A general, mild, and efficient 1,2-migration/cycloisomerization methodology toward multisubstituted 3-thio-, seleno-, halo-, aryl-, and alkyl-furans and pyrroles, as well as fused heterocycles, valuable building blocks for synthetic chemistry, has been developed. Moreover, regiodivergent conditions have been identified for C-4 bromo- and thio-substituted allenones and alkynones for the assembly of regioisomeric 2-hetero substituted furans selectively. It was demonstrated that, depending on reaction conditions, ambident substrates can be selectively transformed into furan products, as well as undergo selective 6-exo-dig or Nazarov cyclizations. Our mechanistic investigations have revealed that the transformation proceeds via allenylcarbonyl or allenylimine intermediates followed by 1,2-group migration to the allenyl sp carbon during cycloisomerization. It was found that 1,2-migration of chalcogens and halogens predominantly proceeds via formation of irenium intermediates. Analogous intermediate can also be proposed for 1,2-aryl shift. Furthermore, it was shown that the cycloisomerization cascade can be catalyzed by Brønsted acids, albeit less efficiently, and commonly observed reactivity of Lewis acid catalysts cannot be attributed to the eventual formation of proton. Undoubtedly, thermally induced or Lewis acid-catalyzed transformations proceed via intramolecular Michael addition or activation of the enone moiety pathways, whereas certain carbophilic metals trigger carbenoid/oxonium type pathway. However, a facile cycloisomerization in the presence of cationic complexes, as well as observed migratory aptitude in the cycloisomerization of unsymmetrically disubstituted aryl- and alkylallenes, strongly supports electrophilic nature for this transformation. Full mechanistic details, as well as the scope of this transformation, are discussed.

An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents with significant clinical potential. The synthesis is convergent and involved the assembly of C(3)-C(16) segment 4 and C(17)-C(28) segment 5 by Julia olefination. The sensitive C(2)-C(3) cis-olefin functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed by hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts of intramolecular Still's variant of Horner-Emmons olefination between the C(19)-phosphonocetate and C(3)-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photoisomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefin metathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalize the dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C(20)-hydroxyl stereochemistry, and a novel Julia olefination protocol for the installation of the C(13)-exo-methylene unit. The sensitive epoxide at C(16)-C(17) was introduced in a highly stereoselective manner by Sharpless epoxidation at the final stage of the synthesis.

Monte Carlo simulations using free energy perturbation theory have been used to guide the selection of bicyclic heterocycles in the lead optimization of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Good correlation is found between predicted and observed activities. Six compounds are reported with EC50 values below 20 nM for protection of human MT-2 cells against the cytopathogenicity of HIV-1. Striking variation in activity is found and analyzed for an isomeric pyrrolopyrimidine and pyrrolopyrazine pair.

Virtual screening of the Maybridge library of ca. 70,000 compounds was performed using a similarity filter, docking, and MM-GB/SA post-processing to seek potential non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Though known NNRTIs were retrieved well, purchase and assaying of representative, top-scoring compounds from the library failed to yield any active anti-HIV agents. However, the highest-ranked library compound, oxadiazole 1, was pursued as a potential "near-miss" with the BOMB program to seek constructive modifications. Subsequent synthesis and assaying of several polychloro-analogs did yield anti-HIV agents with EC 50 values as low as 310 nM. The study demonstrates that it is possible to learn from a formally unsuccessful virtual-screening exercise and, with the aid of computational analyses, to evolve efficiently a false positive into a true active. In addition, the need for adequate structure validation was confirmed by the apparent misrepresentation of a purchased compound elsewhere as the present oxadiazole core compound, 16.

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Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst-substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C-C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)- and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of ">or=80% yield with >or=20:1 stereoselectivity in the presence of

The copper‐catalyzed cycloisomerization of thioalkynyl ketones 1 a and thioalkynyl imines 1 b allows the efficient synthesis of 3‐thio‐substituted furans 3 a and pyrroles 3 b, an important class of heterocyclic unit previously inaccessible by standard cycloisomerization techniques. A plausible mechanism for this unusual cascade involves a 1,2‐migration of the thio group in the intermediate keto‐ and iminoallenyl sulfides 2. DMA=N,N‐dimethylacetamide.

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.