Total synthesis of halichondrin C.

The first total synthesis of halichondrin C has been completed, highlighted by development of the synthetic method to construct the C8-C14 polycycle. Cr-mediated coupling reactions are used seven times to form a new C-C bond. The acid stability of halichondrin C is studied, demonstrating that the macrolactone stabilizes the C8-C14 polycycle, relative to the one present in the C1-C16 model.

Catalytic asymmetric formation of delta-lactones from unsaturated acyl halides.

Previously unexplored enantiopure zwitterionic ammonium dienolates have been utilized in this work as reactive intermediates that act as diene components in hetero-Diels-Alder reactions (HDAs) with aldehydes to produce optically active delta-lactones, subunits of numerous bioactive products. The dienolates were generated in situ from E/Z mixtures of alpha,beta-unsaturated acid chlorides by use of a nucleophilic quinidine derivative and Sn(OTf)(2) as co-catalyst. The latter component was not directly involved in the cycloaddition step with aldehydes and simply facilitated the formation of the reactive dienolate species. The scope of the cycloaddition was considerably improved by use of a complex formed from Er(OTf)(3) and a simple commercially available norephedrine-derived ligand that tolerated a broad range of aromatic and heteroaromatic aldehydes for a cooperative bifunctional Lewis-acid-/Lewis-base-catalyzed reaction, providing alpha,beta-unsaturated delta-lactones with excellent enantioselectivities. Mechanistic studies confirmed the formation of the dienolate intermediates for both catalytic systems. The active Er(III) complex is most likely a monomeric species. Interestingly, all lanthanides can catalyze the title reaction, but the efficiency in terms of yield and enantioselectivity depends directly on the radius of the Ln(III) ion. Similarly, use of the pseudolanthanides Sc(III) and Y(III) also resulted in product formation, whereas the larger La(III) and other transition metal salts, as well as main group metal salts, proved to be inefficient. In addition, various synthetic transformations of 6-CCl(3)- or 4-silyl-substituted alpha,beta-unsaturated delta-lactones, giving access to a number of valuable delta-lactone building blocks, were investigated.

New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach.

With sequential use of catalytic asymmetric Cr-mediated coupling reactions, E7389 C14-C35 and halichondrin C14-C38 building blocks have been stereoselectively synthesized. The C19-C20 bond is first formed via the catalytic asymmetric Ni/Cr-mediated coupling, i.e., 8 + 9 --> 10 (90%; dr = 22:1), in which vinyl iodide 8 is used as the limiting substrate. The C23-C24 bond is then formed via the catalytic asymmetric Co/Cr-mediated coupling, i.e., 13 + 14 --> 4 (82%; dr = 22:1), in which the alkyl-iodide bond in 14 is selectively activated over the vinyl-iodide bond. The catalytic asymmetric Ni/Cr-mediated reaction is employed to couple C14-C26 segment 19 with E7389 C27-C35 segment 20 (91%; dr = >55:1). In this synthesis, the C23-O bond is stereoselectively constructed via a double-inversion process, i.e., 21 --> 22, to furnish E7389 C14-C35 building block 22 in 84% yield. The same synthetic sequence has been employed to synthesize halichondrin C14-C38 building block 18b, i.e., 16a + 19 --> 18b.

Lewis acid-Lewis base catalyzed enantioselective hetero-Diels-Alder reaction for direct access to delta-lactones.

A complex formed in situ from Er(OTf)3 and a simple commercially available norephedrine ligand promotes an unprecedented [4 + 2] cycloaddition of alpha,beta-unsaturated acid chlorides with a broad range of aromatic and heteroaromatic aldehydes by a cooperative bifunctional Lewis acid-Lewis base catalytic mode of action providing valuable delta-lactone building blocks with excellent enantioselectivity.

Synthesis and preliminary biological characterization of new semisynthetic derivatives of ramoplanin.

Ramoplanin is a glycolipodepsipeptide antibiotic active against Gram-positive bacteria including vancomycin-resistant enterococci. Ramoplanin inhibits bacterial cell wall biosynthesis by a mechanism different from that of glycopeptides and hence does not show cross-resistance with these antibiotics. The systemic use of ramoplanin has been so far prevented because of its low local tolerability when injected intravenously. To overcome this problem, the fatty acid side chain of ramoplanin was selectively removed and replaced with a variety of different carboxylic acids. Many of the new ramoplanin derivatives showed antimicrobial activity similar to that of the natural precursor coupled with a significantly improved local tolerability. Among them the derivative in which the 2-methylphenylacetic acid has replaced the di-unsaturated fatty acid side chain (48) was selected as the most interesting compound and submitted to further in vitro and in vivo characterization studies.