.

Propellanes are a unique class of compounds with well over 10000 members with an inverted tetrahedral configuration featuring a weak single bond between two carbon atoms linked by three additional bridge. Not only structurally interesting, these propella-type compounds exhibit unusual reactivities. In this review, we highlight their synthesis and applications in material sciences, natural product chemistry and medicinal chemistry. We feature the chemistry of [1.1.1]propellane like the synthesis of oligomeric and polymeric structures derived from it such as bicyclo[1.1.1]pentanes and staffanes. A selected number of natural products are discussed in detail. Heteropropellanes and inorganic propellanes are also addressed. The historical background is given in brief showing the pioneering work of David Ginsburg, Gunther Snatzke, Gunter Szeimies, Kenneth Wiberg and others.

Broad-spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here aimed at identifying minimal structural elements that confer β5c or β5i selectivity on proteasome inhibitors. Based on the natural product belactosin C, we synthesized two β-lactones featuring a dimethoxybenzyl moiety and either a methylpropyl (pseudo-isoleucin) or an isopropyl (pseudo-valine) P1 side chain. Although the two compounds differ only by one methyl group, the isoleucine analogue is six times more potent for β5i (IC50=14 nM) than the valine counterpart. Cell culture experiments demonstrate the cell-permeability of the compounds and X-ray crystallography data highlight them as minimal fragments that occupy primed and non-primed pockets of the active sites of the proteasome. Together, these results qualify β-lactones as a promising lead-structure motif for potent nonpeptidic proteasome inhibitors with diverse pharmaceutical applications.

Typ-unselektive Proteasominhibitoren werden in der Krebstherapie eingesetzt. Selektive Hemmung des Immunproteasoms konnte dagegen der Therapie von Autoimmunkrankheiten dienen. Im Rahmen dieser Arbeit wurden minimale Strukturelemente identifiziert, welche die Selektivitat von Inhibitoren fur die proteasomalen Untereinheiten β5c und β5i bestimmen. Ausgehend von dem Naturstoff Belactosin C wurden zwei β-Lactone synthetisiert, die neben einer Dimethoxybenzyl-Einheit entweder eine Methylpropyl- (Pseudo-Isoleucin) oder eine Isopropyl-P1-Seitenkette (Pseudo-Valin) tragen. Das Isoleucin-Derivat ist gegenuber der β5i-Untereinheit (IC50=14 nM) sechsfach wirksamer als das Valin-Pendant. Zellkulturexperimente bestatigen die Zellgangigkeit beider Substanzen, und rontgenkristallographische Daten visualisieren die Besetzung der gestrichenen und nichtgestrichenen Substratbindekanale des Proteasoms. β-Lactone sind somit bestens fur die Entwicklung nichtpeptidischer Proteasominhibitoren geeignet.

In this Editorial, Professors Hashmi and de Meijere talk about a brief history of OMCOS and the current and emerging roles that organometallic chemistry plays in organic synthesis. All of these lead to OMCOS 20 to be held on July 21-25, 2019 in Heidelberg, Germany.

(E,E)-1,2,3,4-Tetracyclopropylbuta-1,3-diene (3) and (Z,Z)-1,4-diodo-1,2,3,4-tetracyclopropylbuta-1,3-diene (4) were prepared from dicyclopropylacetylene via an intermediate 2,3,4,5-tetracyclopropyltitanacyclopentadiene (2) in 91 and 77 % yield, respectively. In the crystal, 3 adopts a conformation with an almost coplanar (φ = 163°) 1,3-diene core, with the inner vinylcyclopropane units in an orthogonal and the outer vinylcyclopropane moieties in an s-trans orientation. This diene, like 2,3-cyclopropylbuta-1,3-diene (5), undergoes facile concerted [4+2] cycloadditions at 130 °C with dimethyl acetylenedicarboxylate as well as N-phenylmaleimide and at 0 °C with N-phenyltriazolinedione. An X-ray crystal structure analysis of 2,3-dicyclopropylbuta-1,3-diene (5) also reveals a coplanar inner core with the vinylcyclopropane units in essentially orthogonal (φav = 89.3°) orientation. Differential scanning calorimetry (DSC) measurements indicate that 3 undergoes significant internal reorganization on going from the liquid to the crystalline phase, and a gauche conformer of 3 may well be favored over the s-trans conformer in the liquid.

A wide range of five- and six-membered sultams bearing an α-ethoxycarbonyl-α-methyl substituent or an α-aryl group (17 examples) were synthesized by the cyclodialkylation of α-substituted methanesulfonanilides with α,ω-dihaloalkanes in the presence of K2CO3 or under phase-transfer catalysis (PTC) conditions. Upon treatment with K2CO3 in N,N-dimethylformamide (DMF) or NaH in dimethyl sulfoxide (DMSO), N-(2,3-dibromopropyl)-α-toluenesulfonanilides furnished different 1,3-diaryl-2-thia-3-azabicyclo[3.1.0]hexane 2,2-dioxides in good to excellent yields (51–88 %, 16 examples). The 4-methoxyphenyl (PMP) group was easily removed from the sultam nitrogen atom by treatment of the corresponding bicyclic sultams with cerium(IV) ammonium nitrate in acetonitrile (71–84 % yield, 6 examples).

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)-8 and (1R,3S)-8] and (dibromodispiro[2.0.2.1]heptyl)methanols (1R,3S,4R)-9, (1S,3R,4S)-9 and (1S,3R,4R)-9 in 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 2 and 10-H were generated from the amide N2-ZGlnOEt 3 in 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 8 with ZNCO (Z = PhCH2OCO) followed by hydrolytic removal of both Z groups gave 5-(carbamoylimino)proline amide 12-CONH2 (via 2 and orthoamidine 11-CONH2) in 70 % overall yield from 3.

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.

Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl-substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2-dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20-25 in 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 20-28 without 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 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N-dicyclopropyl-N-alkylamines 55 can 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.

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 1-azathiabicyclo[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 inter/intramolecular alkylation of corresponding monocyclic sultams 9 and 10 with α,ω-dihalides 11 in K 2 CO 3 /DMF in 56, 68, 52 and 52 % yield, respectively. On the other hand, a 1-aza-9-thiabicyclo[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.

Under a newly developed set of mild conditions [EtN(iPr) 2 , LiI, DMF, 20 °C, 3 d], methyl 2-chloro-2-cyclopropylideneacetate (1) smoothly undergoes Michael addition of various benzylamines (4 examples) with ensuing ring enlargement and elimination to give in very good yields (81-99%) the correspondingly substituted methyl 2-(benzylamino)cyclobutenecarboxylates 3a-d, which were subsequently converted into the N-Boc-protected derivatives 4a-d. After hydrolysis of the esters, the free β-amino acids 5a,b were cleanly condensed with the methyl esters of glycine, (S)-proline, (S)-phenylglycine and (S)-tryptophan to give the dipeptides 6a-8a, 9b in 58-89 % yield. The cyclic dipeptides 15e,f, consisting of a 2-aminocyclobutenecarboxylic acid and a glycine fragment, were obtained in 38 and 45 % yield, respectively, upon treatment of the spirocyclopropanated chlorohexahydrodiazepinediones 10e,f with sodium cyanide in DMSO at elevated temperatures. Palladium-catalyzed hydrogenation of 4a afforded methyl N-Boc-2-amino-cyclobutanecarboxylate 19 as a mixture of cis and trans isomers.

1-Bromo-1-cyclopropylcyclopropane (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 bromine/ lithium exchange without rearrangement upon treatment with tert-butyllithium in diethyl ether/pentane at ―78 °C, and the resulting 1-lithio-1-cyclopropylcyclopropane can be trapped with various electrophiles to give the correspondingly 1-substituted bicyclopropyl derivatives 10 in yields ranging from 38 to over 90 % (13 examples). The (1-cyclopropylcyclopropyl)boronate 10m, which is also obtained from the 1-lithio derivative, has been subjected to Suzuki cross couplings with a number of aryl halides to furnish 1-aryl-1,1'-bicyclopropyl compounds 11 (4 examples, 14―50 % yield), predominantly without rearrangement. Further transformations of 1-cyclopropylcyclopropanecarbaldehyde (10e) have provided 2-(1-cyclopropylcyclopropyl)glycine (16), ethyl 3-(1-cyclopropylcyclopropyl)acrylate (17), and its cycloadducts with the nitrone 18 and cyclopentadiene 19, albeit the latter only in poor yield.

Various 1-substituted cyclopentylamines (25 examples, 10― 89 % yield) have been prepared according to a one-pot procedure by the addition of tetramethylenebismagnesium dibromide in the presence of Ti(OiPr) 4 to aliphatic, aromatic and heteroaromatic nitriles, respectively.

o-Bromophenyl isocyanide (1-Br) reacts with various primary amines under CuI catalysis to afford 1-substituted benzimidazoles 4 in moderate to good yields (38–70 %, 13 examples). Analogously, 2-bromo-3-isocyanothiophene (6) furnishes 3-substituted 3H-thieno[2,3-d]imidazoles 7 (44–49 %, 3 examples). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Palladium(Pd)-catalyzed oligocyclizations of 2-bromotetradec-1-ene-7,13-diynes with an unsubstituted terminal acetylene moiety like 3 and 5 and 15-bromohexadec-15-ene-3,9-diyn-2-ones like 4 and 6 afforded fulvene derivatives 20 and 21 (Scheme 7) and bis(cyclohexane)-annulated methylenecyclopentene systems 16 and 18 (Schemes 5 and 6), respectively. These transformations constitute cascades of cyclizing carbopalladation steps with ensuing [1,5]-sigmatropic H-atom and acyl shifts, respectively (Scheme 8). In contrast, analogous substrates with one three-atom and one four-atom tether between the unsaturated C,C-bonds, such as 1 and 2, behave differently in that the Pd-substituted hexa-1,3,5-triene intermediates 12 undergo a 6p-electrocyclization instead of a 5-exo-trig carbopalladation followed by s-hydride elimination to furnish tricyclic bis-annulated benzene derivatives 13 and 14 (Scheme 4).

N-(2,3-Dibromopropyl)- and N-(3,4-dibromobutyl)(methoxycarbonyl)methanesulfanilides upon treatment with potassium carbonate in DMF furnish methyl 3-aryl-2,2-dioxo-2-thia-3-azabicyclo[n.1.0]alkane-1-carboxylates in yields ranging from 54 to 84 % (10 examples). The starting materials were obtained by sulfonylation of N-alkenylanilines with methyl (chlorosulfonyl)acetate and subsequent bromination. For the N-alkenylanilines (10 examples, 60–77 % yield) an efficient new synthesis employing a 2-nitrophenylsulfonyl substituent as a protective as well as an activating group has been developed. The 4-methoxyphenyl (PMP) group could easily be removed from the sultam nitrogen atom by treatment with cerium(IV) ammonium nitrate.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Cyclopropane- and alkylcyclopropane-annelated methyl imidazolidinecarboxylates 5 are 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 5 with alkyl substituents on the spirocyclopropane moiety are formed diastereoselectively.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Methyl 2-(benzyloxycarbonylamino)-2-cyclopropylideneacetate (2) was prepared in nine steps starting from L-serine 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 cyclopropyl-containing amino acids in protected form. An application of 2 in the synthesis of methyl 4-tert-butoxycarbonylmethyl-5-oxo-4,7-diazaspiro[2.5]octane-8-carboxylate (15), a precursor for geometrically constrained bicyclic peptidomimetics of type 16, has also been proved.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The formal cycloaddition of alpha-metallated methyl isocyanides 1 onto the triple bond of electron-deficient acetylenes 2 represents 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 Cu(I)-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 palladium-catalyzed Heck-type cascade oligocyclizations of various 2-bromoalkenediynes 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 three-atom tethers, 2-bromotridec-1-ene-6,13-diynes 10a,b with one three- and one four-atom tether undergo two consecutive intramolecular 5- and 6-exo-dig carbopalladations with subsequent 6 pi-electrocyclization and beta-hydride elimination to form tricycles 35a,b with a central benzene ring in 67 and 61 % yield, respectively, independent of the fact that 10a contains an electron donor and lob an electron acceptor at the acetylene terminus. However, when 2-bromotetradec-1-ene-7,13-diynes 22, 29 on one side and 16, 27, 31 on 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 36 and 37 are formed from 22 and 29 in 79 and 18 % yield, respectively, whereas 16, 27 and 31 with their methoxycarbonyl substituents at the acetylenic end yield tetracyclic systems 38, 39 and 40, consisting of a central five-membered and two annelated six-membered as well as an additional annelated three-membered ring, predominantly (54, 19 and 18 % yield, respectively). The cascade reaction leading to the latter products must involve a 5-exo-trig carbopalladation rather than 6 pi-electrocyclization as the third step. Apparently, the nature and the substitution pattern of the tether in the substrates 16, 22, 31 linking the vinyl bromide moiety with the internal acetylene affect the yield of the tetracyclic product

A number of tertiary sec-alkylamines (22 examples, 29–80 % yield) have been prepared according to a simple one-pot procedure by the addition of Grignard reagents to N,N-dialkylformamides in the presence of Ti(OiPr)4 and Me3SiCl. (© Wiley-VCH 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, L-cystine tert-butyl ester was acetylated and the product reductively cleaved to L-cysteine tert-butyl ester, which reacted with carbamoyl[D3]oxirane (obtained from [D3]acrylonitrile and 30 % aq. H2O2 at pH = 7.0–7.5) and afforded a separable mixture of tert-butyl N-acetyl-S-(2-hydroxy-2-carbamoyl[D3]ethyl)cysteinate and tert-butyl N-acetyl-S-(1-carbamoyl-2-hydroxy[D3]ethyl)cysteinate (ca. 9:1). Removal of the tert-butyl 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 tBuMe2SiCl/imidazole in DMF followed by dehydration of the carbamoyl group (trifluoroacetic anhydride/pyridine in CH2Cl2) and stepwise removal of the tert-butyl and tBuMe2Si protecting groups (TFA, Et3SiH,CH2Cl2; aq. HF in MeCN) yielded N-acetyl-S-(2-cyano-2-hydroxy[D3]ethyl)cysteine. Monoprotection of [D4]ethylene glycol with tBuMe2SiCl and NaH in THF, oxidation to tBuMe2SiOCD2CDO, conversion to tBuMe2SiOCD2CD(OH)CN and tBuMe2SiOCD2CD(OTs)CN followed by nucleophilic substitution of the tosyloxy group with N-acetyl-L-cysteine (MeOD, Et3N) and deprotection with 4 M HCl in dioxane resulted in N-acetyl-S-(1-cyano-2-hydroxy[D3]ethyl)cysteine. All transformations (except the last but one) gave the respective products in good yields.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Various steroid analogues were synthesized by Stille coupling of bicyclo[4.3.0]nonenylstannanes cis-/trans-8 and 14 with cyclohexenol triflates 17 and 18 and subsequent Diels-Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0]nonenylstannanes cis- and trans-8 were 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 14 was obtained from the [2+2] cycloadduct 10 a produced from addition of dichloroketene to the enantiomerically pure and protected bishydroxycyclohexadiene 9 a (65 %). Treatment of 10 a with 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-19 in good yields (73-77 %), whereas the tricyclic diene 20 was obtained in only 34 % yield at best. Diels-Alder reactions of trans-19 with various reactive dienophiles yielded the novel steroidal compounds trans-21 to trans-26 with complete diastereoselectivity. Heating the dienes cis-19 or 20 with maleic acid derivatives provided the corresponding tetracycles cis-23alpha,beta and 27alpha,beta 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-19 to furnish several stereoisomeric forms of trans-28 and trans-29 in significantly lower yields (31-45 %). The selected steroid analogues trans-22 and trans-23 were deprotected in two steps by using acid catalysis to provide trans-31 and trans-33 (91 and 80 % over two steps). Cyclopropanation of trans-30 yielded the cyclopropasteroid analogue 34 (74 %), treatment of which with trifluoroacetic acid furnished the cyclopropasteroid 35 and the 2-methyl-substituted steroid analogue 36 in 40 and 12 % yield, respectively. Aromatic B-ring steroids 38 (69 %) and 39 (5 %) were accessed by dehydrogenation of trans-24 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Michael additions of carboxamides 2a–d under 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–d were obtained by hydrolysis in excellent yield (89–93 %). Coupling reactions of 4a–d with different o-hydroxyaniline derivatives in the presence of HOAt/EDC and 2,4,6-collidine gave the anilides 5 in 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,d were aminated with various secondary amines under Buchwald–Hartwig reaction conditions to give the 2-(aminophenyl)oxazolinecarboxanilides 9 (12–90 %). Suzuki cross-couplings of 8c with arene- and hetareneboronic acids provided theoxazolines with 2-biaryl substituents 10–13 (65–90 %). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

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-pi* 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)

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)

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)

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(k(7)/s(-1)) = (13.03 +/- 0.19) - (48.0 +/- 0.6) kcal mol(-1)/RT.ln 10 and lg(k(8)/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. ((c) Wiley-VCH Verlag GmbH & Co.

Intramolecular cycloadditions of various nitrone functionalities with different substituents (R = Me, Bn, tBu) at the nitrogen atom tethered to a bicyclopropylidene unit through a two-carbon chain led to cis-fused tricyclic isoxazolidines (3-alkyl-3,3a,4,5,5a,6-hexahydrocyclopropa[2,3]cyclopenta[1,2-c]isoxazolespiro[1,1′]cyclopropanes) 26 in 42–58 % yield with complete regio- and diastereoselectivity. The thermal rearrangement of the cycloadducts 26 under neutral conditions afforded the corresponding tricyclic tetrahydropyridones 27 (52–53 %). The analogous starting materials with a three-carbon tether, the 4-(bicyclopropyliden-2-yl)butylidenenitrones furnished tricyclic isoxazolidines 28 (54–58 %) and tetrahydropyridones 29 (55–64 %) by subsequent thermal rearrangement. Under acidic conditions (TFA), the cycloadducts 26 and 28 underwent fragmentative rearrangements to afford the tricyclic β-lactams 30 and 32 (50–66 %), respectively, of which the former suffered amide-bond cleavage in situ to provide the corresponding N-trifluoroacetyl β-amino acid derivatives 31 (68–71 %). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

A series of pyrene-based polycyclic aromatic compounds, indeno[cd]pyrene, diindeno[cd,fg]pyrene, diindeno[cd,jk]pyrene, tris-(tert-butylindeno[cd,fg,jk])pyrene, and tetrakis-(tert-butylindeno[cd,fg,jk,mn])pyrene, were reduced with alkali metals in [D8]tetrahydrofuran, and the resulting anions were studied by NMR spectroscopy. It was found that the diatropic character of the dianions obtained depends on the number of annulated indeno groups. When one such group is present, a paratropic dianion is obtained, which is similar to the dianion of the parent pyrene; the effect, however, is weak. When more indeno groups are annulated, the dianions become diatropic owing to the greater number of five-membered rings that can acquire aromatic character as a result of reduction. The 1H NMR chemical shifts of tetrakis-(tert-butylindeno[cd,fg,jk,mn])pyrene in the neutral state show an interesting dependence on concentration that reflects an association of the molecules in solution by pi stacking. This phenomenon was not observed for the reduced species. The trianion radicals of tris-(tert-butylindeno[cd,fg,jk])pyrene and tetrakis-(tert-butylindeno[cd,fg,jk,mn])pyrene undergo reductive dimerization and form bilayered hexaanions.