An efficient and practical protocol for the enantioselective cobalt-catalyzed hydrovinylation of vinylarenes with ethylene at low (1.2 bar) pressure has been developed. As precatalysts, stable [L₂CoCl₂] complexes are employed that are activated in situ with Et₂AlCl. A modular chiral TADDOL-derived phosphine–phosphite ligand was identified that allows the conversion of a broad spectrum of substrates, including heterocyclic vinylarenes and vinylferrocene, to smoothly afford the branched products with up to 99 % ee and virtually complete regioselectivity. Even polar functional groups, such as OH, NH₂, CN, and CO₂R, are tolerated.

The first total synthesis of houttuynoid B, a powerful antiviral flavonoid glycoside from the Chinese plant Houttuynia cordata, is described. In a key step, a Baker–Venkataraman rearrangement employing an already glycosylated substrate was used to efficiently set up the fully functionalized carbon skeleton. The required benzofuran building block was prepared through a domino Sonogashira coupling/5-endo-dig cyclization and converted into a stable 1-hydroxybenzotriazole-derived active ester prior to linking with a galactosylated hydroxyacetophenone unit. The elaborated synthesis requires only nine steps (11 % overall yield) along the longest linear sequence and paves the way for the preparation of structurally related compounds for further biological evaluation.

Wir berichten über die Entwicklung Protease-aktivierter Kohlenmonoxid-freisetzender Moleküle (CORMs). Die Tragfähigkeit des gewählten Konzeptes wurde durch die Synthese von Verbindungen belegt, bei denen eine η⁴-Oxydien-Fe(CO)₃-Substruktur mit einer durch Penicillin-G-Amidase (PGA) spaltbaren Einheit über einen “selbstlösenden” Linker verknüpft ist. Die Geschwindigkeit der PGA-induzierten Hydrolyse wurde per HPLC und die nachfolgende CO-Freisetzung durch Headspace-GC bestimmt. Bei gemeinsamer Gabe eines unserer CORMs und PGA konnten die Inhibition der Entzündungsantwort sowie die Induktion der Expression von Hämoxygenase-1 in humanen Endothelzellen als typische biologische Effekte von CO in vitro nachgewiesen werden. Auf diese Weise wurde eine vielversprechende Basis für die zukünftige Entwicklung Protease-spezifischer CORMs für potenzielle klinische Anwendungen geschaffen.

Protease-triggered CO-releasing molecules (CORMs) were developed. The viability of the approach was demonstrated through the synthesis of compounds consisting of an η⁴-oxydiene–Fe(CO)₃ moiety connected to a penicillin G amidase (PGA)-cleavable unit through a self-immolative linker. The rate of PGA-induced hydrolysis was investigated by HPLC analysis and the subsequent CO release was quantitatively assessed through headspace gas chromatography. In an in vitro assay with human endothelial cells, typical biological effects of CO, that is, inhibition of the inflammatory response and the induction of heme oxygenase-1 expression, were observed only upon co-administration of the CORM and PGA. This work forms a promising basis for the future development of protease-specific CORMs for potential medicinal applications.

Polycyclic proline-derived scaffolds (ProMs) have recently demonstrated their value as conformationally defined dipeptide analogs for the modular construction of secondary structure mimetics, specifically interfering with PPII helix-mediated protein–protein interactions. We disclose the stereoselective synthesis of two new tricyclic amino acid scaffolds (ProM-4 and ProM-8) that differ from the first generation scaffold ProM-1 by the size of ring A. Conformational preferences and subtle structural differences of the three homologous scaffolds were analyzed by X-ray crystallography, computational calculations, and NMR spectroscopy. N-tert-butoxycarbonyl(Boc)-3-(1-propenyl)azetidine-2-carboxylic acid was prepared from L-aspartic acid through β-lactam intermediates. The corresponding piperidine-based building block rac-N-Boc-3-vinylpipecolic acid was synthesized by Cu-catalyzed 1,4-addition of vinyl-MgBr to methyl N-Boc-2,3-dehydropipecolate. Target molecules were prepared through peptide coupling of the respective ring A building blocks with cis-5-vinylproline tert-butyl ester and subsequent ring-closing metathesis. Selective deprotection of a tert-butyl carbamate (N-Boc protecting group) in the presence of a tert-butyl ester was achieved with trifluoroacetic acid at 0 °C.

Starting from tartaric acid derived chiral diols or dicarboxylic acid dichlorides with either a 2,2-dimethyl-1,3-dioxolane (Taddol) or a 2,3-dimethoxy-2,3-dimethyl-1,4-dioxane (Tatrol) core structure, and BH₃-protected ortho-phosphanyl phenols, a set of fourteen new C₂-symmetric diphosphine ligands was synthesized. In addition, three related ligands were obtained from ortho-diphenylphosphino-anilines. The fully characterized ligands were then tested in the Pd-catalyzed enantioselective O-allylation of 4-methoxyphenol using crotyl methyl carbonate as a reagent. In addition, a pseudo-intramolecular variant of the reaction, using crotyl 4-methoxyphenyl carbonate as a substrate, was studied. The so-called Trost ligand was used as a reference. Although the Trost ligand (3 mol-%) gave up to 84 % ee, one of the new ligands showed higher activity (50 % ee with 0.075 mol-%).

A novel strategy for the total synthesis of α-tocopherol (“vitamin E”) was elaborated on the basis of the conjugate addition of AlMe₃ (as a methyl anion equivalent) to a 2-substituted chromenone. Starting from trimethylhydroquinone and (R,R)-hexahydrofarnesol, the required chromenone substrate was efficiently prepared in a short sequence exploiting a TiCl₄-mediated Fries rearrangement and a KOtBu-induced Baker–Venkatamaran rearrangement. The envisioned key step, which sets up the quaternary center at C2, was performed in virtually quantitative yield through Ni-catalyzed conjugate addition of AlMe₃. However, this transformation, which likely proceeds through a radical mechanism, could not be rendered stereoselective by means of chiral ligands. Nevertheless, the elaborated synthesis of (2RS,4′R,8′R)-α-tocopherol (2-ambo-α-tocopherol) is efficient and challenges the future development of suitable protocols for the asymmetric 1,4-addition.

Following a peptide coupling/metathesis-based strategy, the two diastereomeric scaffolds ProM-3 and ProM-7 were stereoselectively synthesized (as 9-fluorenylmethoxycarbonyl derivatives), and their configuration was unambiguously proven by means of X-ray crystallography. The required dehydroisoleucine building blocks were prepared by applying the enantioselective Kazmaier–Claisen rearrangement. The target compounds represent dipeptide analogs rigidified in a PPII helix conformation, which are of interest for the development of new proteomimetics that selectively bind to protein domains specialized in the recognition of ligands adopting a PPII helix secondary structure.

By introducing a disposable activating substituent at C-3, the asymmetric 1,4-addition to a notoriously unreactive 2-substituted chromenone was achieved with high levels of (2R)-stereoselectivity in the presence of a chiral Cu^I-phosphoramidite complex as a catalyst. This paved the way for an efficient and conceptually novel synthesis of (R,R,R)-α-tocopherol from readily available starting materials.

The synthesis and stereochemical assignment of two classes of iron-containing nucleoside analogues, both of which contain a butadieneFe(CO)₃ substructure, is described. The first type of compounds are Fe(CO)₃-complexed 3′-alkenyl-2′,3′-dideoxy-2′,3′-dehydro nucleosides (2,5-dihydrofuran derivatives), from which the second class of compounds is derived by formal replacement of the ring oxygen atom by a CH₂ group (carbocyclic nucleoside analogues). These compounds were prepared in a stereoselective manner through the metal-assisted introduction of the nucleobase. Whilst the furanoid intermediates were prepared from carbohydrates (such as methyl-glucopyranoside), the carbocyclic compounds were obtained by using an intramolecular Pauson–Khand reaction. Stereochemical assignments based on NMR and CD spectroscopy were confirmed by X-ray structural analysis. Biological investigations revealed that several of the complexes exhibited pronounced apoptosis-inducing properties (through an unusual caspase 3-independent but ROS-dependent pathway). Furthermore, some structure–activity relationships were identified, also as a precondition for the design and synthesis of fluorescent and biotin-labeled conjugates.

Copper(I) complexes of TADDOL-based phosphane–phosphite ligands catalyze enantioselective conjugate additions of various Grignard reagents to cyclic enones. Through trapping of the resulting chiral magnesium enolates with N-benzylidene-4-methylbenzenesulfonamide (as an imine) in one-pot procedures, the corresponding Mannich products (i.e., β-aminocarbonyl compounds) were obtained in good yields and high enantiomeric purities, although with only low diastereoselectivities.

Asymmetric conjugate additions (1,4-additions) of aryl-Grignard reagents to cyclohex-2-enone, currently a more or less unsolved challenge, were investigated. For this purpose, a small library of phenol-derived chiral phosphane-phosphite ligands containing TADDOL- or BINOL-based phosphite moieties was evaluated. These ligands are easily prepared by a short modular scheme previously developed in this laboratory. Two particularly powerful ligands (4a and 4b, both TADDOL-derived and each possessing a bulky tert-butyl substituent ortho to the phosphite group) were identified. Conditions were optimized with use of the addition of (4-methoxyphenyl)magnesium bromide to cyclohexenone as a standard reaction system. Under optimized conditions [CuBr·SMe₂ (4 mol-%), ligand 4a (6 mol-%), 2-methyl-THF, –78 °C, slow addition of Grignard reagent] the 1,4-product was obtained with high enantioselectivity (up to 95 % ee) and good regioselectivity (r.r. = 90:10). The scope of the method was probed with different aryl-Grignard reagents. It was found that reagents with electron-donating substituents in meta- or para-positions performed particularly well, whereas the presence of F or CF₃ substituents led to decreased ee values. Only ortho-substituted aryl-Grignard reagents did not give rise to useful results. A series of phosphane-phosphite ligands were also tested in the Rh-catalyzed 1,4-addition of phenylboronic acid to cyclohexenone, but enantioselectivities did not exceed 70 % ee in this case.

A synthetic approach towards (5R)-5-methyl-6-oxa-desacetamido colchicine as a conformationally defined non-natural colchicine analog with a modified B-ring was undertaken. The synthetic strategy was based on a Rh-catalyzed cascade reaction involving a [5+2] cycloaddition of a carbonyl ylide intermediate as a key step, in which both seven-membered rings of the polycyclic framework are formed in a single operation. Starting from 2-iodo-3,4,5-trimethoxy-acetophenone, an upper side-chain was constructed through enantioselective CBS reduction (up to 75 % ee) and propargylation, while a lower succinoyl side-chain was attached either throughiodine–magnesium–copper exchange and subsequent reaction with methyl 4-chloro-4-oxobutanoate, or by Pd-catalyzed Stille cross-coupling with 2-tributylstannyl-5-methoxyfuran followed by hydrolytic furan-opening. Treatment of an α-diazoketone intermediate with Rh₂(OAc)₄ (3 mol-%)initiated the diastereoselective key cyclization cascade (≥97:3 dr). Treatment of the cycloadduct 3 with Et₂AlCl afforded an interesting 11,12-dihydrocolchicine analog 24, which, however, could not be oxidized to the corresponding tropolone. Structural assignments were confirmed by X-ray crystallography. While compounds 3 and 24 did not exhibit noteworthy cytotoxic activity by themselves, they were found to strongly enhance the cytostatic (apoptosis-inducing) activity of doxorubicin against resistant Nalm-6 cells (i.e., in a synergy effect).

A series of novel pyrrolo-allocolchicine derivatives (containing a 1-methyl-1H-indol-5-yl moiety replacing ring C) was synthesized. The tetracyclic ring system was constructed by Suzuki–Miyaura cross-coupling of a 1-methylindole-5-boronate with an ortho-iodo-dihydrocinnamic acid derivative and subsequent intramolecular Friedel–Crafts acylation. After reduction of the resulting ketone, the nitrogen functionality was introduced in a Mitsunobu-type reaction by using zinc azide followed by LiAlH₄ reduction. Structural assignments were supported by X-ray crystallography. The compounds synthesized were then tested against BJAB tumor cells and found to exhibit pronounced cytotoxic activity (proliferation inhibition and apoptosis induction). The ketone 24 b was even active at sub-nanomolar concentration. In addition, the antitumor potential of the compounds was confirmed by using B lymphoid cell lines.

The use of modular α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)- and 1,1′-bi-2-naphthol (BINOL)-derived phosphine-phosphite ligands (L₂*) in the asymmetric rhodium-catalyzed intramolecular [4+2] cycloaddition (“neutral” Diels–Alder reaction) of (E,E)-1,6,8-decatriene derivatives (including a 4-oxa and a 4-aza analogue) was investigated. Initial screening of a small ligand library led to the identification of a most promising, TADDOL-derived ligand bearing a phenyl group adjacent to the phosphite moiety at the arene backbone. In the course of further optimization studies, the formation of a new, more selective catalyst species during the reaction time was observed. By irradiating the pre-catalyst with microwaves prior to substrate addition high enantioselectivities (up to 93% ee) were achieved. The new cyclization protocol was successfully applied to all three substrates investigated to give the bicyclic products in good yield and selectivity. ³¹P NMR and ESI-MS measurements indicated the formation of a [Rh(L₂*)₂]⁺ species as the more selective (pre-) catalyst.

As previous studies in the field of bioorganometallic chemistry have unveiled, metal-containing analogues of natural products frequently exhibit surprising biological activities. In this context, a synthetic approach to analogues of the eicosanoids 5-HETE and 8-HETE possessing a 1,3-butadiene–Fe(CO)₃ substructure was elaborated. The chosen structures are characterized by a central (2E,4Z)-hexa-2,4-dien-1-ol–Fe(CO)₃ moiety (as the potential “metal pharmacophore”) and carry a lipophilic ω-6-substituent as well as a hydrophilic α-side chain (carboxylic acid). Using the cationic complex tricarbonyl[η⁵-1-(methoxycarbonyl)pentadienyl]iron hexafluorophosphate (rac-4) as a starting material, the synthesis of a simplified Fe(CO)₃-complexed HETE analogue (rac-3) was achieved by exploiting the addition of an alkynyl Cu species to rac-4. The carbon skeleton was completed through diastereo(Ψ-exo)selective addition of a titanium–zinc organyl [prepared from ethyl 4-iodobutyrate, activated Zn powder, and Ti(OiPr)₃Cl] as a butyrate D⁴ synthon to an aldehyde function by using 2-Me-THF as the solvent of choice. The (sensitive) target compound rac-3 was shown to induce apoptosis at moderate concentrations in cancer cells (BJAB and Nalm-6).

The stereoselective synthesis of a set of four stable 5-hydroxyeicosatetraenoic acid (HETE) analogues with a ferrocene backbone is described. The common substructure of all HETEs, the (2E,4Z)-1-hydroxyhexadiene moiety, was formally replaced by a ferrocenylmethanol fragment. Whereas the hydrophilic side chain remained the same as that of 5-HETE (butyrate), the lipophilic side chain was simplified by replacing the “natural” (Z,Z)-1,4-decadiene side chain with (Z)-1-heptene, 1-heptyne, 1-octyne, or phenylacetylene. As a key building block, Kagan's chiral acetal (derived from ferrocenecarbaldehyde) was used for the stereoselective generation of the planar-chiral substructure through diastereoselective ortho-lithiation and subsequent formylation, methoxycarbonylation or iodination, respectively. The lipophilic side chain was installed either by a “salt-free” Wittig reaction or (better) by Pd-catalyzed Sonogashira coupling. The (Z)-selective semi-reduction of a (hindered) triple bond was achieved with NaBH₄, PdI₂ and PEG200. The introduction of the hydrophilic side chain was found to proceed with complete diastereoselectivity through addition of a titanium–zinc organyl [prepared from ethyl 4-iodobutyrate, activated Zn powder and Ti(OiPr)₃Cl] as a butyrate D⁴ synthon to an aldehyde function using 2-methyltetrahydrofuran (2-Me-THF) as a solvent. The expected (R_p,5S) configuration of the products was confirmed by X-ray crystallography of an intermediate and by chemical correlation and NMR spectroscopy of a Mosher-type derivative. Preliminary biological experiments revealed that compound 4 [with a (Z)-heptenyl side chain] displayed significant apoptosis induction, whereas analogues with an alkynyl side chain were inactive. None of the HETE analogues prepared showed significant inhibition of lipoxygenase (15-LOX) or cyclooxygenase (COX-2).

Attempts to convert 3β-acetoxy-5,19-cyclo-pregna-6,20-dione (8) into a cyclocitrinol-related steroid with a bicyclo[4.4.1]-undecane AB-ring substructure through a Lewis acid-assisted fragmentation failed. Instead, treating 8 with an excess of Ac₂O and BF₃·Et₂O afforded B-homo steroid 9 in 90 % yield. This unexpected rearrangement is assumed to proceed via an intermediate bicyclobutonium cation. Remarkably, tricyclo[4.4.1.0]undecane-1-one (rac-13), prepared as a model substrate, did not react under the same conditions. However, by screening various Lewis acids, stannous triflate was identified as a particularly efficient reagent for this and related Lewis acid-assisted ring-opening reactions of cyclopropyl ketones in the presence of Ac₂O, and even catalytic amounts of Sn(OTf)₂ (5 mol-%) proved to be effective.

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 prolin-rich motifs (PRDs).

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.

The copper(I)-catalysed S_N2′-type allylic substitution of E-3-aryl-allyl chlorides (cinnamyl chlorides) using Grignard reagents represents a powerful method for the synthesis of compounds carrying a benzylic stereocentre. By screening a small library of modular chiral phosphine-phosphite ligands a new copper(I)-based catalyst system was identified which allows the performance of such reactions with exceptional high degrees of regio- and enantioselectivity. Best results were obtained using TADDOL-derived ligands (3 mol%), copper(I) bromide⋅dimethyl sulfide (CuBr⋅SMe₂) (2.5 mol%) and methyl tert-butyl ether (MTBE) as a solvent. Various (1-alkyl-allyl)benzene derivatives were prepared with up to 99% ee (GC) in isolated yields of up to 99%. In most cases the product contained less than 3% of the linear regioisomer (except for ortho-substituted substrates). Both electron-rich and electron-deficient cinnamyl chlorides were successfully employed. The absolute configuration of the products was assigned by comparison of experimental and calculated CD spectra. The substrates were prepared from the corresponding alcohols by reaction with thionyl chloride. Initially formed mixtures of regioisomeric allylic chlorides were homogenised by treatment with CuBr⋅SMe₂ (2.5 mol%) in the presence of triphenyl phosphine (PPh₃) (3 mol%) in MTBE at low temperature to give the pure linear isomers. In reactions with methylmagnesium bromide (MeMgBr) an ortho-diphenylphosphanyl-arylphosphite ligand with an additional phenyl substituent in ortho′-position at the aryl backbone proved to be superior. In contrast, best results were obtained in the case of higher alkyl Grignard reagents (such as ethyl-, n-butyl-, isopropyl-, and 3-butenylmagnesium bromides) with a related ligand carrying an isopropyl substituent in ortho′-position. The method was tested on a multi-mmol scale and is suited for application in natural product synthesis.

Inflammation is a hallmark of microbial infection in mammals and is the result of a pathogen-induced release of inflammatory effectors. In humans a variety of germ-line encoded receptors, so-called pattern-recognition receptors, respond to conserved signatures on invading pathogens, which results in the transcriptional activation of pro-inflammatory responses. Inflammation is often detrimental to the host and leads to tissue damage and/or systemic dysfunctions. Thus, specific inhibitors of these pathways are desirable for medical interventions. Herein we report on the synthesis and use of some chromium-containing compounds (areneCr(CO)₃ complexes) with a core structure related to anti-inflammatory diterpenes produced by the sea whip Pseudopterogorgia elisabethae. By using cell-based reporter assays we identified complexes with a potent inhibitory activity on tumour necrosis factor (TNF), Toll-like receptor (TLR), and nucleotide binding domain, leucine-rich repeat-containing receptor (NLR) pathways. Moreover, we found one complex to be a specific inhibitor of inflammatory responses mediated by the NLR protein NOD2, a pivotal innate immune receptor involved in bacterial recognition. Synthesis and characterisation of a set of derivatives of this substance revealed structural requirements for NOD2 specificity. Taken together, our studies suggest this type of areneCr(CO)₃ complex as a potential lead for the development of antiphlogistica and pharmacologically relevant NOD2 inhibitors.

As a contribution to bioorganometallic chemistry, a dia- and enantioselective synthesis of novel carbocyclic amino acid analogues with a 1,2-ferroceno-fused cyclopentene backbone has been developed. Using two related planar-chiral intermediates, i.e. (1S,E)-ethyl-3-[2-(phenylsulfonylacetyl)ferrocen-1-yl]acrylate, (1S,E)-ethyl-3-[2-(methoxycarbonyl)ferrocen-1-yl]acrylate, stereoselective entries to different tBoc- or Fmoc-protected ferroceno-fused 1-amino-3-carboxyalkyl-2-cyclopentenes were elaborated. These compounds were then used for the preparation of metal-containing peptides by means of solid-phase peptide synthesis (SPPS). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

An efficient and modular approach to bidentate phosphine-phosphite ligands formally derived from a 6-alkyl-2-phosphanylphenol, a chiral diol and phosphorus trichloride has been developed. In a key step, a borane-protected phosphinite, prepared from an o-bromophenol by O-phosphanylation, is reacted with n-butyllithium to afford the corresponding ortho-phosphanylphenol (as the stable borane adduct) through bromine-lithium exchange and anionic migration rearrangement. Treatment with phosphorus trichloride in the presence of a base and subsequent reaction of the in situ formed dichlorophosphite with a chiral diol (such as TADDOL or BINOL) affords the target P,P ligands in good overall yield (up to 60% over 4 steps). In contrast to an earlier approach, the new methodology is very general and tolerates bulky ortho-substituents. The reliability of the operationally convenient protocol was demonstrated in the synthesis of a library of 16 new phosphine-phosphite ligands, starting from different ortho-alkylphenols. The modular concept opens a rapid access to a broad variety of ligands and might be useful in the search for and structural optimization of suitable ligands for specific chirogenic transition metal-catalyzed transformations.