Torsten Bruhn

Good Computational Practice in the Assignment of Absolute Configurations by TDDFT Calculations of ECD Spectra

Quantum-mechanical calculations of chiroptical properties have rapidly become the most popular method for assigning absolute configurations (AC) of organic compounds, including natural products. Black-box time-dependent Density Functional Theory (TDDFT) calculations of electronic circular dichroism (ECD) spectra are nowadays readily accessible to nonexperts. However, an uncritical attitude may easily deliver a wrong answer. We present to the Chirality Forum a discussion on what can be called good computational practice in running TDDFT ECD calculations, highlighting the most crucial points with several examples from the recent literature. Chirality 28:466-474, 2016.

Helimeric Porphyrinoids: Stereostructure and Chiral Resolution of meso-Tetraarylmorpholinochlorins

The synthesis and chiral resolution of free-base and Ni(II) complexes of a number of derivatives of meso-tetraphenylmorpholinochlorins, with and without direct β-carbon-to-o-phenyl linkages to the flanking phenyl groups, is described. The morpholinochlorins, a class of stable chlorin analogues, were synthesized in two to three steps from meso-tetraphenylporphyrin. The conformations and the relative stereostructures of a variety of free-base and Ni(II) complexes of these morpholinochlorins were elucidated by X-ray diffractometry. Steric and stereoelectronic arguments explain the relative stereoarray of the morpholino-substituents, which differ in the free-base and Ni(II) complexes, and in the monoalkoxy, β-carbon-to-o-phenyl linked morpholinochlorins, and the dialkoxy derivatives. The Ni(II) complexes were all found to be severely ruffled whereas the free-base chromophores are more planar. As a result of the helimeric distortion of their porphyrinoid chromophores, the ruffled macrocycles possess a stable inherent element of chirality. Most significantly, resolution of the racemic mixtures was achieved, both by classical methods via diastereomers and by HPLC on a chiral phase. Full CD spectra were recorded and modeled using quantum-chemical computational methods, permitting, for the first time, an assignment of the absolute configurations of the chromophores. The report expands the range of known pyrrole-modified porphyrins. Beyond this, it introduces large chiral porphyrinoid π-systems that exist in the form of two enantiomeric, stereochemically stable helimers that can be resolved. This forms the basis for possible future applications, for example, in molecular-recognition systems or in materials with chiroptic properties.

Cleavage of four carbon-carbon bonds during biosynthesis of the griseorhodin a spiroketal pharmacophore.

The rubromycins, such as gamma-rubromycin, heliquinomycin, and griseorhodin A, are a family of extensively modified aromatic polyketides that inhibit HIV reverse transcriptase and human telomerase. Telomerase inhibition crucially depends on the presence of a spiroketal moiety that is unique among aromatic polyketides. Biosynthetic incorporation of this pharmacophore into the rubromycins results in a dramatic distortion of the overall polyketide structure, but how this process is achieved by the cell has been obscure. To identify the enzymes involved in spiroketal construction, we generated 14 gene-deletion variants of the griseorhodin A biosynthetic gene cluster isolated from the tunicate-associated bacterium Streptomyces sp. JP95. Heterologous expression and metabolic analysis allowed for an assignment of most genes to various stages of griseorhodin tailoring and pharmacophore generation. The isolation of the novel advanced intermediate lenticulone, which exhibits cytotoxic, antibacterial, and elastase-inhibiting activity, provided direct evidence that the spiroketal is formed by cleavage of four carbon-carbon bonds in a pentangular polyketide precursor. This remarkable transformation is followed by an epoxidation catalyzed by an unusual cytochrome P450/NADPH:ubiquinone oxidoreductase pair that utilizes a saturated substrate. In addition, the absolute configuration of griseorhodin A was determined by quantum-chemical circular dichroism (CD) calculations in combination with experimental CD measurements.

Baculiferins A–O, O-sulfated pyrrole alkaloids with anti-HIV-1 activity, from the Chinese marine sponge Iotrochota baculifera

Fifteen new DOPA-derived pyrrole alkaloids, named baculiferins A-O (2-16), were isolated from the Chinese marine sponge Iotrochota baculifera, together with the known alkaloids purpurone (1) and ningalin A (17). Most of the new compounds contain one to three O-sulfate units. Their structures were determined by extensive spectroscopic analysis including (1)H and (13)C NMR (COSY, HMQC, HMBC) and ESIMS data. A possible pathway for the biosynthetic origin of the isolated alkaloids is proposed, in which DOPA is assumed to be a joint biogenetic precursor. Baculiferins C, E-H, and K-N (4, 6-9, 12-15) were found to be potent inhibitors against the HIV-1 IIIB virus in both, MT4 and MAGI cells. Additional bioassay revealed that baculiferins could dramatically bind to the HIV-1 target proteins Vif, APOBEC3G, and gp41, for which structure-activity relationships are discussed.

Regiodivergent NC and NN Aryl Coupling Reactions of Indoloterpenes and Cycloether Formation Mediated by a Single Bacterial Flavoenzyme

Indoloterpenoid natural products play an eminent role as drugs, and their significance for medicine has propelled a plethora of synthetic and biosynthetic studies. Interestingly, these alkaloids are a hallmark of plant and fungal metabolism, but virtually nothing was known about the corresponding bacterial pathways. Only recently, in the context of profiling the bacterial endophytes of widespread mangrove trees, we discovered the unprecedented bacterial indolosesquiterpenes xiamycin (1), indosespene (2), and sespenine (3 ; Figure 1). Together with oridamycin (4) and oxiamycin (5) these multicyclic alkaloids constitute a new family of bacterial indoloterpenes. The co-occurrence of these diverse hybrid metabolites in a single organism implies a biogenetic relationship. Thus, we and another research group have independently analyzed xiamycin (xia) biosynthesis gene clusters. Through mutational analyses and heterologous expression, we found that the pathway involves an unparalleled cyclization sequence to yield diverse ring systems. The heterologous expression of the entire gene cluster also led to the discovery of N C and N N coupled xiamycin dimers, which had been overlooked in the wild-type strain owing to their low production. These structurally intriguing bixiamycins represent the first examples of bacterial bisindolosesquiterpenes (BIST), and their biosynthesis has remained enigmatic. Herein, we report the discovery and full characterization of a series of highly regiodivergent, N C and N N aryl-coupled xiamycin dimers, and reveal their potent antibacterial activities. Furthermore, we show that a single flavoprotein not only mediates diverse aryl couplings, but also ether formation. Finally, we support a radical-based mechanism by a biomimetic synthesis of the xiamycin derivatives. To reveal the range of bixiamycins produced, we inspected the metabolic profile of Streptomyces albus carrying the entire xia biosynthesis gene cluster. HPLC-HRMS analyses indicated that the strain produces a number of compounds that likely result from the dimerization of xiamycin (1), as they have the same molecular formula (C46H48N2O6), but differ in retention times. To obtain sufficient amounts of these new compounds for a full structural characterization, the culture was scaled up. Both mycelia and culture filtrate of a scaled-up fermentation (50 L) were extracted with ethyl acetate, and the combined extracts were subjected to fractionation by flash chromatography, first through silica, then through a Sephadex LH-20 column. Final purification by preparative HPLC yielded various dimers, including the atroposiomeric pair of N N coupled bixiamycins (6a/6b) and other types of dimers (Figure 2) as pure compounds: 6a (10 mg), 6b (5 mg), 7a (3 mg), 7b (1.0 mg), and 8 (23.1 mg). NMR analysis of the new dimers revealed that they all possess the xiamycin backbone. Compounds 7a and 7b were obtained as a pair of atropodiastereomers. Their H NMR spectra show two sets of signals, thus indicating that the coupling sites of the two moieties of the molecule are not identical. As only a signal for H21 is visible, whereas the counterpart (H21’) is missing in the H NMR spectrum, a N C coupling between N1 and C21’ was proposed. COSY and HMBC correlations confirmed the proposed structure for the two halves of the dimer. Comparison of the experimental CD spectra with the TDCAMB3LYP/6-31G*//B97D/TZVP calculated ones revealed that 7a has a P configuration, whereas the minor atropodiastereomer 7b has an M configuration at the N C axis (Figure 3; see the Supporting Information for details). Figure 1. Structures of bacterial indolosesquiterpenes, xiamycin (1), indosespene (2), sespenine (3), oridamycin (4), and oxiamycin (5).

Circularly Polarized Luminescence from Axially Chiral BODIPY DYEmers: An Experimental and Computational Study

With our new home-built circularly polarized luminescence (CPL) instrument, we measured fluorescence and CPL spectra of the enantiomeric pairs of two quasi-isomeric BODIPY DYEmers 1 and 2, endowed with axial chirality. The electronic circular dichroism (ECD) and CPL spectra of these atropisomeric dimers are dominated by the exciton coupling between the main π-π* transitions (550-560 nm) of the two BODIPY rings. Compound 1 has strong ECD and CPL spectra (glum =4×10-3 ) well reproduced by TD-DFT and SCS-CC2 (spin-component scaled second-order approximate coupled-cluster) calculations using DFT-optimized ground- and excited-state structures. Compound 2 has weaker ECD and CPL spectra (glum =4×10-4 ), partly due to the mutual cancellation of electric-electric and electric-magnetic exciton couplings, and partly to its conformational freedom. This compound is computationally very challenging. Starting from the optimized excited-state geometries, we predicted the wrong sign for the CPL band of 2 using TD-DFT with the most recommended hybrid and range-separated functionals, whereas SCS-CC2 or a DFT functional with full exact exchange provided the correct sign.

Synthesis, Resolution, and Absolute Configuration of Difunctionalized Tröger's Base Derivatives

Two racemic derivatives of Trögers base, the 2,8-diboronic acid ester 6 and the 3,9-dibromo-substituted derivative 5, were synthesized and successfully resolved by HPLC on a chiral stationary Whelk-01 phase on a semipreparative scale, thereby giving rise to both enantiomers in a pure form. These functionalized C(2)-symmetric building blocks are valuable precursors for a variety of further applications. Their absolute configurations were determined by comparison of their quantum chemically calculated CD and UV/Vis spectra with the experimental ones and were independently confirmed by X-ray diffraction analysis.

Synthesis and Stereochemistry of Highly Unsymmetric β,Meso-Linked Porphyrin Arrays

Porphyrin arrays with tailor-made photophysical properties and well-defined three-dimensional geometries constitute attractive synthetic targets in porphyrin chemistry. The paper describes a variable, straightforward synthetic procedure for the construction of beta,meso-linked porphyrin multichromophores in good to excellent yields. In a Suzuki-type coupling reaction beta-borylated 5,10,15,20-tetraarylporphyrins (TAPs) served as versatile building blocks for the preparation of a plethora of directly linked, unsymmetrically substituted di- and triporphyrins. Besides their interesting photophysical properties, especially the trimeric porphyrin arrays show exciting stereochemical features. The established protocols thus open a convenient entry into the synthesis of achiral and chiral, unsymmetrically substituted beta,meso-linked oligoporphyrins, e.g., for applications in biomedicine or nonlinear optics.

Antitumoral and antileishmanial dioncoquinones and ancistroquinones from cell cultures of Triphyophyllum peltatum (Dioncophyllaceae) and Ancistrocladus abbreviatus (Ancistrocladaceae)

From the methanolic extracts of solid callus cultures from two species of the closely related palaeotropical plant families Dioncophyllaceae and Ancistrocladaceae seven new natural naphthoquinones were isolated, dioncoquinones A (4) and B (5) from Triphyophyllum peltatum, and ancistroquinones B (6), C (7), D (9), E (10), and F (12) from Ancistrocladus abbreviatus. Their structures were elucidated by spectroscopic, chemical, and computational methods. Furthermore, the already known naphthoquinones plumbagin (2), droserone (3), malvone A (8), and nepenthone A (11) were found in the extract of A. abbreviatus. Dioncoquinones A (4) and B (5) showed good - and specific - activity against Leishmania major, while they were not active against other protozoic parasites. Moreover, treatment with 4 and 5 strongly induced apoptosis in human tumor cells derived from two different B cell malignancies, B cell lymphoma and multiple myeloma, without any significant toxicity towards normal peripheral mononuclear blood cells.

Synthesis and recognition behaviour of allosteric hemicarcerands

Abstract Bipyridine bridged bis(resorcinarenes) have been prepared. Upon co-ordinating to a transition metal ion, e.g. Ag+, the respective metal complex forms a hemicarcerand-like structure with the two resorcinarene moieties capable of binding non-polar organic molecules in a co-operative fashion, as shown qualitatively by NMR spectroscopy.