Amphidinolide T1 Research Articles

Dinoflagellate-Related Amphidinolides from the Brazilian Octocoral Stragulum bicolor.

Benthic cnidarians are colonial marine animals that host a rich population of associated and symbiotic microorganisms. In a recent paper we described for the first time the isolation of amphidinolide P (1) from the Brazilian octocoral Stragulum bicolor. Amphidinolides and similar compounds had been previously reported only from dinoflagellates of the genus Amphidinium; thus the presence of 1 in the invertebrate opens intriguing questions on the role and occurrence of these molecules in marine ecosystems. Here we report the identification of four further amphidinolides from the same soft coral, including the known amphidinolide T1 (2) and the new analogues here named amphidinolides C4 (3), B8 (4), and B9 (5). The chemical structures have been elucidated mainly by extensive study of spectroscopic data. Cytotoxic activities of 3 and 4 were evaluated against the colon adenocarcinoma cell line HCT-116.

ChemInform Abstract: Nickel Catalysis: Synergy Between Method Development and Total Synthesis

AbstractReview: 51 refs.

Nickel Catalysis: Synergy between Method Development and Total Synthesis.

Nickel(0) catalysts have proven to be powerful tools for multicomponent coupling reactions in our laboratories over the past 15 years. This interest was originally sparked by the ubiquity of allylic alcohol motifs in natural products, such as (-)-terpestacin, which we envisioned assembling by the coupling of two π components (alkyne and aldehyde) with concomitant reduction. Mechanistic investigations allowed us to elucidate several modes of controlling the regioselectivity and stereoselectivity in the oxidative cyclization, and these insights enabled us to leverage combinations of alkenes and phosphine ligands to direct regioselective outcomes. The initial success in developing the first intermolecular reductive alkyne-aldehyde coupling reaction launched a series of methodological investigations that rapidly expanded to include coupling reactions of alkynes with other electrophilic π components, such as imines and ketones, as well as electrophilic σ components, such as epoxides. Aziridines proved to be more challenging substrates for reductive coupling, but we were recently able to demonstrate that cross-coupling of aziridines and alkylzinc reagents is smoothly catalyzed by a zero-valent nickel/phenanthroline system. Moreover, the enantioselective alkyne-aldehyde coupling and the development of novel P-chiral ferrocenyl ligands enabled the total synthesis of (-)-terpestacin, amphidinolides T1 and T4, (-)-gloeosporone, and pumiliotoxins 209F and 251D. We subsequently determined that alkenes could be used in place of alkynes in several nickel-catalyzed reactions when a silyl triflate activating agent was added. We reason that such an additive functions largely to enhance the electrophilicity of the metal center by coordination to the electrophilic π component, such that less nucleophilic alkene π donors can undergo productive combination with nickel complexes. This activation manifold was further demonstrated to be effective for alkene-aldehyde couplings. In a related manner, electrophilic promoters were also successfully employed for allylic substitution reactions of allylic carbonates with simple alkenes and in the Mizoroki-Heck reaction of both benzyl and aryl electrophiles. In these instances, it is proposed that counterion exchange from a more strongly coordinating anion to the weakly or noncoordinating triflate counterion enables reaction at an electrophilic Ni(II) center rather than by coordination to one of the coupling components. Mechanistic insights also played an important role in the development of mixed N-heterocyclic carbene/phosphite ligand systems to overcome challenges in regioselective alkene-aldehyde coupling reactions. We hope that, taken together, the body of work summarized in this Account demonstrates the constructive interplay among total synthesis, methodological development, and mechanistic investigation that has driven our research program.

Total Syntheses of Amphidinolides T1, T3, and T4

Concise and high-yielding total syntheses of amphidinolides T1, T3, and T4 have been completed using an alkynyl macrolactone as a common late-stage intermediate. The required α-hydroxy ketone motif was installed by sequential alkyne hydrosilylation, epoxidation, and Fleming-Tamao oxidation. An oxonium ylide rearrangement formed the trisubstituted tetrahydrofuran core found in the natural products.

Total Syntheses of Amphidinolides T1, T3, and T4

Kurz und bündig: Die Totalsynthesen der Amphidinolide T1, T3 und T4 wurden über ein Alkinylmakrolacton als gemeinsames spätes Intermediat erreicht. Die benötigte α-Hydroxyketon-Funktion wurde durch sequenzielle Alkinhydrosilylierung, Epoxidierung und Fleming-Tamao-Oxidation aufgebaut. Eine Oxonium-Ylid-Umlagerung ergab den trisubstituierten Tetrahydrofuran-Teil in diesen Naturstoffen.

A Concise Total Synthesis of Amphidinin B

AbstractA concise total synthesis of amphidinin B, a cytotoxic linear dicarboxylic acid associated with amphidinolide T marine macrolides, has been accomplished from the 19‐membered cycloalkene intermediates designed for diverted total synthesis of amphidinolide T1 and T3–T5. The 1H and 13C NMR spectra of the synthesized amphidinin B in C6D6 and CDCl3 were compared with those for the natural and synthetic forms reported in the literature, showing solvent‐dependence of the 1H and 13C NMR signals of amphidinin B in C6D6 and CDCl3.

Concise Diverted Total Synthesis of Amphidinolide T1 and T4 from a (12E)-Cycloalkene by Selective Functionalization of the C12-C13 Double Bond

Concise Diverted Total Synthesis of Amphidinolide T1 and T4 from a (12E)-Cycloalkene by Selective Functionalization of the C12-C13 Double Bond

Concise synthesis of the C-1–C-12 fragment of amphidinolides T1–T5

The C-1-C-12 segment of the amphidinolides T1-T5 has been synthesised in an efficient manner. The key transformations are highly diastereoselective rearrangement of an oxonium ylide, or metal-bound ylide equivalent, produced by intramolecular reaction of a copper carbenoid with an allylic ether, and macrocyclic fragment coupling by one-pot ring-closing metathesis and hydrogenation.

Stereoselective synthesis of an advanced seco ester intermediate as a precursor toward the synthesis of amphidinolides T1, T3, and T4

An efficient, convergent, and stereoselective synthesis of a very advanced intermediate toward the total synthesis of amphidinolides T1, T3, and T4 utilising Evan’s aldol and alkylation reactions, oxy-Michael, cross metathesis, stereoselective Grignard addition, and Yamaguchi esterification reactions as key steps is described.

Stereoselective Synthesis of Amphidinolide T1

A highly stereoselective total synthesis of amphidinolide T1 is achieved using Sharpless asymmetric epoxidation, base-induced epoxide opening, radical cyclization, diastereoselective reduction followed by allylation, Evans methylation, base-induced reductive elimination, umpolung reaction, chemoselective oxidation, and regioselective macrolactonization.

Synthesis of the C1–C12 fragment of amphidinolide T1

A synthesis of the C1–C12 fragment of amphidinolide T1 utilising Evans’ aldol, oxy-Michael and cross metathesis reactions as the key steps is described.

First Total Synthesis of (+)‐Amphidinolide T1

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total Syntheses of Amphidinolides T1 and T4 via Catalytic Stereoselective, Reductive Macrocyclizations.

Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used to effect a macrocyclization, form a C-C bond, and install a stereogenic center with >10:1 selectivity in both natural product syntheses. Alternative approaches in which intermolecular alkyne-aldehyde reductive coupling reactions would serve to join key fragments were investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne-aldehyde coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne-epoxide reductive couplings were instrumental in the construction of key fragments corresponding to approximately half of the molecule of both natural products. In one case (T4 series), the alkyne-epoxide coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed in the macrocyclizations is also proposed.

Total Syntheses of Amphidinolides T1 and T4 via Catalytic, Stereoselective, Reductive Macrocyclizations

Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used to effect a macrocyclization, form a C-C bond, and install a stereogenic center with >10:1 selectivity in both natural product syntheses. Alternative approaches in which intermolecular alkyne-aldehyde reductive coupling reactions would serve to join key fragments were investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne-aldehyde coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne-epoxide reductive couplings were instrumental in the construction of key fragments corresponding to approximately half of the molecule of both natural products. In one case (T4 series), the alkyne-epoxide coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed in the macrocyclizations is also proposed.

Synthesis of Amphidinolide T1 (I) via Catalytic, Stereoselective Macrocyclization.

Synthesis of Amphidinolide T1 (I) via Catalytic, Stereoselective Macrocyclization.

Total Syntheses of Amphidinolide T1, T3, T4, and T5.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of amphidinolide T1 via catalytic, stereoselective macrocyclization.

Two nickel-catalyzed reductive coupling reactions of alkynes were instrumental in a modular, stereoselective synthesis of amphidinolide T1 (1). The C13-C21 fragment was prepared from two simple starting materials that were joined in a catalytic alkyne-epoxide fragment coupling operation, whereas an intramolecular aldehyde-alkyne reductive coupling simultaneously formed the final carbon-carbon bond of the macrocycle and established the C13 carbinol configuration with complete selectivity in the desired fashion.

Total syntheses of amphidinolide T1, T3, T4, and T5.

A concise, flexible, and high yielding entry into the family of amphidinolide T macrolides, a series of cytotoxic natural products of marine origin, has been developed. All individual members, except amphidinolide T3 (3), derive from compound 39 as a common synthetic intermediate which is formed from three building blocks of similar size and complexity. The fragment coupling steps involve a highly diastereoselective SnCl(4) mediated reaction of the furanosyl sulfone derivative 11 with the silyl enol ether 18 and a palladium-catalyzed Negishi type coupling reaction between the polyfunctional organozinc reagent derived from iodide 32a and the enantiopure acid chloride 24b. The 19-membered macrocyclic ring is then formed by a high yielding ring closing metathesis (RCM) reaction of diene 33 catalyzed by the "second generation" ruthenium carbene complex 34. The efficiency of the RCM transformation stems, to a large extent, from the conformational bias introduced by the syn-syn-configured stereotriad at C12-C14 of the substrate which constitutes a key design element of the synthesis plan. The use of Nysted's reagent 38 in combination with TiCl(4) was required for the olefination of the sterically hindered ketone group in 36, whereas more conventional alkene formations were unsuccessful for this elaboration. Finally, it is shown that the inversion of a single and seemingly remote stereocenter (C12) in one of the building blocks not only affects the efficiency and stereochemical outcome of the RCM step but also exerts a significant influence on the course of the acyl-Negishi reaction, allowing a radical manifold to compete with productive cross coupling.

Enantioselective Total Synthesis of (+)‐Amphidinolide T1.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective total synthesis of (+)-amphidinolide t1.

An enantioselective first total syntheis of amphidinolide T1 (1) is described. Amphidinolide T1 (1), a 19-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent and involves the assembly of C1-C10 segment 2 and C11-C21 segment 3 by an oxocarbenium ion-mediated alkylation and Yamaguchi macrolactonization sequence. The synthesis of fragment 2 involves an efficient cross metathesis and hydrogenation sequence between the terminal olefins of 5 and 6 to form the C4-C5 carbon-carbon bond. Enol ether 4 is designed to be the surrogate of fragment 3 where the sensitive C16-exo-methylene and the C13-hydroxyl group were protected as the bromoether derivative during the Lewis acid-catalyzed alkylation process. Both stereocenters in fragment 5 as well as the C2 and C3 stereocenters in fragment 4 are accessed by a highly diastereoselective ester-derived titanium enolate-mediated syn-aldol reaction. The bromoether derivative 24 was unraveled at the final stage of the synthesis, providing (+)-amphidinolide T1.