ALBERT

Notes: By the tether-directed remote functionalization method, a series of bis- to hexakis-adducts of C60, i.e., 1-7 (Fig. 1), had previously been prepared with high regioselectivity. An efficient method for the removal of the tether-reactive-group conjugate was now developed and its utility demonstrated in the regioselective synthesis of bis- to tetrakis(methano)fullerenes ( = di- to tetracyclopropafullerenes-C60-Ih) 9-11 starting from 4, 5, and 7, respectively (Schemes 2, 4, and 5). This versatile protocol consists of a 1O2 ene reaction with the two cyclohexene rings in the starting materials, reduction of the formed mixture of isomeric allylic hydroperoxides to the corresponding alcohols, acid-promoted elimination of H2O to cyclohexa-1,3-dienes, Diels-Alder addition of dimethyl acetylenedicarboxylate, retro-Diels-Alder addition, and, ultimately, transesterification. In the series 9-11, all methano moieties are attached along an equatorial belt of the fullerene. Starting from C2v-symmetrical tetrakis-adduct 15, transesterification with dodecan-1-ol or octan-1-ol yielded the octaesters 16 and 17, respectively, as noncrystalline fullerene derivatives (Scheme 3). The X-ray crystal structure of a CHCl3 solvate of 11 (Fig. 3) showed that the residual conjugated π-chromophore of the C-sphere is reduced to two tetrabenzopyracylene substructures connected by four biphenyl-type bonds (Fig. 5). In the eight six-membered rings surrounding the two pyracylene (= cyclopent[fg]acenaphthylene) moieties, 6-6 and 6-5 bond-length alteration (0.05 Å) was reduced by ca. 0.01 Å as compared to the free C60 skeleton (0.06 Å) (Fig. 4). The crystal packing (Fig. 6) revealed short contacts between Cl-atoms of the solvent molecule and sp2- and sp3-C-atoms of the C-sphere, as well as short contacts between Cl-atoms and O-atoms of the EtOOC groups attached to the methano moieties of 11. The physical properties and chemical reactivity of compounds 1-11 were comprehensively investigated as a function of degree and pattern of addition and the nature of the addends. Methods applied to this study were UV/VIS (Figs. 7-11), IR, and NMR spectroscopy (Table 2), cyclic (CV) and steady-state (SSV) voltammetry (Table 1), calculations of the energies of the lowest uunoccupied mmolecular orbitals (LUMOs) and electron affinities (Figs. 12 and 13), and evaluation of chemical reactivity in competition experiments. It was found that the properties of the fullerene derivatives were not only affected by the degree and pattern of addition but also, in a remarkable way, by the nature of the addends (methano vs. but-2-ene-1, 4-diyl) anellated to the C-sphere. Attachment of multiple thano moieties along an equatorial belt as in the series 8-11 induces only a small perturbation of the original fullerene π-chromophore. In general, with increasing attenuation of the conjugated fullerene π-chromophore, the optical (HOMO-LUMO) gap in the UV/VIS spectrum is shifted to higher energy, the number of reversible one-electron reductions decreases, and the first reduction potential becomes increasingly negative, the computed LUMO energy increases and the electron affinity decreases, and the reactivity of the fullerene towards nucleophiles and carbenes and as dienophile in cycloadditions decreases.

Notes: As previously shown, oligo- and poly(β-hydroxyalkanoates) have a high tendency to form lamellar crystallites with ca. 50-Å thickness which corresponds to chain lengths of 16 units (Fig. 1). To have monodisperse model compounds, we have now prepared bicyclic derivatives with three parallel (27-29) or two parallel and an antiparallel chain (68-70) consisting of up to 16 3-hydroxybutanoate (3-HB) units. We also prepared dendritic compounds (71-75, 82-85) containing oligo(3-HB) chains which cannot possibly be arranged as in the lamellae; the branching units were prepared from trimesic acid (= benzene-1,3,5-tricarboxylic acid). So far, none of the prepared samples formed crystals or contained crystalline domains which would have been suitable for single-crystal or powder-diffraction X-ray analysis. The terminally deprotected dendrimers (74, 75, and 85) are multi-anionic (up to 12 peripheral CO2H groups) and biodegradable. The macromolecular HB derivatives (molecular weight up to 10150 Da) have been fully characterized by IR, 1H- and 13C-NMR, [α]D, and elemental analysis. Especially important is the analysis by mass spectrometry with the MALDI-TOF technique (Fig. 2), proving that the products are monodisperse; application of a new variation of this MS method (post source decay = PSD or fragment analysis by structural time of flight = FASTTM) allows for the observation of metastable fragment ions and, thus, is a tool for structural oligomer analysis (Fig. 3).

Notes: The partial synthesis of 10,22-dihydro-4,5-dioxo-4,5-secopheophorbide a (1) from pheophorbide a methyl ester (2) is described. A regioselective, photooxygenolytic reaction of (pheophorbidato a methyl ester)cadmium(II)(3) provides the entry to the crucial 4,5-secoporphinoid structure in form of the (10,22-dihydro-4,5-dioxo-4,5-seco-pheophorbidato a methyl ester)cadmium(II) (4). The hydride reduction of this 4,5-dioxo-4,5-secophytoporphyrin ester occurs selectively at the ‘eastern’ meso-position to lead (after demetallation) to 10,22-dihydro-4,5-dioxo-4,5-secopheophorbide a methyl ester (5). This oxobilin-carbaldehyde has the structure assigned earlier to an ester of an isolation form of the red pigment(s) from Chlorella protothecoides. Hydrolysis of the propanoate ester function of 5, selectively catalyzed by pig liver esterase, then yields the title compound 1. The red tetrapyrrole 1 may represent an intermediary chlorophyll catabolite in degreening plants.

Notes: The inhibition of δ-chymotrypsin with optically active, axially and equatorially substituted trans-3-(2,4-dini-trophenoxy)-2,4-dioxa-3λ5-phospbubicyclo[4.4.0]decan-3-ones ( = hexahydro-4H-1,3,2-benzodioxaphosphorin 3-oxides) was investigated. Their inhibitory power was determined by kinetic measurements, and the stereochemical course of the reaction of stoichiometric amounts of the enzyme and inhibitor was monitored with 31P-NMR spectroscopy at pH 7.8. The irreversible inhibitors show significant enantioselectivity (the (Sp)-enantiomer reacting faster) and yield diastereoisomeric, covalently phosphorylated derivatives of δ-chymotrypsin.31P-NMR Spectroscopic studies of the inhibition by the axially substituted inhibitor revealed for the racemic (±)-2a first a resonance at -4.4 ppm and later, while inhibition proceeded, a second one at -4.5 ppm. The reaction with optically active (+)-2a showed only one signal at -4.4 ppm and its enantiomer (-)-2a only one signal at -4.5 ppm. Using the equatorially substituted racemic epimer (±)-2b, we observed the main resonance at -5.3 ppm and two minor ones at -4.4 and -4.5 ppm. The optically active compound (+)-2b showed two peaks at -4.5 and -5.3 ppm, whereas its antipode (-)-2b revealed two signals at -4.4 and -5.3 ppm.Comparing the 31P chemical shifts of the corresponding covalent phosphoserine derivatives 4a (-5.7 ppm, axial) and 4b (-4.5 ppm, equatorial) shows the inhibition with the axial compounds 2a to proceed via neat inversion of the configuration at the P-atom, whereas the equatorial epimers 2b with a higher conformational flexibility seem to follow a different stereochemical pathway which results in both inversion and retention.

Notes: Water-soluble dendritic cyclophanes (dendrophanes) of first (1, 4), second (2 5), and third generation (3 6) with poly(ether amide) branching and 12, 36, and 108 terminal carboxylate groups, respectively, were prepared by divergent synthesis, and their molecular recognition properties in aqueous solutions were investigated. Dendrophanes 1-3 incorporate as the initiator core a tetraoxa[6.1.6.1]paracyclophane 7 with a suitably sized cavity for inclusion complexation of benzene or naphthalene derivatives. The initiator core in 4-6 is the [6.1.6.1]cyclo-phane 8 shaped by two naphthyl(phenyl) methane units with a cavity suitable for steroid incorporation. The syntheses of 1-6 involved sequential peptide coupling to monomer 9, followed by ester hydrolysis (Schemes 1 and 4), Purification by gel-permeation chromatography (GPC; Fig. 3) and full spectral characterization were accomplished at the stage of the intermediate poly(methyl carboxylates) 10-12 and 23-25, respectively. The third-generation 108-ester 25 was also independently prepared by a semi-convergent synthetic strategy, starting from 4 (Scheme 5). All dendrophanes with terminal ester groups were obtained in pure form according to the 13C-NMR spectral criterion (Figs, 1 and 5). The MALDI-TOF mass spectra of the third-generation derivative 25 (mol. wt. 19328 D) displayed the molecular ion as base peak, accompanied by a series of ions [M - n(1041 ± 7)]+, tentatively assigned as characteristic fragment ions of the poly(ether amide) cascade. A similar fragmentation pattern was also observed in the spectra of other higher-generation poly(ether amide) dendrimers. Attempts to prepare monodisperse fourth-generation dendrophanes by divergent synthesis failed. 1H-NMR and fluorescence binding titrations in basic aqueous buffer solutions showed that dendrophanes 1-3 complexed benzene and naphthalene derivatives, whereas 4-6 bound the steroid testosterone. Complexation occurred exclusively at the cavity-binding site of the central cyclophane core rather than in fluctuating voids in the dendritic branches, and the association strength was similar to that of the complexes formed by the initiator cores 7 and 8, respectively (Tables 1 and 3). Fluorescence titrations with 6-(p-toluidino)naphthalene-2-sulfonate as fluorescent probe in aqueous buffer showed that the micropolarity at the cyclophane core in dendrophanes 1-3 becomes increasingly reduced with increasing size and density of the dendritic superstructure; the polarity at the core of the third-generation compound 3 is similar to that of EtOH (Table 2). Host-guest exchange kinetics were remarkably fast and, except for receptor 3, the stabilities of all dendrophane complexes could be evaluated by 1H-NMR titrations. The rapid complexation-decomplexation kinetics are explained by the specific attachment of the dendritic wedges to large, nanometer-sized cyclophane initiator cores, which generates apertures in the surrounding dendritic superstructure.