Martin E. Maier

Coordination chemistry of gold catalysts in solution: a detailed NMR study.

Coordination chemistry of gold catalysts bearing eight different ligands [L=PPh(3), JohnPhos (L2), Xphos (L3), DTBP, IMes, IPr, dppf, S-tolBINAP (L8)] has been studied by NMR spectroscopy in solution at room temperature. Cationic or neutral mononuclear complexes LAuX (L=L2, L3, IMes, IPr; X=charged or neutral ligand) underwent simple ligand exchange without giving any higher coordinate complexes. For L2AuX the following ligand strength series was determined: MeOH≪hex-3-yne <MeCN≈OTf(-) ≪Me(2)S<2,6-lutidine<4-picoline<CF(3)CO(2)(-) ≈DMAP<TMTU<PPh(3) <OH(-) ≈Cl(-). Some heteroligand complexes DTBPAuX exist in solution in equilibrium with the corresponding symmetrical species. Binuclear complexes dppf(AuOTf)(2) and S-tolBINAP(AuOTf)(2) showed different behavior in exchange reactions with ligands depending on the ligand strength. Thus, PPh(3) causes abstraction of one gold atom to give mononuclear complexes LLAuPPh(3)(+) and (Ph(3)P)(n)Au(+), but other N and S ligands give ordinary dicationic species LL(AuNu)(2)(2+). In reactions with different bases, LAu(+) provided new oxonium ions whose chemistry was also studied: (DTBPAu)(3)O(+), (L2Au)(2)OH(+), (L2Au)(3)O(+), (L3Au)(2)OH(+), and (IMesAu)(2)OH(+). Ultimately, formation of gold hydroxide LAuOH (L=L2, L3, IMes) was studied. Ligand- or base-assisted interconversions between (L2Au)(2)OH(+), (L2Au)(3)O(+), and L2AuOH are described. Reactions of dppf(AuOTf)(2) and S-tolBINAP(AuOTf)(2) with bases provided more interesting oxonium ions, whose molecular composition was found to be [dppf(Au)(2)](3)O(2)(2+), L8(Au)(2)OH(+), and [L8(Au)(2)](3)O(2)(2+), but their exact structure was not established. Several reactions between different oxonium species were conducted to observe mixed heteroligand oxonium species. Reaction of L2AuNCMe(+) with S(2-) was studied; several new complexes with sulfide are described. For many reversible reactions the corresponding equilibrium constants were determined.

Total Synthesis and Biological Activity of Neopeltolide and Analogues

Combining the core structure of neopeltolide, lactone 16 a, with the oxazole-containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still-Gennari Horner-Emmons reaction. By changing the Leighton reagent in the allylation step, the 11-epimer of lactone 16 a, compound 50 was prepared. This led to 11-epi-neopeltolide 51. The 5-epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself.

Formal total synthesis of neopeltolide.

A concise synthesis of the core structure of the macrolide neopeltolide was developed featuring a Prins cyclization to fashion the pyran ring. Key steps in the synthesis of aldehyde 16 were a Leighton allylation and a Feringa-Minnaard asymmetric methyl cuprate addition to an unsaturated thioester. For lactonization, a classical Yamaguchi macrolactonization was used. The longest linear sequence consists of 17 steps providing lactone 26 with an overall yield of 23%.

The Mechanism of Gold(I)‐Catalyzed Hydroalkoxylation of Alkynes: An Extensive Experimental Study

An extensive experimental study of the mechanism of gold(I)-catalyzed hydroalkoxylation of internal alkynes has been conducted by using NMR spectroscopy. This study was focused on the organogold intermediates, observations of actual catalytic intermediates in situ, and the reaction kinetics that are involved in this reaction. Based on the experimental results, a complete mechanistic picture was established, including on- and off-cycle processes that explain the role of diaurated species. We have shown that gold-catalyzed hydroalkoxylation of internal alkynes is a reaction that requires only one gold atom for the catalytic cycle, disproving a recent hypothesis regarding the involvement of cooperative gold catalysis.

Mechanistic Study of Gold(I)‐Catalyzed Hydroamination of Alkynes: Outer or Inner Sphere Mechanism?

An experimental mechanistic study of the gold(I)-catalyzed hydroamination shows the formation of conformationally flexible auro-iminium salts Au-Im, which originate from the protonation of a vinyl gold species. Rotation around the C-CAu bond is the reason for the loss of stereospecificity of protodeauration, which explains the stereochemical result of the Stradiotto reaction. The ambiguity about inner or outer sphere mechanism is thus resolved in favor of the outer sphere mechanism.

Synthesis and characterization of a smart contrast agent sensitive to calcium

A novel first-generation Ca2+ sensitive contrast agent, Gd-DOPTRA has been synthesized and characterized. The agent shows approximately 100% relaxivity enhancement upon addition of Ca2+. The agent is selective and sensitive to Ca2+ also in the presence of Mg2+ and Zn2+. The relaxivity studies carried out in physiological fluids prove the prospects of the agent for in vivo measurements.

Synthesis and Biological Evaluation of Cruentaren A Analogues

The complex macrolide cruentaren A is a highly selective and potent inhibitor of F-ATPase (F-type adenosine triphosphatase). As it shows some resemblance to benzolactone enamides like apicularen A, it was of interest to perform some structure-activity studies to delineate the key functional groups that are responsible for the activity. Building upon our previously developed route to cruentaren A, which is based on a ring-closing alkyne metathesis reaction (RCAM), several cruentaren analogues were prepared. Replacement of the 3-hydroxy hexanoic part with acids that lack the hydroxy group function resulted in a significant drop in cytotoxicity and F-ATPase inhibition. Furthermore, two enamide analogues 23 and 50 were synthesized. However, these compounds were only cytotoxic in the micromolar range. Under the conditions for cleavage of the C3 aromatic methyl ether, the enamide function was transformed to the corresponding oxazinanone, resulting in analogues 25 and 52.

Diastereospecific synthesis of 2.6-dideoxy- and 2.4.6-trideoxy-sugars via hetero-Diels-Alder-reaction

Abstract β-Acyloxy-a-phenylthio a,β-unsaturated carbonyl compounds and ethyl-vinylether afforded in a endo-specific hetero-Diels-Alder reaction functionalized 3.4-dihydro-2H-pyrans. These compounds were transfered diastereospecifically into deoxy sugars this way allowing a stereocontrolled generation of up to four chiral centers.

Total synthesis and biological evaluation of (-)-9-deoxy-englerin A.

An effective total synthesis of (-)-9-deoxy-englerin (4), an analogue of the natural guaiane sesquiterpene englerin A (1), has been achieved. The synthesis features a transannular epoxide opening to construct the 5,7-fused ring system followed by transannular ether formation with mercury(II) trifluoroacetate.

Activity of Plasma Membrane V-ATPases Is Critical for the Invasion of MDA-MB231 Breast Cancer Cells

Background: The V-ATPase has been proposed to function at the plasma membrane in tumor cell invasion. Results: Inhibition of plasma membrane V-ATPases prevented invasion of MDA-MB-231 cells. Conclusion: Activity of plasma membrane V-ATPases is critical for breast cancer cell invasion. Significance: Plasma membrane V-ATPases are a possible therapeutic target to limit metastasis. The vacuolar (H+)-ATPases (V-ATPases) are a family of ATP-driven proton pumps that couple ATP hydrolysis with translocation of protons across membranes. Previous studies have implicated V-ATPases in cancer cell invasion. It has been proposed that V-ATPases participate in invasion by localizing to the plasma membrane and causing acidification of the extracellular space. To test this hypothesis, we utilized two separate approaches to specifically inhibit plasma membrane V-ATPases. First, we stably transfected highly invasive MDA-MB231 cells with a V5-tagged construct of the membrane-embedded c subunit of the V-ATPase, allowing for extracellular expression of the V5 epitope. We evaluated the effect of addition of a monoclonal antibody directed against the V5 epitope on both V-ATPase-mediated proton translocation across the plasma membrane and invasion using an in vitro Matrigel assay. The addition of anti-V5 antibody resulted in acidification of the cytosol and a decrease in V-ATPase-dependent proton flux across the plasma membrane in transfected but not control (untransfected) cells. These results demonstrate that the anti-V5 antibody inhibits activity of plasma membrane V-ATPases in transfected cells. Addition of the anti-V5 antibody also inhibited in vitro invasion of transfected (but not untransfected) cells. Second, we utilized a biotin-conjugated form of the specific V-ATPase inhibitor bafilomycin. When bound to streptavidin, this compound cannot cross the plasma membrane. Addition of this compound to MDA-MB231 cells also inhibited in vitro invasion. These studies suggest that plasma membrane V-ATPases play an important role in invasion of breast cancer cells.