Jörg-Martin Neudörfl

Acyloxybutadiene Iron Tricarbonyl Complexes as Enzyme‐Triggered CO‐Releasing Molecules (ET‐CORMs)

Molecular hazardous materials transport: Enzyme-triggered CO-releasing molecules (ET-CORMs) offer new options for the delivery of CO. The cleavage of dienylester iron tricarbonyl complexes by an esterase under mild oxidative conditions generates CO, which causes a strong inhibiting activity of the compounds to inducible nitric oxide synthase as shown in a cellular assay.

A [2 + 2 + 2]-cycloaddition approach toward 6-oxa-allocolchicinoids with apoptosis-inducing activity.

Following an A --> ABC strategy, a new synthesis of 6-oxa-allocolchicinoids was developed exploiting a microwave-promoted Co- or Rh-catalyzed intramolecular [2 + 2 + 2]-cycloaddition (alkyne cyclotrimerization) as a key step. The approach opens a short and efficient access to a variety of novel compounds, some of which were found to exhibit significant and selective apoptosis-inducing activities against BJAB tumor cells.

Total Synthesis of the Marine Antibiotic Pestalone and its Surprisingly Facile Conversion into Pestalalactone and Pestalachloride A

In 2001, Fenical and co-workers reported the isolation and structure elucidation of pestalone (1), a chlorinated, highly functionalized benzophenone produced by a marine fungus of the genus Pestalotia in response to bacterial challenge. Besides a moderate in vitro cytotoxicity against various tumor cell lines (mean GI50 = 6.0 mm), pestalone (1) was reported to exhibit highly potent antibiotic activity against methicillin-resistant Staphylococcus aureus (MIC = 37 ng mL ) and vancomycin-resistant Enterococcus faecium (MIC = 78 ng mL ). This prompted Fenical to emphasize that “the potency of this agent toward drug-resistant pathogens suggests that pestalone should be evaluated in more advanced, whole animal models of infectious disease.” Consequently, pestalone (1) is considered a particularly promising molecule with antibiotic properties. Recently, Che and co-workers identified a few strongly antifungal metabolites (e.g. 3 and 4) from the plant endophytic fungus Pestalotiopsis adusta which they named the pestalachlorides. These compounds are structurally closely related to 1 and, interestingly, were obtained as racemates indicating a non-enzymatic biosynthesis or a particularly facile mode of racemization. Owing to their obvious biological potential, their limited availability from natural sources, and their challenging chemical structures, pestalone (1) and its congeners are interesting target molecules for chemical synthesis. Our first study in 2003 resulted in the synthesis of deformylpestalone, and little later a total synthesis of 1 (and its demethylated derivative 2) was communicated by Nishiyama et al. Remarkably, no further biological studies have been reported since then. We describe herein a highly efficient and practicable synthesis of 1 which makes it possible for the first time to prepare substantial amounts of this natural product for further chemical and biological studies. Moreover, we report some surprising transformations (including the onestep transformation of 1 to rac-3) shedding light on the possible “biosynthetic” relationship of 1 with the pestalachlorides. The strategy behind our synthesis is summarized in Scheme 1. As a key consideration, we intended to assemble the benzophenone scaffold from a 2,6-dibromobenzaldehyde

N-Capping of primary amines with 2-acyl-benzaldehydes to give isoindolinones.

A unique reactivity pattern, first observed in the conversion of the marine natural product pestalone into pestalachloride A, was investigated. It was shown that 2-formyl-arylketones smoothly react with ammonia and primary amines, respectively, under mild conditions to afford 3-substituted isoindolinones in high yield. The reaction represents a new option for the derivatization (N-capping) of primary amines. As the substrates are readily accessible the methodology opens a short and modular access to pharmaceutically relevant substituted isoindolinones.

Azides Derived from Colchicine and their Use in Library Synthesis: a Practical Entry to New Bioactive Derivatives of an Old Natural Drug

Colchicine (1 a), the main alkaloid isolated from colchicum autumnale (meadow saffron) has long been known for its remarkable antimitotic activity. It is an established drug in the treatment of acute gout and familial Mediterranean fever. The biological activity of 1 a mainly results from its ability to selectively bind to tubulin leading to inhibition of microtubule formation (tubulin polymerization) and mitotic arrest in the metaphase. While high toxicity has prevented its use as an antitumor agent, colchicine still represents an important lead structure for drug discovery. Furthermore, due to its unique molecular scaffold, it remains a challenging and fascinating target molecule for total synthesis. Recently, allocolchicine (2 a) and its analogues (with a six-membered aromatic ring C) have also emerged as promising antitumor agents (Figure 1).

Total Synthesis of cyclo‐Mumbaistatin Analogues through Anionic Homo‐Fries Rearrangement

The structurally unique polyketide mumbaistatin is the strongest naturally occurring inhibitor of glucose-6-phosphate translocase-1 (G6P-T1), which is a promising target for drugs against type-2 diabetes mellitus and angiogenic processes associated with brain tumor development. Despite its high relevance, mumbaistatin has so far withstood all attempts towards its total synthesis. In the present study an efficient total synthesis of a deoxy-mumbaistatin analogue containing the complete carbon skeleton and a spirolactone motif closely resembling the natural product in its cyclized form was elaborated. Key steps of the synthesis are a Diels-Alder cycloaddition for the construction of the fully functionalized anthraquinone moiety and an anionic homo-Fries rearrangement to build up the tetra-ortho-substituted benzophenone core motif, from which a spiroketal lactone forms in a spontaneous process. The elaborated strategy opens an entry to a variety of new analogs of mumbaistatin and cyclo-mumbaistatin and may be exploited for the total synthesis of the natural product itself in the future.

Synthesis and characterization of 1,3,4,6-tetraarylpyrrolo[3,2-b]-pyrrole-2,5-dione (isoDPP)-based donor–acceptor polymers with low band gap

The synthesis of new π-conjugated donor–acceptor (D–A) polymers containing tetraaryl-diketopyrrolo[3,2-b]-pyrrole (isoDPP) as the building block is described. Polymers were prepared upon palladium-catalyzed Stille coupling of 3,6-bis(5-bromothien-2-yl)-1,4-diphenyl-pyrrolo[3,2-b]pyrrole-2,5-dione (M1) with 4,4′-bis(2-ethylhexyl)-5,5′-bis(trimethyltin)dithieno[3,2-b:2′,3′-d]silole (M2) or (4,8-bis-(2-ethylhexyloxy)benzo[1,2-b:4,5-b]dithiophene-2,6-diyl)bis(trimethylstannane) (M3). The polymers exhibit low band gaps of 1.53 and 1.67 eV, broad absorption bands with maxima of 523 nm and 620 nm, and high extinction coefficients of 6.5 × 104 L mol−1 cm−1, and 2.6 × 104 L mol−1 cm−1, respectively. Low fluorescence quantum yields between 0.13% and 0.82% were detected. Quantum chemical calculations indicated a nearly planar backbone with highly delocalized HOMO orbitals and localization of the LUMO electrons at the thienyl-isoDPP units. The X-ray structure analysis of M1 indicated a dihedral angle of 14.1° between the thienyl groups and the isoDPP core, and a 76.6° dihedral angle of the lactam phenyl group and the isoDPP core, the latter preventing any π-stacking of the monomers. The polymers show high glass transitions (Tg) and excellent thermal stability. Photoirradiation studies indicate that the polymers are extremely stable to UV and visible light in solution. Spectroelectrochemical studies indicated a reversible electrochromism with isosbestic point near 710 nm.

A practical synthesis of trans-3-substituted proline derivatives through 1,4-addition.

A practical four-step synthesis of 3-alkyl-, vinyl-, and aryl-substituted proline derivatives, which are important building blocks for conformationally restrained peptide analogs, was developed. The method relies on a Cu-catalyzed 1,4-addition of Grignard reagents to N-protected 2,3-dehydroproline esters, efficiently prepared in a new one-pot protocol. The 1,4-addition products are obtained with good trans-selectivity (dr 5:1 to 25:1). A nonracemic sample of N-Cbz-3-vinylproline (74% ee) was obtained using Evans oxazolidinone as a chiral auxiliary.

Exercises in Pyrrolidine Chemistry: Gram Scale Synthesis of a Pro–Pro Dipeptide Mimetic with a Polyproline Type II Helix Conformation

A practical and scalable synthesis of a Fmoc-protected tricyclic dipeptide mimetic (6), that is, a 1,4-diaza-tricyclo-[8.3.0(3,7)]-tridec-8-ene derivative resembling a rigidified di-L-proline in a polyproline type II (PPII) helix conformation, was developed. The strategy is based on a Ru-catalyzed ring-closing metathesis of a dipeptide (4) prepared by PyBOP coupling of cis-5-vinylproline tert-butylester (2) and trans-N-Boc-3-vinylproline (rac-3) followed by chromatographic diastereomer separation. Building block 2 was prepared from L-proline in six steps via electrochemical C5-methoxylation, cyanation and conversion of the nitrile into a vinyl substituent. Building block rac-3 was prepared in five steps exploiting a Cu-catalyzed 1,4-addition of vinyl-MgBr to a 2,3-dehydroproline derivative in the key step. In the course of the investigation subtle dependencies of protecting groups on the reactivity of the 2,3- and 2,5-disubstituted pyrrolidine derivatives were observed. The configuration and conformational preference of several intermediates were determined by X-ray crystallography. The developed synthesis allows the preparation of substantial amounts of 6, which will be used in the search for new small molecules for the modulation of protein-protein interactions involving proline-rich motifs (PRDs).

Enantiopure Monoprotected cis‐1,2‐Diaminocyclohexane: One‐Step Preparation and Application in Asymmetric Organocatalysis

Over the past few years, organocatalysis has gained increasing importance in modern organic synthesis. In particular, asymmetric aminocatalysis has emerged as a powerful tool for the enantioselective functionalization of carbonyl compounds by activation modes such as enamine, iminium, singly occupied molecular orbital (SOMO), and dienamine catalysis. In recent years, primary amine catalysis has gained prominence as a complementary method for the activation of ketones. Due to reduced steric constraints, primary amine catalysis often allows processes between sterically demanding partners, overcoming some limitations of chiral secondary amine catalysis. Trans-1,2-diaminocyclohexane (trans-DACH, 1) is a privileged 1,2-diamine scaffold which has been used in many applications in asymmetric catalysis (both metal-based and metal-free). 7] In contrast to the wide range of catalysts based on trans-DACH 1, there appears to be no application in catalysis of its cis counterpart 2 (Figure 1). Maruoka et al. were the first to