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.

d-Lactones are subunits of numerous natural and unnatural products that display a wide range of biological activity. In many cases they show high efficacy as antibacterial, [1] antiviral (HIV protease inhibitors), [2] anticancer, [3] immunosuppressive, [4] or cholesterol-lowering agents (HMGR inhibitors). [5] For example, the majority of statin drugs such as Lipitor and Zocor, the worlds best-selling drugs in 2004, contain a bhydroxy-d-lactone moiety or the corresponding open-chain dhydroxy carboxylate form. [6] In addition, d-lactones are very useful building blocks for the synthesis of bioactive compounds. [7] Many approaches, most often multistep procedures, have been elaborated for the preparation of d-lactones. [8] The most direct route to a,b-unsaturated d-lactones is based on hetero-Diels-Alder (HDA) reactions. [9] In order to generate directly the desired oxidation state, a vinylketene equivalent such as a vinylketene acetal is required as the diene component. It has been reasoned though that twofold substitution at the butadiene terminus has a deleterious effect upon the enantioselectivity of HDA reactions, thus explaining why these dienes have been less frequently used in asymmetric HDA reactions than Danishefsky-type dienes. [10] Up to now, only three highly enantioselective, catalytic HDA-based methodologies using a vinylketene acetal have been reported, [11][12][13] which are all restricted to the use of Brassard-type dienes (1,3dialkoxy-1-(trimethylsiloxy)butadienes) [14] and aromatic aldehydes [15] and which all require long reaction times (48-72 h) to provide useful yields.We present herein a new concept for the synthesis of a,bunsaturated d-lactones 6 which circumvents the preformation, isolation, and purification of moisture-and acid-sensitive vinylketene acetals. Our work was based on the hypothesis that substituted vinylketenes 2 should be formed in situ by dehydrohalogenation of a,b-unsaturated acid chlorides 1 (Scheme 1). [16] Vinylketenes are known to be inherently unstable species, [17] but they might be trapped and at the same time activated as a diene component of a Diels-Alder reaction by an enantiopure tertiary amine, thus forming an enantiomerically pure zwitterionic dienolate 4. This type of species was supposed to be reactive enough, in an s-cis conformation, to undergo [4+2] cycloadditions with aldehydes, by either a stepwise or a concerted mechanism. Our investigations were inspired by the tertiary-amine-catalyzed asymmetric synthesis of b-lactones from ketene via zwitterionic enolate intermediates. [18] Because of the considerable homology of 4 to vinylketene acetals, the intermediate formation of these dienolates was anticipated to overcome the pronounced tendency of vinylketenes to preferentially undergo [2+2] cycloaddition reactions. [19] 3,4-Dimethylpent-2-enoyl chloride (1 a; R 1 = iPr) and trichloroacetaldehyde (chloral, 5 a; R 2 = CCl 3 ) were chosen as model substrates for the development of this process. Initial experiments in acetonitrile at À15 8C using stoichiometric ...

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.

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.

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.