Synthesis of Aristotelia-type alkaloids. Part VIII. Synthesis of (±)-aristolasicone

The revised structure of the indole alkaloid aristolasicone ( 2 ) was confirmed through a convergent total synthesis of the racemic form of this metabolite. The key step involves a one-pot condensation/cyclization reaction between 1-(4-methoxyphenylsulfonyl)-1H-indole-2-acetaldehyde ( 9 ) and (±)-trans-5-(2,6-difluorobenzyloxy)-p-menth-l-en-8-amine ((±)-7). The resulting allohobartine derivative (±)- 13 , obtained in 84% yield, was deprotected and oxidized to (±)-alloscrratenone ((±)- 15 ) which cyclized smoothly to the target molecule (±)-2 upon exposure to BF₃ · Et₂O.     

Synthesis of Aristotelia-type alkaloids. Part V. Biomimetic synthesis of (±)-aristomakine and (±)-aristomakinine

Biomimetic syntheses of racemic aristomakinine ((±)- 3 ) and aristomakine ((±)- 4 ), an unusual indole alkaloid bearing an N-isopropyl group, are described. The key step is a Grob-type fragmentation of anti-15-aristotelinyl methanesulfonate ((±)- 2 ) to the intermediate iminium ion I which, upon subsequent hydrolysis, furnished aristomakinine ((±)- 3 ). On the other hand, the same intermediate could be reduced in situ to aristomakine ((±)- 4 ). The controversial relative configurations of the two alkaloids have been firmly established by means of NOE difference experiments.     

Synthesis and transformations of (±)-trans-4aβ(H), saα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one

Hydrogenation of 4,7-dimethylcoumarin ( 1 ) in alkaline medium has been shown to furnish a mixture of (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one ( 2 ), (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 3 ) and (±)-cis-4aα(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 4 ) in 40:25:35:ratio, respectively. The stereochemistry of the major hydrogenation product 2 , has been established by transforming it to p-menthane derivatives e.g. (±)-2 (R)-[2′(R)hydroxy-4′(R) methylcyclohex-(1′S)-yl]propan-1-ol ( 20 ) and (±)-trans-3α,6β-dimethyl-3aβ(H),7aα(H)-octahydrobenzofuran ( 12 ). Starting from a mixture of lactones 2, 3 and 4 , lactone 3 has been obtained in pure state employing a sequence of reactions.     

New methodology for the characterization of (±)-anti-BPDE-DNA adducts and tetrol I-1 with solid-matrix phosphorescence

Novel solid-matrix phosphorescence (SMP) methods were developed for the detection and characterization of (±)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide ((±)-anti-BPDE)-DNA adducts and a hydrolysis product of the (±)-anti-BPDE-DNA adducts, tetrol I-1, by using the heavy-atom salts, thallium nitrate and sodium iodide, to enhance the solid-matrix phosphorescence. Thallium nitrate was much more effective for enhancing the SMP of the (±)-anti-BPDE-DNA adducts and tetrol I-1. Thus, the results from TlNO₃ were emphasized. The amount of TlNO₃ adsorbed on the solid matrix was varied over a wide range, and SMP intensities, lifetimes, and spectra were acquired. Fundamental equations and calculated photophysical parameters were used to interpret the data and characterize the samples. The data indicated that there were two major populations of the (±)-anti-BPDE-DNA adducts and tetrol I-1 adsorbed on the solid matrix. Because DNA was adsorbed so strongly to the solid matrix, the (±)-anti-BPDE-DNA adducts interacted in a uniform manner with increasing amounts of TlNO₃. However, tetrol I-1 responded in a more random fashion with the increase in the amount of TlNO₃. The methods developed can be used to compare the SMP of small molecular-weight metabolites and DNA samples modified at different levels of (±)-anti-BPDE. Also, the methodology can be employed for DNA samples that are adducted with any material that would give measurable SMP.     

Thermal Reactions of Guaiazulene and Its 3-Methyl Derivative with Dimethyl Acetylenedicarboxylate

The thermal reaction of 7-isopropyl-1,3,4-trimethylazulene (3-methylguaiazulene; 2 ) with excess dimethyl acetylenedicarboxylate (ADM) in decalin at 200° leads to the formation of the corresponding heptalene- ( 5a/5b and 6a/6b ; cf. Scheme 3) and azulene-1,2-dicarboxylates ( 7 and 8 , respectively). Together with small amounts of a corresponding tetracyclic compound (‘anti’- 13 ) these compounds are obtained via rearrangement (→ 5a/5b and 6a/6b ), retro-Diels-Alder reaction (→ 7 and 8 ), and Diels-Alder reaction with ADM (→ ‘anti’- 13 ) from the two primary tricyclic intermediates ( 14 and 15 ; cf. Scheme 5) which are formed by site-selective addition of ADM to the five-membered ring of 2 . In a competing Diels-Alder reaction, ADM is also added to the seven-membered ring of 2 , leading to the formation of the tricyclic compounds 9 and 10 and of the Diels-Alder adducts ‘anti’- 11 and ‘anti’- 12 , respectively of 9 and of a third tricyclic intermediate 16 which is at 200° in thermal equilibrium with 9 and 10 (cf. Scheme 6). The heptalenedicarboxylates 5a and 5b as well as 6a and 6b are interconverting slowly already at ambient temperature (Scheme 4). The thermal reaction of guaiazulene ( 1 ) with excess ADM in decalin at 190° leads alongside with the known heptalene- ( 3a ) and azulene-1,2-dicarboxylates ( 4 ; cf. Schemes 2 and 7) to the formation of six tetracyclic compounds ‘anti’- 17 to ‘anti’- 21 as well as ‘syn’- 19 and small amounts of a 4:1 mixture of the tricyclic tetracarboxylates 22 and 23 . The structure of the tetracyclic compounds can be traced back by a retro-Diels-Alder reaction to the corresponding structures of tricyclic compounds ( 24--29 ; cf. Scheme 8) which are thermally interconverting by [1,5]-C shifts at 190°. The tricyclic tetracarboxylates 22 and 23 , which are slowly equilibrating already at ambient temperature, are formed by thermal addition of ADM to the seven-membered ring of dimethyl 5-isopropyl-3,8-dimethylazulene-1,2-dicarboxylate ( 7 ; cf. Scheme 10). Azulene 7 which is electronically deactivated by the two MeOCO groups at C(1) and C(2) shows no more thermal reactivity in the presence of ADM at the five-membered ring (cf. Scheme 11). The tricyclic tetracarboxylates 22 and 23 react with excess ADM at 200° in a slow Diels-Alder reaction to form the tetracyclic hexacarboxylates 32 , ‘anti’- 33 , and ‘anti’- 34 (cf. Schemes 10–12 as well as Scheme 13). A structural correlation of the tri- and tetracyclic compounds is only feasible if thermal equilibration via [1,5]-C shifts between all six possible tricyclic tetracarboxylates ( 22, 23 , and 35–38 ; cf. Scheme 13) is assumed. The tetracyclic hexacarboxylates 32 , ‘anti’- 33 , and ‘anti’- 34 seem to arise from the most strained tricyclic intermediates ( 36–38 ) by the Diels-Alder reaction with ADM.     

Synthesis of Abscisic Acid

A stereoselective synthesis of (±)-abscisic acid ( 7 ) is described in which 2-cis 3-methylpent-2-en-4-yn-1-ol ( 2 ) is used to introduce the 2-cis, 4-trans geometry.     

Synthesis of Aristotelia-Type Alkaloids. Part III. (3R,4R)- and (3R,4S)-1-p-menthene-3,8-diol and the corresponding racemates: Preparation and assignment of configuration

A 1:1 mixture of the racemic trans- and cis-1-p-menthene-3,8-diols ((±)- 3 and (±)- 4 , resp.) was readily prepared in 3 steps starting from 3-methyl-2-cyclohexen-1-one. The relative configuration of the diols, purified via the corresponding cyclocarbonates, was assigned by ¹H-NMR spectroscopy and found to be at variance with tentative claims in the literature. Optically active samples of 3 and 4 were prepared by resolution of the racemates with (R)-1-phenylethylamine. The absolute configuration of the resulting diols was determined by chemical correlation with standards of known absolute configuration.     

Total Asymmetric Synthesis of Doubly Branched Carba-hexopyranoses and Amino Derivatives Starting from the Diels-Alder Adducts of Maleic Anhydride to Furfuryl Esters

The Diels-Alder adducts of maleic anhydride to furfuryl esters were reduced into 7-oxabicyclo[2.2.1]hept-5-ene-1,2-exo,3-exo-trimethanol (±)- 15 and enantiomerically pure (−)- 15 (Scheme 1). The tripivalate of (±)- 15 was converted into (1RS,2RS,3RS,4RS,5SR,6SR)-1,5,6-tris(hydroxymethyl)cyclohexane-1,2,3,4-tetrol ((±)- 23 ; Scheme 2). Reaction of BBr₃ with the triacetate (±)- 30 of (±)- 15 gave (1RS,2RS,5RS,6RS)-5-bromo-6-hydroxycyclohex-3-ene-1,2,3-trimethyl triacetate ((±)- 31 ) at −78°, and (1RS,2RS,5SR,8SR)-2-endo-hydroxy-6-oxabicylo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((±)- 32 ) at 0° (Scheme 3). Single-crystal X-ray diffraction of (1RS,2RS,5SR,8SR)-2-acetoxy-6-oxabicyclo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((±)- 33 ) was carried out. Displacement of bromide (+)- 31 (derived from (−)- 15 ) with azide anion gave (+)- 38 which was transformed into (+)-(1R,2R,5S,6S)-5-amino-6-hydroxycyclohex-3-ene-1,2,3-trimethanol ((+)- 40 ) (Scheme 4). Reaction of (±)- 31 with BBr₃ at 0°, followed by azide disubstitution led to (1RS,2RS,5SR,6SR)-5-amino-3-(aminomethyl)-6-hydroxycyclohex-3-ene-1,2-dimethanol ((±)- 45 ). Dihydroxylation of (±)- 38 and further transformations gave (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-1,4,6-trihydroxycyclohexane-1,2,3-trimethanol ((±)- 49 ) and (1RS,2RS,3SR,4RS,5SR,6RS)-2,3-dihydroxy-7-oxabicyclo[4.1.0]heptane-2,3,4-trimethanol ((±)- 55 ) (Schemes 5 and 6). Expoxidation of the 4-nitrobenzoate (±)- 61 of (±)- 38 allowed the preparation of (1RS,2RS,3SR,4RS,5RS)-5-amino-1,4-dihydroxycyclohexane-1,2,3-trimethanol ((±)- 65 ) and of (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-4-hydroxy-7-oxabicyclo[4.1.0]heptane-1,2,3-trimethanol ((±)- 67 ) (Scheme 7). The new unprotected polyols and aminopolyols were tested for their inhibitory activity toward commercially available glycohydrolases. At 1 mM concentration, 34, 30, and 31% inhibition of β-galactosidase from bovine liver was observed for (+)- 40 , (±)- 65 , and (±)- 67 , respectively.     

Synthesis,stereochemistry, and opioid receptor binding activity of heterocyclic analogues of BW373U86

The synthesis of a series of heterocyclic analogues of (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazmyl)-3-hydroxybenzyl)-N,N-diethylbenzarrude (BW373U86) for screening against opioid receptors is described. The intermediate α-heterocyclic benzyl alcohols 24 were synthesized either by low temperature reaction of lithioheterocycles with 3-((tert-butyldimethylsilyl)oxy)benzaldehyde ( 10 ) or by reaction of 3-((tert-butyldimethylsilyl)oxy)phenylmagnesium bromide ( 19 ) with heterocyclic carbaldehydes. The α-heterocyclic benzyl alcohols 24 were converted to chloromethines ( 25 ) with thionyl chloride and used to alkylate with trans-1-allyl-2,5-dimethylpiperazine ( 5 ) to give diastereomeric pairs of the target compounds. The bromoheterocycles were then derivatized to produce amides. Compounds that are potent and selective for the 5 or μ opioid receptors and some mixed δ/μ analogues are reported.     

Enzymatic resolution of (±)-cis- and (±)-trans-1-aminoindan-2-ol and (±)-cis- and (±)-trans-2-aminoindan-1-ol

Pseudomonas cepacia lipase (PSL) efficiently catalyses the kinetic resolution of (±)-cis- and (±)-trans-1-aminoindan-2-ol through the O-acylation reaction of the corresponding N-benzyloxycarbonyl derivative using vinyl acetate as the acyl donor. In a similar way, cis-N-Cbz-2-aminoindan-1-ol is resolved when isopropenyl acetate is used as the acylating agent. The enantioselectivity of the reaction was lower for (±)-trans-N-Cbz-2-aminoindan-1-ol due to the different steric requirements for the two conformers of this substrate.     

Synthesis of Some C2‐Symmetric Bidentate Ligands and Their Complexes Derived from Feist's Acid

Various new C₂‐symmetric bidentate ligands, bearing phosphorus, nitrogen, and sulfur, were obtained in an efficient manner, starting from (±)‐trans‐3‐methylidenecyclopropane‐1,2‐dicarboxylic acid (Feist's acid; (±)‐trans‐ 3 ). The structures of the new bidentate ligands, di(tert‐butyl) (±)‐[(trans‐3‐methylidenecyclopropane‐1,2‐diyl)dimethanediyl]biscarbamate ((±)‐ 9 ), (±)‐(trans‐3‐methyldienecyclopropane‐1,2‐diyl)dimethanaminium dichloride ((±)‐ 10 ), (±)‐S,S′‐[(trans‐3‐methylidenecyclopropane‐1,2‐diyl)dimethanediyl] diethanethioate ((±)‐ 11 ), and (±)‐[(trans‐3‐methylidenecyclopropane‐1,2‐diyl)dimethanediyl]bis(diphenylphosphane) ((±)‐ 12 ), were fully characterized by standard spectroscopic techniques. These new classes of C₂‐symmetric bidentate ligands have the potential to be used in asymmetric catalysis.     

Enzyme-Mediated Preparation of (+)- and (–)-cis-α-Irone and (+)- and (–)-trans-α-Irone

The preparation of (−)- and (+)-trans-α-irone ( 1a and 1b , resp.) and of (+)- and (−)-cis-α-irone ( 1c and 1d , resp.) from commercially available Irone alpha ^® is reported. The relevant step in the synthetic sequence is the initial chromatographic separation of crystalline (±)-4,5-epoxy-4,5-dihydro-cis-α-irone ((±)- 5 ) from oily (±)-4,5-epoxy-4,5-dihydro-trans-α-irone ((±)- 4 ). The latter was subsequently converted, after NaBH₄ reduction, into the crystalline 3,5-dinitrobenzoate ester (±)- 8 , thus allowing a complete separation of the two corresponding diastereoisomeric alcohol derivatives. Suitable enantiomerically pure precursors of the desired products 1a – d were obtained by kinetic resolution of the racemic allylic alcohols derived from (±)- 5 and (±)- 8 , mediated by lipase PS (Amano). The last steps consisted of MnO₂ oxidation and removal of the epoxy moiety with Me₃SiCl/NaI in MeCN. External panel olfactory evaluation showed that (−)-cis-α-irone ( 1d ) has the finest and most distinct `orris butter' character.     

Thermal Reaction of Azulene and Some of Its Symmetrically Substituted Methyl Derivatives with Dimethyl Acetylenedicarboxylate

It is shown that azulene ( 1 ) and dimethyl acetylenedicarboxylate (ADM) in a fourfold molar excess react at 200° in decalin to yield, beside the known heptalene- ( 5 ) and azulene-1,2-dicarboxylates ( 6 ), in an amount of 1.6% tetramethyl (1RS,2RS,5SR,8RS)-tetracyclo[6.2.2.2^2,50^1,5]tetradeca-3,6,9,11,13-pentaene-3,4,9,10-tetracarboxylate(‘anti’-7) as a result of a SHOMO (azulene)/LUMO(ADM)-controlled addition of ADM to the seven-membered ring of 1 followed by a Diels-Alder reaction of the so formed tricyclic intermediate 16 (cf. Scheme 3) with a second molecule of ADM. The structure of ‘anti’-7 was confirmed by an X-ray diffraction analysis. Similarly, the thermal reaction of 5,7-dimehtylazulene ( 3 ) with excess ADM in decalin at 120° led to the formation of ca. 1% of ‘anti’- 12 , the 7,12-dimethyl derivative of‘anti’-7, beside of the corresponding heptalene- 10 and azulene-1,2-dicaboxylated (cf Scheme 2). The introduction of Me groups at C(1)and C(3)of azulene ( 1 ) and its 5,7-dimethyl derivative 3 strongly enhance the thermal formation of the corresponding tetracyclic compound. Thus, 1,3-dimethylazulene ( 2 ) in the presence of a sevenfold molar excess of ADM at 200° yielded 20% of ‘anti’- 9 beside an equal amount of dimethyl 3-mehtylazulene-1,2-dicarboxylate ( 8 ;cf. Scheme 1), and 1,3,5,7-tetramethylazulene ( 4 ) with a fourfold molar excess of ADM AT 200° gave a yield of 37% of‘anti’- 15 beside small amount of the corresponding heptalene- 13 and azulene-1,2-dicarboxylates 14 (cf.Scheme 2).     

Atom transfer radical cyclization (ATRC) applied to a chemoenzymatic synthesis of Quercus lactones

The natural fragrances (+)-trans whisky lactone 2 and (+)-trans cognac lactone 4, together with a minor amount of their (−)-cis stereoisomers, were prepared in 50% and 42% overall yield, respectively, starting from racemic 1-hepten-3-ol (±)-5 and 1-octen-3-ol (±)-6. The procedure involved first the enantioconvergent, lipase mediated transformation of the secondary allylic alcohols derived dichloroacetates (±)-7 and (±)-8 into the corresponding homochiral (+)-7 and (+)-8, combined with their cyclization under a transition metal catalyzed atom transfer process.     

The Synthesis of (±)-11-Deoxydaunomycinone via Regioselective Tandem Diels-Alder Reactions

The 2,5-dimethylidene-3,6-bis[(Z)-(2-nitrophenyl)sulfenylmethylidene]-7-oxabicyclo[2.2.1]heptane ( 13 ) can be used to generate polyfunctional and multicyclic molecules with high regio- and stereoselectivity via two successive Diels-Alder additions using two different dienophiles. This principle has been applied to the synthesis of (±)-11-deoxydaunomycinone ( 7 ), the aglycone of an important antitumor drug. The 2,3-didehydroanisole adds to 13 and gives the monoadduct 14 with high regioselectivity. No trace of bis-adduct is observed. The 1,4-epoxy-1,2,3,4-tetrahydro-5-methoxy-3-methylidene-2-[(Z)-(2-nitrophenyl)sulfenylmethylidene]anthracene ( 15 ) obtained on treating 14 with K₂CO₃ adds to methyl vinyl ketone to give [(1RS, 2SR, 5RS,12RS)-5,12-epoxy-1,2,3,4,5,12-hexahydro-7-methoxy-1-(2-nitrophenyl)sulfenyl-2-naphthacenyl]methyl ketone ( 16 ) with high regio- and stereoselectivity. The acid-catalyzed 7-oxanorbornadiene→phenol rearrangement of 16 is regioselective and gives (5-acetoxy-3,4-dihydro-7-methoxy-2-naphthacenyl) methyl ketone ( 20 ) which was transformed into (±)-7,11-dideoxydaunomycinone ((±)- 24 ), a known precursor of 7 .     

Enzymatic resolution of racemic secondary cyclic allylic alcohols

The resolutions of five racemic cyclic alcohols: 6,6-dimethylcyclohex-2-en-1-ol (±)-5, 4,4-dimethylcyclohex-2-en-1-ol (±)-7, 5,5-dimethylcyclohex-2-en-1-ol (±)-11 and isomeric trans-(±)-13 and cis-piperitols (±)-14 are presented. They were resolved by enzymatic esterification with vinyl esters or by enzymatic hydrolysis of their racemic esters in phosphate buffer. The following lipases were used as biocatalysts: Novozyme 435 (Candida antarctica), Amano PS (Burkholderia cepacia) and lipase from Candida cylindracea. All isomers of alcohols were obtained with at least 96% ee.     

Stereochemical Analysis of an Aromatic Triplet Di-π-methane Rearrangement

It is shown that (−)-(S)-N,N-dimethyl-2-(1′-methylallyl)aniline ((−)-(S)- 4 ), on direct irradiation in MeCN at 20°, undergoes in its lowest-lying triplet state an aromatic di-π-methane (ADPM) rearrangement to yield (−)-(1′R,2′R)- and (+)-(1′R,2′S)-N,N-dimethyl-2-(2-methylcyclopropyl)aniline ((−)-trans- and (+)-cis- 7 ) in an initial trans/cis ratio of 4.71 ± 0.14 and in optical yields of 28.8 ± 5.2% and 15 ± 5%, respectively. The ADPM rearrangement of (−)-(S)- 4 to the trans- and cis-configurated products occurs with a preponderance of the path leading to retention of configuration at the pivot atom (C(1′) in the reactant and C(2′) in the products) for (−)-trans- 7 and to inversion of configuration for (+)-cis- 7 , respectively. The results can be rationalized by assuming reaction paths which involve the occurrence of discrete 1,4- and 1,3-diradicals (cf. Schemes 10, 12, and 13). A general analysis of such ADPM rearrangements which allows the classification of these photochemical reactions in terms of borderline cases is presented (Scheme 14). It is found that the optical yields in these ‘step-by-step’ rearrangements are determined by the first step, i.e. by the disrotatory bond formation between C(2) of the aromatic moiety and C(2′) of the allylic side chain leading to the generation of the 1,4-diradicals. Moderation of the optical yields can occur in the ring closure of the 1,3-diradicals to the final products, which may take place with different trans/cis-ratios for the individual 1,3-diradicals. Compounds (−)-trans- 7 as well as (+)-cis- 7 easily undergo the well-known photochemical trans/cis-isomerization. It mainly leads to racemization. However, a small part of the molecules shows trans/cis-isomerization with inversion of configuration at C(1′), which is best explained by a photochemical cleavage of the C(1′)–C(3′) bond.     

Plant-Derived Stilbenoids as DNA-Binding Agents: From Monomers to Dimers

Stilbenoids are natural compounds endowed with several biological activities, including cardioprotection and cancer prevention. Among them, (±)-trans-δ-viniferin, deriving from trans-resveratrol dimerization, was investigated in its ability to target DNA duplex and G-quadruplex structures by exploiting NMR spectroscopy, circular dichroism, fluorescence spectroscopy and molecular docking. (±)-trans-δ-Viniferin proved to bind both the minor and major grooves of duplexes, whereas it bound the 3’- and 5’-ends of a G-quadruplex by stacking on the outer quartets, accompanied by rearrangement of flanking residues. Specifically, (±)-trans-δ-viniferin demonstrated higher affinity for the investigated DNA targets than its monomeric counterpart. Additionally, the methoxylated derivatives of (±)-trans-δ-viniferin and trans-resveratrol, i. e. (±)-pterostilbene-trans-dihydrodimer and trans-pterostilbene, respectively, were evaluated, revealing similar binding modes, affinities and stoichiometries with the DNA targets as their parent analogues. All tested compounds were cytotoxic at μM concentration on several cancer cell lines, showing DNA damaging activity consistent with their ability to tightly interact with duplex and G-quadruplex structures.     

Stereoselective Double Functionalization of Iron-Carbonyl Complexes of 5,6,7,8-Tetramethylidenebicyclo[2.2.2]oct-2-ene. Crystal Structure and Absolute Configuration of (–)-trans-μ-[(2S,5R,7S)-C,5,6,C-η:C,7,8,C-η-(6,7,8-trimethylidene-5-((Z)-2-oxopropylidene)-2-bicyclo[2.2.2]octyl acetate)]-bis(tricarbonyliron)

The Friedel-Crafts monoacylation of trans-η-[(1RS,2RS,4SR,5SR,6RS,7SR,8SR)-C,5,6,C-η:C,7,8,C-η-(5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octyl acetate)]-bis(tricarbonyliron) ((±)- 5 ) is highly stereoselective and yields trans-η-[(1RS,2RS,4RS,5SR,6RS,7RS,8SR)-C,6-η,oxo-σ:C,7,8,C-η-(6,7,8-trimethylidene-5-((Z)-2-oxopropylidene)-2-bicyclo[2.2.2]octyl acetate)]-bis(tricarbonyliron) ((±)- 8 ) which equilibrates with the trans-η-[(1RS,2RS,4RS,5SR,6RS,7RS,8SR)-C,5,6,C-η:C,7,8,C-η-(6,7,8-trimethylidene-5-((Z)-2-oxopropylidene)-2-bicyclo[2.2.2]octyl acetate)]-bis(tricarbonyliron) ((±)- 9 ) on heating. Optically pure (–)- 9 has been prepared from the corresponding optically pure alcohol (+)- 4 . The structure and absolute configuration of (–)- 9 was established by single-crystal X-ray diffraction.     

Cyclophane-Type Fullerene-dibenzo[18]crown-6 Conjugates with trans-1, trans-2, and trans-3 Addition Patterns: Regioselective Templated Synthesis,X-Ray Crystal Structure,Ionophoric Properties,and Cation-Complexation-Dependent Redox Behavior

The fullerene-crown ether conjugates (±)- 1 to (±)- 3 with trans-1 ((±)- 1 ), trans-2 ((±)- 2 ), and trans-3 ((±)- 3 ) addition patterns on the C-sphere were prepared by Bingel macrocyclization. The trans-1 derivative (±)- 1 was obtained in 30% yield, together with a small amount of (±)- 2 by cyclization of the dibenzo[18]crown-6(DB18C6)-tethered bis-malonate 4 with C₆₀ (Scheme 1). When the crown-ether tether was further rigidified by K⁺-ion complexation, the yield and selectivity were greatly enhanced, and (±)- 1 was obtained as the only regioisomer in 50% yield. The macrocyclization, starting from a mixture of tethered bis-malonates with anti ( 4 ) and syn ( 10 ) bisfunctionalized DB18C6 moieties, afforded the trans-1 ((±)- 1 , 15%), trans-2 ((±)- 2 , 1.5%), and trans-3 ((±)- 3 , 20%) isomers (Scheme 2). Variable-temperature ¹H-NMR (VT-NMR) studies showed that the DB18C6 moiety in C₂-symmetrical (±)- 1 cannot rotate around the two arms fixing it to the C-sphere, even at 393 K. The planar chirality of (±)- 1 was confirmed in ¹H-NMR experiments using the potassium salts of (S)-1,1′-binaphthalene-2,2′-diyl phosphate ((+)-(S)- 19 ) or (+)-(1S)-camphor-10-sulfonic acid ((+)- 20 ) as chiral shift reagents (Fig. 1). The DB18C6 tether in (±)- 1 is a true covalent template: it is readily removed by hydrolysis or transesterification, which opens up new perspectives for molecular scaffolding using trans-1 fullerene derivatives. Characterization of the products 11 (Scheme 3) and 18 (Scheme 4) obtained by tether removal unambiguously confirmed the trans-1 addition pattern and the out-out geometry of (±)- 1 . VT-NMR Studies established that (±)- 2 is a C₂-symmetrical out-out trans-2 and (±)- 3 a C₁-symmetrical in-out trans-3 isomer. Upon changing from (±)- 1 to (±)- 3 , the distance between the DB18C6 moiety and the fullerene surface increases and, correspondingly, rotation of the ionophore becomes increasingly facile. The ionophoric properties of (±)- 1 were investigated with an ion-selective electrode membrane (Fig. 2 and Table 2), and K⁺ was found to form the most stable complex among the alkali-metal ions. The complex between (±)- 1 and KPF₆ was characterized by X-ray crystal-structure analysis (Figs. 3 and 4), which confirmed the close tangential orientation of the ionophore atop the fullerene surface. Addition of KPF₆ to a solution of (±)- 1 resulted in a large anodic shift (90 mV) of the first fullerene-centered reduction process, which is attributed to the electrostatic effect of the K⁺ ion bound in close proximity to the C-sphere (Fig. 5). Smaller anodic shifts were measured for the KPF₆ complexes of (±)- 2 (50 mV) and (±)- 3 (40 mV), in which the distance between ionophore and fullerene surface is increased (Table 3). The effects of different alkali- and alkaline-earth-metal ion salts on the redox properties of (±)- 1 were investigated (Table 4). These are the first-ever observed effects of cation complexation on the redox properties of the C-sphere in fullerene-crown ether conjugates.